SK164297A3 - 1,6-disubstituted isochromans for treatment of migraine headaches - Google Patents

Abstract

The present invention is 1,6-disubstituted isochromans of formula (I) and aromatic bicyclic amines (ABA) which are useful for the treatment of headaches, especially migraine and cluster headaches and also useful as antipsychotics and for the treatment of other CNS and/or cardiovascular disorders and as analgesics.

Description

Oblasť technikyTechnical field

Vynález sa týka izochróman-alkyl-piperazinyl/piperidinyl-aryl zlúčenín, ktoré je možné použiť na liečenie bolestí hlavy, hlavne migrény aklastrových bolestí hlavy, ako analgetiká a tiež ako antipsychotiká a na liečbu iných chorôb CNS a/alebo kardiovaskulárnych chorôb.The invention relates to isochroman-alkyl-piperazinyl / piperidinyl-aryl compounds which can be used for the treatment of headaches, especially migraine and aclastral headaches, as analgesics and also as antipsychotics, and for the treatment of other CNS and / or cardiovascular diseases.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Chrómany (známe tiež ako 1-benzopyrány, kde je kyslíkový atóm súčasťou aromatického kruhu), a izochrómany (známe tiež ako 2-benzopyrány, kde kyslíkový atóm nie je súčasťou aromatického kruhu) sú už skôr známe ako arylpiperazíny (alebo 4arylpiperidíny). Chrómany a arylpiperazíny spojené alkylovým reťazcom sú tiež známe. Európsky patent 300 908 opisuje (l-benzopyrán)]-alkyl-(piperazinyl alebo aminopiperidín)aryly používané ako antiarytmiká a antifibrilačné protizrážavé prostriedky. Zlúčeniny podľa vynálezu vyžadujú -alkyl-piperazinyl (alebo piperidinyl)-aryl na uhlíku číslo 1 2benzopyránového kruhu a tiež substitúciu na 6 polohe izochrómanu, ktoré sú užitočné na liečbu vaskulámych (migrény aklastrových) bolestí hlavy, CNS a kardiovaskulárnych chorôb.Chromates (also known as 1-benzopyrans where the oxygen atom is part of the aromatic ring) and isochromates (also known as 2-benzopyrans where the oxygen atom is not part of the aromatic ring) are earlier known as arylpiperazines (or 4arylpiperidines). Alkyl chromates and arylpiperazines are also known. European Patent 300 908 discloses (1-benzopyran)] -alkyl- (piperazinyl or aminopiperidine) aryls used as antiarrhythmic and anti-fibrillating anticoagulants. The compounds of the invention require -alkyl-piperazinyl (or piperidinyl) -aryl on carbon number 1 of the 2-benzopyran ring, as well as substitution at the 6-position of the isochroman, useful for the treatment of vascular headache, CNS and cardiovascular diseases.

Známe sú rôzne izochrómany, tioizochrómany, benzotiepíny s hydroxy, alkoxy alebo o-metyléndioxy substitúciou na aromatických kruhoch a spojené k arylpiperazínom (piperidínom) alkylovými reťazcami. Tieto zlúčeniny sa využívajú ako antipsychotiká a hypotenzíva. Zlúčeniny podľa vynálezu nedovoľujú substitúciu kyslíka na aromatickom kruhu izochrómanu, tioizochrómanu, benzoxepínu alebo benzotiepínu na aromatickom systéme na využitie u CNS a u kardiovaskulárnych porúch.Various isochromates, thioisochromates, benzotiepines with hydroxy, alkoxy or o-methylenedioxy substitution on aromatic rings and linked to arylpiperazines (piperidines) by alkyl chains are known. These compounds are used as antipsychotics and hypotensives. The compounds of the invention do not allow oxygen substitution on the aromatic ring of isochroman, thioisochroman, benzoxepine or benzothiepine on the aromatic system for use in CNS and cardiovascular disorders.

Známa je ešte iná skupina izochrómanov, tioizochrómanov, benzoxepínov a benzotiepínov s hydroxy, alkoxy alebo o-metyléndioxy funkčnými skupinami pripojenými s aromatickým kruhom, a naviazané na arylpiperazíny (piperidíny) alkylovými reťazcami, ktoré sa používajú ako antipsychotiká a hypotenzíva. Zlúčeniny podľa vynálezu nedovoľujú substitúciu kyslíka na aromatickom kruhu izochrómanu, tioizochrómanu, benzoxepínu alebo na benzotiepínovom aromatickom systéme na svoje využitie u CNS a u kardiovaskulárnych chorôb.Yet another class of isochromates, thioisochromates, benzoxepines and benzothiepines with hydroxy, alkoxy or o-methylenedioxy functional groups attached to the aromatic ring and attached to the arylpiperazines (piperidines) by alkyl chains, which are used as antipsychotics, is known. The compounds of the invention do not allow oxygen substitution on the aromatic ring of isochroman, thioisochroman, benzoxepine or the benzothiepine aromatic system for their use in the CNS and cardiovascular diseases.

USA patent 4179 510av celom rade jeho častí sa uvádza izochrómanalkylpiperazinyl (alebo aminopiperidinyl)-aryly so substituovaným kyslíkom na aromatickom kruhuU.S. Pat. No. 4,179,510 and a number of its parts disclose isochromanalkylpiperazinyl (or aminopiperidinyl) -aryls with substituted oxygen on the aromatic ring

-2izochrómanu. Tieto zlúčeniny sa uvádzajú ako používané hypotenzíva a antipsychotické látky.-2izochrómanu. These compounds are reported to be used as hypotensive and antipsychotic agents.

Uvádza sa tiež izochróman-, izotiochróman-, 2-benzoxepín-, a 2-benzotiepínalkyloxyetanoly, používané na prípravu vyššie uvedených zlúčenín. Hlavne 7,8dimetoxybenzoxepíny ako l-[(6,7-dimetoxyizochróman)alkyl]-4-(aryl) piperazíny. Ďalej sa uvádzajú 2-benzoxepíny-alkyl-piperazín(aminopiperidín)-aryly, 2-benzotiepíny a 2benzoxepíny s atómom kyslíka substituovaným na aromatickom kruhu, používané na rovnaké účely.Also disclosed are isochroman-, isothiochroman-, 2-benzoxepine-, and 2-benzothiepinalkyloxyethanols used to prepare the above compounds. In particular, 7,8-dimethoxybenzoxepines such as 1 - [(6,7-dimethoxyisochroman) alkyl] -4- (aryl) piperazines. Further disclosed are 2-benzoxepines-alkyl-piperazine (aminopiperidine) -aryls, 2-benzothiepines and 2-benzoxepines having an oxygen atom substituted on the aromatic ring used for the same purposes.

Dánsky patent 8 001 981 uvádza l-(2-chlórfenyl)-4-[2-(l,2,3,4,5-tetrahydro-7,8dimetoxy-2-benzoxepín-l-yl)etyl]piperazín používaný ako antipsychotická látka.Danish Patent 8,001,981 discloses 1- (2-chlorophenyl) -4- [2- (1,2,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl) ethyl] piperazine used as an antipsychotic material.

Medzinárodná patentová publikácia WO 92/18089 uvádza izochrómany-alkylpiperazinyl (alebo aminopiperidinyl)-aryly s požiadavkou, že kyslík je prítomný na aromatickom kruhu izochrómanu, ktoré sa využívajú na senzibilizovaných bunkách proti liekovej polyrezistencii.International patent publication WO 92/18089 discloses isochromans-alkylpiperazinyl (or aminopiperidinyl) -aryls with the requirement that oxygen is present on the aromatic ring of the isochroman which is used on sensitized cells against drug resistance.

Medzinárodná patentová publikácia WO 88/08424 uvádza izochrómany-alkylpiperazinyl (alebo aminopiperidinyl)-aryly s požiadavkou, že kyslík je prítomný na aromatickom kruhu izochrómanu, používané pri úrazoch hlavy, poraneniach chrbtice a infarktoch.International patent publication WO 88/08424 discloses isochromans-alkylpiperazinyl (or aminopiperidinyl) -aryls with the requirement that oxygen is present on the aromatic ring of the isochromate used in head injuries, spinal injuries and heart attacks.

Medzinárodná patentová publikácia WO 90/15056 a USA patentu 5 140 040 uvádza izochrómany, tetralíny a dihydroanaftalény substituované rôznymi alkylamínmi na liečenie zeleného očného zákalu, depresie, hypertenzie, kongestívnych srdečných zlyhaní a porúch cievnej kontraktibility.International Patent Publication WO 90/15056 and US Patent 5,140,040 disclose isochromans, tetralins and dihydroanaphthalenes substituted with various alkylamines for the treatment of glaucoma, depression, hypertension, congestive heart failure and vascular contractility disorders.

USA patent 4 994 486 opisuje izochróman-alkyl-amíny na liečbu psychóz, Parkinsonovej choroby a návykových správaní.U.S. Patent 4,994,486 discloses isochroman-alkyl-amines for the treatment of psychoses, Parkinson's disease and addictive behaviors.

Japonský Patent 61083080 uvádza izochróman-alkyl-(alkyl)amíny ako protivredové látky.Japanese Patent 61083080 discloses isochroman-alkyl- (alkyl) amines as anti-ulcer agents.

Európsky Patent 404 197 opisuje izochróman-alkyl-piperazín-alkyl-keto(alkohol)aryly s bronchodilatačnou a antialergickou aktivitou.European Patent 404 197 discloses isochroman-alkyl-piperazine-alkyl-keto (alcohol) aryls with bronchodilator and antiallergic activity.

Japonský patent 51125287 (J 52083846) opisuje izochróman-alkyl-amíny (piperazín) s antidepresívnou, analgetickou, diuretickou, protizápalovou a antiastmatickou aktivitou.Japanese patent 51125287 (J 52083846) discloses isochroman-alkyl-amines (piperazine) with antidepressant, analgesic, diuretic, anti-inflammatory and antiasthmatic activity.

Nemecký patent DE 2 624 693 a anglický patent GB 1552004 uvádza izochrómanalkyl-amíny vrátane arylpiperazínov ako analgetiká, hypotenzivá, antidepresíva, diuretiká, protizápalové látky, látky spôsobujúce svalovú relaxáciu a vazodilatanty. Zlúčeniny sa líšiaGerman patent DE 2 624 693 and English patent GB 1552004 disclose isochromanalkylamines including arylpiperazines as analgesics, hypotensive drugs, antidepressants, diuretics, anti-inflammatory agents, muscle relaxants and vasodilators. The compounds differ

-3od zlúčenín podľa vynálezu tým, že sa požaduje substitúcia kyslíka na aromatickom kruhu izochrómanu.Compounds of the invention by requiring oxygen substitution on the aromatic ring of isochroman.

Japonský patent 57159713 uvádza izochróman- a tetralín-(bez alkylového článku)piperazín-aryly ako antialergetiká. Zlúčeniny podľa vynálezu vyžadujú najmenej jeden spojovací uhlík.Japanese Patent 57159713 discloses isochroman- and tetralin- (without an alkyl cell) piperazine-aryls as anti-allergic drugs. The compounds of the invention require at least one linking carbon.

USA patenty 3 549 656 a 3 467 675 a belgický patent 678 035 uvádza ftalan-, izochróman- a izochromén-alkylén-amíny na liečbu depresie.U.S. Patents 3,549,656 and 3,467,675 and Belgian Patent 678,035 disclose phthalate, isochroman, and isochromene-alkylene-amines for the treatment of depression.

Európsky patent 458 387 a USA patent 5 137 911 opisujú izochróman-alkylénpiperazín-alkylén-aryly používané ako inhibítory zrážania krvných doštičiek, ako intracelulárne vápnikové antagonisty a na liečbu srdcových arytmií, angíny pektoris, mŕtvice a infarktu myokardu.European Patent 458,387 and US Patent 5,137,911 disclose isochroman-alkylene-piperazine-alkylene-aryls used as platelet-clotting inhibitors, as intracellular calcium antagonists and for the treatment of cardiac arrhythmias, angina pectoris, stroke and myocardial infarction.

Nemecký patent DE 3 409 612 uvádza dimetoxyizochróman- a benzoxepín-alkylamino-alkyly na prevenciu srdcových cievnych chorôb alebo hypertenzie.German Patent DE 3 409 612 discloses dimethoxyisochroman- and benzoxepine-alkylamino-alkyls for the prevention of cardiovascular diseases or hypertension.

Japonský patent 6 1083180 uvádza izochrómany-alkyl-amíny na liečbu vredov. Európsky patent 457 686 uvádza ftalan a indanalkylaminopiperidinylmočoviny alebo karbamáty na liečbu stresov, bolesti a schizofrénie.Japanese Patent 6,108,380 discloses isochromans-alkyl amines for the treatment of ulcers. European patent 457 686 discloses phthalate and indanalkylaminopiperidinylureas or carbamates for the treatment of stress, pain and schizophrenia.

J. Med. Chem., 25(1), 75-81 (1982) uvádza 6,7-dimetoxyizochróman-alkylpiperazinyl-arylový typ zlúčenín s hypotenznou aktivitou.J. Med. Chem., 25 (1), 75-81 (1982) discloses a 6,7-dimethoxyisochroman-alkylpiperazinyl-aryl type of compounds with hypotensive activity.

USA patenty 5 132 598 a 5 215 989 geneticky združuje izochrómany atetralíny podľa vynálezu, ak sú vhodne vybrané variabilné substituenty.U.S. Patents 5,132,598 and 5,215,989 genetically associate the atetraline isochromans of the invention when variable substituents are suitably selected.

Medzinárodná publikácia č. WO 88/08424 a USA patent 5 120 843 opisujú dialkoxyizochróman obsahujúci substituovaný pyridinylpiperazinyletylový postranný reťazec. Avšak zlúčeniny podľa vynálezu nedovoľujú alkoxy substitúciu.International publication no. WO 88/08424 and U.S. Pat. No. 5,120,843 disclose a dialkoxy isochroman comprising a substituted pyridinylpiperazinylethyl side chain. However, the compounds of the invention do not allow alkoxy substitution.

Medzinárodná publikácia č. WO 95/18118 (PCT/US94/13284) uvádza rôzne izochrómany, napríklad 6-(substituovaný)amino (6-NRR) a 6-(substituovaný)amid (6-CONRR) izochrómany používané na liečbu pacientov s chorobami centrálneho nervového systému vrátane psychózy, parafrénie, psychotickej depresie, mánie, schizofrénie a schizofrénnych foriem ochorenia. Tieto zlúčeniny sa tiež používajú pri liečbe vaskulámych belostí hlavy, predovšetkým bolestí hlavy pri migréne. Ďalšie choroby centrálneho nervového systému, ktoré sa môžu liečiť týmito zlúčeninami, zahŕňajú úzkosť, liekovú závislosť, kŕčové stavy, poruchy zrakového vnímania, poruchy osobnosti, zníženú pozornosť u detí a dospelých, syndróm posttraumatického stresu aarytmiu. WO 95/18118 uvádza racemický l-(4-metoxyfenyl)-4-[2-(6-aminokarbonylizochróman-l-yl)-etylpiperazín (príklad 138) a 1(4-metoxyfenyl)-4-[2-(6-metylaminokarbonylizochróman-l-yl)-etylpiperazín (príklad 139).International publication no. WO 95/18118 (PCT / US94 / 13284) discloses various isochromans, for example 6- (substituted) amino (6-NRR) and 6- (substituted) amide (6-CONRR) isochromans, used to treat patients with diseases of the central nervous system including psychosis, paraphrenia, psychotic depression, mania, schizophrenia, and schizophrenic forms of the disease. These compounds are also used in the treatment of vascular whiteness of the head, particularly headache in migraine. Other central nervous system diseases that can be treated with these compounds include anxiety, drug addiction, seizures, visual perception disorders, personality disorders, reduced attention in children and adults, post-traumatic stress syndrome, and arrhythmia. WO 95/18118 discloses racemic 1- (4-methoxyphenyl) -4- [2- (6-aminocarbonylisochroman-1-yl) ethylpiperazine (Example 138) and 1- (4-methoxyphenyl) -4- [2- (6- methylaminocarbonylisochroman-1-yl) ethylpiperazine (Example 139).

-4Podstata vynálezu4. Summary of the Invention

1,6-disubstituované izochrómany sú uvedené vzorcom (I) kde:The 1,6-disubstituted isochromates are represented by the formula (I) wherein:

(I) (I) Wi je dusíkový (-N-) alebo uhlíkový atóm (-CH-);(I) (I) W 1 is a nitrogen (-N-) or carbon atom (-CH-);

(Π) X! je:(Π) X! is a:

(A) -(CH2)ni - kde ni je 0 až 3, (B) -CH=CH-;(A) - (CH 2) n 1 - wherein n 1 is 0 to 3, (B) -CH = CH-;

(III) R, je:(III) R, is:

(A) -H, (B) -F, -Cl,-Br,-J, (C) C,-C₈ alkyl, (D) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=).(A) -H, (B) -F, -Cl, -Br, -J, (C) C 1 -C ₈ alkyl, (D) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=).

(E) C₂-Cs alkinyl obsahujúci 1 až 2 trojité väzby (=), (F) C3-C8 cykloalkyl, (G) -Ci-C3 alkyl -C3-C8 cykloalkyl, (H) -NO₂, (I) ON, (J) -cf₃, (K) -O-Rm, kde -Rm je:(E) C ₂ -C 8 alkynyl having 1 to 2 triple bonds (=), (F) C 3 -C 8 cycloalkyl, (G) -C 1 -C 3 alkyl -C 3 -C 8 cycloalkyl, (H) -NO ₂ , (I) ON, (J) -cf ₃ , (K) -O-Rm, where -Rm is:

(1) -H, (2) Ci-C₈ alkyl, (3) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C3-C8 cykloalkyl, (6) -C1-C3 alkyl -C₃-Cs cykloalkyl, (7) -CF₃,(1) -H, (2) C 1 -C ₈ alkyl, (3) C 2 -C 8 alkenyl having 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyl having 1 or 2 triple bonds (=), ( 5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl -C ₃ -C 8 cycloalkyl, (7) -CF ₃ ,

-5(8) -S0₂- CF₃, (9) -(0¼)¾^ kde 112 je O až 4 a kde -φ je voliteľne substituovaný jediným alebo dvoma:-5 (8) -S0 ₂ - CF _3, (9) - (0¼) wherein ¾ ^ 112 a to 4, and wherein the -φ is optionally substituted with only one or two of:

(a) -F, -Cl, -Br, -J, (b) -ON, (c) -CF₃, (d) Cj-C, alkyl, (e) -O-Rma, kde Rma je -H, -Ci-C₆ alkyl, -CF₃ alebo -CH₂^, (f) -NRmaRi-ib kde -Rma a -Rub sú zhodné alebo sa líšia, a kde Rmb je -H, -Ci-Cô alkyl, -CF₃ alebo -ΌΗ2-φ a kde Rma sú definované vyššie (g) -CO-NRma Rmb sú definované vyššie, (h) -S02-NRm_ARmb kde Rma a Rmb sú definované vyššie, (i) -NRma-S02-Rmb kde Rma a Rmb sú vyššie definované, (j) -no₂, (k) -O-SO₂ -CF₃, (L) -N(Rm), kde Rm sú zhodné alebo rôzne ako je definované vyššie, (M) -CO-N(Rm)₂ kde Rm sú zhodné alebo rôzne ako je definované vyššie, (N) -SO2-R1.3, kde Ri.₃ je:(a) -F, -Cl, -Br, -J, (b) -ON, (c) -CF ₃ , (d) C 1 -C 6 alkyl, (e) -O-Rma, wherein Rma is -H , -C 1 -C ₆ alkyl, -CF _3, or -CH ₂ R 4, (f) -NR 11 R 13-ib wherein -R 11 and -R 14 are the same or different, and wherein Rmb is -H, -C 1 -C 6 alkyl, - CF ₃ or -ΌΗ2-φ and wherein Rma is as defined above (g) -CO-NRma Rmb is as defined above, (h) -SO 2 -NR m _A Rmb wherein Rma and Rmb are as defined above, (i) -NRma-SO 2 - Rmb where Rma and Rmb are as defined above, (j) -no ₂ , (k) -O-SO ₂ -CF ₃ , (L) -N (R m) wherein R m are the same or different as defined above, (M) -CO-N (R m) ₂ wherein R m are the same or different as defined above, (N) -SO 2 -R 1, wherein R 1. ₃ je:

(1) -H, (2) -CF₃, (3) -Cr-Cs alkyl, (4) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (6) C₃-C₈ cykloalkyl, (7) -Ci-C₃ alkyl-C₃-C8 cykloalkyl, (8) -<€Η2)η2-φ, kde Π2 je vyššie definované a -φ je voliteľne substituovaný jediným alebo dvoma:(1) -H, (2) -CF ₃ , (3) -C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C ₈ cycloalkyl, (7) _{-C-C3 alkyl-C3-C8} cycloalkyl, (8) - <€ η2) η2-φ, wherein Π2 defined above, and -φ is optionally substituted with one or two:

(a) -F, -Cl,-Br,-J, (b) -C=N, (c) -CF₃, (d) C,-C₃ alkyl, (e) -O-Rma, kde Rma je -H, -Ci-Cô alkyl, -CF₃ alebo -CHi-φ,(a) -F, -Cl, -Br, -J, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Rma, wherein Rma is -H, -C 1 -C 6 alkyl, -CF ₃ or -CH 1 -f,

-6(f) -NRi-3aRi-3a» kde -R1-3A a -Rub sú zhodné alebo sa líšia a kde Ríša je definované vyššie, (g) -CO-NRi-_3aRi-3b, kde Rua a Ri-3b sú definované vyššie, (h) -SOj-NRmaRi -3B, kde R i-3a a Rub sú definované vyššie, (i) -NR1.3A-SO2-R1-3B kde Rua a Ri-₃b sú vyššie definované, (j) -no₂, (k) -O-SO2 -CF₃, (9) -Ο-Rua, kde Rua a -Rub sú definované vyššie, (10) -NRua Rub, kde -Rua a -Rub sú definované vyššie, (O) -NRu -SO2 -Ru, kde Ru a Ru môžu byť zhodné alebo sa líšia ako je definované vyššie, (P) -(0½)¾ -<j>, kde n₂ je vyššie definované, a kde -φ je voliteľne substituovaný jediným alebo dvoma:-6 (f) -NR-3aRi-3 »wherein -R1-3A a RUB are identical or different and the Realm wherein is as defined above, (g) -CO-R ₃ NRi--3b wherein Rua and Ri- 3b are as defined above, (h) -SO 3 -NR a R 1-3 -3B, wherein R 1-3 -a and Rub are as defined above, (i) -NR 1,3A-SO 2 -R 1-3B wherein R 1a and R _1-3 b are as defined above, (j) -no ₂ , (k) -O-SO 2 -CF ₃ , (9) -Ο-Rua, where Rua and -Rub are as defined above, (10) -NRua Rub, wherein -Rua and -Rub are defined above, (O) -NRu -SO 2 -Ru, where Ru and Ru may be the same or different as defined above, (P) - (0½) ¾ - <j>, where n ₂ is as defined above, and wherein - φ is optionally substituted with one or two:

(1) -F,-Cl,-Br,-J, (2) -CsN, (3) -CF₃, (4) Ci-C₆ alkyl, (5) -O-Ru, kde Ruje definovaný vyššie, (6) -N(Ru)₂, kde Ru sú zhodné alebo sa líšia a sú definované vyššie, (7) -CO -N(Ru)₂, kde Ru sú zhodné alebo sa líšia a sú definované vyššie, (8) -SO₂-N(Ru)₂, kde Ru sú zhodné alebo sa líšia a sú definované vyššie, (9) -NRu-S0₂-Ru, kde Ru sú zhodné alebo sa líšia a sú vyššie definované, (10) -NO₂, (11) -O-SO₂-CF₃;(1) -F, -Cl, -Br, -J, (2) -ČSN, (3) _-CF3, (4) _Ci-6 alkyl, (5) -O-Ru wherein oestrus defined above, (6) -N (Ru) ₂ , where Ru is the same or different and is as defined above, (7) -CO -N (Ru) ₂ , where Ru is the same or different, and is as defined above, (8) - SO ₂ -N (Ru) ₂ , where Ru is the same or different and is as defined above, (9) -NRu-SO ₂ -Ru, where Ru is the same or different, and is as defined above, (10) -NO ₂ (11) -O-SO ₂ -CF ₃ ;

(Q) -CO-Ru, kde Ru je definované vyššie, (R) -CO-O -Qi-₂, kde -Qu je definované nižšie, (IV) R₂ je totožné s Ri, R₂ môže byť totožné alebo rôzne s Ri_; (V) Qije:(Q) -CO-Ru wherein Ru is as defined above, (R) -CO-O -Qi- _2, wherein -Qu defined below, (IV) R ₂ is the same as R, R ₂ may be the same or different, with R 1 _; (V) Qije:

-7(A) -CO-NQmQi.2, kde -Qm je:-7 (A) -CO-NQmQi.2, wherein -Qm is:

(1) -H, (2) -C,-C_salkyl, (3) C2-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C3-C8 cykloalkyl, (6) -C1-C3 alkyl-C₃-C8 cykloalkyl, (7) -CF₃, (8) -SO₂-CF₃, (9) -(Ο^ηγ-φ, kde ηγ je 0 až 4 a kde -φ je voliteľne substituovaný jediným alebo dvoma;(1) -H, (2) C, -C _s alkyl, (3) C 2 -C alkenyl having 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=) , (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl-C ₃ -C 8 cycloalkyl, (7) -CF ₃ , (8) -SO ₂ -CF ₃ , (9) - (Ο ^ ηγ- φ, where ηγ is 0 to 4 and wherein -φ is optionally substituted with one or two;

(a) -F,-Cl,-Br,-J, (b) -ON, (c) -CF₃, (d) C,-C₃ alkyl, (e) —O—Q i-ί a, kde Qma je —H, Ci -Cď alkyl, —CF₃ alebo —CH2 -φ, (f) -NQmaQmb, kde -Qma a -Qi-ib sú zhodné alebo sa líšia, a kde Qmb je -H, Ci-Cf, alkyl, -CF₃ alebo -ΌΗ₂-φ, a kde -Qma je definované vyššie, (g) -CO-NQmaQmb, kde Qma a Qmb sú definované vyššie, (h) -SC>2-NQmaQmb, kde Qi -ia a Qmb sú definované vyššie, (i) -NQma-S02-Qmb, kde Qma a Qmb sú vyššie definované,(a) -F, -Cl, -Br, -J, (b) -ON, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-C 1-6, wherein Qma is -H, C 1 -C 6 alkyl, -CF _3, or -CH 2 -f, (f) -NQma Qmb, wherein -Qma and -Qi-ib are the same or different, and wherein Qmb is -H, C 1 -C 6 , alkyl, -CF ₃ or -ΌΗ ₂ -φ, and wherein -Qma is as defined above, (g) -CO-NQmaQmb, wherein Qma and Qmb are as defined above, (h) -SC> 2-NQmaQmb, wherein Q 1 - ia and Qmb are as defined above, (i) -NQma-SO 2 -Qmb, wherein Qma and Qmb are as defined above,

G) -no₂, (k) -O-SO2 -CF3, a kde Qm je:G) -no ₂ , (k) -O-SO 2 -CF 3, and wherein Q m is:

(1) -H, (2) -C,-C8alkyl, (3) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C3-C8 cykloalkyl, (6) —Cj—C₃ alkyl-C₃-C8 cykloalkyl, (7) -CF₃, (8) -(ϋΗ2)η2-φ, kde n₂ je definovaný vyššie, a -φ je voliteľne substituovaný jediným alebo dvoma.(1) -H, (2) -C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl having 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyl having 1 or 2 triple bonds (=), ( 5) C 3 -C 8 cycloalkyl, (6) -C ₃ -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (7) -CF ₃ , (8) - (ϋΗ 2) η 2-, wherein n ₂ is as defined above, and - φ is optionally substituted with one or two.

-8(a)-F,-Cl, -Br,-J, (b) -C=N, (c) -CF₃, (d) Ci-Cfi alkyl, (e) -O-Q1-2A kde Q1-2A je:-8 (a) -F, -Cl, -Br, -J, (b) -C =N, (c) -CF ₃ , (d) C 1 -C 6 alkyl, (e) -O-Q 1-2A wherein Q1-2A is:

0) -H, (ii) Ci-Có alkyl, (iii) -CF₃, (iv) -(CH₂H, (9) -(CH2)n9-Qi.2B(CH2)nio -Qi-2c, kde n? a nio sú zhodné alebo sa líšia a od 0 do 4, kde Q1-2B je -O- alebo -NQ1.2D-, kde Q1-2D je:O) -H, (ii) C 1 -C 6 alkyl, (iii) -CF ₃ , (iv) - (CH ₂ H, (9) - (CH 2) n 9 -C 12,2B (CH 2) n 10 -Q 1 -2c, where n 1 and n 10 are identical or different and from 0 to 4, wherein Q 1-2B is -O- or -NQ 1 2 D-, wherein Q 1-2D is:

(a) -H, (b) -Ci-Cj alkyl, (c) C2-Cg alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby, (e) C₃-C₈ cykloalkyl, (f) -Ci-C₃ alkyl-C₃-Cs cykloalkyl, (g) -cf₃, (h) -(CH2)nn-<|>, kde nn je 0 až 4 a -<J> je voliteľne substituovaný jediným alebo dvoma:(a) -H, (b) -C 1 -C 3 alkyl, (c) C 2 -C 8 alkenyl having 1 to 3 double bonds, (d) C 2 -C 8 alkynyl having 1 or 2 triple bonds, (e) C ₃ -C 8 ₈ cycloalkyl, (f) -C 1 -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (g) -cf ₃ , (h) - (CH 2) n n ->, where n n is 0 to 4 and - <J> is optionally substituted with one or two:

(i) (u) (iii)(i) (u) (iii)

(iv) Ci-C₃ alkyl, (v) -O-Q1.2E, kde Q1-2E je -H, Ci-Cô alkyl, -CF₃ alebo -CH₂-<|>, (vi) -NQ1.2E Q1-2F, kde -Q1.2E a -Q1.2F sú zhodné alebo sa líšia, a kde Qi-2F je -H, Ci-C₃ alkyl, -CF₃ alebo -ΌΗ₂-φ a kde -Qi-2e je definované vyššie, (vii) -CO-NQ1.2E -Q1-2F, kde -Q1-2E a -Q1.2F sú definované vyššie, (viii) -SO2-NQ1.2E Q1-2F a Qi-2F sú definované vyššie, (ix) -NQ1.2E -SO₂ -Q1.2F, kde -Q1-2E a -Q1-2F sú definované vyššie, (x) -NO2,(iv) _Ci-C3 alkyl, (v) -O-Q1.2, where Q1-2 is H, Ci -CO alkyl, -CF _3, or -CH ₂ - <|>, (vi) -NQ1. 2E Q1-2F where -Q1.2E -Q1.2F and are the same or different, and wherein Q is H-2 F, C ₃ alkyl, -CF ₃ or -φ and -ΌΗ ₂ wherein -Qi- 2e is as defined above, (vii) -CO-NQ1.2E -Q1-2F, wherein -Q1-2E and -Q1.2F are as defined above, (viii) -SO2-NQ1.2E Q1-2F and Qi-2F are as defined above, (ix) -SO ₂ -NQ1.2E -Q1.2F wherein -Q1-2E -Q1-2F and are as defined above, (x) -NO 2,

-9(xi) -O—SO2 -CF3, a kde Q1-2C je zhodné s Q1-2D a Q1-2C a Q1-2D môžu byť zhodné alebo sa líšiť, a kde Qm a Q1.2 tvoria spolu a atómom dusíka 5 alebo 6 členný kruh, ktorý môže obsahovať ešte ďalší dusíkový alebo kyslíkový atóm;-9 (xi) -O-SO2 -CF3, and wherein Q1-2C is identical to Q1-2D and Q1-2C and Q1-2D may be identical or different, and wherein Qm and Q1.2 form together and a nitrogen atom A 5 or 6 membered ring which may contain yet another nitrogen or oxygen atom;

(B) -SO2 -NQ1-1 Qm, kde Qm a Q1.2 sú definované vyššie, (C) -CO-O-Qm, kde Q1.3 je:(B) -SO2 -NQ1-1 Qm, wherein Qm and Q1.2 are as defined above, (C) -CO-O-Qm, wherein Q1.3 is:

(1) -H, (2) -CF₃, (3) Ci-Cgalkyl, (4) C₂-C_g alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (6) C3-C8 cykloalkyl, (7) -C1-C3 alkyl-C₃-C8 cykloalkyl, (8) -ýCH₂)n7-<J>, kde n₇ je definovaný vyššie a -φ je voliteľne substituovaný jedným alebo dvoma:(1) -H, (2) _-CF3, (3) Ci-Cgalkyl, (4) _C2-g alkenyl having 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=), (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl-C ₃ -C 8 cycloalkyl, (8) -CH ₂ ) n _{7 -} , wherein n ₇ is as defined above, and - φ is optionally substituted by one or two:

(a)-F, -Cl,-Br,-J, (b) -ON, (c) -€F₃, (d) C1-C3 alkyl, (e) -O-Qi-3a, kde Q1-3a je -H, Ci -C₆ alkyl, -CF₃ alebo -CH₂ -φ, (f) —NQmaQmb, kde -Qma a Qmb sú zhodné alebo sa líšia a kde Qi-3Bje H, Ci-Có alkyl, -CF3 alebo -€Η₂-φ, a kde -Qma je definované vyššie, (g) -CO-NQmaQmb, kde Qma a Qmb sú definované vyššie, (h) -SO₂-NQmaQmb, kde Qma a Qmb sú definované vyššie, (i) -NQma-SO₂ -Qmb, kde Qma a Qmb sú vyššie definované, (i) -no₂, (k) -O-SO2 -CF₃, (D) -CO-Qm, kde Qm je definované vyššie, (E) -CO-imidazol, (F) -NQmQi-2, kde Qm a Qm sú definované vyššie, (F ) -NQm-CO -Qm, kde Qm a Qm sú definované vyššie, (G) -C(Qm)=N-O-Qm, kde Qm je zhodné s Qm a Qm je definované vyššie, Qm a Qm môže byť zhodné alebo sa líšiť, (H) -SO2 -Qm, kde Qm je definované vyššie,(a) -F, -Cl, -Br, -J, (b) -ON, (c) - C ₃ , (d) C 1 -C 3 alkyl, (e) -O-Q 1 -3a, wherein Q 1 - 3a is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, (f) -NQma Qmb, wherein -Qma and Qmb are the same or different and wherein Q 1-3-3 is H, C 1 -C 6 alkyl, - CF 3 or - € Η ₂ -φ, and wherein -Qma is as defined above, (g) -CO-NQmaQmb, wherein Qma and Qmb are as defined above, (h) -SO ₂ -NQmaQmb, wherein Qma and Qmb are as defined above, (i) -NQma-SO ₂ -Qmb, wherein Qma and Qmb are as defined above, (i) -no ₂ , (k) -O-SO 2 -CF ₃ , (D) -CO-Qm, wherein Qm is as defined above (E) -CO-imidazole, (F) -NQmQi-2, wherein Qm and Qm are as defined above, (F) -NQm-CO -Qm, wherein Qm and Qm are as defined above, (G) -C (Qm) ) = NO-Qm, where Qm is equal to Qm and Qm is as defined above, Qm and Qm may be the same or different, (H) -SO2 -Qm, where Qm is as defined above,

- 10(I) -N(Qi_i) -SO2 -Q1-3, kde Qm a Q1-3 je definované vyššie, (J) 5-oxadiazol voliteľne substituovaný jedným Q1.5, kde Q1.5 je:- 10 (I) -N (Q1-i) -SO2 -Q1-3, wherein Qm and Q1-3 are as defined above, (J) 5-oxadiazole optionally substituted with one Q1.5, wherein Q1.5 is:

(1) -H, (2) -F, -Cl, -Br, -I, (3) C_rC₈ alkyl, (4) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (6) C₃-C₈ cykloalkyl, (7) -C1-C3 alkyl-Cj-Cs cykloalkyl, (8) -NO₂, (9) -CsN, (10) -CF₃, (11) -O-Q1-5A, kde -Qi-sa je:(1) -H, (2) -F, -Cl, -Br, -I, (3) C _r -C ₈ alkyl, (4) C 2 -C 8 alkenyl having 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (ξ), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C 3 alkyl-C 1 -C 8 cycloalkyl, (8) -NO ₂ , (9) -C 8 N (10) -CF ₃ , (11) -O-Q1-5A, wherein -Q 1 -s is:

(a) -H, (b) Ci-C₈ alkyl, (c) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby, (e) C3-C8 cykloalkyl, (f) -C1-C3 alkyl-C3-C8 cykloalkyl, (g) -CF₃, (h) -SO2-CF₃, (i) -(CH2)n7 -φ, kde n?je 0 až 4, (12) -NQ1.5A-Q1-5D, kde Qi-sa je vyššie definované, Q1-50:(a) -H, (b) C 1 -C ₈ alkyl, (c) C 2 -C 8 alkenyl having 1 to 3 double bonds, (d) C 2 -C 8 alkynyl having 1 or 2 triple bonds, (e) C 3 -C 8 cycloalkyl (f) -C 1 -C 3 alkyl-C 3 -C 8 cycloalkyl, (g) -CF ₃ , (h) -SO 2 -CF ₃ , (i) - (CH 2) n 7 -φ, where n is 0 to 4, (12) -NQ1.5A-Q1-5D, where Q1-sa is as defined above, Q1-50:

(a) -H, (b) Ci-C₈ alkyl, (c) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (d) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (e) C3-C8 cykloalkyl, (f) -C1-C3 alkyl-C₃-C8 cykloalkyl, (g) -CF₃, (h) -(CH2)n7 -φ, kde n7 je definované vyššie, (13) -CO-NQ1.5A-Q1-5D, kde Qi-sa sú vyššie definované, (14) -SO2-Q1-5K, kde -Q1.5K je:(a) -H, (b) C 1 -C ₈ alkyl, (c) C 2 -C 8 alkenyl having 1 to 3 double bonds (=), (d) C 2 -C 8 alkynyl having 1 or 2 triple bonds (ξ), ( e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl-C ₃ -C 8 cycloalkyl, (g) -CF ₃ , (h) - (CH 2) n 7 -φ, wherein n 7 is as defined above, (13) - CO-NQ1.5A-Q1-5D, wherein Q1-s are as defined above, (14) -SO2-Q1-5K, wherein -Q1.5K is:

- 11 (a) -Η, (b) -CF₃, (c) Ci-C₈ alkyl, (d) Cr-Ce alkenyl obsahujúci 1 až 3 dvojité väzby (=), (e) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (f) C3-C8 cykloalkyl, (g) -C1-C3 alkyl-C₃-C_g cykloalkyl, (h) -(CH2)n7 -φ, kde n?je definované vyššie, (15) NQ1.5A-SO2-Q1.5K, kde Qi-sa a -Qi-sk môžu byť zhodné alebo sa líšia a sú definované vyššie, (16) -{CH₂)n7 -φ, kde n₇ je definované vyššie a kde -φ je voliteľne substituovaný jedným alebo dvoma:- 11 (a) -Η, (b) -CF ₃ , (c) C 1 -C ₈ alkyl, (d) C 1 -C 6 alkenyl containing 1 to 3 double bonds (=), (e) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=), (f) C3-C8 cycloalkyl, (g) -C 1 -C 3 alkyl-C ₃ -C _g cycloalkyl, (h) - (CH 2) n 7 -φ, where n? is as defined above, (15) NQ1.5A Q1.5K-SO 2, wherein Q and -Q-is-in may be the same or different and are as defined above, (16) - _{CH2) n 7 -φ wherein n ₇ is as defined above and wherein -φ is optionally substituted with one or two:

(a) -F, -Cl,-Br,-J, (b) -CsN, (c) -CF₃, (d) C,-C₆ alkyl, (e) -O-Qi.sa, kde Qi-sa je definované vyššie, (f) NQi-5aQi-5d, kde -Qi-sa a Q1.5D sú definované vyššie, (g) -CO-NQ i-saQi-sd, kde Qi-sa a Qi-sd sú definované vyššie, (h) -SO2 -NQi-saQi-sd, kde Qi-sa a Qi-sd sú definované vyššie, (í)-NQi.5a-SO2-Qi-5d, kde Qi-sa a Qi-sd sú vyššie definované, (j)-NO₂, (k) -O-SO2 -CF₃;(a) -F, -Cl, -Br, -J, (b) -C 5 N, (c) -CF ₃ , (d) C 1 -C ₆ alkyl, (e) -O- Q 1, wherein Q 1 - as defined above, (f) NQi-5aQi-5d, wherein -Qi-sa and Q1.5D are as defined above, (g) -CO-NQi-saQi-sd, wherein Qi-sa and Qi-sd are as defined above, (h) -SO 2 -NQ 1 -saQ 1 -dd, wherein Q 1 -sa and Q 1 -dd are as defined above, (i) -NQ 1 5a -SO 2 -Q 1 -d 5d, where Q 1 -sa and Q 1 -dd are as defined above, (j) -NO ₂ , (k) -O-SO 2 -CF ₃ ;

(K) 3-oxadiazol voliteľne substituovaný jedným Q1-5, kde Q1-5 je definované vyššie, (L) triazol voliteľne substituovaný jedným alebo dvoma Q1-5, ktoré môžu byť zhodné alebo sa líšiť, kde Q1-5 je definovaný vyššie, (M) 5-tiadiazol voliteľne substituovaný jedným Q1.5, kde Q1-5 je definované vyššie, (N) 3-tiadiazol voliteľne substituovaný jedným Q1-5, kde Q1-5 je definované vyššie, (O) 2-oxazol voliteľne substituovaný jedným alebo dvoma Q1-5, ktoré môžu byť zhodné alebo rôzne, kde Q1-5 je definované vyššie, (P) 2-tiazol voliteľne substituovaný jedným alebo dvoma Q1-5, ktoré môžu byť zhodné alebo rôzne, kde Qi-5 je definované vyššie,(K) 3-oxadiazole optionally substituted with one Q1-5, wherein Q1-5 is as defined above, (L) triazole optionally substituted with one or two Q1-5, which may be the same or different, wherein Q1-5 is as defined above, (M) 5-thiadiazole optionally substituted with one Q1.5 wherein Q1-5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1-5 wherein Q1-5 is as defined above, (O) 2-oxazole optionally substituted one or two Q1-5, which may be identical or different, wherein Q1-5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1-5, which may be identical or different, wherein Q1-5 is defined higher,

- 12(Q) 2-imidazol voliteľne substituovaný jedným, dvoma alebo troma Q1-5, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (R) l-imidazol substituovaný jedným, dvoma alebo troma Q1.5, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (S) tetrazol voliteľne substituovaný jedným Q 1.5, kde Q1.5 je definované vyššie, (T) cyklobuténdión voliteľne substituovaný jedným Qm a jedným Q1.5, kde Qm a Q1-5 sú definované vyššie, (U) 1-pyrimidinyl voliteľne substituovaný jedným Qm, kde Q1.5 je definované vyššie, (V) 2-pyridinyl voliteľne substituovaný jedným Qi-5, kde Q1-5 je definované vyššie, (W) 3-pyridinyl voliteľne substituovaný jedným Q1.5, kde Q1.5 je definované vyššie, (X) 4-pyridinyl voliteľne substituovaný jedným Q 1.5, kde Q 1.5 je definované vyššie, (Y) -Zi -CO -Z₂ -Qm, kde Qm je definované vyššie a -Zi je -O- alebo -Nqm, kde -Q1-1 je definované vyššie, kde -Z₂ je -O- alebo- 12 (Q) 2-imidazole optionally substituted with one, two or three Q1-5, which may be identical or different, wherein Q1.5 is as defined above, (R) 1-imidazole substituted with one, two or three Q1.5, which may be identical or different, wherein Q1.5 is as defined above, (S) tetrazole optionally substituted with one Q1.5, wherein Q1.5 is as defined above, (T) cyclobutenedione optionally substituted with one Qm and one Q1.5, wherein Qm and Q1-5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one Qm, wherein Q1.5 is as defined above, (V) 2-pyridinyl optionally substituted with one Q1-5, wherein Q1-5 is as defined above, (W) 3-pyridinyl optionally substituted with one Q1.5, Q1.5 wherein is as defined above, (X) 4-pyridinyl optionally substituted by Q 1.5, Q 1.5 wherein is as defined above, (Y) -Z-CO ₂ -Z -QM, wherein Q m is as defined above and -Z 1 is -O- or -Nqm, wherein -Q 1-1 is as defined above, wherein -Z ₂ is -O- or

-Nqm, kde -Qm je definované vyššie, s výhradou, že pokiaľ Xi je -{CH₂)ni-, kde nje O a Qt je:-Nqm, where -Qm is as defined above, with the proviso that when X 1 is - (CH ₂ ) n 1 -, where n is 0 and Q t is:

-CO-NQmQi-2,-CO-NQmQi-2,

-SO₂-NQmQi-2 alebo -NQmQi-2,-SO ₂ -NQmQi-2 or -NQmQi-2,

NQmCO-Qi-2, potom -Qm a -Qm nemôžu byť obidva vybrané z:NQmCO-Qi-2, then -Qm and -Qm cannot both be selected from:

-H,-H.

-Ci-C₆ alkyl,-C 1 -C ₆ alkyl,

-C3-C7 cykloalkyl,-C3-C7 cycloalkyl,

-C1-C3 alkyl -(C3-C7) cykloalkyl a ich farmaceutický prijateľné soli.-C 1 -C 3 alkyl - (C 3 -C 7) cycloalkyl and pharmaceutically acceptable salts thereof.

Opísané sú tiež aromatické bicyklické amíny vzorca (ABA)Also described are aromatic bicyclic amines of formula (ABA).

kde:where:

(I) Wi je dusíkový (-N-) alebo uhlíkový atóm (-CH-); (Π) Xi je -(CH₂)_ni a m je 0, (ABA)(I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (Π) Xi is - (CH ₂ ) _{n and} y is 0, (ABA)

- 13 (ffl)Qije (A)-CO-NQi-i Qi-2, kde Qm je:13 (ffl) Q 1i (A) -CO-NQi-1 Qi-2, where Qm is:

(1) -H, (2) Cj-Cg alkyl, (3) Cí-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C2-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) -(CH₂)n₇^, kde n₇ je 0 až 4 a kde -φ je voliteľne substituovaný jedným alebo dvoma:(1) -H, (2) C 1 -C 8 alkyl, (3) C 1 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=), (5) ) - (CH ₂ ) n _{7 -} , wherein n ₇ is 0 to 4 and wherein -φ is optionally substituted by one or two:

(a) -F, -Cl, -Br,-J, (b) -CsN, (c) -CF₃, (d) Q-C3 alkyl, (e) -O-Qm_A kde Qma je -H, Ci-Cé alkyl, -CF₃ alebo -(CH₂) -φ, (f) kde Qma a Qmb sú rovnaké alebo rôzne a kde(a) -F, -Cl, -Br, -J, (b) -ČSN, (c) _-CF3, (d) -C 3 -alkyl, (e) -O-Q m wherein _A is QMA-H, C 1 -C 6 alkyl, -CF ₃ or - (CH ₂ ) -φ, (f) wherein Qma and Qmb are the same or different and wherein

Qmb je -H, Ci-Cô alkyl, -CF₃ alebo -(ΟΗ^-φ, a kde Qma je ako je uvedený vyššie.Q m 4 is -H, C 1 -C 6 alkyl, -CF _3, or - (R 2 -f), and wherein Qma is as above.

(g) -CO-NQma Qmb kde Qma a Qmb sú ako je uvedené vyššie, (h) -SO2-NQ1 -1A Qi -iB kde Qma a Qmb sú ako je uvedené vyššie, (i) -NQma-S02-Qmb kde Qma a Qmb sú ako je uvedené vyššie, (j) -NO2, (k) -O-SO2 -CF₃, a kde Qm je:(g) -CO-NQma Qmb wherein Qma and Qmb are as above, (h) -SO2-NQ1 -1A Qi-iB wherein Qma and Qmb are as above, (i) -NQma-SO2-Qmb wherein Qma and Qmb are as above, (j) -NO 2, (k) -O-SO 2 -CF ₃ , and wherein Q m is:

(6) Ci-C₈ alkyl, (7) C₂-C₈ alkenyl, obsahujúci 1 až 3 dvojité väzby (=) (8) C2-C8 alkinyl, obsahujúci 1 až 2 trojité väzby (ξ) (9) -{ΟίΟ^-φ kde n₂ je ako je definované vyššie a -φ je výhodne substituované s jedným alebo dvoma:(6) C 1 -C ₈ alkyl, (7) C ₂ -C ₈ alkenyl, containing 1 to 3 double bonds (=) (8) C 2 -C 8 alkynyl, containing 1 to 2 triple bonds (ξ) (9) - { Where n ₂ is as defined above and -φ is preferably substituted with one or two:

(a) -F,-Cl,-Br,-J, ' (b) -CbN, (c) -CF₃, (d) Ci-C₆ alkyl, (e) -O-QmA kde Qma je:(a) -F, -Cl, -Br, -J, (b) -CbN, (c) -CF ₃ , (d) C 1 -C ₆ alkyl, (e) -O-QmA wherein Qma is:

(0-H (ii) Ci-C₆ alkyl,(O-H (ii) C 1 -C ₆ alkyl,

- 14(iii) -CF₃, (iv) -(CH2)-φ, (B) -SO2-NQ1.1 Qi_2,kde Qm a Q1.2 sú definované vyššie, (C) -NQm Qm, kde Qm a Qm sú definované vyššie, (D) -NQm -CO Qm, kde Qm a Qm sú definované vyššie,(Iii) -CF ₃ , (iv) - (CH 2) -φ, (B) -SO 2 -NQ1.1 Qi_2, where Qm and Q1.2 are as defined above, (C) -NQm Qm, wherein Qm and Qm are as defined above, (D) -NQm -CO Qm, wherein Qm and Qm are as defined above,

(III) R, je: (III) R, is: (A) -H, (B) -F,-Cl,-Br, -J, (C) Ci-C₈alkyl, (D) -C=N, (E) -CF₃, (F) -O-Rm, kde -Ri-ije: (1) -H, (2) Ci-C₈alkyl, (3) -CF₃, (4) -SO₂-CF₃, (5) -(0¾)¾ -φ, kde Π2 je 0 až 4 (G) -N(Rm)₂, kde Rm sú zhodné alebo rôzne a sú definované vyššie, (H) -C0-N(Rm)2, kde Rm sú zhodné alebo rôzne a sú definované(A) -H, (B) -F, -Cl, -Br, -J, (C) C 1 -C ₈ alkyl, (D) -C = N, (E) -CF ₃ , (F) -O -R m where -R 1 -i is: (1) -H, (2) C 1 -C ₈ alkyl, (3) -CF ₃ , (4) -SO ₂ -CF ₃ , (5) - (0 ') ¾ - φ, where Π2 is 0 to 4 (G) -N (R m) ₂ , where R m are identical or different and are as defined above, (H) -CO-N (R m) 2, wherein R m are identical or different and are defined vyššie, higher, (I) — SO2-Ri-3,kde Ri-₃ je: (1) -CF₃, (2) Ci-C₈alkyl, (3) -O-Ri-_3A, kde Ri-₃Aje definovaný vyššie, (4) -NRi-₃aRmb, kde -Ri-₃a a -Ri-₃b sú definované vyššie,(I) - SO2-R-3, wherein Ri- ₃ is: (1) _-CF3, (2) _Cl-C8 alkyl, (3) -O-Ri- _3A wherein Ri- ₃ A is as defined above, (4) -NRi- Armb ₃ wherein AA ₃ -Ri- -Ri- ₃ b are as defined above,

(J) -CO-Rm, kde Rm je definované vyššie;(J) -CO-R m, wherein R m is as defined above;

(IV) R2 je zhodné sRi, R2 môže byť zhodné alebo rôzne s Ri; a ich farmaceutický prijateľné soli.(IV) R 2 is identical to R 1, R 2 may be the same or different to R 1; and pharmaceutically acceptable salts thereof.

Ďalej sú v príkladoch 1, 2, 11, 12, 14, 24, 40, 72, 84, 86 a 88 uvedené aromatické bicyklické amíny.Furthermore, aromatic bicyclic amines are shown in Examples 1, 2, 11, 12, 14, 24, 40, 72, 84, 86 and 88.

- 15Vynález sa týka nových zlúčenín, 1,6-disubstituovaného izochrómanu (I) a malej skupiny aromatických bicyklických amínov (ABA), ktorá je už ako celok opísaná v medzinárodnej publikácii WO 95/18118 (PCT/US94/13284), s jedinečným spektrom aktivity, vysoko aktívnym proti vaskulámym bolestiam hlavy, hlavne proti migréne aklastrovým bolestiam hlavy. Spôsoby výroby nových nárokovaných zlúčenín podľa vynálezu sú odborníkom v danej oblasti známe. Za použitia vhodných východiskových látok a zoradením jednotlivých za sebou nasledujúcich krokov výroby (použitie protektívnych skupín, pokiaľ je to nutné) vznikajú nové zlúčeniny podľa vynálezu. Postup každého kroku podľa vynálezu je odborníkom v danej oblasti známy. Odborník v danej oblasti by mohol na základe chemickej štruktúry ľahko pripraviť zo známych zlúčenín už známymi postupmi ktorýkoľvek z 1,6-disubstituovaných izochrómanov (I) alebo aromatických bicyklických amínov (ABA) bez konzultácií či príkladov nižšie.The invention relates to novel compounds, 1,6-disubstituted isochroman (I) and a small group of aromatic bicyclic amines (ABA), which are already described in their entirety in WO 95/18118 (PCT / US94 / 13284), with a unique spectrum. activity, highly active against vascular headaches, especially against migraine and aclastral headaches. Methods for making the novel claimed compounds of the invention are known to those skilled in the art. Using the appropriate starting materials and sequencing the successive production steps (use of protective groups, if necessary), the novel compounds of the invention are formed. The process of each step of the invention is known to those skilled in the art. A person skilled in the art could readily prepare any of the 1,6-disubstituted isochromates (I) or aromatic bicyclic amines (ABA) from the known compounds by known methods without prior consultation or examples below.

Schéma A opisuje tvorbu 6-brómizochrómanu (VI), ktorý je užitočným medziproduktom pre mnoho 1,6-disubstituovaných izochrómanov (I) a aromatických bicyklických amínov (ABA). Reakciou 3-brómfenetanolu (Π) s etyl 3,3-dietoxypropionátom za prítomnosti chloridu titaničitého v nitrometáne alebo dichlórmetáne vzniká ester izochrómanu (ΙΠ). Štandardnou hydrolýzou za použitia hydroxidu lítneho v THF-vode vzniká kyselina (IV), ktorá sa môže viazať k mnohým substituovaným arylpiperazínom alebo 4arylpiperidínom za vzniku amidov (V), Arylpiperazínová časť nesie Ria R2 substituenty. Je výhodné, pokiaľ sú substituenty Ria R2 na arylovej skupine pred vznikom amidu (V). Východiskové Ria R2 arylové skupiny sú odborníkom v danej oblasti známe, lebo môžu byť ľahko pripravené známymi metódami zo známych zlúčenín. Veľa arylpiperazínov je komerčne dostupných alebo známych z chemickej literatúry. Tie, ktoré nie sú komerčne dostupné alebo známe sa môžu pripraviť, ako je ukázané zo schémy Q a R. Tieto amidy sa redukujú bóranom za vzniku brómizochrómanov (VI).Scheme A describes the formation of 6-bromoisochroman (VI), which is a useful intermediate for many 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA). Reaction of 3-bromophenethanol (Π) with ethyl 3,3-diethoxypropionate in the presence of titanium tetrachloride in nitromethane or dichloromethane affords an isochromate ester (Π). Standard hydrolysis using lithium hydroxide in THF-water gives the acid (IV), which can bind to many substituted arylpiperazines or 4arylpiperidines to form amides (V). The arylpiperazine moiety carries R 1 R 2 substituents. It is preferred that the substituents R 1 and R 2 are on the aryl group before the formation of the amide (V). Starting R 1 and R 2 aryl groups are known to those skilled in the art since they can be readily prepared by known methods from known compounds. Many arylpiperazines are commercially available or known from the chemical literature. Those that are not commercially available or known can be prepared as shown in Schemes Q and R. These amides are reduced with borane to form bromoisochromates (VI).

Schéma B opisuje premenu 6-brómizochrómanu (VI) na príslušný 6-amid a 6-esterové analógy. Konverzia arylbromidu na primárny amid sa dosiahne kovhalogénovou výmenou použitím t-butyl lítia a potlačením vznikajúceho arylového aniónu trimetylsilylizokyanátom, pozri J. Med. Chem, 36, 2208 (1993). Arylový anión tiež môže reagovať s plynným oxidom uhličitým s nasledovným pôsobením oxalyl chloridu v DMF a ďalšou reakciou s amínmi pri priamom vzniku amidov (IX). Alternatívne, 6-brómizochróman (VI) môže reagovať s oxidom uhoľnatým za prítomnosti octanu paládnatého, 1,3-bisdifenylfosfínpropánu, diizopropylamínu a hexametyldisilazánu v rozpúšťadlách, napríklad DMF za vzniku amidu (VII). Môžu saScheme B describes the conversion of 6-bromoisochroman (VI) to the corresponding 6-amide and 6-ester analogs. Conversion of the aryl bromide to the primary amide is achieved by metal halide exchange using t-butyl lithium and suppression of the resulting aryl anion with trimethylsilyl isocyanate, see J. Med. Chem., 36, 2208 (1993). The aryl anion can also be reacted with carbon dioxide gas followed by treatment with oxalyl chloride in DMF and further reaction with amines to directly form amides (IX). Alternatively, 6-bromoisochroman (VI) can be reacted with carbon monoxide in the presence of palladium acetate, 1,3-bisdiphenylphosphine propane, diisopropylamine and hexamethyldisilazane in solvents such as DMF to form amide (VII). They can

-16použiť tiež iné katalyzátory paládia, napríklad in situ pripravené paládium s organofosfínmi alebo dopredu pripravené paládium fosfinové katalyzátory. Amid (VII) sa môže premeniť buď na substituované amidy (IX) alebo estery (X) pomocou bis-BOC derivátu (VIII) postupom opísaným v J. Org. Chem., 56, 5482 (1991). 6-Brómizochróman (VI) sa môže premeniť na N-metyl substituované amidy (IX) priamo použitím metylamínu alebo Nmetylformamidu namiesto hexametyldisilazánu vpaládiom sprostredkovanej reakcii vyššie opísanej (pozri príklad 5 a 6). Alternatívne sa môžu vpaládiom sprostredkovanej vyššie opísanej reakcii získať iné N-substitúcie, použitím iných primárnych alebo sekundárnych amínov namiesto hexametyldisilazánu.Other palladium catalysts may also be used, for example in situ prepared palladium with organophosphines or preformed palladium phosphine catalysts. The amide (VII) can be converted to either substituted amides (IX) or esters (X) by the bis-BOC derivative (VIII) according to the procedure described in J. Org. Chem., 56, 5482 (1991). 6-Bromoisochroman (VI) can be converted to N-methyl substituted amides (IX) directly using methylamine or N-methylformamide instead of hexamethyldisilazane in the palladium-mediated reaction described above (see Examples 5 and 6). Alternatively, other N-substitutions may be obtained in the palladium-mediated reaction described above, using other primary or secondary amines instead of hexamethyldisilazane.

Schéma C opisuje enzymatický rozklad racemátu (Π). Zmiešaním (II) s enzýmom, napríklad lipázou odvodenou od Pseudomonas cepacia vo vodnom tlmivom roztoku ( s výhodou pH 5 až 8) s nasledovnou selektívnou hydrolýzou (-)-esteru vznikne (-)kyselina (XI). Je výhodné uskutočňovať reakcie pri izbovej teplote (20 až 35 °C) za použitia 5 - 20 % hmotnostných enzýmu. Reakcia sa monitoruje známym spôsobom odobratím alikvótu, okyslením a uskutočnením HPCL. Po skončení reakcie sa produkty (XI), (-)kyselina a (XII), (+)-ester odstránia a oddelia sa separačnými technikami kyselina/báza, ktoré sú dobre známe odborníkom v danej oblasti. Tieto opticky aktívne zlúčeniny sa môžu vhodne použiť, pokiaľ je to vhodné, akýmkoľvek spôsobom z uvedených schém na prípravu opticky čistých verzií opísaných zlúčenín.Scheme C describes the enzymatic decomposition of the racemate (Π). Mixing (II) with an enzyme, for example a lipase derived from Pseudomonas cepacia in an aqueous buffer (preferably pH 5-8) followed by selective hydrolysis of the (-) - ester results in (-) acid (XI). It is preferred to carry out the reactions at room temperature (20-35 ° C) using 5-20% by weight of enzyme. The reaction is monitored in a known manner by taking an aliquot, acidifying and performing HPCL. Upon completion of the reaction, the products (XI), (-) acid and (XII), (+) - ester are removed and separated by acid / base separation techniques well known to those skilled in the art. These optically active compounds can be conveniently used, if appropriate, by any of the above schemes to prepare optically pure versions of the disclosed compounds.

Vedľajší produkt, enantiomér, (+)-etyl (izochróman-l-yl)acetát (ΧΠ), vzniknutý z Pseudomonas cepacia, sprostredkovaný kinetickým rozkladom enantiomérov, sa môže účinne recyklovať späť do racemickej zmesi, kde je následne podrobený ďalšiemu pôsobeniu Pseudomonas lipázy. Tento opakovaný proces optimalizuje celkový výťažok požadovanej (-)izochróman-l-yl-octovej kyseliny (XI). Vhodné bázy pre túto racemizáciu majú pKa vyššie než 11, s výhodou vyššie než 12, Vhodné bázy predstavujú amidy alkalických kovov, alkoxidy alkalických kovov a uhličitany alkalických kovov, ktoré môžu indukovať racemizáciu. Je výhodné, keď sú bázami bázy amidov alkalických kovov, alkoxidy alkalických kovov; výhodnejšie je, keď sú bázy alkoxidy alkalických kovov, napríklad tbutoxid sodný alebo draselný alebo etoxid. Ku koncu racemizácie sa reakcia potlačí donorom protónu. Potenciálne je možný akýkoľvek donor protónu, napríklad voda môže potlačiť reakciu. Voda však nie je najvýhodnejšia. Väčšinou je donorom protónu kyselina. Na potlačenie enolátových aniónov sa tiež v tomto prípade môžu použiť najbežnejšie protónovéThe by-product, enantiomer, (+) - ethyl (isochroman-1-yl) acetate (ΧΠ), formed from Pseudomonas cepacia, mediated by kinetic decomposition of enantiomers, can be effectively recycled back to the racemic mixture, where it is subsequently subjected to further lipase treatment with Pseudomonas. This repeated process optimizes the overall yield of the desired (-) isochroman-1-yl-acetic acid (XI). Suitable bases for this racemization have a pK a of greater than 11, preferably greater than 12. Suitable bases are alkali metal amides, alkali metal alkoxides and alkali metal carbonates which can induce racemization. Preferably, the bases are alkali metal amide bases, alkali metal alkoxides; more preferably, the bases are alkali metal alkoxides such as sodium or potassium t-butoxide or ethoxide. At the end of racemization, the reaction is quenched by a proton donor. Potentially any proton donor is possible, for example water can suppress the reaction. However, water is not the most advantageous. Typically, the proton donor is an acid. The most common proton can also be used in this case to suppress the enolate anions

- 17donory (kyselina chlorovodíková, chlorid amónny), avšak pre jednoduchšie zaobchádzanie a čistenie sa s výhodnou použije kyselina octová alebo trifluóroctová kyselina.17-donors (hydrochloric acid, ammonium chloride), but acetic acid or trifluoroacetic acid is preferably used for easier handling and purification.

Schéma D opisuje prípravu amidov a esterov, ktoré sú pripojené k izochrómanovému jadru jedným metylénovým článkom (I, Xi = -CH₂-). Pôsobením arylbromidu (VI) s trimetylsilylacetylénom v prítomnosti octanu paládnatého, jodidu med’ného a trietylamínu vzniká izochróman acetylénu (XIII). Reakciou izochrómanu acetylénu (XIII) s dialkylbóranom, napríklad dicyklohexylbóranom s následnou oxidáciou za použitia bázického peroxidu vodíka vzniká karboxylová kyselina (XIV, Q1.3 = H), od ktorej sa môžu odvodiť generalizované estery (XIV) alebo amidy (XV) štandardnými technikami, ktoré sú odborníkom v danej oblasti známe.Scheme D describes the preparation of amides and esters that are attached to the isochroman nucleus by one methylene cell (I, X 1 = -CH ₂ -). Treatment of the aryl bromide (VI) with trimethylsilylacetylene in the presence of palladium (II) acetate, copper (I) iodide and triethylamine gives the acetylene isochromate (XIII). Reaction of the acetylene isochromate (XIII) with a dialkylborane, for example dicyclohexylborane, followed by oxidation with basic hydrogen peroxide affords the carboxylic acid (XIV, Q1.3 = H) from which generalized esters (XIV) or amides (XV) can be derived by standard techniques, known to those skilled in the art.

Schéma E opisuje prípravu amidov a esterov, ktoré sú pripojené k izochrómanovému jadru dvojuhlíkovým článkom, ktoré môže byť buď nasýtené (I, Xi = -CH2CH2-) alebo nenasýtené (I, Xi = -CH=CH-). Reakciou bromidu (VI) s esterom akrylátu v prítomnosti katalyzátora paládia, s výhodou octanu paládnatého s 1,3-bisdifenylfosfínopropánom a diizopropylamínom v organickom rozpúšťadle, napríklad v dimetylformamide vzniká (XIV). Hydrogenáciou (XVI) štandardnými technikami, ktoré sú odborníkom v danej oblasti známe, vznikajú nasýtené druhy (XVII). Podobne, reakciou bromidu (VI) s akrylamidom v prítomnosti katalyzátora paládia, s výhodou octan paládnatý a nasledovne s 1,3bisdifenylfosfínopropánom a diizopropylamínom v organickom rozpúšťadle ako je dimetylformamid vzniká (VHI). Hydrogenáciou (XVIII) štandardnými technikami, ktoré sú známe odborníkom v danej oblasti, vznikajú nasýtené druhy (XIX).Scheme E describes the preparation of amides and esters that are attached to the isochroman nucleus by a double carbon cell that may be either saturated (I, X 1 = -CH 2 CH 2 -) or unsaturated (I, X 1 = -CH = CH-). Reaction of the bromide (VI) with an acrylate ester in the presence of a palladium catalyst, preferably palladium acetate with 1,3-bisdiphenylphosphinopropane and diisopropylamine in an organic solvent, for example dimethylformamide, yields (XIV). Hydrogenation (XVI) by standard techniques known to those skilled in the art produces saturated species (XVII). Similarly, reaction of bromide (VI) with acrylamide in the presence of a palladium catalyst, preferably palladium acetate, followed by 1,3-bis diphenylphosphinopropane and diisopropylamine in an organic solvent such as dimethylformamide is formed (VHI). Hydrogenation (XVIII) using standard techniques known to those skilled in the art produces saturated species (XIX).

Schéma F opisuje prípravu amidov a esterov, ktoré sú spojené s izochrómanovým jadrom trojuhlíkovým metylénovým článkom (I, Xi, = -CH2CH2CH2 -). Karboxylová kyselina (X, Q1.3 = H) reaguje s dvojnásobným množstvom propyllítia za vzniku butyrofenónu (XX). Na teplotu refluxu sa zahreje roztok butyrofenónu (XX) v morfolíne s ekvivalentným množstvom elementárnej síry a morfolínu 10-20 hodín vzniká tiolaktám (XXI, pozri Org. Reactions, roč. HL, kapitola 2, str. 83, 1946, John Wiley & Sons New York). Hydrolýzou tiolaktámu (XXI) s vodnou kyselinou chlorovodíkovou za použitia techník, ktoré sú známe odborníkom v danej oblasti, vzniká karboxylová kyselina (ΧΧΠ, Q1.3 = H), z ktorej sa môžu získať estery (XXII) a amidy (XXIII) použitím už dobre známych techník.Scheme F describes the preparation of amides and esters that are linked to the isochroman nucleus by a tri-carbon methylene cell (I, X 1, = -CH 2 CH 2 CH 2 -). The carboxylic acid (X, Q1.3 = H) reacts with twice the amount of propyl lithium to form butyrophenone (XX). A solution of butyrophenone (XX) in morpholine with an equivalent amount of elemental sulfur and morpholine is heated to reflux for 10-20 hours to give thiolactam (XXI, see Org. Reactions, Vol. HL, Chapter 2, p. 83, 1946, John Wiley & Sons New York). Hydrolysis of thiolactam (XXI) with aqueous hydrochloric acid using techniques known to those skilled in the art produces a carboxylic acid (ΧΧΠ, Q1.3 = H) from which esters (XXII) and amides (XXIII) can be obtained using well-known techniques.

Schéma G opisuje prípravu izochrómanov nesúcich 6-acylový substituent, napríklad kyselina, ester, ketón alebo oxím. Kov-halogénovou výmenou akrylbromidu (VI) vzniká aryl-lítiové činidlo, ktoré sa môže potlačiť oxidom uhličitým za vznikuScheme G describes the preparation of isochromates bearing a 6-acyl substituent, for example an acid, ester, ketone or oxime. Metal-halogen exchange of acrylic bromide (VI) produces an aryl-lithium reagent which can be quenched with carbon dioxide to form

- 18karboxylových kyselín (X, Q1.3 = H). Paládiom sprostredkovanou karbonyláciou arylbromidu (IV) v prítomnosti alkoholu vznikajú príslušné estery (X) za podmienok opísaných v literatúre. Podobne, paládiom sprostredkovanou skríženou interakciou (VI) s etanolovými estermi vznikajú ketóny (XXTV) pri nasledovne štandardnej kyslej hydrolýze enol-eterového mezdiproduktu. Alternatívne, reakciou karboxylovej kyseliny (X, Q1.3 = H) s dvoma ekvivalentmi alkyl-lítiového činidla vzniká odpovedajúci ketón (XXIV). Kondenzáciou ketónu (XXIV) s hydroxylamínom alebo s niektorým vhodným O-substituovaným hydroxylamínom za použitia toluénu ako rozpúšťadla a Dean-Starkovej aparatúry odstránenia vody vznikajú žiadané oxímy (XXV).18-carboxylic acids (X, Q1.3 = H). Palladium-mediated carbonylation of the aryl bromide (IV) in the presence of an alcohol gives the corresponding esters (X) under conditions described in the literature. Similarly, palladium-mediated cross-interaction (VI) with ethanol esters produces ketones (XXTV) following standard acid hydrolysis of the enol-ether intermediate. Alternatively, reaction of a carboxylic acid (X, Q1.3 = H) with two equivalents of an alkyl lithium reagent provides the corresponding ketone (XXIV). Condensation of ketone (XXIV) with hydroxylamine or some suitable O-substituted hydroxylamine using toluene as solvent and a Dean-Stark water removal apparatus produces the desired oximes (XXV).

Schéma H opisuje prípravu sulfónamidov (XXVII) a sulfónov (XXIX). Reakcia arylbromidu (VI) s t-butyl lítiom má za následok kov-halogénovú výmenu a vznikajúci aryl lítium môže byť potlačený oxidom siričitým za vzniku lítnej soli (XXVI). Táto soľ potom reaguje s chloridom fosforečným a vznikajúci sulfonylchlorid sa zmieša s príslušným amínom za vzniku odpovedajúceho sulfónamidu (XXVII). Alternatívne, arylbromid (VI) sa premení na aryl lítiové produkty, ako je opísané vyššie, a pridaním príslušného disulfidu vznikne sulfid (XXVIII). Tento sulfid potom oxiduje použitím štandardných postupov a oxidantov, napríklad m-chlórperoxybenzoová kyselina za vzniku sulfónu (XXIX).Scheme H describes the preparation of sulfonamides (XXVII) and sulfones (XXIX). Reaction of the aryl bromide (VI) with t-butyl lithium results in a metal-halogen exchange and the resulting aryl lithium can be quenched with sulfur dioxide to form the lithium salt (XXVI). This salt is then reacted with phosphorus pentachloride and the resulting sulfonyl chloride is mixed with the appropriate amine to give the corresponding sulfonamide (XXVII). Alternatively, the aryl bromide (VI) is converted to the aryl lithium products as described above, and the addition of the appropriate disulfide affords the sulfide (XXVIII). This sulfide is then oxidized using standard procedures and oxidants, for example, m-chloroperoxybenzoic acid to give the sulfone (XXIX).

Schéma I opisuje prípravu sulfónov (XXXTV), kde je sulfónová časť pripojená na izochrómanové jadro pomocou metylénového Článku z 1, 2 nebo 3 uhlíkových atómov. V schémach I až N je tak tento uhlíkový atóm (ktorý sa stal súčasťou Xi článku) s funkčným významom označený indexom “n“ = 0 až 2, čo odpovedá n, u 1,6-disubstituovaných izochrómanov (I). Karboxylové kyseliny (XXX) sa môžu redukovať na primáme alkoholy (XXXI) použitím známych techník a činidiel, napríklad tetrahydridohlinitan lítny alebo bóran. Alkoholy (XXXI) sa môžu premeniť na odpovedajúce bromidy (ΧΧΧΠ) použitím známych techník a činidiel ako bromid fosforitý nebo tetrabrómmetán a trifenylfosfín. Bromidy (ΧΧΧΠ) sa môžu použiť na alkyláciu tiolov už známymi technikami za vzniku sulfidov (XXXIII). Sulfidy (ΧΧΧΙΠ) sa môžu oxidovať na sulfóny (XXXTV) použitím štandardných oxidačných techník a činidiel, napríklad oxid osmičelý a N-metylmorfolínN-oxid.Scheme I describes the preparation of sulfones (XXXTV) wherein the sulfone moiety is attached to the isochroman nucleus by a methylene cell of 1, 2 or 3 carbon atoms. Thus, in Schemes I through N, this carbon atom (which became part of the X1 cell) with functional meaning is denoted by the index “n” = 0 to 2, corresponding to n, for 1,6-disubstituted isochromates (I). The carboxylic acids (XXX) can be reduced to primary alcohols (XXXI) using known techniques and reagents, for example lithium aluminum hydride or borane. The alcohols (XXXI) can be converted to the corresponding bromides (ΧΧΧΠ) using known techniques and reagents such as phosphorus tribromide or tetra-bromomethane and triphenylphosphine. Bromides (ΧΧΧΠ) can be used for the alkylation of thiols by known techniques to form sulfides (XXXIII). Sulfides (ΧΧΧΙΠ) can be oxidized to sulfones (XXXTV) using standard oxidation techniques and reagents such as osmium tetroxide and N-methylmorpholine N-oxide.

Schéma J opisuje prípravu sulfónamidov (XXXVII), v ktorých je sulfónamidová časť pripojená k izochrómanovému jadru metylénovým článkom s 1,2 nebo 3 uhlíkovými atómami. Bromidy (XXXII môžu reagovať so siričitanom sodným pri refluxe v 10 % vodnom roztoku hydroxidu sodného za vzniku sulfónanovej soli (XXXV). Sulfónanové soli sa meniaScheme J describes the preparation of sulfonamides (XXXVII) in which the sulfonamide moiety is attached to the isochroman nucleus by a methylene cell having 1, 2 or 3 carbon atoms. Bromides (XXXII) can react with sodium sulfite at reflux in a 10% aqueous sodium hydroxide solution to form the sulfonate salt (XXXV).

- 19na sulfonylchloridy (XXXVI) použitím chloridu fosforečného a oxychloridu fosforu. Reakciou (XXXVI) s amínmi (NQ1.1Q1.2) vznikajú sulfónamidy (XXXVII).- 19 for sulfonyl chlorides (XXXVI) using phosphorus pentachloride and phosphorus oxychloride. Reaction (XXXVI) with amines (NQ1.1Q1.2) produces sulfonamides (XXXVII).

Schéma K opisuje prípravu substituovaných imidazolov a triazolov, ktoré sú pripojené k izochrómanovému jadru metylénovým článkom s 1, 2 nebo 3 uhlíkovými atómami. V schéme K, ak je “X“ v substituente dusík, substituentom je triazol a ak je “X“ uhlíkový atóm, substituentom je imidazol. Tieto zlúčeniny sa získajú alkyláciou príslušného imidazolu alebo triazolu bromidy (ΧΧΧΠ). Imidazoly a triazoly sú komerčne dostupné alebo sa môžu pripraviť podľa postupu z chemickej literatúry použitím techník už známych. Tak sa získajú zlúčeniny (XXXVin).Scheme K describes the preparation of substituted imidazoles and triazoles that are attached to the isochroman nucleus by a methylene cell having 1, 2 or 3 carbon atoms. In Scheme K, when "X" in the substituent is nitrogen, the substituent is triazole, and when the "X" is a carbon atom, the substituent is imidazole. These compounds are obtained by alkylation of the corresponding imidazole or triazole with bromides (ΧΧΧΠ). Imidazoles and triazoles are commercially available or can be prepared according to the procedure of the chemical literature using techniques already known. This gave compounds (XXXVin).

II

Schéma L opisuje prípravu imidazolov (XL), ktoré sú pripojené k izochrómanovému jadru metylénovým článkom s 1, 2 nebo 3 uhlíkovými atómami. Potrebné oxímamidy sa pripravia z odpovedajúcich nitrilov použitím hydroxylamín hydrochloridu a sodíka v metanole podľa postupu opísaného v J. Med. Chem., 36, 1529 (1993). Nitrily sú komerčne dostupné alebo sa môžu pripraviť podľa opisu z chemickej literatúry použitím techník už známych odborníkom v danej oblasti. Oxímové amidy reagujú s hydridom sodným alebo sodíkom a ďalej s esterom (XXXIX) podľa postupu opísanom v J. Med. Chem., 36, 1529 (1993) za vzniku heterocyklických produktov (XL).Scheme L describes the preparation of imidazoles (XL) which are attached to the isochroman nucleus by a methylene cell having 1, 2 or 3 carbon atoms. The necessary oxime amides are prepared from the corresponding nitriles using hydroxylamine hydrochloride and sodium in methanol according to the procedure described in J. Med. Chem., 36, 1529 (1993). Nitriles are commercially available or can be prepared as described in the chemical literature using techniques already known to those skilled in the art. The oxime amides are reacted with sodium hydride or sodium followed by an ester (XXXIX) according to the procedure described in J. Med. Chem., 36, 1529 (1993) to give heterocyclic products (XL).

Schéma M opisuje prípravu mono-(XLII) alebo di-substituovaných tetrazolov (XLIII), ktoré sú pripojené k izochrómanovému jadru metylénovým ramenom s 1, 2 nebo 3 uhlíkovými atómami. Bromidy (ΧΧΧΠ) premenia na odpovedajúce nitrily (XLI) kyanidovou výmennou reakciou, ktorá je dobre známa odborníkom v danej oblasti. Tieto nitrily potom premenia na monosubstituované tetrazoly (XLII) reakciou azidu sodného v rozpúšťadle, napríklad N-metyl-2- pyrolidinonu podľa postupu opísanom v J. Med. Chem., 38, 1799 (1995). Monosubstituované tetrazoly sa premenia na di-substituované tetrazoly (XLIII) štandardnou alkylačnou reakciou (R-X acetonitril, trietylamín).Scheme M describes the preparation of mono- (XLII) or di-substituted tetrazoles (XLIII), which are attached to the isochroman nucleus by a methylene arm having 1, 2 or 3 carbon atoms. The bromides (ΧΧΧΠ) are converted to the corresponding nitriles (XLI) by a cyanide exchange reaction well known to those skilled in the art. These nitriles are then converted to the monosubstituted tetrazoles (XLII) by reaction of sodium azide in a solvent such as N-methyl-2-pyrrolidinone according to the procedure described in J. Med. Chem., 38, 1799 (1995). Monosubstituted tetrazoles are converted to di-substituted tetrazoles (XLIII) by standard alkylation reaction (R-X acetonitrile, triethylamine).

Schéma N opisuje prípravu izomémych triazolov (XLIII) a (XLIV), ktoré sú pripojené k izochrómanovému jadru metylénovým článkom s 1, 2 nebo 3 uhlíkovými atómami. Nitrily (XLI) sa môžu premeniť na imidoestery (XLII ) pomocou etanolickej chlorovodíkové kyseliny podľa postupu opísaného v J. Med Chem., 38, 1799 (1995). Rovnakým postupom, reakciou (XLII) s alkylhydrazínmi (komerčne dostupnými alebo pripravenými podľa literatúry) v rozpúšťadle, napríklad etanole a nasledovnou reakciou s kyselinou mravčou vzniká zmes (XLIII) a (XLIV). Zmes sa môže rozdeliť na zložky štandardnými laboratórnymi technikami, napríklad chromatografiou alebo kryštalizáciou.Scheme N describes the preparation of isomeric triazoles (XLIII) and (XLIV), which are attached to the isochroman nucleus by a methylene cell having 1, 2, or 3 carbon atoms. Nitriles (XLI) can be converted to imidoesters (XLII) using ethanolic hydrochloric acid according to the procedure described in J. Med Chem., 38, 1799 (1995). By the same procedure, reaction of (XLII) with alkylhydrazines (commercially available or prepared according to the literature) in a solvent such as ethanol and subsequent reaction with formic acid affords a mixture of (XLIII) and (XLIV). The mixture may be separated into components by standard laboratory techniques, for example chromatography or crystallization.

-20Schéma O opisuje prípravu substituovaných triazolov a oxidazolov z primárnych karboxamidov (VII) použitím už známych metód, napríklad z J. Org. Chem., 44, 4160-4164 (1979). Pokiaľ je “X“ v (0-2) dusík, produktom je tetrazol. Pokiaľ je “X“ v (0-2) kyslík, produktom je oxadiazol. Reakcia amidov (VII) s dimetylamid acetálmi v nepolámych rozpúšťadlách s vysokou teplotou varu, napríklad toluén pri 50-100 °C, vzniká mezdiprodukt (0-1). Tento medziprodukt potom reaguje s éterom hydrazínu, 1substituovanými hydrazínmi, hydroxylamínom alebo N-substituovanými hydroxylamínmi v kyslom reakčnom prostredí (väčšinou kyselina octová) pri izbovej teplote (20-25 °C) za vzniku uvedeného produktu (O-2).Scheme O describes the preparation of substituted triazoles and oxidazoles from primary carboxamides (VII) using known methods, for example from J. Org. Chem., 44, 4160-4164 (1979). If the "X" in (0-2) is nitrogen, the product is tetrazole. When "X" in (0-2) is oxygen, the product is oxadiazole. Reaction of the amides (VII) with dimethylamide acetals in non-polar high boiling solvents such as toluene at 50-100 ° C affords intermediate (0-1). This intermediate is then reacted with hydrazine ether, 1-substituted hydrazines, hydroxylamine or N-substituted hydroxylamines in an acidic reaction medium (mostly acetic acid) at room temperature (20-25 ° C) to give the product (0-2).

Schéma P opisuje prípravu derivátov monosubstituovaného oxazolu (P-2) z odpovedajúcich propargylových amidov (P-l ) použitím už známych metód, napríklad z J. Med. Chem., 36, 1529 (1993). Reakciou (P-l ) s octanom ortuťnatým pri vare s chladičom v kyseline octovej vznikajú znázornené oxazoly (P-2).Scheme P describes the preparation of monosubstituted oxazole derivatives (P-2) from the corresponding propargyl amides (P-1) using known methods, for example from J. Med. Chem., 36, 1529 (1993). Reaction of (P-1) with mercuric acetate by boiling with an acetic acid condenser produces the oxazoles shown (P-2).

Schéma Q uvádza syntézu piperazínu (Q-3), kde Ri je elektronegatívny substituent v orto alebo para polohe k anilinovému dusíku piperazínu. Amín (Q-l) a arylhalogenid (Q-2) s fluoridovým nebo bromidovým atómom v orto nebo para polohe k elektronegatívnemu substituentu sa zahreje bez rozpúšťania v polárnom rozpúšťadle, napríklad vo vode, DMF, dimetylacetamide alebo v inom takom rozpúšťadle s bázou (s prebytkom (Q-l) alebo diizopropyletylamínu, uhličitanu draselného a tak podobne) pri vhodnej teplote (60-200 °C) za vzniku piperazínu (Q-3).Scheme Q shows the synthesis of piperazine (Q-3), wherein R 1 is an electronegative substituent at the ortho or para position to the aniline nitrogen of piperazine. The amine (Q1) and the aryl halide (Q-2) having a fluoride or bromide atom in the ortho or para position to the electronegative substituent are heated without dissolution in a polar solvent such as water, DMF, dimethylacetamide or another such solvent with a base (with excess ( Q1) or diisopropylethylamine, potassium carbonate and the like) at an appropriate temperature (60-200 ° C) to give piperazine (Q-3).

Schéma R opisuje syntézu piperazínu (R-3). Nitroaryl (R-l ) sa redukuje na anilín (R-2) pri použití vodíka a katalyzátora, napríklad paládia na uhlíku, Raney niklu, chloridu cínatého a podobne. Alternatívne, (R-2) sa môže získať komerčne. Anilín (R-2) sa zahreje (asi na 80 až 165 °C) s bis(2-halogénetyl)amín hydrochloridom s alebo bez prídavku bázy v rozpúšťadlách ako je THF, toluén, etylénglykol alebo chlórbenzén za vzniku piperazínu (R3)·Scheme R describes the synthesis of piperazine (R-3). Nitroaryl (R-1) is reduced to aniline (R-2) using hydrogen and a catalyst such as palladium on carbon, Raney nickel, stannous chloride and the like. Alternatively, (R-2) can be obtained commercially. Aniline (R-2) is heated (about 80 to 165 ° C) with bis (2-haloethyl) amine hydrochloride with or without the addition of a base in solvents such as THF, toluene, ethylene glycol or chlorobenzene to give piperazine (R3).

Schéma S znázorňuje prípravu dôležitého medziproduktu na prípravu zlúčenín nárokovaných vo vynáleze. Hydroxyamid (S-3) sa štandardne pripraví z hydroxy bromidu (S1; pozri schéma T) paládiom sprostredkovanou amidačnou reakciou (zhodná so znázornenou v schéme B) alebo cez ester ako medziprodukt (S-2). Tento ester sa syntetizuje z (S-l) karbonylačnou reakciou s použitím paládia, ktorá je odborníkom v danej oblasti známa a jeScheme S depicts the preparation of an important intermediate for the preparation of compounds claimed in the invention. Hydroxyamide (S-3) is normally prepared from hydroxy bromide (S1; see Scheme T) by a palladium mediated amidation reaction (as shown in Scheme B) or via an ester intermediate (S-2). This ester is synthesized from the (S-1) carbonylation reaction using palladium, which is known to the person skilled in the art and is

-21podobná už opísanej reakcii. Premena (S-2) na amid (S-3) sa uskutoční reakciou (S-2) s roztokom alkoholu (obvykle metanol) obsahujúci príslušné aminačné činidlo podobným spôsobom, ako je opísané v J. Org. Chem., 52, 2033-2036 (1987). Táto reakcia môže prebiehať pri izbovej teplote (20- 25 °C) alebo lepšie pri 50-100 °C.-21 similar to the reaction described above. The conversion of (S-2) to the amide (S-3) is carried out by reacting (S-2) with an alcohol solution (usually methanol) containing the appropriate amine reagent in a similar manner to that described in J. Org. Chem., 52, 2033-2036 (1987). This reaction can take place at room temperature (20-25 ° C) or better at 50-100 ° C.

Schéma T znázorňuje dva dôležité alternatívne postupy vedúce k zlúčeninám nárokovaným vo vynáleze. Redukciou skôr opísaných kyselín (IV) pri štandardných reakčných podmienkach a činidiel (s výhodou bóranu) vzniká primárny alkohol (S-l ). Táto zlúčenina sa potom premení na hydroxy amid (S-3), ako je opísané v schéme S. Tento hydroxyamid se premení na alkylačné činidlo (T-2, X je obvykle metánsulfonát alebo bromid) štandardnými chemickými transformáciami, ktoré sa použije k alkylácii vhodného 4arylpiperazinu alebo 4-arylpiperidínu za vzniku konečnej zlúčeniny (XI). Alternatívne, sa hydroxybromid (S-l ) premení na alkylačné činidlo (T-l, X je obvykle metánsulfonát alebo bromid) štandardnými chemickými transformáciami a použije sa k alkylácii vhodného 4arylpiperazínu alebo 4-arylpiperidínu za vzniku bromidov (VI). Tieto bromidy sa potom premenia na konečné zlúčeniny (IX) ako už bolo opísané.Scheme T illustrates two important alternative procedures leading to the compounds claimed in the invention. Reduction of the above-described acids (IV) under standard reaction conditions and reagents (preferably borane) yields the primary alcohol (S-1). This compound is then converted to the hydroxy amide (S-3) as described in Scheme S. This hydroxyamide is converted to an alkylating agent (T-2, X is usually a methanesulfonate or bromide) by standard chemical transformations that are used to alkylate the appropriate. 4-arylpiperazine or 4-arylpiperidine to give the final compound (XI). Alternatively, the hydroxybromide (S-1) is converted to an alkylating agent (T-1, X is usually a methanesulfonate or bromide) by standard chemical transformations and used to alkylate the appropriate 4arylpiperazine or 4-arylpiperidine to form bromides (VI). These bromides are then converted to the final compounds (IX) as described above.

Schéma U znázorňuje premenu chirálnej kyseliny brómu (U-l), čo predstavuje (XI) v schéme C na alkoholamid (U-5), čo predstavuje (S-3) v schéme T. Brómkyselina (U-l ) sa alkyluje na brómester (U-2) použitím metód už známych odborníkom v danej oblasti. Príkladom je reakcia kyseliny bromitej (U-l) s l,ľ-karbonyldiimidazolom v rozpúšťadle, napríklad THF za vzniku aktivovaného esteru s jeho nasledovnou reakciou s alkoholom za vzniku brómesteru (U-2). Brómester (U-2) potom reaguje za podmienok zo schémy V a premení sa z (V-l ) na (V-2) za vzniku amidesteru (U-3). Hydrolýzou amidesteru (U-3) s vodnou bázou so zreteľom, aby sa zabránilo takej hydrolýze amidovej skupiny (U-3), pri naslednovnom pôsobení vodnej kyseliny vzniká amid kyseliny (U-4). Na amid kyseliny (U-4) potom pôsobia redukčné činidlá, napríklad bór nebo bór-metyl sulfid v THF ako rozpúšťadle za vzniku amid alkoholu (U-5).Scheme U shows the conversion of the chiral bromine acid (U1) representing (XI) in Scheme C to the alkoholamide (U-5) which represents (S-3) in Scheme T. The bromoacid (U1) is alkylated to the bromo ester (U-2). ) using methods already known to those skilled in the art. An example is the reaction of bromoic acid (U-1) with 1,1'-carbonyldiimidazole in a solvent such as THF to form the activated ester followed by reaction with an alcohol to form the bromo ester (U-2). The bromo ester (U-2) is then reacted under the conditions of Scheme V and converted from (V-1) to (V-2) to form the amidester (U-3). Hydrolysis of the amidester (U-3) with an aqueous base with a view to preventing such hydrolysis of the amide group (U-3) results in the acid amide (U-4) following treatment with aqueous acid. The acid amide (U-4) is then treated with reducing agents such as boron or boromethyl sulfide in THF as the solvent to form the alcohol amide (U-5).

Schéma V znázorňuje spôsob premeny esteru (V-l) na diamid (V-4). Ester (V-l) pripravený z brómizochrómanu (T-l) a piperazínu (Q-3), schéma Q, spôsobmi opísanými v schéme T. Ester (V-l ) sa premení na amidester (v-2) použitím octanu paládnatého a kokatalyzátora, napríklad bis(difenylfosfino)propánu, diizopropyletylamínu, oxidu uhoľnatého a metylamín, ako je uvedené v schéme B. Rozpúšťadlom pre premenu môže byť DMF, dimetylacetamid, N-metylformamid, acetonitril s dimetylacetamidom a N-metylformamid, sScheme V shows a process for converting an ester (V-1) to a diamide (V-4). The ester (Vl) prepared from bromoisochromate (T1) and piperazine (Q-3), Scheme Q, by the methods described in Scheme T. The ester (Vl) is converted to the amidester (v-2) using palladium acetate and a cocatalyst such as bis (diphenylphosphino) ) propane, diisopropylethylamine, carbon monoxide and methylamine as shown in Scheme B. The solvent for conversion may be DMF, dimethylacetamide, N-methylformamide, acetonitrile with dimethylacetamide and N-methylformamide,

-22výhodou sa použije metyl amínový plyn. Teplota je s výhodou 50 až 120 °C. Amidester (V-2) sa ďalej premení na odpovedajúcu kyselinu amidu (V-3) použitím vodnej bázy s následnou neutralizáciou kyseliny a vznikom (V-3) alebo jej soli. Pokiaľ je ester terc-butylester, použije sa trifluóroctová kyselina alebo kyselina chlorovodíková v roztokoch ako je éter alebo octan etylnatý k premene amidesteru (V-2) na odpovedajúcu kyselinu amidu (V-3). Amid kyseliny (V-3) potom reaguje s kondenzačným činidlom a amínom za vzniku odpovedajúceho diamidu (V-4) použitím metód už známych odborníkom v danej oblasti, ako je uvedené v schéme W.Preferably methyl amine gas is used. The temperature is preferably 50 to 120 ° C. The amidester (V-2) is further converted to the corresponding amide acid (V-3) using an aqueous base followed by neutralization of the acid and formation of (V-3) or a salt thereof. When the ester is a tert-butyl ester, trifluoroacetic acid or hydrochloric acid in solutions such as ether or ethyl acetate is used to convert the amidester (V-2) to the corresponding amide acid (V-3). The acid amide (V-3) is then reacted with a condensing agent and an amine to form the corresponding diamide (V-4) using methods already known to those skilled in the art as outlined in Scheme W.

Schéma W znázorňuje syntézu derivátov hydroxamovej kyseliny (W-7) a (W-8). Tieto zlúčeniny sa taktiež pripravia postupom schémy A a B. Alkoholová skupina esteru alkoholu (S-2), schémy S, sa chráni vhodnou protektívnou skupinou, napríklad dihydropyranylovou skupinou, ktorá je stabilná za bázických podmienok, za vzniku tetrahydropyranyl éteru (W-2). Esterová skupina éteru (W-2) potom hydrolyzuje s vodnou bázou a opatrne sa okyslí (aby sa neodstránila ochranná skupina) za vzniku karboxylovej kyseliny (W-3). Karboxylová kyselina (W-3) potom reaguje s kondenzačným činidlom, napríklad karbonyldiimidazolom, dietylkyanofosfonátom, dicyklohexylkarbodiimidom alebo iným vhodným kondenzačným činidlom (pozri napríklad Major Methods of Peptide Bond Formation, Volume One of the Peptides: Asnalysis, Synthesis, Biology, E.Gross and J. Meinhofer, eds., Academic Press) v rozpúšťadlách, napríklad v dichlórmetáne alebo DMF a báze, napríklad trietylamíne v prítomnosti amínu, napríklad O-alkyl, N-alkylhydroxylamínu (pripravený metódou Sulský et al., Tet. Lett. 30, 31-34 (1989) za vzniku éterhydroxamátu (W-4). Z éterhydroxamátu (W-4) sa potom odstráni protektívna skupina použitím metód uvedených v Protective Groups v Organic Synthesis od Theodora W. Greene publikovanou Johnem Wileyem a synmi za vzniku alkoholu hydroxamátu (W-5). Hydroxylová skupina alkoholu hydroxamátu (W-5) sa potom premení na ostávajúcu skupinu, jednou z mnohých známych metód ako je tvorba metánsulfonátu, tosylátu, chloridu, bromidu alebo jodidu za vzniku hydroxamátu (W-6); hydroxamát (W-6) sa potom spojí s amínom, napríklad piperazínom (Q-3) zo schémy Q alebo piperazínom (R-3) zo schémy R alebo komerčne dostupnými amínmi za vzniku aminohydroxamátu (W-7). Aminohydroxamát (W-7) sa potom môže ďalej premeniť na aminohydroxamové kyseliny (W-8), pokiaľ alkyl-1 je ochrannou skupinou, napríklad benzyl s paládiom na uhlíku nebo inými už známymi metódami.Scheme W illustrates the synthesis of hydroxamic acid derivatives (W-7) and (W-8). These compounds are also prepared by the procedure of Schemes A and B. The alcohol group of the alcohol ester (S-2), Scheme S, is protected with a suitable protecting group, for example, a dihydropyranyl group that is stable under basic conditions to form tetrahydropyranyl ether (W-2) . The ether group of the ether (W-2) is then hydrolyzed with an aqueous base and is carefully acidified (not to remove the protecting group) to form the carboxylic acid (W-3). The carboxylic acid (W-3) is then reacted with a condensing agent such as carbonyldiimidazole, diethyl cyanophosphonate, dicyclohexylcarbodiimide, or other suitable condensing agent (see, e.g., Major Methods of Peptide Bond Formation, Volume One of the Peptides: Asnalysis, Synthesis, Biology, E.Gross J. Meinhofer, eds., Academic Press) in solvents such as dichloromethane or DMF and a base such as triethylamine in the presence of an amine such as O-alkyl, N-alkylhydroxylamine (prepared by Sulsky et al., Tet. Lett. 30, 31) -34 (1989) to form the etherhydroxamate (W-4), then the protective group is removed from the etherhydroxamate (W-4) using the methods outlined in The Protective Groups in Organic Synthesis by Theodor W. Greene published by John Wiley and sons to produce the hydroxamate alcohol ( The hydroxyl group of the alcohol hydroxamate (W-5) is then converted to the remaining group by one of many known methods such as meth an sulfonate, tosylate, chloride, bromide or iodide to give the hydroxamate (W-6); the hydroxamate (W-6) is then coupled with an amine, for example piperazine (Q-3) from Scheme Q or piperazine (R-3) from Scheme R, or commercially available amines to form the aminohydroxamate (W-7). The aminohydroxamate (W-7) can then be further converted to the aminohydroxamic acids (W-8) when alkyl-1 is a protecting group, for example, benzyl with palladium on carbon or other known methods.

Schéma X znázorňuje syntézu karbamátu (X-6). Fenol/anilín (X-l) reaguje s alkyl dietoxyproprionátom podobným spôsobom ako je transformácia 3- brómfenetanolu (II) na odpovedajúci ester izochrómanu (III) schémy A za vzniku fenol/anilínového esteru (X-2). Fenol/anilínový ester (X-2) hydrolyzuje na fenol/anilínovú kyselinu (X-3) vodnou bázou aScheme X shows the synthesis of carbamate (X-6). Phenol / aniline (X-1) is reacted with an alkyl diethoxypropionate in a similar manner to the transformation of 3-bromophenethanol (II) to the corresponding ester of the isochroman (III) of Scheme A to give the phenol / aniline ester (X-2). Phenol / aniline ester (X-2) hydrolyzes to phenol / aniline acid (X-3) with an aqueous base and

-23následne vodnou kyselinou. Fenol/anilínová kyselina (X-3) potom kondenzuje s piperazínmi (Q-3) schémy Q alebo (R-3) schémy R alebo s komerčne dostupnými amínmi na fenol/anilínový amid (X-4) použitím metód zo schémy W. Fenol/anilínový amid (X-4) sa potom redukuje na fenol/anilínový amín (X-5) redukčnými činidlami, napríklad bóranom alebo bóranmetylsulfidom v rozpúšťadlách, napríklad THF. Fenol/anilínový amín (X-5) potom reaguje s l,8-diazabicyklo[5,4,0]undek-7-én (DBU) alebo hydridom sodným alebo inými takými bázami a izokyanátom v dichlórmetáne alebo THF ako rozpúšťadle za vzniku karbamát/močoviny (X-6).-23 followed by aqueous acid. Phenol / aniline acid (X-3) is then condensed with piperazines (Q-3) of Scheme Q or (R-3) of Scheme R or with commercially available amines to phenol / aniline amide (X-4) using the methods of Scheme W. Phenol The aniline amide (X-4) is then reduced to the phenol / aniline amine (X-5) with reducing agents such as borane or borane methylsulfide in solvents such as THF. The phenol / aniline amine (X-5) is then reacted with 1,8,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or sodium hydride or other such bases and an isocyanate in dichloromethane or THF as solvent to form the carbamate / urea (X-6).

Schéma Y znázorňuje syntézu racemátu (Y-5) z východiskového fenolu (Y-l). Fenol (Y-l) reaguje s chlórpropiónaldehyddietyl acetálom v prítomnosti Lewisovej kyseliny, napríklad éterátu trifluoridu boritého alebo chloridu titaničitého v rozpúšťadlách, napríklad dichlórmetáne alebo nitrometáne za vzniku chlórfenolu (Y2). Fenol chlórfenolu (Y-2) sa potom premení na opúšťajúcu skupinu použitím trifluórmetánsulfonového anhydridu alebo Nfenyltrifluórmetánsulfónimidu v prítomnosti bázy, napríklad trietylamínu a prídavku katalyzátora, napríklad 4- dimetylaminopyridínu a v rozpúšťadle, napríklad dichlórmetáne za vzniku triflátu (Y-3). Triflát (Y-3) sa potom premení na hydrochlorid amidu (Y-4) použitím octanu paládnatého) a ko-katalyzátora, diizopropyletylamínu, oxidu uhoľnatom a metyl amínu, ako je uvedené v schéme W. Rozpúšťadlá na premenu zahŕňajú DMF, dimetylacetamid, N-metylformamid a acetonitril, dimetylacetamid a N-metylformamid, je výhodné pokiaľ sa použije metylamínový plyn. Výhodná teplota je asi od 50 °C do 120 °C.Scheme Y shows the synthesis of racemate (Y-5) from the starting phenol (Y-1). Phenol (Y-1) is reacted with chloropropionaldehyde diethyl acetal in the presence of a Lewis acid such as boron trifluoride etherate or titanium tetrachloride in solvents such as dichloromethane or nitromethane to form chlorophenol (Y2). The chlorophenol phenol (Y-2) is then converted to a leaving group using trifluoromethanesulfonic anhydride or N-phenyltrifluoromethanesulfonimide in the presence of a base such as triethylamine and addition of a catalyst such as 4-dimethylaminopyridine and a solvent such as dichloromethane to give triflate (Y-3). The triflate (Y-3) is then converted to the amide hydrochloride (Y-4) using palladium acetate) and a co-catalyst, diisopropylethylamine, carbon monoxide and methyl amine as shown in Scheme W. Conversion solvents include DMF, dimethylacetamide, N methylformamide and acetonitrile, dimethylacetamide and N-methylformamide are preferred when methylamine gas is used. The preferred temperature is from about 50 ° C to 120 ° C.

Chlorid amidu (Y-4) sa potom mieša pri 60 °C až 110 °C v prítomnosti piperazínu (Q-3) alebo (R-3) nebo komerčných amínov, bázy, napríklad trietylamínu alebo diizopropyletylamínu a rozpúšťadiel, napríklad etylénglykolu, THF, DMF alebo acetonitrilu za vzniku amidu amínu (Y-5).The amide chloride (Y-4) is then stirred at 60 ° C to 110 ° C in the presence of piperazine (Q-3) or (R-3) or commercial amines, a base such as triethylamine or diisopropylethylamine and solvents such as ethylene glycol, THF, DMF or acetonitrile to give the amine amide (Y-5).

Schéma Z znázorňuje výrobu mnohých derivátov na báze anilínu (Z-2), (Z-3), (Z-4), (Z-5), (Z-6) a (Z-7). Tieto zlúčeniny sú štandardné deriváty anilínu (Z-l), samostatne pripravené z bromidu (VI) kov-halogénovou výmenou (použitím n-butyllítia alebo tbutyllítia), následným prídavkom difenylfosforyl azidu (väčšinou v THF pri -78 °C) a redukciou pomocou bis(2-metoxyetoxy)alumínium hydridu. Táto premena (VI) na (Z-l) pokračuje presne podľa chemicky známej cesty, pozri Tetrahedron Leíters, 25, 429-432 (1984) a J. Am. Chem. Soc., 94, 6203-6205 (1972). Reakčné premeny (Z-l) na deriváty (Z-2)(Z-7) sú štandardné transformácie známe odborníkom v danej oblasti a zahrňujú acylácieScheme Z shows the production of many aniline-based derivatives (Z-2), (Z-3), (Z-4), (Z-5), (Z-6) and (Z-7). These compounds are standard aniline derivatives (Zl), separately prepared from metal halide (VI) bromide (VI) (using n-butyllithium or t-butyllithium), followed by addition of diphenylphosphoryl azide (mostly in THF at -78 ° C) and reduction by bis (2). -methoxyethoxy) aluminum hydride. This conversion of (VI) to (Z-1) proceeds following the chemically known pathway, see Tetrahedron Leiers, 25, 429-432 (1984) and J. Am. Chem. Soc., 94, 6203-6205 (1972). Reaction transformations (Z-1) to derivatives (Z-2) (Z-7) are standard transformations known to those skilled in the art and include acylations

-24(typické s chloridmi kyselín alebo anhydridmi), mezylácie a štandardné laktámové redukcie ako bolo skôr uvedené.-24 (typical with acid chlorides or anhydrides), mesylations and standard lactam reductions as mentioned above.

Schéma AA znázorňuje prípravu jednouhlíkových homológov izochróman-6karboxamidov (AA-5). Postup zahrňuje kov-halogénovú výmenu bromidu (VI) použitím alkyllítiových činidiel (najčastejšie t*butyllítia) s následným potlačením vzniknutého aniónu pomocou DMF a vzniku aldehydu (AA-1 ). Tento aldehyd sa redukuje štandardnými činidlami (napríklad tetrahydroboritanom sodným v THF) a výsledný alkohol (AA-2) sa premení na nitril (AA-3) aktiváciou pomocou metánsulfonylchloridu a nahradením výsledného metánsulfonátu kyanidovým aniónom. Hydrolýza nitrilu sa uskutoční roztokom (AA-3) v DMF s 30% peroxidom vodíka v prítomnosti uhličitanu draselného a pri trepaní reakčnej zmesi pri izbovej teplote (20-25 °C) 20 hodín. Výsledný amid (AA-4) premení na substituované amidy (AA-5) ako už bolo skôr opísané.Scheme AA illustrates the preparation of single carbon homologs of isochroman-6-carboxamides (AA-5). The process involves metal-halogen exchange of bromide (VI) using alkyllithium reagents (most commonly t-butyllithium) followed by suppression of the formed anion by DMF and formation of the aldehyde (AA-1). This aldehyde is reduced with standard reagents (e.g. sodium borohydride in THF) and the resulting alcohol (AA-2) is converted to the nitrile (AA-3) by activation with methanesulfonyl chloride and replacing the resulting methanesulfonate with a cyanide anion. Hydrolysis of the nitrile is performed with a solution (AA-3) in DMF with 30% hydrogen peroxide in the presence of potassium carbonate and shaking the reaction mixture at room temperature (20-25 ° C) for 20 hours. The resulting amide (AA-4) is converted to substituted amides (AA-5) as previously described.

Schéma BB znázorňuje celý postup prípravy možných amínov, napríklad (BB2) redukciou odpovedajúcich amidov (BB-1 ) za štandardných podmienok pre amidovú redukciu, ako bolo skôr opísané (bežne s bóranom alebo tetrahydridohlinitanom lítným v THF).Scheme BB illustrates the entire process for preparing possible amines, for example (BB2) by reducing the corresponding amides (BB-1) under standard amide reduction conditions as previously described (commonly with boron or lithium aluminum hydride in THF).

Schéma CC znázorňuje to, že funkčné skupiny arylpiperazínovej časti týchto molekúl (Ri a R2) sa môžu transformovať na iné funkčné skupiny. Opísaná je štandardná hydrogénolytická debenzylácia aryléteru (CC-1 ) za vzniku odpovedajúceho fenolu (CC-2). Premena fenolu (CC-2) na odpovedajúci trifluórmetánsulfonát (CC-3) štandardnými metódami je typickým príkladom odvodenia fenolov, napríklad (CC-2). Premena triflátu (CC3) na množstvo derivátov sa môže uskutočniť pomocou paládiom sprostredkovaného spojenia. Napríklad, spájaním (CC-3) s enol-étermi vznikajú ketón-substituované aryl deriváty. Tieto reakcie bežne prebiehajú v DMF alebo acetonitrile použitím octanu paládnatého, 1,3- bis(difenylfosfino)propánu a trietylamínu pri vhodných teplotách (50-120Scheme CC shows that the functional groups of the arylpiperazine moiety of these molecules (R 1 and R 2) can be transformed into other functional groups. Standard hydrogenolytic debenzylation of the aryl ether (CC-1) to give the corresponding phenol (CC-2) is described. Conversion of phenol (CC-2) to the corresponding trifluoromethanesulfonate (CC-3) by standard methods is a typical example of phenol derivation, for example (CC-2). Conversion of the triflate (CC3) to a number of derivatives can be accomplished using a palladium-mediated linkage. For example, coupling (CC-3) with enol ethers produces ketone-substituted aryl derivatives. These reactions are conveniently carried out in DMF or acetonitrile using palladium acetate, 1,3-bis (diphenylphosphino) propane and triethylamine at appropriate temperatures (50-120).

Schéma DD znázorňuje alternatívnu prípravu izochróman-6-triazolov (DD-4) a izochróman-6-oxadiazolov (DD-G). Primárny alkohol skorej opísaného amidu (DD-1 ) je chránený štandardnými technikami, najlepšie benzyléterom (P= -CH2 -fenyl). Táto látka reaguje s amidacetálmi, ako je opísané v schéme O a výsledný medziprodukt (DD-2) reaguje s hydrazínom, substituovaným hydrazínom, hydroxylamínom alebo N-substituovanými hydroxylamínmi, ako je opísané v schéme O za vzniku triazolov (DD-3) alebo oxadiazolovScheme DD shows an alternative preparation of isochroman-6-triazoles (DD-4) and isochroman-6-oxadiazoles (DD-G). The primary alcohol of the previously described amide (DD-1) is protected by standard techniques, preferably benzyl ether (P = -CH 2 -phenyl). This compound is reacted with amidacetals as described in Scheme O and the resulting intermediate (DD-2) reacts with hydrazine, substituted hydrazine, hydroxylamine or N-substituted hydroxylamines as described in Scheme O to give triazoles (DD-3) or oxadiazoles

-25(DD-5). Ochranná skupina “P“ sa odstráni za štandardných podmienkach (bežne hydrogenolýzou pri využití premeny kovového katalyzátora, napríklad paládia alebo platiny) a výsledný alkohol sa môže aktivovať (väčšinou ako sulfonát ester alebo halogenid) a reagovať s vhodným arylpiperazínom ako bolo už skôr uvedené v schéme T.-25 (DD-5). The "P" protecting group is removed under standard conditions (usually by hydrogenolysis using a metal catalyst conversion such as palladium or platinum) and the resulting alcohol can be activated (mostly as sulfonate ester or halide) and reacted with an appropriate arylpiperazine as previously outlined in the scheme. T.

U 1,6-disubstituovaných izochrómanov (I) by malo byť m = 0 nebo 1; s výhodou ni = 0. Je výhodné, že Ri je -O -Rm, -CF3, -C0-N(Rm)2, -CO-Rm a je výhodné, že Rm je Ci -C3 alkyl. Ďalej je výhodné, že R2 je -H. Je tiež výhodné, že Qi je vybrané zo skupiny pozostávajúcej z -CO-NQm Qi.₂, -S0₂ -, NQm, Q1-2 a-NQ_M Qi.₂; výhodnejšie je, keď Qi je -CO-NQm Qi-2.For 1,6-disubstituted isochromanates (I), m = 0 or 1; preferably n 1 = 0. It is preferred that R 1 is -O-R m, -CF 3, -CO-N (R m) 2, -CO-R m, and it is preferred that R m is C 1 -C 3 alkyl. It is further preferred that R 2 is -H. It is also preferred that Qi is selected from the group consisting of -CO-NQm Qi. ₂ , -SO ₂ -, NQm, Q1-2 and -NQ _M Qi. ₂ ; more preferably, Qi is -CO-NQm Qi-2.

Pre aromatické bicyklické amíny (ABA) je výhodné, keď Wi je dusík (-N-) a je tiež výhodné, keď jeden z Ri nebo R₂ je -H. Je výhodné, keď Qi je (A) -CONQm Qi.₂ a Qu je H a keď Qi.₂ je -CH₃ (Ci alkyl).For aromatic bicyclic amines (ABA), it is preferred that W 1 is nitrogen (-N-) and it is also preferred that one of R 1 or R ₂ is -H. It is preferred that Q 1 is (A) -CONQ m Q 1. ₂ and Qu is H and when Q 1. ₂ is -CH ₃ (C 1 alkyl).

1,6-disubstituovaný izochroman (I) a aromatické bicyklické amíny (ABA) obsahujú asymetrické centrum, a preto tvoria dva enantioméry; “S“, ktorý je (-) a “R“, ktorý je (+). V niektorých prípadoch sa obidva enantioméry (+) a (-) používajú rovnakým spôsobom ako opticky nečistá (racemická, ±) zmes. Preto sa môžu použiť v racemickej forme bez separácie. Napriek tomu je však žiadané použitie jedného z enantiomérov, opticky nečistá zmes sa môže rozdeliť už známymi metódami. Výhodná je analýza racemického medziproduktu (Π) pomocou lipázovej metódy opísanej v schéme C alebo už známymi metódami, pozri napríklad Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471,1978. Opticky nečistá zmes sa môže tiež rozdeliť pomocou chromatografických techník na chirálnych stacionárnych fázach, pozri Chromatographic Enantioseparation, 2nd edition John Wiley & Sons, NY,1992. Opticky čisté zlúčeniny sa potom použijú rovnakým spôsobom ako racemická zmes. V patentovej prihláške 1,6disubstituované izochrómany (I) aromatických bicyklických aminov (ABA) zahŕňajú oba enantioméry, rovnako ako ich opticky nečisté formy, najčastejšie ich racemickú zmes (±).The 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) contain an asymmetric center and therefore form two enantiomers; “S” which is (-) and “R” which is (+). In some cases, both the (+) and (-) enantiomers are used in the same manner as the optically impure (racemic, ±) mixture. Therefore, they can be used in racemic form without separation. However, the use of one of the enantiomers is desired, the optically impure mixture can be resolved by methods already known. Preferred is the analysis of the racemic intermediate (Π) by the lipase method described in Scheme C or by known methods, see for example Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471, 1978. The optically impure mixture can also be resolved by chromatography on chiral stationary phases, see Chromatographic Enantioseparation, 2nd edition John Wiley & Sons, NY, 1992. The optically pure compounds are then used in the same manner as the racemic mixture. In the patent application, 1,6-disubstituted isochromans (I) of aromatic bicyclic amines (ABA) include both enantiomers as well as their optically impure forms, most often their racemic mixture (±).

Niektorý 1,6-disubstituovaný izochroman (I) a aromatické bicyklické amíny (ABA) obsahujú dve asymetrické centrá, a preto štyri existujúce stereoizoméry (SS, RR, SR, RS) tvoria dva diastereomerické páry enantiomérov, ktoré sa môžu oddeliť známymi technikami.Some 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) contain two asymmetric centers and therefore the four existing stereoisomers (SS, RR, SR, RS) form two diastereomeric pairs of enantiomers that can be separated by known techniques.

1,6-disubstituovaný izochroman (I) a aromatické bicyklické amíny (ABA) v patentovej1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA)

-26prihláške zahŕňajú všetky štyri enantioméry, rovnako ako ich opticky nečisté formy, najčastejšie ich racemickú zmes (±).The present application encompasses all four enantiomers as well as their optically impure forms, most commonly their racemic mixture (±).

1,6-disubstituovaný izochróman (I) a aromatické bicyklické amíny (ABA) sú amíny a tvoria kyslé soli, pokiaľ reagujú s dostatočne silnou kyselinou. Farmaceutický využiteľné soli zahŕňajú ich anorganické i organické soli. Farmaceutický využiteľné soli sú niekedy, ale nie vždy, uprednostňované pred čistými amínmi, pretože tvoria zlúčeniny, ktoré sú lepšie rozpustné vo vode a sú viac kryštalické. Výhodné farmaceutický využiteľné soli zahŕňajú soli kyseliny metánsulfonovej, chlorovodíkovej, bromovodíkovej, sírovej, fosforečnej, dusičnej, benzoovej, citrónovej, vínnej, fumarovej, maleínovej, CH3-(CH2)n COOH, kde n je 0 až 4, HOOC -(CH2)n -COOH, kde n je vyššie definované.The 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are amines and form acid salts when reacted with a sufficiently strong acid. Pharmaceutically useful salts include both inorganic and organic salts thereof. Pharmaceutically useful salts are sometimes, but not always, preferred over pure amines because they form compounds that are more soluble in water and more crystalline. Preferred pharmaceutically useful salts include salts of methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 - (CH 2) n COOH, where n is 0 to 4, HOOC - (CH 2) n -COOH, wherein n is as defined above.

1,6-disubstituovaný izochróman (I) a aromatické bicyklické amíny (ABA) podľa vynálezu majú selektívne farmakologické vlastnosti a sú užitočné na liečbu pacientov s vaskulámymi bolesťami hlavy, hlavne pri migréne a klastrových bolestiach hlavy. Tento 1,6disubstituovaný izochróman (I) a aromatické bicyklické amíny (ABA) sú tiež využiteľné ako analgetické látky.The 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) of the invention have selective pharmacological properties and are useful for the treatment of patients with vascular headaches, particularly in migraine and cluster headaches. This 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are also useful as analgesic agents.

V klinickej praxi sú 1,6-disubstituovaný izochróman (I) a aromatické bicyklické amíny (ABA) podľa vynálezu aplikované orálne, nazálne, rektálne, vaginálne nebo injekčné vo forme farmaceutických zlúčenín obsahujúce aktívne zložky buď ako voľné bázy alebo farmaceutický vhodný kyslý prídavok soli na jednom alebo viac farmakologicky vhodnom nosiči. Uprednostňuje sa orálne alebo nazálne podávanie 1,6-disubstituovaného izochrómanu (I) a aromatických bicyklických amínov (ABA).In clinical practice, the 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) of the invention are administered orally, nasally, rectally, vaginally or by injection in the form of pharmaceutical compounds containing the active ingredients either as free bases or pharmaceutically acceptable acid addition of salt. one or more pharmacologically acceptable carriers. Oral or nasal administration of 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) is preferred.

Na terapeutickú liečbu migrény alebo klastrových bolestí hlavy a na liečbu bolestí sú ako analgetické látky vhodné denné dávky 1,6-disubstituovaného izochrómanu (I) a aromatických bicyklických amínov (ABA) asi od 0,005 po 50 mg/kg pre orálne alebo nazálne aplikácie, s výhodou asi od 0,1 do 30 mg/kg a asi od 0,05 do 10 mg/kg pre parenterálnu aplikáciu a s výhodou asi od 0,03 do 3 mg/kg. Dávkovanie na klinickú liečbu pacienta je ľahko zrejmé odborníkovi v danej oblasti.For the therapeutic treatment of migraine or cluster headache and for the treatment of pain, daily doses of 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) from about 0.005 to 50 mg / kg for oral or nasal administration are suitable as analgesic agents. preferably about 0.1 to 30 mg / kg and about 0.05 to 10 mg / kg for parenteral administration, and preferably about 0.03 to 3 mg / kg. Dosage for clinical treatment of a patient is readily apparent to one skilled in the art.

Presné dávkovanie a jeho frekvencia závisí od použitého 1,6- disubstituovaného izochrómanu (I) a aromatického bicyklického amínu (ABA), od špecifických podmienok liečby, veku, hmotnosti, celkovej fyzickej kondície pacienta, ostatného zdravotného stavu, ďalších používaných liekoch a môže sa presnejšie určiť meraním hladiny alebo koncentrácieThe exact dosage and frequency depends on the 1,6-disubstituted isochroman (I) and aromatic bicyclic amine (ABA) used, the specific treatment conditions, age, weight, general physical condition of the patient, other medical conditions, other drugs used, and may be more accurate. determined by measuring level or concentration

-271,6-disubstituovaného izochrómanu (I) a/alebo aromatického bicyklického amínu (ABA) v krvi pacienta a/alebo podľa pacientovej reakcie na liečbu.-271,6-disubstituted isochroman (I) and / or aromatic bicyclic amine (ABA) in the patient's blood and / or in response to the patient's response to treatment.

Nižšie uvedené definície a vysvetlenia pre použitie v celom dokumente zahŕňajú tiež opis a patentové nároky.The definitions and explanations below for use throughout the document also include a description and claims.

Chemické vzorce charakterizujúce rôzne zlúčeniny alebo molekulárne fragmenty môžu obsahovať v opise a patentových nárokoch rôzne substituenty, ktoré definujú štrukturálne vlastnosti. Tieto rôzne substituenty sú opísané písmenami alebo písmenami s číslom v dolnom indexe, napríklad “Zi“ nebo “Ri“, kde “i“ vyjadruje celkový počet. Tieto rôzne substituenty sú monovalentné alebo bivalentné, vyjadrujú skupinu pripojenú ku vzorcu jednou nebo dvoma chemickými väzbami. Napríklad Zi vyjadruje bivalentnú a premenlivú skupinu s vzorcom CH3 -C(=Zi)H. Skupiny Rj aRj vyjadrujú monovalentný variabilný substituent s vzorcom CH3 -CH2 -C(Rj)(Rj)-H. Pokiaľ sú chemické vzorce zapísané v lineárnom tvare ako vyššie uvedené, rôzne substituenty obsiahnuté v zátvorkách sa viažu na atóm priamo vľavo od variabilného substituentu v zátvorkách. Pokiaľ je za sebou viacej rôznych substituentov v zátvorkách, každý následujúci variabilný substituent sa viaže priamo na predchádzajúci atóm, ktorý nie je v zátvorke. Vo vyššie uvedenom vzorci sa tak Rj i Rj viaže priamo na predchádzajúci atóm uhlíka.Chemical formulas characterizing various compounds or molecular fragments may contain various substituents in the specification and claims that define structural properties. These different substituents are described by letters or letters with a number in the lower index, for example "Zi" or "Ri", where "i" denotes the total number. These various substituents are monovalent or bivalent, expressing a group attached to the formula by one or two chemical bonds. For example, Z 1 represents a bivalent and variable group with the formula CH 3 -C (= Z 1) H. The groups Rj and Rj represent a monovalent variable substituent of the formula CH 3 -CH 2 -C (R j) (R j) -H. When the chemical formulas are represented in a linear form as above, the various substituents contained in parentheses bind to the atom directly to the left of the variable substituent in parentheses. When there are multiple different substituents in brackets, each subsequent variable substituent binds directly to the previous atom that is not in brackets. Thus, both Rj and Rj in the above formula bind directly to the preceding carbon atom.

Chemické vzorce alebo ich časti znázornené v lineárnej forme predstavujú atómy v lineánom reťazci. CH3-O -CH₂ -CH(Ri) -CH3 tak predstavuje 2-substituovanú-lmetoxypropánovú zlúčeninu. V podobnom vzorci symbol “=“ vyjadruje dvojitú väzbu, napríklad CH2 =C(Ri) -O -CH3 a symbol “s“ vyjadruje trojitú väzbu, napríklad HC =C CH(Ri) -CH2 -CH3. Karbonylové skupiny sú vyjadrené jedným z dvoch možných spôsobov. CO- alebo -C(=0)-, kde prvý spôsob sa pre jednoduchosť používa častejšie.The chemical formulas or portions thereof shown in linear form represent atoms in a linear chain. Thus, CH 3 -O-CH ₂ -CH (R 1) -CH 3 represents a 2-substituted-1-methoxypropane compound. In a similar formula, "=" represents a double bond, for example, CH 2 = C (R 1) -O -CH 3, and "s" represents a triple bond, for example, HC = C CH (R 1) -CH 2 -CH 3. Carbonyl groups are expressed in one of two possible ways. CO- or -C (= O) -, where the first method is used more frequently for simplicity.

Chemické vzorce cyklických (kruhových) zlúčenín alebo molekulových fragmentov môžu byť vyjadrené v lineárnej podobe. Zlúčenina 4-chlór-2-metylpyridín tak môže byť vyjadrená lineárnym vzorcom N*=C(CH3)-CH=CCI-CH=C*H, čím sa rozumie, že atómy s hviezdičkou (*) sa viažu vzájomne, takže sa vytvorí kruh. Podobne, cyklický molekulový fragment, 4-(etyl)-l-piperazinyl sa môže vyjadriť vzorcom -N*-(CH2)2 -N^Hs) -CH2 C*H₂. Rigidná cyklická (kruhová) štruktúra každej zlúčeniny tu definuje orientáciu s ohľadom na planámu štruktúru kruhu pre substituenty naviazané na každý uhlíkový atóm rigidnej cyklickej zlúčeniny. U nasýtených zlúčenín s dvoma substituentmi naviazanými naThe chemical formulas of the cyclic (ring) compounds or molecular fragments may be expressed in linear form. Thus, the 4-chloro-2-methylpyridine compound can be represented by the linear formula N * = C (CH 3) -CH = CCI-CH = C * H, meaning that the asterisks (*) bind together to form circle. Similarly, the cyclic molecular fragment, 4- (ethyl) -1-piperazinyl, can be represented by the formula -N * - (CH 2) 2 -NH 2) -CH 2 C * H ₂ . The rigid cyclic (ring) structure of each compound herein defines the orientation with respect to the planar ring structure for the substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds with two substituents attached to

-28uhlíkový atóm, ktorý je súčasťou cyklického systému, -C(Xi)(X₂)- môžu byť tieto dva substituenty v axiálnej alebo ekvatoriálnej polohe vzhľadom ku kruhu a môžu meniť axiálnu/ekvatoriálnu polohu. Avšak pozícia týchto dvoch substituentov vzhľadom k sebe a ku kruhu je tuhá. Aj keď môže niektorý substituent občas ležať v rovine kolmej na kruh (ekvatoriálne) skôr než nad alebo pod kruhom (axiálne), jeden substituent je vždy nad druhým. V chemickom štruktúrnom vzorci, vyjadrujúcom takéto zlúčeniny, je substituent (Xi), ktorý je “pod“ iným substituentom (X₂) označovaný ako alfa (a) konfigurácia a je vyznačený prerušovanou čiarkovanou alebo bodkovanou čiarou, pripojenou k uhlíkovému atómu, to znamená symbolom “— “ alebo “. . Odpovedajúci substituent pripojený “nad“ (X₂) k druhému (Xi) je označovaný ako beta (β) konfigurácia a je vyznačený neprerušovanou čiarou k uhlíkovému atómu.-28uhlíkový atom which is part of a cyclic system, -C (XI) (X ₂₎ - may be the two substituents in the axial or equatorial position relative to the ring and may change the axial / equatorial position. However, the position of the two substituents relative to each other and to the ring is rigid. Although a substituent may at times lie in a plane perpendicular to the ring (equatorial) rather than above or below the ring (axial), one substituent is always above the other. In the chemical structural formula expressing such compounds, the substituent (Xi), which is "below" another substituent (X ₂ ), is referred to as the alpha (a) configuration and is indicated by a dashed dotted or dotted line attached to a carbon atom, i.e. “-” or “. . The corresponding substituent attached "above" (X ₂ ) to the second (Xi) is referred to as the beta (β) configuration and is indicated by a continuous line to the carbon atom.

Pokiaľ je variabilný substituent bivalentný, valencie môžu byť v definícii variabilné, prepojené alebo oddelené. Napríklad variabilný “R“ pripojený k uhlíkovému atómu ako C(=Rj)- môže byť bivalentný a definovaný ako oxo alebo keto (tvoriaci tak karbonylovú skupinu (-CO) alebo dva oddelene pripojené monovalentné variabilné substituenty α-Ri.j a βR,._k. Pokiaľ je variabilný bivalent, Ri je definovaný ako zlúčenina dvoch monovalentných variabilných substituentov, podľa zvyklosti sa na označenie bivalentných variabilných substituentov používa vzorec “α-Ri-j : β-Rj-k“ alebo niektoré jeho varianty. V niektorých prípadoch sú a-R,_j ai β-Rj-k pripojené na uhlíkový atóm v podobe -C( α-Rj.j ) ( β-Ri-k )-. Napríklad, pokiaľ bivalentný variabilný R$, definovaný ako -C(=R6)- obsahuje dva monovalentné variabilné substituenty, tieto dva monovalentné variabilné substituenty sú a-Ró.If the variable substituent is bivalent, the valencies may be variable, linked or separated by definition. For example, a variable "R" attached to a carbon atom such as C (= R 1) - may be bivalent and defined as oxo or keto (both a carbonyl group (-CO) or two separately attached monovalent variable substituents α-R 1 and βR, _k). When a variable bivalent, R 1 is defined as a compound of two monovalent variable substituents, the formula "α-Ri-j: β-Rj-k" or some variants thereof is customarily used to denote bivalent variable substituents. j and i β-Rj-k attached to a carbon atom in the form -C (α-Rj.j) (β-R 1 -k) - For example, if a bivalent variable R 8, defined as -C (= R 6) - contains two monovalent variable substituents, the two monovalent variable substituents are α-R 6.

i. β-Ró-i,.... a-Ré-9. β-Ró-io, čo tu predstavuje -C( a-Rs-i)( β-Ρ<,-2)-, ... -C( a-Ré-₉)( β-Κβ-ιο)atď. Podobne, pre bivalentný variabilný Ru, -C(=Rn)-, dva monovalentné variabilné substituenty sú α-R iu : β-Ri 1-2· Pre kruhový substituent, pre ktorý neexistuje zvláštna a a β orientácia (napríklad kvôli prítomnosti dvojitej väzby medzi uhlíkmi v kruhu) a pre substituent naviazaný na uhlíkový atóm, ktorý nie je súčasťou kruhu, platí taktiež vyššie uvedené pravidlo, ale a a β označenie je vypustené.i. β-R 6 -i, .... and-R 6 -9. β-R-io, which here is -C (a-R-I) (β-Ρ <- 2) - ... -C _(a-RE-9) (β-Κβ-ιο) etc. Similarly, for a bivalent variable Ru, -C (= Rn) -, two monovalent variable substituents are α-R iu: β-Ri 1-2 · For a ring substituent for which there is no particular aa β orientation (for example due to the presence of a double bond between the ring rule) and for a substituent attached to a carbon atom that is not part of the ring, the above rule also applies, but the aa β designation is deleted.

Ako bivalentné variabilné môžu byť tiež definované dva oddelené monovalentné variabilné substituenty a dva oddelené monovalentné variabilné substituenty môžu byť defnované ako bivalentné variabilné. Napríklad vo vzorci -Ci(Ri)H -C2(Rj)H -(Ci a C2 definuje ľubovoľne prvý a druhý uhlíkový atóm) R, a Rj môžu byť definované dohromady ako (1 ) s dvojitou väzbou medzi Ci a C₂ alebo (2) s bivalentnou skupinou, napríklad oxa (-O-) aTwo separate monovalent variable substituents may also be defined as bivalent variable, and two separate monovalent variable substituents may be defined as bivalent variable. For example, in the formula -Ci (R 1) H -C 2 (R j) H - (C 1 and C 2 optionally define the first and second carbon atoms) R 1, and R j may be defined together as (1) with a double bond between C 1 and C ₂ or ( 2) with a bivalent group, for example oxa (-O-) a

-29vzorec potom opisuje epoxid. Pokiaľ R, a Rj tvoria dohromady komplexnejší celok, napríklad skupinu -X -Y-, potom je celková orientácia tak, že Ci vo vyššie uvedenom vzorci je naviazaný na X a C2 sa viaže na Y. Potom podľa ustanoveného označenia ... R; a Rj tvoria dohromady -CH₂ -CH2-O -CO-...“, čo predstavuje laktón, v ktorom sa karbonyl viaže na C2. Avšak pokiaľ označené . Rj a R, tvoria dohromady -CO -O -CH2 -CH₂-, podľa ustanovení to znamená laktón, v ktorom sa karbonyl viaže na Ci.The sample then describes the epoxide. When R 1 and R 1 together form a more complex whole, for example -X -Y-, then the overall orientation is such that C 1 in the above formula is bonded to X and C 2 binds to Y. Then according to the designated designation ... R; and R 1 together form -CH ₂ -CH 2 -O -CO -... ", which represents a lactone in which the carbonyl binds to C2. However, if marked. R 1 and R 1 together form -CO-O -CH 2 -CH ₂ -, according to the provisions, i.e. a lactone in which the carbonyl is bound to C 1-6.

Celkový počet uhlíkových atómov vo variabilných substituentoch sa označí jedným z dvoch možných spôsobov. Prvý spôsob používa prefix na označenie variability ako “Ci - C4“, kde “1“ a “4“ predstavujú minimálny a maximálny počet variabilných uhlíkových atómov. Prefix je oddelený od variabilného označenia medzerou. Napríklad, “Ci -C4 alkyl“ znamená alkyl s 1 až 4 uhlíkovými atómami, (zahrňujúci jeho izoméme formy pokiaľ nie je označené inak). Kedykoľvek sa uvedie tento jednoduchý prefix, znamená to celkový počet variabilných uhlíkových atómov. Podľa tohto označenia C2-C4 opisuje skupinu CH3 -(CH)n -O-CO-, kde n je nula, jedna alebo dva. Podľa druhého spôsobu sa celkový počet uhlíkových atómov len určitej časti uvádza zvlášť označením “Ci-Cj“ v zátvorkách hneď (bez medzery) pred časťou, ktorú označuje. Podľa tohto označenia (Ci- C3) alkoxykarbonyl má rovnaký význam ako C2 -C₄ alkoxykarbonyl, pretože “C1-C3“ znamená len obsah uhlíkových atómov v alkoxy skupine. Podobne C2-C6 alkoxyalkyl a (Ci-C3)alkoxy(Ci-C3)alkyl znamená alkoxyalkylové skupiny obsahujúce 2 až 6 uhlíkových atómov. Predchádzajúca definícia opisuje zvlášť alkoxy alebo alylovú časť obsahujúcu 4 alebo 5 uhlíkových atómov, zatiaľ čo ďalšia definícia obmedzuje tieto skupiny na 3 uhlíkové atómy.The total number of carbon atoms in the variable substituents is indicated in one of two possible ways. The first method uses a prefix to denote variability as "Ci - C4", where "1" and "4" represent the minimum and maximum number of variable carbon atoms. The prefix is separated from the variable space by a space. For example, "C 1 -C 4 alkyl" means alkyl of 1 to 4 carbon atoms (including its isomeric forms unless otherwise indicated). Whenever this simple prefix is given, it means the total number of variable carbon atoms. According to this designation, C2-C4 describes the group CH3 - (CH) n -O-CO-, wherein n is zero, one or two. According to the second method, the total number of carbon atoms of only a portion is indicated separately by the designation "C 1 -C 3" in brackets immediately (without a space) in front of the portion it indicates. According to this designation (C 1 -C 3) alkoxycarbonyl has the same meaning as C 2 -C ₄ alkoxycarbonyl, since "C 1 -C 3" means only the carbon atom content of the alkoxy group. Similarly, C 2 -C 6 alkoxyalkyl and (C 1 -C 3) alkoxy (C 1 -C 3) alkyl mean alkoxyalkyl groups having 2 to 6 carbon atoms. The foregoing definition particularly describes an alkoxy or allyl moiety containing 4 or 5 carbon atoms, while a further definition limits these groups to 3 carbon atoms.

Pretože patentové nároky zahrňujú dosť veľký (cyklický) substituent, na konci pomenovania/označenia má tento substituent odkaz (v zátvorkách), ktorý odpovedá rovnakému pomenovaniu/označeniu v schémach, kde je tiež uvedený chemický štruktúrny vzorec určitého substituenta.Because the claims include a fairly large (cyclic) substituent, at the end of the naming / designation, this substituent has a reference (in parentheses) that corresponds to the same naming / designation in the schemes, where the chemical structural formula of a particular substituent is also indicated.

Je niekoľko spôsobov na pomenovanie zlúčenín podľa vynálezu, ktoré sa v princípe odlišujú použitím termínu “izochróman“ alebo “3,4-dihydro-lH-2-benzopyrán“ pre bicyklickú skupinu v zlúčenine. Napríklad jedno označenie pre zlúčeninu z príkladu 6 je (S)(-)-1 -[2-[4-[4-(aminokarbonyl)fenyl]-1 -piperaziny l]etyl]-N-metylizochróman-6-karboxamid alebo (S)-(-)-1 -(benzamid-4-yl)-4-[2-(6-metylaminokarbony lizochróman-1 -yl)etylpiperazín. Iný názov je (S)-l-[2-[4-[4-(aminokarbonyl)fenyl]“l-piperazinyl]etyl]-3,4-dihydro-N-metyl-l H-2-benzopyrán-6-karboxamid.There are several methods for naming the compounds of the invention that differ in principle by the use of the term "isochroman" or "3,4-dihydro-1H-2-benzopyran" for the bicyclic group in the compound. For example, one designation for the compound of Example 6 is (S) (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide or ( S) - (-) - 1- (Benzamid-4-yl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine. Another name is (S) -1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -3,4-dihydro-N-methyl-1H-2-benzopyran-6- carboxamide.

-30Všetky teploty sú v stupňoch Celzia.-30All temperatures are in degrees Celsius.

-(CH₂ )ni, -COO'¹, kde n je vyššie definované, ⁴00C-CITďľ H-COO¹ -COO'¹.- (CH ₂ ) n 1, -COO ^-1 , wherein n is as defined above, ^{40 C} -CIT 1 H-COO ¹ -COO ^-1 .

TLC - tenkovrstvová chromatografiaTLC - thin layer chromatography

HPLC - vysokotlaková kvapalinová chromatografiaHPLC - high pressure liquid chromatography

THF - tetrahydrofuránTHF - tetrahydrofuran

DMF - dimetylformamidDMF - dimethylformamide

DMSO - dimetylsulfoxidDMSO-dimethylsulfoxide

LDA - lítium diizopropylamid p-TSA - monohydrát p-toluénsulfónovej kyselinyLDA - lithium diisopropylamide p-TSA - p-toluenesulfonic acid monohydrate

TEA - trietylamínTEA - triethylamine

BOC - 1,1-dimetyletoxykarbonyl alebo terc.-butoxykarbonyl -CO-O-C(CH3)3BOC-1,1-dimethylethoxycarbonyl or tert-butoxycarbonyl -CO-O-C (CH3) 3

DMAP - dimetylaminopyridín, (CH₃)₂-N-pyridín-l-ylDMAP-dimethylaminopyridine, (CH ₃ ) ₂ -N-pyridin-1-yl

TFA - trifluóroctová kyselina, CF3-COOH soľ - nasýtený vodný roztok chloridu sodnéhoTFA - trifluoroacetic acid, CF3-COOH salt - saturated aqueous sodium chloride solution

Chromatografia (kolónová a rýchla chromatografia - čištenie/separáciou zlúčenín (nanesenie; elúcia). Tým sa rozumie, že určité funkcie sú nazhromaždené a zakoncentrované na získanie požadovanej zlúčeniny (-nín).Chromatography (column and flash chromatography - purification / separation of compounds (loading; elution)) This means that certain functions are pooled and concentrated to give the desired compound (s).

IR - infračervenou spektroskopiouIR - infrared spectroscopy

CMR - C-13 magnetickou rezonančnou spektrometriou, chemické posuny sú vyjadrené v ppm (δ) vzhľadom na TMSCMR - C-13 magnetic resonance spectrometry, chemical shifts are expressed in ppm (δ) relative to TMS

NMP - nukleová (protónová) magnetická rezonančná spektroskopia, chemické posuny sú vyjadrené v ppm (δ) vzhľadom na tetrametylsilán fenyl (C₆H₅) [a]d - uhol rotácie planáme polarizovaného svetla (špecifická optická rotácia) pri 25 °C pre sodíkovú D čiaru (589A)NMP - nuclear (proton) magnetic resonance spectroscopy, chemical shifts are expressed in ppm (δ) with respect to tetramethylsilane phenyl (C ₆ H ₅ ) [a] d - angle of rotation of flame polarized light (specific optical rotation) at 25 ° C for sodium D Line (589A)

-31 MS - hmotnostnej spektrometru v jednotkách hmota/energia alebo hmota/náboj.-31 MS - mass / energy or mass / charge mass spectrometer.

[M + H]⁺ kladný ión obsahujúci donor a vodíkový atóm[M + H] ⁺ positive ion containing donor and hydrogen atom

El - elektrónový vplyvEl - electron influence

CI - chemická ionizáciaCI - chemical ionization

FAB - rýchle atómové bombardovanieFAB - fast atomic bombing

HRMS - hmotnostná spektrometria s vysokým rozlíšenímHRMS - high resolution mass spectrometry

Éter - dietyléterEther - diethyl ether

Farmakologická vhodnosť označuje také vlastnosti látok, ktoré sú vhodné pre pacienta z farmakologicky/toxikologického hľadiska a výrobu farmakologickej látky z fyzikálne/chemického hľadiska s ohľadom na zloženie, formu, stabilitu, znášanlivosť pacientom a biologickú vhodnosť. Pokiaľ sa používajú dve rozpúšťadlá, pomer použitých rozpúšťadiel je objem/objem (v/v). Farmakologicky prijateľné anióny solí zahŕňajú metánsulfonát, chlorid, síran, fosforečnan, dusičnan, citrát, CH₃-(CH2)ni, kde ni je 0 až 4, ' ’OOC-ÍCHjJni-COO'¹, kde n je definované vyššie, *OOC -CH^H-COO¹, φ-COO¹.Pharmacological suitability refers to those properties of the substances which are suitable for the patient from a pharmacological / toxicological point of view and the manufacture of the pharmacological substance from a physical / chemical point of view with respect to the composition, form, stability, patient compatibility and biological suitability. If two solvents are used, the ratio of solvents used is volume / volume (v / v). Pharmacologically acceptable salt anions include methanesulfonate, chloride, sulphate, phosphate, nitrate, citrate, CH ₃ - (CH 2) n 1 where n 1 is 0 to 4, "OOC-ICH 3 -n-COO" ¹ , where n is as defined above, * OOC -CH 2 H-COO ¹ , φ-COO ¹ .

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Podľa nasledujúcich postupov vynálezu sa dosiahne rovnako uspokojujúci výsledok ako známymi metódami. Nasledujúce podrobné príklady opisujú prípravu rôznych zlúčenín a/alebo rôzne procesy vynálezu a sú zostavené ako ilustratívne, ale nie jediné, na vysvetlenie akékoľvek prípravy. Sú tu zrejme rôzne obmeny už známych postupov, reakčných látok, reakčných podmienok a techník.According to the following processes of the invention, a satisfactory result is obtained as well as by known methods. The following detailed examples describe the preparation of various compounds and / or various processes of the invention and are set forth as illustrative, but not the only, to explain any preparation. Obviously, there are various variations of the already known methods, reagents, reaction conditions and techniques.

Príprava 1 4-(piperazín-l-yl)benzamidPreparation 1 4- (Piperazin-1-yl) benzamide

Zmes 4-fluórbenzamidu (2,45 g, 17,6 mmol), piperazínu (7,56 g, 87,9 mmol) a vody (10 ml) sa mieša pri 100 °C 24 hodín. Po ochladení sa tuhá časť odstráni a premyje vodou a toluénom a potom vysuší za zníženého tlaku za vzniku uvedenej zlúčeniny, teplota topenia = 240-248 °C; MS (M/Z ) pri 205; NMR (DMSO-d6) 2,59, 2, 80, 3,14,6, 90, 7, 02, 7, 72 a 7, 73 δ.A mixture of 4-fluorobenzamide (2.45 g, 17.6 mmol), piperazine (7.56 g, 87.9 mmol) and water (10 mL) was stirred at 100 ° C for 24 hours. After cooling, the solid was removed and washed with water and toluene and then dried under reduced pressure to give the title compound, mp = 240-248 ° C; MS (M / Z) at 205; NMR (DMSO-d 6) 2.59, 2, 80, 3.14.6, 90, 7, 02, 7, 72 and 7.73 δ.

-32Príprava 2-32Preparing 2

N-[4-(trifluórmetyl)fenyl]piperazínN- [4- (trifluoromethyl) phenyl] piperazine

100 ml nádoba, vybavená miešacou tyčinkou, sa naplní 4-brómbenzotrifluoridom (19,70 g, 0,088 mol) a piperazínom (37,71 g, 0,438 mol). Reagijúce látky se zahrejú na 130 °C. Po 48 hodinách zmes obsahuje signifikantné množstvo zrazeniny a ochladí sa na 20-25 °C. Počas chladenia sa reakčná zmes riedi hydroxidom sodným (3N, 200 ml) za vzniku ďalšieho množstva zrazeniny a následnej dvojnásobnej extrakcie octanom etylnatým (200 ml). Pokiaľ sa zmes ochladí na 20 až 25 °C pred prídavkom vodnej bázy, v reakcii vznikne tuhá fáza, ktorá sťažuje ďalšiu manipuláciu. Spojené organické zložky sa premyjú jedenkrát soľankou (300 ml), vysušia pomocou síranu horečnatého, prefiltrujú a zahustia za vzniku výsledného produktu. Rekryštalizáciou z hexánu vzniká uvedená zlúčenina, teplota topenia 87-89 °C (v literatúre 86-88 °C), Rf = 0,20 (metanol/dichlórmetán, 7/93).A 100 mL flask equipped with a stir bar was charged with 4-bromobenzotrifluoride (19.70 g, 0.088 mol) and piperazine (37.71 g, 0.438 mol). The reagents are heated to 130 ° C. After 48 hours the mixture contains a significant amount of precipitate and is cooled to 20-25 ° C. On cooling, the reaction mixture was diluted with sodium hydroxide (3N, 200 mL) to give an additional amount of precipitate, followed by extraction twice with ethyl acetate (200 mL). If the mixture is cooled to 20-25 ° C before the addition of the aqueous base, a solid phase is formed in the reaction, which makes further handling difficult. The combined organics were washed once with brine (300 mL), dried over magnesium sulfate, filtered and concentrated to give the title product. Recrystallization from hexane gave the title compound, m.p. 87-89 ° C (86-88 ° C), R f = 0.20 (methanol / dichloromethane, 7/93).

Príklad 1 (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperaziny l]etyl)izochróman-6-karboxamid (S)-(VII) známy tiež ako (S)-(-)-l-(4-metoxyfenyl)-4-[2-(6aminokarbonylizochróman-1 -yl)-etylpiperazínExample 1 (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl) isochroman-6-carboxamide (S) - (VII) also known as (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6-aminocarbonylisochroman-1-yl) ethylpiperazine

1. krok: etyl (6-brómizochróman-l-yl)acetát (M)Step 1: Ethyl (6-bromoisochroman-1-yl) acetate (M)

Zmes 3-brómfenetyl alkoholu (11,14,8 g) v dichlórmetáne (37 ml) sa ochladí na O °C v ľadovom kúpeli a argónovej atmosfére. Etyl 3,3-dietoxypropionát (90 %,19,1 ml) sa pridá pomocou injekčnej striekačky. Roztok chloridu titaničitého (1 M v metylénchloride, 236 ml) sa pridá počas jednej hodiny pomocou hadičky a lievika po kvapkách do reakčnej zmesi. Reakcia sa potom refluxovala so spätným chladičom počas 18 hodín, potom sa naleje do zmesi vodnej kyseliny chlorovodíkovej (1 N) a soľanky (1/2) a extrahuje metylénchloridom. Organické fázy sú spojené, vysušené nad síranom sodným, prefíltrované a zakoncentrované. Koncentrát sa prečistí chromatograficky (silikagél; octan etylnatý/hexán, 10/90) za vzniku etyl( 6-brómizochróman-l-yl)acetát (ΙΠ); Rf '= 0,40 ( octan etylnatý/hexán, 25/75); IR (čistá látka) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm'¹; NMR (300 MHz, CDC1₃) 7,30, 7,28, 6,92, 5,17, 4,20, 4,10, 3,79, 3,01-2,91, 2,87-2,65 a 1,28 δ; CMR (75 MHz, C DC1₃) 170, 7, 136, 0, 135, 5, 131, 6, 129,1, 126, 0, 120, 2, 62, 6, 60, 5, 41, 3, 28, 3, a 13,9 δ; HRMS vypočítané pre CuHnOsBr = 298,0205, nájdená = 298,0204.A mixture of 3-bromophenethyl alcohol (11.14.8 g) in dichloromethane (37 mL) was cooled to 0 ° C in an ice bath and argon atmosphere. Ethyl 3,3-diethoxypropionate (90%, 19.1 mL) was added via syringe. A solution of titanium tetrachloride (1 M in methylene chloride, 236 mL) was added over one hour via a tube and funnel dropwise to the reaction mixture. The reaction was then refluxed for 18 hours, then poured into a mixture of aqueous hydrochloric acid (1 N) and brine (1/2) and extracted with methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered and concentrated. The concentrate is purified by chromatography (silica gel; ethyl acetate / hexane, 10/90) to give ethyl (6-bromoisochroman-1-yl) acetate (ΙΠ); R f '= 0.40 (ethyl acetate / hexane, 25/75); IR (neat) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.30, 7.28, 6.92, 5.17, 4.20, 4.10, 3.79, 3.01-2.91, 2.87-2, 65 and 1.28 δ; CMR (75 MHz, C DC1 ₃₎ 170, 7, 136, 0, 135, 5, 131 6, 129.1, 126, 0, 120, 2, 62, 6, 60, 5, 41, 3, 28 , 3, and 13.9 δ; HRMS calcd for C 11 H 11 O 5 Br = 298.0205, found = 298.0204.

2. krok: (R)-(+)-etyl (6-brómizochróman-l-yl)acetát (ΧΠ) a (S)-(-)-(6brómizochróman-l-yl)octová kyselina (XI).Step 2: (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (ΧΠ) and (S) - (-) - (6-bromoisochroman-1-yl) acetic acid (XI).

-33Zmieša sa etyl (6-brómizochróman-l-yl)acetát (III, 1. krok, 29,49 g), Amano v P-30 lipázy (15 g, lot # LPSARO1520, aktivita = 312,600 u/g) atlmivý roztok s pH 7 (590 ml). Reakcia prebieha pri dôkladnom miešaní a po hydrolýze nasleduje HPLC. Pre vyjasnení sa pridá 100 μΐ alikvotnej časti obsahujúcej kyselinu chlorovodíkovú (jedna kvapka). Do nádoby sa potom pridá octan etylnatý (1,5 ml) a obsah sa dobre premieša. Výsledná zmes sa potom filtruje cez celit a analyzuje pomocou HPLC (uBondapak C18 3,9 mm x 30 cm kolóna s reverznou fázou, 10 % acetonitril/90 % fosfátový tlmivý roztok (4 1 vody, 5,22 g dihydrogénfosforečnanu sodného (hydrát), 0,76 ml kyseliny fosforečnej) gradient na 85/15 počas 15 minút, potom izokratická elúcia v pomere 2 ml/min, detektor pre 215 nm), (XI) Rt =10,5 min., (XII) Rt =13,5 min. Keď reakcia dosiahne bod 50 % konverzie, uskutoční sa filtrácia a filtrát sa premyje niekoľkokrát vodnou kyselinou chlorovodíkovou (1 N) a niekoľkokrát octanom etylnatým. Filtráty sa spoja a extrahujú (dvakrát) octanom etylnatým. Spojené organické extrakty sa premyjú ekvivalentným objemom nasýteného vodného uhličitanu sodného (3 x), vysušia síranom sodným, filtrujú a zahustia za vzniku enantiomérov (ΧΠ). Premytý nasýtený vodný uhličitan sodný sa okyslí koncentrovanou kyselinou chlorovodíkovou a extrahuje trikrát metylénchloridom, vysuší pomocou síranu sodného, prefiltruje a zahustí za vzniku (XI). Pri kyseline (XI) sa merala enantiomérná čistota, ako je uvedené ďalej. Zmes kyseliny (XI, 15 mg) v THF (0,5 ml) sa redukuje komplexom bóranTHF (IM v THF, 0,12 ml) od 5 °C do 20 až 25 °C počas 18 hodín. Reakcia sa ochladí na O °C, zastaví metanolom (0,1 ml), potom zahreje na 20-25 °C a pipetou sa pridá kyselina chlorovodíková (1 N, 0,4 ml). Reakcia sa potom zahreje na teplotu refluxu na 10 minút, pri zníženom tlaku sa odstránia prchavé látky a zvyšok sa rozdelí na octan etylnatý a nasýtený vodný uhličitan sodný. Organické fázy sa oddelia, vysušia pomocou horčíka, prefiltrujú a zahustia. Zvyšok sa zváži a rozpustí na koncentráciu 10 mg/ml roztokom izopropanolu v hexáne (7 %). Zmes sa potom meria na kolóne Chiracel OJ pri použití zmesi hexán/izopropanol 90/10,15 min.,1 ml/min), potom 80/20 počas ďalších 10 min., (2 ml/min.), vlnová dĺžka 254 nm; (S)-alkohol Rt =12,46 min., (R)-alkohol Rt = 10,46 min. Ester (ΧΠ) sa môže analyzovať podobným spôsobom pomocou hydrolýzy (ďaleké infra). Pokiaľ je treba, enantiomericky bohatý ester sa môže previesť späť do ďalšieho cyklu enzymatickej hydrolýzy, pokiaľ je indikované HPLC analýzou. Takto sa získa (R)-(+)-etyl(6brómizochróman-l-yl)octan (ΧΠ), (96 % s vyhradením omylu); Rf = 0,40 (octan etylnatý/hexán, 25/75); [a]o +72° (c= 0,383, etanol); BR. (čisté látky) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm'¹; NMR 300 MHz CDC1₃) 7,30, 7,28, 6,92, 5,17,-33Mix ethyl (6-bromoisochroman-1-yl) acetate (III, Step 1, 29.49 g), Amano in P-30 lipase (15 g, lot # LPSARO1520, activity = 312,600 u / g) buffer pH 7 (590 mL). The reaction proceeds with vigorous stirring and hydrolysis is followed by HPLC. For clarification, add a 100 μΐ aliquot containing hydrochloric acid (one drop). Ethyl acetate (1.5 mL) was then added to the flask and mixed well. The resulting mixture was then filtered through celite and analyzed by HPLC (uBondapak C18 3.9 mm x 30 cm reverse phase column, 10% acetonitrile / 90% phosphate buffer (4 L water, 5.22 g sodium dihydrogen phosphate (hydrate), 0.76 ml phosphoric acid) gradient to 85/15 over 15 minutes, then 2 ml / min isocratic elution, 215 nm detector), (XI) R t = 10.5 min, (XII) R t = 13, 5 min. When the reaction reaches a 50% conversion point, filtration is performed and the filtrate is washed several times with aqueous hydrochloric acid (1 N) and several times with ethyl acetate. The filtrates were combined and extracted (twice) with ethyl acetate. The combined organic extracts were washed with an equivalent volume of saturated aqueous sodium carbonate (3x), dried over sodium sulfate, filtered, and concentrated to give the enantiomers (ΧΠ). The washed saturated aqueous sodium carbonate was acidified with concentrated hydrochloric acid and extracted three times with methylene chloride, dried over sodium sulfate, filtered and concentrated to give (XI). For acid (XI), the enantiomeric purity was measured as described below. A mixture of the acid (XI, 15 mg) in THF (0.5 mL) is reduced with borane-THF (IM in THF, 0.12 mL) from 5 ° C to 20-25 ° C for 18 hours. The reaction was cooled to 0 ° C, quenched with methanol (0.1 mL), then warmed to 20-25 ° C and hydrochloric acid (1 N, 0.4 mL) was added by pipette. The reaction is then heated to reflux for 10 minutes, the volatiles are removed under reduced pressure and the residue is partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic phases are separated, dried over magnesium, filtered and concentrated. The residue was weighed and dissolved to a concentration of 10 mg / ml with a solution of isopropanol in hexane (7%). The mixture is then measured on a Chiracel OJ column using hexane / isopropanol 90 / 10.15 min, 1 mL / min), then 80/20 for a further 10 min, (2 mL / min), wavelength 254 nm ; (S) -alcohol Rt = 12.46 min., (R) -alcohol Rt = 10.46 min. The ester (ΧΠ) can be analyzed in a similar way by hydrolysis (far infrared). If desired, the enantiomerically rich ester can be transferred back to the next cycle of enzymatic hydrolysis, if indicated by HPLC analysis. There was thus obtained (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (ΧΠ) (96% except for error); Rf = 0.40 (ethyl acetate / hexane, 25/75); [α] D + 72 ° (c = 0.383, ethanol); BR. (pure substances) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm ^-1 ; NMR 300 MHz CDCl ₃ ) 7.30, 7.28, 6.92, 5.17,

-344,20, 4,10 3,79, 3,01-2,91, 2,87-2,65 a 1,28; CMR (75 MHz, CDC1₃) 170,7, 136,0, 135,5,-344.20, 4.10 3.79, 3.01-2.91, 2.87-2.65 and 1.28; CMR (75 MHz, CDC1 ₃₎ 170.7, 136.0, 135.5,

131,6, 129,1, 126,0, 120,2, 62,6, 60,5, 41,3, 28,3, 13,9; HRMS vypočítaná pre Ci₃HuO₃Br = 298,0205, nájdená =298,0206. (S)-(-)-(6-brómizochróman-l-.yl) octová kyselina sa vyizoluje (99%ee); teplota topenia = 160- 161 °C; Rf = začiatok (octan etylnatý/hexán, 25/75); [ajo = 90° (c=l, etanol); IR (čisté látky) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003, 971 cm·’; NMR (300MHz, CDC1₃) 7,30, 6,92, 5,17, 4,18-4,11, 3,86-3,78 a 3,04-2,69; CMR (75 MHz, CDC1₃) 175,7, 136,2, 135,1, 132,0, 129,6, 126,2, 120,8, 72,4, 63,1, 45,5, 41,1 a131.6, 129.1, 126.0, 120.2, 62.6, 60.5, 41.3, 28.3, 13.9; HRMS calculated for C ₃ Huo ₃ Br = 298.0205, found = 298.0206. (S) - (-) - (6-Bromoisochroman-1-yl) acetic acid was isolated (99% ee); mp = 160-161 ° C; Rf = origin (ethyl acetate / hexane, 25/75); [α] D = 90 ° (c = 1, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003, 971 cm -1; NMR (300MHz, CDCl ₃ ) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69; CMR (75 MHz, CDCl ₃ ) 175.7, 136.2, 135.1, 132.0, 129.6, 126.2, 120.8, 72.4, 63.1, 45.5, 41, 1 a

28,5 δ.28,5 δ.

krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)acetyl} -4-(4-metoxyfenyl)piperazín (S)-(V)step: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl} -4- (4-methoxyphenyl) piperazine (S) - (V)

Zmieša sa (S)-(-)-(6~brómoizochróman-l-yl)octová kyselina (XI, 2. krok, 3 g), N-(4metoxyfenyl)piperazín (2,34 g) s dichlórmetánom (20 ml} a ochladí na O °C. Dietylkyanofosťat (2,0 ml) a trietylamín (1,7 ml) sa pridajú pomocou injekčnej striekačky. V ľadovom kúpeli sa zmes mieša pri 20-25 °C počas 18 hodín. Reakčná zmes sa zahustí pod zníženým tlakom a vnikne surová látka, ktorá sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán, 60-80/40-20) za vzniku (S)-(-)l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4metoxyfenyl)-piperažín (S)-(V) (po rekryštalizácii z octanu etylnatého/hexánu), teplota topenia = 122-123 °C; Rf = 0,26 (octan etylnatý/hexán, 70/30); [oc]d = -86° (c= 0,99, etanol); IR (suspenzia) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 cm’¹; NMR (300Combine (S) - (-) - (6-bromoisochroman-1-yl) acetic acid (XI, Step 2, 3 g), N- (4-methoxyphenyl) piperazine (2.34 g) with dichloromethane (20 mL). Diethyl cyanophostate (2.0 mL) and triethylamine (1.7 mL) were added via syringe and the mixture was stirred at 20-25 ° C for 18 hours in an ice bath. pressure to give a crude material which is chromatographed (silica gel; ethyl acetate / hexane, 60-80 / 40-20) to give (S) - (-) 1- [2- (6-bromoisochroman-1-yl) acetyl]. ] -4- (4-methoxyphenyl) -piperazine (S) - (V) (after recrystallization from ethyl acetate / hexane), mp = 122-123 ° C; R f = 0.26 (ethyl acetate / hexane, 70/30) [α] D = -86 ° (c = 0.99, ethanol) IR (suspension) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 cm ^-1 ;

MHz, CDClj) 7,32-7,26, 7,00, 6,88, 5,27, 4,16-4,07, 3,89, 3,80-3,60, 3,77, 3,05, 2,97-2,90, 2, 76 a 2,65 δ. CMR (75 MHz, CDC1₃) 168,9, 154,3, 145,2, 136,5, 136,2, 131,7, 129,3, 126,4, 120, 3, 118, 8, 114, 4, 73, 4, 63, 4, 55, 5, 51, 3, 50,7, 46,1, 41, 9, 39, 9 a 28,7 δ.MHz, CDCl 3) 7.32-7.26, 7.00, 6.88, 5.27, 4.16-4.07, 3.89, 3.80-3.60, 3.77, 3, 05, 2.97-2.90, 2, 76 and 2.65 δ. CMR (75 MHz, CDC1 ₃₎ 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120, 3, 118, 8, 114, 4, 73, 4, 63, 4, 55, 5, 51, 3, 50.7, 46.1, 41, 9, 39, 9 and 28.7 δ.

.krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)piperazín (S)(VI) (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)acetyl]-4-(4-metoxyfenyl)-piperazín ((S)-(V),.step: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) (VI) (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine ((S) - (V),

3. krok, 3,7 g) v THF (84 ml) sa ochladí na O °C a injekčnou striekačkou sa pridá komplex bóran-THF, (1 M v THF, 25 ml). Ľadový kúpeľ sa odstráni a zmes sa zahreje na teplotu refluxu počas 18 hodín. Reakcia sa ochladí na O °C, pomaly sa zastavuje vodnou kyselinou chlorovodíkovou (1 N, 100 ml) a refluxuje sa ďalšie 1,5 hodiny. Zmes sa ochladí na 20-25 °C a rozpúšťadlá sa odstránia pri zníženom tlaku, vodný zvyšok sa zriedi soľankou a zvýši sa pH pomocou vodného hydroxidu sodného. Zmes sa extrahuje dichlórmetánom a spojené organické fázy sa vysušia nad síranom sodným, uskutoční sa filtrácia a zakoncentrovanie.Step 3, 3.7 g) in THF (84 mL) was cooled to 0 ° C and borane-THF complex (1 M in THF, 25 mL) was added via syringe. The ice bath was removed and the mixture was heated to reflux for 18 hours. The reaction was cooled to 0 ° C, slowly quenched with aqueous hydrochloric acid (1 N, 100 mL) and refluxed for an additional 1.5 hours. The mixture is cooled to 20-25 ° C and the solvents are removed under reduced pressure, the aqueous residue is diluted with brine and the pH is raised with aqueous sodium hydroxide. The mixture was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated.

-35Koncentrát sa čistí rekryštalizáciou zo zmesi octan etylnatý/hexán za vzniku (S)-(-)-l-[2-(6brómizochróman-l-yl)etyl]-4-(4- metoxyfenyl)-piperazínu (S)-(VI), teplota topenia = 85-86 °C; R_f =0,23 (octan etylnatý); [a]_D = 48° (c= 0,73, etanol); IR (čisté látky) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, 818 cm’¹, H NMR (300 MHz, CDC1₃) 7 29, 7,27, 6,97,The concentrate is purified by recrystallization from ethyl acetate / hexane to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (S) - ( VI), m.p. = 85-86 ° C; _Rf = 0.23 (ethyl acetate); [α] _D = 48 ° (c = 0.73, ethanol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, 818 cm ^-1 , 1 H NMR (300 MHz, CDCl ₃ ) δ 29, 7.27, 6.97,

6,85, 4,78, 4,14-4, 07, 3,76-3,69, 3,76, 3,10, 2,95, 2,70-2,50, 2,13 a 2,02 δ. CMR (75 M Hz, CDCb) 153,5, 145,5, 136,8, 136,0, 131, 4, 129,0, 126,3, 119,7, 117,9, 114,2, 74,1, 62,5, 55,3,6.85, 4.78, 4.14-4, 07, 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and 2, 02 δ. CMR (75MHz, CDCl3) 153.5, 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74, 1, 62.5, 55.3,

54,4, 53,3, 50,4, 32,9 a 28,6 δ; HRMS vypočítaná pre C22H27, Ν₂θ2Βη = 430,1256, nájdená = 430,1270.54.4, 53.3, 50.4, 32.9 and 28.6 δ; HRMS calcd for C ₂₂ H 27, Ν ₂ θ 2Βη = 430.1256, found = 430.1270.

5.krok: (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamid (S)-(VII) (S)^-(—)—1 -[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperazín ((S)(VI), 4. krok 364 mg), octan paládnatý (98 %, 9,7 mg) a 1,3-bis-difenylfosfmopropán (97 %, 22 mg). V nádobke sa pripraví atmosféra oxidu uhoľnatého a pomocou injekčnej striekačky sa do reakcie pridá DMF (2 ml), 1,1, 1,3,3,3-hexametyldisilazán (98 %, 1,25 ml) a diizopropyletylamín (0,29 ml). Zmes sa varí pri 100 °C počas 18 hodín. Po ochladení na 2025 °C sa reakcia rozdelí na dve fázy. Reakcia sa naleje do vodnej kyseliny chlorovodíkovej (1 N) a dvakrát sa premyje éterom. U kyslého roztoku sa zvýši pH pomocou vodného roztoku hydroxidu sodného a trikrát sa extrahuje octanom etylnatým. Fázy octanu etylnatého sa spoja a zahustia. Potom sa čistia chromatograficky (silikagél; metanol/dichlórmetán, 5/95) za vzniku (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-izochróman-6-karboxamid (S)(VII), teplota topenia = 186-187 °C, Rf = 0,27 (metanol/octan etylnatý, 10/90); [o,]d = -53° (c= 0,92, metylénchlorid/metanol (1/1 ); IR (suspenzia) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 a 815 cm’¹; NMR (300MHz, CDClj ) 7,61-7,58, 7,18, 6,85, 5,90, 4,86,Step 5: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VII) (S) ^- ( -) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine ((S) (VI), Step 4 364 mg), palladium acetate (98%, 9.7 mg) and 1,3-bis-diphenylphosphmopropane (97%, 22 mg). A carbon monoxide atmosphere is prepared in the vial and DMF (2 mL), 1,1,1,3,3,3-hexamethyldisilazane (98%, 1.25 mL) and diisopropylethylamine (0.29 mL) are added via syringe. ). The mixture was boiled at 100 ° C for 18 hours. After cooling to 2025 ° C, the reaction is separated into two phases. The reaction was poured into aqueous hydrochloric acid (1 N) and washed twice with ether. The acidic solution was adjusted to pH with aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate phases are combined and concentrated. They are then purified by chromatography (silica gel; methanol / dichloromethane, 5/95) to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide (S) (VII), mp = 186-187 ° C, R f = 0.27 (methanol / ethyl acetate, 10/90); [α] D = -53 ° (c = 0.92, methylene chloride / methanol (1/1); IR (suspension) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109, and 815 cm -1). ¹ ; NMR (300MHz, CDCl 3) 7.61-7.58, 7.18, 6.85, 5.90, 4.86,

4,18-4,11, 3,80-3,72, 3,76, 3,10, 2,99, 2,73, 2,66-2,49, 2,15 a 2,04 δ; CMR (75 MHz, CDCI3)4.18-4.11, 3.80-3.72, 3.76, 3.10, 2.99, 2.73, 2.66-2.49, 2.15 and 2.04 δ; CMR (75MHz, CDCl3)

168,7, 153,3, 145,4, 142,0, 134,3, 131,0, 127,9, 124,8, 124,6, 117,8, 114,7, 74,2, 62,6, 55,2,168.7, 153.3, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.7, 74.2, 62, 6, 55.2,

54,3, 53,2, 50,3, 32,8, 28,7 a 27,2 δ; HRMS vypočítaná pre C23H29N3O3 = 395,2209, nájdená = 395,2227.54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 δ; HRMS calcd for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2227.

Príklad 2 (R)-(+)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-izochróman-6-karboxamid (R)-(VH), známy tiež ako (R)-(+)-l-(4-metoxyfenyl)-4-[2-(6-aminokarbonylizochróman-lyl)-etylpiperazínExample 2 (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VH), also known as (R) - (+) - l- (4-methoxyphenyl) -4- [2- (6-aminokarbonylizochróman-yl) -etylpiperazín

-361. krok: (R)-(+)-6-(brómizochróman-l-yl) octová kyselina (R)-IV.-361. step: (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (R) -IV.

K (R)-(+)-etyl(6-brómizochróman-l-yl)octanu (XII, PRÍKLAD 12.krok, 13,3 g) v THF (150 ml) sa pridá zmes hydroxidu lítneho (3M, 150 ml) a zmes sa mieša 18 hodín pri 20-25 °C. Prchavé rozpúšťadlá sa odstránia pri zníženom tlaku a zvyšok sa potom okyslí vodnou kyselinou chlorovodíkovou na pH =1. Zvyšná zmes sa extrahuje metylénchloridom a spojené organické látky sa vysušia nad síranom sodným, sfiltrujú sa a zahustia. Koncentrát sa prečistí rekryštalizáciou zo zmesi dichlórmetán/hexán za vzniku (R)-(+)-6-(brómizochróman-l-yl) octovej kyseliny (R)-IV, teplota topenia =160-161 °C; Rf = začiatok (octan etylnatý/hexán, 25/75); [a]_D = +83° (c= 0,99, etanol); IR (čisté látky) 1711, 1482, 1428,14406, 1330, 1297, 1111, 1101, 1003 a 971 cm'¹; NMR (300 MHz, CDC1₃) 7,30, 6,92, 5,17, 4,18-4,11, 3,86-3,78 a 3,04-2,69 δ; CMR (75 MHz, CDC1₃) 175,7, 136,2, 135,1, 132,0, 129,6, 126,2, 120,8, 72,4,To (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (XII, EXAMPLE 12 step, 13.3 g) in THF (150 mL) was added a mixture of lithium hydroxide (3M, 150 mL). and the mixture was stirred at 20-25 ° C for 18 hours. The volatile solvents were removed under reduced pressure and the residue was then acidified with aqueous hydrochloric acid to pH = 1. The remaining mixture was extracted with methylene chloride and the combined organics were dried over sodium sulfate, filtered and concentrated. The concentrate was purified by recrystallization from dichloromethane / hexane to give (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (R) -IV, mp = 160-161 ° C; Rf = origin (ethyl acetate / hexane, 25/75); [α] _D = + 83 ° (c = 0.99, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003 and 971 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 δ; CMR (75 MHz, CDC1 ₃₎ 175.7, 136.2, 135.1, 132.0, 129.6, 126.2, 120.8, 72.4,

63,1,45,5,41,1 a 28,5 δ.63,1,45,5,41,1 and 28,5 δ.

2. krok: (R)-(+)-1 -[2-(6-brómizochróman-1 -yl)acetyl]-4-(4-metoxyfenyl)piperazín (R)-(V).Step 2: (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (R) - (V).

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z východiskovej (R)-(+)-6-(brómizochróman-l-yl)octovej kyseliny (príklad 2, 1. krok, (R)-(IV)) surový produkt. Ten sa prečistí najprv chromatografiou na silikagéle pomocou gradientu 60- 80 % octan etylnatý/hexán a výsledná tuhá fáza rekryštalizuje (octan etylnatý/hexán) za vzniku: (R)-(+)-l-(2-(6-brómizochróman-l-yl)acetyl]-4-(4- metoxyfenyl)-piperazínu (R)-(V), teplota topenia = 122-123 °C; Rf = 0,26 (octan etylnatý/hexán, 70/30); [a]_D = +89° (c=l,00, etanol); IR (suspenzia) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028 820 cm'¹; NMR (300Following the procedure of Example 1, Step 3, with minor variations, starting from (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (Example 2, Step 1, (R) - (IV)) is crude product. This was first purified by silica gel chromatography using a 60-80% ethyl acetate / hexane gradient and the resulting solid was recrystallized (ethyl acetate / hexane) to give: (R) - (+) - 1- (2- (6-bromoisochroman-1)) -yl) acetyl] -4- (4-methoxyphenyl) -piperazine (R) - (V), mp = 122-123 ° C; R f = 0.26 (ethyl acetate / hexane, 70/30); [ _Α ] _D = + 89 ° (c = 1.00, ethanol) IR (suspension) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 cm ^-1 ;

MHz, CDC1₃) 7,32-7,26, 7,0, 6,88, 5,27, 4,16-4,07, 3,89, 3,80-3,60, 3,77, 3,05, 2,97-2,90,MHz, CDC1 ₃₎ 7.32-7.26, 7.0, 6.88, 5.27, 4.16-4.07, 3.89, 3.80-3.60, 3.77, 3 05, 2.97-2.90,

2,76 a 2,65 Ô; CMR (75 MHz, CDCb) 168,9, 154,3, 145,2, 136,5, 136,2, 131,7, 129,3, 126,4,2.76 and 2.65 Ô; CMR (75 MHz, CDCl 3) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4,

120,3, 118, 8, 114, 4, 73,4, 63,4, 55,5, 51,3, 50,7, 46,1, 41,9, 39,9 a 28,7 Ô.120.3, 118, 8, 114, 4, 73.4, 63.4, 55.5, 51.3, 50.7, 46.1, 41.9, 39.9 and 28.7 Ô.

3. krok: (R)-(+)-l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)piperazín (R)(VI).Step 3: (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (R) (VI).

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z východiskového (R)-(+)-1 -[2-(6-brómoizochróman-1 -yl)acetylJ-4-(4-metoxyfenyl)piperazínu (R)-(V) ((príkladFollowing the procedure of Example 1, Step 4, with minor variations, starting from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (R) - (Example)

-372, 2. krok) (R)-(+)-l-[2-(6-brómizochróman-l-yl)etyl]-4- (4-metoxyfenyl)-piperazín (R)-(VI), teplota topenia = 85-86 °C; Rf = 0,23 (octan etylnatý); [a]_D = 47° (c= 0,49 etanol); IR (čisté látky) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041 a 818 cm'¹; NMR (300 MHz,-372, Step 2) (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (R) - (VI), temperature mp = 85-86 ° C; R f = 0.23 (ethyl acetate); [α] _D = 47 ° (c = 0.49 ethanol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041 and 818 cm ^-1 ; NMR (300 MHz,

CDCI3) 7,29, 7,27, 6,97, 6,85 ,4,78, 4,14-4,07, 3,76-3,69, 3,76, 3,10, 2,95, 2,70-2,50, 2,13 aCDCl 3) 7.29, 7.27, 6.97, 6.85, 4.78, 4.14-4.07, 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and

2,02 δ; CMR(75 MHz, CDCI3) 153,5, 145,5, 136,8, 136,0, 131,4, 129,0, 126,3, 119,7, 117,9,2,02 δ; CMR (75 MHz, CDCl 3) 153.5, 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9,

114,2, 74,1, 62,5, 55,3, 54,4, 53,3, 50,4, 32,9 a 28,9; HRMS vypočítaná pre C₂₂H₂₇, N₂O₂Bn = 430,1256, nájdená = 430,1274.114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.9; HRMS calcd for C ₂₂ H ₂₇ N ₂ O ₂ Bn = 430.1256, found = 430.1274.

4.krok: (R)-(+)-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6karboxamid (R)-(VII)Step 4: (R) - (+) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VII)

Postupom podľa príkladu 1,5. kroku s drobnými obmenami vzniká z východiskového (R)-(+)-1 -[2-(6-brómizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)-piperazínu (R)-( VI)) (2. príklad, 3. krok) surová látka. Tá sa prečistí rýchlou chromatografiou (silikagél, 50 g; metanol/octan etylnatý, 5/95) za vzniku (R)-(+)-l-[2-[4-(4- metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu (R)-(VH), teplota topenia =187-187,5 °C; Rf = 0,27 (metanol/octan etylnatý, 10/90); [cc]d = +52° (c = 0,92, metylénchlorid/metanol,l/l ); IR (suspenzia) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 a 815 cm'¹; NMR (300Following the procedure of Example 1.5. step with minor variations, starting from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (R) - (VI)) ( Example 2, Step 3) crude material. This was purified by flash chromatography (silica gel, 50 g; methanol / ethyl acetate, 5/95) to give (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] (R) - (VH) isochroman-6-carboxamide, m.p. = 187-187.5 ° C; Rf = 0.27 (methanol / ethyl acetate, 10/90); [α] D = + 52 ° (c = 0.92, methylene chloride / methanol, 1/1); IR (slurry) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109, and 815 cm ^-1 ; NMR (300

MHz, CDCI3) 7,61-7,58, 718, 6,85, 5,90, 4,86, 4,18-4,11, 3,80, 3,72, 3,76, 3,10, 2,99, 2,73,MHz, CDCl 3) 7.61-7.58, 718, 6.85, 5.90, 4.86, 4.18-4.11, 3.80, 3.72, 3.76, 3.10, 2.99, 2.73,

2,66-2,49, 2,15 a 2,04 δ; CMR (75 MHz, CDC1₃) 168,7, 153,5, 145,4, 142,0, 134,3, 131,0, 127,9, 124,8, 124,6, 117,8, 114,1, 74,2, 62,6, 55,2, 54,3, 53,2, 50,3, 32,8, 28,7 a 27,2 δ;2.66-2.49, 2.15 and 2.04 δ; CMR (75 MHz, CDC1 ₃₎ 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114, 1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 δ;

HRMS vypočítaná pre C^H^NjCb = 395,2209, nájdená = 395,2208.HRMS calcd for C 23 H 27 N 3 O 2 Cl = 395.2209, found = 395.2208.

Príklad 3 (S)-(-)-1 -(2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6karboxamid (S)-(IX), známy tiež ako (S)-(-)- l-)4-metoxyfeny 1)-4-(2-(6metylaminokarbonylizochróman-1 -yl)etylpiperazínExample 3 (S) - (-) - 1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), also known as (S) - (-) - 1- (4-Methoxyphenyl) -4- (2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine)

1. krok: (S)-(-)-N, N-di-t-butyloxykarbonyl-l-[2-[4-(4-metoxy fenyl)-1piperazinyljetyl]- izochróman-6-karboxamid (S)-(VHI)Step 1: (S) - (-) - N, N-di-t-butyloxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-6-carboxamide (S) - ( VHI)

Zmes (S)—(—)—1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl)etyl]-izochróman-6- karboxamidu (S)-(VII), príklad 1, 5. krok, 0,71 g), di-terc.butyl dikarbonátu (0,86 g) a 4dimetylaminopyridínu (0,02 g) v dichlórmetánu (20 ml) sa mieša pri 20-25 °C v argónovej atmosfére. Po 72 hodinách sa reakcia zahustí pri zníženom tlaku a produkt sa prečistí(S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl) ethyl] -isochroman-6-carboxamide (S) - (VII), Example 1, Step 5, 0.71 g), di-tert-butyl dicarbonate (0.86 g) and 4-dimethylaminopyridine (0.02 g) in dichloromethane (20 mL) were stirred at 20-25 ° C under an argon atmosphere. After 72 hours, the reaction is concentrated under reduced pressure and the product is purified

-38pomocou stĺpcovej chromatografie (silikagél, použitie vymývacieho gradientu začínajúc 25 % octanom etylnatým v hexáne a ďalej 100 % octanom etyinatým) za vzniku (S)-(-)-N, N-di-tbutyloxykarbonyl-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamid (S)-(VIII), [a]o = -32° (c= 0,7201, etanol); HRMS vypočítaná pre C33H45N3O7 = 595,3257, nájdená = 595,3282.-38 using column chromatography (silica gel, eluting with a gradient starting with 25% ethyl acetate in hexane followed by 100% ethylacetate) to give (S) - (-) - N, N-di-butyloxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VIII), [α] D = -32 ° (c = 0.7201, ethanol); HRMS calcd for C 33 H 45 N 3 O 7 = 595.3257, found = 595.3282.

2. krok: (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid (S)-(IX)Step 2: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Zmes (S)-(-)-N, N-di-t-butoxykarbonyl-1 -[2-[4-(4-metoxyfenyl)~ 1 -piperazinyl]etyl]izochróman-6-karboxamidu (S)-(VIII) (1,09 g) v dichlórmetáne (18 ml) v uzavierateľnej skúmavke sa ochladí dusíkom za použitia acetónu a oxidu uhličitého. Do ochladenej skúmavky potom kondenzuje metylamín (nadbytok; obvykle 50 ekvivalentov ), skúmavka sa uzavrie a zahreje na izbovú teplotu. Po 16 hodinovom trepaní pri izbovej teplote sa obsah skúmavky zahustí za zníženého tlaku a výsledný surový produkt sa prečistí stĺpcovou chromatografiou (silikagél; použitie zmesi metanol/dichlórmetán 5/95) za vzniku (S)-(-)-l-(2[4-(4-metoxyfeny 1)-1-piperazinyl]etyl]-N-metyl-izochróman-6-karboxamidu (S)-(IX), [a]o = -51° (c= 0,9953, metanol/dichlórmetán, 1/1 ); Analýzou vypočítané pre C24H31N3O3, C, 70,39; H, 7,63; N, 10,26 - nájdené: C, 70,16; H, 7,84; N, 10,27.(S) - (-) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VIII) (1.09 g) in dichloromethane (18 mL) in a sealable tube was cooled with nitrogen using acetone and carbon dioxide. Methylamine (excess; usually 50 equivalents) is then condensed into the cooled tube, the tube is sealed and warmed to room temperature. After shaking at room temperature for 16 hours, the contents of the tube are concentrated under reduced pressure and the resulting crude product is purified by column chromatography (silica gel; using methanol / dichloromethane 5/95) to give (S) - (-) - 1- (2 [4]). - (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), [α] D = -51 ° (c = 0.9953, methanol / dichloromethane Calcd for C 24 H 31 N 3 O 3, C, 70.39; H, 7.63; N, 10.26. Found: C, 70.16; H, 7.84; N, 10.27.

Príklad 4 (R)-(+)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6karboxamid (R)-(IX), známy tiež ako (R)-(+)-l-(2-[4-(4-metoxyfenyl)-4-[2-(6metylaminokarbonylizochróman-1 -yl)-etylpiperazínExample 4 (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX), also known as (R) - (+) - 1- (2- [4- (4-methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine]

1. krok: (R)-(+)-N,N-di-t-butoxykarbonyl- l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (R)-(VIII)Step 1: (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (R) - (VIII)

Postupom podľa príkladu 3, 1. kroku s drobnými obmenami vzniká z východiskového R)-(+)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-izochróman-6- karboxamidu ((R)-(VII), príklad 2, 4. krok, 0,60 g), (R)-(+)-N,N-di-t-butoxykarbonyl-1 -[2-[4-(4-metoxyfenyl)-1piperazinyl]etyl]-izochróman-6-karboxamid (R)-(VIII), ktorý sa použije priamo v ďalšom kroku.Following the procedure of Example 3, Step 1, with minor variations, starting from R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide ((R) (VII), Example 2, Step 4, 0.60 g) (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl)] -1piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VIII), which is used directly in the next step.

2. krok: (R)-(+)-l-(2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid (R)-(IX)Step 2: (R) - (+) - 1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX)

-39Postupom podľa príkladu 3, 2. kroku s drobnými obmenami vzniká z východiskového (R) -(+)-N,N-di-t-butoxykarbonyl-1 -[2-[4-(4-metoxyfenyl)-1 - piperazinyl]etyl]-izochróman-6karboxamidu (R)-(VUI) (R)-(+)-1 -(2-[4-(4-metoxyfeny 1)-1 -piperaziny 1] etyl)-N-metylizochróman-6-karboxamid (R)-(IX), [a]o = +48° (c= 0,9745, metanol/dichlórmetán, 1/1 ); HRMS vypočítaná pre C24H31N3O3 = 409,2365, nájdená = 409,2391.-39 Following the procedure of Example 3, Step 2, with minor variations, starting from (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] (ethyl) -isochroman-6-carboxamide (R) - (VUI) (R) - (+) - 1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl) -N-methylisochroman-6 -carboxamide (R) - (IX), [α] D = + 48 ° (c = 0.9745, methanol / dichloromethane, 1/1); HRMS calcd for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2391.

Príklad 5 (S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (S)-(IX), známy tiež ako (S)-(-)-l-(4-trifluórmetylfenyl)-4-[2-(6metylaminokarbonylizochróman-1 -y l)-etylpiperazínExample 5 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), also known as (S) S) - (-) - 1- (4-Trifluoromethylphenyl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine

1. krok: (S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-trifluórmetylfenyl)piperazín (S) -(V) (S)-(-)-(6-brómizochróman-l-yl)octová kyselina (príklad 1, XI, 542 mg, 2,0 mmol), 10 ml dichlórmetánu, l-(4-trifluórmetyl)piperazín (507 mg, 3,3 mmol) a dietylkyanofosfonát (0,33 ml, 2,2 mmol) sa zmiešajú a ochladia na O °C, pridá sa trietylamín (0,42 ml, 3,0 mmol) bez viditeľnej zmeny a zmes sa zahreje na 20-25 °C. Po 16 hodinách sa reakčná zmes zahustí. Koncentrát sa prečistí pomocou LC na 58 g (230-400) silikagélu, elúcie pomocou octanu etynatého/hexán (40/60) za vzniku (S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4trifluórmetylfenyl)-piperazínu (S)-(V), Rf= 0,25 (octan etylnatý/hexán (40/60).Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (V) (S) - (-) 1- (6-bromoisochroman-1-yl) acetic acid (Example 1, XI, 542 mg, 2.0 mmol), 10 mL dichloromethane, 1- (4-trifluoromethyl) piperazine (507 mg, 3.3 mmol) and diethyl cyanophosphonate (0.33 mL, 2.2 mmol) was mixed and cooled to 0 ° C, triethylamine (0.42 mL, 3.0 mmol) was added without visible change and the mixture was warmed to 20-25 ° C. After 16 hours, the reaction mixture is concentrated. Purify the concentrate by LC on 58 g (230-400) silica gel, eluting with ethyl acetate / hexane (40/60) to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl)] acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) - (V), R f = 0.25 (ethyl acetate / hexane (40/60)).

2. krok: (S)-(-)-l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-trifluórmetylfenyl)piperazín (S)-(VI).Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (VI).

(S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-trifluórmetylfenyl)-piperazín (S)(V) (1. krok, 876 mg, 1,8 mmol) a 18,0 ml čerstvo vydestilovaného tetrahydroíuránu sa ochladí na O °C. Na zmes sa nechá pôsobiť kvapka 1 M roztoku bóranu v tetrahydrofuráne (5,4 ml, 5,4 mmol) za vzniku peny. Reakcia sa zahrieva pri 20-25 °C počas 16 hodín. Potom prebieha reakcia s 1 M kyselinou chlorovodíkovou (6,0 ml), napojí sa spätný chladič a zmes refluxuje 1 hodinu. Reakcia sa potom ochladí na 20-25 °C a prchavé látky sa odstránia pri zníženom tlaku. Výsledný vodný zvyšok sa zriedi vodou (30 ml), upraví sa pH na >10 a dvakrát sa extrahuje octanom etylnatým (30 ml). Zmiešané organické extrakty sa raz premyjú soľankou (30 ml), vysušia pomocou síranu horečnatého, prefiltrujú a zahustia. Koncentrát sa prečistí pomocou LC na 43 g (230-400) silikagélu a eluuje zmesou octan etylnatý/hexán(S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) (V) (Step 1, 876 mg, 1, 8 mmol) and 18.0 ml of freshly distilled tetrahydrofuran were cooled to 0 ° C. The mixture was treated with a drop of 1M borane in tetrahydrofuran (5.4 mL, 5.4 mmol) to give a foam. The reaction was heated at 20-25 ° C for 16 hours. The reaction was then treated with 1 M hydrochloric acid (6.0 mL), refluxed and refluxed for 1 hour. The reaction is then cooled to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting aqueous residue was diluted with water (30 mL), adjusted to pH > 10, and extracted twice with ethyl acetate (30 mL). The combined organic extracts were washed once with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by LC on 43 g (230-400) silica gel and eluted with ethyl acetate / hexane

-40(40/60) za vzniku (S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-trifluórmetylfenyl)piperazínu (S)(VI), teplota topenia =104-105 °C, Rf = 0,30 (octan etylnatý/hexán, 40/60).-40 (40/60) to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) piperazine (S) (VI), temperature mp = 104-105 ° C, R f = 0.30 (ethyl acetate / hexane, 40/60).

3.krok: (S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-1 -piperazinyl]etyl]-N-metylizochróman 6karboxamid (S)-(IX)Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman 6-carboxamide (S) - (IX)

Zmieša sa (S)-(-)-l-[2-(6-brómizochróman-l-yl)etyl]-4-(4trifluórmetylfenyl)piperazín (S)-(VI) (2. krok, 703 mg, 1,5 mmol), octanu paládnatého (17 mg, 0.075 mmol), l,3-bis(difenylfosfino)propán (37 mg, 0,09 mmol), 3,0 ml dimetylformamidu, diizopropyletylamín (0,52 ml, 3,0 mmol) a N-metylformamid (1,8 ml, 30 mmol), šesťkrát prečistí oxidom uhoľnatým za vákua a zahreje na 120 °C. Po 16 hodinách sa zmes ochladí na 20-25 °C, zmieša s 25 ml 1 M kyseliny chlorovodíkovej a mieša 10 minút. Pri kyslom roztoku sa pH upraví na 12 a potom sa trikrát extrahuje octanom etylnatým (20 ml). Zmiešané organické extrakty sa raz premyjú soľankou (30 ml), vysušia nad síranom horečnatým, prefíltrujú a zahustia. Koncentrát sa prečistí pomocou LC na 33 g (230-400) silikagélu a eluuje zmesou acetón/hexán (40/60) za vzniku (S)-(-)-l-(2-(4-(4trifluórmetylfenyl)-1 -piperazinyl)etyl]-N-metyl-izochróman-6i-karboxamidu (S)-(IX), teplota topenia = 169-170 °C; Rf - 0,30 (acetón/hexán 40/60).Combine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (VI) (Step 2, 703 mg, 1, 5 mmol), palladium acetate (17 mg, 0.075 mmol), 1,3-bis (diphenylphosphino) propane (37 mg, 0.09 mmol), 3.0 mL of dimethylformamide, diisopropylethylamine (0.52 mL, 3.0 mmol) ) and N-methylformamide (1.8 mL, 30 mmol), purified six times with carbon monoxide under vacuum and heated to 120 ° C. After 16 hours, the mixture is cooled to 20-25 ° C, treated with 25 mL of 1 M hydrochloric acid and stirred for 10 minutes. The pH of the acidic solution was adjusted to 12 and then extracted three times with ethyl acetate (20 mL). The combined organic extracts were washed once with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by LC on 33 g (230-400) silica gel and eluted with acetone / hexane (40/60) to give (S) - (-) - 1- (2- (4- (4-trifluoromethylphenyl) -1-piperazinyl) (ethyl) -N-methyl-isochroman-6'-carboxamide (S) - (IX), mp = 169-170 ° C, Rf = 0.30 (acetone / hexane 40/60).

Príklad 6 (S)-(-)-l-[2-(4-[4-(aminokarbonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochróman6-karboxamid (R)-(IX), známy tiež ako (S)-(-)-l-(benzamid-4-yl)-4-[2-(6metylaminokarbonylizochróman-1 -yl)-etylpiperazínExample 6 (S) - (-) - 1- [2- (4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX), also known as (S) - (-) - 1- (Benzamid-4-yl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine

1. krok: (S)-(-)-2-(6-brómizochróman-2-yl)etyl alkohol (S)-(-)-2-(6-brómizochróman-2-yl)octová kyselina (XI) (1. príklad, 2. krok, 16,27 g, 60 mmol) sa zmieša s 100 ml tetrahydrofúránu. K tejto zmesi sa pridá 10 M roztok bóran metylsulfidu (18,0 ml, 0,18 mol) pri teplote 20-25 °C vo vodnom kúpeli. Po 1 hodine sa reakčná zmes ochladí na O °C a pomaly sa pridá 160 ml metanolu. Poznámka: reakcia začne prebiehať po 1-2 minútach prudkým vznikom vodíka. Zmes sa zahreje na 20-25 °C a prchavé látky sa odstránia pri zníženom tlaku. Výsledná tuhá fáza sa zriedi 1 M hydroxidom sodným (150 ml) a trikrát extrahuje octanom etylnatým (100 ml). Získané organické extrakty sa raz premyjú soľankou (100 ml), vysušia nad síranom horečnatým, prefíltrujú a zahustia za vzniku tuhej fázy. Táto surovina rekryštalizuje zo zmesi octan etylnatý/hexán (S)-(-)-2-(6-41 brómizochróman-2-yl)etyl alkoholu (S-l ), teplota topenia = 95-96 °C, R_f = 0,28 (acetón/hexán 30/70).Step 1: (S) - (-) - 2- (6-bromoisochroman-2-yl) ethyl alcohol (S) - (-) - 2- (6-bromoisochroman-2-yl) acetic acid (XI) ( Example 1, Step 2 (16.27 g, 60 mmol) was mixed with 100 mL tetrahydrofuran. To this mixture was added a 10 M solution of borane methyl sulfide (18.0 mL, 0.18 mol) at 20-25 ° C in a water bath. After 1 hour, the reaction mixture was cooled to 0 ° C and 160 mL of methanol was slowly added. Note: the reaction starts after 1-2 minutes of violent hydrogen formation. The mixture is warmed to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting solid phase was diluted with 1 M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The obtained organic extracts were washed once with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give a solid. This material was recrystallized from ethyl acetate / hexane (S) - (-) - 2- (6-41 bromoisochroman-2-yl) ethyl alcohol (S1), mp = 95-96 ° C, R _f = 0.28 (acetone / hexane 30/70).

2. krok: (S)-(-)-6-bróm-l-(brómetyl)izochróman (S)-(-)-2-(6-brómizochróman-2-yl)etyl alkohol (S-l ) (1. krok, 14,0 g, 54 mmol) sa zmieša s 91 ml dichlórmetánu. K výslednej zmesi sa pridá 25 ml tertrahydrofuránu. Suspenzia potom reaguje s bromidom uhličitým (22,6 g, 68 mmol), ochladí sa na O °C a postupne sa pridá trifenylfosfin (21,4 g, 82 mmol). Výsledná zmes sa zahrieva tri hodiny pri 20-25 °C a nasleduje zakoncentrovanie pri zníženom tlaku a vznik tuhej fázy. Trifenylfosfínoxid sa odstráni rekryštalizáciou zo zmesi octan etylnatý/hexán, kedy s pôvodným alkoholom vznikne tuhá fáza. Táto látka sa absorbuje do 70 g silikagélu a prečistí na LC na 700 g (230-400) silikagélu pri elúcii zmesi octan etylnatý/hexán (5/95) a vzniku (S)-(-)-6-bróm-l(brómetyl)izochróman (IV), Rf = 0,47 (10 % acetón/hexán).Step 2: (S) - (-) - 6-bromo-1- (bromomethyl) isochroman (S) - (-) - 2- (6-bromoisochroman-2-yl) ethyl alcohol (S1) (Step 1) (14.0 g, 54 mmol) was mixed with 91 mL of dichloromethane. To the resulting mixture was added 25 mL of tertrahydrofuran. The suspension was then treated with carbon tetrabromide (22.6 g, 68 mmol), cooled to 0 ° C, and triphenylphosphine (21.4 g, 82 mmol) was gradually added. The resulting mixture was heated at 20-25 ° C for three hours followed by concentration under reduced pressure to form a solid phase. The triphenylphosphine oxide is removed by recrystallization from ethyl acetate / hexane to give a solid phase with the parent alcohol. This material was absorbed into 70 g of silica gel and purified by LC on 700 g (230-400) silica gel eluting with ethyl acetate / hexane (5/95) to give (S) - (-) - 6-bromo-1 (bromomethyl). isochroman (IV), Rf = 0.47 (10% acetone / hexane).

3. krok: (S)-(-)-4-[4-[2-(6-brómizochróman-1 -yl)ety 1)-1 -piperazinyljbenzamidStep 3: (S) - (-) - 4- [4- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -1-piperazinyl] -benzamide

Zmes (S)-(-)-6-bróm-l-(brómetyl)izochrómanu (IV) (2. krok, 17,22 g, 53,8 mmol), 14,36 g (67,0 mmol) 4-(piperazinyl-l-yl)benzamidu (príprava 1,10,43 g (80,7 mmol) diizopropyletylamínu a 125 ml etylén glykolu sa zahrieva pri 85-90 °C cez noc. Po schladení sa pridá voda (300 ml), výsledná tuhá fáza sa odoberie a prefiltruje. Filtračný koláč sa trikrát premyje vodou (celkom asi 200 ml a potom toluénom (celkom asi 200 ml). Filtrační koláč sa potom vysuší za zníženého tlaku. Po vysušení sa surový produkt rozsuspenduje v zmesi metanol/dichlórmetán a pridá sa silikagél pre absorpciu zmesi. Po odstránení rozpúšťadla sa silikagélová suspenzia naleje do hornej časti silikagélovej kolóny so zmesou dichlórmetán/metanol (95/5). Elúcia začne zmesou dichlórmetán/metanol (95/5) a potom dichlórmetán/metanol (92/8) pri elúcii (S)-(-)-4-[4-[2-(6-brómizochróman-l-yl)etyl]-lpiperazinyljbenzamidu (VI), ktorý sa získa ako tuhá fáza po nazhromaždení určitých frakcií a zahustení.A mixture of (S) - (-) - 6-bromo-1- (bromomethyl) isochroman (IV) (Step 2, 17.22 g, 53.8 mmol), 14.36 g (67.0 mmol) 4- (piperazinyl-1-yl) benzamide (preparation of 1.10.103 g (80.7 mmol) of diisopropylethylamine and 125 mL of ethylene glycol was heated at 85-90 ° C overnight. After cooling, water (300 mL) was added, resulting in The solid is collected and filtered, and the filter cake is washed three times with water (about 200 ml total, then toluene (about 200 ml total). The filter cake is then dried under reduced pressure. After drying, the crude product is suspended in methanol / dichloromethane and added. After removal of the solvent, the silica gel slurry is poured onto the top of a silica gel column with dichloromethane / methanol (95/5), eluting with dichloromethane / methanol (95/5) and then dichloromethane / methanol (92/8). eluting with (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] -benzamide (VI), which is obtained as a solid after collection certain fractions and thickenings.

4. krok: (S)-(-)-1 -[2-[4-[4-(aminokarbonyl)fenyl)-1 -piperazinyl]etyl]-Nmetylizochrómanyl-6-karboxamid (S)-(-)-4-[4-[2-(6-brómizochróman-l-yl)etyl]-l-piperazinyl]benzamid (VI) (3. krok,Step 4: (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl) -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (S) - (-) - 4 - [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzamide (VI) (Step 3,

3,34 g, 7,52 mmol) sa rozsuspenduje v 55 ml suchého DMF odstráni sa plyn za vzniku vákua(3.34 g, 7.52 mmol) was suspended in 55 mL of dry DMF and the gas removed under vacuum.

-42(pomocou argónu). Suspenzia sa potom prenesie na dno nádoby s tromi guľatými hrdlami (pomocou 10 ml prídavku DMF pre prepláchnutie nádoby) obsahujúci octan paládnatý (0,084 g, 0,376 mmol) a l,3-bis(difenylfosfino) propán (0,232 g, 0,564 mmol) a nádoba sa umiestni do olejového kúpeľa. Pridá sa diizopropyletylamín (2,6 ml, 15,3 mmol) a u zmesi sa uskutoční opäť ľahké zníženie tlaku pomocou argónu. Hneď ako teplota kúpeľa dosiahne 60 °C, oxid uhoľnatý vybuble na povrch zmesi a po niekoľkých minútach tiež metylamín. Počas 6 hodín sa pokračuje s prídavkom oxidu uhoľnatého a metyl amínu alebo než sa spotrebuje východisková látka, zmes sa potom ochladí a odstráni sa DMF pri zníženom tlaku. Zvyšok sa nanesie na silikagélovú kolónu a eluuje zmesou metanol/dichlórmetán (8/92), dokiaľ sa nevymyjú menej polárne nečistoty. Eluent sa potom pridá do zmesi metanol/dichlórmetán (10/90) a po nazhromaždení a zakoncentrovaní určitých frakcií a kryštalizácie zo zmesi metanol/dichlórmetán sa získa (S)-(-)-l-[2-[4-[4-(aminokarbonyl)fenyl]-l-piperazinyl]etyl]N-metylizochrómanyl-6-karboxamid (IX), teplota topenia = 231,5 - 232,5 °C.-42 (using argon). The suspension was then transferred to the bottom of a three-necked flask (using 10 ml DMF to rinse the flask) containing palladium acetate (0.084 g, 0.376 mmol) and 1,3-bis (diphenylphosphino) propane (0.232 g, 0.564 mmol) and the flask was stirred. placed in an oil bath. Diisopropylethylamine (2.6 mL, 15.3 mmol) was added and the mixture was again slightly pressurized with argon. As soon as the bath temperature reaches 60 ° C, the carbon monoxide is emitted to the surface of the mixture and after a few minutes also methylamine. Carbon monoxide and methyl amine are added for 6 hours, or until the starting material is consumed, the mixture is then cooled and DMF is removed under reduced pressure. The residue was applied to a silica gel column and eluted with methanol / dichloromethane (8/92) until less polar impurities were eluted. The eluent is then added to a methanol / dichloromethane (10/90) mixture, and after collection and concentration of certain fractions and crystallization from a methanol / dichloromethane mixture, (S) - (-) - 1- [2- [4- [4- ( aminocarbonyl) phenyl] -1-piperazinyl] ethyl] N-methylisochromanyl-6-carboxamide (IX), m.p. = 231.5-232.5 ° C.

Príklad 7 l-[2-[4-4-metylfenyl)-l-piperazinyl]etyl-izochróman-6-karboxamid (VII)Example 7 1- [2- [4-4-methylphenyl) -1-piperazinyl] ethyl isochroman-6-carboxamide (VII)

1. krok: 6-brómizochróman-l-yl-octová kyselina (IV)Step 1: 6-bromoisochroman-1-yl-acetic acid (IV)

Postupom podľa príkladu 2, 1. kroku s drobnými obmenami vzniká z racemického etyl 6-brómizochróman-l-yl-acetátu (ΠΙ) 6-brómizochróman-l-yl-octová kyselina (IV), teplota topenia = 160-161 °C, NMR (300 MHz. CDCb) 7,30, 6,92, 5,17, 4,18-4,11, 3,86-3,78 a 3,04-2,69 δ.Following the procedure of Example 2, Step 1, with minor variations, racemic ethyl 6-bromoisochroman-1-yl acetate (ΠΙ) 6-bromoisochroman-1-yl-acetic acid (IV) is obtained, m.p. = 160-161 ° C. NMR (300 MHz, CDCl 3) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 δ.

//

2. krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-metylfenyl)piperazín (V)Step 2: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká za použitia 6brómizochróman-l-yl-octovej kyseliny (IV) a metylfenylpiperazínu, l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metylfenyl)-piperazín (V), ktorý sa potom analyzuje rýchlou chromatografiou (silikagél 80 g; octan etylnatý/hexán, 50/50), Rf = 0,20 ( octan etylnatý/hexán, 50/50); IR (čisté látky) 1642, 1515, 1481,1462, 1443,1234,1208, 1107, 1031 a 813 cm'¹, NMR (300 MHz, CDC1₃) 7,30, 7,09, 7,01, 6,84, 5,26, 4,13-4,07, 3,95-3,87, 3,823,60, 3,12, 3,05-2,89, 2,77, 2,65 a 2,28 δ; CMR (75 MHz, CDC1₃) 168,2, 148,3, 136,5, 136,5,Following the procedure of Example 1, Step 3, with minor variations, 6-bromoisochroman-1-yl-acetic acid (IV) and methylphenylpiperazine, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) are formed. -piperazine (V) which is then analyzed by flash chromatography (silica gel 80 g; ethyl acetate / hexane, 50/50), Rf = 0.20 (ethyl acetate / hexane, 50/50); IR (neat) 1642, 1515, 1481, 1462, 1443, 1234, 1208, 1107, 1031 and 813 cm ^-1 , NMR (300 MHz, CDCl ₃ ) 7.30, 7.09, 7.01, 6, 84, 5.26, 4.13-4.07, 3.95-3.87, 3.823.60, 3.12, 3.05-2.89, 2.77, 2.65 and 2.28 δ ; CMR (75 MHz, CDC1 ₃₎ 168.2, 148.3, 136.5, 136.5,

-43 136, 8, 131,7, 129,6, 129,2, 126,3, 121,2, 116,8, 73,3, 63,3, 60,2,48,7, 45,9, 41,7, 29,8, 26,6 a-43 136.8, 131.7, 129.6, 129.2, 126.3, 121.2, 116.8, 73.3, 63.3, 60.2, 48.7, 45.9, 41.7, 29.8, 26.6 and

20,3 δ.20,3 δ.

3. krok: l-[2-(6-brómizochróman-l (VI)Step 3: 1- [2- (6-bromoisochroman-1 (VI))

-y l)acetyl ] -4-(4-mety lfeny l)-piperazí n(yl) acetyl] -4- (4-methylphenyl) piperazine

Postupom podľa príkladu 1,4. kroku s drobnými obmenami sa z l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metylfenyl)-piperazínu (V) získa l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metylfenyl)-piperazín (VI), Rf = 0,21 (octan etylnatý/hexán, 50/50); IR (čisté látky) 29,41, 29,25, 2818, 1515, 1481, 1379, 1239, 1143, 1111 a 813 cm'¹; NMR (300 MHz, CDCb) 7,32-7,26-7,07, 6,97, 6,84, 4,78, 4,14-3,07, 3,783,69, 3,16, 2,94, 2,7-2,48, 2,26, 2,15-1,90 δ; CMR (75 MHz, CDCb) 149,0, 136,9, 136,1,Following the procedure of Example 1.4. of the small variation step, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (V) yields 1- [2- (6-bromoisochroman-1-yl) acetyl] -4 - (4-methylphenyl) -piperazine (VI), Rf = 0.21 (ethyl acetate / hexane, 50/50); IR (neat) 29.41, 29.25, 2818, 1515, 1481, 1379, 1239, 1143, 1111, and 813 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.32-7.26-7.07, 6.97, 6.84, 4.78, 4.14-3.07, 3.783.69, 3.16, 2.94 , 2.7-2.48, 2.26, 2.15-1.90 δ; CMR (75 MHz, CDCl 3) 149.0, 136.9, 136.1,

131,4, 129,4, 129,0, 128,9, 126,3, 119,8, 116,1, 74,1, 62,6, 54,4, 53,2, 49,5, 33,0, 28,6 a 20,2131.4, 129.4, 129.0, 128.9, 126.3, 119.8, 116.1, 74.1, 62.6, 54.4, 53.2, 49.5, 33, 0, 28.6 and 20.2

δ.δ.

4. krok: l-[2-[4-4-metylfenyl)-l-piperazinyl]etyl-izochróman-6- karboxamid (IX)Step 4: 1- [2- [4-4-methylphenyl) -1-piperazinyl] ethyl isochroman-6-carboxamide (IX)

Postupom podľa PRÍKLADU 1, 5. kroku s drobnými obmenami vzniká za použitia l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-metylfenyl)-piperazínu (VI) l-[2-[4-4-metylfenyl)l-piperazinyl]etylizochróman-6-karboxamid (VII), Rf - 0,2 (metanol/octan etylnatý 10/90); IR (suspenzia) 3373, 3180, 1647, 1623, 1571, 1520, 1406, 1242, 1111 a 817 cm'¹; NMR (300Following the procedure of EXAMPLE 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (VI) 1- [2- [4] is formed. 4-methylphenyl) 1-piperazinyl] ethylisochroman-6-carboxamide (VII), Rf-0.2 (methanol / ethyl acetate 10/90); IR (suspension) 3373, 3180, 1647, 1623, 1571, 1520, 1406, 1242, 1111 and 817 cm ^-1 ; NMR (300

MHz, CDCb) 7,59, 7,18, 7,07, 6,84, 6,05, 4,86, 4,13, 3,77, 3,17, 3,00, 2,76-2,45, 2,26, 2,14 aMHz, CDCl3) 7.59, 7.18, 7.07, 6.84, 6.05, 4.86, 4.13, 3.77, 3.17, 3.00, 2.76-2, 45, 2.26, 2.14 and

2,02 δ; HRMS vypočítaná pre C23H29N3O2 = 379,2260, nájdená = 379,2269.2,02 δ; HRMS calcd for C 23 H 29 N 3 O 2 = 379.2260, found = 379.2269.

Príklad 8 l-[2-[4-4-chlórfenyl)-l-piperazinyl]etyl-izochróman-6- karboxamid (VII)Example 8 1- [2- [4-4-Chlorophenyl) -1-piperazinyl] ethyl isochroman-6-carboxamide (VII)

1. krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-chlórfenyl)piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (V)

Postupom podľa procedúry príkladu 1, 3. kroku s drobnými obmenami vzniká za použitia racemickej 6-brómizochróman-l-yl-octovej kyseliny (IV) a 4- chlórfenylpiperazínu l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-chlórfenyl)piperazín (V), Rf = 0,20 (octan etylnatý/hexán, 50/50); IR (suspenzia) 1642, 1594, 1496, 1482, 1443, 1275, 1232, 1107, 1030 a 821 cm'¹; NMR (300 MHz, CDCb) 7,32-7,21, 7,01, 6,84, 5,26, 4,11, 3,94, 3,79-3,60, 3,14, 3,09-2,89, 2,77 a 2,65 Ô; CMR (75 MHz, CDCb) 178,1, 148,5, 136,0, 131,8, 129,1, 128,8,Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-chlorophenylpiperazine of 1- [2- (6-bromoisochroman-1-yl) acetyl] - 4- (4-chlorophenyl) piperazine (V), Rf = 0.20 (ethyl acetate / hexane, 50/50); IR (slurry) 1642, 1594, 1496, 1482, 1443, 1275, 1232, 1107, 1030, and 821 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.32-7.21, 7.01, 6.84, 5.26, 4.11, 3.94, 3.79-3.60, 3.14, 3.09 -2.89, 2.77 and 2.65 Ô; CMR (75 MHz, CDCl 3) 178.1, 148.5, 136.0, 131.8, 129.1, 128.8,

125,8, 125,0, 120,0, 117,5, 73,0, 63,2, 49,7, 49,2, 55,0,41,9, 39,6 a 28,5 δ.125.8, 125.0, 120.0, 117.5, 73.0, 63.2, 49.7, 49.2, 55.0.41.9, 39.6 and 28.5 δ.

-442. krok: 1 -[2-(6-brómizochróman-1 -yl)acetyl]-4-(4-chlórfenyl)piperazín (VI).-442. step: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (VI).

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-[2(6-brómizochróman-1 -yl)acetyl]-4-(4-chlórfenyl)piperazínu (V) I -[2-(6-brómizochróman-1 yl)acetyl)-4-(4-chlórfenyl)piperazín (VI), teplota topenia = 94-96 °C; Rf = 0,22 (octan etylnatý/hexán, 50/50); IR (suspenzia) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102 a 815 cm'¹; NMR (300 MHz, CDC1₃) 7,32-7,26, 7,19, 6,97, 6,83, 4,78, 4,14-4,07, 3,78-3,69, 3,16, 3,00-2,90, 2,7-2,48 a 2,15, 1,90 Ô; CMR (75 MHz, CDC1₃) 149,6, 137,1, 136,0, 131,4,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (V) 1- [2- (6-bromoisochroman) was formed (1-yl) acetyl) -4- (4-chlorophenyl) piperazine (VI), m.p. = 94-96 ° C; Rf = 0.22 (ethyl acetate / hexane, 50/50); IR (suspension) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102, and 815 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26, 7.19, 6.97, 6.83, 4.78, 4.14-4.07, 3.78-3.69, 3, 16, 3.00-2.90, 2.7-2.48 and 2.15, 1.90 Ô; CMR (75 MHz, CDC1 ₃₎ 149.6, 137.1, 136.0, 131.4,

129,1, 128,7, 126,3, 124,6, 120,0,116,9, 74,0, 62,6, 54,3, 53,3, 53,0,48,9, 33,0 a 28,6 5.129.1, 128.7, 126.3, 124.6, 120.0, 116.9, 74.0, 62.6, 54.3, 53.3, 53.0, 48.9, 33.0 and 28,6 5.

3. krok: l-[2-[4-4-chlórfenyl)-l-piperazinyl]etylizochróman-6- karboxamid (IX)Step 3: 1- [2- [4-4-chlorophenyl) -1-piperazinyl] ethylisochroman-6-carboxamide (IX)

Postupom podľa príkladu 1, 5. kroku s drobnými obmenami vzniká za použitia l-[2-(6brómizochróman-1 -yl)acetyl]-4-(4-chlórfenyl)piperazínu (VI) 1 -[2-[4-4-chlórfenyl)-1 piperazinyl]etylizochróman-6-karboxamid (VII), teplota topenia =169-171 °C; Rf = 0,22 (metanol/octan etylnatý 10/90); IR (suspenzia) 3365, 1649, 1661, 1623, 1500, 1403, 1241, 1112, 1096 a 821 cm·’; NMR (300 MHz, CDC1₃) 7,59, 7,18, 6,84, 6,05, 4,88, 4,15, 3,77, 3,17, 3,00, 2,76-2,45,2,14 a 2,02 Ô.Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (VI) 1- [2- [4-4- chlorophenyl) -1 piperazinyl] ethylisochroman-6-carboxamide (VII), m.p. = 169-171 ° C; Rf = 0.22 (methanol / ethyl acetate 10/90); IR (slurry) 3365, 1649, 1661, 1623, 1500, 1403, 1241, 1112, 1096, and 821 cm -1; NMR (300 MHz, CDCl ₃ ) 7.59, 7.18, 6.84, 6.05, 4.88, 4.15, 3.77, 3.17, 3.00, 2.76-2, 45.2.14 and 2.02 Ô.

Príklad 9 1 -[2-[4-4-fenylmetyloxyfény 1)-1 -piperaziny l]etyl]-izochróman-6karboxamid (VII) .krok: l-(4-fenylmetoxyfenyl)-4-[2-(6-brómizochróman-1 -yl)acetyl]piperazín (V)Example 9 1- [2- [4-4-Phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII). Step: 1- (4-Phenylmethoxyphenyl) -4- [2- (6-bromoisochroman) -1-yl) acetyl] piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká za použitia racemickej 6-brómizochróman-l-yl-octovej kyseliny (IV) a 4-fenylmetyloxopiperazínu l-(4fenylmetoxyfenyl)-4-[2-(6-brómizochróman-l-yl)acetyl]piperazín (V), Rf = 0,47 (octan etylnatý); IR (suspenzia) 1510, 1481, 1463, 1453, 1445, 1239, 1231, 1101 a 1027 cm'¹; NMR (300 MHz, CDC1₃) 7,43-7,25, 7,00, 5,27, 5,02, 4,23-4,06, 3,93-3,87, 3,80-3,59, 3,06, 2,982,89, 2,76 a 2,65 δ; CMR (75 MHz, CDC1₃) 168,9, 153,4, 145,3, 137,1, 136,4, 136,2, 131,6,Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-phenylmethyloxopiperazine of 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl)] were obtained. yl) acetyl] piperazine (V), Rf = 0.47 (ethyl acetate); IR (suspension) 1510, 1481, 1463, 1453, 1445, 1239, 1231, 1101, and 1027 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.43-7.25, 7.00, 5.27, 5.02, 4.23-4.06, 3.93-3.87, 3.80-3, 59, 3.06, 2,982.89, 2.76 and 2.65 δ; CMR (75 MHz, CDC1 ₃₎ 168.9, 153.4, 145.3, 137.1, 136.4, 136.2, 131.6,

-45129,3, 128,4, 127,8, 127,3, 126,4, 120,2, 118,6, 115,5, 73,3, 70,3, 63,4, 51,1, 50,5, 46,0, 41,8,-45129.3, 128.4, 127.8, 127.3, 126.4, 120.2, 118.6, 115.5, 73.3, 70.3, 63.4, 51.1, 50 , 5, 46.0, 41.8,

39,8 a 28,7 δ.39.8 and 28.7 δ.

2. krok: 1 -(4-fenylmetoxyfenyl)-4-[2-(6-brómizochróman-1 -yl)-etyl]piperazín (VI)Step 2: 1- (4-Phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) ethyl] piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-(4fenylmetoxyfenyl)-4-[2-(6-brómizochróman-1 -yl)acetyl]piperazínu (VI) 1 -(4-fenyl metoxyfenyl)-4-[2-(6-brómizochróman-l-yl)acetyl)piperazín (VI), teplota topenia = 87- 90 °C; Rf = 0,43 (octan etylnatý); IR (čisté látky) 1578, 1517, 1452, 1258, 1153, 1113, 1054, 1049, 818 a 737 cm¹; NMR (300 MHz, CDClj) 7,43-7,26 (m 7H, aromatické H), 6,97 (d 1 H, J=8,2 Hz), 6,90 (so širokou základnou líniou, 4H, aromatické H), 5,1 (2H, PI1C-H2), 4,77 (m z d,lH, > 5,5 Hz, PhC-H), 4,14-4,07 (m,lH), 3,74 (d z t, 1H, Ja=3,9 Hz, Jb=9,4 Hz), 3,11 (t, 4H, > 4,9 Hz, štyri z pip-H), 2,95 (m, 1H), 2,7- 2,54 (niekoľko m, 7H), 2,11 (m,lH, pipCHH), 2,02 (m,lH, pipCH-H) δ; CMR (75 MHz, CDC1₃) 153,0, 145,1, 137,4, 137,1, 136,3,Following the procedure of Example 1, Step 4, with minor variations, 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) acetyl] piperazine (VI) 1- (4-phenylmethoxyphenyl) -4 was obtained. [2- (6-bromoisochroman-1-yl) acetyl) piperazine (VI), m.p. = 87-90 ° C; Rf = 0.43 (ethyl acetate); IR (neat) 1578, 1517, 1452, 1258, 1153, 1113, 1054, 1049, 818, and 737 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.43-7.26 (m 7H, aromatic H), 6.97 (d 1 H, J = 8.2 Hz), 6.90 (with broad baseline, 4H, aromatic) H), 5.1 (2H, PI 1 C-H 2), 4.77 (mt, 1H,> 5.5 Hz, PhC-H), 4.14-4.07 (m, 1H), 3.74 ( dzt, 1H, J a = 3.9 Hz, J b = 9.4 Hz), 3.11 (t, 4H,> 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2 7-7.54 (several m, 7H), 2.11 (m, 1H, pipCH-H), 2.02 (m, 1H, pipCH-H) δ; CMR (75 MHz, CDC1 ₃₎ 153.0, 145.1, 137.4, 137.1, 136.3,

131,6, 128,5, 127,8, 126,5, 120,0, 118,0, 115,6, 74,3, 70,5, 62,8, 54,6, 53,5, 50,5, 33,1 a 28,9131.6, 128.5, 127.8, 126.5, 120.0, 118.0, 115.6, 74.3, 70.5, 62.8, 54.6, 53.5, 50, 5, 33.1 and 28.9

Ô.ABOUT.

3. krok: l-[2-[4-4-fenylmetyloxyfenyl)-l-piperazinyl]etyl]-6izochróman-karboxamid (VII)Step 3: 1- [2- [4-4-phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -6-isochromanecarboxamide (VII)

Postupom podľa príkladu 1,5. kroku s drobnými obmenami vzniká za použitia l-(4fenylmetoxyfenyl)-4-[2-(6-brómizochróman-1 -yl)-etyl]piperazínu (VI) 1 -[2-[4-4fenylmetyloxyfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamid (VII), IR (suspenzia) 33,68, 31,78, 1647, 1623, 1611, 1570, 1515, 1334, 124,6 a 1111 cm'¹, NMR (300 MHz,Following the procedure of Example 1.5. a small variation step produces 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) ethyl] piperazine (VI) 1- [2- [4-4phenylmethyloxyphenyl) -1-piperazinyl] ethyl ] -isochroman-6-carboxamide (VII), IR (suspension) 33.68, 31.78, 1647, 1623, 1611, 1570, 1515, 1334, 124.6 and 1111 cm ^-1 , NMR (300 MHz,

CDCI3) 7,58 (m, 2H, aromatické H), 7,43,7,30 (m, 5H, aromatické H), 7,15 (d,lH, >8,4 Hz, aromatické H), 6,90 (s, 4H, aromatické H), 6,20-5,80 (dva široké singlety, C(0)N-H2), 5,0 (s, 2H, PhC-Hj-O), 4,87 (m z d,lH, >5,8 Hz), 4,18- 4,10 (m, 1H), 3,81-3,73 (m, 1H), 3,10 (t, 4H, >4,8 Hz, štyri z pip-H), 3,0 (m, 1H), 2,75 (m,lH), 2,650-2,54 (m, 6H), 2,15 (m,lH), 2,05 (m,lH) ; CMR (75 MHz, CDClj) 169,0, 152,9, 145,8, 142,3, 137,3, 137,3, 134,5, 131,3,CDCl 3) 7.58 (m, 2H, aromatic H), 7.43.7.30 (m, 5H, aromatic H), 7.15 (d, 1H,> 8.4 Hz, aromatic H), 6, 90 (s, 4H, aromatic H), 6.20-5.80 (two broad singlets, C (O) N-H 2), 5.0 (s, 2H, PhC-H 3 -O), 4.87 ( m / z, 1H,> 5.8 Hz), 4.18-4.10 (m, 1H), 3.81-3.73 (m, 1H), 3.10 (t, 4H,> 4.8 Hz) , four of pip-H), 3.0 (m, 1H), 2.75 (m, 1H), 2.650-2.54 (m, 6H), 2.15 (m, 1H), 2.05 (m, 1H); m, 1H); CMR (75 MHz, CDCl 3) 169.0, 152.9, 145.8, 142.3, 137.3, 137.3, 134.5, 131.3,

128,5, 128,1, 127,8, 127,4, 125,0, 124,9, 118,0, 115,5, 74,5, 70,4, 62,8, 54,6, 53,4, 50,4, 33,1 a 29,0 δ.128.5, 128.1, 127.8, 127.4, 125.0, 124.9, 118.0, 115.5, 74.5, 70.4, 62.8, 54.6, 53, 4, 50.4, 33.1 and 29.0 δ.

-46Príklad 10 l-[2-[4-4-butoxyfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamid (VII)Example 46 1- [2- [4-4-butoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

l.krok: l-[2-(6-brómizochróman-I.yl)acetyl]-4-(4butoxyfenyl)- piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-butoxyphenyl) piperazine (V)

Postupom podľa príkladu 1,3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl-octovej kyseliny (IV) a 4-butoxyfenylpiperazínu l-[2- (6brómizochróman-l-yl)acetyl]-4-(4-butoxyfenyl)-piperazín (V), Rf = 0,24 (octan etylnatý/hexán, 50/50); IR (suspenzia) 1640, 1513, 1482, 1441, 1422, 1245, 1232, 1103, 1031, 829 cm'¹; NMR (300 MHz, CDC1₃) 7,29, 7,00, 6,90, 5,26, 4,13-4,07, 3,92, 3,93-3,87,Following the procedure of Example 1.3. a small variation step results from racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-butoxyphenylpiperazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-butoxyphenyl) -piperazine (V), Rf = 0.24 (ethyl acetate / hexane, 50/50); IR (suspension) 1640, 1513, 1482, 1441, 1422, 1245, 1232, 1103, 1031, 829 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29, 7.00, 6.90, 5.26, 4.13-4.07, 3.92, 3.93-3.87,

3,80-3,60, 3,06, 2,98-2,89, 2,76, 2,65, 1,74, 1,48, 0,96 δ. (CMR 75 MHz, CDC1₃) 168,8,3.80-3.60, 3.06, 2.98-2.89, 2.76, 2.65, 1.74, 1.48, 0.96 δ. (CMR 75 MHz, CDC1 ₃₎ 168.8,

153,8, 145,0, 136,4, 136,2, 131,6, 129,3, 126,3, 120,2, 118,7, 115,1, 73,3, 67,9, 63,3, 51,2, 50,7, 46,1, 41,8, 39,8, 31,3,28,7, 19,1, 17,3 a 13,7 δ.153.8, 145.0, 136.4, 136.2, 131.6, 129.3, 126.3, 120.2, 118.7, 115.1, 73.3, 67.9, 63, 3, 51.2, 50.7, 46.1, 41.8, 39.8, 31.3.28.7, 19.1, 17.3 and 13.7 δ.

2.krok: l-[2-(6-brómizochróman-l.yl)-etyl]-4-(4-butoxyfenyl)- piperazín (VI)Step 2: 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-butoxy-phenyl) -piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-[2-(6-brómizochróman-l ,yl)acetyl]-4-)4-butoxyfenyl)-piperazínu (V) -l-[2-(6brómizochróman-l.yl)-etyl]-4-(4-butoxyfenyl)-piperazín (VI), Rf = 0,43 (octan etylnatý); IR (čisté látky) 2957, 2931, 28872, 1511, 1481, 1261, 1243, 1233, 1112, 1057 cm'¹; NMR (300 MHz, CDC1₃) 7,32 (d, 2H, J=8,3 Hz, aromatické H), 7,06 (d, 1 H, J=8,3 Hz, aromatické H),Following the procedure of Example 1, Step 4, with minor variations, using 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-butoxyphenyl) -piperazine (V) -1- [2- ( 6-bromoisochroman-1-yl) -ethyl] -4- (4-butoxyphenyl) -piperazine (VI), R f = 0.43 (ethyl acetate); IR (neat) 2957, 2931, 28872, 1511, 1481, 1261, 1243, 1233, 1112, 1057 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32 (d, 2H, J = 8.3 Hz, aromatic H), 7.06 (d, 1H, J = 8.3 Hz, aromatic H),

6,85 (q, 4H, J=9,7 Hz, aromatické H), 4,80 (m z d,l H, J=6,l Hz), 4,13-4,08 (m,lH), 3,983,89 (m, 3H), 3,71 (d z t,l H, J_a=3,7 Hz, J_b=l3,7 Hz), 3,28 (široké s, 4H), 3,10-2,72 (široké m, 7H), 2,65 (m z d, 1H), J=16,5 Hz), 2,40 (m,lH), 2,22 (m,lH),l,74 (kvintet, 2H, J= 6,6 Hz),1,46 (sextet, 2H, J= 7,3 Hz), 1,25 (t, 2H, J= 7,0 Hz), 0,96 )t, 3H, J= 7,3 Hz) δ; HRMS vypočítaná pre C25H₃₃N2C>2Bri = 473,1804, nájdená = 473,1796.6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.80 (wd, 1H, J = 6.1 Hz), 4.13-4.08 (m, 1H), 3.983 .89 (m, 3H), 3.71 (dzt, 1H, J _a = 3.7 Hz, J _b = 13.7 Hz), 3.28 (broad s, 4H), 3.10-2, 72 (broad m, 7H), 2.65 (broad m, 1H), J = 16.5 Hz), 2.40 (m, 1H), 2.22 (m, 1H), 1.74 (quintet, 2H J = 6.6 Hz), 1.46 (sextet, 2H, J = 7.3 Hz), 1.25 (t, 2H, J = 7.0 Hz), 0.96) t, 3H, J = 7.3 Hz) δ; HRMS calcd for C ₂₅ H ₃₃ N ₂ Cl 2 Br = 473.1804, found = 473.1796.

3. krok: l-[2-[4-4-butoxyfenyl)-l-piperazinyl]etyl]izochróman-6- karboxamid (VII)Step 3: 1- [2- [4-4-butoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Postupom podľa príkladu 1, 5. kroku s drobnými obmenami vzniká za použitia l-[2-(6-brómizochróman-l.yl)-etyl]-4-(4-butoxyfenyl)-piperazínu (VI) l-[2-[4-4butoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (VII), Rf - 0,18 (metanol/octan etylnatý), 10/90); IR (suspenzia) 3364, 2820, 1647, 1624, 1570, 1413, 1260, 1245, 1111 cm'¹; NMR (300 MHz, CDC1₃) 7,60, (m, 2H, aromatické H), 7,18 (d,lH, J= 8,5 Hz, aromatické H),Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-butoxyphenyl) -piperazine (VI) 1- [2- [ 4-4 (butoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), Rf = 0.18 (methanol / ethyl acetate), 10/90); IR (suspension) 3364, 2820, 1647, 1624, 1570, 1413, 1260, 1245, 1111 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.60, (m, 2H, aromatic H), 7.18 (d, 1H, J = 8.5 Hz, aromatic H),

-476,86 (q, 4H, J= 9,2 Hz, aromatické H), 6,20- 5,80 (dva široké singlety, C(0)N-H₂), 4,85 (m z d,l H, J=18 Hz), 4,15 (m, 1 H), 3,90 (t, 2H, J= 6,5 Hz, -0- C- H₂ -CH₂CH₂Me), 3,77 (m,lH),-476.86 (q, 4H, J = 9.2 Hz, aromatic H), 6,20- 5.80 (two broad singlets, C (0) _NH2), 4.85 (MH, lH, J = 18 Hz), 4.15 (m, 1H), 3.90 (t, 2H, J = 6.5 Hz, -O-C ₂ H ₂ -CH ₂ CH ₂ Me), 3.77 (m , H),

3,10 (t, 4H, J= 4,8 Hz, štyri z pip-H), 2,96 (m, 1H), 2,80-2,50 (m, 6H), 2,15 (m,lH), 2,05 (m,lH), 1,74 (kvintet, 2H, J= 6,8 Hz, -OCH₂C-H₂-CH₂Me), 1,48 (kvintet, 2H, J= 7,5 Hz, OCH₂C-H₂C-H₂- Me), 0,96 (ζ 3H, J= 7,3 Hz, -0CH₂ CH₂ CH₂ C-H₃) δ; CMR (75 MHz,3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.96 (m, 1H), 2.80-2.50 (m, 6H), 2.15 (m, 1 H), 2.05 (m, 1 H), 1.74 (quintet, 2H, J = 6.8 Hz, -OCH ₂ CH ₂ -CH ₂ Me), 1.48 (quintet, 2H, J = 7, 5 Hz, OCH ₂ CH ₂ CH ₂ -Me), 0.96 (ζ 3H, J = 7.3 Hz, -0CH ₂ CH ₂ CH ₂ CH ₃ ) δ; CMR (75MHz,

CDCb) 169,1, 160,8, 153,4, 145,6, 142,4, 134,6, 131,3, 130,3, 128,2, 127,6, 125,1, 125,0,(CDCl 3) 169.1, 160.8, 153.4, 145.6, 142.4, 134.6, 131.3, 130.3, 128.2, 127.6, 125.1, 125.0,

118,1, 115,1, 74,5, 68,1, 62,9, 54,7, 53,5, 50,6, 41,4, 33,2, 31,5, 29,0, 19,3 a 13,9 δ; HRMS vypočítaná pre CMH35N3O3 = 437,2673, nájdená = 437,2678.118.1, 115.1, 74.5, 68.1, 62.9, 54.7, 53.5, 50.6, 41.4, 33.2, 31.5, 29.0, 19, 3 and 13.9 δ; HRMS calcd for CMH35N3O3 = 437.2673, found = 437.2678.

Príklad 11 l-[2-[4-4-dietylaminofenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamid (VII)Example 11 1- [2- [4-4-Diethylaminophenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

1. krok; 1 -[2-(6-brómizochróman-1. yl)acetyl]-4-(4-dietyIaminofenyl)-piperazín (V)Step 1; 1- [2- (6-Bromo-iso-chroman-1-yl) -acetyl] -4- (4-diethylaminophenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká pri racemickej 6brómizochróman-l-yl-octovej kyseline (IV) a 4-dietylaminofenylpiperazíne l-[2-(6brómizochróman-l.yl)acetyl]-4-(4-dietylaminofenyl)-piperazín (V), Rf = 0,21 (acetón/hexán, 30/70); IR (suspenzia) 1633, 1518, 1482, 1446, 1423, 1261, 1232, 1196, 1109, 809 cm'¹; ’H NMR (300 MHz, CDC1₃) 7,32-7,26 (m, 2H, aromatické H), 7,0 (d,l H, J= 8,2 Hz, aromatické H), 6,88 (d, 2H, J= 9,0 Hz, aromatické H), 6,68 (d, 2H, J= 9,0 Hz, aromatické H), 5,27 (m z dm,l H, J= 5,9 Hz, ArC-H), 4,16-4,07 (m, 1H), 3,89 (m, 1H), 3,89 (m, 1H), 3,76 (m, 2H),Following the procedure of Example 1, Step 3 with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-diethylaminophenylpiperazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (V), Rf = 0.21 (acetone / hexane, 30/70); IR (suspension) 1633, 1518, 1482, 1446, 1423, 1261, 1232, 1196, 1109, 809 cm ^-1 ; 1 H NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.88 ( d, 2H, J = 9.0 Hz, aromatic H), 6.68 (d, 2H, J = 9.0 Hz, aromatic H), 5.27 (mz dm, 1H, J = 5.9 Hz) ArC-H), 4.16-4.07 (m, 1H), 3.89 (m, 1H), 3.89 (m, 1H), 3.76 (m, 2H),

3,64 (m, 2H), 3,28 (q, 4H, J= 7,1 Hz, dva z PhNC-H2), 2,98 (m, 5H), 2,76 (d z d, 1H, Ja= 3,7 HZ), Jb=14,9 HZ), 2,65 (m Z d, 1H, J=16,4 HZ) 1,12 (t, 6H, J= 7,0 HZ, dva zNCH₂C-H₃ δ; CMR (75 MHz, CDC1₃) 168,8, 143,2, 141,6, 136,4, 136,2, 131,6, 129,2, 126,3, 120,2, 119,2,3.64 (m, 2H), 3.28 (q, 4H, J = 7.1 Hz, two of PhNC-H2), 2.98 (m, 5H), 2.76 (dzd, 1H, Ja = 3.7 Hz, Jb = 14.9 Hz), 2.65 (m Z d, 1H, J = 16.4 Hz) 1.12 (t, 6H, J = 7.0 Hz, two of NCH ₂ CH) ₃ δ; CMR (75 MHz, CDCl ₃ ) 168.8, 143.2, 141.6, 136.4, 136.2, 131.6, 129.2, 126.3, 120.2, 119.2 .

113,7, 73,3, 63,3, 51,6,46,1,44,6, 41,9, 39,8, 33,1, 28,6 a 12,4 δ.113.7, 73.3, 63.3, 51.6, 46.1, 44.6, 41.9, 39.8, 33.1, 28.6 and 12.4 δ.

2. krok; l-[2-(6-brómizochróman-l.yl)acetyl]-4-(4-dietylaminofenyl)-piperazín (VI)Step 2; 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-[2(6-brómizochróman-l .yl)acetyl]-4-(4-dietylaminofenyl)-piperazínu (V) l-[2-(6brómizochróman-l.yl)acetyl]-4-(4-dietylaminofenyl)-piperazín (VI), Rf = 0,26 (octan etylnatý); IR (čisté látky) 2931, 2965, 2814, 1516, 1374, 1262, 1232, 1144, 1109, 813 cm’¹; NMR (300 MHz, CDCb) 7,3-7,26 (m, 2H, aromatické H), 6,68 (d, 2H, J= 9,0 Hz, aromatické H), 4,77 (m z d, 1H, J= 5,9 Hz, ArC-H), 4,14-4,07 (m, 1H), 3,74 (d Z f,lH, J_a= 3,9 HZ, J_b=Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (V) 1- [2- (6-bromoisochroman- 1.yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (VI), Rf = 0.26 (ethyl acetate); IR (neat) 2931, 2965, 2814, 1516, 1374, 1262, 1232, 1144, 1109, 813 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.3-7.26 (m, 2H, aromatic H), 6.68 (d, 2H, J = 9.0 Hz, aromatic H), 4.77 (mzd, 1H, J = 5.9 Hz, ArC-H), 4.14-4.07 (m, 1H), 3.74 (d Z f, 1H, J _a = 3.9 Hz, J _b =

9,3 HZ), 3,26 (q, 4H, J= 7,1 HZ, dva Z PhNC-H₂), 3,08 (t, 4H, J= 4,8 Hz, štyri z pip-H), 2,95 (m,lH), 2,70-2,53 (m, 7H), 2,11 (m,lH, pipCH-H), 2,00 (m, 1H, pipCH-H), 1,11 (t, 6H, J=9.3 HZ), 3.26 (q, 4H, J = 7.1 HZ, two Z PhNC-H ₂ ), 3.08 (t, 4H, J = 4.8 Hz, four of pip-H) 2.95 (m, 1H), 2.70-2.53 (m, 7H), 2.11 (m, 1H, pipCH-H), 2.00 (m, 1H, pipCH-H), 1 11 (t, 6H, J =

-487,0 Hz, dva zNCH₂C-H₃) δ; HRMS vypočítaná pre C^Hj^OiBn s 0,152, C+H^O: = 472,1964, nájdená - 472,1956.-487.0 Hz, two of NCH ₂ CH ₃ ) δ; HRMS calcd for C 14 H 14 N 3 O 2 Bn 0.152, C + H 2 O 3 = 472.1964, found - 472.1956.

3.krok: l-[2-[4-4-dietylaminofenyl)-l-piperazinyl]etyl]-izochróman-6- karboxamid (VII)Step 3: 1- [2- [4-4-diethylaminophenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

Postupom podľa príkladu 1, 5. kroku s drobnými obmenami vzniká za použitia l-[2-(6brómizochróman-1 -yl)-etyl]-4-(4-dietylaminofenyl)piperazínu (VI) l-[2-[4-4dietylaminofenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (VII), Rf = 0,25 (metanol/octan etylnatý, 10/90); NMR (300 MHz, CDCb) 7,59, 7,18, 6,87, 6,68, 6,1, 5,7, 4,87,4,13, 3,78, 3,26, 3,06, 2,78-2,57, 2,17,2,5 a 1,11 δ.Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-diethylaminophenyl) piperazine (VI) 1- [2- [4-4-diethylaminophenyl] was formed. -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), Rf = 0.25 (methanol / ethyl acetate, 10/90); NMR (300 MHz, CDCl 3) 7.59, 7.18, 6.87, 6.68, 6.1, 5.7, 4.87, 13.13, 3.78, 3.26, 3.06 , 2.78-2.57, 2.17.2.5 and 1.11 δ.

Príklad 12 l-[2-[4-(3-trifluórmetylfenyl)-l-piperazinyl]etyl]izochróman-6- karboxamid (VU)Example 12 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VU)

1. krok: 1 - [2-(6-brómizochróman-1 -yl)acetyl]-4-(3 -trifluórmetylfenyl)-piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká za použitia racemickej 6-brómizochróman-l-yl-octovej kyseliny (IV) a 3- trifluórmetylfenylpiperazínu 1[2-(6-brómizochróman-l-yl)acetyl]-4-(3-trifluórmetylfenyl)-piperazín (V), Rr= 0,30 (octan etylnatý/hexán, 40/60); IR (kvapaliny) 1643, 1610, 1592, 1496, 1482, 1448, 1374, 1351, 1320, 1309, 1282, 1233, 1164, 1121, 1076 cm‘^l; NMR (300 MHz, CDCI3) 7,34 (m, 3H, aromatické), 7,08 (m, 4H, aromatické), 5,25 (široké d, 1H, J= 5,6 Hz, metín), 4,11 (m, 1H, OCH_2a), 3,94 (m, 1H, O=C-N-CH_2a), 3,80-3,65 (m, 4H; 0=C-N-CH_2bcd, OCH_2b), 3,23 (m, 4H, Ph-NCH_2s), 2,95(m, 2H, Ph-CH_2a & N-COCH_2a), 2,78 (dd, 1H, J=14,8 HZ & J= 3,7 HZ, NCO-CH_2b), 2,66 (bd, 1H, J=16,4 HZ, Ph-CH_2b) δ; CMR (75 MHz, CDCb) 169,2, 151,1,Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 3-trifluoromethylphenylpiperazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (V), R f = 0.30 (ethyl acetate / hexane, 40/60); IR (liquids) 1643, 1610, 1592, 1496, 1482, 1448, 1374, 1351, 1320, 1309, 1282, 1233, 1164, 1121, 1076 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.34 (m, 3H, aromatic), 7.08 (m, 4H, aromatic), 5.25 (broad d, 1H, J = 5.6 Hz, meth), 4, 11 (m, 1H, OCH _{2 a} ), 3.94 (m, 1H, O = CN-CH _{2 a} ), 3.80-3.65 (m, 4H; O = CN-CH 2 _bcd , OCH _{2 b} ), 3 23 (m, 4H, Ph-NCH _{2 s} ), 2.95 (m, 2H, Ph-CH _2a & N-COCH _2a ), 2.78 (dd, 1H, J = 14.8 Hz & J = 3) 7 HZ, NCO-CH _2b ), 2.66 (bd, 1H, J = 16.4 Hz, Ph-CH _2b ) δ; CMR (75 MHz, CDCl 3) 169.2, 151.1,

136,4, 136,3, 131,8, 131,4, 129,7, 1129,5, 126,5, 126,0, 122,4, 120,5, 119,2, 116,6, 112,7,136.4, 136.3, 131.8, 131.4, 129.7, 1129.5, 126.5, 126.0, 122.4, 120.5, 119.2, 116.6, 112, 7

73,6, 63,6, 49,2,48,8,41,6,45,8, 41,6,40,0 a 28,8 δ; MS (EI, m/z) = 482.73.6, 63.6, 49.2, 48.8, 41.6, 45.8, 41.6, 40.0 and 28.8 δ; MS (EI, m / z) = 482;

2. krok: l-[2-(6-brómizochróman-l-yl)-etyl]-4-(3-trifluórmetylfenyl)-piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (3-trifluoromethylphenyl) -piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)acetyl]-4-(3-trifluórmetylfenyl)-piperazínu (V) produkt. Látka sa prečistí pomocou LC (silikagél, 230-400, 142 g; octan etylnatý/hexán, 30/70) za vzniku l-[2(6-brómizochróman-l-yl)acetyl]-4-(3-trifluórmetylfenyl)-piperazínu (VI), Rf = 0,40 (octan etylnatý/hexán, 40/60); IR (kvapaliny) 2824, 1610, 1496, 1481, 1449, 1357, 1319, 1293,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (V) was formed. Purify by LC (silica gel, 230-400, 142 g; ethyl acetate / hexane, 30/70) to give 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) - piperazine (VI), Rf = 0.40 (ethyl acetate / hexane, 40/60); IR (liquids) 2824, 1610, 1496, 1481, 1449, 1357, 1319, 1293,

-491239, 1164, 1123, 1076, 993, 949 a 695 cm’¹, NMR (300 MHz, CDC1₃) 7,32 (m, 3H, aromatické), 7,07 (m, 3H, aromatické), 6,97 (d, 1H, J= 8,2 Hz, aromatické), 4,79 (široké d, 1H, J= 5,7 Hz, metín), 4,11 (m, 1H, OCH_2a), 3,73 (m, 7H, Ph-NC(H₂)-CH_2s-NCH₂ & PhCH_2b), 2,10 (m, 1H, C(H)-CH_2a), 2,00 (m, 1H, C(H)CH_2b) δ; CMR (75 MHz, CDC1₃) 151,4, 137,0, 136,3, 131,7, 131,4 (qrt, J_CF= 36 Hz), 129,5, 129,3, 126,5, 126,2, 120,0, 118,6, 115,7 (d, J_CF= 4 Hz),112,1 (d, J_CF= 4 Hz), 74,2, 62,9, 54,5, 53,2, 48,7, 33,2, 28,9 δ; MS (El, m/z) = 468.-491239, 1164, 1123, 1076, 993, 949 and 695 cm ^-1 , NMR (300 MHz, CDCl ₃ ) 7.32 (m, 3H, aromatic), 7.07 (m, 3H, aromatic), 6, 97 (d, 1H, J = 8.2 Hz, aromatic), 4.79 (broad d, 1H, J = 5.7 Hz, meth), 4.11 (m, 1H, OCH _2a ), 3.73 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ & PhCH _{2 b} ), 2.10 (m, 1H, C (H) -CH _2a ), 2.00 (m, 1H, C ( H) CH2 ( _b ) δ; CMR (75 MHz, CDC1 ₃₎ 151.4, 137.0, 136.3, 131.7, 131.4 (qrt, _JCF = 36 Hz), 129.5, 129.3, 126.5, 126 , 2, 120.0, 118.6, 115.7 (d, J _CF = 4 Hz), 112.1 (d, J _CF = 4 Hz), 74.2, 62.9, 54.5, 53 , 2, 48.7, 33.2, 28.9 δ; MS (EI, m / z) = 468.

3.krok: 1 -[2-[4-(3-trifluórmetylfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamid (VII)Step 3: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)acetyl]-4-(3-trifluórmetylfenyl)-piperazínu (VI) produkt. Látka sa prečistí pomocou LC (silikagél, 230-400,120 g; acetón/hexán, 50/50) za vzniku 1- [2-[-4-(3trifluórmetylfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu (VII). Táto látka rekryštalizuje zo zmesi octan etylnatý/hexán za vzniku l-[2-[4-(3- trifluórmetylfenyl)-!piperazinyl]etyl]izochróman-6-karboxamidu (VII), teplota topenia = 129-131 °C, Rf = 0,22 (acetón/hexán, 50/50); IR (suspenzia) 3383, 1647, 1618, 1606, 1567, 1407, 1359, 1322, 1312, 1287, 1161, 1139, 1115, 1098, 952 cm'¹; NMR (300 MHz, CDC1₃ ) 7,60, 7,33, 7,18, 7,07, 6,00, 4,88, 4,14, 3,77, 3,24, 3,01, 2,78-2,48, 2,01 δ; CMR (75 MHz, CDCb) 169,1, 151,4,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (VI) was formed. Purify by LC (silica gel, 230-400.120 g; acetone / hexane, 50/50) to give 1- [2 - [- 4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) . This material was recrystallized from ethyl acetate / hexane to give 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), mp = 129-131 ° C, Rf = 0.22 (acetone / hexane, 50/50); IR (suspension) 3383, 1647, 1618, 1606, 1567, 1407, 1359, 1322, 1312, 1287, 1161, 1139, 1115, 1098, 952 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.60, 7.33, 7.18, 7.07, 6.00, 4.88, 4.14, 3.77, 3.24, 3.01, 2, 78-2.48, 2.01 δ; CMR (75 MHz, CDCl 3) 169.1, 151.4,

142,4, 134,6, 131,5, (qrt, J_CF = 32 Hz), 131,4, 139,5, 128,2, 125,1, 122,5, 118,6, 115,8 (d, J_CF = 4Hz), 112,1 (d, J_CF= 4Hz), 74,4, 63,0, 54,5, 53,2, 48,7, 33,2, 29,18; HRMS (El) vypočítaná pre C₂₃H₂eF₃N₃O₂ = 433,1977, nájdená = 433,1979.142.4, 134.6, 131.5, (qrt, J _CF = 32 Hz), 131.4, 139.5, 128.2, 125.1, 122.5, 118.6, 115.8 ( d, J _CF = 4Hz), 112.1 (d, J _CF = 4Hz), 74.4, 63.0, 54.5, 53.2, 48.7, 33.2, 29.18; HRMS (El) calculated for C ₂₃ H ₂ eF ₃ N ₃ O ₂ = 433.1977, found = 433.1979.

Príklad 13 1 -[2-[4-(4-metylsulfonylfeny 1)-1 -piperazinyl)etyl]-izochróman-6-karboxamid(VII)Example 13 1- [2- [4- (4-Methylsulfonylphenyl) -1-piperazinyl) ethyl] -isochroman-6-carboxamide (VII)

1. krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-metylsulfonylfenyl)-piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl-octovej kyseliny (IV) a 4-metylsulfonylfenylpiprazínu produkt. Táto látka sa prečistí pomocou LC (silikagél, 230-400,150 g; octan etylnatý) za vzniku l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metylsulfonylfenyl)-piperazínu (V), Rf = 0,30 (octan etylnatý); IR.(suspenzia) 1639, 1593, 1508, 1481, 1405, 1295, 1239, 1145, 1105, 1096, 1027, 1000, 958, 825, 779 cm'¹; NMR (300 MHz, CDCb) 7,77 (d, 2H, J = 8,9 Hz, aromatické), 7,28 (m, 2H, aromatické), 7,00 (d, 1H, J = 8,2 Hz, aromatické), 6,91 (d, 2H, J = 9,0 Hz,Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-methylsulfonylphenylpiprazine are formed. This material is purified by LC (silica gel, 230-400.150 g; ethyl acetate) to give 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) -piperazine (V), Rf = 0 30 (ethyl acetate); IR (suspension) 1639, 1593, 1508, 1481, 1405, 1295, 1239, 1145, 1105, 1096, 1027, 1000, 958, 825, 779 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.77 (d, 2H, J = 8.9 Hz, aromatic), 7.28 (m, 2H, aromatic), 7.00 (d, 1H, J = 8.2 Hz) aromatic) 6.91 (d, 2H, J = 9.0 Hz)

-50aromatické), 5,24 (široké d, 1H, J = 5,7 Hz, metín), 4,10 (m, 1H, 0CH_2a), 3,94 (m, 1H, O=CN-CH_2a), 3,78-3,60 (m, 4H, OCH_2b, 0=C-N-CH_2bcd), 3,38 (m, 4H, Ph-N-CH_2s), 3,00-2,88 (m, 5H, Ph-CH_2a, CH₃, N-C=O-CH_2a), 2,78 (dd, 1H, J= =14,7 Hz & 3,6 Hz, N-C=0-CH_2b), 2,65 (široké d, 1H, J =16,4 Hz, Ph-CH_2b) δ; CMR (75 MHz, CDCb) 169,3, 153,9, 136,3, 131,8,-50aromatic), 5.24 (broad d, 1H, J = 5.7 Hz, meth), 4.10 (m, 1H, OCH _2a ), 3.94 (m, 1H, O = CN-CH _{2 a} ) , 3.78-3.60 (m, 4 H, OCH _{2 b,} 0 = CN-CH _2bcd), 3.38 (m, 4H, Ph-N-CH _{2 S),} 3.00-2.88 (m, 5H, Ph-CH _{2 a} , CH ₃ , NC = O-CH _{2 a} ), 2.78 (dd, 1H, J = 14.7 Hz & 3.6 Hz, NC = O-CH _2b ), 2.65 (broad d, 1H, J = 16.4 Hz, Ph- _CH2b ) δ; CMR (75 MHz, CDCl 3) 169.3, 153.9, 136.3, 131.8,

129,5, 129,2, 126,4, 120,5, 114,1, 73,7, 63,6, 47,5, 47,2, 45,5, 44,9, 41,3, 40,0 a 28,8 δ;129.5, 129.2, 126.4, 120.5, 114.1, 73.7, 63.6, 47.5, 47.2, 45.5, 44.9, 41.3, 40, 0 and 28.8 δ;

HRMS (EI) vypočítaná pre C₂₂H₂5BrN₂O₄S = 492.0719, nájdená =1492,0714.HRMS (EI) for C ₂₂ H ₂ 5BrN ₂ O ₄ S = 492.0719, found = 1492.0714.

2.krok 1 -[2-(6-brómizochróman-1 -yl)- l-etyl]-4-(4-metylsulfonylfenyl)piperazín (VI)Step 2 - 1- [2- (6-Bromoisochroman-1-yl) -1-ethyl] -4- (4-methylsulfonylphenyl) piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-[2(6-brómizochróman-1 -yl)acetyl)-4-(4-metylsulfony lfenyl)piperazínu (V) 1 -[2-(6brómizochróman-l-yl)-l-etyl]-4-(4-metylsulfonylfenyl)piperazín (VI), Rf - 0,26 (octan etylnatý); IR (suspenzia) 3586, 1592, 1507, 1481, 1424, 1405, 1296, 1249, 1145, 1109, 1095, 1004, 956, 822, 779 cm⁴, NMR (300 MHz, CDC1₃) 7,75 (d, 2H, J= 9,0 Hz, aromatické),Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) piperazine (V) 1- [2- (6-bromoisochroman- 1-yl) -1-ethyl] -4- (4-methylsulfonylphenyl) piperazine (VI), R f = 0.26 (ethyl acetate); IR (mull) 3586, 1592, 1507, 1481, 1424, 1405, 1296, 1249, 1145, 1109, 1095, 1004, 956, 822, 779 cm ^4, NMR (300 MHz, CDC1 ₃₎ 7.75 (d, 2H, J = 9.0 Hz, aromatic),

7,27 (m, 2H, aromatické), 6,95 (d, 1H, J = 8,3 Hz, aromatické), 6,90 (d, 2H, J = 9,0 Hz, aromatické), 4,78 (široké d, 1H, J = 5,7 Hz, metín), 4,10 (m, 1H, OCH_2a), 3,74 (m, 1H, OCH_2b), 3,35 (t, 4H, J = 5,0 Hz, Ph-NCH_2s), 3,00 (s, 3H, CH₃), 2,94 (m, 1H, Ph-CH_2a), 2,54 (m, 7H, Ph-NC(H₂)-CH_2s-NCH₂ a dva z Ph-CH_2b), 2,09 (m, 1H, C(H)-CH2a) δ; CMR (757.27 (m, 2H, aromatic), 6.95 (d, 1H, J = 8.3 Hz, aromatic), 6.90 (d, 2H, J = 9.0 Hz, aromatic), 4.78 (broad d, 1H, J = 5.7 Hz, methine), 4.10 (m, 1H, OCH _{2 a} ), 3.74 (m, 1H, OCH _2b ), 3.35 (t, 4H, J = 5.0 Hz, Ph-NCH _{2 s} ), 3.00 (s, 3H, CH ₃ ), 2.94 (m, 1H, Ph-CH _{2 a} ), 2.54 (m, 7H, Ph-NC (H) ₂ ) -CH ₂ -NCH ₂ and two of Ph-CH _2b ), 2.09 (m, 1H, C (H) -CH _2a ) δ; CMR (75

MHZ, CDCb) 154,3, 136,9, 136,4,131,7, 129,3, 129,1, 128,6, 126,4, 120,1, 113,8, 74,1, 62,9,MHZ, CDCl 3) 154.3, 136.9, 136.4, 131.7, 129.3, 129.1, 128.6, 126.4, 120.1, 113.8, 74.1, 62.9,

54,4, 52,9, 47,3, 45,0, 33,1 a 28,9 Ô; HRMS (EI) vypočítaná pre C₂₂H₂₇BrN₂O₃S = 480,0906, nájdená = 480,0903.54.4, 52.9, 47.3, 45.0, 33.1 and 28.9 Ô; HRMS (EI) calcd for C ₂₂ H ₂₇ BrN ₂ O ₃ S = 480.0906, found = 480.0903.

3. krok: l-[2-[4-(4-metylsulfonylfenyl)-l-piperazinyl]etyl]izochróman-6- karboxamid (VII)Step 3: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Postupom podľa príkladu 1, 5. kroku s drobnými obmenami vzniká z l-[2-(6brómizocbróman-l-yl)-etyl]-4-(4-metylsulfonylfenyl)-piperazínu (VI) produkt. Táto látka sa prečistí pomocou LC (silikagél, 230-400 veľkosti sieťoviny, 75 g; metanol/dichlórmetán, 5/95) za vzniku l-[2-[4-(4-metylsulfbnylfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu (VH), teplota topenia = 217-219 °C, Rf = 0,17 (metanol/dichlórmetán, 5/95); IR (suspenzia) 3433, 1668, 1619, 1587, 1568, 1507, 1288, 1140, 1115, 1105, 1095, 1023, 998, 812, 780 cm⁴, NMR (300 MHz, DMSO-de) 790 (široké s, 1H, NH), 7,66 (m, 4H, aromatické), 4,79 (široké d, 1 H, J = 6,5 Hz, metín), 4,08 (m, 1H, OCH_2a), 3,67 (m, 1H, OCH_2b), 3,32 (t, 4H, J = 4,0 Hz, Ph-N-CH_2s), 3,08 (s, 3H, CH₃), 2,88 (m, 1H, OCH₂), 2,71 (dm, 1H, J =16,4 Hz, Ph-CH_2b),Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisocroman-1-yl) -ethyl] -4- (4-methylsulfonylphenyl) -piperazine (VI) was formed. This material was purified by LC (silica gel, 230-400 mesh size, 75 g; methanol / dichloromethane, 5/95) to give 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman- 6-carboxamide (VH), m.p. = 217-219 ° C, R f = 0.17 (methanol / dichloromethane, 5/95); IR (suspension) 3433, 1668, 1619, 1587, 1568, 1507, 1288, 1140, 1115, 1105, 1095, 1023, 998, 812, 780 cm &^lt; ⁴ &gt; H NMR (300 MHz, DMSO-d6) 790 (br s, 1H, NH), 7.66 (m, 4H, aromatic), 4.79 (broad d, 1H, J = 6.5 Hz, meth), 4.08 (m, 1H, OCH _{2 a} ), 3, 67 (m, 1H, OCH _2b ), 3.32 (t, 4H, J = 4.0 Hz, Ph-N-CH _{2 s} ), 3.08 (s, 3H, CH ₃ ), 2.88 (m 1 H, OCH ₂ ), 2.71 (dm, 1H, J = 16.4 Hz, Ph-CH _2b ),

2,53 (m, 5H, Ph-NC(H₂)-CH_2s-VNH_2a), 2,37 (m, 1H, NCH_2b), 2,13 (m, 1H, C(H)-CH_2a), 1,98 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHZ, DMSO-d₆) 168,2, 154,3, 141,8, 134,1, 132,6, 129,0,2.53 (m, 5H, Ph-NC _{(H2) -CH2S} -VNH _2), 2.37 (m, 1 H, NC H _{2 b),} 2.13 (m, 1 H, C (H) -CH ₂ ), 1.98 (m, 1 H, C (H) -CH _2b) δ; CMR (75 MHz, _DMSO-d6) 168.2, 154.3, 141.8, 134.1, 132.6, 129.0,

-51 128,9, 128,5, 125,6, 125,2, 114,0, 74,1, 62,7, 54,6, 53,0, 47,2, 44,7, 32,9 a 29,0 δ; HRMS (FAB) vypočítaná pre C23H29N3O4S+H1 = 444,1957, nájdená = 444,1959.-51 128.9, 128.5, 125.6, 125.2, 114.0, 74.1, 62.7, 54.6, 53.0, 47.2, 44.7, 32.9 and 29.0 δ; HRMS (FAB) Calcd for C 23 H 29 N 3 O 4 S + H 1 = 444.1957, found = 444.1959.

Príklad 14 (S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-l-piperazinyl]etyl]izochróman-6karboxamid (S)-(VII)Example 14 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VII)

Postupom podľa príkladu 1,5. kroku s drobnými obmenami vzniká z (S)-(-)-l - [2-(6brómizochróman-l-yl)-l-etyl]-4-(4-trifluórmetylfenyl)-piperazínu (VI, príklad 5, 2. krok, 13,15 g, 28,0 mmol) produkt. Látka sa prečistí pomocou LC (silikagél, 230-400 ôk/25,4 mm, 780 g; metanol/dichlórmetán, 5/95) za vzniku surového produktu, ktorý rekryštalizuje zo zmesi metanol/octan etylnatý za vzniku (S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-lpiperazinyl]etyl]izochróman-6-karboxamidu (S)-(VH), teplota topenia =166-168 °C, Rf = 0,20 (metanol/dichlórmetán, 5/95); [a] = -50° (c = 0,8533, metanol); IR (suspenzia) 3365, 3203, 1654, 1619, 1337, 1317, 1243, 1164, 1149, 1138, 1122, 1114, 1107, 1074, 825 cm’¹; NMR (300 MHz, CDCI3) 7,57 (m, 2H, aromatické), 7,42 (d, 2H, J = 8,7 Hz, aromatické), 7,14 (d, 1H, J= 7,8 Hz, aromatické), 6,87 (d, 2H, J = 8,7 Hz), 4,83 (široké d,lH, J = 5,8 Hz, metín),Following the procedure of Example 1.5. The small variation step results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -1-ethyl] -4- (4-trifluoromethylphenyl) -piperazine (VI, Example 5, Step 2). , 13.15 g, 28.0 mmol) of product. Purify by LC (silica gel, 230-400 mesh / 25.4 mm, 780 g; methanol / dichloromethane, 5/95) to give a crude product which is recrystallized from methanol / ethyl acetate to give (S) - (-) ) -1- [2- [4- (4-trifluoromethylphenyl) -1piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VH), mp = 166-168 ° C, R f = 0.20 (methanol / dichloromethane, 5/95); [α] D = -50 ° (c = 0.8533, methanol); IR (slurry) 3365, 3203, 1654, 1619, 1337, 1317, 1243, 1164, 1149, 1138, 1122, 1114, 1107, 1074, 825 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.57 (m, 2H, aromatic), 7.42 (d, 2H, J = 8.7 Hz, aromatic), 7.14 (d, 1H, J = 7.8 Hz) aromatic), 6.87 (d, 2H, J = 8.7 Hz), 4.83 (broad d, 1H, J = 5.8 Hz, meth),

4.10 (m, 1H, OCH_2a), 3,73 (m, 1H, OCH_2b), 3,25 (t, 4H, J = 4,9 Hz, Ph-N-CH_2s), 2,97 (m,lH, Ph-CH_2a) 2,68-2,45 (m, 7H, Ph-NC(H₂)-CH_2s NCH_2s Ph-CH_2b), 2,13 (m, 1H, C(h)CH_2a) 2,02 (m,lH, C(H)-CH_2b) Ô; CMR (75 MHZ, CDC1₃) 169,6, 153,2, 142,1, 134,5, 131,3, 128,2,4.10 (m, 1H, OCH _{2 a} ), 3.73 (m, 1H, OCH _{2 b} ), 3.25 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 2.97 (m 1 H, Ph-CH _{2 a} ) 2.68-2.45 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH ₂ Ph-CH _{2 b} ), 2.13 (m, 1H, C (h) CH _2a ) 2.02 (m, 1H, C (H) -CH _2b ) Ô; CMR (75 MHz, CDCl ₃ ) 169.6, 153.2, 142.1, 134.5, 131.3, 128.2,

126,5, 126,3 (d, J_CF = 4Hz),125,0 (d, J_CF = 4Hz),122,9, 120,5 (qrt, J_CF= 33Hz), 114,5, 74,4, 63,0, 54,5, 53,0, 47,8, 32,8 a 29,0 δ; HRMS (EI) vypočítaná pre C₂₃H₂₆F₃N3O₂ = 433,1977, nájdená = 433,1978.126.5, 126.3 (d, J _CF = 4Hz), 125.0 (d, J _CF = 4Hz), 122.9, 120.5 (qrt, J _CF = 33Hz), 114.5, 74, 4, 63.0, 54.5, 53.0, 47.8, 32.8 and 29.0 δ; HRMS (EI) calcd for C ₂₃ H ₂₆ F ₃ N ₃ O ₂ = 433.1977, found = 433.1978.

Príklad 15 1 -[2-[4-(4-etoxyfenyl)-1 -piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (IX)Example 15 1- [2- [4- (4-Ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

1. krok: l-[-2-(6-brómizochróman-l-yl)acetyl]-4-(4-etoxyfenyl)-piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká za použitia racemické 6-brómizochróman-l-yl-octovej kyseliny (IV) a 4-etoxyfenylpiprazínu l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-etoxyfenyl)-piperazín (V), Rf = 0,46 (octan etylnatý/hexán, 70/30), IR (čisté látky) 1641, 1511, 1480, 1463, 1443, 1278, 1243, 1231, 1108, 1049 cm'¹; NMR (300 MHz, CDCb) 7,28 (m, 25, aromatické H), 7,0 (d, 1H, J = 8,2 Hz, aromatické H), 6,86 (d, 4H, J = 8,2 Hz, aromatické H), 5,25 (m z d, 1H, J = 6,5 Hz, PhC-H),Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-ethoxyphenylpiprazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- ( 4-ethoxyphenyl) -piperazine (V), Rf = 0.46 (ethyl acetate / hexane, 70/30), IR (pure) 1641, 1511, 1480, 1463, 1443, 1278, 1243, 1231, 1108, 1049 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.28 (m, 25, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 (d, 4H, J = 8, 2 Hz, aromatic H), 5.25 (wt, 1H, J = 6.5 Hz, PhC-H),

4.11 (m, 1H), 3,99 (q, 2H, J = 7,0 Hz, Proc-H₂), 3,89 (m, 1H), 3,80-3,59 (m, 4H), 3,05 (t, 4H.4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, _Proc-H2), 3.89 (m, 1H), 3.80-3.59 (m, 4H); 3.05 (t, 4 H).

-52J = 5,0 Hz), 3,03-2,89 (m's 2H), 2,77 (d z d, 1H, J_a = 3,6 Hz, J_b = 14,9 Hz), 2,66 (m z d, 1H, J = 16,4 Hz), 1,39 (t, 3H, J = 7,0 Hz, PhOCH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 168,9, 153,6,-52J = 5.0 Hz), 3.03-2.89 (m's 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 ( m / z, 1H, J = 16.4 Hz), 1.39 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 168.9, 153.6,

145,0, 136,4, 136,2, 131,6, 129,3, 126,4, 120,2, 118,7, 115,1, 73,3, 63,7, 63,55, 63,47, 63,4,51,2, 50,7, 46,0, 41,8, 39,8, 28,7 ,14,8 δ; HRMS vypočítaná pre C₂₃H₂7N₃O₃Br = 458,1205, nájdená = 458,1217.145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 120.2, 118.7, 115.1, 73.3, 63.7, 63.55, 63, 47, 63.4, 51.2, 50.7, 46.0, 41.8, 39.8, 28.7, 14.8 δ; HRMS calculated for C ₂₃ H 7 N ₃ O ₂ Br ₃ = 458.1205, found = 458.1217.

2. krok: l-[2-(6-brómizochróman-l-yl)-etyl]-4-(4-etoxyfenyl)-piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethoxyphenyl) -piperazine (VI)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-1 -yl)acetyl]-4-(4-etoxyfenyl)-piperazínu (V) 1 -[2-(6-brómizochróman-1 yl)etyl]-4-(4-etoxyfenyl)-piperazín (VI), Rf = 0,56 (octan etylnatý/hexán, 70/30); IR (čisté látky) 2850, 2810, 1512, 1482, 1251, 1231, 1153, 1108, 1048, 826 cm'¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatické H), 7,27 (s, 1H, aromatické H), 6,97 (d, 1H, J =Following the procedure of Example 1, Step 3, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (V) 1- [2- (6-bromoisochroman- 1 yl) ethyl] -4- (4-ethoxyphenyl) -piperazine (VI), Rf = 0.56 (ethyl acetate / hexane, 70/30); IR (neat) 2850, 2810, 1512, 1482, 1251, 1231, 1153, 1108, 1048, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J =

8,3 Hz, aromatické H), 6,85 (q, 4H, J = 9,7 Hz, aromatické H), 4,78 (m z d, 1H, J = 6,1 Hz), 4,14-4,07 (m, 1 H), 3,97 (q, 2H, J = 7,0 Hz, PhOC-H2), 3,76-3,69 (m, 1 H), 3,10 (t, 4H, J =8.3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4, 07 (m, 1H), 3.97 (q, 2H, J = 7.0 Hz, PhOC-H2), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J =

4,9 Hz, 4 z pip-H), 2,95 (m, 1H), 2,70-2,50 (m's, 7H, štyri z pip-H, dva PhCH-H a NCH-H),4.9 Hz, 4 of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four of pip-H, two PhCH-H and NCH-H),

2,13 (m, 1 H, PhCHCH-H), 2,02 (m, 1 H, PhCHCH-H), 1,38 (t, 3H, J = 6,9 Hz, PhOCH₂CH₃) δ; CMR (75 MHz, CDC1₃) 153,1, 145,6, 137,1, 136,3, 131,6, 129,3, 126,5, 1120,0, 118,1,2.13 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.38 (t, 3H, J = 6.9 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl ₃ ) 153.1, 145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0, 118.1,

115,2, 74,3, 62,8, 55,6, 53,5, 50,6, 33,2,28,9,15,0 δ.115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9, 15.0 δ.

3. krok: l-[2-[4-(4-etoxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6- karboxamid (IX)Step 3: 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 5, 3. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)etyl]-4-(4-etoxyfenyl)-piperazínu (VI) l-[2-[4-(4-etoxyfenyl)lpiperazinyl]etyl]-N-metyl-izochróman-6-karboxamid (IX), teplota topenia =148-149 °C, Rf = 0,22 (metanol/metylénchlorid, 5/95); IR (suspenzia) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108, 1050 cm'¹; NMR (300 MHz, CDC1₃) 7,54 (s, 2H, aromatické H), 7,15 (d,l H, J = 8,5 Hz, aromatické H), 6,85 (d z d, 4H, J_a = 9,2 Hz, J_b = 19,2 Hz, štyri aromatické H), 6,15 (široké s,l H, C(O)N-H), 4,85 (m z d, 1H, J= 6,0 Hz, PhC-H), 4,13 (m, 1H, PhCH₂CHH), 3,97 (q, 2H, J = 7 Hz, PhOC-H₂), 3,77 (m, 1H, PhCH₂CH-H), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (d, 3H, J = 4,9 Hz C(O)NHC-H₃), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko s, 7H, štyri pip-H, dva PhCHH a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,37 (t, 3H, J = 7,0 Hz, PhOCH₂C-H₃ δ; CMR (75 MHz, CDCb) 168,0, 153,1,Following the procedure of Example 5, Step 3, with minor variations, 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-ethoxyphenyl) -piperazine (VI) 1- [2- [4- (4) -ethoxyphenyl) piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX), m.p. = 148-149 ° C, R f = 0.22 (methanol / methylene chloride, 5/95); IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108, 1050 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8.5 Hz, aromatic H), 6.85 (dzd, 4H, J _and = 9.2 Hz, J _b = 19.2 Hz, four aromatic H), 6.15 (broad s, 1H, C (O) NH), 4.85 (wd, 1H, J = 6.0 Hz) PhC-H), 4.13 (m, 1H, PhCH ₂ CHH), 3.97 (q, 2H, J = 7Hz, PhOC-H ₂ ), 3.77 (m, 1H, PhCH ₂ CH- H), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz C (O) NHC-H ₃ ), 3 00 (m, 1H, NCH-H), 2.76-2.45 (several s, 7H, four pip-H, two PhCHH and NCH-H), 2.14 (m, 1H, PhCHCH-H) 2.02 (m, 1H, PhCHCH-H), 1.37 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ δ; CMR (75 MHz, CDCl 3) 168.0, 153.1,

-53145,6, 141,6, 134,5, 132,7, 127,7, 126,3, 125,0, 124,4, 118,1, 115,2, 74,5, 63,8, 62,9, 54,7,-53145.6, 141.6, 134.5, 132.7, 127.7, 126.3, 125.0, 124.4, 118.1, 115.2, 74.5, 63.8, 62 , 9, 54.7,

53,5, 50,6, 33,2,29,1, 26,8 a 15,0 δ.53.5, 50.6, 33.2, 29.1, 26.8 and 15.0 δ.

Príklad 16 1 -[2-[4-(4-propoxyfenyl)-1 -piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (IX)Example 16 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

1. krok: l-[-2-(6-brómizochróman-l-yl)acetyl]-4-(4-propoxyfenyl)-piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-propoxyphenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl-octovej kyseliny (IV) a p-propoxyfenylpiperazínu l-[-2-(6brómizochróman-l-yl)acetyl]-4-(4-propoxyfenyl)-piperazín (V), Rf = 0,50 (octan etylnatý/hexán, 70/30); IR (čisté látky) 1641, 1511, 1481, 1464, 1443, 1278, 1242, 1230, 12108, 825 cm'¹; NMR (300 MHz, CDC1₃) 7,28 (m, 2H, aromatické H), 7,0 (d, 1H, J = 802 Hz, aromatické H), 6,87 (d, 4H, J = 8,2 Hz, aromatické H), 5,25 (m z d, 1H, J = 6,5 Hz, PhC-H), 4,11 (m,lH), 3,87 (t, 2H, J = 7,0 Hz, Proc-H₂), 3,86 (m,lH), 3,80-3,59 (m, 4H), 3,05 (ζ 4H, J = 5,0 Hz), 3,03-2-89 (m's, 2H), 2,77 (d z d, 1H, J_a = 3,6 Hz, J_b =14,9 Hz), 2,66 (m z d, 1H, J =16,4 Hz), 1,78 (sextet, 2H, J = 7,0 Hz, PhOCH₂C-H₂),l,02 (ζ 3H, J = 7,0 Hz, PhOCH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 168,9, 153,6, 145,0, 136,4, 136,2, 131,6, 129,3,Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and p-propoxyphenylpiperazine 1 - [- 2- (6-bromoisochroman-1-yl) acetyl] -4- (4- propoxyphenyl) -piperazine (V), Rf = 0.50 (ethyl acetate / hexane, 70/30); IR (neat) 1641, 1511, 1481, 1464, 1443, 1278, 1242, 1230, 12108, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J = 802 Hz, aromatic H), 6.87 (d, 4H, J = 8.2) Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.87 (t, 2H, J = 7.0 Hz, Proc-H ₂ ), 3.86 (m, 1H), 3.80-3.59 (m, 4H), 3.05 (ζ 4H, J = 5.0 Hz), 3.03-2-89 (m's, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (mzd, 1H, J = 16.4 Hz), 1.78 (sextet, 2H, J = 7.0 Hz, PhOCH ₂ CH ₂ ), 1.02 (ζ 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3,

126,4, 118,7, 115,1, 69,8, 63,4, 41,8, 39,8, 28,7, 22,5 a 10,4 δ; HRMS vypočítaná pre C₂₄H₂₉N₂O₃Br = 472,1362, nájdená = 472,1356.126.4, 118.7, 115.1, 69.8, 63.4, 41.8, 39.8, 28.7, 22.5 and 10.4 δ; HRMS calcd for C ₂₄ H ₂₉ N ₂ O ₃ Br = 472.1362, found = 472.1356.

2. krok: l-[-2-(6-brómizochróman-l-yl)-etyl]-4-(4-propoxyfenyl)-piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-propoxyphenyl) -piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká za použitia l-[-2(6-brómizochróman-1 -yl)acetyl]-4-(4-propoxyfenyl)-piperazínu (V) 1 - [-2-(6brómizochróman-l-yl)-etyl]-4-(4-propoxyfenyl)piperazín (VI), Rf = 0,52 (octan etylnatý/hexán, 70/30); IR (suspenzia) 1516, 1448, 1261, 1244, 1196, 1131, 1117, 1103,1005, 985 cm¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatické H), 7,27 (s, 1H, aromatické H), 6,97 (d,l H, J = 8,3 Hz, aromatické H), 6,85 (q, 4H, J = 9,7 Hz, aromatické H), 4,78 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m, 1H, PhCH₂CHH), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhcH-H a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,77 (sextet, 2H, J = 6,9 Hz, PhOCH₂C-H₂), 1,01 (t, 3H, J = 7,6 Hz, PhOCH₂CH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 153,3,Following the procedure of Example 1, Step 4, with minor variations, 1- [-2- (6-bromoisochroman-1-yl) acetyl] -4- (4-propoxyphenyl) -piperazine (V) 1- [-2- ( 6-bromoisochroman-1-yl) ethyl] -4- (4-propoxyphenyl) piperazine (VI), R f = 0.52 (ethyl acetate / hexane, 70/30); IR (suspension) 1516, 1448, 1261, 1244, 1196, 1131, 1117, 1103, 1005, 985 cm &^lt; -1 ^&gt;; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8.3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.0 Hz, PhC-H), 4, 13 (m, 1H, PhCH ₂ CHH), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76- 2.45 (several m, 7H, four pip-H, two PhcH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.77 (sextet, 2H, J = 6.9 Hz, PhOCH ₂ CH ₂ ), 1.01 (t, 3H, J = 7.6 Hz, PhOCH ₂ CH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 153.3,

145,4, 136,8, 136,2, 131,5, 129,2, 126,4, 119,9, 118,1, 115,0, 69,8, 62,7, 54,5, 53,3, 50,4,145.4, 136.8, 136.2, 131.5, 129.2, 126.4, 119.9, 118.1, 115.0, 69.8, 62.7, 54.5, 53, 3, 50.4,

-5432,9, 28,7, 22,6, 10,4 δ; HRMS vypočítaná pre C₂₄H3iN₂O₂Bri = 458,1561, nájdená = 458,1569.-5432.9, 28.7, 22.6, 10.4 δ; HRMS calculated for C ₂₄ H ₃₁ N ₂ O ₂ Bri = 458.1561, found = 458.1569.

3.krok:l-[2-[4-(4-propoxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (IX)Step 3: 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 5, 3. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)-etyl]-4-(4-propoxyfenyl)-piperazínu (VI) produkt. Rekryštalizácia z horúceho octanu etylnatého a hexánu dáva vznik l-[2-[4-(4-propoxyfenyl)-lpiperazinyl]etyl]-N-metylizochróman-6-karboxamidu (IX), Rf - 0,20 (metanol/metylénchlorid, 5/95); IR (suspenzia) 3296, 1635, 1569, 1559, 1553, 1512, 1289, 1251, 1242, 1109 cm'¹, NMR (300 MHz, CDClj) 7,54 (s, 2H, aromatické H), 7,15 (d, 1H, J = 8,5 Hz, aromatický H), 6,58 (d z d, 4H, Ja = 9,2 Hz, Jb =19,2 Hz, štyri aromatické H), 6,15 (široké d,lH, C(O)N-H), 4,85 (m z d, 1H, J = 6,0 Hz, PhCH), 4,13 (m, 1H, PhCH₂CH-H), 3,86 (t, 2H, J = 6,6 Hz, PhOC-H₂), 3,77 (m, 1H, PhCH₂CH-H), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (d, 3H, J = 4,9 Hz, C(0)NHC-H₃), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,77 (sextet, 2H, J = 6,9 Hz, PhOCH₂C-H₂), 1,01 (t, 3H, J = 7,4 Hz, PhOCH₂CH₂C-H₃) δ; CMR (75 MHz, CDClj) 167,9, 153,2, 145,4, 141,5, 134,3, 132,5, 127,5, 124,9, 124,3, 118,0, 115,0, 69,8, 62,8, 54,5, 53,4, 50,5, 33,0, 30,5, 28,9, 26,7,22,5 a 10,4 δ.Following the procedure of Example 5, Step 3, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-propoxyphenyl) -piperazine (VI) was formed. Recrystallization from hot ethyl acetate and hexane gives 1- [2- [4- (4-propoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), Rf = 0.20 (methanol / methylene chloride, 5). / 95); IR (suspension) 3296, 1635, 1569, 1559, 1553, 1512, 1289, 1251, 1242, 1109 cm ^-1 , NMR (300 MHz, CDCl 3) 7.54 (s, 2H, aromatic H), 7.15 ( d, 1H, J = 8.5 Hz, aromatic H), 6.58 (dzd, 4H, J a = 9.2 Hz, Jb = 19.2 Hz, four aromatic H), 6.15 (broad d, 1H) C (O) NH), 4.85 (mt, 1H, J = 6.0 Hz, PhCH), 4.13 (m, 1H, PhCH ₂ CH-H), 3.86 (t, 2H, J = 6.6 Hz, PhOC-H ₂ ), 3.77 (m, 1H, PhCH ₂ CH-H), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 3 00 (d, 3H, J = 4.9 Hz, C (0) _NHC-H3), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.77 (sextet, 2H, J) = 6.9 Hz, PhOCH ₂ CH ₂ ), 1.01 (t, 3H, J = 7.4 Hz, PhOCH ₂ CH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl3) 167.9, 153.2, 145.4, 141.5, 134.3, 132.5, 127.5, 124.9, 124.3, 118.0, 115.0 , 69.8, 62.8, 54.5, 53.4, 50.5, 33.0, 30.5, 28.9, 26.7, 22.5 and 10.4 δ.

Príklad 17 (S)-(-)-1 -[2-[4-(4-trifluórmetoxyfeny 1)-1 -piperazínyl]etyl]-N-metylízochróman6-karboxamid (IX)Example 17 (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

l.krok:(S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-trifluórmetoxyfenyl)piperazín (S)-(V)Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (V)

Postupom podľa príkladu 5, 3. kroku s drobnými obmenami vzniká z 4trifluórmetoxyfenylpiperazínu (S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-trifluórmetoxyfenyl)piperazín (S)-(V), [<x]d = -70° (c = 0,68, etanol); Rf = 0,52 (octan etylnatý/hexán, 70/30); IR (čisté látky) 1641, 1511, 1482, 1465, 1445, 1266, 1232, 1211, 1160, 1108 cm'¹; NMR (300 MHz, CDClj) 7,28 (m, 2H, aromatické H), 7,14 (d, 2H, J = 8,9 Hz, aromatické H), 7,0 (d, 1H, J = 8,2 Hz, aromatický H), 6,87 (d, 2H, J = 8,9 Hz, aromatické H), 5,205 (m z d, 1 H, J = 6,5 Hz, PhC-H), 4,11 (m, 1H), 3,92 (m,lH), 3,75 (m, 4H), 3.,16 (t, 4H, J = 5,0 Hz), 3,03-2,89 (M s, 2H), 2,77 (d z d, 1H, J_a = 3,6 HZ, J_b =14,9 HZ), 2,66 (m Z d,Following the procedure of Example 5, Step 3, with minor variations, 4-trifluoromethoxyphenylpiperazine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) is formed. [.Alpha.] D @ 20 = -70 DEG (c = 0.68, ethanol); Rf = 0.52 (ethyl acetate / hexane, 70/30); IR (neat) 1641, 1511, 1482, 1465, 1445, 1266, 1232, 1211, 1160, 1108 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.28 (m, 2H, aromatic H), 7.14 (d, 2H, J = 8.9 Hz, aromatic H), 7.0 (d, 1H, J = 8, 2 Hz, aromatic H), 6.87 (d, 2H, J = 8.9 Hz, aromatic H), 5.205 (wd, 1H, J = 6.5 Hz, PhC-H), 4.11 (m 1H, 3.92 (m, 1H), 3.75 (m, 4H), 3.16 (t, 4H, J = 5.0 Hz), 3.03-2.89 (Ms, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (m Z d,

-551Η, J =16,4 HZ) δ; CMR (75 MHZ, CDC1₃) 1678,9, 149,8, 145,0, 136,9, 136,4, 131,6, 129,3,-551Η, J = 16.4 Hz); CMR (75 MHz, CDCl ₃ ) 1678.9, 149.8, 145.0, 136.9, 136.4, 131.6, 129.3,

126,3, 122,0, 120,7, 117,1, 73,4, 63,4, 49,8, 48,2, 45,8, 42,0, 39,8, 28,7 δ; HRMS vypočítaná pre C₂₂H₂₂N₂F₃O₃Br = 498,0766, nájdená = 498,0764.126.3, 122.0, 120.7, 117.1, 73.4, 63.4, 49.8, 48.2, 45.8, 42.0, 39.8, 28.7 δ; HRMS calcd for C ₂₂ H ₂₂ N ₂ F ₃ O ₃ Br = 498.0766, found = 498.0764.

2. krok: (S)-(-)-l-[2-(6-brómizochróman-l-yl)-etyl]-4-(4-trifluórmetoxyfenyl)piperazín (S)(VI)Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) (VI)

Postupom podľa príkladu 1,3. kroku drobnými obmenami vzniká z (S)-(-)-l-[2- (6brómizochróman-1 -yl)acetyl]-4-(4-trifluórmetoxyfenyl)piperazínu (S)-(V) (S)-(-)-1 - [2-(6brómizochróman-l-yl)-etyl]-4-(4-trifluórmetoxyfenyl)-piperazín (S)-(VI), Rf = 0,54 (octan etylnatý/hexán, 70/30); [a] = -42 (c = 1,1, etanol); DR. (čisté látky) 2825, 1513, 1281, 1263, 1240, 1204, 1184, 1157, 1112, 11Ô6 cm’¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatický H), 7,27 (s, 1H, aromatický H), 7,11 (d, 2H, J = 9 Hz, aromatické H), 6,97 (d, 1H, J = 8,2 Hz, aromatický H), 6,87 (q, 2H, J = 9,1 Hz, dva aromatické H), 4,78 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,11 (m, 1H, PhCH₂CH-H), 3,18 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (m,lH, NCH-H), 2,76-2-45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H) δ; CMR (75 MHz,Following the procedure of Example 1.3. step by slight variation results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (V) (S) - (-) -1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-trifluoromethoxyphenyl) -piperazine (S) - (VI), R f = 0.54 (ethyl acetate / hexane, 70/30); [α] = -42 (c = 1.1, ethanol); DR. (pure substances) 2825, 1513, 1281, 1263, 1240, 1204, 1184, 1157, 1112, 11-6 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 7.11 (d, 2H, J = 9) Hz, aromatic H), 6.97 (d, 1H, J = 8.2 Hz, aromatic H), 6.87 (q, 2H, J = 9.1 Hz, two aromatic H), 4.78 (wd) 1 H, J = 6.0 Hz, PhC-H), 4.11 (m, 1H, PhCH ₂ CH-H), 3.18 (t, 4H, J = 4.8 Hz, four of pip-H) 1.00 (m, 1H, NCH-H), 2.76-2-45 (several m, 7H, four pip-H, two PhCH-H) δ; CMR (75MHz,

CDC1₃) 150,0, 136,5, 135, 5, 131,5, 129,2, 126,3, 121,9, 120,1, 116,4, 74,1, 62,7, 54,9, 53,1,CDC1 ₃₎ 150.0, 136.5, 135, 5, 131.5, 129.2, 126.3, 121.9, 120.1, 116.4, 74.1, 62.7, 54.9 , 53,1,

49,1, 33,0 a 28,7 δ; HRMS vypočítaná pre C₂₂H₂4N₂O₂F₃Bri (+1 ) - 486,0954, nájdená =49.1, 33.0 and 28.7 δ; HRMS calculated for C ₂₂ H ₂₄ N ₂ O ₂ F ₃ Bri (+1) - 486.0954, found =

486, 0956.486, 0956.

3. krok: (S)-(-)-1 -[2-[4-(4-trifluórmetoxyfenyl)-1 -piperazÍnyl]etyl]-N-metyí izochróman-6karboxamid (S)-(IX)Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 5, 3. kroku drobnými obmenami vzniká z (S)-(-)-l-[2- (6brómizochróman-1 -yl)-etyl]-4-(4-trifluórmetoxyfenyl)-piperazínu (S)-(VI) produkt.Following the procedure of Example 5, Step 3, slight variation results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-trifluoromethoxyphenyl) -piperazine (S) - ( VI) product.

Rekryštalizáciou z horúceho octanu etylnatého a hexánu vznikne (S)-(-)-l-[2-[4-(4trifluórmetoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid (S)-(IX), Rf = 0,20 (metanol/metylénchlorid, 5/95); IR (suspenzia) 1636, 1614, 1572, 1551, 1513, 1450, 1270, 1238, 1157, 1107 cm'¹; NMR (300 MHz, CDC1₃) 7,54 (s, 2H, aromatické H), 7,15 (d, 1H, J = 8,9 Hz, dva aromatické H), 6,19 (široké d, 1H, C(O)N-H), 4,86 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m, 1H, PhCH₂CH-H), 3,77 (m, 1H, PhCH₂CH-H), 3,18 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (d, 3H, J = 4,9 Hz, C(0)NHC-H₃), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H,Recrystallization from hot ethyl acetate and hexane affords (S) - (-) - 1- [2- [4- (4-trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), Rf = 0.20 (methanol / methylene chloride, 5/95); IR (suspension) 1636, 1614, 1572, 1551, 1513, 1450, 1270, 1238, 1157, 1107 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8.9 Hz, two aromatic H), 6.19 (broad d, 1H, C (O) NH), 4.86 (mzd, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH) ₂ CH-H), 3.18 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz, C (O) NHC-H) ₃ ), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 (m, 1 H, PhCHCH-H), 2.02 (m, 1 H,

-56PhCHCH-H) δ; CMR (75 MHz, CDClj) 167,8, 149,8, 144,7, 141,3, 134,3, 132,6, 127,5,-56PhCHCH-H) δ; CMR (75 MHz, CDCl 3) 167.8, 149.8, 144.7, 141.3, 134.3, 132.6, 127.5,

124,8, 124,3, 121,8, 116,5, 86,2, 74,3, 62,8, 54,54, 63,4, 48,9, 32,9, 28,9 a 26,7 δ; HRMS vypočítaná pre C24HN3O3F3 = 463,2083, nájdená = 463,2086.124.8, 124.3, 121.8, 116.5, 86.2, 74.3, 62.8, 54.54, 63.4, 48.9, 32.9, 28.9 and 26, 7 δ; HRMS calcd for C24HN3O3F3 = 463.2083, found = 463.2086.

Príklad 18 (S)-(-)-l-[2-[4-(4-etylfenyl)-l-piperazinyl]etyl]-N- metylizochróman6-karboxamid (S)-(IX)Example 18 (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

1. krok: (S)-(-)-1 -[2-(6-brómizochróman-l -yl)acetyl]-4-(4-etylfenyl)-piperazín (S)-(V)Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethylphenyl) -piperazine (S) - (V)

Postupom podľa príkladu 1, 3. kroku drobnými obmenami vzniká z 4etylfenylpiperazínu (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)acetyl)-4-(4-etylfenyl)piperazín (S)(V), Rf = 0,70 (octan etylnatý/hexán, 70/30); [a]o = -81° (c = 0, 7 etanol); LR (čisté látky) 1640, 1614, 1516, 1482, 1462, 1444, 1428, 1232, 1108 a 826 cm¹; NMR (300 MHz, CDClj)Following the procedure of Example 1, Step 3, minor variations resulted from 4-ethylphenylpiperazine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl) -4- (4-ethylphenyl) piperazine (S) ( V), R f = 0.70 (ethyl acetate / hexane, 70/30); [α] D = -81 ° (c = 0.7 ethanol); LR (neat) 1640, 1614, 1516, 1482, 1462, 1444, 1428, 1232, 1108, and 826 cm ^{@ -1} ; NMR (300 MHz, CDCl 3)

7,27 (m, 2H, aromatické H), 7,11 (d, 2H, J = 8,4 Hz, aromatické H) 7,0 (d, 1H, J = 8,2 Hz, aromatické H), 6,86 (d, 2H, J = 8,2 Hz, aromatické H), 5,25 (m z d, 1H, J = 6,5 Hz, PhC-H), 4,08 (m,lH), 3,89 (m,lH), 3,80- 3,59 (m, 4H), 3,11 (t, 4H, J = 5,0 Hz), 3,03-2,89 (m s, 2H),7.27 (m, 2H, aromatic H), 7.11 (d, 2H, J = 8.4 Hz, aromatic H) 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6 86 (d, 2H, J = 8.2Hz, aromatic H), 5.25 (mzd, 1H, J = 6.5Hz, PhC-H), 4.08 (m, 1H), 3.89 (m, 1H), 3.80-3.59 (m, 4H), 3.11 (t, 4H, J = 5.0 Hz), 3.03-2.89 (ms, 2H),

2,77 (d z d, 1H, J_a = 3,6 Hz, J_b =14,9 Hz), 2,66 (m, 1H), 2,57 (q, 2H, J = 7,6 Hz, PhC-H₂),2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (m, 1H), 2.57 (q, 2H, J = 7.6 Hz, PhC -H ₂ ),

1,20 (t, 3H, J = 7,6 Hz, PhCH₂C-H₃) δ; CMR (75 MHz, CDClj) 169,0, 149,0, 136,5, 136,3,1.20 (t, 3H, J = 7.6Hz, PhCH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl 3) 169.0, 149.0, 136.5, 136.3,

131,8, 129,4, 128,6, 126,5, 120,4, 116,9, 73,5, 63,5, 50,3, 49,8, 46,1, 41,9, 39,9, 28,8, 27,9 a131.8, 129.4, 128.6, 126.5, 120.4, 116.9, 73.5, 63.5, 50.3, 49.8, 46.1, 41.9, 39, 9, 28.8, 27.9 and

15,7 δ.15.7 δ.

2. krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)-etyl]-4-(4- etylfenyl)piperazín (S)-(VI)Step 2: (S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethyl-phenyl) -piperazine (S) - (VI)

Postupom podľa príkladu 1, 4. kroku drobnými obmenami vzniká z (S)-(-)-l-[2- (6brómizochróman-1 -yl)acetyl]-4-(4-etylfenyl)-piperazínu (S)-(V) (S)-(-)-l -[2-(6brómizochróman-l-yl)-etyl]-4-(4-etylfenyl)-piperazín (S)-(VI), Rf = 0,61 (octan etylnatý/hexán, 30/70); IR (suspenzia) 2960, 2929, 2819, 1516, 1481, 1379, 1237, 1143, 1111 a 822 cm¹; NMR (300 MHz, CDClj) 7,29 (d, 1H, J = 8,3 Hz, aromatický H), 7,27 (s, 1H, aromatický H), 7,09 (d, 2H, J = 8,6 Hz, aromatické H), 6,98 (d, 1H, J = 8,2 Hz, aromatický H), 6,87 (d, 2H, J = 8,6 Hz, aromatické H), 4,77 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m,lH, PhCH₂CH-H), 3,75 (m, 1H, PhCH2CH-H), 3,17 (t, 4H, = 4,8 Hz, štyri z pip-H), 3,00 (m,lH, NCH-H), 2,70-2,53 (niekoľko m, 9H, štyri pip-H, dva PhCH-H, PhC-H₂ a NCH-H), 2,14 (m,Following the procedure of Example 1, Step 4, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethylphenyl) -piperazine (S) - (V) (S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethyl-phenyl) -piperazine (S) - (VI), Rf = 0.61 (ethyl acetate) (hexane, 30/70); IR (suspension) 2960, 2929, 2819, 1516, 1481, 1379, 1237, 1143, 1111, and 822 cm ^{@ -1} ; NMR (300 MHz, CDCl 3) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 7.09 (d, 2H, J = 8, 6 Hz, aromatic H), 6.98 (d, 1H, J = 8.2 Hz, aromatic H), 6.87 (d, 2H, J = 8.6 Hz, aromatic H), 4.77 (wd) 1 H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.75 (m, 1H, PhCH 2 CH-H), 3.17 (t, 4H , = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.70-2.53 (several m, 9H, four pip-H, two PhCH-H, PhC-H ₂ and NCH-H), 2.14 (m,

-571Η, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,20 (t, 3H, J = 7,6 Hz, PhCH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 149,4, 137,1, 136,3, 135,6, 135,6, 131,6, 129,3, 128,4, 126,5, 120,0, 116,3,-571 °, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.20 (t, 3H, J = 7.6Hz, PhCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 149.4, 137.1, 136.3, 135.6, 135.6, 131.6, 129.3, 128.4, 126.5, 120.0, 116, 3

74,3, 62,8, 54,7, 53,5, 49,6, 33,5, 30,3, 28,9, 27,9, a 15,7 δ; HRMS vypočítaná pre C₂₃H₂9N₂O i Br i = 430,1444, náj dená = 430,1443.74.3, 62.8, 54.7, 53.5, 49.6, 33.5, 30.3, 28.9, 27.9, and 15.7 δ; HRMS calculated for C ₂₃ H 9 N ₂ O ₂ Br and i = 430.1444, found = 430.1443 DeNá.

3. krok: (S)-(-)-l-[2-[4-(4-etylfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX)Step 3: (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 5, 3. kroku drobnými obmenami vzniká z (S)-(-)-l-[2- (6brómizochróman-l-yl)-etyl]-4-(4-etylfenyl)-piperazínu (S)-(V) požadovaný produkt. Rekryštalizáciou z horúceho octanu etylnatého a hexánu vznikne (S)-(-)-l-[2-[4-(4etylfenyl]etyl]-N-metyl-izochróman-6-karboxamid (S)-(IX), teplota topenia = 138-140 °C; Rf =0,28 (metanol/metylénchlorid, 5/95); [oto] = -50° (c= 0,93, metanol/metylénchlorid, 50/50); IR (suspenzia) 3321, 13635, 1614, 1539, 1405, 1312, 1238, 1107 a 822 cm'¹; NMR (300 MHz, CDC1₃) 7,54 (s, 2H, aromatické H), 7,15 (d, 1H, J = 8,6 Hz, aromatický H), 7,09 (d, 2H, J =8,5 Hz, 2 aromatické H), 6,86 (d, 2H, J =6,0 Hz, PhC-H), 4,13 (m, 1H, PhCH₂CH-H), 3,77 (m, 1H, PhCH₂CH-H), 2,76-2,45 (niekoľko m, 9H, štyri pip-H, dva PhCH-H, PhC-H₂ a NCHH), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,20 (t, 3H, J = 7,6 Hz, PhCH₂CH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 168,0, 149,3, 141,6, 135,7, 134,5, 132,7, 128,4,Following the procedure of Example 5, Step 3, slight variation results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethylphenyl) -piperazine (S) - ( V) desired product. Recrystallization from hot ethyl acetate and hexane gave (S) - (-) - 1- [2- [4- (4-ethylphenyl) ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), m.p. = 138-140 ° C; R f = 0.28 (methanol / methylene chloride, 5/95); [α] D = -50 ° (c = 0.93, methanol / methylene chloride, 50/50); IR (suspension) 3321, 13635, 1614, 1539, 1405, 1312, 1238, 1107 and 822 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8) 6 Hz, aromatic H), 7.09 (d, 2H, J = 8.5 Hz, 2 aromatic H), 6.86 (d, 2H, J = 6.0 Hz, PhC-H), 4, 13 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH ₂ CH-H), 2.76-2.45 (several m, 9H, four pip-H, two PhCH-H , PhC-H ₂ and NCHH), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.20 (t, 3H, J = 7.6 Hz, PhCH ₂ CH ₂ CH ₃ ) δ CMR (75 MHz, CDCl ₃ ) 168.0, 149.3, 141.6, 135.7, 134.5, 132.7, 128.4,

127,7, 125,0, 124,4, 116,3, 62,9, 54,7, 53,4, 49,6, 33,1, 29,1, 27,9, 26,8 a 15,7 δ; HRMS vypočítaná pre C₂sH₃₃N₃O₃ = 407,2573, nájdená = 407,2581.127.7, 125.0, 124.4, 116.3, 62.9, 54.7, 53.4, 49.6, 33.1, 29.1, 27.9, 26.8 and 15, 7 δ; HRMS calculated for C ₂ sH ₃₃ N ₃ O ₃ = 407.2573, found = 407.2581.

Príklad 19 (S)-(-)-l-[2-[4-(4-etoxyfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX) .krok: (S)-(-)-l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4etoxyfenyl)-piperazín (S)-(V)Example 19 (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX). Step: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V)

Postupom podľa príkladu 1, 3. krok vzniká z 4-etoxyfenylpiperazínu (S)-(-) l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-etoxyfenyl)-piperazín (S)-(V), Rf = 0,60(octan etylnatý/hexán, 70/30); [cíd] = -78° (c= 0,82, etanol); IR (čisté látky) 1627, 1515, 1478, 1441, 1429, 1250, 1230, 1102, 1031 a 821 cm'¹; NMR (300 MHz, CDC1₃) 7,28 (m, 2H, aromatické H), 7,0 (d, 1H, JH = 8,2 Hz, aromatický H), 6,86 (d, 4H, J = 8,2 Hz, aromatické H), 5,25 (m z d, 1H, J = 6,5 Hz, PhC-H), 4,11 (m, 1H), 3,99 (q, 2H, J = 7,0 Hz, PhOC-H₂), 3,89 (m, 1H),Following the procedure of Example 1, Step 3 results from 4-ethoxyphenylpiperazine (S) - (-) 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V). Rf = 0.60 (ethyl acetate / hexane, 70/30); [α] D = -78 ° (c = 0.82, ethanol); IR (neat) 1627, 1515, 1478, 1441, 1429, 1250, 1230, 1102, 1031 and 821 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J H = 8.2 Hz, aromatic H), 6.86 (d, 4H, J = 8) 2 Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, PhOC-H ₂ ), 3.89 (m, 1 H),

-583,80-3,59 (m, 4H), 3,05 (t, 4H, J = 5, 0 Hz), 3, 03-2, 89 (m's, 2H), 2, 77 (d z d, 1H, J_a = 3, 6 Hz, J_b =14, 9 Hz), 2,66 (m z d, 1H, J = 16,4 Hz), 1,39 (t, 3H, J = 7,0 Hz, PhCH₂C-H₃); CMR (75 MHz, CDCh) 168,9, 153,5, 145,2, 136,3, 136,2, 131,6, 129,3, 126,4, 118,7, 115,1, 73,3,-583.80-3.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03-2.89 (m's, 2H), 2.77 (dzd, 1H) J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (wd, 1H, J = 16.4 Hz), 1.39 (t, 3H, J = 7.0 Hz, PhCH) ₂ CH ₃ ); CMR (75 MHz, CDCl 3) 168.9, 153.5, 145.2, 136.3, 136.2, 131.6, 129.3, 126.4, 118.7, 115.1, 73.3 .

63,7, 63,4, 51,2, 50,7, 46,1, 41,9, 39,8, 28,7 a 14,8 δ; HRMS vypočítaná pre C₂₃H₂₇N₂O₃Br = 458,1205, nájdená = 458,1203.63.7, 63.4, 51.2, 50.7, 46.1, 41.9, 39.8, 28.7 and 14.8 δ; HRMS calcd for C ₂₃ H ₂₇ N ₂ O ₃ Br = 458.1205, found = 458.1203.

2.krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)-ety 1]-4-(4etoxyfenyl)-piperazín (S)-(VI)Step 2: (S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethoxyphenyl) -piperazine (S) - (VI)

Postupom podľa príkladu 1, 4. kroku vzniká z (S)-(-)-l-[2-(6-brómizochróman-lyl)acetyl]-4-(4-etoxyfenyl)-piperazínu (S)-(V) (S)-(-)-l-[2-(6-brómizochróman-l- yl)-etyl]-4(4-etoxyfenyl)-piperazín (S)-(VI), teplota topenia = 85-87 °C; Rf = 0,28 (octan etylnatý/nhexán, 30/70); [ao] = -46° (c= 0,60, etanol); IR (čisté látky) 1516, 1476, 1261, 1246, 1196, 1130, 1117, 1104, 1060 a 932 cm¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatický H), 7,27 (s, 1H, aromatický H), 6,97 (d, 1H, J = 8,3 Hz, aromatický H), 6,85 (q, 4H, J= 9,7 Hz, aromatické H), 4,78 (m z d, 1H, J = 6,1 Hz), 4,14-4,07 (m,lH), 3,97 (q, 2H, J = 7,0 Hz, PhOC-H₂), 3,76-3,69 (m, 1H), 3,10 (t, 4H, J = 4,9 Hz, štyri z pip-H), 2,95 (m, 1H), 2,70-2,50 (m's, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,13 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,38 (t, 3H, J = 6,9 Hz, PhOCH₂C-H₃) 8; CMR (75 MHz, CDCh) 153,1,Following the procedure of Example 1, Step 4, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V) ( S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethoxyphenyl) -piperazine (S) - (VI), m.p. = 85-87 ° C; Rf = 0.28 (ethyl acetate / n-hexane, 30/70); [α] D = -46 ° (c = 0.60, ethanol); IR (neat) 1516, 1476, 1261, 1246, 1196, 1130, 1117, 1104, 1060 and 932 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, IH), 3.97 (q, 2H, J = 7.0 Hz, _PhOC-H2), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J = 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H and NCH-H), 2, 13 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.38 (t, 3H, J = 6.9 Hz, PhOCH ₂ CH ₃ ) 8; CMR (75 MHz, CDCl3) 153.1,

145,6, 137,1, 136,3, 131,6, 129,3, 126,5, 1120,0, 118,1, 115,2, 74,3, 62,8, 55,6, 53,5, 50,6,145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53, 5, 50.6,

33,2, 28,9 a 15,0 Ô.33.2, 28.9 and 15.0 Ô.

3.krok: (S)-(-)-l-[2-[4-(4-etoxyfenyl)-l-piperazinyl]etyl]-Nmetyl izochróman-6-karboxamid (S)-(IX)Step 3: (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 5, 3. kroku drobnými obmenami vzniká z (S)-(-)-1-(2-(6brómizochróman-1 -yl)-etyl]-4-(4-etoxyfenyl)piperazínu (S)-(VI) (S)-(-)-1 -(2-(4-(4etoxyfenyl)-1 -piperazinyl]etyl]-N-metyl-izochróman-6-karboxamid (S)-(IX).Following the procedure of Example 5, Step 3, slight variation results from (S) - (-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-ethoxyphenyl) piperazine (S) - (VI). (S) - (-) - 1- (2- (4- (4-ethoxyphenyl) -1-piperazinyl] ethyl) -N-methyl-isochroman-6-carboxamide (S) - (IX).

Rekryštalizáciou z horúceho octanu etylnatého a hexánu vznikne prečistený produkt, teplota topenia =156-157 °C; Rf = 0,20 (metanol/metylénchlorid, 5/95); [ccd] = -48° (c= 0,94, etanol); IR (suspenzia) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 a 1050 cm’¹; NMR (300 MHz, CDCh) 7,54 (s, 2H, aromatické H), 7,15(d, 1H, J = 8,5 Hz, aromatický H), 56,85 (d z d, 4H, J_a = 9,2 Hz, Jb =19,2 Hz, štyri aromatické H), 6,15( široké d, 1H, C(O)N-H), 4,85 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m, 1H, J = 4,8 Hz, štyri z pip-H), 3,00 (d, 3H, J = 4,9 Hz, C(0)NHC-H₃), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dvaRecrystallization from hot ethyl acetate and hexane gave the purified product, m.p. = 156-157 ° C; Rf = 0.20 (methanol / methylene chloride, 5/95); [α] D = -48 ° (c = 0.94, ethanol); IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108, and 1050 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8.5 Hz, aromatic H), 56.85 (dzd, 4H, J _a = 9) 2 Hz, Jb = 19.2 Hz, four aromatic H), 6.15 (broad d, 1H, C (O) NH), 4.85 (wd, 1H, J = 6.0 Hz, PhC-H) 4.13 (m, 1H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz, C (O) NHC-H ₃ ), 3 .00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two

-59PhCHCH-H a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H) 1,37 (t, 3H, J = 7,0 Hz, PhOCH₂ C-H₃) δ; CMR (75 MHz, CDCb) 168,0, 153,1, 145,6, 141,6, 134,5, 132,7,-59PhCHCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H) 1.37 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl 3) 168.0, 153.1, 145.6, 141.6, 134.5, 132.7,

127,7, 126,3, 125,0, 124,4, 118,1, 115,2, 74,5, 63,8, 62,9, 54,7, 53,5, 50,6, 33,2, 29,1, 26,8 a127.7, 126.3, 125.0, 124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33, 2, 29.1, 26.8 and

15,0 δ; HRMS vypočítaná pre C25H33N3O3 = 423,2522, nájdená = 432,2518.15.0 δ; HRMS calcd for C 25 H 33 N 3 O 3 = 423.2522, found = 432.2518.

Príklad 20 (S)-(-)-1 -[2-[4-(4-fenylmetoxyfenyl)-1 -piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX) .krok:(S)-(-)-l-[2-(6-brómizochróman-l -yl)acetyl)-4-(4fenylmetyloxyfenyl)piperazín (S)-(V)Example 20 (S) - (-) - 1- [2- [4- (4-Phenylmethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX). Step: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - (V)

Postupom podľa príkladu 1, 3. kroku drobnými obmenami vzniká z 4menylmetyloxyfenylpiperazínu (3,38 g, 12,6 mmol) produkt. Látka sa prečistí pomocou HPLC na silikagélovej kolóne za elúcie zmesou octan etylnatý/hexán (70/30) a vzniku (S)-(-)l-[2-(6-brómizochróman-l-yl )acetyl]-4-(4-fenylmetyloxyfenyl)piperazín (S)-(V), Rf= 0,30 (octan etylnatý/hexán, 50/50); [a©] = -34° (c= 0,50, metanol); NMR (300 MHz, CDCI3) 7,35 (m, 7H, aromatický), 6,96 (d, 1H, J = 8,2 Hz, aromatické), 6,90 (m, 4H, aromatické), 5,26 (široké d, J = 5,4 Hz, metín), 5,02 (s, 2H, Ph-CH₂-O), 4,09 (m, 1H, OCH_2a), 3,89 (m, 1H, O=C-N-CH_2a), 3,81-3,64 (m, 4H, OCH_2b, O=C-N-CH_2bcd), 3,05 (m, 4H. Ph-N-CH_2s), 3,002,89 (m, 2H, Ph-CH_2a & N-C=O-CH_2b), 2,66 (široké d, 1H, J = 16,4 Hz, Ph-CH_2b) δ; CMR (75 MHz, CDCb) 169,0, 153,6, 145,5, 137,3, 136,6, 131,8, 129,4, 128,6, 127,9, 127,5, 126,5,Following the procedure of Example 1, Step 3, slight variations gave 4-phenylmethyloxyphenylpiperazine (3.38 g, 12.6 mmol). Purify by HPLC on a silica gel column eluting with ethyl acetate / hexane (70/30) to give (S) - (-) 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4). -phenylmethyloxyphenyl) piperazine (S) - (V), Rf = 0.30 (ethyl acetate / hexane, 50/50); [α] D = -34 ° (c = 0.50, methanol); NMR (300 MHz, CDCl 3) 7.35 (m, 7H, aromatic), 6.96 (d, 1H, J = 8.2 Hz, aromatic), 6.90 (m, 4H, aromatic), 5.26 (broad d, J = 5.4 Hz, methine), 5.02 (s, 2H, _Ph-CH2-O), 4.09 (m, 1 H, OCH _2), 3.89 (m, 1 H, O = CN-CH _{2 a} ), 3.81-3.64 (m, 4H, OCH _{2 b} , O = CN-CH 2 _bcd ), 3.05 (m, 4H, Ph-N-CH _{2 s} ), 3,002.89 (m, 2H, Ph-CH ₂ & NC = O-CH _2b ), 2.66 (broad d, 1H, J = 16.4 Hz, Ph-CH _2b ) δ; CMR (75 MHz, CDCl 3) 169.0, 153.6, 145.5, 137.3, 136.6, 131.8, 129.4, 128.6, 127.9, 127.5, 126.5 .

120,4, 118,8, 115,7, 76,7, 73,5, 70,5, 63,5, 51,3, 50,7, 46,2, 42,0, 40,0 a 28,8 δ.120.4, 118.8, 115.7, 76.7, 73.5, 70.5, 63.5, 51.3, 50.7, 46.2, 42.0, 40.0 and 28, 8 δ.

2.krok: (S)-(-)-l-[2-(6-brómizochróman-l-yl)-etyl]-4-(4fenylmetyloxyfenyl)piperazín (S)-(VI)Step 2: (S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-phenyl-methyloxy-phenyl) -piperazine (S) - (VI)

Postupom podľa príkladu 1, 4. kroku drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-fenylmetyloxyfenyl)piperazínu (V, 5,96 g, 11,4 mmol) (S)-(-)-l-(2-(6-brómizochróman-l-yl)-etyl]-4-(4-fenylmetyloxyfenyl)piperazín (S)-(VI), Rf = 0,40 (octan etylnatý/hexán, 50/50); [ao] = -63° (c= 0,925, metanol); NMR (300 MHz, CDCb) 7,27 (m, 7H, aromatické), 6,91 (d, 1H, J = 8,3 Hz, aromatické), 6,83 (s, 4H, aromatické), 4,94 (s, 2H, Ph-CH₂-0), 4,73 (široké d, 1H, J = 5,7 Hz, metín), 4,03 (m, 1H, OCH_2a), 3,67 (m, 1H, OCH_2b), 3,05 (t, 4H, J = 4,8 Hz, Ph-NCH_2s), 2,88 (m, 1H, Ph-CH_2a), 2,60 (m, 7H, Ph-NC(H₂)-CH_2sNCH₂ a§!! PhCH_2b), 2,05 (m, 1H, C(H)-CH_2a), 1,97 (m, 1H,Following the procedure of Example 1, Step 4, slight variations resulted from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-phenylmethyloxyphenyl) piperazine (V, 5.96 g). (11.4 mmol) (S) - (-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-phenylmethyloxyphenyl) piperazine (S) - (VI), Rf = 0.40 (ethyl acetate / hexane, 50/50); [α] D = -63 ° (c = 0.925, methanol); NMR (300 MHz, CDCl 3) 7.27 (m, 7H, aromatic), 6.91 (d, 1H, J = 8.3 Hz, aromatic), 6.83 (s, 4H, aromatic), 4.94 (s, 2H, Ph-CH ₂ -O), 4.73 (broad d, 1H J = 5.7 Hz, meth), 4.03 (m, 1H, OCH _{2 a} ), 3.67 (m, 1H, OCH _2b ), 3.05 (t, 4H, J = 4.8 Hz, Ph-NCH _{2 s} ), 2.88 (m, 1H, Ph-CH _{2 a} ), 2.60 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH ₂ and PhCH _{2 b} ), 05 (m, 1H, C (H) -CH _{2 -} ), 1.97 (m, 1H,

-60C(H)-CH_2b) δ; CMR (75 MHz, CDCb) 153,1, 145,8, 137,4, 136,9, 136,3, 131,7, 129,3, 128,5,-60C (H) -CH _2b) δ; CMR (75 MHz, CDCl 3) 153.1, 145.8, 137.4, 136.9, 136.3, 131.7, 129.3, 128.5,

127,9, 127,5, 126,5,120,1, 118, 2, 115,6, 70,5, 62,9, 54,6, 53,4, 50,4, 32,9 a 28,9 δ.127.9, 127.5, 126.5, 120.1, 118, 2, 115.6, 70.5, 62.9, 54.6, 53.4, 50.4, 32.9 and 28.9 δ .

krok. (S)-(-)- l-[2-[4-(4-fenylmetyloxy fenyl)-1 -piperazinyl]etyl]-Nmetyl-izochróman-6-karboxamid (S)-(IX)step. (S) - (-) - 1- [2- [4- (4-Phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 5, 3. kroku drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-l-yl)-etyl]-4-(4-fenylmetyloxyfenyl)piperazínu (S)-(VI, 5,08 g, 11,4 mmol) produkt. Látka sa prečistí pomocou LC (silikagél, pórovitosť 230-400, 270 g; octan etylnatý) a rekryštalizáciou z octanu etylnatého vznikne (S)-(-)-l-[2-[4-(4-fenylmetoxyfenyl)-lpiperazinyl]etyl]-N-metyl-izochróman-6-karboxamid (S)-(IX), teplota topenia =164-167 °C; Rf = 0,40 (metanol/octan etylnatý, 5/95); [ao] = -40° (c= 0,9323,metanol); IR (suspenzia) 3302, 1639, 1544, 1515, 1498, 1314, 1291, 1272, 1252, 1153, 1138, 1111, 818, 735 a695 cm'¹; NMR (300 MHz, CDCb) 7,53 (m, 2H, aromatické), 7,54 (m, 2H, aromatické), 7,43-723 (m, 5H, aromatické), 7,14 (d, 1H, J= 8,6 Hz, aromatické), 6,89 (s, 4H, aromatické), 6,19 (široké m, NH), 5,01 (s, 2H, PhO-CH₂), 4,86 (široké d, 1H, J = 5,9 Hz, metín), 4,14 (m, 1H, OCH_2a), 3,76 (m, 1H, OCH_2b), 3,10 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 3,00 (d, 4H, J = 4,8 Hz, N-CH₃ & PhCH_2a), 2,76-2,49 (m, 7H, Ph-NC(H₂)-CH_2s, Ph-CH_2b), 2,14 (m, 1H, C(H)-CH_2a),Following the procedure of Example 5, Step 3, slight variation results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - (VI). (5.08 g, 11.4 mmol) of product. Purify by LC (silica gel, 230-400 porosity, 270 g; ethyl acetate) and recrystallize from ethyl acetate to give (S) - (-) - 1- [2- [4- (4-phenylmethoxyphenyl) -1-piperazinyl] ethyl N-methyl-isochroman-6-carboxamide (S) - (IX), m.p. = 164-167 ° C; Rf = 0.40 (methanol / ethyl acetate, 5/95); [α] D = -40 ° (c = 0.9323, methanol); IR (suspension) 3302, 1639, 1544, 1515, 1498, 1314, 1291, 1272, 1252, 1153, 1138, 1111, 818, 735, and 695 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.53 (m, 2H, aromatic), 7.54 (m, 2H, aromatic), 7.43-723 (m, 5H, aromatic), 7.14 (d, 1H, J = 8.6 Hz, aromatic), 6.89 (s, 4 H, aromatic), 6.19 (br m, NH), 5.01 (s, 2H, _Ph-CH2), 4.86 (bs d, 1H, J = 5.9 Hz, meth), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3.10 (t, 4H, J = 4, 8 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J = 4.8 Hz, N-CH ₃ & PhCH _{2 a} ), 2.76-2.49 (m, 7H, Ph-NC (H ₂ ) -CH ₂ S, Ph-CH _2b ), 2.14 (m, 1H, C (H) -CH _2a ),

2,04 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDCb) 168,0, 153,0, 145,9, ,141,6, 137,4, 134,5,2.04 (m, 1 H, C (H) -CH _2b) δ; CMR (75 MHz, CDCl 3) 168.0, 153.0, 145.9, 141.6, 137.4, 134.5,

132,7, 128,5, 127,9, 127,7, 127,5, 125,0, 124,4, 118,0, 115,6, 145,9, 141,6, 137,4, 134,5,132.7, 128.5, 127.9, 127.7, 127.5, 125.0, 124.4, 118.0, 115.6, 145.9, 141.6, 137.4, 134, 5

132,7, 128,5, 127,9 a 26,9 δ; MS (EI, m/z) = 485; HRMS (EI) vypočítaná pre C₃oH₃₅N₃0₃ = 485,2678, nájdená = 485,2675.132.7, 128.5, 127.9 and 26.9 δ; MS (EI, m / z) = 485; HRMS (EI) for C ₃ oH ₃₅ N ₃ 0 ₃ = 485.2678, found = 485.2675.

Príklad 21 (R)-(+)-l-(2-[4-(4-etoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid (R)-(IX)Example 21 (R) - (+) - 1- (2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX)

1. krok: (R)-(+)-1 -(2-(6-brómizochróman-1 -yI)acetyl)-4-(4-etoxyfenyl)-piperazín (R-V)Step 1: (R) - (+) - 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4-ethoxyphenyl) -piperazine (R-V)

Postupom podľa príkladu 2, 2. kroku s drobnými obmenami vzniká zFollowing the procedure of Example 2, Step 2, with minor variations, it results from

4-etyloxy fény lpiperazínu (R)-(+)-1 -[2-(6-brómizochróman-1 -yl)acetyl]-4-(4-etyloxyfeny 1)piperazín (R-V), Rf = 0,60 (octan etylnatý/hexán, 70/30); [ao] = +76° (c= 0,71,etanol); IR (čisté látky) 1626, 1515, 1478, 1442, 1249, 1246, 1230, 1102, 1030 a 821 cm'¹; NMR (300 MHz, CDCb) 7,28 (m, 2H, aromatické H), 7,0 (d, 1H, J = 8,2 Hz, aromatichý H), 6,86 (d, 4H,4-Ethyloxy-phenylpiperazine (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethyloxyphenyl) piperazine (RV), Rf = 0.60 (acetate) ethyl / hexane, 70/30); [α] D = + 76 ° (c = 0.71, ethanol); IR (neat) 1626, 1515, 1478, 1442, 1249, 1246, 1230, 1102, 1030, and 821 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 (d, 4H,

-61J = 8,2 Hz, aromatické H), 5,25 (m z d, 1H, J = 6,5 Hz, PhC-H), 4,11 (m,lH), 3,99 (q, 2H, J = 7,0 Hz, PhOC-H₂), 3,89 (m, 1H), 3,80- 3,59 (m, 4H), 3,05 (t, 4H, J = 5,0 Hz), 3,03-2,89 (m's, 2H), 2,77 (d z d, 1H, J_a = 3,6 Hz, J_b =14,9 Hz), 2,66 (m z d, 1H, J =16,4 Hz), 1,39 (t, 3H, J = 7,0 Hz, PhCH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 168,9, 153,6, 145,0, 136,4, 136,2, 131,6,-61J = 8.2 Hz, aromatic H), 5.25 (mzd, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, PhOC-H ₂ ), 3.89 (m, 1H), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03-2.89 (m's, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (mzd, 1H, J = 16, 4 Hz), 1.39 (t, 3H, J = 7.0 Hz, PhCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 168.9, 153.6, 145.0, 136.4, 136.2, 131.6,

129,3, 126,4, 120,2, 118,7, 115,1, 73,3, 63,7, 63,55, 63,47, 63,4, 51,2, 50,7, 46,0, 41,8, 39,8,129.3, 126.4, 120.2, 118.7, 115.1, 73.3, 63.7, 63.55, 63.47, 63.4, 51.2, 50.7, 46, 0, 41.8, 39.8,

28,7 a 14,8 δ; HRMS vypočítaná pre C₂₃H₂7N₂O₃Br (na 81. Br iónu) = 460,1185, nájdená = 460,1179.28.7 and 14.8 δ; HRMS calculated for C ₂₃ H 7 N ₂ O ₃ Br ₂ (at 81 Br ion) = 460.1185, found = 460.1179.

2. krok: (R)-(+)-l-[2-(6-brómizochróman-l-yl)-etyl]-4-(4etyloxyfenyl)-piperazín (R-VI)Step 2: (R) - (+) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethyloxy-phenyl) -piperazine (R-VI)

Postupom podľa príkladu 2, 3. kroku drobnými obmenami vzniká z (R)-(+)-l- [2-(6brómizochróman-1 -yl)acetyl]-4-(4-etyloxyfenyl)-piperazínu (R-V) (R)-(+)-1-(2-(6brómizochróman-l-yl)-etyl)-4-(4-etyloxyfenyl)piperazín (R-VI), Rf = 0,25 (octan etylnatý/nhexán, 30/70); [a_D] = +43° (c= 0,73 etanol); IR (čisté látky) 2820, 1511, 1478, 1446, 1250, 1225, 1116, 1108, 1047 a 825 cm’¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatický H), 7,27 (s, 1H, aromatický H), 6,97 (d, 1H, J = 8,3 Hz, aromatický H), 6,85 (g, 4H, J = 9,7 Hz, aromatické H), 4,78 (m z d, 1H, J= 6,1 Hz), 4,14-4,07 (m,lH), 3,97 (q, 2H, J = 7,0 Hz, PhOC-H₂), 3,76-3,69 (m, 1H), 3,10 (t, 4H, J = 4,9 Hz, štyri z pip-H), 2,95 (m, 1H), 2,70-2,50 (m's, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,13 (m, 1H, PhCHCH-H), 2,02 (m,Following the procedure of Example 2, Step 3, slight variation results from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethyloxyphenyl) -piperazine (RV) (R). - (+) - 1- (2- (6-Bromoisochroman-1-yl) ethyl) -4- (4-ethyloxyphenyl) piperazine (R-VI), Rf = 0.25 (ethyl acetate / n-hexane, 30/70) ; [ _α ] _D = + 43 ° (c = 0.73 ethanol); IR (neat) 2820, 1511, 1478, 1446, 1250, 1225, 1116, 1108, 1047 and 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (g, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, IH), 3.97 (q, 2H, J = 7.0 Hz, _PhOC-H2), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J = 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H and NCH-H), 2, 13 (m, 1H, PhCHCH-H), 2.02 (m,

1H, PhCHCH-H), 1,38 (t, 3H, J = 6,9 Hz, PhOCH₂C-H₃) δ; CMR (75MHz, CDC1₃) 153,1,1H, PhCHCH-H), 1.38 (t, 3H, J = 6.9 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 153.1,

145,6, 137,8, 136,3, 131,6, 129,3, 126, 5, 1120,0, 118,1, 115,2, 74,3, 62,8, 55,6, 53,5, 50,6,145.6, 137.8, 136.3, 131.6, 129.3, 126, 5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53, 5, 50.6,

33,2,28,9 a 15,0 δ; HRMS vypočítaná pre C₂₃H₂9N₂O₂Bri = 444,1413, nájdená = 444,1413.33.2, 28.9 and 15.0 δ; HRMS calculated for C ₂₃ H 9 N ₂ O _{2 2} Bri = 444.1413, found = 444.1413.

3. krok: (R)-(+)-1 -(2-[4-(4-etoxyfenyl)-1 -piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (R)-(IX)Step 3: (R) - (+) - 1- (2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (R) - (IX)

Postupom podľa príkladu 5, 3. kroku drobnými obmenami vzniká z (R)-(+)-1-(2-(6brómizochróman-l-yl)-etyl]-4-(4-etyloxyfenyl)piperazínu (R-VI) (R)-(+)-1-(2-(4-(4etoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid (R)-(IX), Rf = 0,20 (metanol/metylénchlorid, 5/95); [ccd] = +49° (c = 0,93 metanol/metylénchlorid, 50/50); IR (suspenzia) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 a 1050 cm'¹, NMR (300 MHz, CDC1₃) 7,54 (s, 2H, aromatické H), 7,15 (d, 1H, J = 4,8 Hz, štyri z pip-H), 3,00 (d, 3H, J = 4,9 Hz, C(O)NHC-H), 4,85 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m,lH, NCH-H), 3,97Following the procedure of Example 5, Step 3, slight variations resulted from (R) - (+) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-ethyloxyphenyl) piperazine (R-VI) ( R) - (+) - 1- (2- (4- (4-ethoxyphenyl) -1-piperazinyl] ethyl) -N-methylisochroman-6-carboxamide (R) - (IX), Rf = 0.20 (methanol / methylene chloride) IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 and (ccd) = + 49 ° (c = 0.93 methanol / methylene chloride, 50/50); 1050 cm ^-1 , NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9Hz, C (O) NHC-H), 4.85 (mzd, 1H, J = 6.0Hz, PhC-H), 4.13 (m, 1H, NCH) -H), 3.97

-62(q, 2H, J = 7 Hz, PhOC-H₂), 3,77 (m, 1H, PhCH₂CH-H), 2,76-2,45 (niektoré m, 7H, štyri pipH, dva PhCH-H a NCH-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H),l,37 (t, 3H, J = 7,0 Hz, PhOCH₂C-H₃) δ; CMR (75 MHz, CDC1₃) 168,0, 153,1, 145,6, 141,6, 134,5,-62 (q, 2H, J = 7 Hz, _PhOC-H2), 3.77 (m, 1 H, CH ₂ Ph-H), 2.76-2.45 (several m, 7H, four Piphat two PhCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.37 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDC1 ₃₎ 168.0, 153.1, 145.6, 141.6, 134.5,

26,8 a 15,0 δ; HRMS vypočítaná pre C₂sH₃₃N₃O₃ = 423,2522, nájdená = 423,2516.26.8 and 15.0 δ; HRMS calculated for C ₂ sH ₃₃ N ₃ O ₃ = 423.2522, found = 423.2516.

Príklad 22 l-[2-[4-(3-trifluórmetylfenyl)-l-piperazinyl]etyl]-N-metylizochróman6- karboxamid (IX) krok: 1 -[2-[4-(3 -trifluórmetyl fenyl)-1 -piperazinyl] etyl ]-N,N-di-tbutyloxykarbonyl izochróman-6-karboxamid (VIII)Example 22 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX) Step: 1- [2- [4- (3-trifluoromethylphenyl) -1- piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VIII)

Postupom podľa príkladu 3,1. kroku drobnými obmenami vzniká z l-[2-[4-(3trifluórmetylfenyl)-l-piperazinyI]etyl]-izochróman-6-karboxamidu surový produkt. Látka sa prečistí pomocou LC (silikagél, pórovitosť 230-400, 60 g; acetón/hexán, 25/75) za vzniku 1[2-(4-(3-trifluórmetylfenyl)-l-piperazinyl]etyl]-N,N-di-t-butyloxykarbonylizochróman-6karboxamidu (VIII), Rf = 0,37 (acetón/hexán, 25/75).Following the procedure of Example 3.1. Step, with minor variations, the crude product is obtained from 1- [2- [4- (3-trifluoromethyl-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxamide. Purify by LC (silica gel, porosity 230-400, 60 g; acetone / hexane, 25/75) to give 1- [2- (4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N- di-t-butyloxycarbonylisochroman-6-carboxamide (VIII), Rf = 0.37 (acetone / hexane, 25/75).

2. krok: l-[2-[4-(3-trifluórmetylfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (IX)Step 2: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Postupom podľa príkladu 3, 2. kroku s drobnými obmenami vzniká z l-[2-[4-(3trifluórmetylfenyl)-l-piperazinyl]etyl]-N,N-di-t-butyloxykarbonyIizochróman-6-karboxamidu (VIII, 1,13 g, 1,8 mmol) surový produkt. Látka sa prečistí pomocou LC (silikagél, 230-400 pórovitosť, 66 g; acetón/hexán, 50/50) a vznikne l-[2-[4-(3- trifluórmetylfenyl)-1piperaziny 1] etyl] -N,N-di-t-butyloxykarbonylizochróman-6-karboxamid (IX), ktorý rekryštalizuje zo zmesi octan etylnatý/hexán, teplota topenia = 142-143 °C ; Rf = 0,33 (acetón/hexán, 50/50); IR (suspenzia) 3307, 1637, 1612, 1606, 1558, 1443, 1311, 1290, 1247, 1151, 1136, 1122, 1109, 1099 a 951 cm'¹; NMR (300 MHz, CDC1₃) 7,55 (m, 2H, aromatické), 7,33 (t, 1H, J = 8,0 Hz, aromatické), 7,12 (d, 1H, J = 8,6 Hz, aromatické), 7,6 (m, 4H, aromatické), 6,14 (široké m, 1H, NH), 4,87 (široké d, 1H, J = 5,9 Hz, metín), 4,14 (m,Following the procedure of Example 3, Step 2, with minor variations, 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VIII, 1, 13 g, 1.8 mmol) of crude product. Purify by LC (silica gel, 230-400 porosity, 66 g; acetone / hexane, 50/50) to give 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N- di-t-butyloxycarbonylisochroman-6-carboxamide (IX), which recrystallizes from ethyl acetate / hexane, m.p. = 142-143 ° C; Rf = 0.33 (acetone / hexane, 50/50); IR (suspension) 3307, 1637, 1612, 1606, 1558, 1443, 1311, 1290, 1247, 1151, 1136, 1122, 1109, 1099, and 951 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.55 (m, 2H, aromatic), 7.33 (t, 1H, J = 8.0 Hz, aromatic), 7.12 (d, 1H, J = 8.6) Hz, aromatic), 7.6 (m, 4H, aromatic), 6.14 (broad m, 1H, NH), 4.87 (broad d, 1H, J = 5.9 Hz, meth), 4.14 (m,

-63132,7, 131,4(qrt,J_CF = 32Hz),129,5, 127,7, 125,0, 124,4, 118,6, 115,7, (d, J_CF = 4 Hz ),112,1 (d, Jcf = 4 Hz), 74,4, 63,0, 54,6, 53,2, 48,7, 33,2, 29,1 a 26,9 δ; HRMS (El) vypočítaná pre C24H28F3N3O2 = 447,2133, nájdená = 447,2132.-63132.7, 131.4 (qrt, J _CF = 32Hz), 129.5, 127.7, 125.0, 124.4, 118.6, 115.7, (d, J _CF = 4 Hz ), 112.1 (d, J Cf = 4 Hz), 74.4, 63.0, 54.6, 53.2, 48.7, 33.2, 29.1 and 26.9 δ; HRMS (EI) calcd for C 24 H 28 F 3 N 3 O 2 = 447.2133, found = 447.2132.

Príklad 23 l-[2-[4-(4-metylsulfonyIfenyl)-l -piperazinyl]etyl]-Nmetylizochróman-6karboxamid (IX)Example 23 1- [2- [4- (4-Methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

l.krok:l-[2-[4-(4-metylsulfonylfenyl)-l-piperazinyl]etyl]-N,N-di-tbutyloxykarbonylizochróman-6-karboxamid (Vili)Step 1: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di-butyloxycarbonylisochroman-6-carboxamide (VII)

Postupom podľa PRÍKLADU 3, 1. kroku s drobnými obmenami vzniká z l-[2- [4-(4metylsulfonylfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamidu (825 mg, 1,9 mmol) surový produkt. Látka sa prečistí pomocou LC (silikagél, pórovitosť 230-400, 58 g; acetón/hexán 45/55) za vzniku l-[2-[4-(4-metylsulfonylfenyl)-l-piperazinyl]etyl)-N,N-di-tbutyloxykarbonylizochróman-6-karboxamidu (VEH), Rf = 20 (acetón/hexán, 40/60).Following the procedure of EXAMPLE 3, Step 1, with minor variations, 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (825 mg, 1.9 mmol) was obtained from the crude product. Purify by LC (silica gel, 230-400 porosity, 58 g; acetone / hexane 45/55) to give 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N- di-t-butyloxycarbonylisochroman-6-carboxamide (VEH), Rf = 20 (acetone / hexane, 40/60).

2. krok: l-[2-[4-(4-metylsulfonylfenyl)-l-piperazinyI]etyl]-Nmetylizochróman-6-karboxamid (IX)Step 2: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Postupom podľa príkladu 3, 2. kroku drobnými obmenami vzniká z l-[2-[4-(4metylsulfonylfenyl)-l-piperazinyl]etyl]-N,N-di-t-butyloxykarbonylizochróman-6karboxamidu (VIII, 650 mg, 1,0 mmol) surový produkt. Látka sa prečistí pomocou LC (silikagél, 230-400 pórovitosť, 71 g; metanol/dichlórmetán, 5/95) za vzniku l-[2[4-(4-metylsulfonylfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamidu (IX), Rf = 0,30 (metanol/dichlórmetán, 5/95); IR (suspenzia) 1645, 1612, 1593, 1571, 1545, 1508, 1496, 1409, 1296, 1145, 1106, 1095, 957 a 780 cm⁴;NMR (300 MHz, CDCI3) 7,73 (d,Following the procedure of Example 3, Step 2, slight variations resulted in 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 650 mg, 1, 0 mmol) crude product. Purify by LC (silica gel, 230-400 porosity, 71 g; methanol / dichloromethane, 5/95) to give 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 6-carboxamide (IX), Rf = 0.30 (methanol / dichloromethane, 5/95); IR (suspension) 1645, 1612, 1593, 1571, 1545, 1508, 1496, 1409, 1296, 1145, 1106, 1095, 957, and 780 cm ⁴ ; NMR (300 MHz, CDCl 3) 7.73 (d,

2H, J = 8,9 Hz, aromatické), 7,55 (m, 2H, aromatické), 7,15 (d, 1H, J = 7,9 Hz, aromatické),2H, J = 8.9 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.15 (d, 1H, J = 7.9 Hz, aromatic),

6,91 (d, 1H, J = 8,9 Hz, aromatické), 6,14 (široké d, 1H, J = 4,4 Hz, NH), 4,86 (široké d, 1H, J = 6,2 Hz, metín), 4,12 (m, 1H, OCH_2a), 3,75 (m, 1H, OCH₂b), 3,35 (t, 4H, J = 4,9 Hz, Ph-NCH_2s), 2,99 (široké s, 7H, N-CH3, OCH₃, Ph-CH_2a), 2,75-2,46 (m, 7H, Ph-NC(H₂)-CH_2sNCH_2s, Ph-CH_2b), 2,14 (m, 1H, C(H)-CH_2a), 2,02 (m, 1H, C(H)-CH₂b) ) δ; CMR (75MHz, CDCb) 167,9, 154,3, 141,4, 134,5, 132,7, 129,1, 128,6, 127,7, 124,9, 124,5, 113,8, 74,3, 63,0,6.91 (d, 1H, J = 8.9 Hz, aromatic), 6.14 (broad d, 1H, J = 4.4 Hz, NH), 4.86 (broad d, 1H, J = 6, 2 Hz, meth), 4.12 (m, 1H, OCH _{2 a} ), 3.75 (m, 1H, OCH ₂ b), 3.35 (t, 4H, J = 4.9 Hz, Ph-NCH _{2 s)} ), 2.99 (broad s, 7H, N-CH 3, OCH ₃ , Ph-CH _{2 a} ), 2.75-2.46 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH _{2 s} , Ph CH _2b), 2.14 (m, 1 H, C (H) CH _2), 2.02 (m, 1 H, C (H) _-CH2 b)) δ; CMR (75MHz, CDCl3) 167.9, 154.3, 141.4, 134.5, 132.7, 129.1, 128.6, 127.7, 124.9, 124.5, 113.8, 74.3, 63.0,

54,5, 52,9, 47,3, 45,0, 33,1, 29,1 a 26,8 δ; HRMS (El) vypočítaná pre C24H31N3O4S =54.5, 52.9, 47.3, 45.0, 33.1, 29.1 and 26.8 δ; HRMS (EI) calcd for C 24 H 31 N 3 O 4 S =

-64457,2035, nájdená = 457,2032; obsah voľnej vody = 0,87 %; tekuté rozpúšťadlá = 0,53 % octanu etylnatého a 0,34 % hexánu.-64457.2035, found = 457.2032; free water content = 0.87%; liquid solvents = 0.53% ethyl acetate and 0.34% hexane.

Príklad 24 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6karboxamid (VII)Example 24 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

1. krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-metoxyfenyl)-piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (V)

Postupom podľa príkladu 1, 3. kroku drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl-octovej kyseliny (IV) a 4-metoxyfenylpiperazínu l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metoxyfenyl)-piperazín (V), Rf = 0,26 (octan etylnatý/hexán, 70/30); I (suspenzia) 1639, 1512, 1446, 1439, 1249, 1214, 1030, 1028 a 820 cm¹; NMR (300 MHz, CDC1₃) 7,32-7,26 (m, 2H, aromatické H), 7,0 (d, 1H, J = 8,2 Hz, aromatický H), 6,88 (d, 4H, aromatické H), 5,27 (m z d, 1H, J = 5,9 Hz, ArC-H), 4,16-4,07 (m, 1H), 3,89 (m, 1H), 3,80-3,60 (m, 4H), 3,77 (s, 3H, -OC-H₃), 3,05 (m, 4H, štyri z pip-H), 2,97-2,90 (m, 2H), 2,76 (d z d, 1H, J_a = 3,7 Hz, J_b = 14,9 Hz), 2,65 (m z d, 1H, J = 16,4 Hz) δ; CMR (75MHz, CDC1₃) 168,9, 154,3, 145,2, 136,5, 136,2, 131,7, 129,3, 126,4, 120,3,Following the procedure of Example 1, Step 3, a slight variation of racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-methoxyphenylpiperazine of 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (V), Rf = 0.26 (ethyl acetate / hexane, 70/30); I (suspension) 1639, 1512, 1446, 1439, 1249, 1214, 1030, 1028, and 820 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.88 (d, 4H) aromatic H), 5.27 (mt, 1H, J = 5.9 Hz, ArC-H), 4.16-4.07 (m, 1H), 3.89 (m, 1H), 3.80 -3.60 (m, 4H), 3.77 (s, 3H, -OC-H ₃ ), 3.05 (m, 4H, four of pip-H), 2.97-2.90 (m, 2H), 2.76 (dzd, 1H, J _a = 3.7 Hz, J _b = 14.9 Hz), 2.65 (wd, 1H, J = 16.4 Hz) δ; CMR (75 MHz, CDC1 ₃₎ 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3,

118,8,114,4, 73,4, 63,4, 55,5, 51,3, 50,7,46,1, 41,9, 39,9, 28,7 δ.118.8, 114.4, 73.4, 63.4, 55.5, 51.3, 50.7.46.1, 41.9, 39.9, 28.7 δ.

2. krok: l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-1 -yl)acetyl]-4-(4--metoxyfenyl)-piperazínu (V) 1 -[2-(6-brómizochrómanl-yl)acetyl]-4-(4—metoxyfenyl)-piperazín (VI), Rf = 0,23 (octan etylnatý); IR (čisté látky) 1518, 1479, 1250, 1155, 1140, 1112, 1103, 1041 a 818 cm'¹; NMR (300 MHz, CDC1₃) 7,29 (d, 1H, J = 8,3 Hz, aromatický H), 7,27 (s, 1H, aromatický H), 6,97 (d, 1H, J = 8,3 Hz, aromatický H), 6,85 (q, 4H, J = 9,7 Hz, aromatické H), 4,78 (m z d, 1H, J = 6,1 Hz), 4,144,07 (m, 1H), 3,76-3,69 (m, 1H), 3,76 (s, 3H, -OC-H₃), 3,10 (t, 4H, J = 4,9 Hz, štyri z pipH), 3,95 (m, 1H), 2,70-2,50 (m’s, 7H), 2,13 (m, 1H, pipCH-H), 2,02 (m, 1H, pipCH-H) δ; CMR (75 MHz, CDC1₃) 153,5, 145,5, 136,8, 136,0, 131,4, 129,0, 126,3, 119,7, 117,9, 114,2,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (V) 1- [2- (6-bromoisochromanil) was obtained. -yl) acetyl] -4- (4-methoxyphenyl) -piperazine (VI), R f = 0.23 (ethyl acetate); IR (neat) 1518, 1479, 1250, 1155, 1140, 1112, 1103, 1041 and 818 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.144.07 (m, 1H ), 3.76-3.69 (m, 1H), 3.76 (s, 3H, -OC-H ₃ ), 3.10 (t, 4H, J = 4.9 Hz, four of pipH), 3.95 (m, 1H), 2.70-2.50 (m's, 7H), 2.13 (m, 1H, pip CH-H), 2.02 (m, 1H, pip CH-H) δ; CMR (75 MHz, CDC1 ₃₎ 153.5, 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2,

74,1, 62,5, 55,3, 54,4, 53,3, 50,4, 32,9 a 28,6 δ.74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6 δ.

3. krok:l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6karboxamid (VTI)Step 3: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VTI)

-65Suchá 100 ml nádoba s guľatým dnom sa naplní THF (18 ml) a ochladí na -78 °C v kúpeli suchý ľad/acetón. Potom sa naraz pridá t-butyllítium v hexáne (1,7 M, 5,4 ml, 9,2 mmol). Po 5 minútovom miešaní sa pomocou hadičky pridá zmes l-[2-(6-brómizochrómanl-yl)acetyl]-4-(4-metoxyfenyl)-piperazínu (VI) v THF (20 ml). Po 15 minútovom miešaní pri -78 °C sa pomocou hadičky pridá trimetylsilylizokyanát (0,88 ml, 6,55 mmol) a dioxán (3,52 ml). Po 15 minútach sa chladiaca zmes odstráni a reakcia sa mieša 1,5 hodiny pri 2025 °C. Reakcia sa potom zastaví nasýteným vodným chloridom amónnym, prchavé látky sa odstránia za zníženého tlaku a zvyšok sa upraví na zásadité pH pomocou vodného hydroxidu sodného. Surový bázický roztok sa extrahuje chloridom metylnatým. Organické extrakty sa odoberú, vysušia síranom sodným, prefiltrujú a zahustia. Surová látka sa prečistí rýchlou chromatografiou (silikagél, 25 g; za použitia gradientu 0-10 % metanol/octan etylnatý a vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (VII), teplota topenia = 180-182 °C; Rf = 0,27 (metanol/octan etylnatý, 10/90), IR (suspenzia) 3366, 3198,A dry 100 mL round bottom flask was charged with THF (18 mL) and cooled to -78 ° C in a dry ice / acetone bath. Then t-butyllithium in hexane (1.7 M, 5.4 mL, 9.2 mmol) was added in one portion. After stirring for 5 minutes, a mixture of 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (VI) in THF (20 mL) was added via a tube. After stirring at -78 ° C for 15 min, trimethylsilyl isocyanate (0.88 mL, 6.55 mmol) and dioxane (3.52 mL) were added via a tube. After 15 minutes, the cooling mixture was removed and the reaction was stirred at 2025 ° C for 1.5 hours. The reaction is then quenched with saturated aqueous ammonium chloride, the volatiles are removed under reduced pressure, and the residue is brought to basic pH with aqueous sodium hydroxide. The crude basic solution was extracted with methyl chloride. The organic extracts are collected, dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 25 g; 0-10% methanol / ethyl acetate gradient) to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), m.p. = 180-182 ° C; R f = 0.27 (methanol / ethyl acetate, 10/90), IR (suspension) 3366, 3198,

1628, 1642, 1602, 1514, 1437, 1245, 1109 a 815 cm¹; NMR (300 MHz, CDC1₃) 7,61-7,58 (m, 2H, aromatické H), 5,90 (veľmi široké d, 2H, C(O)N-H2), 4,86 (m z d, 1H, J = 5,8 Hz, PhC -H), 4,18-4,11 (m, 1H), 3,80-3,72 (m, 1H), 3,76 (s, 3H, PhOC-H₃), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 (m, 1H), 2,73 (m z d, 1H, J = 16,4 Hz), 2,66-2,49 (m’s, 6H), 2,15 (m, 1H, pipCH-H), 2,04 (m, 1H, pipCH-H) δ; CMR (75 MHz, CDC1₃) 168,7, 153,5, 145,4, 142,0, 134,3, 131,0, 127,9, 124,8, 124,6, 117,8, 114,1, 74,2, 62,6, 55,2, 54,3, 53,2, 50,3,1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm ^{@ -1} ; NMR (300 MHz, CDCl ₃ ) 7.61-7.58 (m, 2H, aromatic H), 5.90 (very broad d, 2H, C (O) N-H 2), 4.86 (wd, 1H) J = 5.8 Hz, PhC-H), 4.18-4.11 (m, 1H), 3.80-3.72 (m, 1H), 3.76 (s, 3H, PhOC-H) ₃ ), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (wd, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H) δ; CMR (75 MHz, CDC1 ₃₎ 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114, 1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3,

32,8,28,7 a 27,2 δ; HRMS vypočítaná pre C₂3H₂₉N₃O₃ = 395,2209, nájdená = 395,2219.32,8,28,7 and 27,2 δ; HRMS calcd for _C2 3 H ₂₉ N ₃ O ₃ = 395.2209, found = 395.2219.

Príklad 25 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-propyl- izochróman-6karboxamid (IX)Example 25 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-propyl isochroman-6-carboxamide (IX)

1. krok: l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N,N-di-tbutyloxykarbonylizochróman-6-karboxamid (VIII)Step 1: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-butyloxycarbonylisochroman-6-carboxamide (VIII)

Postupom podľa príkladu 3, 1. kroku drobnými obmenami vzniká z l-[2-[4(4-metoxy fény 1)-1 -piperaziny 1] etyl] izochróman-6-karboxamidu (VII,Following the procedure of Example 3, Step 1, minor variations resulted in 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII,

Príklad 24: l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N,N-di-t-butyloxy karbonyl izochróman-6-karboxamid (VIII).Example 24: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VIII).

2. krok: l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-propyl- izochróman -6-karboxamid (IX)Step 2: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propyl isochroman-6-carboxamide (IX)

-66V peci vysušená 100 ml nádoba s miešacou tyčinkou sa naplní l-[2-[4-(4metoxyfenyl)-l-piperazinyl]etyl]-N,N-di-t-butyloxykarbonylizochróman-6-karboxamidom (VIII, 566 mg, 0,95 mmol) a 20 ml dichlórmetánu. Zmes reaguje s propylamínom (0,78 ml,A -66-kiln-dried 100 mL stir bar was charged with 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 566 mg, 0.95 mmol) and 20 mL of dichloromethane. The mixture is treated with propylamine (0.78 ml,

9,5 mmol). Po 16 hodinách sa prchavé látky odstránia za zníženého tlaku na surový produkt. Táto látka sa prečistí pomocou LC (silikagél, pórovitosť 230-400, 30 g; metanol/octan etylnatý, 5/95) za vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl] etyl]-N-propylizochróman-6-karboxamidu (IX), teplota topenia = 147-149 °C; Rf = 0,37 etanol/octan etylnatý, 5/95); IR (suspenzia) 3302, 2815, 1639, 1539, 1515, 1320, 1310, 1293, 1278, 1247, 1153, 1112, 1107, 1041 a 824 cm'¹; NMR (300 MHz, CDCb) 7,54 (m, 2H, aromatické, 7,16 (d, 1H, J = 8,6 Hz, aromatické), 6,87 (m, 4H, aromatické), 6,16 (široké t, 1H, NH), 4,87 (široké d, 1H, J = 6 Hz, metín), 4,14 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ & OCH_2b), 2,17 (m, 1H, C(H(-CH_2a), 2,77,2,53 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s, Ph-CH_2b), 2,17 (m, 1H, C(H)CH_2a), 2,05 (m, 1H, C(H)-CH_2b), 1,63 (sxt, 2H, J = 7,4 Hz, C(H₃>CH₂), 0,98 (t, 3H, J = 7,4 Hz, CH₃-C(H₂) δ; CMR (75 MHz, CDCb) 167,1, 153,6, 145,5, 141,3, 134,3, 132,7, 127,4,9.5 mmol). After 16 hours the volatiles were removed under reduced pressure to give the crude product. This material was purified by LC (silica gel, porosity 230-400, 30 g; methanol / ethyl acetate, 5/95) to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N -propylisochroman-6-carboxamide (IX), m.p. = 147-149 ° C; Rf = 0.37 ethanol / ethyl acetate, 5/95); IR (suspension) 3302, 2815, 1639, 1539, 1515, 1320, 1310, 1293, 1278, 1247, 1153, 1112, 1107, 1041, and 824 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.54 (m, 2H, aromatic, 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 6.16 ( broad t, 1H, NH), 4.87 (broad d, 1H, J = 6 Hz, meth), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ & OCH _2b) ), 2.17 (m, 1H, C (H (-CH ₂ )), 2.77.2.53 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ) , 2.17 (m, 1 H, C (H) CH _2), 2.05 (m, 1 H, C (H) -CH _2b), 1.63 (sxt, 2H, J = 7.4 Hz, C (H ₃ > CH ₂ ), 0.98 (t, 3H, J = 7.4 Hz, CH ₃ -C (H ₂ ) δ; CMR (75 MHz, CDCl 3) 167.1, 153.6, 145, 5, 141.3, 134.3, 132.7, 127.4,

124,8, 124,2, 117,9, 114,2, 74,3, 62,8, 55,4, 54,5, 53,3, 50,4, 41,5, 33,0, 28,9, 22,8 a 11,6 δ;124.8, 124.2, 117.9, 114.2, 74.3, 62.8, 55.4, 54.5, 53.3, 50.4, 41.5, 33.0, 28, 9, 22.8 and 11.6 δ;

MS (EI, m/z) = 437.MS (EI, m / z) = 437 (M + H) +.

Príklad 26 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-allylizochróman-6-karboxamid (IX)Example 26 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-allylisochroman-6-carboxamide (IX)

Postupom podľa príkladu 25, 2. kroku s drobnými obmenami vzniká z alylamínu (0,69 mL, 9,1 mmol) surový produk. Látka sa prečistí pomocou LC (silikagél, pórovitosť 230-400, 30 g; metanol/octan etylnatý 3/97) za vzniku produktu, ktorý rekryštalizuje zo zmesi octan etylnatý/hexán, teplota topenia = 146-148 °C; R_f = 0,34 (metanol/octan etylnatý , 5/95); IR (suspenzia) 3295, 2814, 1640, 1536, 1515, 1494, 1443, 1310, 1281, 1246, 1148, 1107, 1037, 923 a 823 cm⁴; NMR (300 MHz, CDCb) 7,57, 7,17, 6,85, 6,2, 5,92, 5,26, 5,19, 4,87, 4,08,Following the procedure of Example 25, Step 2, with minor variations, crude product was obtained from allylamine (0.69 mL, 9.1 mmol). The material is purified by LC (silica gel, 230-400 porosity, 30 g; methanol / ethyl acetate 3/97) to give a product which is recrystallized from ethyl acetate / hexane, mp = 146-148 ° C; _Rf = 0.34 (methanol / ethyl acetate, 5/95); IR (suspension) 3295, 2814, 1640, 1536, 1515, 1494, 1443, 1310, 1281, 1246, 1148, 1107, 1037, 923, and 823 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl 3) 7.57, 7.17, 6.85, 6.2, 5.92, 5.26, 5.19, 4.87, 4.08,

3,76, 3,11, 3,01, 2,78-2,50, 127,8, 125,1, 124,5, 118,2, 116,8, 114,4, 74,6, 63,0, 55,6, 54,7,3.76, 3.11, 3.01, 2.78-2.50, 127.8, 125.1, 124.5, 118.2, 116.8, 114.4, 74.6, 63, 0, 55.6, 54.7,

53,5, 50,7, 42,5, 33,2 a 29,1 δ; MS (EI, m/z) = 435; HRMS (EI) vypočítaná pre C₂₆H₃₃N₃O₃ = 435,2522, nájdená 435,2516.53.5, 50.7, 42.5, 33.2 and 29.1 δ; MS (EI, m / z) = 435; HRMS (EI) calcd for C ₂₆ H ₃₃ N ₃ O ₃ = 435.2522, found 435.2516.

Príklad 27 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-etyl- izochróman-6Example 27 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-ethyl-isochroman-6

-karboxamid (IX)-carboxamide (IX)

Postupom podľa príkladu 25, 2. kroku s drobnými obmenami vzniká z etylaminu (asi 2 ml, kondenzovaný pri 0 °C) surový produkt. Látka sa prečistí pomocou LC (silikagél,Following the procedure of Example 25, Step 2 with minor variations, the crude product was formed from ethylamine (about 2 mL, condensed at 0 ° C). Purify by LC (silica gel,

-67pórovitosť 230-400, 30 g; metanol/octan etylnatý 5/95) za vzniku produktu. Táto látka sa rozmelí zmesou octan etylnatý/hexán za vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]N-etyl-izochróman-6-karboxamidu (IX), teplota topenia = 127-129 °C ; R_f = 0,30 (metanol/octan etylnatý , 5/95); IR (suspenzia) 3308, 2815, 1640, 1541, 1514, 1442, 1359, 1312, 1283, 1246, 1149, 1112, 1037 a 826 cm'¹; NMR (300 MHz, CDCb) 7,55 (m, 2H, aromatické), 7,16 (d, 1H, J = 8,6 Hz, aromatické), 6,87 (m, 4H, aromatické), 6,12 (široké t, 1H, NH), 4,87 (široké d, 1H, J = 8,1 Hz, metín), 4,15 (m, 4H, OCH_2a), 3,77 (m, 4H, OCH₃ a OCH_2b), 3,49 (qt, 2H, J = 7,2 Hz, N(H)-CH₂), 3,11 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 3,00 (m, 1H, Ph-CH_2a), 2,77-2,50 (m, 1H, Ph-NC(H₂)-CH_2s-NCH_2s, Ph-CH_2b), 2,15 (m, 1H, C(H)CH_2a), 2,05 (m, 1H, C(H)-CH_2b), 1,25 (t, 3H, J = 7,2 Hz, CH₃ -C(H₂) δ; CMR (75 MHz,-67 porosity 230-400, 30 g; methanol / ethyl acetate 5/95) to give the product. This material was triturated with ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] N-ethyl-isochroman-6-carboxamide (IX), mp = 127-129 ° C; _Rf = 0.30 (methanol / ethyl acetate, 5/95); IR (suspension) 3308, 2815, 1640, 1541, 1514, 1442, 1359, 1312, 1283, 1246, 1149, 1112, 1037, and 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.55 (m, 2H, aromatic), 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 6.12 (broad t, 1H, NH), 4.87 (broad d, 1H, J = 8.1 Hz, meth), 4.15 (m, 4H, OCH _{2 a} ), 3.77 (m, 4H, OCH ₃₎ and OCH _2b ), 3.49 (qt, 2H, J = 7.2 Hz, N (H) -CH ₂ ), 3.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s)} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.77-2.50 (m, 1H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2, 15 (m, 1H, C (H) CH _{2 a} ), 2.05 (m, 1H, C (H) -CH _{2 b} ), 1.25 (t, 3H, J = 7.2 Hz, CH ₃ -C (H ₂ ) δ CMR (75 MHz,

CDCb) 166,9, 153,4, 14, 4, 141,2, 134,1, 132,5, 127,3, 124,7, 124,1, 117,8, 114,1, 74,2, 62,6,(CDCl 3) 166.9, 153.4, 14, 4, 141.2, 134.1, 132.5, 127.3, 124.7, 124.1, 117.8, 114.1, 74.2, 62.6.

55,2, 54,3, 53,2, 50,3, 34,6, 32,9, 28,7 a 14,6 δ; MS (EI, m/z) = 423.55.2, 54.3, 53.2, 50.3, 34.6, 32.9, 28.7 and 14.6 δ; MS (EI, m / z) = 423;

Príklad 28 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-propargyl- izochróman-6karboxamid (IX)Example 28 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-propargyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 25, 2. kroku s drobnými obmenami vzniká z propargylamínu (1,6 ml, 23,0 mmol) surový produkt. Táto látka sa prečistí pomocou LC na 75 g (230-400) silikagélu za elúcie octanom etylnatým, produkt rekryštalizuje zo zmesi octan etylnatý/hexán za vzniku 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-propargyl-izochróman-6karboxamidu (IX), teplota topenia = 162-164 °C; Rf = 0,40 (metanol/octan etylnatý, 5/95); IR (suspenzia) 3287, 1643, 1636, 1611, 1535, 1515, 1495, 1443, 1303, 1283, 1246, 1147, 1107, 1033 a 822 cm'¹; NMR (300 MHz, CDCb) 7,57 (m, 2H, aromatické), 7,17 (d, 1H, J =8,6 Hz, aromatické), 6,85 (m, 4H, aromatické), 6,35 (široké t, 1H, NH), 4,88 (široké d, 1H, J = 8,0 Hz, metín), 4,25 (DD, 2H, J = 5,2 Hz a J = 2,5 Hz, N(H)-CH₂), 4,12 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a OCH_2b), 3,10 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 3,01 (m, 1H, Ph-CH_2a), 2,78-2,50 (m, 7H, Ph-NC(H₂)-CH_2s, Ph-CH_2b), 2,29 (t, 1H, J = 2,5 Hz, alkyl), 2,18 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H)-CH_2b) δ; CMR(75MHz, CDCb) 166,7, 153,6, 145,5, 142,0, 134,4, 131,6,Following the procedure of Example 25, Step 2, with minor variations, the crude product was obtained from propargylamine (1.6 mL, 23.0 mmol). This material was purified by LC on 75 g (230-400) silica gel eluting with ethyl acetate, the product recrystallized from ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargyl-isochroman-6-carboxamide (IX), m.p. = 162-164 ° C; Rf = 0.40 (methanol / ethyl acetate, 5/95); IR (slurry) 3287, 1643, 1636, 1611, 1535, 1515, 1495, 1443, 1303, 1283, 1246, 1147, 1107, 1033, and 822 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.57 (m, 2H, aromatic), 7.17 (d, 1H, J = 8.6 Hz, aromatic), 6.85 (m, 4H, aromatic), 6.35 (broad t, 1H, NH), 4.88 (broad d, 1H, J = 8.0 Hz, meth), 4.25 (DD, 2H, J = 5.2 Hz and J = 2.5 Hz, N (H) -CH ₂ ), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.8 Hz Ph-N-CH _{2 s} ), 3.01 (m, 1H, Ph-CH _{2 a} ), 2.78-2.50 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} , Ph-CH _2b 2.29 (t, 1H, J = 2.5 Hz, alkyl), 2.18 (m, 1H, C (H) -CH _{2 -} ), 2.05 (m, 1H, C (H) - CH _2b ) δ; CMR (75MHz, CDCl3) 166.7, 153.6, 145.5, 142.0, 134.4, 131.6,

127,6, 124,9, 124,4, 118,0, 114,2, 79,3, 74,3, 71,8, 62,7, 55,4, 54,5, 53,3, 50,4, 33,0, 29,6 a127.6, 124.9, 124.4, 118.0, 114.2, 79.3, 74.3, 71.8, 62.7, 55.4, 54.5, 53.3, 50, 4, 33.0, 29.6 and

28,8 δ ; MS (EI, m/z) = 433; HRMS (EI) vypočítaná pre C₂₆H₃iN₃O₃ = 433,2365, nájdená28.8 δ; MS (EI, m / z) = 433; HRMS (EI) calcd for C ₂₆ H ₃ N ₃ O ₃ = 433.2365, found

433.2367.433.2367.

-68Príklad 29 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-(4- metoxy fenyl mety 1)izochróman-6-karboxamid (IX)EXAMPLE 29 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N- (4-methoxyphenylmethyl) isochroman-6-carboxamide (IX)

Postupom podľa príkladu 25, 2. kroku s drobnými obmenami vzniká z 4metoxyfenylmetylamínu (1,2 ml, 9,2 mmol) surový produkt. Tento sa prečistí pomocou rýchlej chromatografie na 67 g silikagélu za použitia zmesi metanol/octan etylnatý, 10/90);Following the procedure of Example 25, Step 2, with minor variations, the crude product was obtained from 4-methoxyphenylmethylamine (1.2 mL, 9.2 mmol). This was purified by flash chromatography on 67 g of silica gel using methanol / ethyl acetate (10/90);

[a]_D = -40° (c = 0,98, etanol); IR (suspenzia) 3306, 1642, 1540, 1515, 1313, 1251, 1244, 1235, 1110, 1036 cm'¹; NMR (300 MHz, CDCb) 7,57 (m, 2H, aromatické H), 7,28 (d, 2H, J = 8,7 Hz, aromatický H), 7,16 (d, 2H, J = 8,7 Hz, aromatický H), 6,92-6,82 (m’s, 6H, aromatické H), 6,27 (m, 1H, C(O)N-H), 4,86 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,8-4,11 (m, 1H), 3,80 (s, 3H, PhOC-Hj), 3,80-3-72 (m, 1H), 3,76 (s, 3H, PhOC-H₃), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 (m, 1H), 2,73 (m z d, 1H, J = 16,4 Hz), 2,66-2,49 (m’s, 6H), 2,15 (m, 1H, pipCH-H), 2,04 (m, 1H, pipCH-H) δ; CMR (75 MHz, CDCb) 166,9, 145,7, 141,7,[α] _D = -40 ° (c = 0.98, ethanol); IR (suspension) 3306, 1642, 1540, 1515, 1313, 1251, 1244, 1235, 1110, 1036 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.57 (m, 2H, aromatic H), 7.28 (d, 2H, J = 8.7 Hz, aromatic H), 7.16 (d, 2H, J = 8, 7 Hz, aromatic H), 6.92-6.82 (m's, 6H, aromatic H), 6.27 (m, 1H, C (O) NH), 4.86 (wt, 1H, J = 5, 8 Hz, PhC-H), 4.8-4.11 (m, 1H), 3.80 (s, 3H, PhOC-H 3), 3.80-3-72 (m, 1H), 3.76 (s, 3H, PhOC-H ₃ ), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (mzd, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H) δ; CMR (75 MHz, CDCl 3) 166.9, 145.7, 141.7,

134,5, 132,4, 130,2, 129,3, 127,7, 125,0, 124,5, 118,12, 114,4, 114,2, 74,5, 62,9, 55,5, 55,3,134.5, 132.4, 130.2, 129.3, 127.7, 125.0, 124.5, 118.12, 114.4, 114.2, 74.5, 62.9, 55, 5, 55.3,

54,6, 53,5, 50,6, 43,6, 33,1, 29,0 δ; HRMS vypočítaná pre C₃iH₃7N₃O4 = 515,2784, nájdená54.6, 53.5, 50.6, 43.6, 33.1, 29.0 δ; HRMS calcd for C 31 H ₃₇ N ₃ O ₄ = 515.2784, found

515,2806.515.2806.

Príklad 30 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-fenylmetyl-izochróman6-karboxamid (IX)Example 30 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-isochroman-6-carboxamide (IX)

V peci vysušená 15 ml skúmavka, vybavená Claisenovým chladičom, vodným chladičom a adaptérom sa naplní l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-metoxyfenyl)piperazínom (VI, 646 mg, 1,5 mmol), octanom paládnatým (98 %, 17,2 mg, 0,075 mmol) aOven-dried 15 ml tube equipped with a Claisen condenser, water condenser and adapter is charged with 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (VI, 646 mg, 1, 5 mmol), palladium acetate (98%, 17.2 mg, 0.075 mmol) and

1,3-bis-difenylfosfinopropánom (97 %, 38,3 mg, 0,09 mmol). V skúmavke sa udržuje atmosféra oxidu uhoľnatého. Do reakčnej nádobky sa pomocou striekačky pridá DMF (3,75 ml), fenylmetylamín 1,15 ml, 10,5 mmol) a diizopripyletylamín (0,52 ml, 3 mmol). Zmes sa zahreje na 100 °C počas 10 hodín. Po schladení na 20-25 °C sa rozdelí na dve fázy. Reakčná zmes sa potom naleje do octanu etylnatého. Zmes sa raz premyje vodným hydroxidom sodným (IN), Organická vrstva potom kondenzuje za zníženého tlaku, po odstránení prebytočných rozpúšťadiel a reaktantov vznikne surový produkt, ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu za použitia octanu etylnatého ako elučného činidla a vznikne l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-fenylmetyl-izochróman-6-karboxamid (IX), teplota topenia =153,0-153,5 °C; Rf = 0,25 (metanol/octan etylnatý, 10/90); IR (suspenzia) 3263, 2819, 1640, 1543, 1513, 1245, 1234, 1112, 1039 a 826 cm'¹; NMR (300 MHz, CDCb) 7,58 (d, 2H, J = 6,9 Hz, aromatické H), 7,36-7,28 (m’s, 5H, aromatické H),1,3-bis-diphenylphosphinopropane (97%, 38.3 mg, 0.09 mmol). A carbon monoxide atmosphere is maintained in the tube. DMF (3.75 mL), phenylmethylamine (1.15 mL, 10.5 mmol) and diisopripylethylamine (0.52 mL, 3 mmol) were added via syringe to the reaction vessel. The mixture was heated to 100 ° C for 10 hours. After cooling to 20-25 ° C, it is separated into two phases. The reaction mixture was then poured into ethyl acetate. The organic layer was then condensed under reduced pressure to remove excess solvents and reactants to give a crude product which was purified by flash chromatography on 100 g of silica gel using ethyl acetate as eluent to give 1- [1 -]. 2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-isochroman-6-carboxamide (IX), m.p. = 153.0-153.5 ° C; Rf = 0.25 (methanol / ethyl acetate, 10/90); IR (slurry) 3263, 2819, 1640, 1543, 1513, 1245, 1234, 1112, 1039, and 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.58 (d, 2H, J = 6.9 Hz, aromatic H), 7.36-7.28 (m's, 5H, aromatic H),

-696,42 (t, 1H, C(O)N-H), 4,86 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,64 (d, 2H, J = 5,7 Hz, PhCH₂), 4,17-4,10 (m, 1H), 3,80-3,72 (m, 1H), 3,76 (s, 3H, PhOC-H₃), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 2,73 (m z d, 1H, J = 16,4 Hz, 2,66-2,49 (m’s, 6H), 2,15 (m, 1H, pipCHH), 2,04 (m, 1H, pipCH-H) δ; CMR (75MHz, CDCb) 189,7, 167,1, 153,8, 145,7, 141,8,-696.42 (t, 1H, C (O) NH), 4.86 (wd, 1H, J = 5.8 Hz, PhC-H), 4.64 (d, 2H, J = 5.7 Hz) PhCH ₂ ), 4.17-4.10 (m, 1H), 3.80-3.72 (m, 1H), 3.76 (s, 3H, PhOC-H ₃ ), 3.10 (t 4H, J = 4.8 Hz, four of pip-H), 2.99 2.73 (mt, 1H, J = 16.4 Hz, 2.66-2.49 (m's, 6H), 2, 15 (m, 1H, pip CHH), 2.04 (m, 1H, pip CH-H) δ; CMR (75MHz, CDCl 3) 189.7, 167.1, 153.8, 145.7, 141.8,

138,2, 134,5, 132,4, 128,8, 127,9, 127,8, 127,6, 125,1, 124,6, 74,5, 62,9, 55,6, 54,6, 53,5,138.2, 134.5, 132.4, 128.8, 127.9, 127.8, 127.6, 125.1, 124.6, 74.5, 62.9, 55.6, 54, 6, 53.5,

50,6,44,1, 33,1, 29,0 δ; HRMS vypočítaná pre C30H35N3O3 = 485,2678, nájdená = 485,2664.50.6,44.1, 33.1, 29.0 δ; HRMS calcd for C 30 H 35 N 3 O 3 = 485.2678, found = 485.2664.

Príklad 31 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-butyl- izochróman-6karboxamid (IX)Example 31 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-butyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z n-butylamínu (1,04 ml,Following the procedure of Example 30 with minor variations, it was formed from n-butylamine (1.04 ml,

10,5 mmol) surový produkt, ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu za použitia octanu etylnatého ako elučného činidla a vzniku produktu, ktorý rekryštalizuje z horúceho octanu etylnatého za vzniku uvedenej zlúčeniny, teplota topenia = 158,5-159,5 °C; Rf= 0,28 (octan etylnatý); IR (suspenzia) 3301, 2816, 1637, 1537, 1515, 1444, 1308, 1244, 1111 a 823 cm⁴; NMR (300 MHz, CDCb) 5,53, 7,16, 6,87, 6,10, 4,85, 3,80-3,67, 3,45, 3,11,(10.5 mmol) of crude product which was purified by flash chromatography on 100 g of silica gel using ethyl acetate as eluent to give a product which was recrystallized from hot ethyl acetate to give the title compound, mp = 158.5-159.5 ° C; Rf = 0.28 (ethyl acetate); IR (suspension) 3301, 2816, 1637, 1537, 1515, 1444, 1308, 1244, 1111 and 823 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl 3) 5.53, 7.16, 6.87, 6.10, 4.85, 3.80-3.67, 3.45, 3.11,

3,10, 2,73, 2,66-2,49, 2,15, 2,04, 1,59, 1,43, 0,96 δ; CMR (75 MHz, CDCb) 167,3, 153,8,3.10, 2.73, 2.66-2.49, 2.15, 2.04, 1.59, 1.43, 0.96 δ; CMR (75 MHz, CDCl 3) 167.3, 153.8,

145,7, 141,5, 134,5, 132,9, 127,6, 125,0, 124,4, 118,2, 114,4, 74,5, 63,0, 55,6, 54,7, 53,5, 50,6,40,0, 39,8, 33,2, 31,8, 29,1, 20,2, 13,8 δ.145.7, 141.5, 134.5, 132.9, 127.6, 125.0, 124.4, 118.2, 114.4, 74.5, 63.0, 55.6, 54, 7, 53.5, 50.6.40.0, 39.8, 33.2, 31.8, 29.1, 20.2, 13.8 δ.

Príklad 32 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-[(R)-ametylfenylnetyl]-izochróman-6-karboxamid (IX)Example 32 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -amethylphenylmethyl] -isochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z (R)-(+)-ametylfenylnetylamínu (98 %, 0,90 ml, 7 mmol) surový produkt, ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu a použitím gradientu 0-4 %metanolu v octane etylnatom. Produkt rekryštalizuje z horúcej zmesi metylénchlorid/octan etylnatý/hexán za vzniku l-[2[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-[(R)-a-metylfenylnetyl]izochróman-6-karboxamidu (IX) ako zmesi diastereomérov, teplota topenia - 140,5-141,0 °C; Rf = 0,28 (octan etylnatý); [α]ϋ - +25° (c = 0,94, etanol); IR (suspenzia) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm⁴; NMR (300 MHz, CDCb) 7,58 (d, 2H, J = 6,9 Hz, aromatické H), 7,41-7,28 (m’s, 5H, aromatické H), 7,16 (d, 1H, J = 8,7 Hz, aromatický H), 6,85 (q, 4H, J = 9,2 Hz, aromatické H). 6,29 (d, 1H, J = 7,8 Hz, C(O)N-H), 5,34 (kvintet, 1H, J = 7,2 Hz, PhC-H),Following the procedure of Example 30 with minor variations, (R) - (+) - Amethylphenylnethylamine (98%, 0.90 mL, 7 mmol) gave the crude product which was purified by flash chromatography on 100 g silica gel using a gradient of 0-4% methanol. in ethyl acetate. The product was recrystallized from hot methylene chloride / ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -α-methylphenylmethyl] isochroman-6-carboxamide ( IX) as mixtures of diastereomers, m.p. = 140.5-141.0 ° C; Rf = 0.28 (ethyl acetate); [α] D = + 25 ° (c = 0.94, ethanol); IR (suspension) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl 3) 7.58 (d, 2H, J = 6.9 Hz, aromatic H), 7.41-7.28 (m's, 5H, aromatic H), 7.16 (d, 1H, J = 8.7 Hz, aromatic H), 6.85 (q, 4H, J = 9.2 Hz, aromatic H). 6.29 (d, 1H, J = 7.8Hz, C (O) NH), 5.34 (quintet, 1H, J = 7.2Hz, PhC-H),

4,86 (m z d, 1H, J = 5,8 Hz, PhC-H). 4,17-4,10 (m, 1H)- 3,80-3,72 (m, 1H), 3,76 (s, 3H, PhOC-Hs), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 (,m 1H), 2,73 (m z d, 1H, J = 16,4 Hz),4.86 (m of d, 1H, J = 5.8 Hz, PhC-H). 4.17-4.10 (m, 1H); 3.80-3.72 (m, 1H); 3.76 (s, 3H, PhOC-H5); 3.10 (t, 4H, J = 4) 8 Hz, four of pip-H), 2.99 (m 1H), 2.73 (mzd, 1H, J = 16.4 Hz),

-702,66-2,49 (m’s, 6H), 2,15 (m, 1H, pipCH-H), 2,04 (m, 1H, pipCH-H), 1,61 (d, 3H, J = 6,9 Hz, PhC(H)C-Hj) δ; CMR (75 MHz, CDClj) 166,2, 153,7, 145,7, 143,0, 141,7, 134,5, 132,6,-702.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H), 1.61 (d, 3H, J = 6.9 Hz, PhC (H) C-H 3 δ; CMR (75 MHz, CDCl 3) 166.2, 153.7, 145.7, 143.0, 141.7, 134.5, 132.6,

128,7, 127,6, 127,4, 126,2, 125,0, 124,5, 118,1, 114,4, 74,5, 62,9, 55,5, 54,6, 53,4, 50,5, 49,1, 33,1,29,0,21,6 δ..128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9, 55.5, 54.6, 53, 4, 50.5, 49.1, 33.1, 29.0, 21.6 δ ..

Príklad 33 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-[(S)-ametylfenylnetyl]izochróman-6-karboxamid (IX)Example 33 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) -amethylphenylmethyl] isochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z (S)-(-)-ametylfenylnetylamínu (98 %, 0,90 ml, 7 mmol) surový produkt, ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu za použitia gradientu 0-7 % metanolu v octane etylnatom. Produkt rekryštalizuje z horúcej zmesi metylénchlorid/octan etylnatý/hexán za vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-[(S)-a-metylfenylnetyl]izochróman-6karboxamidu (IX) ako zmesi diastereomérov, teplota topenia = 140,0-141,5 °C, Rf = 0,28 (octan etylnatý); [oc]d = -24° (c = 0,98, etanol); IR (suspenzia) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm'¹; NMR (300 MHz, CDClj) 7,58 (d, 2H, J = 6,9 Hz, aromatické H), 7,41-7,28 (m’s, 5H, aromatické H), 7,16 (d, 1H, J = 8,7 Hz, aromatický H), 6,85 (q, 4H, J =Following the procedure of Example 30 with minor variations, (S) - (-) - Amethylphenylnethylamine (98%, 0.90 mL, 7 mmol) gave the crude product which was purified by flash chromatography on 100 g silica gel using a gradient of 0-7% methanol. in ethyl acetate. The product is recrystallized from hot methylene chloride / ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) -α-methylphenylmethyl] isochroman-6-carboxamide (IX) ) as mixtures of diastereomers, m.p. = 140.0-141.5 ° C, R f = 0.28 (ethyl acetate); [α] D = -24 ° (c = 0.98, ethanol); IR (suspension) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl 3) 7.58 (d, 2H, J = 6.9 Hz, aromatic H), 7.41-7.28 (m's, 5H, aromatic H), 7.16 (d, 1H, J = 8.7 Hz, aromatic H), 6.85 (q, 4H, J =

9,2 Hz, aromatické H), 6,29 (d, 1H, J = 7,8 Hz, C(O)N-H), 5,34 (kvintet, 1H, J = 7,2 Hz, PhCH), 4,86 (m z d, 1H, J = 5,8 Hz, PhC-H). 4,17-4,10 (tn, 1H)- 3,80-3,72 (m, 1H), 3,76 (s, 3H, PhOC-Hj), 3,10 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 (m 1H), 2,73 (m z d, 1H, J = 16,4 Hz),9.2 Hz, aromatic H), 6.29 (d, 1H, J = 7.8 Hz, C (O) NH), 5.34 (quintet, 1H, J = 7.2 Hz, PhCH), 4 86 (m / z, 1H, J = 5.8 Hz, PhC-H). 4.17-4.10 (tn, 1H); 3.80-3.72 (m, 1H); 3.76 (s, 3H, PhOC-H3); 3.10 (t, 4H, J = 4) 8 Hz, four of pip-H), 2.99 (m IH), 2.73 (mzd, 1H, J = 16.4 Hz),

2,66-2,49 (m’s, 6H), 2,15 (m, 1H, pipCH-H), 2,04 (m, 1H, pipCH-H), 1,61 (d, 3H, J = 6,9 Hz, PhC(H)C-Hj) Ô; CMR (75 MHz, CDClj) 166,2, 153,7, 145,7, 143,0, 141,7, 134,5, 132,6,2.66-2.49 (m's, 6H), 2.15 (m, 1H, pipCH-H), 2.04 (m, 1H, pipCH-H), 1.61 (d, 3H, J = 6) .9 Hz, PhC (H) (C-H) -; CMR (75 MHz, CDCl 3) 166.2, 153.7, 145.7, 143.0, 141.7, 134.5, 132.6,

128,7, 127,6, 127,4, 126,2, 125,0, 124,5, 118,1, 114,4, 74,5, 62,9, 55,5, 54,6, 53,4, 50,5, 49,1, 33,1,29,0,21,6 δ..128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9, 55.5, 54.6, 53, 4, 50.5, 49.1, 33.1, 29.0, 21.6 δ ..

Príklad 34 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-fenyl- izochróman-6karboxamid (IX)Example 34 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z anilínu (0,64 ml, 7 mmol) surový produk, ktorý sa prečistí pomocou LC chromatografie na 29 g (230-400) silikagélu za elúcie zmesou octan etylnatý/hexán (75/25) a vzniku l-[2-[4-(4-metoxyfenyl)-lpiperazinyl]etyl]-N-fenyl-izochróman-6-karboxamidu (IX), Rf = 0,25 (octan etylnatý/hexán, 75/25); IR (suspenzia) 2817, 1652, 1599, 1531, 1513, 1442, 1320, 1298, 1246, 1145, 1112, 1038, 823, 754, 693 cm’¹; NMR (300 MHz, CDClj) 7,87 (s, 1H, NH), 7,63 (m, 4H, aromatické), 7,37 (t, 2H, J = 7,7 Hz, aromatické), 7,21 (d, 1H, J = 7,9 Hz, aromatické), 7,18Following the procedure of Example 30 with minor variations, an aniline (0.64 mL, 7 mmol) was obtained which was purified by LC chromatography on 29 g (230-400) silica gel, eluting with ethyl acetate / hexane (75/25); formation of 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenyl-isochroman-6-carboxamide (IX), R f = 0.25 (ethyl acetate / hexane, 75/25); IR (suspension) 2817, 1652, 1599, 1531, 1513, 1442, 1320, 1298, 1246, 1145, 1112, 1038, 823, 754, 693 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.87 (s, 1H, NH), 7.63 (m, 4H, aromatic), 7.37 (t, 2H, J = 7.7 Hz, aromatic), 7.21 (d, 1H, J = 7.9 Hz, aromatic), 7.18

-71(t, 1H, J = 6,3 Hz, aromatické), 6,85 (m, 4H, aromatické), 4,88 (široké d, 1H, J = 6,0 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a 0CH_2b), 3,11 (t, 4H, J = 4,9 Hz, Ph-NCH_2s), 2,15 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H>CH_2b) ) δ; CMR (75MHz, CDC1₃) 165,5,-71 (t, 1H, J = 6.3 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.88 (broad d, 1H, J = 6.0 Hz, meth), 4.15 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.11 (t, 4H, J = 4.9 Hz, Ph-NCH _{2 s} ), 2.15 (m 1 H, C (H) -CH _{2 a} ), 2.05 (m, 1H, C (H 2 CH _{2 b} )) δ; CMR (75 MHz, CDC1 ₃₎ 165.5,

153,8, 145,7, 142,2, 137,9, 134,8, 133,0, 129,1,127,8, 125,3, 124,6, 124,5, 118,2, 114,4, 74,5,153.8, 145.7, 142.2, 137.9, 134.8, 133.0, 129.1, 127.8, 125.3, 124.6, 124.5, 118.2, 114.4, 74.5.

62,9, 55,6, 54,7, 53,5, 50,6, 33,2, 29,1 δ.62.9, 55.6, 54.7, 53.5, 50.6, 33.2, 29.1 δ.

Príklad 35 1 -[2-[4-(4-metoxyfenyl)-1 -piperaziny l]etyl]-N-fenylmetyl-N-metylizochróman-6-karboxamid (IX)Example 35 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-N-methylisochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z fenylmetymetylamínu (1,4 ml, 10,5 mmol) surový produkt, ktoiý sa prečistí pomocou LC chromatografie na 77 g (230-400) silikagélu za elúcie zmesou acetón/hexán (40/60), postupného zvýšenia pomeru acetón/hexán (60/40) a vzniku produktu. Látka sa rozpustí v éteri a pôsobí sa na ňu plynnou kyselinou chlorovodíkovou za vzniku tuhej zložky. Voľná báza Rf = 0,30 (acetón/hexán, 40/60); disoľ IR (suspenzia) 3423, 2352, 2192, 1627, 1513, 1495, 1400, 1331, 1310, 1294, 1259, 1193, 1106, 1073, 1028 cm’¹; NMR voľnej bázy (300 MHz, CDC1₃) 7,26 (m, 8H, aromatické), 6,84 (m, 4H, aromatické), 4,84 (bs, 1H, metín), 4,75 (bs, 1H, Ph-CH_2a-N), 4,54 (m, 1H, Ph-CH_2b-N), 4,12 (m, 1H, OCH_2a), 3,76 (m, 4H, 0CH₃ a OCH_2b), 3,08 (t, 4H, J = 4,7 Hz, Ph-CH_2s, Ph-CH_2s), 3,02-2,88 (m, 4H, NCH₃ a PH-CH_2a), 2,64 (m, 7H, Ph-NC(H₂)-CH_2sNCH_2s, Ph-CH_2b), 2,15 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H)-CH_2b) δ ; HRMS (El) vypočítaná pre C₃iH₃₇N₃O₃ = 499,2835, nájdená = 499,2842.Following the procedure of Example 30 with minor variations, phenylmethylamine (1.4 mL, 10.5 mmol) was obtained, which was purified by LC chromatography on 77 g (230-400) silica gel, eluting with acetone / hexane (40/60). , gradually increasing the acetone / hexane ratio (60/40) and forming the product. Dissolve the substance in ether and treat with gaseous hydrochloric acid to form a solid. Rf = 0.30 (acetone / hexane, 40/60) free base; IR (suspension) 3423, 2352, 2192, 1627, 1513, 1495, 1400, 1331, 1310, 1294, 1259, 1193, 1106, 1073, 1028 cm ^-1 ; NMR of free base (300 MHz, CDCl ₃ ) 7.26 (m, 8H, aromatic), 6.84 (m, 4H, aromatic), 4.84 (bs, 1H, meth), 4.75 (bs, 1H) Ph-CH ₂ -N), 4.54 (m, 1H, Ph-CH _2b -N), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b) ), 3.08 (t, 4H, J = 4.7 Hz, Ph-CH _{2 s} , Ph-CH _{2 s} ), 3.02-2.88 (m, 4H, NCH ₃ and PH-CH _{2 a} ), 2 64 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH _{2 s} , Ph-CH _2b ), 2.15 (m, 1H, C (H) -CH _2a ), 2.05 (m, 1H , C (H) -CH _2b) δ; HRMS (El) calculated for C ₃ H ₃₇ N ₃ O ₃ = 499.2835, found = 499.2842.

Príklad 36 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N,N-dimetyl- izochróman-6karboxamid (IX)Example 36 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX)

Plameňom vysušená 50 ml nádoba vybavená miešacou tyčinkou a prídavným lievokom sa naplní čerstvo vydestilovaným tetrahydrofuránom (6 ml), schladeným na -78 °C a pridá sa 1,7 M roztok terc.-butyllítia (3,0 ml, 5,0 mmol). Do výslednej zmesi sa počas 10 minút nakvapká roztok l-(2-)6-bromoizochróman-l-yl)-etyl)-4-(4-metoxyfenyl)piperazínu (VI, 1,08 g, 2,5 mmol) a 4 ml tetrahydrofuránu (507 mg, 3,3 mmol). Aryllítium sa mieša 10 minút a potom sa pridá oxid uhoľnatý (najlepšie suchý). Po tomto prídavku sa za 10 minút zahreje aryl karboxylát na 20-25 °C so suspendovaným pridaným plynom. K zmesi sa pridá dietylformamid (2 kvapky) a oxalyl chlorid (0,33 ml, 3,75 mmol) za vývinu množstva plynu a tmavého sfarbenia. Po 45 minútach sa na zmes nechá pôsobiť plynný dimetylamín. Po 20 minútach sa pridávanie amínu zastaví a reakčná zmes sa rozpustí v 40 ml 5M hydroxiduA flame dried 50 mL flask equipped with a stir bar and an addition funnel was charged with freshly distilled tetrahydrofuran (6 mL), cooled to -78 ° C, and 1.7 M tert-butyllithium solution (3.0 mL, 5.0 mmol) was added. . To the resulting mixture was added dropwise a solution of 1- (2-) 6-bromoisochroman-1-yl) -ethyl) -4- (4-methoxyphenyl) piperazine (VI, 1.08 g, 2.5 mmol) and 4 mL of water over 10 minutes. mL of tetrahydrofuran (507 mg, 3.3 mmol). The aryl lithium is stirred for 10 minutes and then carbon monoxide (preferably dry) is added. After this addition, the aryl carboxylate is heated to 20-25 ° C with the added gas suspended in 10 minutes. Diethylformamide (2 drops) and oxalyl chloride (0.33 mL, 3.75 mmol) were added to the mixture to evolve a lot of gas and dark color. After 45 minutes, the mixture was treated with dimethylamine gas. After 20 minutes the addition of the amine is stopped and the reaction mixture is dissolved in 40 ml of 5M hydroxide

-72sodného a dvakrát extrahuje octanom etylnatým (40 ml). Zmiešané organické látky sa dvakrát premyjú v soľanke (30 ml), vysušia pomocou síranu horečnatého, prefiltrujú a zahustia za vzniku produktu, prečistia pomocou LC chromatografie na 63 g (230-400) silikagélu za elúcie zmesou acetón/hexán (50/50) a vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N,Ndimetyl-izochróman-6-karboxamidu (IX), teplota topenia = 94-96 °C ; Rf = 0,31 (acetón/hexán, 50/50); IR (suspenzia) 2808, 2792, 1624, 1610, 1513, 1488, 1444, 1414, 1275, 1253, 1231, 1152, 1109, 1036, 833 cm'¹; NMR (300 MHz, CDClj) 7,19 (m, 2H, aromatické),Sodium bicarbonate and extracted twice with ethyl acetate (40 mL). The combined organics were washed twice in brine (30 mL), dried over magnesium sulfate, filtered and concentrated to give the product, purified by LC chromatography on 63 g (230-400) silica gel eluting with acetone / hexane (50/50) and to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX), m.p. = 94-96 ° C; Rf = 0.31 (acetone / hexane, 50/50); IR (suspension) 2808, 2792, 1624, 1610, 1513, 1488, 1444, 1414, 1275, 1253, 1231, 1152, 1109, 1036, 833 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl 3) 7.19 (m, 2H, aromatic),

7,12 (d, 1H, J = 7,9 Hz, aromatické), 6,85 (m, 4H, aromatické), 4,85 (široké d, 1H, J = 56,0 Hz, metín), 4,13 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃a OCH_2b), 3,13-3,00 (m, 11H, NCH₃s,7.12 (d, 1H, J = 7.9 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.85 (broad d, 1H, J = 56.0 Hz, meth), 4, 13 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.13-3.00 (m, 11H, NCH ₃ s,

Ph-NCH₂s, Ph-CH_2a), 2,65 (m, 7H, Ph-NC(H₂)-CH_2s-NCH₂ aPh-CH_2b), 2,17 (m, 1H, C(H)CH_2a), 2,05 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDC1₃) 171,2, 153,5, 145,5, 139,4, 134,2,Ph-NCH ₂ s, Ph-CH _{2 a} , 2.65 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ and Ph-CH _{2 b} ), 2.17 (m, 1H, C (H) 1 CH ₂ ), 2.05 (m, 1H, C (H) -CH _2b ) δ; CMR (75 MHz, CDC1 ₃₎ 171.2, 153.5, 145.5, 139.4, 134.2,

134,0, 127,5, 124,6, 124,4, 117,9, 114,2, 74,3, 62,7, 55,3, 54,5, 53,3, 50,4, 39,4, 35,1, 33,0,134.0, 127.5, 124.6, 124.4, 117.9, 114.2, 74.3, 62.7, 55.3, 54.5, 53.3, 50.4, 39, 4, 35.1, 33.0,

28,8 δ; HRMS (EI) vypočítaná pre C₂jH₃₃N₃O₃ = 423,2522, nájdená = 423,2520.28.8 δ; HRMS (EI) calcd for C ₂₁ H ₃₃ N ₃ O ₃ = 423.2522, found = 423.2520.

Príklad 37 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-metyl- izochróman-6karboxamid (IX)Example 37 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z plynného metylamínu a za zachovania množstva všetkých ďalších reagencií l-[2-[4-(4-metoxyfenyl)-lpiperazinyl]etyl]-N-metylizochróman-6-karboxamid (IX), ktorý rekryštalizuje z octanu etylnatého za vzniku uvedenej zlúčeniny, teplota topenia = 174-176 °C; Rf = 0,40 (metanol/dichlórmetán, 5/95); IR (suspenzia) 3270, 1639, 1543, 1515, 1418, 1319, 1260, 1248, 1235, 1152, 1141, 1112, 1037, 832 a 820 cm’¹; NMR (300 MHz, CDC1₃) 7,53 (m, 2H, aromatické), 7,16 (d, 1 H, J = 8,6 Hz, aromatické), 6,87 (m, 4H, aromatické)6,19 (široké m, 1H, NH), 4,86 (široké d, 1H, J = 5,9 Hz, metín), 4,14 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃a OCH_2b), 3,10 (t, 4H, J = 4,8 Hz, Ph_N-CH_2s), 3,00 (d, 4H, N_CH₃a Ph-CH_2a), 2,77-2,49 (m, 7H, Ph-NC(H₂)- CH_2s-NCH_2s, Ph-CH_2b), 2,14 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H)-CH_2b) Ô; CMR (75MHz, CDC1₃) 168,0, 153,8, 145,7, 141,6, 134,5, 132,7, 125,0, 124,4, 118,2,Following the procedure of Example 30, with minor variations, it was formed from methylamine gas and retained the amount of all other reagents 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), which recrystallized from ethyl acetate to give the title compound, m.p. = 174-176 ° C; Rf = 0.40 (methanol / dichloromethane, 5/95); IR (slurry) 3270, 1639, 1543, 1515, 1418, 1319, 1260, 1248, 1235, 1152, 1141, 1112, 1037, 832, and 820 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.53 (m, 2H, aromatic), 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m, 4H, aromatic) 6, 19 (broad m, 1H, NH), 4.86 (broad d, 1H, J = 5.9 Hz, meth), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH) ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.8 Hz, Ph_N-CH _{2 s} ), 3.00 (d, 4H, N-CH ₃ and Ph-CH _{2 a} ), 2.77-2, 49 (m, 7H, Ph-NC (H ₂ ) - CH _{2 s} -NCH _{2 s} , Ph-CH _{2 b} ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2.05 (m, 1H , C (H) -CH _2b) delta; CMR (75 MHz, CDC1 ₃₎ 168.0, 153.8, 145.7, 141.6, 134.5, 132.7, 125.0, 124.4, 118.2,

114,4, 74,5, 62,9, 55,6, 54,6, 53,5, 50,6, 33,1, 29,1, 26,8 δ; HRMS (EI) vypočítaná pre C₂4H₃iN₃O₃ = 409,2365, nájdená = 409,2366.114.4, 74.5, 62.9, 55.6, 54.6, 53.5, 50.6, 33.1, 29.1, 26.8 δ; HRMS (EI) for C ₂ 4 H ₃ IN ₃ O ₃ = 409.2365, found = 409.2366.

Príklad 38 1 -[2-[4-(4-chlórfenyI)-1 -piperazinyl]etyl]-N-metyl-izochróman-6karboxamid (IX)Example 38 1- [2- [4- (4-Chloro-phenyl) -1-piperazinyl] -ethyl] -N-methyl-isochroman-6-carboxamide (IX)

-Ti Postupom podľa príkladu 36 s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)-etyl]-4-(4-chlórfenyl)-piperazínu (VI, Príklad 8, 2. krok, 188 mg, 0,43 mmol) a metylamínu produkt, ktorý sa prečistí na LC na 10 g (230-400) silikagélu za elúcie 40 % zmesou acetón/hexán a vzniku l-[2-[4-(4-chlórfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamidu (IX), teplota topenia = 158-160 °C; Rf = 0,21 (40 % acetón/hexán); IR (suspenzia) 3319, 3263, 1613, 1597, 1571, 1545, 1497, 1334, 1314, 1239, 1150, 1139, 1109, 816 cm'¹; NMR (300 MHz, CDCb), 7,54 (široké s, 2H, aromatické), 7,16 (m, 3H, aromatické), 6,84 (d, 2H, J = 9,0 Hz, aromatické), 6,21 (široké m, 1H, NH), 4,86 (široké d, 1H, J = 6,0 Hz, metín), 4,12 (m, 1H, OCH_2a), 3,77 (m, 1H, NH), 3,17 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 3,00 (d, 4H, J = 4,9 Hz, N-CH₃ a Ph-CH_2a), 2,77-2,45 (m, 7H, Ph-NC(H₂)CH_2s-NCH_2s, Ph-CH_2b), 2,18 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H(-CH_2b) δ; CMR (75MHz, CDCb) 167,7, 149,7, 141,3, 134,2, 132,4, 128,7, 127,4, 124,7, 124,2, 124,1, 112,9,The procedure of Example 36, with slight variations, gave 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-chlorophenyl) -piperazine (VI, Example 8, Step 2, 188 mg, 0). , 43 mmol) and methylamine product, which is purified by LC on 10 g (230-400) silica gel eluting with 40% acetone / hexane to give 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), m.p. = 158-160 ° C; Rf = 0.21 (40% acetone / hexane); IR (suspension) 3319, 3263, 1613, 1597, 1571, 1545, 1497, 1334, 1314, 1239, 1150, 1139, 1109, 816 cm ^-1 ; NMR (300 MHz, CDCl 3), 7.54 (broad s, 2H, aromatic), 7.16 (m, 3H, aromatic), 6.84 (d, 2H, J = 9.0 Hz, aromatic), 6 21 (broad m, 1H, NH), 4.86 (broad d, 1H, J = 6.0 Hz, meth), 4.12 (m, 1H, OCH _{2 a} ), 3.77 (m, 1H, NH), 3.17 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J = 4.9 Hz, N-CH ₃ and Ph-CH _{2 a)} ), 2.77-2.45 (m, 7H, Ph-NC (H ₂ ) CH ₂ -NCH _{2 s} , Ph-CH _{2 b} ), 2.18 (m, 1H, C (H) -CH _2a ), 2.05 (m, 1 H, C (H (CH _{2 b)} δ; CMR (75 MHz, CDCl) 167.7, 149.7, 141.3, 134.2, 132.4, 128.7, 127, 4, 124.7, 124.2, 124.1, 112.9,

74,2, 62,7, 54,3, 53,0, 48,9, 32,9, 28,8, 26,6 δ; HRMS (EI) vypočítaná pre C₂₃H₂₈C1N₃O₂ = 413,1870, nájdená 413,1867.74.2, 62.7, 54.3, 53.0, 48.9, 32.9, 28.8, 26.6 δ; HRMS (EI) calcd for C ₂₃ H ₂₈ ClN ₃ O ₂ = 413.1870, found 413.1867.

Príklad 39 1 -[2-[4-(4-chlórfenyl)-1 -piperazinyl]etyl]-N,N-dimetyl-izochróman-6karboxamid (IX)Example 39 1- [2- [4- (4-Chloro-phenyl) -1-piperazinyl] -ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX)

Postupom podľa príkladu 36 s drobnými obmenami vzniká z 1-(2-(6brómizochróman-l-yl)-etyl]-4-(4-chlórfenyl)-piperazínu (VI, Príklad 8, 2. krok, 188 mg, 0,43 mmol) a dimetylamínu 50 mg (27 %) l-[2-[4-(4-chlórfenyl)-l-piperazinyl]etyl]-N,N-dimetylizochróman-6-karboxamid (IX). Táto látka sa prevedie na dichloridovú soľ pomocou plynnej kyseliny chlorovodíkovej a rekryštralizácie, teplota topenia = 119-122 °C ; Rf = 0,41 (40 % acetón/hexán); IR (suspenzia) 3411, 2507, 2421, 2336, 1628, 1570, 1496, 1397, 1334, 1286, 1263, 1170, 1110, 1095, 1057 cm'¹; voľná báza; NMR (300 MHz, CDCb) 7,20 (m, 4H aromatické), 7,12 (d, 1H, J = 7,9 Hz, aromatické), 6,83 (d, 2H, J = 9,1 Hz, aromatické), 4,86 (široké d, 1H, J = 6,0 Hz, metín), 4,13 (m,lH, OCH_2a), 3,76 (m, 1H, OCH_2b), 3,18 (t, 4H, J =Following the procedure of Example 36 with minor variations, 1- (2- (6-bromoisochroman-1-yl) -ethyl) -4- (4-chlorophenyl) -piperazine (VI, Example 8, Step 2, 188 mg, 0.43) was formed. mmol) and dimethylamine 50 mg (27%) of 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (IX). hydrochloric acid salt and recrystallization, m.p. = 119-122 ° C; R f = 0.41 (40% acetone / hexane); IR (suspension) 3411, 2507, 2421, 2336, 1628, 1570, 1496, 1397, 1334, 1286, 1263, 1170, 1110, 1095, 1057 cm ^-1 ; free base; NMR (300 MHz, CDCl 3) 7.20 (m, 4H aromatic), 7.12 (d, 1H, J = 7.9) Hz, aromatic), 6.83 (d, 2H, J = 9.1 Hz, aromatic), 4.86 (broad d, 1H, J = 6.0 Hz, meth), 4.13 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _{2 b} ), 3.18 (t, 4H, J =

4,9 Hz, Ph-NCH_2s), 3,10-3,00 (m, 1H, NCH₃s a Ph-CH_2a), 2,60 (m, 7H, Ph-NC(H₂)-CH_2sNCH₂a Ph-CH_2b), 2,14 (m, 1H, C(H)-CH_2a), 2,60 (m, 1H, C(H)-CH_2b) ) δ; CMR (75 MHz, CDCb) 171,3, 149,7, 139,3, 134,3, 134,1, 128,8, 127,5, 124,7, 124,5, 117,0, 74,3, 62,8, 54,4, 53,0,48,9, 39,4, 35,2, 32,9,28,8 δ; HRMS vypočítaná pre C₂₄H₃₀ClN₃O₂ = 427,2026, nájdená = 427,2020.4.9 Hz, Ph-NCH _{2 s} ), 3.10-3.00 (m, 1H, NCH ₃ with Ph-CH _{2 a} ), 2.60 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s)} NCH ₂ and Ph-CH _2b ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2.60 (m, 1H, C (H) -CH _{2 b} )) δ; CMR (75 MHz, CDCl 3) 171.3, 149.7, 139.3, 134.3, 134.1, 128.8, 127.5, 124.7, 124.5, 117.0, 74.3 , 62.8, 54.4, 53.0, 48.9, 39.4, 35.2, 32.9, 28.8 δ; HRMS calcd for C ₂₄ H ₃₀ ClN ₃ O ₂ = 427.2026, found = 427.2020.

Príklad 40 l-[2-[4-fenylpiperazinyl]etyl]izochróman-6-karboxamid (VII)Example 40 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII)

-741. krok:l-[2-(6-brómizochróman-l-yl)acetyl]-4-fenylpiperazín (V)-741. step: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V)

Postupom podľa príkladu 1,3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman 1-yl-octovej kyseliny (IV, Príklad 7, 1. krok) a N-fenylpiperazínu [2-(6brómizochróman-l-yl)acetyl]-4-fenylpiperazín (V), Rf = 0,20 (40 % octan etylnatý/hexán); IR (suspenzia) 1641, 1599, 1495, 1482, 1442, 1406, 1329, 1278, 1232, 1171, 1156, 1107, 1027, 760, 694 cm¹; NMR (300 MHz, CDC1₃) 7,29 (m, 4H, aromatické), 7,00 (d, 1H, J = 8,2 Hz, aromatické), 6,91 (m, 3H, aromatické), 5,26 (široké d, 1H, J = 5,8 Hz, metín), 4,11 (m, 1H, OCH_2a), 3,91 (dt, 1H, J = 136 Hz a J = 5,1 Hz, O=C-N-CH_2a), 3,72 (m, 4H, O=C-N-CH_2bcd„ OCH_2b), 3,18 (t, 4H, J = 4,9 Hz, Ph-NCH₂s), 2,95 (m, 2H, Ph-CH_2a a N-CO-CH_2a), 2,76 (dd,Following the procedure of Example 1.3. Step with minor variations is formed from racemic 6-bromoisochroman-1-yl-acetic acid (IV, Example 7, Step 1) and N-phenylpiperazine [2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V), Rf = 0.20 (40% ethyl acetate / hexane); IR (suspension) 1641, 1599, 1495, 1482, 1442, 1406, 1329, 1278, 1232, 1171, 1156, 1107, 1027, 760, 694 cm &^lt; -1 ^&gt;; NMR (300 MHz, CDCl ₃ ) 7.29 (m, 4H, aromatic), 7.00 (d, 1H, J = 8.2 Hz, aromatic), 6.91 (m, 3H, aromatic), 5, 26 (broad d, 1H, J = 5.8 Hz, meth), 4.11 (m, 1H, OCH _{2 a} ), 3.91 (dt, 1H, J = 136 Hz and J = 5.1 Hz, O = CN-CH _{2 a} ), 3.72 (m, 4H, O = CN-CH _2bcd OCH _2b ), 3.18 (t, 4H, J = 4.9 Hz, Ph-NCH ₂ s), 95 (m, 2H, Ph-CH _{2 a} and N-CO-CH _{2 a} ), 2.76 (dd,

1H, J = 14,8 Hz aJ = 4,9 Hz, N-C0-CH_2b), 2,65 (bd, 1H, J =16,4 Hz, Ph-CH_2b) δ; CMR (75 MHz, CDC1₃) 168,8, 150,7, 136,2, 136,1, 131,5, 129,2, 129,0, 126,2, 120,2, 120,1, 116,3,1H, J = 14.8 Hz and J = 4.9 Hz, N-CO-CH2 ₂ ), 2.65 (bd, 1H, J = 16.4 Hz, Ph-CH2 _2b ) δ; CMR (75 MHz, CDC1 ₃₎ 168.8, 150.7, 136.2, 136.1, 131.5, 129.2, 129.0, 126.2, 120.2, 120.1, 116, 3

73,2, 63,3, 49,5, 49,0, 45,8, 41,6, 39,7, 28,5 δ; HRMS (EI) vypočítaná pre C₂iH₂₃BrN₂O₂ = 414,0943, nájdená 414,0937.73.2, 63.3, 49.5, 49.0, 45.8, 41.6, 39.7, 28.5 δ; HRMS (EI) for C ₂ H ₂₃ BrN ₂ O ₂ = 414.0943, found 414.0937.

2. krok: l-[2-(6-brómizochróman-l-yl)-etyl]-4-fenylpiperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4-phenylpiperazine (VI)

Postupom podľa príkladu 1,4. krok s drobnými obmenami vzniká z 1-(2-(6brómizochróman-1 -yl)acetyl]-4-fenylpiperazínu (V) 1 -[2-(6-brómizochróman-1 -yl)-ety 1]-4fenylpiperazín (VI), ktorý sa rozpustí v éteri (30 ml) a vystaví sa pôsobeniu plynnej kyseliny chlorovodíkovej. Surová soľ rekryštalizuje zo zmesi octan etylnatý/hexán, teplota topenia = 241-242 °C; Rf = 0,25 (40 % octan etylnatý/hexán,); dvojsoľ IR (suspenzia) 2532, 2510, 2482, 2348, 2205, 1596, 1494, 1425, 1407, 1112, 1100, 980, 884, 764, 694 cm'¹; voľná báza NMR (300 MHz, CDC1₃) 7,26 (m, 4H, aromatické), 6,94 (m, 3H, aromatické), 6,85 (ζ 1H, J = 7,3 Hz, aromatické), 4,78 (široké d, 1H, J = 5,8 Hz, metín), 4,11 (m, 1H, OCH_2a), 3,74 (m, 1H, OCH_2b), 3,20 (t, 4H, J = 4,9 Hz, Ph-NCH₂s), 2,93 (m, 1H, Ph-CH_2a), 2,65 (m, 7H, PhNC(H₂)-CH_2s-NCH₂ a Ph-CH_2b), 2,09 (m, 1H, C(H)-CH_2a), 2,00 (m, 1H, C(H)-CH_2b) δ; CMR(75MHz, CDC1₃) 151,6, 137,8, 136,3, 131,6, 129,3, 129,1, 126,5, 120,0, 119,6, 116,0,Following the procedure of Example 1.4. a small variation step results from 1- (2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V) 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperazine (VI) The crude salt was recrystallized from ethyl acetate / hexane, mp = 241-242 ° C; R f = 0.25 (40% ethyl acetate / hexane), m.p. IR salt (suspension) 2532, 2510, 2482, 2348, 2205, 1596, 1494, 1425, 1407, 1112, 1100, 980, 884, 764, 694 cm ^-1 ; free base NMR (300 MHz, CDCl ₃ ) 7.26 (m, 4H, aromatic), 6.94 (m, 3H, aromatic), 6.85 (ζ 1H, J = 7.3 Hz, aromatic), 4.78 (broad d, 1H, J = 5.8 Hz, meth), 4.11 (m, 1H, OCH _{2 a} ), 3.74 (m, 1H, OCH _2b ), 3.20 (t, 4H, J = 4.9 Hz, Ph-NCH ₂ s), 2.93 (m, 1H, Ph-CH _{2 a} ), 2.65 (m, 7H, PhNC (H ₂ ) -CH ₂ -NCH ₂ and Ph-CH _2b ), 2.09 (m, 1H, C (H) -CH _2a ), 2.00 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 151.6, 137.8, 136.3, 131, 6, 129.3, 129.1, 126.5, 120.0, 119.6, 116.0,

74,3, 62,8, 54,6, 53,4, 49,1, 33,2, 28,8, δ; MS (EI, m/z) = 400.74.3, 62.8, 54.6, 53.4, 49.1, 33.2, 28.8, δ; MS (EI, m / z) = 400;

3. krok: l-[2-[4-fenylpiperazinyl]etyl]izochróman-6-karboxamid (VII)Step 3: 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII)

Plameňom vysušená 10 ml nádoba vybavená miešacou tyčinkou a lievikom sa naplní čerstvo vydestilovaným tetrahydrofuránom (2 ml), schladený na -78 °C a zmieša sa s roztokom terc.-butyllítia (1,7M, 1,3 ml, 2,3 mmol). Výsledná zmes sa 5 minút mieša a poA flame dried 10 mL flask equipped with a stir bar and a funnel was charged with freshly distilled tetrahydrofuran (2 mL), cooled to -78 ° C, and mixed with a solution of tert-butyllithium (1.7M, 1.3 mL, 2.3 mmol). . The resulting mixture was stirred for 5 min

-75kvapkách sa pridá roztok l-[2-(6-brómizochróman-l-yl)-etyl]-4-fenylpiperazínu (VI, 431 mg,A solution of 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4-phenylpiperazine (VI, 431 mg,

1,1 mmol) v 6 ml tetrahydrofuránu. Aryl lítium sa 10 minút mieša a pomocou hadičky sa pridá do plameňom vysušenej 25 ml fľaše s tyčinkou obsahujúcou čerstvo vydestilovaný trimetylsilylizokyanát (0,22 ml, 1,6 mmol) a 2 ml tetrahydrofuránu, tiež schladené na -78 °C. Výsledná zmes sa zahreje na 20-25 °C na 2 hodiny, zriedi 25 ml nasýteného chloridu amónneho, prchavé látky sa odstránia za zníženého tlaku , upaví sa pH na 13, dvakrát sa extrahuje octanom etylnatým (35 ml) a zmiešané organické extrakty sa dvakrát premyjú soľankou (25 ml), vysušia pomocou chloridu horečnatého, prefiltrujú a zahustia. Látka sa prečistí pomocou LC na 27 g (230-400) silikagélu za elúcie 5 % zmesi metanol/octan etylnatý a vzniku l-[2-[4-fenylpiperazinyl]etyl]izochróman-6-karboxamidu (VII), IR (suspenzia) 3350, 3189, 3057, 1663, 1600, 1570, 1503, 1496, 1427, 1336, 1238, 1143, 1110, 760, 692 cm' báza NMR (300 MHz, CDC1₃), 7,599 (m, 2H, aromatické), 7,26 (t, 2H, J = 8,2 Hz, aromatické), 7,18 (d, 1H, J = 8,5 Hz, aromatické), 6,93 (d, 2H, J = 7,9 Hz, aromatické), 6,85 (t, 1H, J = 7,2 Hz, aromatické), 6,10 (široké s, 1H, NH), 5,75 (široké s, 1H, NH), 5,75 ), 4,88 (široké d, 1H, J = 5,9 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,77 (m, 1H, OCH_2b), 3,21 (t, 4H, J =1.1 mmol) in 6 mL of tetrahydrofuran. The aryl lithium was stirred for 10 minutes and added to a flame dried 25 mL bar flask containing freshly distilled trimethylsilyl isocyanate (0.22 mL, 1.6 mmol) and 2 mL tetrahydrofuran, also cooled to -78 ° C, via a tube. The resulting mixture was warmed to 20-25 ° C for 2 hours, diluted with 25 mL saturated ammonium chloride, the volatiles were removed under reduced pressure, the pH was adjusted to 13, extracted twice with ethyl acetate (35 mL), and the combined organic extracts were extracted twice washed with brine (25 mL), dried over magnesium chloride, filtered and concentrated. Purify by LC on 27 g (230-400) silica gel eluting with 5% methanol / ethyl acetate to give 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII), IR (suspension) 3350, 3189, 3057, 1663, 1600, 1570, 1503, 1496, 1427, 1336, 1238, 1143, 1110, 760, 692 cm -1 base NMR (300 MHz, CDCl ₃ ), 7.599 (m, 2H, aromatic), 7.26 (t, 2H, J = 8.2 Hz, aromatic), 7.18 (d, 1H, J = 8.5 Hz, aromatic), 6.93 (d, 2H, J = 7.9 Hz) , aromatic), 6.85 (t, 1H, J = 7.2 Hz, aromatic), 6.10 (broad s, 1H, NH), 5.75 (broad s, 1H, NH), 5.75) 4.88 (broad d, 1H, J = 5.9 Hz, meth), 4.15 (m, 1H, OCH _{2 a} ), 3.77 (m, 1H, OCH _2b ), 3.21 (t, 4H, J =

4,9 Hz, Ph-N-CH^’ 3,02 (m,lH, Ph-CH_2a), 2,79-2,50 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s, PhCH_2b), 2,16 (m, 1 H, C(H>CH_2a, 2,05 (m, 1H, C(H)-CH_2b) δ; CMR (75MHz, CDC1₃) 169,0,4.9 Hz, Ph-N-CH 2 '3.02 (m, 1H, Ph-CH _{2 a} ), 2.79-2.50 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _2s , PhCH _2b ), 2.16 (m, 1H, C (H &gt; CH _2a) , 2.05 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 169.0 .

151,3, 142,4, 134,6, 131,3, 129,1, 128,2, 125,1, 124,9, 119,7, 116,0, 74,5, 62,9, 54,6, 53,4,151.3, 142.4, 134.6, 131.3, 129.1, 128.2, 125.1, 124.9, 119.7, 116.0, 74.5, 62.9, 54, 6, 53.4,

49,1, 33,1, 29,0 δ; HRMS (EI) vypočítaná pre C₂₂H₂₇N₃O₂ = 365,2103, skutočné =49.1, 33.1, 29.0 δ; HRMS (EI) calcd for C ₂₂ H ₂₇ N ₃ O ₂ = 365.2103, real =

365,2108.365.2108.

Príklad 41 1 -[2-[4-(3,4-dichlórfenyl)-1 -piperazinyl]etyl]izochróman-6karboxamid (VII) .krok: 1 -[2-(6-brómizochróman-1 -yl)acetyl] -4-(3,4-dichlorofenyl)piperazín (V)Example 41 1- [2- [4- (3,4-Dichlorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII). Step: 1- [2- (6-bromoisochroman-1-yl) acetyl] - 4- (3,4-dichlorophenyl) piperazine (V)

Postupom podľa príkladu 1,3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl octovej kyseliny (IV, Príklad 7,1. krok) a 3,4-dichlórfenylpiperazínu 1[2-(6-brómizochróman-l-yl)acetyl]-4-(3,4-dichlórfenyl)-piperazín (V), IR (suspenzia) 1640, 1592, 1482, 1448, 1406, 1275, 1234, 1206, 1140, 1107 cm'¹; NMR (300 MHz, CDC1₃) 7,327,26 (m, 3H, aromatické H), 7,01 (d, 1H, J = 8,2 Hz, aromatický H), 6,96 (d, 1H, J = 2,8 Hz, aromatický H), 6,74 (d z d, 1H, J_a = 2,8 Hz, J_b = 8,9 Hz, aromatický H), 5,24 (m z d, 1H, J =Following the procedure of Example 1.3. step with minor variations is formed from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7.1 step) and 3,4-dichlorophenylpiperazine 1 [2- (6-bromoisochroman-1-yl) acetyl] -4- (3 4-dichlorophenyl) -piperazine (V), IR (suspension) 1640, 1592, 1482, 1448, 1406, 1275, 1234, 1206, 1140, 1107 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.327.26 (m, 3H, aromatic H), 7.01 (d, 1H, J = 8.2 Hz, aromatic H), 6.96 (d, 1H, J = 2) 8 Hz, aromatic H), 6.74 (dzd, 1H, J _a = 2.8 Hz, J _b = 8.9 Hz, aromatic H), 5.24 (wd, 1H, J =

9,6 Hz, 4,11 (m, 1H), 3,9 (m, 1H), 3,79-3,60 (m’s, 4H), 3,16 (m, 4H), 3,09-2,89 (m, 2H), 2,77 (d z d, 1H, J_a = 3,6 Hz, J_b = 14,8 Hz), 2,65 (d,lH, J = 10,3 Hz) δ; CMR (75 MHz, CDC1₃)9.6 Hz, 4.11 (m, 1H), 3.9 (m, 1H), 3.79-3.60 (m's, 4H), 3.16 (m, 4H), 3.09-2 .89 (m, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.8 Hz), 2.65 (d, 1H, J = 10.3 Hz) δ; CMR (75 MHz, CDC1 ₃₎

48,5, 47,9, 45,2, 41,5, 39,9,28,7 δ;48.5, 47.9, 45.2, 41.5, 39.9.28.7 δ;

2. krok: 1 -[2-(6-brómizochróman-1 -y l)-ety 1] -4-(3,4-dichlorofenyl)piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (3,4-dichlorophenyl) piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman -1 -yl)acetyl]-4-(3,4-dichlórfenyl)-piperazínu (V) 1 -[2-(6-brómizochróman-1 yl)-etyl]-4-(3,4-dichlórfenyl)-piperazín (VI), ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu použitím 40 % až 50 % gradientu octanu etylnatého v hexáne, Rf = 0,25 (octan etylnatý/hexán, 25/75); IR (čisté látky) 2825, 1593, 1483, 1467, 1455, 1449, 1380, 1239, 1142, 1111 cm‘^l; NMR (300 MHz, CDC1₃) 7,32-7,24 (m, 2H, aromatické H), 6,98 (m, 2H, aromatický H), 6,73 (d z d, 1H, J_a = 2,9 Hz, J_b = 8,9 Hz, aromatické H), 4,78 (m z d, 1H, J =Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3,4-dichlorophenyl) -piperazine (V) 1- [2- (6- bromoisochroman-1-yl) -ethyl] -4- (3,4-dichlorophenyl) -piperazine (VI), which is purified by flash chromatography on 100 g of silica gel using a 40% to 50% gradient of ethyl acetate in hexane, Rf = 0.25 (ethyl acetate / hexane, 25/75); IR (neat) 2825, 1593, 1483, 1467, 1455, 1449, 1380, 1239, 1142, 1111 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.24 (m, 2H, aromatic H), 6.98 (m, 2H, aromatic H), 6.73 (dzd, 1H, J _a = 2.9 Hz, J _b = 8.9 Hz, aromatic H), 4.78 (wd, 1H, J =

5,8 Hz), 4,12 (m, 1H), 3,73 (m, 1H), 3,16 (t, 4H, J = 5,0 Hz), 3,00-2,90 (m, 1H), 2,7-2,48 (m, 7H), 2,12 (m, 1H) δ; CMR (75MHz, CDCb) 150,2, 137,1, 136,0, 132,2, 131,4, 130,1, 129,0, 126,2, 121,8, 120,0,116,9, 114,9, 73,9, 62,6, 54,2, 52,8,48,4, 32,9, 28,6 δ; HRMS vypočítaná pre CiiH^OiBriCh = 468,0371, nájdená 418,0363.5.8 Hz), 4.12 (m, 1H), 3.73 (m, 1H), 3.16 (t, 4H, J = 5.0 Hz), 3.00-2.90 (m, 1H), 2.7-2.48 (m, 7H), 2.12 (m, 1H) δ; CMR (75MHz, CDCl3) 150.2, 137.1, 136.0, 132.2, 131.4, 130.1, 129.0, 126.2, 121.8, 120.0, 116.9, 114, 9, 73.9, 62.6, 54.2, 52.8, 48.4, 32.9, 28.6 δ; HRMS calcd for C 11 H 14 O 3 BrCl 3 = 468.0371, found 418.0363.

3. krok:l-[2-[4-(3,4-dichlórfenyl)etyl)-l-piperazinyl]etyl]izochróman-6karboxamid (VII)Step 3: 1- [2- [4- (3,4-dichlorophenyl) ethyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Postupom podľa príkladu 40,3. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-1 -yl)-etyl]-4-(3,4-dichlórfenyl)-piperazínu (VI) 1 -[2-[4-(3,4dichlórfenyl)etyl)- 1-piperazinyl] etyl] izochróman-6-karboxamid (VII), Rf = 0,13 (octan etylnatý); NMR (300 MHz, CDC1₃) 7,59 (m, 2H, aromatické H), 7,24 (2m, 3H, aromatické H), 6,94 a 5,74 (dva d, 1H, aromatické) 5,90 (široké d, 2H, PhC(O)N-H₂), 4,87 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,15 (m, 1H, PhCH₂CH-H), 3,77 (m, 1H, PhCH₂CH-H), 3,18 (t, 4H, J =Following the procedure of Example 40.3. step with minor variations, it results from 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (3,4-dichlorophenyl) -piperazine (VI) 1- [2- [4- (3,4-dichlorophenyl) ethyl] - 1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), R f = 0.13 (ethyl acetate); NMR (300 MHz, CDCl ₃ ) 7.59 (m, 2H, aromatic H), 7.24 (2m, 3H, aromatic H), 6.94 and 5.74 (two d, 1H, aromatic) 5.90 (broad d, 2H, PhC (O) _NH2), 4.87 (MH, 1 H, J = 6.0 Hz, Ph), 4.15 (m, 1 H, CH ₂ Ph-H), 3 77 (m, 1H, PhCH ₂ CH-H), 3.18 (t, 4H, J =

4,8 Hz, štyri z pip-H), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,15 (m, 1H, PhCHCH-H), 2,03 (m, 1H, PhCHCH-H) δ; CMR (75MHz,4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH- H), 2.15 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H) δ; CMR (75MHz,

53,0, 48,6, 33,0, 28,8 δ; HRMS vypočítaná peo C₂₂H₂6N3FiO₂ = 433,1324, nájdená 433,1325.53.0, 48.6, 33.0, 28.8 δ; HRMS calcd C ₂₂ H peo 6N3FiO _{2 2} = 433.1324, found 433.1325.

Príklad 42 l-[2-[4-(4-fluórfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (VII)Example 42 1- [2- [4- (4-Fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

1. krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(4-fluorofenyl)piperazín (V)Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-fluorophenyl) piperazine (V)

-77Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl octovej kyseliny (IV, Príklad 7, 1. krok) a 4-fluorofenyl piperazínu 1[2-(6-brómizochróman-l-yl)acetyl]-4-(4-fluorofenyl) piperazín (V), IR (čisté látky) 1641, 1510, 1482, 1464, 1444, 1278, 1232, 1107, 827, 817 cm'¹; NMR (300 MHz, CDCb) 7,327.26 (m, 2H, aromatické H), 6,99 (m, 3H, aromatické H), 6,92-6,86 (m, 2H, aromatické H),The procedure of Example 1, Step 3, with minor variations, results from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7, Step 1) and 4-fluorophenyl piperazine 1- [2- (6-bromoisochroman-1-yl)]. acetyl] -4- (4-fluorophenyl) piperazine (V), IR (neat) 1641, 1510, 1482, 1464, 1444, 1278, 1232, 1107, 827, 817 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.327.26 (m, 2H, aromatic H), 6.99 (m, 3H, aromatic H), 6.92-6.86 (m, 2H, aromatic H),

5.26 (m z d, 1H, J = 9,6 Hz), 4,11 (m, 1H), 3,94 (m, 1H), 3,79-3,60 (m’s, 4H), 3,08 (m, 4H), 2,99-2,89 (m, 2H), 2,77 (d z d, 1H, J_a = 3,6 Hz, J_b = 14,8 Hz), 2,65 (d, 1H, J = 10,3 Hz), δ; CMR(75MHz, CDCb) 168,0, 147,2, 136,2, 131,7, 129,2 126,2 120,2 118,3 115,6 115,3 73,25.26 (mt, 1H, J = 9.6 Hz), 4.11 (m, 1H), 3.94 (m, 1H), 3.79-3.60 (m's, 4H), 3.08 (m 4H), 2.99-2.89 (m, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.8 Hz), 2.65 (d, 1H, J = 10.3 Hz), δ; CMR (75MHz, CDCl3) 168.0, 147.2, 136.2, 131.7, 129.2 126.2 120.2 118.3 115.6 115.3 73.2

63,3 50,6 50,1 45,2 41,5 39,7 28,5 δ; HRMS vypočítaná pre C₂iH₂₂N₂O₂FBr = 432,0843, nájdená 432,0849.63.3 50.6 50.1 45.2 41.5 39.7 28.5 δ; HRMS calcd for C ₂ H ₂₂ N ₂ O ₂ FBr = 432.0843, found 432.0849.

2. krok: l-[2-(6-bromoizochróman-l-yl)etyl]-4-(4-fluorofenyl)piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-fluorophenyl) piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-1 -y l)acetyl]-4-(4-fluórfeny l)piperazínu (V) 1 -[2-(6-brómizochróman-1 -y 1) etyl]-4-(4-fluórfenyl)piperazín (VI), ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu použitím 40 % až 50 % gradientu octanu etylnatého v hexáne, Rf = 0,26 (25 % octan etylnatý v hexáne); IR (čisté látky) 2952, 2820, 1510, 1481, 1456, 1379, 1235, 1144, 1109, 817 cm'¹; NMR (300 MHz, CDCb), 7,59 (m, 2H, aromatické H), 7,17 (m, 1H, aromatický H), 6,87 (m, 4H, aromatické H), 6,21 (široké s, 2H, PhC(O)N-H₂), 4,87 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,15 (m, 1H, PhCH₂CH-H), 3,77 (m, 1H, PhCH₂CH-H), 3,13 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,15 (m, 1H, PhCHCH-H), 2,03 (m, 1H, PhCHCH-H) ), δ; CMR (75MHz, CDCb) 158,3, 156,2, 148,2, 137,3, 136,9, 131,7, 129,3, 126,5, 117,8, 117,8, 115,6,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-fluorophenyl) piperazine (V) 1- [2- (6-bromoisochroman- 1-yl) ethyl] -4- (4-fluorophenyl) piperazine (VI), which is purified by flash chromatography on 100 g silica gel using a 40% to 50% gradient of ethyl acetate in hexane, R f = 0.26 (25% acetate) ethyl in hexane); IR (neat) 2952, 2820, 1510, 1481, 1456, 1379, 1235, 1144, 1109, 817 cm ^-1 ; NMR (300 MHz, CDCl 3), 7.59 (m, 2H, aromatic H), 7.17 (m, 1H, aromatic H), 6.87 (m, 4H, aromatic H), 6.21 (broad s , 2H, PhC (O) _NH2), 4.87 (MH, 1 H, J = 6.0 Hz, Ph), 4.15 (m, 1 H, CH ₂ Ph-H), 3.77 ( m, 1H, PhCH ₂ CH-H), 3.13 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76- 2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.15 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H)) , δ; CMR (75MHz, CDCl3) 158.3, 156.2, 148.2, 137.3, 136.9, 131.7, 129.3, 126.5, 117.8, 117.8, 115.6,

115,4, 74,3, 62,8, 54,6, 53,4, 50,2, 33,2, 28,9 δ; HRMS vypočítaná pre C₂iH₂4N₂OOiBriFi = 418,1056, nájdená 418,1057.115.4, 74.3, 62.8, 54.6, 53.4, 50.2, 33.2, 28.9 δ; HRMS calcd for C ₂ H 4 N _{2 2} OOiBriFi = 418.1056, found 418.1057.

3. krok l-[2-[4-(4-fluórfenyl)-l-piperazinyl]etyl]izochróman-6karboxamid (VII)Step 3 1- [2- [4- (4-fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Postupom podľa príkladu 40, 3. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-1 -yl)etyl]-4-(4-fluorofenyl)piperazínu (VI) 1 -[2-[4-(4-fluorofenyl)-l piperazinyl]etyl]izochróman-6-karboxamid (VII), Rf = 0,09 (octan etylnatý); NMR (300 MHz, CDCb) 7,59 (m, 2H, aromatické H), 7,17 (m, 1H, aromatický H), 6,87 (m, 4H, aromatické H), 6,21 (široké s, 2H, PhC(O)N-H₂), 4,87 (m z d, 1H, J = 6,0 Hz, PhCH-H), 4,15Following the procedure of Example 40, Step 3, with minor variations, 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-fluorophenyl) piperazine (VI) 1- [2- [4- (4- fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), R f = 0.09 (ethyl acetate); NMR (300 MHz, CDCl 3) 7.59 (m, 2H, aromatic H), 7.17 (m, 1H, aromatic H), 6.87 (m, 4H, aromatic H), 6.21 (broad s, 2H, PhC (O) _NH2), 4.87 (MH, 1 H, J = 6.0 Hz, Ph-H), 4.15

-78(m, 1H, PhCH₂CH-H), 3,77 (m, 1H, PhCH₂CH-H), 3,13 (t, 4H, J = 4,8 Hz, štyri z pip-H), 3,00 (m,. 1H, PhCHCH-H), 2,03 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDC1₃) 169,1,-78 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH ₂ CH-H), 3.13 (t, 4H, J = 4.8 Hz, four of pip-H) 3.00 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1 ₃₎ 169.1,

158,3, 155,5, 147,5, 142,0, 134,4, 131,2, 128,0, 124,9, 124,8, 117,6, 115,4, 115,1, 74,3, 62,7,158.3, 155.5, 147.5, 142.0, 134.4, 131.2, 128.0, 124.9, 124.8, 117.6, 115.4, 115.1, 74, 3, 62.7,

54,4, 53,1, 499,9, 32,8, 28,8 δ; HRMS vypočítaná pre54.4, 53.1, 499.9, 32.8, 28.8 δ; HRMS calculated for

383,2010.383.2010.

Príklad 43 1 -[2-[4-(3-etoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamid (VII) .krok: l-[2-(6-brómizochróman-l-yl)acetyl]-4-(3-etoxyfenyl)piperazín (V)Example 43 1- [2- [4- (3-Ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII). Step: 1- [2- (6-bromoisochroman-1-yl) acetyl] - 4- (3-ethoxyphenyl) piperazine (V)

Postupom podľa príkladu 1 ,3. kroku s drobnými obmenami vzniká z racemickej 6brómizochróman-l-yl octovej kyseliny (IV, Príklad 7, 1. krok) a 3-etoxyfenylpiperazínul-[2(6-brómizochróman-l-yl)etyl]-4-(3-etoxyfenyl)piperazín (V), ktorý sa prečistí rýchlou chromatografiou na 200 g silikagélu použitím 25 % octanu etylnatého v hexáne, Rf - 0,28 (50 % octan etylnatý v hexáne); IR (čisté látky) 501641, 1501, 1480, 1445, 1241, 1225, 1108, 1040, 1031, 748 cm'¹; NMR (300 MHz, CDCb) 7,32-7,26 (m, 2H, aromatické H), 7,03-6,98 (m, 2H, aromatické H), 6,94-6,86 (m, 3H, aromatické H), 5,28 (m z d, 1H, J = 7,4 Hz), 4,164,05 (m, 4H), 3,98-3,91 (m, 1H), 3,83-3,65 (m, 4H), 3,08-2,91 (m, 6H), 2,80-2,64 (m, 2H), 1,46 (t, 3H, J = 6,9 Hz, -CH₃) δ; CMR (75 MHz, CDCb) 178,5, 152,0, 140,0, 157,0, 156,5,Following the procedure of Example 1, 3. step with minor variations is formed from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7, Step 1) and 3-ethoxyphenylpiperazin [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (V), which was purified by flash chromatography on 200 g silica gel using 25% ethyl acetate in hexane, R f = 0.28 (50% ethyl acetate in hexane); IR (neat) 501641, 1501, 1480, 1445, 1241, 1225, 1108, 1040, 1031, 748 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.32-7.26 (m, 2H, aromatic H), 7.03-6.98 (m, 2H, aromatic H), 6.94-6.86 (m, 3H) aromatic H), 5.28 (mt, 1H, J = 7.4 Hz), 4.164.05 (m, 4H), 3.98-3.91 (m, 1H), 3.83-3.65 (m, 4H), 3.08-2.91 (m, 6H), 2.80-2.64 (m, 2H), 1.46 (t, 3H, J = 6.9 Hz, -CH3 ₎ ) δ; CMR (75 MHz, CDCl 3) 178.5, 152.0, 140.0, 157.0, 156.5,

131,7, 129,4, 126,5, 123,3, 121,0, 120,0, 118,4, 112,5, 73,4, 63,6, 63,5, 60,0, 51,0, 50,5, 46,4,131.7, 129.4, 126.5, 123.3, 121.0, 120.0, 118.4, 112.5, 73.4, 63.6, 63.5, 60.0, 51, 0, 50.5, 46.4,

42,2, 40,0, 28,8, 14,9 δ; HRMS vypočítaná pre C₂3H₂7N₂O₃Bri = 458,1205, nájdená 458,1215.42.2, 40.0, 28.8, 14.9 δ; HRMS calculated for C _{2 2} 3 H 7 N ₂ O ₃ Bri = 458.1205, found 458.1215.

2. krok: l-[2-(6-brómizochróman-l-yl)etyl]-4-(3-etoxyfenyl)piperazín (VI)Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)etyl]-4-(3-etoxyfenyl)piperazínu (V) l-[2-(6-brómizochróman -1yl)etyl]-4-(3-etoxyfenyl)piperazín (VI), ktorý sa prečistí rýchlou chromatografiou na 100 g silikagélu použitím 40 % až 50 % octanu etylnatého v hexáne, Rf = 0,30 (50 % octan etylnatý v hexáne); IR (čisté látky) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110 748 cm'¹ ; NMR (300 MHz, CDCb) 7,31-7,26 (m, 2H, aromatické H), 7,00-6,90 (m, 4H, aromatické H), 6,85-6,83 (m, 1H, aromatický H), 4,78 (m z d, J = 5,9 Hz, 1H), 2,69-2,52 (m, 7H), 2,13 (m,Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (V) 1- [2- (6-bromoisochroman-1-yl) was formed. ethyl] -4- (3-ethoxyphenyl) piperazine (VI), which is purified by flash chromatography on 100 g silica gel using 40% to 50% ethyl acetate in hexane, Rf = 0.30 (50% ethyl acetate in hexane); IR (neat) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110, 748 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.31-7.26 (m, 2H, aromatic H), 7.00-6.90 (m, 4H, aromatic H), 6.85-6.83 (m, 1H , aromatic H), 4.78 (mt, J = 5.9 Hz, 1H), 2.69-2.52 (m, 7H), 2.13 (m,

1H), 1,99 (m, 1H), 1,45 (t, 3H, J = 7,0 Hz) δ; CMR (75MHz, CDCb) 151,37, 141,19, 137,0,1H), 1.99 (m, 1H), 1.45 (t, 3H, J = 7.0 Hz) δ; CMR (75MHz, CDCl3) 151.37, 141.19, 137.0,

136,1, 131,5, 129,1, 126,4, 122,5, 120,8, 119,8, 117,9, 112,2, 74,2, 63,4, 62,6, 54,6, 53,5,136.1, 131.5, 129.1, 126.4, 122.5, 120.8, 119.8, 117.9, 112.2, 74.2, 63.4, 62.6, 54, 6, 53.5,

-7950,4, 33,0, 28,7, 14,8 δ; HRMS vypočítaná pre C₂3H₂₉N₂O₂Bri = 444,1413, nájdená 444,1400.-7950.4, 33.0, 28.7, 14.8 δ; HRMS calculated for C 3 H ₂₉ N ₂ O ₂ = ₂ Bri 444.1413, found 444.1400.

3.krok:l-[2-[4-(3-etoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (vn)Step 3: 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (vn)

Postupom podľa príkladu 36 s drobnými obmenami vzniká z l-[2-(6brómizochróman-l-yl)etyl]-4-(3-etoxyfenyl)piperazínu (VI) produkt, ktorý sa prevedie na soľ kyseliny chlorovodíkovej použitím éterickej kyseliny chlorovodíkovej za vzniku l-[2-[4-(3etoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu (VII), teplota topenia =208-210 °C; Rf = 0,14 (10 % metanol v octane etylnatom); IR (suspenzia) 2417, 2365, 1611, 1520, 1489, 1476, 1448, 1260, 1121, 152 cm'¹ ; NMR (300 MHz, CDC1₃) 7,60 (m, 2H, aromatickéFollowing the procedure of Example 36 with minor variations, 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (VI) is obtained which is converted to the hydrochloric acid salt using ethereal hydrochloric acid to give 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), m.p. = 208-210 ° C; R f = 0.14 (10% methanol in ethyl acetate); IR (suspension) 2417, 2365, 1611, 1520, 1489, 1476, 1448, 1260, 1121, 152 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.60 (m, 2H, aromatic

H), 7,18 (d, 1H, J - 8,5 Hz, aromatický H), 6,94 (m, 3H, aromatické H), 6,84 (m z d, 1H, J =H), 7.18 (d, 1H, J = 8.5 Hz, aromatic H), 6.94 (m, 3H, aromatic H), 6.84 (m of d, 1H, J =

8,2 Hz, aromatický H), 6,00 (široké d, 2H, PhC(O)N-H₂), 4,86 (m z d, 1H, J = 6,0 Hz, PhCH), 4,13 (m, 1H, PhCH₂CH-H), 4,06 (q, 2H, 6,9 Hz, Proc-H₂), 3,77 (m, 1H, PhCH₂CH-H),8.2 Hz, aromatic H), 6.00 (broad d, 2H, PhC (O) NH ₂ ), 4.86 (wd, 1H, J = 6.0 Hz, PhCH), 4.13 (m, 1H, PhCH ₂ CH-H), 4.06 (q, 2H, 6.9 Hz, Proc-H ₂ ), 3.77 (m, 1H, PhCH ₂ CH-H),

3,13 (široké s, 4H, štyri z pip-H), 3,00 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pipH, dva PhCH-H a NCH-H), 2,16 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,45 (t, 3H, J = 7,0 Hz, PhOCH₂C-H₃) δ; CMR (75MHz, CDCb) 151,2, 142,0, 141,2, 134,1, 131,3,3.13 (broad s, 4H, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pipH, two PhCH-H and NCH-H), 2.16 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.45 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃₎ ) δ; CMR (75MHz, CDCl3) 151.2, 142.0, 141.2, 134.1, 131.3,

147,6, 125,0, 124,9, 121,2, 117,9, 112,2, 74,1, 63,0, 62,8, 54,8, 53,3, 50,3, 32,5, 31,5, 27,2,147.6, 125.0, 124.9, 121.2, 117.9, 112.2, 74.1, 63.0, 62.8, 54.8, 53.3, 50.3, 32, 5, 31.5, 27.2,

22,2, 14,5 δ; HRMS vypočítaná pre C₂4H3iN₃O3 = 409,2365, nájdená 409,2364.22.2, 14.5 δ; HRMS calcd for C ₂₄ H 31 N ₃ O ₃ = 409.2365, found 409.2364.

Príklad 44 (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperidinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX) .krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)acetyl]-4-(4-metoxyfenyl)piperidín (S)-(V)Example 44 (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX). Step: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperidine (S) - (V)

Postupom podľa príkladu 1, 3. kroku s drobnými obmenami vzniká z 4metoxyfenylpiperidínu (421 mg, 2,2 mmol) surový produkt, ktorý sa prečistí pomocou LC na 53 g (230-400) silikagélu za elúcie 40 % zmesou octan etylnatý/hexán) a vzniku (S)-(-)-1-[2(6-brómizochróman-l-yl)acetyl]-4-(4-metoxyfenyl)-piperidínu (S)-(V), Rf = 0,26 (50 % octan etylnatý/hexán); [a]o = -86° (c = 0,4975, metanol); IR (kvapaliny) 2933, 1638, 1612, 1513, 1481, 1463, 1446, 1283, 1268, 1247, 1179, 1106, 1036, 1005, 830 cm'¹; NMR (300 MHz, CDCb) 7,28 (m, 2H, aromatické), 7,11 (dd, 2H, J = 8,6 Hz a J = 3,4 Hz, aromatické), 7,03 (m, 1H, aromatické), 6,85 (d, 2H, J = 8,6 Hz, aromatické), 5,29 (široké s, 1H, O-CH), 4,85 (m,Following the procedure of Example 1, Step 3, with minor variations, 4-methoxyphenylpiperidine (421 mg, 2.2 mmol) was obtained which was purified by LC on 53 g (230-400) silica gel, eluting with 40% ethyl acetate / hexane). and (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperidine (S) - (V), Rf = 0.26 (50). % ethyl acetate / hexane); [α] D = -86 ° (c = 0.4975, methanol); IR (liquids) 2933, 1638, 1612, 1513, 1481, 1463, 1446, 1283, 1268, 1247, 1179, 1106, 1036, 1005, 830 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.28 (m, 2H, aromatic), 7.11 (dd, 2H, J = 8.6 Hz and J = 3.4 Hz, aromatic), 7.03 (m, 1H , aromatic), 6.85 (d, 2H, J = 8.6 Hz, aromatic), 5.29 (broad s, 1H, O-CH), 4.85 (m,

-801Η, Ph-CH), 4,10 (m, 2H, OCH_2a a O=C-N-CH_2a, N-CO-CH_2s, Ph-CH_2b ), 1,90-1,50 (m, 4H, Ph-C(H)-CH_2s) Ô; CMR (75MHz, CDC1₃) 168,9, 168,8, 158,2, 137,5, 136,8, 136,3, 131,7,-801Η, Ph-CH), 4.10 (m, 2H, OCH _2a and O = CN-CH _2a , N-CO-CH _{2 s} , Ph-CH _2b ), 1.90-1.50 (m, 4H , Ph-C (H) -CH _{2 s} ); CMR (75 MHz, CDC1 ₃₎ 168.9, 168.8, 158.2, 137.5, 136.8, 136.3, 131.7,

129,4, 127,6, 126,6, 126,3, 120,3, 114,0, 73,5, 63,4, 55,3, 46,8, 42,8, 41,9, 40,2, 40,0, 34,2,129.4, 127.6, 126.6, 126.3, 120.3, 114.0, 73.5, 63.4, 55.3, 46.8, 42.8, 41.9, 40, 2, 40.0, 34.2,

33,2, 33,0, 28,9 δ.33.2, 33.0, 28.9 δ.

2. krok: (S)-(-)-1 -[2-(6-brómizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)piperidín (S)-(VI)Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperidine (S) - (VI)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-l-yl)acetyl]-4-(4-metoxyfenyl)-piperidínu (S)-(V) surový produkt, ktorý sa prečistí pomocou LC na 47 g (230-400) silikagélu za elúcie 75 % zmesou octan etylnatý/hexán) a vzniku (S)-(-)-l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)piperidínu (S)-(VI), Rf = 0,28 (75 % octan etylnatý/hexán); [a]o = -46° (c = 0,6677, metanol); IR (kvapaliny) 2932, 2847, 2832, 2805, 1513, 1481, 1466, 1378, 1274, 1247, 1179, 1127, 1109, 1039, 828 cm'¹; NMR (300 MHz, CDC1₃) 7,29 (m, 2H, aromatické), 7,14 (d, 2H, J =Following the procedure of Example 1, Step 4, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperidine (S) - ( V) crude product which was purified by LC on 47 g (230-400) silica gel eluting with 75% ethyl acetate / hexane to give (S) - (-) - 1- [2- (6-bromoisochroman-1)]. -yl) ethyl] -4- (4-methoxyphenyl) piperidine (S) - (VI), R f = 0.28 (75% ethyl acetate / hexane); [α] D = -46 ° (c = 0.6677, methanol); IR (liquids) 2932, 2847, 2832, 2805, 1513, 1481, 1466, 1378, 1274, 1247, 1179, 1127, 1109, 1039, 828 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (m, 2H, aromatic), 7.14 (d, 2H, J =

8,6 Hz, aromatické), 6,97 (d, IH, J = 8,2 Hz, aromatické), 4,10 (m, 1H, OCH_2a), 3,78 (s, 3HJ, OCH₃), 3,71 (m, 1H, OCH_2b ), 3,04 (m, 2H, NCH_2ab), 2,95 (m, 1H, Ph.CH_2a), 2,70-2,40 (m, 4H, Ph-CH, NCH_2od, Ph-CH_2b), 2,04 (m, 4H, O-C(H)-CH_2s, NCH_2ef), 1,79 (m, 4H, Ph-C(H)CH_2s) δ; CMR (75MHz, CDClj)158,2, 140,3, 137,5, 136,4, 136,2, 131,7, 129,5, 127,7, 126,6,8.6 Hz, aromatic), 6.97 (d, 1H, J = 8.2 Hz, aromatic), 4.10 (m, 1H, OCH _{2 a} ), 3.78 (s, 3HJ, OCH ₃ ), 3.71 (m, 1H, OCH _2b ), 3.04 (m, 2H, NCH _2ab ), 2.95 (m, 1H, Ph. CH _{2 a} ), 2.70-2.40 (m, 4H, Ph-CH, NCH _2od , Ph-CH _2b ), 2.04 (m, 4H, OC (H) -CH _{2 s} , NCH _2ef ), 1.79 (m, 4H, Ph-C (H) CH _{2 s} ) δ; CMR (75MHz, CDCl3) 158.2, 140.3, 137.5, 136.4, 136.2, 131.7, 129.5, 127.7, 126.6,

120,2, 113,9, 74,2, 63,1, 55,3, 54,8, 53,9, 41,14, 32,5, 32,0, 28,8) δ; HRMS (EI) vypočítaná pre C₂₃H₂₈BrNO₂ = 429,1304, nájdená 429,1286.120.2, 113.9, 74.2, 63.1, 55.3, 54.8, 53.9, 41.14, 32.5, 32.0, 28.8) δ; HRMS (EI) calcd for C ₂₃ H ₂₈ BrNO ₂ = 429.1304, found 429.1286.

3. krok: (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperidinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX)Step 3: (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 5, 3. kroku s drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperidínu (S)-(VI, 445 mg, 1,03 mmol) produkt, ktorý sa prečistí pomocou LC na 24 g (230-400) silikagélu za elúcie 75 % zmesou acetón/hexán) a vznikne (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperidinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX), Rf = 0,36 (75 % acetón/hexán); IR (kvapaliny) 3291, 2934, 1636, 1612, 1571, 1551, 1514, 1496, 1497, 1315, 1293, 1247, 1179, 1109, 1036 cm'¹; NMR (300 MHz, CDC1₃) 7,54 (m, 2H aromatické), 7,116 (m, 3H, aromatické), 6,84 (d, 2H, J = 8,7 Hz, aromatické), 6,20 (široké m, 1H, NH), 4,85 (m, 1H, O-CH), 4,13 (m, 1H, OCH_2a), 3,78 (m, 4H, OCH₃ a OCH_2b), 3,00 (m, 6H, Ph-CH_2a, NCH₃, Ph-CH_2b, Ph-CH), 2,77-81 2,40 (m, 4H, N-CH_2s), 2,10-1,94 (m, 4H, N-CH_2s a O-C(H)-CH_2s), 1,80 (m, 4H, Ph-C(H)CH_2s) δ; HRMS (EI) vypočítaná pre C₂₅H₃₂N₂O₃ = 408,2413, nájdená 408,2414.Following the procedure of Example 5, Step 3, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperidine (S) - ( VI, 445 mg, 1.03 mmol), which was purified by LC on 24 g (230-400) silica gel eluting with 75% acetone / hexane to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), Rf = 0.36 (75% acetone / hexane); IR (liquids) 3291, 2934, 1636, 1612, 1571, 1551, 1514, 1496, 1497, 1315, 1293, 1247, 1179, 1109, 1036 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (m, 2H aromatic), 7.116 (m, 3H, aromatic), 6.84 (d, 2H, J = 8.7 Hz, aromatic), 6.20 (broad) m, 1H, NH), 4.85 (m, 1H, O-CH), 4.13 (m, 1H, OCH _{2 a} ), 3.78 (m, 4H, OCH ₃ and OCH _2b ), 3.00 (m, 6H, Ph-CH _{2 a} , NCH ₃ , Ph-CH _2b , Ph-CH), 2.77-81 2.40 (m, 4H, N-CH _{2 s} ), 2.10-1.94 ( m, 4H, N-CH _{2 s} and OC (H) -CH _{2 s} ), 1.80 (m, 4H, Ph-C (H) CH _{2 s} ) δ; HRMS (EI) calcd for C ₂₅ H ₃₂ N ₂ O ₃ = 408.2413, found 408.2414.

Príklad 45 (S)-(-)-1 -[2-[4-(4-trifluórmetylfenyl)-1 -piperazinyl]etyl]-N,Ndimetylizochróman-6-karboxamid (S)-(IX)Example 45 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (S) - (IX)

Postupom podľa príkladu 6, 4. kroku s drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperidínu (S)-(VI, Príklad 5, 2. krok, 21,17 g,Following the procedure of Example 6, Step 4, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperidine (S) - ( VI, Example 5, Step 2, 21.17 g,

45,1 mmol) produkt, ktorý sa prečistí pomocou LC na 780 g (230-400) silikagélu za elúcie 3 % až 5 % zmesou metanol/dichlórmetán a vzniku (S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-lpiperidinyl]etyl]-N,N-dimetylizochróman-6-karboxamidu (S)-(IX), teplota topenia = 149-151 °C; Rf = 0,34 (5 % metanol/dichlórmetán); [a]o = -46° (c = 0,988, metanol); IR (suspenzia)45.1 mmol) of product which is purified by LC on 780 g (230-400) silica gel eluting with 3% to 5% methanol / dichloromethane to give (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperidinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (S) - (IX), m.p. = 149-151 ° C; R f = 0.34 (5% methanol / dichloromethane); [α] D = -46 ° (c = 0.988, methanol); IR (suspension)

1627, 1617, 1527, 1414, 1337, 1315, 1294, 1241, 1160, 1152, 1143, 1135, 1107, 1072, 824 cm'¹; NMR (300 MHz, CDC1₃) 7,46 (d, 2H, J = 8,7 aromatické), 7,20 (m, 2H, aromatické), 7,11 (d, 1H, J = 7,9 Hz, aromatické), 6,90 (d, 2H, J = 8,7 Hz, aromatické), 4,85 (široké d, 1H, J = 5,9 Hz, metín), 4,12 (m, 1H, OCH_2a), 3,75 (m, 1H, OCH_2b), 3,28 (t, 4H, J = 5,0 Hz, Ph-NCH_2s), 3,09 (široké s, 3H, NCH₃), 2,99 (široké s, 4H, NCH₃ a Ph-CH_2a), 2,74-2,48 (m, 7H, Ph-NCfHaX-NCHfc, Ph-CH_2b), 2,12 (m, 1H, C(H)-CH₂a), 2,04 (m, 1H, C(H)-CH_2b) δ; CMR (75MHz, CDC1₃) 171,4, 153,3, 139,5, 134,5, 134,3, 127,7, 126,6, 126,3, (d, J_CF = 4Hz), 126,2,1627, 1617, 1527, 1414, 1337, 1315, 1294, 1241, 1160, 1152, 1143, 1135, 1107, 1072, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.46 (d, 2H, J = 8.7 aromatic), 7.20 (m, 2H, aromatic), 7.11 (d, 1H, J = 7.9 Hz, aromatic), 6.90 (d, 2H, J = 8.7 Hz, aromatic), 4.85 (broad d, 1H, J = 5.9 Hz, meth), 4.12 (m, 1H, OCH _2a) ), 3.75 (m, 1H, OCH _2b ), 3.28 (t, 4H, J = 5.0 Hz, Ph-NCH _{2 s} ), 3.09 (broad s, 3H, NCH ₃ ), 2, 99 (broad s, 4H, NCH ₃ and Ph-CH _2a ), 2.74-2.48 (m, 7H, Ph-NCfHaX-NCHfc, Ph-CH _2b ), 2.12 (m, 1H, C ( H) a _CH2), 2.04 (m, 1 H, C (H) -CH _2b) δ; CMR (75 MHz, CDC1 ₃₎ 171.4, 153.3, 139.5, 134.5, 134.3, 127.7, 126.6, 126.3, (d, J _CF = 4 Hz), 126, 2

124,8, 124,6, 120,,4, (qit, J_CF = 33 Hz), 114,4, 74,4, 63,0, 54,6, 53,1, 48,0, 39,6, 35,4, 33,2,124.8, 124.6, 120.4, (qit, J _CF = 33 Hz), 114.4, 74.4, 63.0, 54.6, 53.1, 48.0, 39.6 , 35.4, 33.2,

29,0 δ; MS (EI, m(z) =461.29.0 δ; MS (EI, m / z) = 461;

Príklad 46 1 -(4-metoxyfenyl)-4-[2-[6-(5-metyloxazol-2-yl)izochróman-1 yl)etyl]piperazín (P-2)Example 46 1- (4-Methoxyphenyl) -4- [2- [6- (5-methyl-oxazol-2-yl) -isochroman-1-yl) -ethyl] -piperazine (P-2)

V peci vysušená 125 ml nádoba vybavená miešacou tyčinkou a chladičom sa naplní 1[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl-N-propargylizochróman-6-karboxamidom (IX, Príklad 28, 433 mg, 1,0 mmol) a octanom ortuťnatým a zahreje sa k varu. Po 3 hodinách sa reakcia ochladí na 20-25 °C, prchavé látky sa odstránia za zníženého tlaku a zvyšok sa zriedi 35 ml hydroxidu sodného a dvakrát extrahuje octanom etylnatým (30 ml). Zmiešané organické extrakty sa dvakrát premyjú soľankou (20 ml), vysušia síranom horečnatým, prefiltrujú a zahustia. Táto látka sa spolu so surovou látkou z identickej 0,25 mmol reakcie prečistí pomocou LC na 41 g (230-400) silikagélu za elúcie 25 % zmesou acetón/hexán a vzniku 1 -(4-metoxyfenyl)-4-[2-[6-(5 -metyloxazol-1 -yl)izochróman-1 -yl)etyl]piperazínu (P-822), ktorý rekryštalizuj e zo zmesi octan etylnatý/hexán, teplota topenia = 129-130 °C, Rf = 0,40 (50 % acetón/hexán).Oven-dried 125 ml flask equipped with a stir bar and a condenser was charged with 1 [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl-N-propargylisochroman-6-carboxamide (IX, Example 28, 433 mg, 1, 0 mmol) and mercuric acetate and heated to boiling. After 3 hours, the reaction is cooled to 20-25 ° C, the volatiles are removed under reduced pressure, and the residue is diluted with 35 mL of sodium hydroxide and extracted twice with ethyl acetate (30 mL). The combined organic extracts were washed twice with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. This material, along with the crude from an identical 0.25 mmol reaction, was purified by LC on 41 g (230-400) silica gel eluting with 25% acetone / hexane to give 1- (4-methoxyphenyl) -4- [2- [ 6- (5-methyloxazol-1-yl) isochroman-1-yl) ethyl] piperazine (P-822), which recrystallizes from ethyl acetate / hexane, mp = 129-130 ° C, Rf = 0.40 (50% acetone / hexane).

Príklad 47 1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)piperazín(Z 1) ml v peci vysušená dvojhrdlová nádoba sa v argónovej atmosfére naplní roztokom l-[2-(6-aminoizochróman-l-yl)-etyl]-4-(4-metoxyfenyl) piperazínu (VI, 406 mg, 0,94 mmol) v THF (2 ml). Zmes sa ochladí na -78 °C a po kvapkách sa pridá t-butyl lítium (1,7 M v pentáne, 1,081 ml, 1,83 mmol). Po 15 minútovom miešaní pri -78 °C sa pomocou hadičky po kvapkách pridá aryllítium do roztoku difenylfosforylazidu (98 %, 0,188 ml, 0,85 mmol) v THF (9 ml) pri -78 °C. Reakčná zmes sa takto ponechá dve hodiny pri -78 °C, potom sa počas 40 minút zahreje na -20 °C a potom opäť ochladí na -78 °C . Za miešania sa injekčnou striekačkou pomaly sodium bis(2-metoxyetoxy)alumínium hydrid (3,4 M v toluéne, 1,11,ml,Example 47 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (Z1) ml oven-dried two-necked flask was charged with 1- [2- ( 6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (VI, 406 mg, 0.94 mmol) in THF (2 mL). The mixture was cooled to -78 ° C and t-butyl lithium (1.7 M in pentane, 1.081 mL, 1.83 mmol) was added dropwise. After stirring at -78 ° C for 15 min, aryl lithium was added dropwise via a tube to a solution of diphenylphosphoryl azide (98%, 0.188 mL, 0.85 mmol) in THF (9 mL) at -78 ° C. The reaction mixture was left at -78 ° C for two hours, then warmed to -20 ° C for 40 minutes and then cooled to -78 ° C again. Sodium bis (2-methoxyethoxy) aluminum hydride (3.4 M in toluene, 1.11 ml,

3,77 mmol). Reakcia sa zahreje na 0 °C za vývinu dusíka. Reakcia sa dve hodiny mieša pri 0 °C a potom 30 minút pri 20-25 °C. Po schladení na 0 °C sa reakcia veľmi pomaly zastaví vodou. Potom, čo prestane vývin dusíka, surový produkt sa zahreje na 20-25 °C, prefiltruje na sklenenej frite, prípadne premyje vodou a octanom etylnatým, až pokiaľ nie je vo filtráte pomocou TLC zrejmý produkt. Filtráty sa prevedú do deliaceho lievika, vysolia chloridom sodným, pretrepú a vrstvy sa oddelia. Organická vrstva sa raz premyje 1 % vodným hydroxidom sodným a raz soľankou, vysuší síranom sodným, prefiltruje a zahustí. Po dvoch plameňových chromatografiách na 20 g silikagélu za použitia 5 % metanolu v metylénchloride ako elučného činidla sa získa l-[2-(6-aminoizochróman-l-yl)-etyl]-4-(4metoxyfenyl)piperazín (Z-l), Rf = 0,18 (5 % metanolu v metylénchloride); IR (čisté látky) 2951, 2828, 1625, 1244, 1104, 1037, 824 cm’¹; NMR (300 MHz, CDC1₃) 6,85 (,m, 5H, aromatické H), 6,53 (d z d, 1H, J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,43 (d, 1H, J - 2,2 Hz, aromatický H), 4,75 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,09 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H ), 3,57 (široké s , 2H, NH₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1₃) 153,8, 145,7, 144,6,3.77 mmol). The reaction was warmed to 0 ° C with nitrogen evolution. The reaction was stirred at 0 ° C for two hours and then at 20-25 ° C for 30 minutes. After cooling to 0 ° C, the reaction is quenched very slowly with water. After the evolution of nitrogen ceased, the crude product was heated to 20-25 ° C, filtered on a glass frit, optionally washed with water and ethyl acetate until no clear product was found in the filtrate by TLC. The filtrates are transferred to a separatory funnel, salted with sodium chloride, shaken and the layers are separated. The organic layer was washed once with 1% aqueous sodium hydroxide and once with brine, dried over sodium sulfate, filtered and concentrated. Two flame chromatography on 20 g of silica gel eluting with 5% methanol in methylene chloride gave 1- [2- (6-aminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (Z1), Rf = 0.18 (5% methanol in methylene chloride); IR (neat) 2951, 2828, 1625, 1244, 1104, 1037, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.85 (, m, 5H, aromatic H), 6.53 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6 43 (d, 1H, J = 2.2 Hz, aromatic H), 4.75 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH- H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.57 (broad s, 2H, NH ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H); 2.00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1 ₃₎ 153.8, 145.7, 144.6,

134,9, 129,6, 128,2, 125,7, 120,2, 118,2, 115,5, 114,9, 113,6, 74,6, 63,2, 55,6, 54,9, 53,5,134.9, 129.6, 128.2, 125.7, 120.2, 118.2, 115.5, 114.9, 113.6, 74.6, 63.2, 55.6, 54, 9, 53.5,

50,6, 33,3, 29,2 δ; HRMS vypočítaná pre C₂₂H₂9N₃O₂ = 367,2260, nájdená = 367,2255.50.6, 33.3, 29.2 δ; HRMS calculated for C ₂₂ H 9 N ₃ O _{2 2} = 367.2260, found = 367.2255.

Príklad 48 (S)-(-)-1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfeny 1)piperazín (S)-(Z-l)Example 48 (S) - (-) - 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (S) - (Z-1)

-83Postupom podľa príkladu 47 s drobnými obmenami vzniká z (S)-(-)-l-[2-(6brómizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)-piperazínu (S)-(VI) (S)-(-)-1 - [2-(6aminoizochróman-l-yl)-etyl]-4-(4-metoxyfenyl)piperazín (S)-(Z-l), Rf = 0,18 (5 % metanol v metylénchloride); [α]ϋ =-53° (c = 1,04, etanol); IR (čisté látky) 2951, 28282819, 1625, 1511, 1262, 1244, 1104, 1037, 824 cm¹; NMR (300 MHz, CDC1₃) 6,85 (m, 5H, aromatické H, 6,53 (d z d, 1H, J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,43 (d, 1H, J = 2,2 Hz, aromatický H), 4,75 (m z d, 1H, J = 5,8 Hz, PhC-H), 3,57 (široké s, 2H, N-H₂), 3,11 (t, 4H, J = 4,9 Hz, štyri pip-H), 2,89 (m, 1H, PhCH-H), 2,60 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1₃) 153,8, 145,7, 144,6,The procedure of Example 47, with slight variations, results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (S) - (VI) ( S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z1), Rf = 0.18 (5% methanol in methylene chloride) ); [α] D = -53 ° (c = 1.04, ethanol); IR (neat) 2951, 28282819, 1625, 1511, 1262, 1244, 1104, 1037, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.85 (m, 5H, aromatic H, 6.53 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.43 (d, 1 H, J = 2.2 Hz, aromatic H), 4.75 (MH, 1 H, J = 5.8 Hz, PhC-H), 3.57 (bs, 2H, NH _2), 3 11 (t, 4H, J = 4.9 Hz, four pip-H), 2.89 (m, 1H, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCl ₃ ) 153.8, 145.7, 144 , 6,

134,9, 129,6, 128,2, 125,7, 120,2, 118,2, 115,5, 114,9, 11,4, 113,6, 74,6, 63,12, 55,6, 54,9,134.9, 129.6, 128.2, 125.7, 120.2, 118.2, 115.5, 114.9, 11.4, 113.6, 74.6, 63.12, 55, 6, 54.9,

53,5, 50,6, 33,3,29,2 δ; HRMS vypočítaná pre C₂₂H₂9N₃O₂ = 367,2260, nájdená = 367,2258.53.5, 50.6, 33.3, 29.2 δ; HRMS calculated for C ₂₂ H 9 N ₃ O _{2 2} = 367.2260, found = 367.2258.

Príklad 49 (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l- yljetyl]6-yl]formamid (S)-(Z-2)Example 49 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] 6-yl] formamide (S) - (Z-2)

Anhydrid kyseliny octovej (0,32 ml, 3,43 mmol) sa ochladí na 0 °C. Prídavkom 98 % kyseliny mravčej (0,20 ml, 5,2 mmol) po kvapkách k anhydridu kyseliny octovej vznikne anhydrid kyseliny acetyl mravčej. Zmes sa zahreje na 55 °C počas 2 hodín a potom sa ochladí na 0 °C. Pomocou striekačky sa pridá THF (1 ml) a potom roztok (S)-(-)-l-[2-(6aminoizochróman-l-yl)-etyl]-4-(metoxyfenyl)piperazínu (S)-(Z-l, 600 mg, 1,63 mmol) v THF (2 ml). Reakčná zmes sa zahreje na 20-25 °C a mieša sa 3 hodiny. Potom sa skoncentruje a prečistí pomocou rýchlej chromatografie za vzniku (S)-(-)-N-izochróman-l-[2-[4-(4metoxyfenyl)piperazín-l-yl]etyl]-6-yl]formamidu (S)-(Z-2), Rf = 0,20 (5 % metanol v metylénchloride); IR (suspenzia) 1692, 1616, 1539, 1512, 1306, 1292, 1266, 1245, 1107, 825 cm¹; NMR (300 MHz, CDCb) 8,65 (d, 1/2 H (rotometer), J = 11,4 Hz, NC(O)-H), 8,36 (d, 1/2 H (rotometer), J = 11,4 Hz, N-H), 7,43 (široké s, 1/2 H (rotometer), N-H), 7,24 (m, 1H, aromatický H), 7,07 (d z d, 1H, J_a - 8,4 Hz, J_b = 10,9 Hz, aromatický H), 6,84 (q, a m, 5H, J =Acetic anhydride (0.32 mL, 3.43 mmol) was cooled to 0 ° C. Addition of 98% formic acid (0.20 mL, 5.2 mmol) dropwise to acetic anhydride gave acetic formic anhydride. The mixture was heated to 55 ° C for 2 hours and then cooled to 0 ° C. THF (1 mL) was added via syringe followed by a solution of (S) - (-) - 1- [2- (6 aminoisochroman-1-yl) ethyl] -4- (methoxyphenyl) piperazine (S) - (Zl, 600). mg, 1.63 mmol) in THF (2 mL). The reaction mixture was warmed to 20-25 ° C and stirred for 3 hours. It is then concentrated and purified by flash chromatography to give (S) - (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] formamide (S) - (Z-2), Rf = 0.20 (5% methanol in methylene chloride); IR (suspension) 1692, 1616, 1539, 1512, 1306, 1292, 1266, 1245, 1107, 825 cm &^lt; -1 ^&gt;; NMR (300 MHz, CDCl 3) 8.65 (d, 1/2 H (rotometer), J = 11.4 Hz, NC (O) -H), 8.36 (d, 1/2 H (rotometer), J = 11.4 Hz, NH), 7.43 (broad s, 1/2 H (rotometer), NH), 7.24 (m, 1H, aromatic H), 7.07 (dzd, 1H, J _and 8.4 Hz, J _b = 10.9 Hz, aromatic H), 6.84 (q, am, 5H, J =

9,2 Hz, aromatické H), 4,80 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,10 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,11 (t, H, J = 4,9 Hz, štyri pip-H), 2,95 (m, 1H, PhCH-H), 2,60 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,18 (m, 1H, PhCHCH-H), 2,06 (m, 1H, PhCHCH-H) δ; HRMS vypočítaná pre C₂₃H₂₉N₃O₃ = 395,22,9, nájdená = 395,2210.9.2 Hz, aromatic H), 4.80 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.10 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.11 (t, H, J = 4.9 Hz, four pip-H), 2.95 (m, 1H, PhCH-H), 2.60 (m, 1H, PhCH-H, NC-H ₂ and four pip-H), 2.18 (m, 1H, PhCHCH-H), 2.06 (m, 1H , PhCHCH-H) δ; HRMS calcd for C ₂₃ H ₂₉ N ₃ O ₃ = 395.22.9, found = 395.2210.

Príklad 50 (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l- yljetyl]tExample 50 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] t

6-yl]acetamid (S)-(Z-2)6-yl] acetamide (S) - (Z-2)

-8425 ml guľatá nádoba sa naplní (S)-(-)-l-[2-(6-aminoizochróman-l-yl)-etyl]-4-(4metoxyfenyl)piperazínom (S)-(Z-l, 200 mg, 0,54 mmol) a 4-dimetylaminopyridínom (6,7 mg, 0,054 mmol). Pomocou injekčnej striekačky sa pridá metylénchlorid (7 ml) a reakčná nádoba sa ochladí na 0 °C. Injekčnou striekačkou sa potom pridá trietylamín (0,114 ml, 0,82 mmol) a acetyl chlorid (0,042 ml, 0,60 mmol). Ľadový kúpeľ sa po 15 minútach odstráni a reakcia sa mieša 1,5 hodiny pri 20-25 °C. Reakcia sa tak rozdelí na 0,5 M vodný hydroxid sodný a metylénchlorid. Vrstvy sa oddelia a vodná vrstva sa extrahuje ešte raz s metylénchloridom. Organické zložky sa zmiešajú, vysušia^ síranom sodným, prefiltrujú a zahustia. U koncentrátu sa uskutoční chromatografia na 17 g silikagélu za použitia 5 % metanolu v metylénchloride ako elučného činidla a vznikne (S)-(-)-N-izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-lyl]etyl]-6-yl]acetamid (S)-(Z-2), Rf = 0,18 (5 % metanol v metylénchloride); [α]π =-44° (c = 0,93 metanol v metylénchloride); IR (suspenzia) 1667, 1615, 1599, 1546, 1512, 1421, 1333, 1312, 1247, 1036 cm'¹; NMR (300 MHz, CDC1₃) 7,35, 7,21, 7,15, 7,04, 6,80, 4,80, 4,1,0, 3,76, 3,71, 3,11, 2,95, 2,60, 2,16, 2,10, 2,02 δ; CMR (75 MHz, CDCh) 168,3, 153,8, 145,7, 136,0, 134,9, 125,3, 120,1, 118,2, 118,0, 114,5, 74,5, 63,1, 55,6, 54,8, 53,5, 50,6, 33,2, 29,2,A -8425 mL round-bottom flask was charged with (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z1, 200 mg, 0 , 54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Methylene chloride (7 mL) was added via syringe and the reaction vessel was cooled to 0 ° C. Triethylamine (0.114 mL, 0.82 mmol) and acetyl chloride (0.042 mL, 0.60 mmol) were then added via syringe. The ice bath was removed after 15 minutes and the reaction was stirred at 20-25 ° C for 1.5 hours. The reaction was partitioned between 0.5 M aqueous sodium hydroxide and methylene chloride. The layers were separated and the aqueous layer was extracted once more with methylene chloride. The organics were combined, dried over sodium sulfate, filtered and concentrated. The concentrate was chromatographed on 17 g of silica gel using 5% methanol in methylene chloride as eluent to give (S) - (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide (S) - (Z-2), R f = 0.18 (5% methanol in methylene chloride); [α] D = -44 ° (c = 0.93 methanol in methylene chloride); IR (suspension) 1667, 1615, 1599, 1546, 1512, 1421, 1333, 1312, 1247, 1036 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.35, 7.21, 7.15, 7.04, 6.80, 4.80, 4.1.0, 3.76, 3.71, 3.11, 2.95, 2.60, 2.16, 2.10, 2.02 δ; CMR (75 MHz, CDCl 3) 168.3, 153.8, 145.7, 136.0, 134.9, 125.3, 120.1, 118.2, 118.0, 114.5, 74.5 , 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2,

24,6 δ; HRMS vypočítaná pre C24H31N3O3 = 409,2365, nájdená = 409,2358.24.6 δ; HRMS calcd for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2358.

Príklad 51 (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 - yljetyl]6-yl]benzamid (S)-(Z-2)Example 51 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] 6-yl] benzamide (S) - (Z-2)

Postupom podľa príkladu 50 s drobnými obmenami vzniká z benzoyl chloridu (S)-(-)N-izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]benzamid (S)-(Z-2), Rf = 0,30 (5 % metanol v metylénchloride); [o.]d =-40° (c = 1,0, 50 % etanol v metylénchloride); IR (suspenzia) 3282, 1651, 1516, 1505, 1339, 1312, 1280, 1244, 1108, 694 cm’¹; NMR (300 MHz, CDCh) 7,86 (d, 2H, J = 6,8 Hz, aromatické H), 7,80 (široké s, 1H, PhN-H), 7,50 (m, 4H, aromatické H), 7,36 (d, 1H, J = 8,3 Hz, aromatický H), 7,10 (d, 1H, J = 8,3 Hz, aromatický H), 6,86 )q, 4H, J = 9,2 Hz, aromatické H), 4,84 (m z d, 1H, J = 5,8 Hz, PhC-H),Following the procedure of Example 50 with minor variations, (S) - (-) N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] benzamide (benzoyl chloride) is formed ( S) - (Z-2), R f = 0.30 (5% methanol in methylene chloride); [α] D = -40 ° (c = 1.0, 50% ethanol in methylene chloride); IR (slurry) 3282, 1651, 1516, 1505, 1339, 1312, 1280, 1244, 1108, 694 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.86 (d, 2H, J = 6.8 Hz, aromatic H), 7.80 (broad s, 1H, PhN-H), 7.50 (m, 4H, aromatic H) 7.36 (d, 1H, J = 8.3 Hz, aromatic H), 7.10 (d, 1H, J = 8.3 Hz, aromatic H), 6.86 q, 4H, J = 9.2 Hz, aromatic H), 4.84 (mzd, 1H, J = 5.8 Hz, PhC-H),

4,13 (m, 1H, PhCH₂CH-H), 2,02 (m, 1H, PhCH-H), 3,76 (s, 3H, OC-H₃), 3,76 (m, 1H, PhCH₂CH-H), 3,12 (t, 4H, J = 4,6 Hz, štyri pip-H), 2,99 (m, 1H, PhCH-H), 2,68 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H) δ; HRMS vypočítaná pre C29H33N3O3 = 471,2522, nájdená = 471,2525.4.13 (m, 1H, PhCH ₂ CH-H), 2.02 (m, 1H, PhCH-H), 3.76 (s, 3H, OC-H ₃ ), 3.76 (m, 1H, PhCH ₂ CH-H), 3.12 (t, 4H, J = 4.6 Hz, four pip-H), 2.99 (m, 1H, PhCH-H), 2.68 (m's, 7H, PhCH) -H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H) δ; HRMS calcd for C 29 H 33 N 3 O 3 = 471.2522, found = 471.2525.

Príklad 52 (S)-(-)-N-izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l- yl]etyl]-6yljpropiónamid (S)-(Z-2)Example 52 (S) - (-) - N-Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide (S) - (Z-2)

-85Postupom podľa príkladu 50 s drobnými obmenami vzniká z propionyl chloridu (S)(-)-N-izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]propionamid (S)-(Z-2), Rf - 0,22 (5 % metanol v metylénchloride); [cc]d =-44° (c = 0,97, 50 % etanol v metylénchloride); IR (suspenzia) 3306, 1659, 1590, 1515, 1421, 1245, 1214, 1110, 1036, 821 cm’¹ ; NMR (300 MHz, CDCb) 7,76 (s, 1H, aromatický H), 7,36 (široké s, 1H, PhN-H), 7,24 (d, 1H, J = 8,3 Hz, aromatický H), 7,00 (d, 1H, J = 8,3 Hz, aromatický H), 6,80 (q, 4H, J = 9,2 Hz, aromatické H), 4,77 (m z d, 1H, PhCH₂CH-H), 3,07 (t, 4H, J = 4,9 Hz, štyri pip-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH-H, NC-H₂ a štyri pip-H), 2,33 (q, 2H, J = 7,5 Hz,-85The procedure of Example 50, with minor variations, yields (S) (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide propionyl chloride (S) - (Z-2), R f = 0.22 (5% methanol in methylene chloride); [α] D = -44 ° (c = 0.97, 50% ethanol in methylene chloride); IR (suspension) 3306, 1659, 1590, 1515, 1421, 1245, 1214, 1110, 1036, 821 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.76 (s, 1H, aromatic H), 7.36 (broad s, 1H, PhN-H), 7.24 (d, 1H, J = 8.3 Hz, aromatic H 7.00 (d, 1H, J = 8.3 Hz, aromatic H), 6.80 (q, 4H, J = 9.2 Hz, aromatic H), 4.77 (wt, 1H, PhCH ₂₎ CH-H), 3.07 (t, 4H, J = 4.9 Hz, four pip-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH-) H, NC-H ₂ and four pip-H), 2.33 (q, 2H, J = 7.5 Hz,

PhNHC(O)CH₂C-H₃) δ; CMR (75 MHz, CDCb) 172,5, 153,7, 145,8, 136,3, 134,7, 133,8,PhNHC (O) CH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl 3) 172.5, 153.7, 145.8, 136.3, 134.7, 133.8,

125,2, 120,2, 118,1, 114,5, 74,4, 63,0, 55,6, 54,8, 53,5, 50,6, 33,3, 30,6, 29,2 a 9,8 δ.125.2, 120.2, 118.1, 114.5, 74.4, 63.0, 55.6, 54.8, 53.5, 50.6, 33.3, 30.6, 29, 2 and 9.8 δ.

Príklad 53 (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l- yljetyl]6-yl]akrylamid (S)-(Z-2)Example 53 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] 6-yl] acrylamide (S) - (Z-2)

Postupom podľa príkladu 50 s drobnými obmenami vzniká z akryl chloridu (S)-(-)-Nizochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]akrylamid (S)-(Z-2), Rf = 0,22 (5 % metanol v metylénchloride); [a]_D =-40° (c = 0,79, 50 % etanol v metylénchloride); IR (suspenzia) 3266, 1661, 1592, 1536, 1512, 1422, 1244, 1218, 1109, 822 cm'¹; NMR (300Following the procedure of Example 50 with minor variations, (S) - (-) - Nizochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acrylamide (S) is obtained from acrylic chloride (S). - (Z-2), Rf = 0.22 (5% methanol in methylene chloride); [α] _D = -40 ° (c = 0.79, 50% ethanol in methylene chloride); IR (slurry) 3266, 1661, 1592, 1536, 1512, 1422, 1244, 1218, 1109, 822 cm &^lt; -1 &gt;; NMR (300

MHz, CDCb) 7,46 (široké s, 1H, PhN-H), 7,26 (s, 1H, aromatický H), 7,06 (d, 1H, J = 8,4 Hz, aromatický H), 6,85 (q, 4H, J = 9,2 Hz, aromatické H), 6,43 (d z d, 1H, J_a = 1,3 Hz, Jb = 16,8 Hz, jeden akryl-H), 6,23 (m, 1H, jeden akryl-H), 5,76 (d z d, 1H, J_a = 1,3 Hz, J_b = 10 Hz, jeden akryl-H), 4,81 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,11 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H3), 3,75 (m, 1H, PhCH₂CH-H), 3,11 (t, 4H, J = 4,9 H, 2,14 (m, 1H, PhCHCH-H), 2,03 (m, 1H, PhCHCH-H) ) δ; CMR (75 MHz, CDC1₃) 163,5, 153,8, 145,8, 135,9, 134,9, 134,4,MHz, CDCl3) 7.46 (broad s, 1H, PhN-H), 7.26 (s, 1H, aromatic H), 7.06 (d, 1H, J = 8.4 Hz, aromatic H), 6 , 85 (q, 4H, J = 9.2 Hz, aromatic H), 6.43 (dzd, 1H, J _a = 1.3 Hz, J b = 16.8 Hz, one acrylic-H), 6.23 (m, 1H, one acrylic-H), 5.76 (dzd, 1H, J _a = 1.3 Hz, J _b = 10 Hz, one acrylic-H), 4.81 (wd, 1H, J = 5) 8 Hz, PhC-H), 4.11 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H 3), 3.75 (m, 1H, PhCH ₂ CH-H) 1.11 (t, 4H, J = 4.9 H, 2.14 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H)) δ; CMR (75 MHz, CDC1 ₃₎ 163.5, 153.8, 145.8, 135.9, 134.9, 134.4,

131,1, 127,9, 125,4, 120,2, 118,2, 118,0, 114,4, 74,5, 63,0, 55,6, 54,8, 53,5, 50,6, 33,2, 29,2131.1, 127.9, 125.4, 120.2, 118.2, 118.0, 114.4, 74.5, 63.0, 55.6, 54.8, 53.5, 50, 6, 33.2, 29.2

Ô; HRMS vypočítaná pre C*₂s H31N3O3 = 421,2365, nájdená = 421,2358.ABOUT; HRMS calcd for C * ₂ with H31N3O3 = 421.2365, found = 421.2358.

Príklad 54 (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l- yljetyl]6-yl]izobutyramid (S)-(Z-2)Example 54 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] 6-yl] isobutyramide (S) - (Z-2)

Postupom podľa príkladu 50 s drobnými obmenami vzniká z i-butyryl chloridu (S)-(-)N-izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]izobutyramid (S)-(Z-2) Rf = 0,27 (5 % metanol v metylénchloride); [a]D =-42° (c = 0,94, 50 % etanol v metylénchloride);Following the procedure of Example 50 with minor variations, (S) - (-) N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] i-butyryl chloride is formed. isobutyramide (S) - (Z-2) R f = 0.27 (5% methanol in methylene chloride); [α] D = -42 ° (c = 0.94, 50% ethanol in methylene chloride);

-86IR (suspenzia) 3289, 1660, 1589, 1524, 1515, 1451, 1422, 1243, 1109, 822 cm'¹, NMR (300 MHz, CDClj) 7,43 (s, 1H, aromatický H), 7,23 (d, 1H, J = 8,4 Hz, aromatický H), 7,13 (široké s, 1H, PhN-H), 7,04 (d, 1H, J = 8,3Hz, aromatický H), 6,84 (q, 4H, J = 9,2 Hz, aromatické H), 4,80 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,10 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-Hj), 3,71 (m, 1H, PhCH₂CH-H), 3,10 (t, 4H, J = 4,9 Hz, šryri pip-H), 2,96 (m, 1H, PhCH-H), 2,60 (m’s, 8H, PhCH-H, NC-H₂, PhNHC(O)C-H) a štyri pip-H), 2,14 (m, 1H, PhCHCH-H), 2,00 (m, 1H, PhCHCH-H), 1,24 (d, 6H, J = 6,9 Hz, dva z PhNHC(O)CHMeCHj) δ; CMR (75 MHz, CDClj) 175,2, 153,8, 145,8, 136,2, 134,9, 125,3, 120,0, 118,2, 117,8,-86IR (suspension) 3289, 1660, 1589, 1524, 1515, 1451, 1422, 1243, 1109, 822 cm ^-1 , NMR (300 MHz, CDCl 3) 7.43 (s, 1H, aromatic H), 7.23 (d, 1H, J = 8.4 Hz, aromatic H), 7.13 (broad s, 1H, PhN-H), 7.04 (d, 1H, J = 8.3 Hz, aromatic H), 6, 84 (q, 4H, J = 9.2Hz, aromatic H), 4.80 (mzd, 1H, J = 5.8Hz, PhC-H), 4.10 (m, 1H, PhCH ₂ CH-H) ), 3.76 (s, 3H, OC-H 3), 3.71 (m, 1H, PhCH ₂ CH-H), 3.10 (t, 4H, J = 4.9 Hz, broad pip-H) , 2.96 (m, 1 H, Ph-H), 2.60 (m's, 8H, PhCH-H, _NC-H2, PhNHC (O) CH) and four pip-H), 2.14 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H), 1.24 (d, 6H, J = 6.9 Hz, two of PhNHC (O) CHMeCH3) δ; CMR (75 MHz, CDCl 3) 175.2, 153.8, 145.8, 136.2, 134.9, 125.3, 120.0, 118.2, 117.8,

114,4, 74,5, 63,1, 60,8, 55,6, 54,8, 53,5, 50,6, 36,7, 33,2, 29,3, 19,6 2 δ, HRMS vypočítaná pre C₂₆H₃₅NjOj = 437,2678, nájdená - 437,2680.114.4, 74.5, 63.1, 60.8, 55.6, 54.8, 53.5, 50.6, 36.7, 33.2, 29.3, 19.6 2 δ, HRMS calcd for C ₂₆ H ₃₅ N ₃ O 3 = 437.2678, found - 437.2680.

Príklad 55 (S)-(-)-l-[2-(6-etylaminoizochróman-l-yl)-etyl]-4-(4metoxyfenyl)piperazín (S)- (Z-4)Example 55 (S) - (-) - 1- [2- (6-ethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-4)

Postupom podľa príkladu 5, 2. kroku s drobnými obmenami vzniká z (S)-(-)-Nizochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]acetamidu (S)-(Z-2, Príklad 50) (S)-(-)-l-[2-(6-etylaminoizochróman-l-yl)-etyl]-4-(4-metoxyfenyl)piperazín (S)-(Z-4), Rf = 0,32 (5 % metanol v metylénchloride); [a]o =-46° (c = 0,54, 50 % etanol v metylénchloride); IR (čisté látky) 2953, 2825,2819,1616,1512, 1268, 1244, 1147, 11104, 824 cm'¹; NMR (300Following the procedure of Example 5, Step 2, with minor variations, (S) - (-) - Nizochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide is obtained. (S) - (Z-2, Example 50) (S) - (-) - 1- [2- (6-ethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-4), R f = 0.32 (5% methanol in methylene chloride); [α] D = -46 ° (c = 0.54, 50% ethanol in methylene chloride); IR (neat) 2953, 2825, 2819, 1616, 1512, 1268, 1244, 1147, 11104, 824 cm ^-1 ; NMR (300

MHz, CDCI3) 6,86 (m, 5H, aromatické H), 6,47 (d z d, 1H, J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,34 (d, 1H, J = 2,2 Hz, aromatický H), 4,76 (m z d, 1H, J = 8,2 Hz, PhC-H), 4,09 (m, 1H, PhCH₂CH-H), 3,76 )s, 3H, OC-Hj), 3,71 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-Hj), 3,71 (m, 1H, PhCH₂CH-H), 3,13 (t a q sa prekrývají, 6H, štyri pip-H a PhNC-H₂),MHz, CDCl 3) 6.86 (m, 5H, aromatic H), 6.47 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.34 (d, 1H, J = 2.2 Hz, aromatic H), 4.76 (mzd, 1H, J = 8.2 Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H), 3, 76) s, 3H, OC-H 3), 3.71 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H 3), 3.71 (m, 1H, PhCH ₂ CH) -H), 3.13 (taq overlapping, 6H, four pip-H and PhNC-H ₂ ),

2,91 (m, 1H, PhCH-H), 2,62 (m’s, 7H, PhCH-H, VN-H₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,00 (m, 1H, PhCHCH-H), 1,25 (t, 3H, J = 7,1 Hz, PhNHCH₂C-H₃) δ; CMR (75 MHz, CDClj) 153,8, 146,8, 145,8, 134,8, 126,8, 125,6, 118,2, 114,4, 112,2,11,6, 74,6,2.91 (m, 1H, PhCHCH-H), 2.62 (m's, 7H, PhCH-H, VN-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2 .00 (m, 1H, PhCHCH-H), 1.25 (t, 3H, J = 7.1 Hz, PhNHCH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl3) 153.8, 146.8, 145.8, 134.8, 126.8, 125.6, 118.2, 114.4, 112.2, 111.6, 74.6 .

63,4, 55,6, 54,9, 53,5, 50,5, 38,6, 33,3, 29,5, 15,0 δ; HRMS vypočítaná pre C₂4H₃₃NjO₂ 395,2573, nájdená = 395,2573.63.4, 55.6, 54.9, 53.5, 50.5, 38.6, 33.3, 29.5, 15.0 δ; HRMS calcd for C ₂₄ H ₃₃ N ₃ O ₂ 395.2573, found = 395.2573.

Príklad 56 (S)-(-)-1 -[2-(4-metoxyfenyl)-4-[2-(6-propylaminoizochróman-1 -y 1)etyljpiperazín (S)-(Z-4)Example 56 (S) - (-) - 1- [2- (4-Methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4)

Postupom podľa príkladu 5, 2. kroku s drobnými obmenami vzniká z (S)-(-)-Nizochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]propionamidu (S)-(Z-2, príklad 45) (S)-(-)-l-[2-(4-metoxyfenyl)-4-[2-(6-propylaminoizochróman-l-yl)-etyl]piperazín (S)-(Z-874), Rf = 0,52 (50 % acetón v hexáne); [a]o =-41^u (c = 0,69, 50 % etanol v metylénchloride); IR (čisté látky) 2812, 2804, 1614, 1514, 1271, 1254, 1247, 1105, 1034, 830 cm’¹; NMR (300 MHz, CDCb) 6,86 (m, 5H, aromatické H), 6,47 (d z d, 1H, J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,34 (d, 1H, J = 2,2 Hz, aromatický H), 4,76 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,09 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,54 (široké s, 1H, PhN-H), 3,09 (t a q sa prekrývajú, 6H, štyri pip-H a PhNC-H₂), 2,91 (m, 1H, PhCH-H), 2,62 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,00, 1,63, 1,25 δ; HRMS vypočítaná pre C₂sH₃sN₃O₂ = 409,2729, nájdená = 409,2722.Following the procedure of Example 5, Step 2, with minor variations, (S) - (-) - Nizochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide is formed. (S) - (Z-2, Example 45) (S) - (-) - 1- [2- (4-Methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine ( S) - (Z-874), R f = 0.52 (50% acetone in hexane); [α] D = -41 ^µ (c = 0.69, 50% ethanol in methylene chloride); IR (neat) 2812, 2804, 1614, 1514, 1271, 1254, 1247, 1105, 1034, 830 cm ^-1 ; NMR (300 MHz, CDCl 3) 6.86 (m, 5H, aromatic H), 6.47 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.34 (d, 1H, J = 2.2 Hz, aromatic H), 4.76 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H) 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.54 (broad s, 1H, PhN-H), 3.09 (taq sa overlap, 6H, four pip-H and PhNC-H ₂ ), 2.91 (m, 1H, PhCH-H), 2.62 (m's, 7H, PhCH-H, NC-H _2, and four pip-H) 2.10 (m, 1H, PhCHCH-H), 2.00, 1.63, 1.25 δ; HRMS calculated for C ₂ sH ₃ with N ₃ O ₂ = 409.2729, found = 409.2722.

Príklad 57 (S)-(-)-l-(4-metoxyfenyl)-4-[2-(6-metylaminoizochróman-l-yl)-etyl]piperazín (S)-(Z-4)Example 57 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4)

Anhydrid kyseliny octovej (0,32 ml, 3,43 mmol) sa ochladí na 0 °C. Prídavkom 98 % kyseliny mravčej (0,20 ml, 5,2 mmol) po kvapkách k anhydridu kyseliny octovej vznikne anhydrid kyseliny acetyl mravčej. Zmes sa zahreje na 55 °C počas 2 hodín a potom sa ochladí na -15 °C v kúpeli etylénglykol/oxid uhoľnatý. Pomocou striekačky sa pridá THF (1 ml) a potom roztok (S)-(-)-l-[2-(6-aminoizochróman-l-yl)-etyl]-4-(metoxyfenyl)piperazínu (S)-(Z1, príklad 48, 1,99 g, 5,41 mmol) v THF (10 ml). Reakcia sa mieša 3 hodiny pri -15 °C. Potom sa zahreje na 20-25 °C a prchavé látky sa odstránia za zníženého tlaku a zostane žltý olej. Roztok so surovým produktom v THF (30 ml) sa umiestni do 250 ml guľatej nádoby s chladičom. Zmes sa ochladí na 0 °C a pomocou injekčnej striekačky sa pomaly pridá komplex boru s metylsulfidom (10M, 1,73 ml, 17,3 mmol). Ľadový kúpeľ sa odstráni, hneď ako sa reakcia ukľudní. Zmes sa potom zahreje k miernemu varu na 3 hodiny a potom sa ponechá tri dni pri 20-25 °C. Reakcia sa ochladí na 0 °C a po kvapkách sa pridá metanol (30 ml) (penenie), potom sa 1 hodinu mieša pri 20-25 °C a na 2 hodiny sa privedie do varu. Po schladení na 20-25 °C sa prchavé látky odstránia za zníženého tlaku a u vodného zvyšku sa zvýši pH pomocou vodného roztoku hydroxidu sodného a extrahuje sa 80ml octanu etylnatého (trikrát). Zmiešané organické produkty sa vysušia síranom sodným, prefiltrujú a zahustia za vzniku surového produktu. Surová látka sa prečistí rýchlou chromatografiou za použitia 25 % acetónu v hexáne ako elučného činidla a vznikne (S)-(-)-l-[2-(4-metoxyfenyl)4-[2-(6-metylaminoizochróman-l-yl)-etyl]piperazín (S)-(Z-4), IR (čisté látky) 2933, 2831, 2817, 1616, 1513, 1275, 1246, 1107, 1038, 826 cm¹; NMR (300 MHz, CDCb) 6,86 (m, 5H, atromatické H), 6,47 (d z d, 1H, J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,35 (d, 1H, J = 2,2 Hz, aromatický H), 4,76 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,09 (m, 1H, PhCH₂CH-H), 3,76 (s,Acetic anhydride (0.32 mL, 3.43 mmol) was cooled to 0 ° C. Addition of 98% formic acid (0.20 mL, 5.2 mmol) dropwise to acetic anhydride gave acetic formic anhydride. The mixture was heated to 55 ° C for 2 hours and then cooled to -15 ° C in an ethylene glycol / carbon monoxide bath. THF (1 mL) was added via syringe followed by a solution of (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) ethyl] -4- (methoxyphenyl) piperazine (S) - (Z1). Example 48, 1.99 g, 5.41 mmol) in THF (10 mL). The reaction was stirred at -15 ° C for 3 hours. It is then warmed to 20-25 ° C and the volatiles are removed under reduced pressure to leave a yellow oil. A solution of the crude product in THF (30 mL) was placed in a 250 mL round-bottom flask. The mixture was cooled to 0 ° C and boron-methyl sulfide complex (10M, 1.73 mL, 17.3 mmol) was added slowly via syringe. The ice bath is removed as soon as the reaction calms down. The mixture is then heated to gentle boiling for 3 hours and then left at 20-25 ° C for three days. The reaction was cooled to 0 ° C and methanol (30 ml) was added dropwise (foaming), then stirred at 20-25 ° C for 1 hour and brought to reflux for 2 hours. After cooling to 20-25 ° C, the volatiles were removed under reduced pressure and the aqueous residue was adjusted to pH with aqueous sodium hydroxide solution and extracted with 80 ml of ethyl acetate (three times). The combined organic products were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by flash chromatography using 25% acetone in hexane as eluent to give (S) - (-) - 1- [2- (4-methoxyphenyl) 4- [2- (6-methylaminoisochroman-1-yl)] -ethyl] piperazine (S) - (Z-4), IR (neat) 2933, 2831, 2817, 1616, 1513, 1275, 1246, 1107, 1038, 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 6.86 (m, 5H, atromatic H), 6.47 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.35 (d, 1H, J = 2.2 Hz, aromatic H), 4.76 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H) 3.76 (s,

-883H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,58 (široké s, 1H, N-H), 3,11 (t, 4H, štyri pip-H),-883H, OC H _3), 3.71 (m, 1 H, CH ₂ Ph-H), 3.58 (bs, 1 H, NH), 3.11 (t, 4H, four pip-H),

2,92 (m, 1H, PhCH-H), 2,82 (s, 3H, NHC-H₃), 2,62 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H),2.92 (m, 1H, PhCH-H), 2.82 (s, 3H, NHC-H ₃ ), 2.62 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H),

2,10 (m, 1H, PhCH-H), 2,00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1₃) 153,8, 147,7,2.10 (m, 1H, PhCHCH-H); 2.00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDC1 ₃₎ 153.8, 147.7,

145,8, 131,8, 126,9, 125,5, 118,2, 114,4, 111,3, 74,64, 63,3, 55,6, 54,9, 53,5, 53,4, 50,6, 33,4,145.8, 131.8, 126.9, 125.5, 118.2, 114.4, 111.3, 74.64, 63.3, 55.6, 54.9, 53.5, 53, 4, 50.6, 33.4,

30,9,29,5 δ; HRMS vypočítaná pre C₂₃H₃iN₃O₂: 381,2416, nájdená = 381,2415.30,9,29,5 δ; HRMS calculated for C ₂₃ H ₃ IN ₃ O _2: 381.2416, found = 381.2415.

Príklad 58 (S)-(-)-1 -(4-metoxyfeny l)-4-[2-(6-dimetylizochróman-1 -y 1)etyljpiperazín (S)-(Z-7)Example 58 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6-dimethylisochroman-1-yl) ethyl] piperazine (S) - (Z-7)

Z prípravy opísanej v príklade 57 sa vyizoluje tiež (S)-(-)-l-(4-metoxyfeny l)-4-[2-(6dimetylizochróman-l-yl)-etyl]piperazín (S)-(Z-7), Rf = 0,22 (acetón / hexán 25/75); NMR (300 MHz, CDC1₃) 6,99-6,81 (m’s, 5H, aromatické H), 6,62 (d z d, 1H J_a = 2,4 Hz, J_b = 8,2 Hz, aromatický H), 6,46 (d, 1H, J = 2,2 Hz, aromatický H), 4,78 (m z d, 1H, J = 5,8 Hz, PhCH), 4,10 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,11 (q, 4H, štyri pip-H), 2,95 (m, 1H, PhCH-H), 2,92 (s, 6H, dva z NC-H₃), 2,62 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,10 (m, 1H, PhCH-H), 2,00 (m, 1H, PhCHCH-H) δ; CMR (75 MHz,Also prepared from the preparation described in Example 57 is (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-dimethylisochroman-1-yl) ethyl] piperazine (S) - (Z-7). Rf = 0.22 (acetone / hexane 25/75); NMR (300 MHz, CDCl ₃ ) 6.99-6.81 (m's, 5H, aromatic H), 6.62 (dzd, 1H J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H) 6.46 (d, 1H, J = 2.2 Hz, aromatic H), 4.78 (mzd, 1H, J = 5.8 Hz, PhCH), 4.10 (m, 1H, PhCH ₂ CH- H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.11 (q, 4H, four pip-H), 2.95 ( m, 1H, PhCH-H), 2.92 (s, 6H, two of NC-H ₃ ), 2.62 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2, 10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H) δ; CMR (75MHz,

CDC1₃) 153,8, 149,2, 145,8, 134,6, 126,3, 125,4, 118,1, 114,4, 112,5, 112,4, 111,4,74,6, 63,4,CDC1 ₃₎ 153.8, 149.2, 145.8, 134.6, 126.3, 125.4, 118.1, 114.4, 112.5, 112.4, 111,4,74,6 , 63,4,

55,6, 55,0, 53,5, 50,6, 46,8,40,7, 33,4, 29,7 Ô.55.6, 55.0, 53.5, 50.6, 46.8.40.7, 33.4, 29.7 Ô.

Príklad 59 (S)-(-)-1 -[2-(6-etylmetylaminoizochróman-1 -y l)-etyl] -4-(4metoxyfenyl)piperazín (S)-(Z-7)Example 59 (S) - (-) - 1- [2- (6-ethylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-7)

Z prípravy opísanej v príklade 57 sa vyizoluje tiež (S)-(-)-l-[2-(6etylmetylaminoizochróman-l-yl)-etyl]-4-(4-metoxyfenyl)piperazín (S)-(Z-7), Rf = 0,22 (acetón/ hexán 25/75); [a]o =-54° (c = 0,83, etanol/metylénchlorid 50/50); IR (suspenzia) 2815, 1611, 1515, 1256, 1245, 1236, 1107, 1095, 1037 a 824 cm⁴; NMR (300 MHz, CDC1₃)(S) - (-) - 1- [2- (6-methylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-7) is also isolated from the preparation described in Example 57. Rf = 0.22 (acetone / hexane 25/75); [α] D = -54 ° (c = 0.83, 50/50 ethanol / methylene chloride); IR (slurry) 2815, 1611, 1515, 1256, 1245, 1236, 1107, 1095, 1037, and 824 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl ₃ )

6,97-6,81, 6,59, 6,42, 4,77, 4,10, 3,76, 3,71, 3,37, 3,11, 2,95, 2,88, 2,62, 2,10, 2,00 a 1,11 δ;6.97-6.81, 6.59, 6.42, 4.77, 4.10, 3.76, 3.71, 3.37, 3.11, 2.95, 2.88, 2, 62, 2.10, 2.00 and 1.11 δ;

CMR (75 MHz, CDC1₃) 153,8, 147,6, 145,8, 134,6, 125,7, 125,5, 118,1, 114,4, 112,1, 111,0,CMR (75 MHz, CDC1 ₃₎ 153.8, 147.6, 145.8, 134.6, 125.7, 125.5, 118.1, 114.4, 112.1, 111.0,

74,7, 63,5, 55,6, 55,0, 53,5, 50,6, 46,8, 37,5, 33,5,29,7 a 11,3 δ.74.7, 63.5, 55.6, 55.0, 53.5, 50.6, 46.8, 37.5, 33.5, 29.7 and 11.3 δ.

Príklad 60 (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 yl]etyl]-6-yl]-N-metylacetamid (S)-(Z-5)Example 60 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide (S) - (Z) -5)

Postupom podľa príkladu 50 s drobnými obmenami vzniká z (S)-(-)-l-[2-(4metoxyfenyl)-4-[2-(6-propylaminoizochróman-1 -yl)-etyl]piperazínu (S)-(Z-4) uvedená zlúčenina, Rf = 0,26 (metanol/metylénchlorid 5/95); [cc]d =-38° (c = 0,69, etanol/metylén-89chlorid 50/50); IR (suspenzia) 1669, 1661, 1513, 1448, 1445, 1275, 1248, 1109, 1036 a 826 cm’¹; NMR (300 MHz, CDCb) 7,13, 6,98, 6,86, 4,83, 4,13, 3,76, 3,76, 3,23, 3,10, 2,97, 2,61, 2,14, 2,02 a 1,87 δ; CMR (75 MHz, CDCb) 170,6, 153,8, 145,7, 142,7, 137,8, 135,7, 127,2,Following the procedure of Example 50 with slight variations, (S) - (-) - 1- [2- (4-methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z) is formed. -4) said compound, R f = 0.26 (methanol / methylene chloride 5/95); [α] D = -38 ° (c = 0.69, ethanol / methylene-89 chloride 50/50); IR (slurry) 1669, 1661, 1513, 1448, 1445, 1275, 1248, 1109, 1036, and 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.13, 6.98, 6.86, 4.83, 4.13, 3.76, 3.76, 3.23, 3.10, 2.97, 2.61 , 2.14, 2.02 and 1.87 δ; CMR (75 MHz, CDCl 3) 170.6, 153.8, 145.7, 142.7, 137.8, 135.7, 127.2,

126,1, 124,8, 118,2, 114,4, 74,5, 62,8, 61,2, 55,6, 54,8, 53,5, 50,7, 32,7, 33,3,29,0 a 22,5 δ.126.1, 124.8, 118.2, 114.4, 74.5, 62.8, 61.2, 55.6, 54.8, 53.5, 50.7, 32.7, 33, 3.29.0 and 22.5 δ.

Príklad 61 (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 yl]etyl]-6-yl]-N-metylizobutyramid (S)-(Z-5)Example 61 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylisobutyramide (S) - (Z) -5)

Postupom podľa príkladu 54 s drobnými obmenami vzniká z (S)-(-)-l-(4metoxyfenyl)-4-[2-(6-metylaminoizochróman-1 -yl)-etyl]piperazínu (S)-(Z-4) (S)-(-)-N[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl]etyl]-6-yl]-N-metylizobutyramid (S)-(Z5), Rf = 0,33 (5 % metanol v metylénchloride); [<x]d =-34° (c = 0,80, 50 % etanol v metylénchloride); IR (suspenzia) 2962, 1658, 1512, 1468, 1457, 1386, 1245, 1109, 1038, 825 cm¹; NMR (300 MHz, CDCb) 7,13 (d, 1H, J = 8,2 Hz, aromatický H), 6,98 (d, 1H, J = 8,2 Hz, aromatický H), 6,86 (m z q, 5H, J - 9,.2 Hz, aromatické H), 4,83 (m z d, 1H, J = 5,8 Hz, PgC-H), 4,13 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,76 (m, 1H, PhCH₂CH-H ), 3,22 (s, 3H, NC-H₃), 3,10 (t, 4H, J = 4,6 Hz, štyri pip-H), 2,97 (m, 1H, PhCH-H), 2,61 (m’s, 8H, NC(O)CMe2-H, PhCH-H,NC-H₂ a štyri pip-H), 2,14 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), 1,03 (d, 6H, J = 6,5 Hz, dva z NC(O)CHC-H₃) δ; CMR (75 MHz, CDCb)Following the procedure of Example 54 with slight variation, (S) - (Z-4) results from (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl) ethyl] piperazine. (S) - (-) - N [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylisobutyramide (S) - (Z5), R f = 0.33 (5% methanol in methylene chloride); [α] D = -34 ° (c = 0.80, 50% ethanol in methylene chloride); IR (suspension) 2962, 1658, 1512, 1468, 1457, 1386, 1245, 1109, 1038, 825 cm &^lt; -1 ^&gt;; NMR (300 MHz, CDCl 3) 7.13 (d, 1H, J = 8.2 Hz, aromatic H), 6.98 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 (mzq) 5H, J = 9.2 Hz, aromatic H), 4.83 (mzd, 1H, J = 5.8 Hz, PgC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.76 (m, 1H, PhCH ₂ CH-H), 3.22 (s, 3H, NC-H ₃ ), 3.10 (t, 4H) J = 4.6 Hz, four pip-H), 2.97 (m, 1H, PhCH-H), 2.61 (m's, 8H, NC (O) CMe 2 -H, PhCH-H, NC-H) ₂ and four pip-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.03 (d, 6H, J = 6.5 Hz, two the NC (O) _CHC-H3) δ; CMR (75MHz, CDCb)

177,4, 153,8, 145,7, 142,4, 137,8, 135,7, 127,4, 126,1, 125,0, 118,2, 114,5, 74,5, 62,8, 55,6,177.4, 153.8, 145.7, 142.4, 137.8, 135.7, 127.4, 126.1, 125.0, 118.2, 114.5, 74.5, 62, 8, 55.6,

54,8, 53,5, 50,7, 37,5, 33,3, 31,0, 29,0, 19,8 δ; HRMS vypočítaná pre C₂7H₃₇N₃O₃ = 451,2835, nájdená = 451,2827.54.8, 53.5, 50.7, 37.5, 33.3, 31.0, 29.0, 19.8 δ; HRMS calculated for C 7 H ₃₇ N ₂ O _{3 3} = 451.2835, found = 451.2827.

Príklad 62 (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-lyl]etyl]-6-yl]-N-metánsulfonamid (S)-(Z-3)Example 62 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methanesulfonamide (S) - (Z- 3)

Zmieša sa (S)-(-)-1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)-piperazín (S)-(Z-l) (200 mg, 0,54 mmol) a 4-dimetylaminopyridín (6,7 mg, 0,054 mmol). Pyridín (2 ml) sa pridá pomocou injekčnej striekačky, zmes sa ochladí na 0 °C a pridá sa metán sulfonyl chlorid (0,045 ml, 0,60 mmol). Po 15 minútach sa ľadový kúpeľ odstráni a reakcia sa miešaCombine (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) -piperazine (S) - (Z1) (200 mg, 0, 54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Pyridine (2 mL) was added via syringe, cooled to 0 ° C and methane sulfonyl chloride (0.045 mL, 0.60 mmol) was added. After 15 minutes, the ice bath was removed and the reaction stirred

1,5 hodiny pri 20-25 °C. Reakcia sa zriedi vodou a dvakrát sa extrahuje octanom etylnatým. Zmiešané organické látky sa raz premyjú nasýteným vodným roztokom síranu meďnatého, potom vodou, vysušia pomocou síranu horečnatého, prefíltrujú a zahustia. Koncentrát sa1.5 hours at 20-25 ° C. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organics were washed once with saturated aqueous copper sulfate solution, then with water, dried over magnesium sulfate, filtered and concentrated. Concentrate up

-90analyzuje chromatograficky na 25 g silikagélu za použitia 50 % acetónu v hexáne ako elučného činidla za vzniku (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-lyl]etyl]-6-yl]-N-metánsulfónamidu (S)-(Z-3), Rf = 0,21 (5 % metanol v metylénchloride);-90 analyzed by chromatography on 25 g of silica gel using 50% acetone in hexane as eluent to give (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] 6-yl] -N-methanesulfonamide (S) - (Z-3), R f = 0.21 (5% methanol in methylene chloride);

[a] d =-43° (c = 0,89, 50 % etanol v metylénchloride); IR (suspenzia) 1512,1339, 1319, 1295, 1244, 1152, 1106, 1037, 973, 826 cm'¹; NMR (300 MHz, CDCb) 7,05 (m’s, 3H, aromatické H), 6,87 (q, 4H, J = 9,0 Hz, aromatické H), 4,80 (m z d, 1H, J = 5,8 Hz PhC-H), 4,11 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 2,60 (m’s, 7H, PhCH-H, NCH₂ a štyri pip-H), 2,11 (m, 1H, PhCHCH-H), 2,01 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCb) 153,8, 145,7, 135,8, 135,6, 134,8, 1126,1, 121,2, 119,0, 118,2, 114,5, 74,4, 62,9, 55,6,[α] D = -43 ° (c = 0.89, 50% ethanol in methylene chloride); IR (suspension) 1512, 1339, 1319, 1295, 1244, 1152, 1106, 1037, 973, 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.05 (m's, 3H, aromatic H), 6.87 (q, 4H, J = 9.0 Hz, aromatic H), 4.80 (wd, 1H, J = 5, 8 Hz PhC-H), 4.11 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H) 2.60 (m's, 7H, PhCH-H, NCH ₂ and four pip-H), 2.11 (m, 1H, PhCHCH-H), 2.01 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCl 3) 153.8, 145.7, 135.8, 135.6, 134.8, 1126.1, 121.2, 119.0, 118.2, 114.5, 74.4 , 62.9, 55.6,

54,8, 53,5, 50,6, 39,4, 33,2, 29,1 δ; HRMS vypočítaná pre C₂3H₃iN₃O₄Si = 445,2035, nájdená = 445,2031.54.8, 53.5, 50.6, 39.4, 33.2, 29.1 δ; HRMS calculated for C 3 H _{3 2} i N ₃ O ₄ Si = 445.2035, found = 445.2031.

Príklad 63 (S)-(-)-6-amino-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]izochróman, metyl močovina (S)-(X-6) (S)-(-)-1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)-piperazín (S)-(Z-1, 376 mg, 1,0 mmol) sa pridá do acetonitrilu (4 ml). Pomocou injekčnej striekačky sa potom pomaly pridá metylizokyanát (0,091 ml, 1,53 mmol), potom ďalší acetonitril (7 ml) a reakcia sa mieša 3 hodiny pri 20-25 °C. Zrazenina sa prefiltruje a dôkladne premyje octanom etylnatým a hexánom za vzniku surového produktu, ktorý sa prečistí rýchlou chromatografiou za použitia 5 % metanolu v metylénchloride a vznikne (S)-(-)-6-amino-l-[2-[4-(4metoxyfenyl)piperazín-l-yl]etyl]-6-yl]-izochróman, metyl močovina (S)-(X-6) Rf = 0,07 (5 % metanol v metylénchloride); [a]o =-43° (c = 0,75, 50 % etanol v metylénchloride ); IR (suspenzia) 3312, 1645, 1614, 1597, 1567, 1512, 1421, 1310, 1244, 1109 cm'¹; NMR (300Example 63 (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] isochroman, methyl urea (S) - (X) -6) (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) -piperazine (S) - (Z-1, 376 mg, 1.0 mmol) was added to acetonitrile (4 mL). Methyl isocyanate (0.091 mL, 1.53 mmol) was then slowly added via syringe, followed by additional acetonitrile (7 mL) and the reaction was stirred at 20-25 ° C for 3 hours. The precipitate was filtered and washed thoroughly with ethyl acetate and hexane to give the crude product, which was purified by flash chromatography using 5% methanol in methylene chloride to give (S) - (-) - 6-amino-1- [2- [4- ( 4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -isochroman, methyl urea (S) - (X-6) R f = 0.07 (5% methanol in methylene chloride); [α] D = -43 ° (c = 0.75, 50% ethanol in methylene chloride); IR (suspension) 3312, 1645, 1614, 1597, 1567, 1512, 1421, 1310, 1244, 1109 cm &^lt; -1 &gt;; NMR (300

MHz, CDCb) 7,11 (s, 1H, aromatický H), 7,02 (m, 2H, aromatické H), 6,84, (q a m, 5H, J =MHz, CDCl 3) 7.11 (s, 1H, aromatic H), 7.02 (m, 2H, aromatic H), 6.84, (q and m, 5H, J =

9,2 Hz, aromatické H), 5,09 (m z d, 1H, J = 5,5 Hz, C(O)NMe-H), 4,77 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,07 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,09 (t, 4H, J = 4,9 Hz, štyri pip-H), 2,90 (m, 1H, PhCH-H), 2,79 (d, 3H, J = 4,7 Hz, C(O(NHC-H₃), 2,60 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,10 (m, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCH-H), δ; CMR (75 MHz, CDCb) 156,8, 153,8, 145,7, 136,8, 135,0,9.2 Hz, aromatic H), 5.09 (wd, 1H, J = 5.5 Hz, C (O) NMe-H), 4.77 (wd, 1H, J = 5.8 Hz, PhC- H, 4.07 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.09 (t, 4H, J = 4.9 Hz, four pip-H), 2.90 (m, 1H, PhCH-H), 2.79 (d, 3H, J = 4.7 Hz, C (O ( NHC-H ₃ ), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), δ CMR (75 MHz, CDCl 3) 156.8, 153.8, 145.7, 136.8, 135.0,

133,5, 125,5, 121,2119,1, 118,2, 114,5, 74,5, 63,1, 55,6, 54,8, 53,5, 50,6, 33,2, 29,2, 27,0 δ;133.5, 125.5, 121.2119.1, 118.2, 114.5, 74.5, 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2, 27.0 δ;

HRMS vypočítaná pre C₂₄H₃₂N4O3 = 424,2474, nájdená = 424,73.HRMS calcd for C ₂₄ H ₃₂ N ₄ O 3 = 424.2474, found = 424.73.

Príklad 64 (S)-(-)-6-amino-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]izochróman, t - butylkarbamát (S)-(X-6)Example 64 (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] isochroman, t-butylcarbamate (S) - ( X-6)

-91(S)-(-)-1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)-piperazín (S)-(Z-1, 200 mg, 0,54 mmol) sa zmieša s hexametyldisilazánom sodným (200 mg, 1,09 mmol). Injekčnou striekačkou sa pridá THF (2 ml) a reakcia sa mieša 15 minút. Pridá sa di-Zbutylpyrokarbonát (108 mg, 0,50 mmol) ako roztok v THF (2 ml). Zmes sa mieša 20 hodín pri 20-25 °C. Reakčná zmes sa naleje do vody (40 ml). Prchavé látky sa odstránia za zníženého tlaku, vodný zvyšok sa extrahuje octanom etylnatým (2 x 50 ml). Zmiešané organické látky sa vysušia pomocou síranu sodného, prefiltrujú a zahustia. Koncentrát sa analyzuje chromatograficky na 30 g silikagélu za použitia 5 % metánu v metylénchloride ako elučného činidla a vznikne (S)-(-)-6-amino-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]izochróman, t-butylkarbamát (S)-(X-6) Rf = 0,38 (5 % metanol v metylénchloride); [a]o =39° (c = 0,65, 50 % etanol v metylénchloride ); IR (suspenzia) 1694, 1522, 1515, 1423, 1367,-91 (S) - (-) - 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (S) - (Z-1, 200 mg, 0 , 54 mmol) was treated with sodium hexamethyldisilazane (200 mg, 1.09 mmol). THF (2 mL) was added via syringe and the reaction was stirred for 15 minutes. Di-Butylpyrocarbonate (108 mg, 0.50 mmol) was added as a solution in THF (2 mL). The mixture was stirred at 20-25 ° C for 20 hours. The reaction mixture was poured into water (40 mL). The volatiles were removed under reduced pressure, and the aqueous residue was extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The concentrate was chromatographed on 30 g of silica gel using 5% methane in methylene chloride as eluent to give (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] [ethyl] -6-yl] isochroman, t-butyl carbamate (S) - (X-6) R f = 0.38 (5% methanol in methylene chloride); [.alpha.] D = 39 DEG (c = 0.65, 50% ethanol in methylene chloride); IR (suspension) 1694, 1522, 1515, 1423, 1367,

1286, 1243, 1167, 1109, 1058 cm·¹; NMR (300 MHz, CDC1₃) 7,24 (s, 1H, aromatický H), 7,02 (m, 2H, aromatické H), 6,86 (q, 4H, J = 9,0 Hz, aromatické H), 6,44 (široké s, 1H, N-H), 4,79 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,10 (m, 1H, PhCH₂CH-H), 3,76 (s, 3H, OC-H₃), 3,71 (m, 1H, PhCH₂CH-H), 3,10 (t, 4H, J = 4,6 Hz, štyri pip-H), 2,94 (m, 1H, PhCH-H), 2,60 (m’s, 7H, PhCH-H, NC-H₂ a štyri pip-H), 2,11 (m, 1H, PhCHCH-H), 2,01 (m, 1H, PhCHCH-H),1286, 1243, 1167, 1109, 1058 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.24 (s, 1H, aromatic H), 7.02 (m, 2H, aromatic H), 6.86 (q, 4H, J = 9.0 Hz, aromatic H) 6.44 (broad s, 1H, NH), 4.79 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.10 (m, 1H, PhCH ₂ CH-H), 3, 76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.10 (t, 4H, J = 4.6 Hz, four pip-H), 2, 94 (m, 1H, PhCHCH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.11 (m, 1H, PhCHCH-H), 2.01 (m, 1 H, PhCHCH-H),

1,52 (s, 9H, tri z CC-H₃) Ô; CMR (75 MHz, CDC1₃) 153,8, 152,8, 145,8, 136,5, 134,8, 132,8,1.52 (s, 9H, three of CC-H ₃ ) Ô; CMR (75 MHz, CDC1 ₃₎ 153.8, 152.8, 145.8, 136.5, 134.8, 132.8,

125,3, 118,6, 118,2, 116,8, 114,4, 80,6, 63,1, 61,1, 55,6, 54,8, 53,5, 50,6, 33,3, 29,3, 28,4 δ.125.3, 118.6, 118.2, 116.8, 114.4, 80.6, 63.1, 61.1, 55.6, 54.8, 53.5, 50.6, 33, 3, 29.3, 28.4 δ.

Príklad 65 l-(4-metoxyfenyl)-4-[2-(6-metylaminometylizochróman-l- yl)etyl]piperazín (BB-2)Example 65 1- (4-Methoxyphenyl) -4- [2- (6-methylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-[4-(4metoxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6-karboxamidu (IX, PRÍKLAD 37) surový produkt. Látka sa prečistí pomocou LC na 13 g (230-400) silikagélu za elúcie 5 % 3M amónia v zmesi metanol/dichlórmetán a vznikne l-(4-metoxyfenyl)-4-[2-(6etylaminometylizochróman-l-yl)etyl]piperazín (BB-2), teplota topenia = 74-76 °C; Rf = 0,36 (5 % 3M NH₃ v zmesi metanol/dichlórmetán); IR (suspenzia) 2788, 1512, 1291, 1276, 1253, 1232, 1180, 1151, 1132, 1107, 1051, 1035, 1012, 927, 831; NMR (300 MHz, CDC1₃) 7,08 (m, 3H, aromatické), 6,85 (m, 4H, aromatické), 4,85 (široké d, 1H, J = 6,0 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,77 (m, 4H, OCH₃ a OCH_2b), 3,71 (s, 2H, Ph-CH₂-N), 3,11 (t, 4H, J = 4,9 Hz, Ph-N-CH_2s), 2,97 (m, 1H, Ph-CH_2a), 2,72-2,50 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s, PhCH_2b), 2,46 (s, 3H, NCH₃), 2,14 (m, 1H, C(H)-CH_2a), 2,04 (m, 1H, C(H)-CH_2b) δ; CMR (75MHz, CDC1₃) 153,6, 145,6, 137,9, 136,7, 1233,9, 128,5, 126,0, 124,7, 118,0, 114,3, 74,5,Following the procedure of Example 1, Step 4, with minor variations, the crude product was obtained from 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX, EXAMPLE 37). Purify by LC on 13 g (230-400) silica gel eluting with 5% 3M ammonium in methanol / dichloromethane to give 1- (4-methoxyphenyl) -4- [2- (6-ethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2), m.p. = 74-76 ° C; R f = 0.36 (5% 3M NH ₃ in methanol / dichloromethane); IR (suspension) 2788, 1512, 1291, 1276, 1253, 1232, 1180, 1151, 1132, 1107, 1051, 1035, 1012, 927, 831; NMR (300 MHz, CDCl ₃ ) 7.08 (m, 3H, aromatic), 6.85 (m, 4H, aromatic), 4.85 (broad d, 1H, J = 6.0 Hz, meth), 4 15 (m, 1H, OCH _{2 a} ), 3.77 (m, 4H, OCH ₃ and OCH _2b ), 3.71 (s, 2H, Ph-CH ₂ -N), 3.11 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} ), 2.72-2.50 (m, 7H, Ph-NC (H ₂ ) -CH -NC H _{2 s 2 s,} PhCH _{2 b),} 2.46 (s, 3H, _NCH3), 2.14 (m, 1 H, C (H) CH _2), 2.04 (m, 1 H, C (H) -CH _2b ) δ; CMR (75 MHz, CDC1 ₃₎ 153.6, 145.6, 137.9, 136.7, 1233.9, 128.5, 126.0, 124.7, 118.0, 114.3, 74.5 .

-9263,0, 55,6, 55,4, 50,5, 35,9, 33,2, 29,0 δ; HRMS vypočítaná pre C24H33N3O2 = 395,2573, nájdená = 395,2573.-9263.0, 55.6, 55.4, 50.5, 35.9, 33.2, 29.0 δ; HRMS calcd for C 24 H 33 N 3 O 2 = 395.2573, found = 395.2573.

Príklad 66 l-(4-metoxyfenyl)-4-[2-(6-dimetylaminometylizochróman-lyl)etyl]piperazín (BB-2)Example 66 1- (4-Methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2)

Postupom podľa príkladu 1, 4. kroku s drobnými obmenami vzniká z l-[2-[4-(4metoxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6-karboxamidu (IX, príklad 36) surový produkt. Látka sa prečistí pomocou LC na 13 g (230-400) silikagélu za elúcie 100 % dichlórmetánom a postupne zvyšujúcou sa polaritou na 5 % amónium v zmesi metanol/dichlórmetán vznikne 1 -(4-metoxyfenyl)-4-[2-(6-dimetylaminometylizochróman-1 yl)etyl]piperazín (BB-2), teplota topenia = 95-98 °C; Rf = 0,33 (5 % 3M NH₃ v zmesi metanol/dichlórmetán ); IR (suspenzia) 2809, 2791, 2770, 2762, 1512, 1442, 1277, 1253, 1232, 1179, 1150, 1107, 1045, 1037, 832 cm'¹; NMR (300 MHz, CDC1₃) 7,07 (m, 3H, aromatické), 6,87 (m, 4H, aromatické), 4,83 (široké d, 1H, J = 6,4 Hz, metín), 4,11 (m, 1H, OCH_2a) 3,76 (m, 4H, OCH₃ a OCH_2b), 3,40 (s, 2H, Ph-CH₂-N), 3,11 (t, 4H, J = 4,9 Hz, PhNCH_2s), 2,97 (m, 1H, Ph-CH_2a), 2.65 (m, 7H, Ph-NC(H₂)-CH_2s-NCH₂ a Ph-CH_2b), 2,26 (s, 6H, NCH_3s), 2,18 (m, 1H, C(H)-CH_2a), 2,05 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDC1₃)Following the procedure of Example 1, Step 4, with minor variations, the crude product was obtained from 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX, Example 36). Purify by LC on 13 g (230-400) silica gel eluting with 100% dichloromethane and gradually increasing the polarity to 5% ammonium in methanol / dichloromethane to give 1- (4-methoxyphenyl) -4- [2- (6- dimethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2), m.p. = 95-98 ° C; R f = 0.33 (5% 3M NH ₃ in methanol / dichloromethane); IR (suspension) 2809, 2791, 2770, 2762, 1512, 1442, 1277, 1253, 1232, 1179, 1150, 1107, 1045, 1037, 832 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.07 (m, 3H, aromatic), 6.87 (m, 4H, aromatic), 4.83 (broad d, 1H, J = 6.4 Hz, meth), 4 11 (m, 1H, OCH _{2 a} ) 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.40 (s, 2H, Ph-CH ₂ -N), 3.11 (t, 4H, J = 4.9 Hz, PhNCH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} ), 2.65 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ and Ph-CH _2b ), 2.26 (s, 6H, NCH _{3 s} ), 2.18 (m, 1H, C (H) -CH _{2 a} ), 2.05 (m, 1H, C (H) -CH _2b ) δ; CMR (75 MHz, CDC1 ₃₎

153,8, 145,8, 137,0, 136,6, 133,9, 129,5, 127,1, 124,6, 118,2, 114,4, 74,6, 64,0, 63,2, 55,6,153.8, 145.8, 137.0, 136.6, 133.9, 129.5, 127.1, 124.6, 118.2, 114.4, 74.6, 64.0, 63, 2, 55.6,

54,9, 53,5, 50,6, 45,3, 33,3, 29,1 δ; HRMS (El) vypočítaná pre C₂₅ H₃3N₃O₂ = 409,2729, nájdená = 409,2733.54.9, 53.5, 50.6, 45.3, 33.3, 29.1 δ; HRMS (El) calculated for C ₂₅ H ₃ 3 N ₃ O ₂ = 409.2729, found = 409.2733.

Príklad 67 etylester l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6karboxylovej kyseliny (X)Example 67 1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxylic acid ethyl ester (X)

V peci vysušená 10 ml nádoba vybavená miešacou tyčinkou, chladičom a trojcestným adaptérom sa naplní l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperazínom (VI, Príklad 24, 2. krok, 431 mg, 1,0 mmol), octanom paládnatým (11 mg, 0,05 mmol), 1,3bis(difenylfosfmo)propánom (25 mg, 0,06 mmol), 2,5 ml dimetylformamidu, diizopropyletanolamínom (0,35 ml, 2,0 mmol) a etanolom (1,2 ml, 20 mmol). Výsledná zmes sa šesťkrát prečistí oxidom uhoľnatým za zníženého tlaku a následného zahriatia na 100 °C. Po 18 hodinách sa zmes ochladí na 20-25 °C, skoncentruje za vysokého vákua, zriedi 20 ml IM hydroxidu sodného a dvakrát extrahuje octanom etylnatým (20 ml). Zmiešané organické látky sa raz premyjú soľankou (20 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia za vzniku produktu. Látka sa prečistí pomocou LC na 22 g (230-400) silikagélu 30 % zmesouAn oven-dried 10 ml vessel equipped with a stir bar, a condenser and a three-way adapter is charged with 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI, Example 24, 2). step, 431 mg, 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3bis (diphenylphosphino) propane (25 mg, 0.06 mmol), 2.5 mL of dimethylformamide, diisopropylethanolamine (0, 35 mL, 2.0 mmol) and ethanol (1.2 mL, 20 mmol). The resulting mixture was purified six times with carbon monoxide under reduced pressure and then heated to 100 ° C. After 18 h, the mixture was cooled to 20-25 ° C, concentrated under high vacuum, diluted with 20 mL of 1 M sodium hydroxide and extracted twice with ethyl acetate (20 mL). The combined organics were washed once with brine (20 mL), dried over magnesium sulfate, filtered and concentrated to give the product. Purify by LC on 22 g (230-400) silica gel with 30% mixture

-93acetón/hexán za vzniku l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6karboxylovej kyseliny, etylesteru (X), teplota topenia = 117-119 °C; Rf = 0,45 (35 % acetón/hexán); IR (suspenzia) 1712, 1513, 1422, 1286, 1260, 1246, 1187, 1145, 1140, 1108, 1053, 1037, 1023, 818, 767 cm'¹; NMR (300 MHz, CDCb) 7,84 (d, 1H, J = 8,2 Hz, aromatické), 7,80 (s, 1H, aromatické), 7,17 (d, 1H, J = 8,1 Hz, aromatické), 6,85 (m, 4H, aromatické), 4,85 (široké d, 1H, J = 6,0 Hz, metín), 4,36 (qrt, 2H, J = 7,1 Hz, CO2CH2), 4,15 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃a OCH_2b), 3,10 (t, 4H, J = 4,7 Hz, Ph-N-CH_2s), 3,00 (m, 1H, Ph-CH_2a), 2,79-2,50 (m, 7H, Ph-NC(H₂)-CH_2s- NCH_2s, Ph-CH_2b), 2,15 (m, 1H, C(H)CH_2a), 2,06 (m, 1H, C(H)-CH_2b), 1,69 (t, 3H, J = 7,1 Hz, C(H₂)-CH₃ δ; CMR (75 MHz, CDCb) 166,2, 153,5, 145,4, 142,9, 1033,9, 129,8, 128,2, 126,9, 124,5, 117,8, 114,1, 74,3,-93-acetone / hexane to give 1- [2- [4- (4-methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxylic acid ethyl ester (X), m.p. = 117-119 ° C; Rf = 0.45 (35% acetone / hexane); IR (suspension) 1712, 1513, 1422, 1286, 1260, 1246, 1187, 1145, 1140, 1108, 1053, 1037, 1023, 818, 767 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.84 (d, 1H, J = 8.2 Hz, aromatic), 7.80 (s, 1H, aromatic), 7.17 (d, 1H, J = 8.1 Hz) , aromatic), 6.85 (m, 4H, aromatic), 4.85 (broad d, 1H, J = 6.0 Hz, meth), 4.36 (qrt, 2H, J = 7.1 Hz, CO2CH2) 4.17 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.7 Hz, Ph-N-CH _{2 s)} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.79-2.50 (m, 7H, Ph-NC (H ₂ ) -CH ₂ - NCH ₂ , Ph-CH _2b ), 2, 15 (m, 1H, C (H) CH _{2 a} ), 2.06 (m, 1H, C (H) -CH _2b ), 1.69 (t, 3H, J = 7.1 Hz, C (H ₂₎ ) -CH ₃ δ CMR (75 MHz, CDCl 3) 166.2, 153.5, 145.4, 142.9, 1033.9, 129.8, 128.2, 126.9, 124.5, 117 , 8, 114.1, 74.3,

62,6, 60,6, 55,2, 54,3, 53,2, 50,3, 32,8, 28,7, 14,0 δ.62.6, 60.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7, 14.0 δ.

Príklad 68 6-acetyl-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyljetyl]izochróman, soľ kyseliny chlorovodíkovej (XXIV)Example 68 6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] isochroman, hydrochloric acid salt (XXIV)

V peci vysušená 10 ml nádoba vybavená miešacou tyčinkou a chladičom sa naplní 1[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperazínom (VI, Príklad 24, 2. krok, 431 mg, 1,0 mmol), octanom paládnatým (11 mg, 0,05 mmol), 1,3bis(difenylfosfin)propánom (25 mg, 0,06 mmol),octanom talnatým, (290 mg, 1,1 mmol, 3,0 ml dimetylformamidu, trietylamínom (0,28 ml, 2,0 mmol) a vinyl butyléterom (0,65 ml, 5,0 mmol). Zmes sa zahreje na 100 °C a po 20 hodinách sa ochladí na 20-25 °C, pridá sa kyselina chlorovodíková (IM, 6 ml) a mieša sa 1 hodinu. Zmes sa zahusti pod vysokým vákuom, zriedi 20 ml 5M hydroxidu sodného a extrahuje dvakrát octanom etylnatým (20 ml). Zmiešané organické látky sa raz premyjú soľankou (20 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia. Látka sa prečistí pomocou LC na 27 g (230-400) silikagélu 25 % zmesou acetón/hexán. Potom sa zriedi zmesou octan etylnatý/metanol a vystaví sa pôsobeniu plynnej kyseliny chlorovodíkovej za výsledného vzniku tuhej zložky, ktorá rekryštalizuje zo zmesi octan etylnatý/metanol za vzniku 6-acetyl-l-[2-[4-(4-metoxyfenyl)-l-piperazinyljetyl]izochrómanu, soli kyseliny chlorovodíkovej (XXIV), teplota topenia = 195-197 °C; Rf = 0,15 (30 % acetón/hexán); IR (suspenzia) 2560, 2516, 2487, 2462, 1675, 1511, 1444, 1425, 1359, 1290, 1265, 1245, 1113, 1035, 837 cm’¹; voľná báze NMR (300 MHz, CDCb) 7,78 (d, 1H, J = 8,1 Hz, aromatické), 7,72 (s, 1H, aromatické), 7,20 (d, 1H, 8,1 Hz, aromatické), 6,87 (m, 4H, aromatické), 4,89 (široké d, 1H, J = 6,0 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃aOCH_2b), 3,11 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 3,00 (m, 1H, Ph-CH_2a), 2,80-2,55 (m,Oven-dried 10 ml flask equipped with a stir bar and a condenser was charged with 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI, Example 24, Step 2, 431 mg) , 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3bis (diphenylphosphine) propane (25 mg, 0.06 mmol), barium acetate, (290 mg, 1.1 mmol, 3, 0 mL of dimethylformamide, triethylamine (0.28 mL, 2.0 mmol) and vinyl butyl ether (0.65 mL, 5.0 mmol) The mixture was heated to 100 ° C and cooled to 20-25 ° C after 20 hours. The mixture was concentrated under high vacuum, diluted with 20 mL of 5M sodium hydroxide and extracted twice with ethyl acetate (20 mL) .The combined organics were washed once with brine (20 mL). The residue was purified by LC on 27 g (230-400) silica gel with 25% acetone / hexane, then diluted with ethyl acetate / methanol and treated with chlorine gas. hydrogen chloride to give a solid which is recrystallized from ethyl acetate / methanol to give 6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] isochroman, hydrochloric acid salt (XXIV), m.p. Mp = 195-197 ° C; Rf = 0.15 (30% acetone / hexane); IR (suspension) 2560, 2516, 2487, 2462, 1675, 1511, 1444, 1425, 1359, 1290, 1265, 1245, 1113, 1035, 837 cm &^lt; -1 &gt;; free base NMR (300 MHz, CDCl 3) 7.78 (d, 1H, J = 8.1 Hz, aromatic), 7.72 (s, 1H, aromatic), 7.20 (d, 1H, 8.1 Hz) , aromatic), 6.87 (m, 4H, aromatic), 4.89 (broad d, 1H, J = 6.0 Hz, meth), 4.15 (m, 1H, OCH _{2 a} ), 3.76 ( m, 4H, OCH ₃ and OCH _2b ), 3.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.80 -2.55 (m,

-9410Η, Ph-NC(H₂)-CH_2s-NCH_2s, COCH₃), 2,15 (m, 1H, C(H)-CH_2a), 2,06 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDClj) 197,8, 153,7, 145,6, 143,5, 135,2, 134,4, 128,9, 126,1, 125,0,-9410Η, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , COCH ₃ ), 2.15 (m, 1H, C (H) -CH _2a ), 2.06 (m, 1H, C (H)) -CH _2b ) δ; CMR (75 MHz, CDCl 3) 197.8, 153.7, 145.6, 143.5, 135.2, 134.4, 128.9, 126.1, 125.0,

118,1, 114,3, 74,5, 62,9, 55,5, 54,6, 53,4, 50,5, 33,0, 29,0, 26,5 δ; HRMS (EI) vypočítaná pre C₂₄H₃₀N₂O₃ = 394,2256, nájdená = 394,2262.118.1, 114.3, 74.5, 62.9, 55.5, 54.6, 53.4, 50.5, 33.0, 29.0, 26.5 δ; HRMS (EI) calcd for C ₂₄ H ₃₀ N ₂ O ₃ = 394.2256, found = 394.2262.

Príklad 69Example 69

6-formyl-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-izochróman (AA-1) l-[2-(6-brómizochróman-l-yl)etyl]-4-(4-metoxyfenyl)-piperazín (VI, príklad 24, 2. krok, 2,80 g, 6,5 mmol) sa zmieša s čerstvo vydestilovaným tetrahydrofuránom (16 ml) a ochladí na -78 °C. K zmesi sa pridá 1,7 M roztok terc.-butyllítia (7,7 ml, 13,0 mmol). Po 15 minútach sa zmieša aryl lítium s dimetylformamidom (1,0 ml, 13 mmol). Zmes sa počas 1,5 hodiny zahreje na 20-25 °C, zriedi 75 ml vody a dvakrát extrahuje octanom etylnatým (75 ml). Zmiešané organické látky sa raz premyjú soľankou (50 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia za vzniku surového produktu. Látka sa prečistí pomocou LC na 160 g (230-400) silikagélu 30 % zmesou acetón/hexán a vznikne 6-formyl-l-[2-[4-(4metoxyfenyl)-l-piperazinyl]etyl]-izochróman (AA-1) Rf = 0,28 (30 % acetón/hexán); IR (kvapaliny) 2949, 2819, 1698, 1608, 1512, 1464, 1456, 1291, 1285, 1244, 1143, 1124, 1110, 1038, 824 cm'¹; NMR (300 MHz, CDCb) 9,97 (s, 1H, CHO), 7,69 (d, 1H, J = 8,0 Hz, aromatické), 7,60 (s, 1H, aromatické), 7,28 (d, 1H, J = 7,7 Hz, aromatické), 6,85 (m, 4H, aromatické), 4,90 (široké d, 1H, J = 6,0 Hz, metín), 4,16 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a oCH_2b), 3,10 (t, 5H, J = 5,0 Hz, Ph-N-CH_2s a Ph-CH_2a), 2,83-2,50 (m, 7H, Ph-NC(H₂)-CH_2sNCH_2s, Ph-CH_2b), 2,16 (m, 1H, C(H)-CH_2a), 2,07 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz,6-Formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman (AA-1) 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-Methoxyphenyl) -piperazine (VI, Example 24, Step 2, 2.80 g, 6.5 mmol) was mixed with freshly distilled tetrahydrofuran (16 mL) and cooled to -78 ° C. To the mixture was added a 1.7 M solution of tert-butyllithium (7.7 mL, 13.0 mmol). After 15 minutes, aryl lithium was mixed with dimethylformamide (1.0 mL, 13 mmol). The mixture was warmed to 20-25 ° C over 1.5 h, diluted with 75 mL of water and extracted twice with ethyl acetate (75 mL). The combined organics were washed once with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product. The material was purified by LC on 160 g (230-400) silica gel with 30% acetone / hexane to give 6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman (AA-1). Rf = 0.28 (30% acetone / hexane); IR (liquids) 2949, 2819, 1698, 1608, 1512, 1464, 1456, 1291, 1285, 1244, 1143, 1124, 1110, 1038, 824 cm ^-1 ; NMR (300 MHz, CDCl 3) 9.97 (s, 1H, CHO), 7.69 (d, 1H, J = 8.0 Hz, aromatic), 7.60 (s, 1H, aromatic), 7.28 (d, 1H, J = 7.7 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.90 (broad d, 1H, J = 6.0 Hz, meth), 4.16 (m , 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and oCH _{2 b} ), 3.10 (t, 5H, J = 5.0 Hz, Ph-N-CH _{2 s} and Ph-CH _{2 a} ), 2.83-2.50 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH _{2 s} , Ph-CH _{2 b} ), 2.16 (m, 1H, C (H) -CH _{2 a} ), 2, 07 (m, 1 H, C (H) -CH _2b) δ; CMR (75MHz,

CDCb) 192,0, 153,8, 145,7, 135,0, 134,7, 130,4, 127,4, 125,6, 118,2, 114,4, 74,6, 62,8, 55,6,(CDCl3) 192.0, 153.8, 145.7, 135.0, 134.7, 130.4, 127.4, 125.6, 118.2, 114.4, 74.6, 62.8, 55.6,

54,6, 53,5, 50,6, 33,1, 29,0 δ; HRMS (EI) vypočítaná pre C₂₃H₂₈ N₂O₃ = 380,2100, nájdená =54.6, 53.5, 50.6, 33.1, 29.0 δ; HRMS (EI) calcd for C ₂₃ H ₂₈ N ₂ O ₃ = 380.2100, found =

380,2098.380.2098.

Príklad 70 2-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -y 1]etyl]-6yljacetamid (AA-4) .krok: l-[2-(6-hydroxymetylizochróman-l-yl)etyl]-4-(4metoxyfenyl)piperazín (AA-2)Example 70 2- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide (AA-4). Step: 1- [2- (6-hydroxymethylisochroman-1)] -yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA-2)

6-formyl-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman (AA-1, Príklad 71, 2,51 g,6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman (AA-1, Example 71, 2.51 g,

6,6 mmol) sa zmieša s 25 ml metanolu a ochladí na 0 °C. Zmes sa potom zmieša s jednou6.6 mmol) is treated with 25 ml of methanol and cooled to 0 ° C. The mixture is then mixed with one

-95časťou boro hydridu sodného (500 mg, 13,2 mmol). Reakcia sa postupne počas dvoch hodín zahreje na 20-25 °C, zriedi 75 ml vody a dvakrát extrahuje octanom etylnatým (75 ml). Zmiešané organické látky sa raz premyjú soľankou (50 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia. Látka sa prečistí pomocou LC na 130 g (230-400) silikagélu za elúcie zmesou metanol/dichlórmetán (5/95) a vznikne l-[2-(6-hydroxymetylizochróman-l -yl)etyl]-4(4-metoxyfenyl)piperazín (AA-2), Rf = 0,15 (35 % acetón/hexán); IR (suspenzia) 1513, 1445, 1428, 14292, 1279, 1248, 1186, 1152, 1140, 1107, 1057, 1034, 1011, 928, 826 cm’¹; NMR (300 MHz, CDCb) 7,17 (d, 1H, J - 8,0 Hz, aromatické), 7,09 (m, 2H, aromatické), 6,86 (m, 4H, aromatické), 4,82 (široké d, 1H, J = 6,3 Hz, metín), 4,64 (s, 2H, Ph-CH₂-O), 4,12 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a OCH_2b), 3,10 (ζ 4H, J = 4,8 Hz, Ph-N-CH_2s), 2,97 (m, 1H, PhCH_2a), 2,72-2,50 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s, Ph-CH_2b), 2,10 (m, 2H, C(H)-CH_2s) δ; MS (EI, m/z) = 382.-95% boron sodium hydride (500 mg, 13.2 mmol). The reaction was gradually warmed to 20-25 ° C over two hours, diluted with 75 mL of water, and extracted twice with ethyl acetate (75 mL). The combined organics were washed once with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purify by LC on 130 g (230-400) silica gel eluting with methanol / dichloromethane (5/95) to give 1- [2- (6-hydroxymethylisochroman-1-yl) ethyl] -4 (4-methoxyphenyl) piperazine (AA-2), Rf = 0.15 (35% acetone / hexane); IR (suspension) 1513, 1445, 1428, 14292, 1279, 1248, 1186, 1152, 1140, 1107, 1057, 1034, 1011, 928, 826 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl 3) 7.17 (d, 1H, J = 8.0 Hz, aromatic), 7.09 (m, 2H, aromatic), 6.86 (m, 4H, aromatic), 4.82 (broad d, 1 H, J = 6.3 Hz, methine), 4.64 (s, 2H, _Ph-CH2-O), 4.12 (m, 1 H, OCH _2), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (ζ 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 2.97 (m, 1H, PhCH _{2 a} ), 2.72-2.50 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _{2 b} ), 2.10 (m, 2H, C (H) -CH _{2 s} ) δ; MS (EI, m / z) = 382;

2. krok: 1 -[2-(6-kyanometylizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)piperazín (AA-3)Step 2: 1- [2- (6-cyanomethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA-3)

-[2-(6-hydroxymetylizochróman-1 -yl)etyl]-4-(4-metoxyfenyl)-piperazínom (AA-2,- [2- (6-hydroxymethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (AA-2,

2,33 g, 6,1 mmol) sa zmieša s 61 ml dichlórmetánu a trietylamínom (1,3 ml, 9,1 mmol) a ochladí na 0 °C. Zmes sa zmieša s metánsulfonylchloridom (0,52 mmol, 6,7 mmol). Reakcia sa počas 1,5 hodiny zahreje na 20-25 °C a skoncentruje za zníženého tlaku. Surový metánsulfonát sa zriedi 31 ml dimetylsulfoxidu a kyanidom sodným (896 mg, 18,3 mmol). Táto zmes sa zahreje na 60 °C. Po 2 hodinách sa prchavé látky odstránia za vysokého vákua, zvyšok sa zriedi 100 ml vody a dvakrát extrahuje octanom etylnatým (75 ml). Zmiešané organické látky sa raz premyjú soľankou (75 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia. Látka sa prečistí pomocou LC na 88 g (230-400) silikagélu za elúcie 30 % zmesou acetón/hexán a vznikne l-[2-(6-(kyanometylizochróman-l-yl)etyl]-4-(4metoxyfenyl)piperazín (AA-3), teplota topenia = 118-119 °C; Rf = 0,36 (35 % acetón/hexán); IR (suspenzia) 2810, 1790, 1512, 1444, 1275, 1253, 1232, 1182, 1151, 1111, 1107, 1058, 1051, 1031 a 831 cm'¹; NMR (300 MHz, CDCb) 7,10 (m, 3H, aromatické), 6,87 (m, 4H, aromatické), 4,82 (široké d, 1H, J = 6,3 Hz, metín), 4,14 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a OCH_2b), 3,74 (s, 2H, NC-CH₂), 3,11 (t, 4H, J = 4,8 Hz, Ph-N-CH_2s), 2.98 (m, 1H, Ph-CH_2a),2.33 g (6.1 mmol) was mixed with 61 mL of dichloromethane and triethylamine (1.3 mL, 9.1 mmol) and cooled to 0 ° C. The mixture was treated with methanesulfonyl chloride (0.52 mmol, 6.7 mmol). The reaction was warmed to 20-25 ° C over 1.5 h and concentrated under reduced pressure. The crude methanesulfonate was diluted with 31 mL of dimethylsulfoxide and sodium cyanide (896 mg, 18.3 mmol). This mixture was heated to 60 ° C. After 2 hours the volatiles were removed under high vacuum, the residue was diluted with 100 mL of water and extracted twice with ethyl acetate (75 mL). The combined organics were washed once with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated. Purify by LC on 88 g (230-400) silica gel eluting with 30% acetone / hexane to give 1- [2- (6- (cyanomethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA). -3), mp = 118-119 ° C; R f = 0.36 (35% acetone / hexane); IR (suspension) 2810, 1790, 1512, 1444, 1275, 1253, 1232, 1182, 1151, 1111, 1107, 1058, 1051, 1031 and 831 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.10 (m, 3H, aromatic), 6.87 (m, 4H, aromatic), 4.82 (broad d, 1H) J = 6.3 Hz, meth), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.74 (s, 2H, NC-CH ₂₎ 1.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 2.98 (m, 1H, Ph-CH _{2 a} ),

2,04 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDCb) 153,8, 145,8, 138,1, 135,1, 128,4, 127,9,2.04 (m, 1 H, C (H) -CH _2b) δ; CMR (75 MHz, CDCl 3) 153.8, 145.8, 138.1, 135.1, 128.4, 127.9,

125,8, 125,6, 118,2, 117,9, 114,3, 74,4, 62,9, 55,6, 54,7, 53,5, 50,6, 33,3, 29,0, 23,2 δ; MS (EI, m/z) = 391.125.8, 125.6, 118.2, 117.9, 114.3, 74.4, 62.9, 55.6, 54.7, 53.5, 50.6, 33.3, 29, 0, 23.2 δ; MS (EI, m / z) = 391;

-963.krok:2-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6yljacetamid (AA-4) l-[2-(6-kyanometyIizochróman-l-yl)etyl]-4-(4-metoxyfenyl)piperazín (AA-3, 785 mg, 2,0 mmol), sa zmieša s 5,0 ml dimetylformamidu a uhličitanom draselným (39 mg, 0,28 mmol). Zmes sa vystaví pôsobeniu 30 % peroxidu vodíka (0,24 ml, 2,3 mmol). Po 20 minútach sa reakcia zriedi 100 ml dichlórmetánu, raz premyje vodou (20 ml), raz soľankou (20 ml), vysuší nad síranom horečnatým, prefiltruje a zahustí. Látka potom rekryštalizuje zo zmesi octan etylnatý/hexán za vzniku 2-[izochróman-l-[2-[4-(4-metoxyfenyl)-lpiperazinyl]etyl]-6-yl]acetamidu (AA-4), teplota topenia = 159-161 °C; Rf = 0,15 (5 % metanol/dichlórmetán); IR (suspenzia) 3381, 3208, 2791, 1658, 1633, 1513, 1444, 1293, 1275, 1255, 1231, 1150, 1108, 1032, 833 cm'¹; NMR (300 MHz, CDC1₃) 7,09 (s, 2H, aromatické), 7,02 (s, 1H, aromatické), 6,86 (m, 4H, aromatické), 5,59 (široké s, 1H, NH), 4,81 (široké d, 1H, J = 6,0 Hz, metín), 4,12 (m, 1H, OCH_2a), 3,76 (m, 4H, OCH₃ a OCH_2b), 3,53 (s, 2H, O=C-CH₂), 3,10 (t, 4H, J = 4,9, Ph-N-CH_2s), 2,96 (m, 1H, C(H(-CH_2a), 2,77 (d, 3H, J =-963 Step: 2- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide (AA-4) 1- [2- (6-cyanomethylisochroman-1-) - yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA-3, 785 mg, 2.0 mmol) was treated with 5.0 mL dimethylformamide and potassium carbonate (39 mg, 0.28 mmol). The mixture was treated with 30% hydrogen peroxide (0.24 mL, 2.3 mmol). After 20 minutes, the reaction was diluted with 100 mL of dichloromethane, washed once with water (20 mL), once with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The material is then recrystallized from ethyl acetate / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -6-yl] acetamide (AA-4), m.p. = 159 -161 ° C; R f = 0.15 (5% methanol / dichloromethane); IR (slurry) 3381, 3208, 2791, 1658, 1633, 1513, 1444, 1293, 1275, 1255, 1231, 1150, 1108, 1032, 833 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.09 (s, 2H, aromatic), 7.02 (s, 1H, aromatic), 6.86 (m, 4H, aromatic), 5.59 (broad s, 1H, NH), 4.81 (broad d, 1H, J = 6.0 Hz, meth), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3 , 53 (s, 2H, O = _C-CH2), 3.10 (t, 4H, J = 4.9, Ph-N-CH _{2 s),} 2.96 (m, 1 H, C (H (- CH _2a ), 2.77 (d, 3H, J =

4,9 Hz, NCH₃,), 2,732-2,56 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s ) 2,03 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDC1₃) 173,4, 153,8, 145,7, 137,4, 134,7, 132,8, 129,8, 127,2, 125,4, 118,1,4.9 Hz, NCH ₃ ), 2.732-2.56 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} ) 2.03 (m, 1H, C (H) -CH _{2 b} ) δ; CMR (75 MHz, CDC1 ₃₎ 173.4, 153.8, 145.7, 137.4, 134.7, 132.8, 129.8, 127.2, 125.4, 118.1,

114,4, 74,5, 55,6, 54,8, 53,5, 50,6, 42,8, 33,2, 29,0 δ; MS (EI, m/z) = 409.114.4, 74.5, 55.6, 54.8, 53.5, 50.6, 42.8, 33.2, 29.0 δ; MS (EI, m / z) = 409 (M + H) +.

Príklad 71 2-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]-Nmetylacetamid (AA-5)Example 71 2- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide (AA-5)

Postupom podľa príkladu 3, 1. kroku s drobnými obmenami vzniká z 2-[izochrómanl-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-6-yl]acetamidu (AA-4, 446 mg, 1,09 mmol) surový produkt. Látka sa prečistí pomocou LC na 40 g (230-400) silikagélu za elúcie 50 % zmesou octan etylnatý/hexán a vznikne 2-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-lyl]etyl]-6-yl]-N,N-di-t-butyloxykarbonylacetamÍd, Rf = 0,45 (60 % octan etylnatý/hexán), Látka reaguje s metylamínom podľa všeobecného postupu príkladu 3, 2. kroku a s drobnými obmenami vznikne požadovaný produkt, ktorý sa prečistí pomocou LC na 13 g (230-400) silikagélu, elúciou 60 % zmesou acetón/hexán a vznikne 2-[izochróman-l-[2-[4-(4metoxyfenyl)piperazín-l-yl]etyl]-6-yl]-N-metylacetamid (AA-5), teplota topenia = 147-148 °C; R_f = 0,20 (50 % acetón/hexán); IR (suspenzia) 3309, 1652, 1550, 1515, 1442, 1426, 1412, 1354, 1251, 1228, 1153, 1147, 1114, 1036, 826 cm'¹; NMR (300 MHz, CDC1₃) 7,09 (s, 2H, aromatické), 7,01 (s, 1H, aromatické), 6,87 (m, 4H, aromatické), 5,45 (široké s, 1H, NH), 4,83Following the procedure of Example 3, Step 1, with minor variations, 2- [isochromo-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -6-yl] acetamide (AA-4, 446 mg, 1.09 mmol) of crude product. Purify by LC on 40 g (230-400) silica gel eluting with 50% ethyl acetate / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] - 6-yl] -N, N-di-t-butyloxycarbonylacetamide, Rf = 0.45 (60% ethyl acetate / hexane), reacted with methylamine according to the general procedure of Example 3, Step 2, with slight variations to give the desired product which Purify by LC on 13 g (230-400) silica gel, eluting with 60% acetone / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6- yl] -N-methylacetamide (AA-5), m.p. = 147-148 ° C; _Rf = 0.20 (50% acetone / hexane); IR (suspension) 3309, 1652, 1550, 1515, 1442, 1426, 1412, 1354, 1251, 1228, 1153, 1147, 1114, 1036, 826 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.09 (s, 2H, aromatic), 7.01 (s, 1H, aromatic), 6.87 (m, 4H, aromatic), 5.45 (broad s, 1H, NH), 4.83

-97(široké d, 1H, J = 6,0 Hz, metín), 4,15 (m, 1H, 0CH_2a), 3,77 (m, 4H, 0CH₃ a 0CH_2b), 3,53 (s, 2H, 0=C-CH₂), 3,12 (t, 4H, J = 4,9, Ph-N-CH_2s), 2,95 (m, 1H, C(H(-CH_2a), 2,77 (d, 3H, J =-97 (broad d, 1H, J = 6.0 Hz, meth), 4.15 (m, 1H, OCH _2a ), 3.77 (m, 4H, OCH ₃ and OCH _2b ), 3.53 (s , 2H, 0 = _C-CH2), 3.12 (t, 4H, J = 4.9, Ph-N-CH _{2 S),} 2.95 (m, 1 H, C (H (CH _2); 2.77 (d, 3H, J =

4,9 Hz, NCH₃,), 2,732-2,56 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s, Ph-CH_2b), 2,15 (m, 1H, C(H)CH_2a), 2,04 (m, 7,09 )s, 2H, aromatické), 7,02 (s, 1H, aromatické), 6,86 (m, 4H, aromatické), 5,59 (široké s, 1H, NH), 4,81 (široké d, 1H, J = 6,0 Hz, metín), 4,12 (m, 1H, 0CH_2a), 3,76 (m, 4H, OCH₃ a OCH_2b), 3,53 (s, 2H, O=C-CH₂), 3,10 (t, 4H, J = 4,9, Ph-N-CH_2s), 2,96 (m, 1H,4.9 Hz, NCH ₃ ), 2.732-2.56 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.15 (m, 1H, C ( H, CH _{2 a} ), 2.04 (m, 7.09) s, 2H, aromatic), 7.02 (s, 1H, aromatic), 6.86 (m, 4H, aromatic), 5.59 (broad) s, 1 H, NH), 4.81 (broad d, 1 H, J = 6.0 Hz, methine), 4.12 (m, 1 H, 0CH _2), 3.76 (m, 4 H, OCH _3, and OCH _2b), 3.53 (s, 2H, O = _C-CH2), 3.10 (t, 4H, J = 4.9, Ph-N-CH _{2 s),} 2.96 (m, 1 H,

C(H(-CH_2a), 2,03 (m, 1H, C(H)-CH_2b) δ; CMR (75 MHz, CDC1₃) 171,6, 153,8, 145,7, 137,4,C (H (-CH ₂ )), 2.03 (m, 1H, C (H) -CH _2b ) δ; CMR (75 MHz, CDCl ₃ ) 171.6, 153.8, 145.7, 137.4 .

134,7, 132,9, 130,0, 127,3, 125,4, 118,2, 114,4, 74,5, 63,0,55,6, 54,9, 53,6, 50,6, 43,3, 33,3,134.7, 132.9, 130.0, 127.3, 125.4, 118.2, 114.4, 74.5, 63.0.55.6, 54.9, 53.6, 50, 6, 43.3, 33.3,

29,0,26,5 δ; MS (EI, m/z) = 423.29,0,26,5 δ; MS (EI, m / z) = 423;

Príklad 72 l-[2-[4-(4-hydroxyfenyl)-l-piperazinyl]etyl]-izochróman-6karboxamid (CC-2)Example 72 1- [2- [4- (4-Hydroxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxamide (CC-2)

Zmieša sa 1 -[2-[4-(4-fenylmetoxyfenyl)-1 -piperazinyl]etyl]-izochróman-6karboxamid (CC-1, Príklad 9, 0,42 mmol, 200 mg), paládium na uhlíku (10 %, 20 mg), etanol (5 ml) a metylénchlorid (2 ml). Po štyroch dňoch sa východisková látka spracuje. Reakčná zmes sa prefiltruje cez guličky z celitu a niekoľkokrát sa premyje etanolom, metanolom, metylénchloridom alebo octanom etylnatým. Zmiešané filtráty sa zahustia. Surová látka rekryštalizuje z horúceho etanolu s malým množstvom metanolu za vzniku l-[2-[4-(4hydroxyfenyl)-l-piperazinyl]etyl]-izochróman-6-karboxamidu (CC-2), IR (suspenzia) 3300, 3255, 3206, 1672, 1615, 1513, 1444, 1426, 1366, 1256 cm'¹; NMR (300 MHz, DMSO) 7,85 (d, 1H, J = 8,2 Hz, aromatický H), 7,82 (s, 1H, aromatický H), 7,43 (d, 1H, J = 8,2 Hz, aromatický H), 6,96 (d, 2H, J = 8,8 Hz, aromatické H), 6,81 (d, 2H, J = 8,8 Hz, aromatické H), 5,00 (široké d, 1H), 4,18 (m, 2H), 3,85 (m, 1H), 3,68 (m, 4H), 3,46-3,0 (niekoľko širokých m, 6H), 2,86 (široké d, 2H, J = 16 Hz), 2,37 (široké m, 1H), δ; HRMS (EI) vypočítaná pre C₂₂H₂₇N₃O₃ = 382,2131, nájdená = 382,2136.1- [2- [4- (4-Phenylmethoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (CC-1, Example 9, 0.42 mmol, 200 mg), palladium on carbon (10%, 20 mg), ethanol (5 mL) and methylene chloride (2 mL). After four days, the starting material was worked up. The reaction mixture is filtered through celite beads and washed several times with ethanol, methanol, methylene chloride or ethyl acetate. The combined filtrates are concentrated. The crude material was recrystallized from hot ethanol with a small amount of methanol to give 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (CC-2), IR (suspension) 3300, 3255, 3206, 1672, 1615, 1513, 1444, 1426, 1366, 1256 cm ^-1 ; NMR (300 MHz, DMSO) 7.85 (d, 1H, J = 8.2 Hz, aromatic H), 7.82 (s, 1H, aromatic H), 7.43 (d, 1H, J = 8, 2 Hz, aromatic H), 6.96 (d, 2H, J = 8.8 Hz, aromatic H), 6.81 (d, 2H, J = 8.8 Hz, aromatic H), 5.00 (broad) d, 1H), 4.18 (m, 2H), 3.85 (m, 1H), 3.68 (m, 4H), 3.46-3.0 (several broad m, 6H), 2.86 (broad d, 2H, J = 16 Hz), 2.37 (broad m, 1H), δ; HRMS (EI) calcd for C ₂₂ H ₂₇ N ₃ O ₃ = 382.2131, found = 382.2136.

Príklad 73 (S)-(-)-1 -[2-[4-(4-hydroxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6-karboxamid (S)-(CC-2)Example 73 (S) - (-) - 1- [2- [4- (4-Hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-2)

Parrova fľaša sa naplní (S)-(-)-l-[2-[4-(4-fenylmetoxyfenyl)- 1-piperazinyl]etyl]-Nmetylizochróman-6-karboxamidom (S)-(CC-l, Príklad 20), 50 ml metanolu, 25 ml tetrahydrofuránu a 10 % paládiom na uhlíku (20 mg). Výsledná čierna suspenzia sa pokryje vodíkom s tlakom 275 kPa a pretrepe. Po 60 hodinách sa tlak vodíka zníži na 186 kPa, reakčná zmes sa prefiltruje cez celit a zahustí. Koncentrát rekryštalizuje zo zmesiA Parr bottle was charged with (S) - (-) - 1- [2- [4- (4-phenylmethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-1, Example 20) 50 ml of methanol, 25 ml of tetrahydrofuran and 10% palladium on carbon (20 mg). The resulting black slurry was covered with hydrogen at 50 psi and shaken. After 60 hours, the hydrogen pressure is reduced to 186 kPa, the reaction mixture is filtered through celite and concentrated. The concentrate is recrystallized from the mixture

-98metanol/octan etylnatý za vzniku (S)-(-)-l-[2-[4-(4-hydroxyfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamidu (CC-2), teplota topenia = 154-162 °C; Rf = 0,11 (5 % metanol/octan etylnatý); [<x]d =-53° (c = 0,9681, 50 % metanol); IR (suspenzia) 3350, 3200, 3174, 2811, 1642,1 1573, 1542, 1517, 1300, 1271, 1248, 1243, 1232, 1104, 825 cm'¹; NMR (300 MHz, DMSO-dé) δ 8,81 (s, 1H, OH), 8,37 (široké d, 1H, J = 4,6 Hz, NH), 7,61 (m, 3H, aromatické), 7,27 (d, 1H, J = 8,1 Hz, aromatické), 6,76 (d, 2H, J = 8,9 Hz, aromatické), 6,63((d, 2H, J = 8,9 Hz, aromatické), 4,78 (široké d, 1H, J = 6,0 Hz, metín), 4,03 (m, 1H, OCH_2a), 3,66 (m, 1H, OCH_2b), 2,93 (m, 4H, Ph-N-CH_2s), 2,76 (d, 4H, J = 4,5 Hz, N-CH₃ a Ph-CH_2a), 2,49 (m, 6H, Ph-NC(H₂)-CH_2s-NCH_2s), 2,35 (m, 1H, Ph-CH_2b), 2,15 (m, 1H, C(H)CH_2a), 1,85 (m, 1H, C(H)-CH_2b) δ; CMR (75MHz, DMSO-d₆) 166,4, 150,8, 144,2, 141,2,-98methanol / ethyl acetate to give (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (CC-2), m.p. = 154-162 [deg.] C .; R f = 0.11 (5% methanol / ethyl acetate); [α] D = -53 ° (c = 0.9681, 50% methanol); IR (suspension) 3350, 3200, 3174, 2811, 1642, 1573, 1542, 1517, 1300, 1271, 1248, 1243, 1232, 1104, 825 cm ^-1 ; NMR (300 MHz, DMSO-d 6) δ 8.81 (s, 1H, OH), 8.37 (broad d, 1H, J = 4.6 Hz, NH), 7.61 (m, 3H, aromatic) 7.27 (d, 1H, J = 8.1 Hz, aromatic), 6.76 (d, 2H, J = 8.9 Hz, aromatic), 6.63 ((d, 2H, J = 8, 9 Hz, aromatic), 4.78 (broad d, 1H, J = 6.0 Hz, meth), 4.03 (m, 1H, OCH _{2 a} ), 3.66 (m, 1H, OCH _2b ), 2 93 (m, 4H, Ph-N-CH _{2 s} ), 2.76 (d, 4H, J = 4.5 Hz, N-CH ₃ and Ph-CH _{2 a} ), 2.49 (m, 6H, Ph -NC (H ₂ ) -CH ₂ -NCH _{2 s} ), 2.35 (m, 1H, Ph-CH _2b ), 2.15 (m, 1H, C (H) CH _{2 a} ), 1.85 (m, 1 H, C (H) -CH _2b) δ; CMR (75 MHz, _DMSO-d6) 166.4, 150.8, 144.2, 141.2,

133,7, 132,3, 127,5, 124,8, 124,6, 117,6, 115,4, 73,6, 62,2, 54,2, 53,1, 50,0, 32,5, 28,5, 26,2;133.7, 132.3, 127.5, 124.8, 124.6, 117.6, 115.4, 73.6, 62.2, 54.2, 53.1, 50.0, 32, 5, 28.5, 26.2;

HRMS (EI) vypočítaná pre C₂₃H₂9N₃O₃ = 395,2209, nájdená = 395,2212; celkový obsah vody = 4,28 %.HRMS (EI) for C ₂₃ H 9 N ₃ O _{2 3} = 395.2209, found = 395.2212; total water content = 4.28%.

Príklad 74 (S)-(-)-l-[2-[4-(4-trifluórmetánsulfonyloxyfenyl)-lpiperazinyl]etyl]-N-metyl-izochróman-6-karboxamid (S)-(CC-3)Example 74 (S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (CC-3)

Zmieša sa (S)-(-)-1 -[2-[4-(4-hydroxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6karboxamid (CC-2, 959 mg, 2,4 mmol) s 24 ml dichlórmetánu a N-fenyltrifluorometánsulfónimidom (910 mg, 2,5 mmol). Zmes sa ochladí na 0 °C a pridá sa trietylamín (0,51 ml,Combine (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (CC-2, 959 mg, 2.4 mmol) with 24 mL of dichloromethane and N-phenyltrifluoromethanesulfonimide (910 mg, 2.5 mmol). The mixture was cooled to 0 ° C and triethylamine (0.51 mL,

3,6 mmol) bez viditeľnej zmeny. Po 16 hodinách sa zmes zriedi 75 ml IM hydroxidu sodného a dvakrát extrahuje dichlórmetánom (75 ml). Zmiešané organické látky sa dvakrát premyjú soľankou (50 ml), vysušia nad síranom horečnatým, prefiltrujú a zahustia. Látka sa prečistí pomocou LC na 88 g (230-400) silikagélu za elúcie 5 % zmesou metanol/dichlórmetán a vznikne (S)-(-)-1 -[2-[4-(4-trifluórmetánsulfonyloxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6-karboxamid (S)-(CC-3) Rf = 0,34 (5 % metanol/dichlórmetán); [cc]d = -39° (c = 0,9447, metanol); IR (suspenzia) 1641, 1571, 1548, 1505, 1417, 1310, 1297, 1240, 1210,1209, 1141, 1110, 885, 826, 609 cm¹; NMR (300 MHz, CDC1₃ ) 7,55 (m, 2H, aromatické), 7,14 (m, 3H, aromatické), 6,87 (d, 2H, J = 9,4 Hz, aromatické), 6,18 (široké d, 1H, J = 4,6 Hz, NH), 4,85 (široké D, 1H, J = 5,8 Hz, metín), 4,13 (m, 1H, OCH_2a), 3,75 (m, 1H, OCH_2b), 3,22 (t, 4H, J = 4,.9 Hz, Ph-N-CH_2s), 3,00 (d, 4H, J = 4,9 Hz, N-CH₃ a Ph-CH_2a), 2,75-2,49 (m, 7H, Ph-NC(H₂>CH_2s-NCH_2s a Ph-CH_2b), 2,15 (m, 1H, C(H)-CH_2a), 2,04 (m, 1H, C(H>CH_2b), Ô; CMR (75MHz, CDC1₃) 168,0, 150,9, 142,1, 141,5, 134,5, 132,7, 127,7,3.6 mmol) without visible change. After 16 hours, the mixture was diluted with 75 mL of 1M sodium hydroxide and extracted twice with dichloromethane (75 mL). The combined organics were washed twice with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purify by LC on 88 g (230-400) silica gel eluting with 5% methanol / dichloromethane to give (S) - (-) - 1- [2- [4- (4-trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-3) R f = 0.34 (5% methanol / dichloromethane); [α] D = -39 ° (c = 0.9447, methanol); IR (suspension) 1641, 1571, 1548, 1505, 1417, 1310, 1297, 1240, 1210, 1209, 1141, 1110, 885, 826, 609 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.55 (m, 2H, aromatic), 7.14 (m, 3H, aromatic), 6.87 (d, 2H, J = 9.4 Hz, aromatic), 6, 18 (broad d, 1H, J = 4.6 Hz, NH), 4.85 (broad D, 1H, J = 5.8 Hz, meth), 4.13 (m, 1H, OCH _2a ), 3, 75 (m, 1H, OCH _2b ), 3.22 (t, 4H, J = 3.9 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J = 4.9 Hz, N -CH ₃ and Ph-CH _{2 a} ), 2.75-2.49 (m, 7H, Ph-NC (H ₂ CH _{2 s} -NCH _{2 s} and Ph-CH _{2 b} ), 2.15 (m, 1H, C (H) -CH _2a ), 2.04 (m, 1H, C (H > CH _2b ), δ; CMR (75MHz, CDCl ₃ ) 168.0, 150.9, 142.1, 141.5, 134 , 5, 132.7, 127.7,

-99125,0, 124,5, 121,9, 166,3, 74,4, 63,0, 54,5, 53,2, 48,7, 33,2, 29,1, 26,9; HRMS (FAB) vypočítaná pre C24H28F3N3O5S+H1 = 528,1780, nájdená = 528,1791.-99125.0, 124.5, 121.9, 166.3, 74.4, 63.0, 54.5, 53.2, 48.7, 33.2, 29.1, 26.9; HRMS (FAB) Calcd for C24H28F3N3O5S + H1 = 528.1780, found = 528.1791.

Príklad 75 (S)-(-)-l-[2-[4-(4-acetylfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX)Example 75 (S) - (-) - 1- [2- [4- (4-Acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Zmieša sa (S)-(-)-1 -[2-[4-(4-trifluórmetánsulfonyloxyfenyl)-1 -piperazinyl]etyl]-Nmetyl-izochróman-6-karboxamid (S)-(CC-3, 527 mg, 1,0 mmol), octan paládnatý (11 mg, 0,05 mmol), l,3-bis(difenylfosfino)propán (25 mg, 0,06 mmol), 3,5 ml dimetylformamidu, trietylamín (0,28 ml, 2,0 mmol) a butylvinyléter (0,65 ml, 5,00 mmol). Výsledná zmes sa zahreje na 50 °C. Po 16 hodinách sa reakcia ochladí na 20-25 °C, pridá sa 8 ml IM kyseliny chlorovodíkovej a 1 hodinu sa všetko mieša. Táto kyslá zmes se zahustí za zníženého tlaku, zriedi 15 ml IM hydroxidu sodného a dvakrát extrahuje dichlóretánom (25 ml). Zmiešané organické látky sa raz premyjú soľou (15 ml), vysušia nad síranom horečnatým, prefíltrujú a zahustia. Látka sa prečistí pomocou LC na 36 g (230-400) silikagélu za elúcie 50 % zmesou acetón/hexán a vznikne (S)-(-)-l-[2-[4-(4-acetylfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(CC-4), ktorý rekryštalizuje zo zmesi octan etylnatý/hexán, teplota topenia = 156-157 °C; Rf = 0,20 (50 % acetón/hexán); [a]o =-41° (c = 0,8481, metanol ); IR (suspenzia) 3331, 1662, 1598, 1570, 1550, 1519, 1427, 1415, 1311, 1284, 1239, 1196, 1150, 1107, 609 cm’¹; NMR (300 MHz, CDCb ) 7,85 (d, 2H, J = 8,9 Hz, aromatické), 7,55 (m, 2H, aromatické), 7,14 (d, 1H, J = 8,5 Hz, aromatické), 6,84 (d, 2H, J =(S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (CC-3, 527 mg, 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol), 3.5 mL dimethylformamide, triethylamine (0.28 mL, 2.0 mmol) and butyl vinyl ether (0.65 mL, 5.00 mmol). The resulting mixture was heated to 50 ° C. After 16 hours, the reaction was cooled to 20-25 ° C, 8 mL of 1M hydrochloric acid was added and stirred for 1 hour. The acidic mixture was concentrated under reduced pressure, diluted with 15 ml of 1M sodium hydroxide and extracted twice with dichloroethane (25 ml). The combined organics were washed once with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated. Purify by LC on 36 g (230-400) silica gel eluting with 50% acetone / hexane to give (S) - (-) - 1- [2- [4- (4-acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-4), which recrystallizes from ethyl acetate / hexane, m.p. = 156-157 ° C; Rf = 0.20 (50% acetone / hexane); [α] D = -41 ° (c = 0.8481, methanol); IR (suspension) 3331, 1662, 1598, 1570, 1550, 1519, 1427, 1415, 1311, 1284, 1239, 1196, 1150, 1107, 609 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl 3) 7.85 (d, 2H, J = 8.9 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.14 (d, 1H, J = 8.5 Hz) , aromatic), 6.84 (d, 2H, J =

8,9 Hz, aromatické), 6,24 (široké d, 1H, J = 4,6 Hz, NH), 4,86 (široké d, 1H, J = 5,8 Hz, metín), 4,12 (m, 1H, OCH_2a), 3,76 (m, 1H, OCH_2b), 3,35 (t, 4H, J = 5,0 Hz, Ph-N-CH_2s), 3,00 (d, 4H, J = 4,9 Hz, N-CH₃ a Ph-CH_2a), 2,75-2,53 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s a PhCH_2b), 2,50 (s, 3H, O=C-CH₃), 2,16 (m, 1H, C(H)-CH_2a), 2,02 (m, 1H, C(H)-CH_2b), CMR (75 MHz, CDCb) 196,6, 168,0, 154,2, 141,5, 1234,5, 132,7, 130,4, 127,7, 125,0, 124,5, 113,4,8.9 Hz, aromatic), 6.24 (broad d, 1H, J = 4.6 Hz, NH), 4.86 (broad d, 1H, J = 5.8 Hz, meth), 4.12 ( m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _{2 b} ), 3.35 (t, 4H, J = 5.0 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H J = 4.9 Hz, N-CH ₃ and Ph-CH _{2 a} ), 2.75-2.53 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} and PhCH _{2 b} ), 2 , 50 (s, 3 H, O = C-CH _3), 2.16 (m, 1 H, C (H) CH _2), 2.02 (m, 1 H, C (H) -CH _2b), CMR (75 MHz, CDCl 3) 196.6, 168.0, 154.2, 141.5, 1234.5, 132.7, 130.4, 127.7, 125.0, 124.5, 113.4,

74,4, 63,0, 54,5, 53,0, 47,3, 33,2, 29,1, 26,9, 26,1 δ HRMS (EI) vypočítaná pre C^HaiNaOj =74.4, 63.0, 54.5, 53.0, 47.3, 33.2, 29.1, 26.9, 26.1 δ HRMS (EI) calculated for C C HHNaNaOj =

421,2365, nájdená = 421,2365.421.2365, found = 421.2365.

Príklad 76 (S)-(-)-3-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-lyl]etyl]-6-yl]- Ν,Ν-dimetylakrylamid (S)-(XVHI)Example 76 (S) - (-) - 3- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -1H-dimethylacrylamide (S) - ( XVHI)

Zmieša sa (S)-(-)-l-[2-(6-brómizochróman-l-yl)-etyl]-[4-(4-metoxy fenyl)-piperazín (S)-(VI) (431,4 mg, 1,0 mmol), octan paládnatý (98 %, 11,4 mg, 0,05 mmol) a 1,3-bisdifenylfosfinopropán (97 %, 24,7 mg, 0,06 mmol). Pripraví sa ozónová atmosféra. InjekčnouCombine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] - [4- (4-methoxy-phenyl) -piperazine (S) - (VI) (431.4) mg, 1.0 mmol), palladium acetate (98%, 11.4 mg, 0.05 mmol) and 1,3-bisdiphenylphosphinopropane (97%, 24.7 mg, 0.06 mmol). An ozone atmosphere is prepared. injection

- 100 striekačkou sa do reakčnej nádobky zavedie DMF (4,1 ml), dimetylakrylamid (0,72 ml, 7,0 mmol) a diizopropyletylamín (0,35 ml, 2,00 mmol). Zmes sa zahrieva 18 hodín pri 100 °C. Po schladení na 20-25 °C sa reakcia zriedi vodným roztokom hydroxidu sodného a trikrát extrahuje octanom etylnatým. Organické látky sa nazhromaždia a zahustia. Prebytočné DMF sa odstráni za vákua. Surová látka sa prečistí pomocou rýchlej chromatografie na 80 g silikagélu za použitia 5 % metanolu v metylénchloride ako elučného činidla a vznikne tuhá fáza, ktorá rekryštalizuje z horúcej zmesi octan etylnatý/hexán za vzniku (S)-(-)-3[izochróman-l-[2-[4-(4-metoxyfenyl) piperazín-l-yl]etyl]-6-yl]-N, N-dimetylakrylamidu (S)(XVIII), teplota topenia =120-121 °C, Rf = 0,30 (5 % metanol v metylénchloride); NMR (300 MHz, CDCl·)) 7,62 (d, 1H, J = 15,4 Hz, aromatický H), 7,34 (d, 1H, J = 8,0 Hz, aromatický H), 7,10 (d, 1H, J = 8,0 Hz, aromatický H), 6,85 (d z d a m, 4H a 1H, J_a = 9,1 Hz, J_b = 21,4 Hz, aromatické H), 4,83 (m z d, 1H, J = 6,0 Hz, PhC-H), 4,13 (m, 1H, PhCH₂CH-H), 3,75 (m, 1H, PhCH₂CH-H), 3,75 (s, 3H, PhOC-H₃), 3,17 (s, 3H, NMeC-H₃), 3,10 (t a s, 4H a 3H, J = 4,8 Hz, štyri z pip-H a jeden z NMe-H₃), 2,94 (m, 1H, NCH-H), 2,76-2,45 (niekoľko m, 7H, štyri pip-H, dva PhCH-H a NCH-H), 2,14 (ra, 1H, PhCHCH-H), 2,02 (m, 1H, PhCHCXH-H), δ; CMR (75 MHz, CDC1₃) 166,7, 153,8, 145,7, 142,0, 139,8, 134,5, 133,5, 128,3, 125,5,DMF (4.1 mL), dimethylacrylamide (0.72 mL, 7.0 mmol) and diisopropylethylamine (0.35 mL, 2.00 mmol) were introduced into the reaction vial via syringe. The mixture was heated at 100 ° C for 18 hours. After cooling to 20-25 ° C, the reaction is diluted with aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organics were collected and concentrated. Excess DMF was removed under vacuum. The crude material was purified by flash chromatography on 80 g silica gel eluting with 5% methanol in methylene chloride to give a solid which was recrystallized from hot ethyl acetate / hexane to give (S) - (-) - 3 [isochroman-1]. - [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N, N-dimethylacrylamide (S) (XVIII), m.p. = 120-121 ° C, Rf = 0 .30 (5% methanol in methylene chloride); NMR (300 MHz, CDCl 3) 7.62 (d, 1H, J = 15.4 Hz, aromatic H), 7.34 (d, 1H, J = 8.0 Hz, aromatic H), 7.10 (d, 1H, J = 8.0 Hz, aromatic H), 6.85 (dt, 4H and 1H, J _a = 9.1 Hz, J _b = 21.4 Hz, aromatic H), 4.83 ( m / z, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.75 (m, 1H, PhCH ₂ CH-H), 3.75 ( s, 3H, PhOC-H ₃ ), 3.17 (s, 3H, NMeC-H ₃ ), 3.10 (tas, 4H and 3H, J = 4.8 Hz, four of pip-H and one of NMe -H ₃ ), 2.94 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 ( ra, 1H, PhCHCXH-H), 2.02 (m, 1H, PhCHCXH-H), δ; CMR (75 MHz, CDC1 ₃₎ 166.7, 153.8, 145.7, 142.0, 139.8, 134.5, 133.5, 128.3, 125.5,

118,1, 117,1, 114,4, 74,6, 63,0, 55,6, 54,8, 53,5, 50,6, 37,4, 35,9, 33,2 a 29,1 δ.118.1, 117.1, 114.4, 74.6, 63.0, 55.6, 54.8, 53.5, 50.6, 37.4, 35.9, 33.2 and 29, 1 δ.

Príklad 77 (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(l,2,4-triazol-3-yl]izochróman-1 -yljetyljpiperazín (S)-(O-2)Example 77 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) - (O) -2)

1. krok: (S)-(-)-l-[2-[4-(4—metoxyfenyl )-l-piperazinyl]etyl]-Ndimetylaminometylénizochróman-6-karboxamid (S)-(O-1)Step 1: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O-1)

Zmieša sa (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl jetyl j-N-izochróman-6karboxamid (S)-(VH, 395,5, mg, 1 mmol) s N,N-dimetylformamiddimetylacetálom (94 %, 0,34 ml, 2,4 mmol) a toluénom (1 ml). Reakčná zmes sa zahreje na 90 °C na 1,5 hodiny. Po zachladení na 20-25 °C sa prchavé látky odstránia za zníženého tlaku. Prečistenie surovej látky sa uskutoční pomocou rýchlej chromatografie na 90 g silikagélu za použitia 5 % metanolu v metylénchloride ako elučného činidla a vznikne (S)-(-)-l-[2-[4-(4-metoxyfenyl)1-piperaziny l]etyl]-N-dimetylaminometylénizochróman-6-karboxamid (S)-(O-l), teplota topenia = 134-135,5 °C; Rf = 0,28 (5 % metanolu v metylénchloride); [ajo =-47° (c = 0,96, 50 % metylénchlorid v etanole ); IR (suspenzia) 1647, 1608, 1593, 1515, 1446, 1417, 1329, 1259, 1247, 1108 cm'¹; NMR (300 MHz, CDC1₃) 8,63 (s, 1H, NMe₂C-H), 8,07 (d, 1H, J = 8,1 Hz, aromatická H), 8,02 (s, 1H, aromatický H), 7,14 (d, 1H, J = 8,1 Hz, aromatický H), 6,85Combine (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] -N-isochroman-6-carboxamide (S) - (VH, 395.5, mg, 1 mmol) with N, N-dimethylformamide dimethyl acetal (94%, 0.34 mL, 2.4 mmol) and toluene (1 mL). The reaction mixture was heated to 90 ° C for 1.5 hours. After cooling to 20-25 ° C, the volatiles are removed under reduced pressure. Purification of the crude material was accomplished by flash chromatography on 90 g silica gel eluting with 5% methanol in methylene chloride to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl]] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O1), m.p. = 134-135.5 ° C; Rf = 0.28 (5% methanol in methylene chloride); [α] D = -47 ° (c = 0.96, 50% methylene chloride in ethanol); IR (slurry) 1647, 1608, 1593, 1515, 1446, 1417, 1329, 1259, 1247, 1108 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 8.63 (s, 1H, NMe ₂ CH), 8.07 (d, 1H, J = 8.1 Hz, aromatic H), 8.02 (s, 1H, aromatic H) 7.14 (d, 1H, J = 8.1 Hz, aromatic H), 6.85

-101(d z d, 4H, J_a = 9,2 Hz, J_b = 21,6 Hz, aromatické H), 4,88 (m z d, 1H, J = 5,1 Hz, PhC-H),-101 (dzd, 4H, J _a = 9.2 Hz, J _b = 21.6 Hz, aromatic H), 4.88 (wd, 1H, J = 5.1 Hz, PhC-H),

4,13 (m, 1H, PhCH₂CH-H), 3,76 (m, 1H, PhCH₂CH-H), 3,75 (s, 3H, OC-H₃), 3,21 (s, 3H, NMeC-Hj), 3,18 (s, 3H, NMeC-Hj), 3,10 (t, 4H, J = 4,9 Hz, štyri pip-H), 2,98 (m, 1H, PhCHH), 2,76 (m z d, 1H, J = 16 Hz, PhCHCH-H), 2,60 (m’s, 6H, NC-H₂ a štyri pip-H), 2,15 (m, 1H, PhCHCH-H), 2,05 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDClj) 177,6, 160,8, 153,7,4.13 (m, 1H, PhCH ₂ CH-H), 3.76 (m, 1H, PhCH ₂ CH-H), 3.75 (s, 3H, OC-H ₃ ), 3.21 (s, 3H, NMeC-H 3), 3.18 (s, 3H, NMeC-H 3), 3.10 (t, 4H, J = 4.9 Hz, four pip-H), 2.98 (m, 1H, PhCHH) ), 2.76 (MH, 1 H, J = 16 Hz, PhCHCH-H), 2.60 (m's, 6H, _NC-H2 and four pip-H), 2.15 (m, 1H, PhCHCH-H 1.05 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCl3) 177.6, 160.8, 153.7,

145.8, 142,0, 134,9, 133,7, 130,3, 127,6, 124,5, 118,1, 114,4, 74,8, 63,1, 55,6, 54,7, 53,5,145.8, 142.0, 134.9, 133.7, 130.3, 127.6, 124.5, 118.1, 114.4, 74.8, 63.1, 55.6, 54.7, 53.5.

50,6,41,4, 35,3, 33,2 a 29,2 δ.50.6, 41.4, 35.3, 33.2 and 29.2 δ.

2. krok: (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(l,2,4-triazol-3-yl]izochróman-lyl]etyl]piperazín (S)-(O-2)Step 2: (S) - (-) -1- (4-methoxyphenyl) -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) ) - (O-2)

Zmieša sa (S)-(-)-l-[2-[4-(4—metoxyfenyl)-l-piperazinyl]etyl]-Ndimetylaminometylénizochróman-6-karboxamid (S)-(O-l, 208 mg, 0,46 mmol) s ľadovou kyselinou octovou (1 ml) v argónovej atmosfére. Za intenzívneho miešania sa pomocou injekčnej striekačky po kvapkách pridá hydrazín monohydrát (0,045 ml, 0,92 mmol). Reakcia sa mieša 24 hodín pri 20-25 °C. Reakčná zmes sa zriedi vodou a rozdelí na nasýtený vodný hydrogénuhličitan sodný a metylénchlorid. Zmiešané organické látky sa vysušia pomocou síranu sodného, prefiltrujú a zahustia. Prečistenie surovej látky sa uskutoční pomocou rýchlej chromatografie na 6 g silikagélu za použitia 5 % metanolu v metylénchloride ako elučného činidla a vznikne (S)-(-)- l-(4-metoxy fény l)-4-[2-[6-( 1,2,4-triazol-3 -y 1] izochróman-1yl]etyl]piperazín (S)-(O-2), teplota topenia = 195,5-196 °C; Rf = 0,17 (5 % metanolu v metylénchloride); NMR (300 MHz, CDClj ) 8,04, 7,47, 7,46, 7,24, 6,85, 4,89, 4,16, 3,99,(S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (Ol, 208 mg, 0.46 mmol) was added. ) with glacial acetic acid (1 mL) under an argon atmosphere. With vigorous stirring, hydrazine monohydrate (0.045 mL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred at 20-25 ° C for 24 hours. The reaction mixture was diluted with water and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification of the crude material was accomplished by flash chromatography on 6 g silica gel using 5% methanol in methylene chloride as eluent to give (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) - (O-2), mp = 195.5-196 ° C; R f = 0.17 (5%) NMR (300 MHz, CDCl 3) 8.04, 7.47, 7.46, 7.24, 6.85, 4.89, 4.16, 3.99,

3,80, 3,75, 3,10, 2,98, 2,77, 2,67-2,59, 2,18 δ; CMR (75 MHz, CDClj) 159,4, 153,9, 146,9,3.80, 3.75, 3.10, 2.98, 2.77, 2.67-2.59, 2.18 δ; CMR (75 MHz, CDCl 3) 159.4, 153.9, 146.9,

145,6, 139,8, 134,7, 127,3, 127,0, 125,3, 124,2, 118,2, 114,5, 63,1, 55,6, 54,7, 53,4, 50,6, 33,0,29,0 δ.145.6, 139.8, 134.7, 127.3, 127.0, 125.3, 124.2, 118.2, 114.5, 63.1, 55.6, 54.7, 53, 4, 50.6, 33.0, 29.0 δ.

Príklad 78 (S)-(-)-1 -(4-metoxyfenyl)-4-[2-[6-(2-metyl-1,2,4-triazol-3-yl]izochróman-1 -yl]etyl]piperazín (S)-(O-2)Example 78 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl Piperazine (S) - (O-2)

Postupom podľa príkladu 77, 2. kroku s drobnými obmenami vzniká z metyl hydrazínu (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(2-metyl-l,2,4-triazol-3-yl]izochróman-lyl]etyl]piperazín (S)-(O-2) , Rf = 0,17 (5 % metanol v metylénchloride); NMR (300 MHz, CDClj) 8,04, 7,47, 7,46, 7,24, 6,85, 4,89, 4,16, 3,99, 3,80, 3,75, 3,10, 2,98, 2,77, 2,67-2,59, 2,18, 2,07 δ; CMR (75 MHz, CDClj) 154,4, 153,8, 150,7, 145,7, 140,4, 134,9, 129,3, 126,2,Following the procedure of Example 77, Step 2, with minor variations, methyl hydrazine (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-methyl-1,2,4- triazol-3-yl] isochroman-1-yl] ethyl] piperazine (S) - (O-2), R f = 0.17 (5% methanol in methylene chloride); NMR (300 MHz, CDCl 3) 8.04, 7.47 , 7.46, 7.24, 6.85, 4.89, 4.16, 3.99, 3.80, 3.75, 3.10, 2.98, 2.77, 2.67-2 , 59, 2.18, 2.07 δ CMR (75 MHz, CDCl3) 154.4, 153.8, 150.7, 145.7, 140.4, 134.9, 129.3, 126.2 .

125.9, 125,3, 118,2,114,4, 74,5,1, 62,9, 55,6, 54,7, 53,5, 50,6, 37,0, 33,2,29,0 δ.125.9, 125.3, 118.2, 114.4, 74.5.1, 62.9, 55.6, 54.7, 53.5, 50.6, 37.0, 33.2.29.09 δ .

- 102Príklad 79 (S)-(-)-1 -(4-metoxyfenyl)-4-[2-[6-(2-fenylmetyl-1,2,4-triazol-3 yl]izochróman-1 -yljetyljpiperazín (S)-(O-2)Example 102 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (2-phenylmethyl-1,2,4-triazol-3-yl) isochroman-1-yl-yl] -piperazine (S) ) - (O-2)

Postupom podľa príkladu 77, 2. kroku s drobnými obmenami vzniká z fenylmetyl hydrazínu (S)-(-)-1 -(4-metoxyfenyl)-4-[2-[6-(2-fenylmety 1-1,2,4-triazol-3 -yl]izochróman-1 yl]etyl]piperazín (S)-(O-3), Rf = 0,28 (5 % metanol v metylénchloride); NMR (300 MHz, CDCb) 8,01 (s, 1H, triazolC-H), 7,37-7,30 (m’s, 5H, aromatické H), 5,43 (s, 2H, PhC-H₂)Following the procedure of Example 77, Step 2, with minor variations, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-phenylmethyl) 1-1,2,4] phenylmethyl hydrazine -triazol-3-yl] isochroman-1-yl] ethyl] piperazine (S) - (O-3), R f = 0.28 (5% methanol in methylene chloride); NMR (300 MHz, CDCl 3) 8.01 (s 1 H, triazole (C-H), 7.37-7.30 (m's, 5H, aromatic H), 5.43 (s, 2H, PhC-H ₂ )

4,87 (m z d, 1H, J = 5,1 Hz, PhC-H), 4,14 (m, 1H, PhCH₂cH-H), 3,79 (m, 1H, PhCH₂cH-H),4.87 (mt, 1H, J = 5.1 Hz, PhC-H), 4.14 (m, 1H, PhCH ₂ cH-H), 3.79 (m, 1H, PhCH ₂ cH-H),

3,78 (s, 3 H, OC-H₃), 3,10 )t, 4H, J = 4,9 Hz, štyri pip-H), 2,97 (m, 1H, PhCHCH-H), 2,732,52 (niekoľko m, 7H, PhCHCH-H, NC-H₂ a štyri pip-H), 2,16 (m, 1H, PhCHCH-H), 2,05 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCb) 155,0, 153,8, 151,3, 145,7, 140,5, 135,9,3.78 (s, 3H, OC-H ₃ ), 3.10 µm, 4H, J = 4.9 Hz, four pip-H), 2.97 (m, 1H, PhCHCH-H), 2.732 52 (several m, 7H, PhCHCH-H, NC-H ₂ and four pip-H), 2.16 (m, 1H, PhCHCH-H), 2.05 (m, 1H, PhCHCH-H) δ; CMR (75 MHz, CDCl 3) 155.0, 153.8, 151.3, 145.7, 140.5, 135.9,

134,9, 129,4, 129,0, 128,1, 126,9, 126,2, 125,8,125,3, 118,2, 114,4, 74,4, 62,9, 55,6, 54,7, 53,5, 52,8, 50,6,33,2, 29,0 δ.134.9, 129.4, 129.0, 128.1, 126.9, 126.2, 125.8, 125.3, 118.2, 114.4, 74.4, 62.9, 55.6, 54.7, 53.5, 52.8, 50.6.33.2, 29.0 δ.

Príklad 80 (S)-(-)-l -(4-metoxyfenyl)-4-[2-[6-(l ,2,4-oxadiazol-5-yl)-izochróman1-yljetyljpiperazín (S)-(O-2)Example 80 (S) - (-) - 1- (4-Methoxy-phenyl) -4- [2- [6- (1,2,4-oxadiazol-5-yl) -isochroman-1-yl-yl] -piperazine (S) - (O- 2)

Zmieša sa hydroxylamín hydrochlorid (83,4 mg, 1,2 mmol) s 5N vodným roztokom hydroxidu sodného (0,24 ml, 1,2 mmol), 70 % kyselinou octovou (1,2 ml) a ihneď sa pridá (S)-(-)-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-dimetylaminometylénizochróman-6karboxamid (S)-(O-l, Príklad 77, l.krok, 450,6 mg, 1,0 mmol). Zmes sa mieša 70 minút pri 20-25 °C. Reakcia sa zriedi vodou a nasýteným vodným hydrogénuhličitanom sodným sa zvýši pH na 8,0. Vodná zmes sa dvakrát extrahuje metylénchloridom. Zmiešané organické látky sa vysušia pomocou síranu sodného, prefiltrujú a zahustia. Táto látka (Rf = 0,18 (5 % metanol v metylchloride)) sa rozpustí v zmesi bezvodej kyseliny octovej (2 ml) a bezvodom p-dioxane (2 ml). Vytvorí sa argónová atmosféra a reakcia sa zahreje na 2 hodiny na 90 °C. Po schladení na 20-25 °C sa zriedi vodou a nasýteným vodným hydrogénuhličitanom sodným sa zvýši pH na 8,0. Vodná zmes sa dvakrát extrahuje metylénchloridom. Zmiešané organické látky sa vysušia pomocou síranu sodného, prefiltrujú a zahustia. Prečistenie surovej látky sa uskutočni pomocou iýchlej chromatografie na 50 g silikagélu za použitia 4 % metanolu v metylénchloride ako elučného činidla a vznikne (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(2fenylmetyl-l,2,4-triazol-3-yl]izochróman-l-yl]etyl]piperazín (S)-(O-2), teplota topenia = 126,-127 °C; Rf = 0,36 (5 % metanolu v metylénchloride); NMR (300 MHz, CDCb ) 8,47 (s,lH, oxadiazolC-H), 7,95 (d, 1H, J = 8,1 Hz, aromatický H), 7,92 (s, 1H, aromatický H),Combine hydroxylamine hydrochloride (83.4 mg, 1.2 mmol) with 5N aqueous sodium hydroxide solution (0.24 mL, 1.2 mmol), 70% acetic acid (1.2 mL) and immediately add (S). - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (Ol, Example 77, Step 1, 450.6 mg, 1.0 mmol). The mixture was stirred at 20-25 ° C for 70 minutes. Dilute the reaction with water and raise the pH to 8.0 with saturated aqueous sodium bicarbonate. The aqueous mixture was extracted twice with methylene chloride. The combined organics were dried over sodium sulfate, filtered and concentrated. This material (Rf = 0.18 (5% methanol in methyl chloride)) was dissolved in a mixture of anhydrous acetic acid (2 mL) and anhydrous p-dioxane (2 mL). An argon atmosphere was created and the reaction was heated to 90 ° C for 2 hours. After cooling to 20-25 ° C, it is diluted with water and the pH is raised to 8.0 with saturated aqueous sodium bicarbonate. The aqueous mixture was extracted twice with methylene chloride. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification of the crude material was accomplished by flash chromatography on 50 g silica gel eluting with 4% methanol in methylene chloride to give (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-phenylmethyl)] -1,2,4-triazol-3-yl] isochroman-1-yl] ethyl] piperazine (S) - (0-2), mp = 126, -127 ° C; R f = 0.36 (5%) NMR (300 MHz, CDCl 3) 8.47 (s, 1H, oxadiazole C-H), 7.95 (d, 1H, J = 8.1 Hz, aromatic H), 7.92 (s, 1H, aromatic H),

7,28 (d, 1H, J = 8,1 Hz, aromatický H), 6,86 (d z d, 4H, Ja = 9,1 Hz, J_b = 21,2 Hz, aromatické7.28 (d, 1H, J = 8.1 Hz, aromatic H), 6.86 (dzd, 4H, J a = 9.1 Hz, J _b = 21.2 Hz, aromatic)

-103Η), 4,90 (m z d, 1H, J = 5,1 Hz, PhC-H), 2,66-2,51 (niekoľko m, 6H, NC-H₂ a štyri pip-H), 2,18 (m, 1H, PhCHCH-H), 2,07 (m, 1H, PhCHCH-H), δ; CMR (75 MHz, CDC1₃) 175,3,-103Η), 4.90 (wt, 1H, J = 5.1Hz, PhC-H), 2.66-2.51 (several m, 6H, NC-H ₂ and four pip-H), 2, 18 (m, 1H, PhCHCH-H), 2.07 (m, 1H, PhCHCH-H), δ; CMR (75 MHz, CDC1 ₃₎ 175.3,

157,8, 153,8, 145,7, 143,6, 153,3, 128,7, 125,8, 125,7, 122,0, 118,2, 114,4, 74,5, 62,8, 55,6,157.8, 153.8, 145.7, 143.6, 153.3, 128.7, 125.8, 125.7, 122.0, 118.2, 114.4, 74.5, 62, 8, 55.6,

54,6, 53,5, 50,6,33,1, 29,0 δ.54.6, 53.5, 50.6.33, 29.0 δ.

Príklad 81 (S)-(-)-N-metyl-l-[2-[4-(4-propionylfenyl)-lpiperazinyl]etyl]izochróman-6-karboxamid (S)-(IX)Example 81 (S) - (-) - N-Methyl-1- [2- [4- (4-propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (IX)

1. krok: (S)-(-)-6-bróm-l-(2-hydroxyetyl)izochróman (S)-(S-l)Step 1: (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochroman (S) - (S-1)

Zmieša sa (S)-(-)-(6-brómizochróman-l-yl)octová kyselina (S)-(XI, Príklad 1, 2. krok, 16,27g, 60 mmol) s 100 ml tetrahydroŕuránu. K zmesi sa pridá 10M roztok metylsulfídu boru (18,0 ml, 0,18 mol) pri 20-25 °C a vo vodnom kúpeli. Za jednu hodinu sa zmes ochladí na 0 °C a pomaly sa pridá 160 ml metanolu. Upozornenie: Po zhruba 1-2 minútach dôjde k prudkému vývinu vodíka. Zmes sa zahreje na 20-25 °C a prchavé látky sa odstránia za zníženého tlaku. Výsledná zmes sa zriedi IM hydroxidom sodným (150 ml) a trikrát extrahuje octanom etylnatým (100 ml). Zmiešané organické látky sa raz premyjú soľou (100 ml), vysušia pomocou síranu sodného, prefiltrujú a zahustia. Zmes rekryštalizuje zo zmesi octan etylnatý/hexán za vžniku (S)-(-)-6-bróm-l-(2-hydroxyetyl)-izochrómanu (S)-(S-l), teplota topenia = 95-96 °C; Rf = 0,28 (30 % acetón/hexán); [<x]d =-107° (c = 0,4069,metanol); IR (suspenzia) 3237, 3022, 1482, 1422, 1326, 1277, 1114, 1053, 1026, 972, 905, 894, 880, 816, 788 cm'¹; NMR (300 MHz, CDC1₃ ) 7,28 (m, 2H, aromatické), 6,92 (d, 1H, J = 8,2 Hz, aromatické), 4,92 (široké d, 1H, J = 6,8 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,81 (t, 2H, J = 5,5 Hz, HO-CH₂) 3,74 (m, 1H, OCH_2b), 3,00 (m, 1H, Ph-CH_2a), 2,66 (dt, 1H, J = 16,4 Hz a J =(S) - (-) - (6-Bromo-iso-chroman-1-yl) -acetic acid (S) - (XI, Example 1, Step 2, 16.27g, 60 mmol) was mixed with 100 mL of tetrahydrofuran. To the mixture was added a 10M solution of boron methyl sulfide (18.0 mL, 0.18 mol) at 20-25 ° C and in a water bath. After one hour, the mixture was cooled to 0 ° C and 160 mL of methanol was slowly added. Caution: Hydrogen evolution will occur after about 1-2 minutes. The mixture is warmed to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting mixture was diluted with 1M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organics were washed once with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The mixture is recrystallized from ethyl acetate / hexane to give (S) - (-) - 6-bromo-1- (2-hydroxyethyl) -isochroman (S) - (S1), m.p. = 95-96 ° C; Rf = 0.28 (30% acetone / hexane); [α] D = -107 ° (c = 0.4069, methanol); IR (slurry) 3237, 3022, 1482, 1422, 1326, 1277, 1114, 1053, 1026, 972, 905, 894, 880, 816, 788 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic), 6.92 (d, 1H, J = 8.2 Hz, aromatic), 4.92 (broad d, 1H, J = 6, 8 Hz, meth), 4.15 (m, 1H, OCH _{2 a} ), 3.81 (t, 2H, J = 5.5 Hz, HO-CH ₂ ) 3.74 (m, 1H, OCH _2b ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.66 (dt, 1H, J = 16.4 Hz and J =

3,1 Hz, Ph-CH_2b), 2,45 (široké s, 1H, HO), 2,18 (m, 1H, C(H)-CH_2a), 2,02 (m, 1H, C(H)CH_2b) δ; CMR (75 MHz, CDC1₃) 136,5, 136,1, 131,8, 129,4, 126,3, 120,2, 75,9, 63,4, 60,8,3.1 Hz, Ph-CH _2b ), 2.45 (broad s, 1H, HO), 2.18 (m, 1H, C (H) -CH _{2 a} ), 2.02 (m, 1H, C ( H) CH2 ( _b ) δ; CMR (75 MHz, CDC1 ₃₎ 136.5, 136.1, 131.8, 129.4, 126.3, 120.2, 75.9, 63.4, 60.8,

37,5,28,8 δ; MS (EI, m/z) = 256.37,5,28,8 δ; MS (EI, m / z) = 256;

2. krok: metylester (S)-(-)-l-(2-hydroxymetyl)izochróman-6-karboxylovej kyseliny, (S)-(S-2)Step 2: (S) - (-) - 1- (2-hydroxymethyl) isochroman-6-carboxylic acid methyl ester, (S) - (S-2)

Zmieša sa (S)-(-)-6-bróm-l-(2-hydroxyetyl)izochróman (S)-(S-l, 5,14 g, 20,0 mmol), octan paládnatý (225 mg, 1,0 mmol), l,3-bis(difenylfosfmo)propán (495 mg, 1,2 mmol) a 40,0 ml dimetylformamidu s diizopropyletanolamínom (10,5 ml, 60,0 mmol) a metanolom (16 ml, 0,40 mmol). Výsledná zmes sa šesťkrát prečistí pomocou monooxidu uhlíka zaCombine (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochroman (S) - (Sl, 5.14 g, 20.0 mmol), palladium acetate (225 mg, 1.0 mmol) 1,3,3-bis (diphenylphosphino) propane (495 mg, 1.2 mmol) and 40.0 mL of dimethylformamide with diisopropylethanolamine (10.5 mL, 60.0 mmol) and methanol (16 mL, 0.40 mmol) . The resulting mixture was purified six times with carbon monooxide to give a white solid

- 104 zníženého tlaku a rýchle sa zahreje na 75 °C. Reakčná zmes sa mieša 19 hodín. Potom sa zmes ochladí na 20-25 °C, zriedi 200 ml vody a dvakrát extrahuje dichlórmetánom (200 ml). Zmiešané organické látky sa raz premyjú vodou (100 ml), raz soľankou (100 ml), vysušia pomocou síranu horečnatého, prefiltrujú a zahustia. Prečistenie surovej látky sa uskutoční pomocou LC na 300 g (230-400) silikagélu za elúcie 50 % zmesou octan etylnatý/hexán a vznikne metylester (S)-(-)-l-(2-hydroxymetyl)izochróman-6-karboxylovej kyseliny (S)-(S2), teplota topenia = 56-58 °C; Rf = 0,23 (50 % octan etylnatý/hexán); [a]o =-114° (c = 0,8773, metanol); IR (suspenzia) 3407, 3336, 1718, 1434, 1418, 1296, 1274, 1261, 1250, 1195, 1112, 1055, 1022, 997, 754 cm⁴; NMR (300 MHz, CDCh) 7,79 (m, 2H, aromatické),104 of reduced pressure and rapidly heated to 75 ° C. The reaction mixture was stirred for 19 hours. The mixture was then cooled to 20-25 ° C, diluted with 200 mL of water and extracted twice with dichloromethane (200 mL). The combined organics were washed once with water (100 mL), once with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the crude by LC on 300 g (230-400) silica gel eluting with 50% ethyl acetate / hexane gave (S) - (-) - 1- (2-hydroxymethyl) isochroman-6-carboxylic acid methyl ester ( S) - (S2), mp = 56-58 ° C; Rf = 0.23 (50% ethyl acetate / hexane); [α] D = -114 ° (c = 0.8773, methanol); IR (suspension) 3407, 3336, 1718, 1434, 1418, 1296, 1274, 1261, 1250, 1195, 1112, 1055, 1022, 997, 754 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl 3) 7.79 (m, 2H, aromatic),

7,11 (d, 1H, J = 8,0 Hz, aromatické), 4,97 (široké d, 1H, J = 6,8 Hz, metín), 4,15 (m, 1H, OCH_2a), 3,88 (s, 3H, CH₃), 3,82 (t, 2H, J = 5,0 Hz, HO-CH₂), 3.75 (m, 1H, OCH_2a), 3,01 (m, 1H, Ph-CH_2a), 2,71 (dt, 2H, J = 16,8 Hz a J = 3,3 Hz, Ph-CH_2b a HO), 2,21 (m, 1H, C(H)CH_2a), 2,03 (m, 1H, C(H)-CH_2b) ) δ; CMR (75 MHz, CDCh) 166,9, 142,8, 134,1, 130,3,7.11 (d, 1H, J = 8.0 Hz, aromatic), 4.97 (broad d, 1H, J = 6.8 Hz, meth), 4.15 (m, 1H, OCH _{2 a} ), 3 88 (s, 3H, CH ₃ ), 3.82 (t, 2H, J = 5.0 Hz, HO-CH ₂ ), 3.75 (m, 1H, OCH _{2 a} ), 3.01 (m, 1H, Ph-CH _{2 a} ), 2.71 (dt, 2H, J = 16.8 Hz and J = 3.3 Hz, Ph-CH _2b and HO), 2.21 (m, 1H, C (H) CH _{2 a)} 1.03, 2.03 (m, 1H, C (H) - CH _{2 b} )) δ; CMR (75 MHz, CDCl 3) 166.9, 142.8, 134.1, 130.3,

128,3, 127,4, 124,8, 75,8, 63,4, 60,6, 52,1, 37,6,28,9 δ.128.3, 127.4, 124.8, 75.8, 63.4, 60.6, 52.1, 37.6.28.9 δ.

3. krok: (S)-(-)-l-(2-hydroxyetyl)-N-metylizochróman-6-karboxamid (SHS-3)Step 3: (S) - (-) - 1- (2-hydroxyethyl) -N-methylisochroman-6-carboxamide (SHS-3)

Zmieša sa (S)-(-)-l-(2-hydroxyetyl)izochróman-6-karboxylová kyselina, metylester (S)-(S-2, 473 mg, 2,0 mmol) a 8,0 ml 6M metylamínu v metanole. Reakčná nádoba sa uzavrie teflónovým skrutkovacím uzáverom a zmes sa zahreje na 75 °C. Po 20 hodinách sa reakčná zmes ochladí na 20-25 °C, skoncentruje za zníženého tlaku a rozotrie s hexánom za vzniku (S)-(-)-l-(2-hydroxyetyl)-N-metylizochróman-6-karboxamidu (S)-(S-3), teplota topenia= 90101 °C; Rf = 0,20 (5 % metanol/dichlórmetán); [a]o =-119° (c = 0,8674,metanol); IR (suspenzia) 3350, 3274, 1648, 1514, 1572, 1564, 1422, 1336, 1320, 1156, 1107, 1078, 1058, 1045, 718 cm⁴; NMR (300 MHz, CDCh) 7,53 (m, 2H, aromatické), 7,08 (d, 1H, J = 8,7 Hz, aromatické), 6,32 (široké s, 1H, NH), 4,97 (široké d, 1H, J = 6,7 Hz, metín), 4,16 (m, 1H, OCH_2a) 3,82 (t, 2H, J = 5,4 Hz, HO-CH₂), 3,74 (m, 1H, OCH_2b ), 3,02 (d, 4H, J = 4,9 Hz, NCHj a Ph-CH_2a), 2,71 (dt, 2H, J = 16,4 Hz a J = 3,2 Hz, Ph-CH_2b a HO), 2,21 (m, 1H, C(H)CH_2a), 2,03 (m, 1H, C(H)-CH_2b) δ.Combine (S) - (-) - 1- (2-hydroxyethyl) isochroman-6-carboxylic acid, (S) - (S-2, 473 mg, 2.0 mmol) methyl ester and 8.0 mL of 6M methylamine in methanol. The reaction vessel was sealed with a Teflon screw cap and the mixture was heated to 75 ° C. After 20 hours, the reaction mixture is cooled to 20-25 ° C, concentrated under reduced pressure and triturated with hexane to give (S) - (-) - 1- (2-hydroxyethyl) -N-methylisochroman-6-carboxamide (S) - (S-3), m.p. = 90101 ° C; Rf = 0.20 (5% methanol / dichloromethane); [α] D = -119 ° (c = 0.8674, methanol); IR (suspension) 3350, 3274, 1648, 1514, 1572, 1564, 1422, 1336, 1320, 1156, 1107, 1078, 1058, 1045, 718 cm &^lt; ^{4 &gt};; NMR (300 MHz, CDCl 3) 7.53 (m, 2H, aromatic), 7.08 (d, 1H, J = 8.7 Hz, aromatic), 6.32 (broad s, 1H, NH), 4, 97 (broad d, 1H, J = 6.7 Hz, methine), 4.16 (m, 1H, OCH _{2 a} ) 3.82 (t, 2H, J = 5.4 Hz, HO-CH ₂ ), 3 74 (m, 1H, OCH _2b ), 3.02 (d, 4H, J = 4.9 Hz, NCH 3 and Ph-CH _{2 a} ), 2.71 (dt, 2H, J = 16.4 Hz and J = 3.2 Hz, Ph-CH _2b and HO), 2.21 (m, 1 H, C (H) CH _2), 2.03 (m, 1 H, C (H) -CH _2b) δ.

4. krok: (S)-(-)-l-(2-metánsulfonyloxyetyl)-N-metylizochróman-6karboxamid (S)-(T-2)Step 4: (S) - (-) - 1- (2-Methanesulfonyloxyethyl) -N-methylisochroman-6-carboxamide (S) - (T-2)

- 105(S)-(-)-l-(2-hydroxyetyl)-N-metylizochróman-6-karboxamid (S)-(S-3, 383 mg, 1,6 mmol) sa zmieša s dichlórmetánom a trietylamínom (0,34 ml, 2,4 mmol) a ochladí na 0 °C. K zmesi sa potom pridá metánsulfonylchlorid (0,15 ml, 1,95 mmol). Po 15 minútach sa reakčná zmes zriedi 10 ml dichlórmetánu, raz premyje 15 ml vody a raz 15 ml soľanky, vysuší nad síranom horečnatým, prefiltruje a skoncentruje za vzniku (S)-(-)-l-(2-metánsulfonyloxyetyl)N-metyl-izochróman-6-karboxamidu (S)-(T-2), Rf = 0,35 (60 % acetón/hexán); NMR (300 MHz, CDCb) 7,53 (m, 2H, aromatické), 7,11 (d, 1H, J = 7,9 Hz, aromatické), 6,23 (široké s, 1H, NH), 4,90 (široké d, 1H, J = 7,4 Hz, metín), 4,46 (m, 1H, OCH_2a), 4,34 (m, 1H, MsOCH_2a), 4,12 (m, 1H, MsO-CH_2b), 3,76 (m, 1H, OCH_2b), 3,00 (m, 7H, NCH₃, S- CH₃, PhCH_2a), 2,73 (dt, 1H, J = 16,1 Hz a J = 3,2 Hz, Ph-CH_2b), 2,42 (m, 1H, C(H)-CH_2a), 2,14 (m, 1H, C(H)-CH_2b) δ.- 105 (S) - (-) - 1- (2-hydroxyethyl) -N-methylisochroman-6-carboxamide (S) - (S-3, 383 mg, 1.6 mmol) was mixed with dichloromethane and triethylamine (0). (34 mL, 2.4 mmol) and cooled to 0 ° C. Methanesulfonyl chloride (0.15 mL, 1.95 mmol) was then added to the mixture. After 15 minutes, the reaction mixture was diluted with 10 mL of dichloromethane, washed once with 15 mL of water and once with 15 mL of brine, dried over magnesium sulfate, filtered and concentrated to give (S) - (-) - 1- (2-methanesulfonyloxyethyl) N-methyl (S) - (T-2) -isochroman-6-carboxamide, R f = 0.35 (60% acetone / hexane); NMR (300 MHz, CDCl 3) 7.53 (m, 2H, aromatic), 7.11 (d, 1H, J = 7.9 Hz, aromatic), 6.23 (broad s, 1H, NH), 4, 90 (broad d, 1H, J = 7.4 Hz, meth), 4.46 (m, 1H, OCH _{2 a} ), 4.34 (m, 1H, M 5 OCH _{2 a} ), 4.12 (m, 1H, M 5 O) CH _2b), 3.76 (m, 1 H, OCH _{2 b),} 3.00 (m, 7H, _NCH3, S-CH _3, PhCH _2), 2.73 (dt, 1 H, J = 16.1 Hz and J = 3.2 Hz, Ph-CH _2b ), 2.42 (m, 1H, C (H) -CH _{2 a} ), 2.14 (m, 1H, C (H) -CH _2b ) δ.

5. krok: (S)-(-)-N-metyl-l-[2-[4-(4-propionylfenyl)-lpiperazinyl]etyl]-izochróman-6-karboxamid (S)-(IX)Step 5: (S) - (-) - N-Methyl-1- [2- [4- (4-propionylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (IX)

Zmes (S)-(-)-1 -(2-metánsulfonyloxyetyl)-N-metyl-izochróman-6-karboxamidu (S)(T-2, 509 mg, 1,5 mmol), 4’-piperazínopropiofenónu (393 mg, 1,8 mmol) a uhličitanu draselného (622 mg, 4,5 mmol) v acetónitrile sa zahreje na 50 °C cez noc a potom sa privedie k varu na ďalších 5 hodín. Reakčná zmes sa potom ochladí na 20-25 °C a zahustí sa zvyšok, ktorý sa rozdelí na vodu a dichlórmetán. Vodná vrstva sa dvakrát extrahuje dichlórmetánom a zmiešané organické vrstvy sa raz premyjú vo vode, raz v soľanke, vysušia nad síranom horečnatým, prefiltrujú a zahustia za vzniku (S)-(-)-N-metyl-l-[2-[4-(4propionylfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu (S)-(IX), teplota topenia= 160-161 °C; Rf = 0,20 (60 % acetón/hexán); IR (suspenzia) 3274, 1669, 1640, 1607, 1543, 1522, 1415, 1407, 1315, 1233, 1200, 1156, 1142, 1111, 798 cm¹; NMR (300 MHz, CDC1₃)A mixture of (S) - (-) - 1- (2-methanesulfonyloxyethyl) -N-methyl-isochroman-6-carboxamide (S) (T-2, 509 mg, 1.5 mmol), 4'-piperazinopropiophenone (393 mg) (1.8 mmol) and potassium carbonate (622 mg, 4.5 mmol) in acetonitrile was heated at 50 ° C overnight and then brought to reflux for an additional 5 hours. The reaction mixture is then cooled to 20-25 ° C and the residue is concentrated and partitioned between water and dichloromethane. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were washed once in water, once in brine, dried over magnesium sulfate, filtered and concentrated to give (S) - (-) - N-methyl-1- [2- [4- (4-Propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (IX), m.p. = 160-161 ° C; Rf = 0.20 (60% acetone / hexane); IR (slurry) 3274, 1669, 1640, 1607, 1543, 1522, 1415, 1407, 1315, 1233, 1200, 1156, 1142, 1111, 798 cm &^lt; -1 ^&gt;; NMR (300 MHz, CDCl ₃ )

7,87 (d, 2H, J = 9,0 Hz, aromatické), 7,55 (m, 2H, aromatické), 7,14 (d, 1H, J = 8,6 Hz, aromatické), 6,85 (d, 2H, J = 9,0 Hz, aromatické), 6,24 (široké d, 1H, J = 4,6 Hz, NH), 4,86 (široké d, 1H, J = 5,7 Hz, metín), 4,13 (m, 1H, OCH_2a), 3,76 (m, 1H, OCH_2b), 3,34 (t, 4H, J = 7,4 Hz, O=C-CH₂), 2,75-2,46 (m, 7H, Ph-NC(H₂)-CH_2s-NCH_2s a Ph-CH_2b), 2,14 (m, 1H, C(H)- CH_2a), 2,02 (m,, C(H> CH_2b), 1,19 (t, 3H, J = 7,4 Hz, C(H₂)-CH₃) δ; CMR (75 MHz,7.87 (d, 2H, J = 9.0 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.14 (d, 1H, J = 8.6 Hz, aromatic), 6.85 (d, 2H, J = 9.0 Hz, aromatic), 6.24 (broad d, 1H, J = 4.6 Hz, NH), 4.86 (broad d, 1H, J = 5.7 Hz, methine), 4.13 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3.34 (t, 4H, J = 7.4 Hz, O = C-CH ₂ ), 2.75-2.46 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} and Ph-CH _{2 b} ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2 02 (m, C (H > CH _2b )), 1.19 (t, 3H, J = 7.4 Hz, C (H ₂ ) -CH ₃ ) δ; CMR (75 MHz,

CDCb) 199,3, 168,0, 154,1, 141,5, 134,5, 132,7, 130,0, 127,7, 127,3, 125,0, 124,5, 113,5,(CDCl3) 199.3, 168.0, 154.1, 141.5, 134.5, 132.7, 130.0, 127.7, 127.3, 125.0, 124.5, 113.5,

74,4, 63,0, 54,5, 53,0, 47,4, 33,2, 31,2, 29,1, 26,8, 8,9 δ; MS (El, m/z) 435.74.4, 63.0, 54.5, 53.0, 47.4, 33.2, 31.2, 29.1, 26.8, 8.9 δ; MS (EI, m / z) 435.

Príklad 82 (S)(-)- l-[2-[4-(4-trifluóracetylfenyl)-1 -piperazinyl]etyl]-Nmetylizochróman-6-karboxamid (S)-(IX)Example 82 (S) (-) - 1- [2- [4- (4-Trifluoroacetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

- 106Postupom podľa príkladu 81, 5. kroku s drobnými obmenami vzniká z 4’piperazínotrifluórmetylfenonu (504 mg, 1,95 mmol) surový produkt. Ten se prečistí pomocou LC na 59 g (230-400) silikagélu za elúcie zmesou 50 % acetón/hexán a vznikne (S)-(-)-l-[2[4-(4-trifluoroacetylfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid (S)-(IX); Rf = 0,20 (60 % acetón/hexán).- 106 Following the procedure of Example 81, Step 5, with minor variations, 4 'piperazinotrifluoromethylphenone (504 mg, 1.95 mmol) yielded a crude product. This was purified by LC on 59 g (230-400) silica gel eluting with 50% acetone / hexane to give (S) - (-) - 1- [2- [4- (4-trifluoroacetylphenyl) -1-piperazinyl] ethyl 1-N-methylisochroman-6-carboxamide (S) - (IX); Rf = 0.20 (60% acetone / hexane).

Príklad 83 1-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-izochróman-6-yl] karbonyl]pyrolidín (IX)Example 83 1-1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-yl] -carbonyl] -pyrrolidine (IX)

Postupom podľa príkladu 30 s drobnými obmenami vzniká z pyrolidínu (1,26 ml, 15,0 mmol) surový produkt. Ten sa prečistí pomocou rýchlej chromatografie na 100 g silikagélu za použitia gradientu 5-10 % metanol v metylénchloride a hexáne a vznikne 1-1-(2-(4-(4metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6-yl]karbonyl]pyrolidín (IX), teplota topenia = 156,0-156,5 °C; Rf = 0,35 (10 % metanol v octane etylnatom); IR (suspenzia) 1615, 1609, 1563, 1514, 1441, 1254, 1234, 1154, 1106, 825 cm'¹; NMR (300 MHz, CDCb) 7,32 (d, 1H, J = 8,0 Hz, aromatický H). 7,29 (s, 1H, aromatický H), 7,12 (d, 1H, J = 7,9 Hz, aromatický H), 6,85 (q, 4H, J = 9,2 Hz, aromatické H), 4,85 (m z d, 1H, J = 5,8 Hz, PhC-H), 4,17-4,10 (m, 1H), 33,80-3,72 (m, 1H), 3,76 (s, 3H, PhOC-H₃), 3,64 (ζ 2H, J = 6,7 Hz, C(O)NC-H₂), 3,11 (t, 2H, J = 6,6 Hz, C(O)NC-H₂), 3,11 (t, 4H, J = 4,8 Hz, štyri z pip-H), 2,99 (m, 1H), 2,73 (m z d, 1H, J = 16,4 Hz), 2.66-2.49 (m’s, 6H), 2,15 (m, 1H, pipCH-H), 2,04 (m, 1H, pipCH-H), 1,99-1,85 (dva slabo sa prekrývajúce kvintety, 4H, J = 7,0 Hz, dva z C(O)NCH₂C-H₂) δ;Following the procedure of Example 30 with minor variations, the crude product was obtained from pyrrolidine (1.26 mL, 15.0 mmol). This was purified by flash chromatography on 100 g of silica gel using a 5-10% methanol in methylene chloride and hexane gradient to give 1-1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) isochroman-6-yl carbonyl] pyrrolidine (IX), m.p. = 156.0-156.5 ° C; R f = 0.35 (10% methanol in ethyl acetate); IR (suspension) 1615, 1609, 1563, 1514, 1441, 1254 1234, 1154, 1106, 825 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.32 (d, 1H, J = 8.0 Hz, aromatic H) 7.29 (s, 1H, aromatic H), 7.12 (d, 1H, J = 7.9 Hz, aromatic H), 6.85 (q, 4H, J = 9.2 Hz, aromatic H), 4.85 (wd, 1H, J = 5, 8 Hz, PhC-H), 4.17-4.10 (m, 1H), 33.80-3.72 (m, 1H), 3.76 (s, 3H, PhOC-H ₃ ), 3, 64 (ζ 2H, J = 6.7 Hz, C (O) NC H _2), 3.11 (t, 2H, J = 6.6 Hz, C (O) NC H _2), 3.11 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (wt, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pipCH-H), 2.04 (m, 1H, pipCH-H), 1.99-1.85 (two weak overlapping quintets, 4H, J = 7.0 Hz, two of C (O) NCH ₂ CH ₂ ) δ;

CMR (75 MHz, CDCb) 169,4, 153,6, 145,6, 139,7, 135,2, 134,0, 127,7, 124,7, 124,4, 118,0,CMR (75 MHz, CDCl 3) 169.4, 153.6, 145.6, 139.7, 135.2, 134.0, 127.7, 124.7, 124.4, 118.0,

114,3, 74,4, 62,9, 55,4, 54,6, 53,4, 50,5,49,5, 46,1, 33,0,28,9, 26,3,24,3 δ.114.3, 74.4, 62.9, 55.4, 54.6, 53.4, 50.5, 49.5, 46.1, 33.0, 28.9, 26.3, 24, 3 δ.

Príklad 84 (+/-)-1 -[2-(4-fenyl-1 -piperidinyl)etyl]izochróman-6-karboxamidExample 84 (+/-) -1- [2- (4-Phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide

1. krok(+/-)-2-(6-brómizochróman-l-yl)octová kyselinaStep 1 (+/-) -2- (6-bromoisochroman-1-yl) acetic acid

Zmes etyl (+/-)-2-(6-brómizochróman-l-yl)acetátu (HL, Príklad 1, 1. krok; 0,77 g, 2,58 mmol), hydroxidu sodného (2N, 1,9 ml) a etanolu (5 ml) sa 75 minút mieša za zníženého tlaku. K zvyšku sa pridá niekoľko ml vody a toľko kyseliny chlorovodíkovej (4N), aby pH zmesi bolo 2. Zmes sa extrahuje éterom a organické vrstvy sa vysušia pomocou síranu horečnatého, prefiltrujú, zahustia a vznikne (+/-)-2-(6-brómizochróman-l-yl)octová kyselina (IV), NMR (CDCb) 2,69-2,97,3,83, 4,16, 5,18, 6,94 a 7,32 δ.A mixture of ethyl (+/-) - 2- (6-bromoisochroman-1-yl) acetate (HL, Example 1, Step 1; 0.77 g, 2.58 mmol), sodium hydroxide (2N, 1.9 mL) ) and ethanol (5 mL) was stirred under reduced pressure for 75 minutes. To the residue were added a few ml of water and enough hydrochloric acid (4N) to bring the pH of the mixture to 2. The mixture was extracted with ether and the organic layers were dried over magnesium sulfate, filtered, concentrated to give (+/-) - 2- (6- bromoisochroman-1-yl) acetic acid (IV), NMR (CDCl 3) 2.69-2.97,3.83, 4.16, 5.18, 6.94 and 7.32 δ.

2. krok:Step 2:

(+/-)-2-(6-brómizochróman-1 -yl)etyl alkohol(+/-) - 2- (6-Bromoisochroman-1-yl) ethyl alcohol

- 107K (+/-)-2-(6-brómizochróman-l-yl)octovej kyseline (IV, 1. krok; 0,82 g, 3,0 mmol) v suchom THF (20 ml) sa pridá metylsulfid boru (0,86 g, 9,1 mmol). Po 2,5 hodinovom miešaní sa pridá metanol a zmes sa zahustí za zníženého tlaku. Opäť sa pridá metanol a zmes sa skoncentruje dvojnásobne. Zvyšok sa potom rozdelí na dichlórmetán a vodný uhličitan sodný a organické vrstvy sa vysušia síranom sodným a zahustia za vzniku (+/-)-2-(6brómizochróman-l-yl)etyl alkoholu (S-l), NMR (CDCb) 2,0, 2,2,2,64, 2,69, 3,02, 3,70-3,79, 3,82-3,86,4,15,4,92,7,28 0.- 107K (+/-) - 2- (6-Bromoisochroman-1-yl) acetic acid (IV, Step 1; 0.82 g, 3.0 mmol) in dry THF (20 mL) is added boron methyl sulfide (20 mL). 0.86 g, 9.1 mmol). After stirring for 2.5 hours, methanol was added and the mixture was concentrated under reduced pressure. Methanol was added again and the mixture was concentrated twice. The residue was then partitioned between dichloromethane and aqueous sodium carbonate and the organic layers were dried over sodium sulfate and concentrated to give (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (Sl), NMR (CDCl 3) 2.0, 2.2.2.64, 2.69, 3.02, 3.70-3.79, 3.82-3.86.4, 15.4, 92.7.28.

3. krok: (+/-)-[2-(6-brómizochróman-l-yl)etyl]-4-fenylpiperidínStep 3: (+/-) - [2- (6-Bromoisochroman-1-yl) ethyl] -4-phenylpiperidine

Metánsulfonyl chlorid (0.22 ml, 2,84 mmol) sa pridá do zmesi (+/-)-2-(6brómizochróman-l-yl)etyl alkoholu (S-l, 2. krok; 0,599 g, 2,33 mmol), 4dimetylaminopyridínu (0,016 g, 0,131 mmol), diizopropyletylamínu (0,49 ml, 2,81 mmol) a suchého THF (7,5 ml) v ľadovom kúpeli. Ľadový kúpeľ sa odstráni a zmes sa zahreje na 2025 °C. Hneď ako je tvorba metánsulfonátu kompletná (podľa TLC), pridá se etylénglykol (2,4 ml), diizopropyletylamín (1,0 ml, 5,7 mmol) a fenylpiperidín (0,452 g, 2,80 mmol) a zmes sa zahrieva pri 80 °C cez noc. Po schladení sa zmes naleje do vody a extrahuje dichlórmetánom. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku. Zvyšok sa analyzuje chromatografícky (silikagél; metanol/dichlórmetán, 2/98) za vzniku (+/)-l-[2-(6-brómizochróman-l-yl)etyl]-4-fenylpiperidínu (VI), NMR (CDCb) 1,85, 1,99-2,17, 2,46-2,60, 2,65-2,71,2,95, 3,09,3,74,4,10,4,77, 6,99 a 7,17-7,32 Ô.Methanesulfonyl chloride (0.22 mL, 2.84 mmol) was added to a mixture of (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (Sl, Step 2; 0.599 g, 2.33 mmol), 4-dimethylaminopyridine ( 0.016 g, 0.131 mmol), diisopropylethylamine (0.49 mL, 2.81 mmol) and dry THF (7.5 mL) in an ice bath. Remove the ice bath and warm to 2025 ° C. Once the methanesulfonate formation is complete (by TLC), ethylene glycol (2.4 mL), diisopropylethylamine (1.0 mL, 5.7 mmol) and phenylpiperidine (0.452 g, 2.80 mmol) are added and the mixture is heated at 80 ° C. ° C overnight. After cooling, the mixture was poured into water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperidine (VI), NMR (CDCl 3) 1.85, 1.99-2.17, 2.46-2.60, 2.65-2.71.2.95, 3.09.3.74.4, 10.47, 6, 99 and 7.17-7.32.

4. krok: (+/-)-l-[2-(4-fenyl-l-piperidinyl)etyl]izochróman-6karboxamidStep 4: (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide

Zmes (+/-)-l-[2-(6-brómizochróman-l-yl)etyl]-4-fenylpiperidínu (VI, 1. krok; 0,422 g, 1,05 mmol), DMF (2,7 ml), 1,1,1,3,3,3-hexametyldisilazánu (Aldrich; 1,6 ml, 7,58 mmol), diizopropyletylamínu (0,38 ml, 2,18 mmol), octanu paládnatého (0,012 g, 0,053 mmol) a 1,3bis(difenylfosfín)propánu (0,026 g, 0,064 mmol) sa šesťkrát odplyní za zníženého tlaku a zakaždým sa odstráni oxid uhoľnatý. Zmes sa zahreje na 90 °C cez noc, potom sa ochladená zmes naleje do kyseliny chlorovodíkovej (IN, 11 ml) a extrahuje éterom. pH vodnej vrstvy sa upraví na 12 za použitia vodného hydroxidu sodného. Vodná vrstva sa potom trikrát extrahuje octanom etylnatým a zmiešané organické vrstvy sa premyjú soľou, vysušia nad síranom horečnatým a zahustia za zníženého tlaku. Zvyšok sa analyzuje chromatografícky (silikagél; metanol/dichlórmetán, 2/98) za vzniku (+/-)-l-[2-(4-fenyl-l-piperidinyl)etyl]izochróman-6- 108 karboxamidu (VII), NMR (CDC1₃) 1,83, 1,99-2,22, 2,51-2,62, 2,74-2,79, 2,97-3,08, 3,78, 4,14,4,78, 5,63,6,05, 7,19-7,33 a 7,59 δ.A mixture of (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperidine (VI, Step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL) , 1,1,1,3,3,3-hexamethyldisilazane (Aldrich; 1.6 mL, 7.58 mmol), diisopropylethylamine (0.38 mL, 2.18 mmol), palladium acetate (0.012 g, 0.053 mmol) and 1,3bis (diphenylphosphine) propane (0.026 g, 0.064 mmol) was degassed six times under reduced pressure and carbon monoxide was removed each time. The mixture was heated at 90 ° C overnight, then the cooled mixture was poured into hydrochloric acid (1N, 11 mL) and extracted with ether. The pH of the aqueous layer was adjusted to 12 using aqueous sodium hydroxide. The aqueous layer was then extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) -1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6,108 carboxamide (VII), NMR (CDC1 ₃₎ 1.83, 1.99 to 2.22, 2.51-2.62, 2.74-2.79, 2.97-3.08, 3.78, 4,14,4, 78, 5,63,6,05, 7,19-7,33 and 7,59 δ.

Príklad 85 N-metyl-1 -[2-(4-fenyl-1 -piperidinyl)etyl]izochróman-6karboxamid, soľ kyseliny maleínovej .krok: (+/-)-N-bis(terc-butyloxykarbonyl)-1 -[2-(4-fenyl-1 piperidinyl)etyl]izochróman-6-karboxamidExample 85 N-Methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide, maleic acid salt Step: (+/-) - N-Bis (tert-butyloxycarbonyl) -1 - [ 2- (4-phenyl-1 piperidinyl) ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 3, 1. kroku s drobnými obmenami vzniká z (+/-)-1-[2-(4fenyl-l-piperidinyl)etyl]izochróman-6-karboxamidu (VII, Príklad 84, 0,231 g, 0,634 mmol) po chromatografii (silikagél; metanol/dichlórmetán, 2/98) (+/-)-N-bis(tertbutyloxykarbonyl)-1 -[2-(4-fenyl-1 -piperidinyl)etyl]izochróman-6-karboxamid (VIII), NMR (CDC1₃) 1,39, 1,84, 2,00-2,20, 2,44-2,63, 2,71-2,81, 2,94-3,15, 3,78, 4,14, 4,89, 7,20-7,30 aFollowing the procedure of Example 3, Step 1, with minor variations, (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide (VII, Example 84, 0.231 g, 0.634 mmol) was formed. after chromatography (silica gel; methanol / dichloromethane, 2/98) (+/-) - N-bis (tertbutyloxycarbonyl) -1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide (VIII) 1 H, NMR (CDCl ₃ ) 1.39, 1.84, 2.00-2.20, 2.44-2.63, 2.71-2.81, 2.94-3.15, 3.78, 4.14, 4.89, 7.20-7.30 and

7,60-7,65 δ.7.60-7.65 δ.

2.krok: N-metyl-1 -[2-(4-fenyl-1 -piperidinyl)etyl]izochróman-6karboxamid, soľ kyseliny maleínovejStep 2: N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide, maleic acid salt

Plyn metyl amínu kondenzuje pri reakcii za vysokého tlaku na sklenenej reakčnej nádobe chladenej na -78 °C (pod argónovou atmosférou), obsahujúcej zmes (+/-)-N-bis(tercbutyloxykarbonyl)-l-[2-(4-fenyl-l-piperidinyl)etyl]izochróman-6-karboxamidu (VIII, 1. krok, 0,2818 g, 0,499 mmol) a dichlórmetánu (4 ml). Po niekoľkých ml metylamínu skondenzovaného na kvapalinu sa reakčná nádoba uzavrie, zmes sa zahreje na 20-25 °C a mieša sa cez noc. Potom sa nádoba opäť ochladí na -78 °C a uzáver sa odstráni. Po opätovnom zahriatí na 20-25 °C sa zmes skoncentruje za zníženého tlaku a zvyšok sa zanalyzuje chromatograficky (silikagél; metanol/dichlórmetán, 3/97 až 5/95) za vzniku Nmetyl-1 -[2-(4-fenyl-1 -piperidinyl)etyl]izochróman-6-karboxamidu(IX). K N-metyl-1 -[2-(4fenyl-l-piperidinyl)etyl]izochróman-6-karboxamidu sa pridá kyselina maleínová (0,0360 g, 0,310 mmol) v zmesi dichlórmetán/metanol za vzniku N-metyl-l-[2-(4-fenyl-lpiperidinyl)etyl]izochróman-6-karboxamidu, soli kyseliny maleínovej (B-IX), NMR (CDC1₃) 1,84, 2,05-2,20, 2,54,2,66, 2,72-2,78, 3,01, 3,41, 3,49, 3,78, 4,13, 4,85, 6,12, 7,16-7,32 a 7,53 Ô.The methyl amine gas condenses in a high pressure reaction on a glass reaction vessel cooled to -78 ° C (under argon atmosphere) containing a mixture of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- (4-phenyl- 1-piperidinyl) ethyl] isochroman-6-carboxamide (VIII, Step 1, 0.2818 g, 0.499 mmol) and dichloromethane (4 mL). After a few ml of liquid-condensed methylamine, the reaction vessel was sealed, warmed to 20-25 ° C and stirred overnight. The vessel was then re-cooled to -78 ° C and the cap removed. After reheating to 20-25 ° C, the mixture was concentrated under reduced pressure and the residue was chromatographed (silica gel; methanol / dichloromethane, 3/97 to 5/95) to give N-methyl-1- [2- (4-phenyl-1)]. piperidinyl) ethyl] isochroman-6-carboxamide (IX). To N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide was added maleic acid (0.0360 g, 0.310 mmol) in dichloromethane / methanol to give N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide, maleic acid salt (B-IX), NMR (CDCl ₃ ) 1.84, 2.05-2.20, 2.54.2, 66, 2.72-2.78, 3.01, 3.41, 3.49, 3.78, 4.13, 4.85, 6.12, 7.16-7.32 and 7.53 Ô .

Príklad 86 (+/-)-1 -[2-[4-(2,4-dichlórfenyl-1 -piperazinyl)etyl]izochróman-6karboxamidExample 86 (+/-) - 1- [2- [4- (2,4-Dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide

-109 1. krok: l-(2,4-dichlorofenyl)piperazín-109 Step 1: 1- (2,4-dichlorophenyl) piperazine

Zmes l,3-dichlór-4-fluórbenzénu (Q-2) (4,21 g, 25,5 mmol), piperazínu (Q-l, 11,0 g, 128 mmol) a dimetylacetamidu (15 ml) sa zahreje na 165 °C na 6,8 hodín, potom sa ochladí a rozdelí na dichlórmetán a vodný uhličitan sodný. Organické vrstvy sa vysušia pomocou síranu sodného, zahustia za vysokého vákua a vznikne l-(2,4-dichlórfenyl)piperazín (Q-3), ktorý je dostatočne čistý pre použitie v druhom kroku bez ďalšieho prečistenia.A mixture of 1,3-dichloro-4-fluorobenzene (Q-2) (4.21 g, 25.5 mmol), piperazine (Q1, 11.0 g, 128 mmol) and dimethylacetamide (15 mL) was heated to 165 °. C for 6.8 hours, then cooled and partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate, concentrated under high vacuum to give 1- (2,4-dichlorophenyl) piperazine (Q-3) which was sufficiently pure for use in the second step without further purification.

2. krok: (+/-)-1 -[2-(6-brómizochróman-1 -y 1) et y 1 ] -4-(2,4-dichlórfenyl) piperazínStep 2: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine

Postupom podľa príkladu 84, 3. kroku s drobnými obmenami (+/-)-2-(6brómizochróman-l-yl) etylalkohol (S-l) (príklad 84, 2. krok; 0,60 g, 2,31 mmol), 4dimetylaminopyridín (0,018 g, 0,147 mmol), diizopropyletylenamín (0,49 ml, 2,81 mmol), metánsulfonyl chlorid (0,22 ml, 2,84 mmol) a suchý THF (7,5 ml) konvertujú na metánsulfonát (T-l). Metánsulfonát reaguje s diizopropyletylenamínom (1,0 ml, 5,7 mmol), l-(2,4-dichlórfenyl)piperazínom (Q-3, 1. krok; 0,65 g, 2,82 mmol) a etylénglykolom, po chromatografíi (silikagél; metanol/dichlórmetán, 2/98) vznikne (+/-)-1-(2-(6brómizochróman-l-yl)etyl]-4-(2,4-dichlórfenyl)piperazín (VI), NMR (CDCl₃)2,01, 2,10, 2,55-2,71, 2,95, 3,05, 3,74,4,11, 4,78, 6,96, 7,18 a 7,26-7,36 Ô.Following the procedure of Example 84, Step 3, with minor variations (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S1) (Example 84, Step 2; 0.60 g, 2.31 mmol), 4-dimethylaminopyridine (0.018 g, 0.147 mmol), diisopropylethyleneamine (0.49 mL, 2.81 mmol), methanesulfonyl chloride (0.22 mL, 2.84 mmol) and dry THF (7.5 mL) were converted to the methanesulfonate (T1). The methanesulfonate is reacted with diisopropylethyleneamine (1.0 mL, 5.7 mmol), 1- (2,4-dichlorophenyl) piperazine (Q-3, Step 1; 0.65 g, 2.82 mmol) and ethylene glycol, after chromatography (silica gel; methanol / dichloromethane, 2/98) yields (+/-) - 1- (2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine (VI), NMR (CDCl 3) ₃ ) 2.01, 2.10, 2.55-2.71, 2.95, 3.05, 3.74, 4.11, 4.78, 6.96, 7.18 and 7.26- 7.36

3. krok: (+/-)-1 -[2-[4-(2,4-dichlorofenyl-1 -piperaziny 1) etyl] izochróman6-karboxamidStep 3: (+/-) - 1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 84, 4. kroku s drobnými obmenami vzniká z (+/-)-1-(2-(6brómizochróman-l-yl)etyl]-4-(2,4-dichlórfenyl)piperazínu (VI, 1. krok; 0,373 g, 0,794 mmol) po chromatografii (silikagél; metanol/dichlórmetán, 2/98) 0,095g (+/-)-1-(2-(4-(2,4dichlórfenyl-l-piperazinyl)etyl]izochróman-6-karboxamid (VII), NMR (CDC1₃) 2,05, 2,15, 2,50-2,80, 3,05, 3,78, 4,15,4,78, 5,62, 6,04, 6,96, 7,19, 7,35 a 7,60 δ.Following the procedure of Example 84, Step 4, with minor variations, (+/-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (2,4-dichlorophenyl) piperazine (VI, Step 1) 0.373 g, 0.794 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 0.095 g (+/-) - 1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6; -carboxamide (VII), NMR (CDCl ₃ ) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.78, 5.62, 6.04 , 6.96, 7.19, 7.35 and 7.60 δ.

Príklad 87 (+/-)-N-metyl-l-[2-(4-(2,4-dichlorofenyl-l- piperazinyl)etyl]izochróman-6-karboxamidExample 87 (+/-) - N-Methyl-1- [2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide

1. krok: (+/-)-N-bis(terc-butyloxykarbonyl)-1-(2-(4-(2,4dichlórfenyl-1 -piperazinyl)etyl]izochróman-6-karboxamidStep 1: (+/-) - N-bis (tert-butyloxycarbonyl) -1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide

- 110 Postupom podľa príkladu 3, 1. kroku s drobnými obmenami vzniká z (+/-)-1-[2-(6brómizochróman-l-yl)etyl]-4-(2,4-dichlórfenyl) piperazínu (VI, príklad 3, 2. krok; 0,0854 g, 0,198 mmol), 4-dimetylaminopyridínu (0,0046 g, 0,0377 mmol) a di-terc-butyl dikarbonátu (0,0982 g, 0,450 mmol), po chromatografii (silikagél; metanol/dichlórmetán, 2/98) (+/-)-Nbis(terc.-butyloxykarbonyl)-l-[2-[4-(2,4-dichlórfenyl-l-piperazinyl)etyl]izochróman-6karboxamid (VHI), NMR (CDCb) 1,40, 2,05, 2,17, 2,51-2,79, 2,95-3,05, 3,78, 4,15, 4,89, 6,96, 7,19, 7,35 a 7,60-7,66 δ.110 Following the procedure of Example 3, Step 1, with minor variations, (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine (VI, Example) is formed. Step 3; 0.0854 g, 0.198 mmol), 4-dimethylaminopyridine (0.0046 g, 0.0377 mmol) and di-tert-butyl dicarbonate (0.0982 g, 0.450 mmol) after chromatography (silica gel) methanol / dichloromethane, 2/98) (+/-) - Nbis (tert-butyloxycarbonyl) -1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide (VHI) 1 H, NMR (CDCl 3) 1.40, 2.05, 2.17, 2.51-2.79, 2.95-3.05, 3.78, 4.15, 4.89, 6.96, 7 , 19, 7.35 and 7.60-7.66 δ.

2.krok:(+/-)-N-metyl-1 -[2-[4-(2,4-dichlórfenyl-1 piperazinyl)etyl]izochróman -6-karboxamidStep 2: (+/-) - N-Methyl-1- [2- [4- (2,4-dichlorophenyl-1 piperazinyl) ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 85, 2. kroku s drobnými obmenami vzniká z (+/-)-Nbis(terc-butyloxykarbonyl)-1 -[2-[4-(2,4-dichlórfenyl-1 -piperazinyl) etyl] izochróman-6karboxamidu (VHI, 1. krok; 0,104 g, 0,164 mmol) po chromatografii (silikagél; metanol/dichlórmetán, 1,5/98,5 až 3/97 až 5/95) tuhá fáza. Táto látka rekryštalizuje zo zmesi acetónitril/hexán za vzniku (+/-)-N-metyl-l-[2-[4-(2,4-dichlorofenyl-lpiperazinyl)etyl]izochróman-6-karboxamidu (IX), MS (m/z) = 447; IR (minerálny olej; najvyšší vrchol) 1637, 1478, 1572, 1558, 1450, 3289 a 1107 cm'¹; NMR (CDCb) 2,05, 2,16, 2,52-2,78, 3,03, 3,77, 4,13, 4,86, 6,10, 6,96, 7,17, 7,36 a 7,54 δ.Following the procedure of Example 85, Step 2, with minor variations, (+/-) - Nbis (tert-butyloxycarbonyl) -1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide is formed. (VHI, Step 1; 0.104 g, 0.164 mmol) after chromatography (silica gel; methanol / dichloromethane, 1.5 / 98.5 to 3/97 to 5/95) solid phase. This material was recrystallized from acetonitrile / hexane to give (+/-) - N-methyl-1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide (IX), MS ( m / z) = 447; IR (mineral oil; highest peak) 1637, 1478, 1572, 1558, 1450, 3289 and 1107 cm ^-1 ; NMR (CDCl 3) 2.05, 2.16, 2.52-2.78, 3.03, 3.77, 4.13, 4.86, 6.10, 6.96, 7.17, 7, 36 and 7.54 δ.

Príklad 88 l-[2-[4-(3-chlór-4-metoxyfenyl)-l- piperazinyl)etyl]izochróman-6-karboxamidExample 88 1- [2- [4- (3-Chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide

1. krok: l-(3-chlor-4-metoxyfenyl)piperazínStep 1: 1- (3-chloro-4-methoxyphenyl) piperazine

Zmes 3-chlór-p-anisidinu (R-2, 0,633 g, 4,00 mmol), bis(2-chlóretyl)amín hydrochloridu (0,860 g, 4,80 mmol), uhličitanu draselného (1,11 g, 8,00 mmol) a dimetylacetamidu (6 ml) sa mieša pri 100 °C počas 18 hodín a potom sa ochladí. Zmes sa rozdelí na dichlórmetán, vodu a vodný uhličitan sodný, organické vrstvy sa vysušia pomocou síranu sodného a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 8/92) a vznikne l-(3-chlór-4-metoxyfenyl)piperazín (R-3), NMR (CDCb) 3,05, 3,86, 6,80, 6,87 a 6,99 δ.A mixture of 3-chloro-p-anisidine (R-2, 0.633 g, 4.00 mmol), bis (2-chloroethyl) amine hydrochloride (0.860 g, 4.80 mmol), potassium carbonate (1.11 g, 8, 00 mmol) and dimethylacetamide (6 ml) were stirred at 100 ° C for 18 hours and then cooled. The mixture was partitioned between dichloromethane, water and aqueous sodium carbonate, the organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel; methanol / dichloromethane, 8/92) to give 1- (3-chloro-4-methoxyphenyl) piperazine (R-3), NMR (CDCl 3) 3.05, 3.86, 6.80 , 6.87 and 6.99 δ.

2. krok: (+/-)-1 -[2-(6-brómizochróman-1 -y 1)ety 1] -4-(3 -dichlór-4metoxyfenyl)piperazínStep 2: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-dichloro-4-methoxyphenyl) piperazine

-111Postupom podľa príkladu 84, 3. kroku , (+/-)-2-(6-brómizochróman-l-yl)etylalkohol (S-l, Príklad 84, 3. krok, 0,450 g, 1,75 mmol), 4-dimetylaminopyridín (0,012 g, 0,0990 mmol), diizopropyletylamín (0,32 ml, 1,84 mmol), metánsulfonylchlorid (0,14 ml, 1,81 mmol) a suchý THF (5,6 ml) konvertujú na metánsulfonát. Pre vytvorenie úplného metánsulfonátu sa pridá ešte diizopropyletylamín (0,18 ml, 1,03 mmol) a chlorid horečnatý (0,08 ml, 1,03 mmol). K metánsulfonátu sa potom pridá diizopropyletylamín (0,65 ml, 4,26 mmol), l-(3-chlór-4-metoxyfenyl)piperazín (1. krok; 0,398 g, 1,75 mmol) a etylénglykol (1,8 ml). Zmes sa potom mieša 3 hodiny pri 80 °C. Pridá sa ďalší l-(3-chlór-4metoxyfenyl)piperazín (0,0443 g, 0,195 mmol) a zmes sa zahrieva ďalšie 3 hodiny. Po schladení sa zmes rozdelí na dichlórmetán a vodný uhličitan sodný. Organické vrstvy sa vysušia pomocou síranu sodného a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 8/92) za vzniku (+/-)-l-[2-(6-brómizochróman-l-yl)etyl]4-(3-dichlór-4-metoxyfenyl)piperazínu (VI), NMR (CDCh) 2,01, 2,10, 2,52-2,71, 2,96,-111 Following the procedure of Example 84, Step 3, (+/-) -2- (6-bromoisochroman-1-yl) ethyl alcohol (S1, Example 84, Step 3, 0.450 g, 1.75 mmol), 4-dimethylaminopyridine (0.012 g, 0.090 mmol), diisopropylethylamine (0.32 mL, 1.84 mmol), methanesulfonyl chloride (0.14 mL, 1.81 mmol) and dry THF (5.6 mL) were converted to the methanesulfonate. Diisopropylethylamine (0.18 mL, 1.03 mmol) and magnesium chloride (0.08 mL, 1.03 mmol) were added to form the complete methanesulfonate. Diisopropylethylamine (0.65 mL, 4.26 mmol), 1- (3-chloro-4-methoxyphenyl) piperazine (Step 1; 0.398 g, 1.75 mmol) and ethylene glycol (1.8 mL) were then added to the methanesulfonate. ). The mixture was then stirred at 80 ° C for 3 hours. Additional 1- (3-chloro-4-methoxyphenyl) piperazine (0.0443 g, 0.195 mmol) was added and the mixture was heated for an additional 3 hours. After cooling, the mixture was partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 8/92) to give (+/-) -1- [2- (6-bromoisochroman-1-yl) ethyl] 4- (3-dichloro-4-methoxyphenyl) piperazine (VI), NMR (CDCl 3) 2.01, 2.10, 2.52-2.71, 2.96,

3,10, 3,75, 3,85,4,10, 4,78, 6,77-6,78, 6,98 a 7,29 δ.3.10, 3.75, 3.85, 4.10, 4.78, 6.77-6.78, 6.98 and 7.29 δ.

.krok: (+/-)-1 -[2-[4-(3-chlór-4-metoxyfeny 1)-1 piperazinyl)etyl]izochróman-6-karboxamid.step: (+/-) -1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide

Postupom podľa Príkladu 84, 4. kroku s drobnými obmenami vzniká z (+/-)-1-(2-(6brómizochróman-l-yl)etyl]-4-(3-dichlór-4-metoxyfenyl)piperazínu (VI, 2. krok; 0,420 g, 0,902 mmol), DMF (2,3 ml), 1,1,1,3,3,3-hexametyldisilazánu (1,4 ml, 6,64 mmol), diizopropyletylamínu (0,34 ml, 1,95 mmol), octanu paládnatého (0,0110 g, 0,049 mmol) a l,3-bis(difenylfosfíno)propánu (0,024 g, 0,0575 mmol) po chromatografii (silikagél; metanol/dichlórmetán, 2/98) l-[2-[4-(3-chloro-4-metoxyfenyl)-lpiperazinyl)etyl]izochróman-6-karboxamid (VII). NMR (CDCb) 2,05, 2,15, 2,53-2,64, 2,742,79,3,02, 3,11, 3,77, 3,84, 4,14, 4,87, 5,60, 6,04, 6,77-6,87, 6,98, 7,18 a 7,60 δ.Following the procedure of Example 84, Step 4, with minor variations, (+/-) -1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (3-dichloro-4-methoxyphenyl) piperazine (VI, 2) was formed. step; 0.420 g, 0.902 mmol), DMF (2.3 mL), 1,1,1,3,3,3-hexamethyldisilazane (1.4 mL, 6.64 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol), palladium acetate (0.0110 g, 0.049 mmol) and 1,3-bis (diphenylphosphino) propane (0.024 g, 0.0575 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII). NMR (CDCl 3) 2.05, 2.15, 2.53-2.64, 2,742.79.3.02, 3.11, 3.77, 3.84, 4.14, 4.87, 5, 60, 6.04, 6.77-6.87, 6.98, 7.18 and 7.60 δ.

Príklad 89 (+/-) 1 -[2-[4-(3-chlór-4-metoxyfenyl)-1 -piperaziny l)etyl]-Nmetylizochróman-6-karboxamidExample 89 (+/-) 1- [2- [4- (3-Chloro-4-methoxy-phenyl) -1-piperazinyl) -ethyl] -N-methyl-isochroman-6-carboxamide

1. krok: (+/-)-N-bis(terc-butyloxykarbonyl)-1 - [2-(4-(3 -chlór-4metoxyfeny 1)-1 -piperazinyl)etyl]-N-metylizochróman-6-kaiboxamid <.Step 1: (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- (4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] -N-methylisochroman-6-kaiboxamide <.

Postupom podľa príkladu 3, 1. kroku s drobnými obmenami vzniká z l-[2-[4-(3-chlór4-metoxyfenyl)-l-piperazinyl)etyl]izochróman-6-karboxamidu (VII, Príklad 3, 1. krok; 0,153 g, 0,355 mmol), 4-dietylaminopyridínu (0,0086 g, 0,0,704 mmol) a di-terc-butyldikabonátuFollowing the procedure of Example 3, Step 1, with minor variations, 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII, Example 3, Step 1) was formed; 0.153 g, 0.355 mmol), 4-diethylaminopyridine (0.0086 g, 0.0.704 mmol) and di-tert-butyl dicarbonate

- 112(0,186 g, 0,853 mmol) po chromatogarafii (silikagél; metanol/dichlórmetán, 2/98) (+/-)-Nbis(terc-butyloxykarbonyl)-1 [2-[4-(3-chlór-4-metoxyfenyl)-1 -piperazinyl)etyl]-Nmetylizochróman-6-karboxamid (VIII). NMR (CDCb) 1,39, 2,03, 2,14, 2,48-2,64, 2,73-2,80, 3,00, 3,11, 3,78, 3,85, 4,14,4,88, 6,80-6,88, 6,98, 7,20 a 7,60-7,65 δ.- 112 (0.186 g, 0.853 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) (+/-) - Nbis (tert-butyloxycarbonyl) -1 [2- [4- (3-chloro-4-methoxyphenyl) (1-piperazinyl) ethyl] -N-methylisochroman-6-carboxamide (VIII). NMR (CDCl 3) 1.39, 2.03, 2.14, 2.48-2.64, 2.73-2.80, 3.00, 3.11, 3.78, 3.85, 4, 14.4.88, 6.80-6.88, 6.98, 7.20 and 7.60-7.65 δ.

2. krok: (+/-)-N-metyl-1 -[2-[4-(3 -chlór-4-metoxyfenyl)-1 piperazinyl)etyl]izochróman-6-karboxamidStep 2: (+/-) - N-Methyl-1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 85, 2. kroku s drobnými obmenami vzniká z (+/-)-Nbis(terc-butyloxykarbonyl)-l-[2-[4-(3-chlór-4-metoxyfenyl)-l-piperazinyl) etyl]izochróman6-karboxamidu (Vín, 1. krok; 0,183 g, 0,290 mmol) po chromatografii (silikagél; metanol/dichlórmetán, 2/98) 0,118 g produktu. Produkt kryštalizuje zo zmesi octan etylnatý/metanol/hexán a potom zo zmesi octan metylnatý/dichlórmetán za vzniku (+/-)-1-(2[4-(3 -chlór-4-metoxyfeny 1)-1 -piperaziny l)etyl]-N-metylizochróman-6-karboxamid (IX), MS (m/z) 443; IR (minerálny olej, najvyššie vrcholy) 1508, 1642, 3266, 1112, 1548, 1274 a 949 cm’¹; NMR (CDCb) 2,09, 2,21, 2,58-2,77, 3,01, 3,15, 3,76, 3,85, 4,15, 4,88, 6,12, 6,77-6,88, 6,98, 7,17 a 7,54 δ.Following the procedure of Example 85, Step 2, with minor variations, (+/-) - Nbis (tert-butyloxycarbonyl) -1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] is obtained. 6-carboxamide isochroman (Vin, Step 1; 0.183 g, 0.290 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 0.118 g of product. The product crystallizes from ethyl acetate / methanol / hexane and then from methyl acetate / dichloromethane to give (+/-) - 1- (2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] 1-N-methylisochroman-6-carboxamide (IX), MS (m / z) 443; IR (mineral oil, highest peaks) 1508, 1642, 3266, 1112, 1548, 1274, and 949 cm ^-1 ; NMR (CDCl 3) 2.09, 2.21, 2.58-2.77, 3.01, 3.15, 3.76, 3.85, 4.15, 4.88, 6.12, 6, 77-6.88, 6.98, 7.17 and 7.54 δ.

Príklad 90 N-(2-hydroxyetyl)-1 -(2-[4-(4-metoxyfenyl)-1 - piperazinyl)etyl]N-metylizochróman-6-karboxamidExample 90 N- (2-hydroxyethyl) -1- (2- [4- (4-methoxyphenyl) -1-piperazinyl) ethyl] N-methylisochroman-6-carboxamide

1. krok: (+/-)-1 -2-(6-brómizochróman-1 -yl)acetyl-4-(4metoxyfenyl)piperazínStep 1: (+/-) -1- 2- (6-bromoisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine

Zmes (+/-)-2-(6-brómizochróman-l-yl)octovej kyseliny (IV, Príklad 84, 1. krok; 4,66 g, 0,0172 mol), dichlórmetánu (18 ml), DMF (18 ml), dietylcyanofosfonátu (3,4 ml, 0,022 mol), l-(4-metoxyfenyl)piperazín hydrochloridu (R-3) (Aldrich; 4,78 g, 0,0,21 mol) a trietylamínu (6,5 ml, 0,0,47 mol) sa mieša pri 20-25 °C počas 2,5 hodín. Do zmesi sa pridá nasýtený hydrogénuhličitan sodný (100 ml), zmes sa mieša ďalších 20 minút a nakoniec sa extrahuje dichlórmetánom. Organické vrstvy sa vysušia nad síranom horečnatým a zahustia za zníženého tlaku. Zvyšok sa dvakrát premyje hexánom (znehodnotiť) a opäť sa skoncentruje za zníženého tlaku. Potom sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 50/50) a vznikne (+/-)- l-2-(6-brómizochróman-l-yl)acetyl-4-(4-metoxyfenyl)piperazín (V), NMR (CDCb) 2,63-2,69,2,74-2,80,2,90-3,08, 3,59-3,96,4,11, 5,26, 6,87, 7,01, 7,31 δ.A mixture of (+/-) - 2- (6-bromoisochroman-1-yl) acetic acid (IV, Example 84, Step 1; 4.66 g, 0.0172 mol), dichloromethane (18 mL), DMF (18 ml), diethylcyanophosphonate (3.4 ml, 0.022 mol), 1- (4-methoxyphenyl) piperazine hydrochloride (R-3) (Aldrich; 4.78 g, 0.0.21 mol) and triethylamine (6.5 ml) (0.0.47 mol) was stirred at 20-25 ° C for 2.5 hours. Saturated sodium bicarbonate (100 mL) was added to the mixture, the mixture was stirred for an additional 20 minutes and finally extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed twice with hexane (discarded) and concentrated again under reduced pressure. It is then chromatographed (silica gel; ethyl acetate / hexane 50/50) to give (+/-) -1- 2- (6-bromoisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (V), NMR (CDCl 3) 2.63-2.69.2.74-2.80.2.90-3.08, 3.59-3.96.4.11, 5.26, 6.87, 7, 01, 7.31 δ.

-1132. krok:(+/-)-1 -[2-(6-brómizochróman-1 -yl)ety 1]-4metoxyfenylpiperazín-1132. step: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-methoxyphenylpiperazine

Postupom podľa príkladu 1, 4. kroku vzniká za použitia metylsulfidu bóranu (14 ml), miesto bóran-THF, a (+/-)-l-2-(6-brómizochróman-l -yl)acetyl-4-(4-metoxyfenyl)piperazínu (V, 1. krok; 5,83 g, 0,013 mol) 4,33 g (+/-)-l-[2-(6-brómizochróman-l-yl)etyl]-4metoxyfenylpiperazín (VI), NMR (CDC1₃) 2,00, 2,12, 2,46-2,71, 2,95, 3,10, 3,75, 4,11, 4,78, 6,87, 6,97 a 7,29 δ.Following the procedure of Example 1, Step 4, using borane methyl sulfide (14 mL) instead of borane-THF, and (+/-) -1- 2- (6-bromoisochroman-1-yl) acetyl-4- (4- methoxyphenyl) piperazine (V, Step 1; 5.83 g, 0.013 mol) 4.33 g (+/-) -1- [2- (6-bromoisochroman-1-yl) ethyl] -4-methoxyphenylpiperazine (VI), NMR (CDC1 ₃₎ 2.00, 2.12, 2.46 to 2.71, 2.95, 3.10, 3.75, 4.11, 4.78, 6.87, 6.97, and 7 , 29 δ.

3. krok: (+/-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl] etyl]izochróman-6karboxamidStep 3: (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 84, 4. kroku vzniká z (+/-)-l-[2-(6-brómizochróman-lyl)etyl]-4-(metoxyfenyl)piperazínu (VI, 2. krok; 4,29 g, 9,95 mmol)(+/-)-l-[2-[4-(4metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid (VII), NMR (CDC1₃) 2,06, 2,16, 2,54-2,79, 2,99, 3,11,4,15,4,87, 5,64, 6,06, 6,87, 7,19 a 7,59 δ.Following the procedure of Example 84, Step 4, starting from (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (methoxyphenyl) piperazine (VI, Step 2; 4.29 g, 9). , 95 mmol) (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), NMR (CDCl ₃ ) 2.06, 2.16, 2.54-2.79, 2.99, 3.11, 15.4, 4.87, 5.64, 6.06, 6.87, 7.19 and 7.59 δ.

4. krok: (+/-)-N-bis(terc-butyloxykarbonyl)-1 -[2-[4-(metoxyfenyl)-1 piperazinyl)etyl]izochróman-6-karboxamidStep 4: (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1 piperazinyl) ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 3, 1. kroku vzniká z (+/-)-l-[2-[4-(4-metoxyfenyI)-lpiperazinyl]etyl]izochróman-6-karboxamidu (VII, 3. krok; 1,97 g, 4,97 mmol), 4dimetylaminopyridínu (0,0816 g, 0,668 mmol) a di-terc-butyl-hydrogénuhličitanu (2,56 g, 0,0117 mol) (+/-)-N-bis(terc-butyloxykarbonyl)-1 -[2-[4-(metoxyfenyl)-1 perazinyl)etyl]izochróman-6-karboxamid (VIII), NMR (CDC1₃) 1,39, 2,03, 2,15, 2,53-2,78, 2,99,3,11, 3,77,4,13,4,88, 6,85, 7,21 a 7,63 δ.Following the procedure of Example 3, Step 1, (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII, Step 3; 1.97 g) was formed. (4.97 mmol), 4-dimethylaminopyridine (0.0816 g, 0.668 mmol) and di-tert-butyl bicarbonate (2.56 g, 0.0117 mol) (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-perazinyl) ethyl] isochroman-6-carboxamide (VIII), NMR (CDCl ₃ ) 1.39, 2.03, 2.15, 2.53-2, 78, 2,99,3,11, 3,77,4,13,4,88, 6,85, 7,21 and 7,63 δ.

.krok:N-(2-hydroxyetyl)-1 -[2-4-[4-(metoxyfenyl)-1 piperazinyl)etyl]izochrómanyl-6-karboxamidStep: N- (2-hydroxyethyl) -1- [2-4- [4- (methoxyphenyl) -1 piperazinyl) ethyl] isochromanyl-6-carboxamide

Zmes(+/-)-N-bis(terc-butyloxykarbonyl)-1 [2-[4-(metoxyfenyl)-1 -piperazinyl) etyl]izochróman-6-karboxamidu (Vín, 4. krok; 0,216 g, 0,362 mmol), dichlórmetánu (7 ml) a etanolamínu (0,2 ml, 3,31 mmol) sa mieša cez noc pri 20-25 °C. Zmes sa tak rozdelí na vodu a dichlórmetán. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán (4/96) za vzniku produktu, ktorý vykryštalizuje zo zmesi dichlórmetán/hexán/octan etylnatý(+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (Vin, step 4; 0.216 g, 0.362 mmol) ), dichloromethane (7 mL) and ethanolamine (0.2 mL, 3.31 mmol) were stirred at 20-25 ° C overnight. The mixture was then partitioned between water and dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane (4/96)) to give a product which crystallizes from dichloromethane / hexane / ethyl acetate.

- 114 za vzniku 0,090 g N-(2-hydroxyetyl)-l-[2-4-[4-(metoxyfenyl)-l-piperazinyl)etyl]izochróman6-karboxamidu (DQ, MS (m/z) 439; IR (minerálny olej) (najvyšší vrchol) 1514, 1631, 1554, 1031, 3293, 1249 a 1613 cm¹; NMR (CDClj) 2,05, 2,15, 2,51-2,78, 3,01, 3,11, 3,63, 3,77, 3,85,4,13, 4,86, 6,59, 6,87, 7,17 a 7,57 δ.114 to give 0.090 g of N- (2-hydroxyethyl) -1- [2-4- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (DQ, MS (m / z) 439; IR ( mineral oil) (highest peak) 1514, 1631, 1554, 1031, 3293, 1249 and 1613 cm ^-1 ; NMR (CDCl 3) 2.05, 2.15, 2.51-2.78, 3.01, 3.11 , 3.63, 3.77, 3.85, 13.13, 4.86, 6.59, 6.87, 7.17 and 7.57 δ.

Príklad 91 l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-(fenylmetoxy) izochróman-6-karboxamidExample 91 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N- (phenylmethoxy) isochroman-6-carboxamide

Zmes (+/-)-N-bis(terc-butyloxykarbonyl)-1 -[2-[4-(metoxyfenyl)-1 -piperazinyl) etyl]izochróman-6-karboxamidu (VIII, EXA ret 7,4. krok; 0,206 g, 0,345 mmol), THF (7 ml), O-benzylhydroxylamín hydrochloridu (0,0645 g, 0,4041 mmol) a diizopropyletylamínu (0,12 ml, 0,689 mmol) sa zahreje a varí 7 hodín. Zmes sa potom dva dni mieša pri 20-25 °C, ku koncu sa pridá ďalší O-benzylhydroxylamín hydrochlorid (0,323 g, 2,03 mmol) a diizopropyletylamín (0,35 ml, 2,01 mmol). Potom sa mieša cez noc pri 85-90 °C , THF sa odstráni zakoncentrovaním za zníženého tlaku a zvyšok sa rozdelí na dichlórmetán a vodu. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku za vzniku surového produktu. Táto látka sa analyzuje chromatograficky (silikagél; metanol dichlórmetán (4/96) za vzniku produktu, ktorý rekryštalizuje zo zmesi hexán/octan etylnatý/dichlórmetán/metanol a vznikne uvedená zlúčenina. MS (m/z) 501; NMR (CDCb) 2,03,2,12, 2,48-2,75, 3,10,3,77, 4,11,4,84, 5,05, 6,86,7,14 a 8,43 δ.A mixture of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VIII, EXA ret 7.4 step; 0.206 g, 0.345 mmol), THF (7 mL), O-benzylhydroxylamine hydrochloride (0.0645 g, 0.4041 mmol) and diisopropylethylamine (0.12 mL, 0.689 mmol) were heated and boiled for 7 hours. The mixture was then stirred at 20-25 ° C for two days, to the end was added additional O-benzylhydroxylamine hydrochloride (0.323 g, 2.03 mmol) and diisopropylethylamine (0.35 mL, 2.01 mmol). After stirring overnight at 85-90 ° C, THF was removed by concentration under reduced pressure and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. This material was chromatographed (silica gel; methanol dichloromethane (4/96)) to give the product, which was recrystallized from hexane / ethyl acetate / dichloromethane / methanol to give the title compound. MS (m / z) 501; NMR (CDCl 3) 2, 03,2,12, 2,48-2,75, 3,10,3,77, 4,11,4,84, 5,05, 6,86,7,14 and 8,43 δ.

Príklad 92 (+/-)-l-[l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-yl]-4-metylpiperazínExample 92 (+/-) -1- [1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-yl] -4-methylpiperazine

Zmes (+/-)-N-bis(terc-butyloxykarbonyl)-1 [2-[4-(4-metoxyfenyl)~ 1 -piperazinyl) etyl]izochróman-6-karboxamidu (VHI, EXA ret 7, 4. krok; 0,211 g, 0,355 mmol), THF (11 ml), diizopropyletylamínu (0,6 ml, 3,4 mmol) a 1-metylpiperazínu (0,4 ml, 3,6 mmol) sa mieša 2 dni pri 20-25 °C, THF sa potom odstráni za zníženého tlaku a zvyšok sa rozdelí na dichlórmetán a vodu. Zmiešané organické vrstvy sa vysušia nad síranom sodným, zahustia za zníženého tlaku a vznikne surový produkt. Táto látka sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 2 /98 až 4/96). Produkt sa vyzráža z octanu etylnatého a hexánu za vzniku uvedenej zlúčeniny a potom rekryštalizuje z octanu etylnatého, MS (m/z) 478; NMR (CDCb) 2,09,2,32,2,48-2,75,2,99, 3,11,3,47, 3,76,4,13,4,86,6,86 a 7,18 δ.(+/-) - N-Bis (tert-butyloxycarbonyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VHI, EXA ret 7, Step 4) 0.211 g, 0.355 mmol), THF (11 mL), diisopropylethylamine (0.6 mL, 3.4 mmol) and 1-methylpiperazine (0.4 mL, 3.6 mmol) were stirred at 20-25 ° for 2 days. The THF was then removed under reduced pressure and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to give the crude product. This material is analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98 to 4/96). The product is precipitated from ethyl acetate and hexane to give the title compound and then recrystallized from ethyl acetate, MS (m / z) 478; NMR (CDCl 3) 2.09, 32.2, 48-2.75, 29.99, 3.11, 4.47, 3.76, 13, 43, 86.6, 86 and 7, 18 δ.

Príklad 93 (+/-)-N-hydroxy-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamidExample 93 (+/-) - N-Hydroxy-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

-115Zmes (+/-)-N-bis(terc-butyloxy karbonyl)-1 -[2-[4-(metoxyfeny 1)-1 -piperazíny 1) etyl]izochróman-6-karboxamidu (Vili, EXA ret 7, 4. krok; 0,205 g, 0,344 mmol), dichlórmetánu (7 ml), N-metylhydroxylamínhydrochloridu (0,271 g, 3,25 mmol) a diizopropyletylamínu (0,60 ml, 3,44 mmol) sa mieša cez noc pri 20-25 °C. Zmes sa rozdelí na dichlórmetán a vodu. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku. Zvyšok sa analyzuje chromatograficky (silikagél; metanol dichlórmetán, 2/98 až 4/96) za vzniku žiadaného produktu, ktorý rekryštalizuje zo zmesi hexán/metanol/dichlórmetán/octan etylnatý a vznikne uvedená zlúčenina. MS (m/z) 425; NMR (CDClj) 2,05, 2,17, 2,54-2,77, 3,00, 3,11, 3,42, 3,77,4,13, 4,85, 6,87, 7,17 a 7,33 δ.-115Zmes (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (Vil, EXA ret 7, Step 4: 0.205 g, 0.344 mmol), dichloromethane (7 mL), N-methylhydroxylamine hydrochloride (0.271 g, 3.25 mmol) and diisopropylethylamine (0.60 mL, 3.44 mmol) were stirred overnight at 20-25 C. The mixture was partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol dichloromethane, 2/98 to 4/96) to give the desired product which is recrystallized from hexane / methanol / dichloromethane / ethyl acetate to give the title compound. MS (m / z) 425; NMR (CDCl 3) 2.05, 2.17, 2.54-2.77, 3.00, 3.11, 3.42, 3.77, 13.13, 4.85, 6.87, 7, 17 and 7.33 δ.

Príklad 94 (S)-(-)-1 -[2-[4-[4-(terc-butyloxykarbonyl)fenyl]-1 - piperazinyl]etyl]-N-metylizochróman-6-karboxamid (V-2)Example 94 (S) - (-) - 1- [2- [4- [4- (tert-Butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (V-2)

1. krok: 4-fluórbenzoová kyselina, terc-butyl esterStep 1: 4-fluorobenzoic acid, tert-butyl ester

K roztoku 4-fluórbenzoovej kyseliny (18,7 g, 0,133 mol) v DMF (140 ml) sa pridáTo a solution of 4-fluorobenzoic acid (18.7 g, 0.133 mol) in DMF (140 mL) was added

1,1-karbonyldiimidazol (21,6 g, 0,134 mol). Zmes sa zahrieva 1 hodinu pri 40 °C, potom sa ochladená zmes naleje do etyléteru (1300 ml) a premyje kyselinou chlorovodíkovou (10 %, 250 ml), následne vodou (250 ml) a potom uhličitanom draselným (10 %, 250 ml). Éterová vrstva sa vysuší nad síranom sodným a zahustí za zníženého tlaku. Zvyšok sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 10/90) za vzniku 4-fluórbenzoovej kyseliny, terc.-butylesteru (Q-2); MS (m/z) 196; NMR (CDCI3) 1,59, 7,07 a 7,99 δ.1,1-carbonyldiimidazole (21.6 g, 0.134 mol). The mixture was heated at 40 ° C for 1 h, then the cooled mixture was poured into ethyl ether (1300 mL) and washed with hydrochloric acid (10%, 250 mL) followed by water (250 mL) followed by potassium carbonate (10%, 250 mL). . The ether layer was dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90) to give 4-fluorobenzoic acid, tert-butyl ester (Q-2); MS (m / z) 196; NMR (CDCl 3) 1.59, 7.07 and 7.99 δ.

2. krok; 4-(piperazín-l-yl)benzoová kyselina, terc.-butyl esterStep 2; 4- (piperazin-1-yl) benzoic acid, tert-butyl ester

Zmes 4-fluórbenzoovej kyseliny, terc-butyl esteru (Q-2) (1. krok; 20,5 g, 0,105 mol), piperazínu (52,8 g, 0,613 mol) a dimetylacetamidu (121 ml) sa zahrieva na 150-155 °C počas 160 minút. Po ochladení sa tuhá časť odstráni filtráciou a premyje hexánom. Zmiešané filtráty sa vysušia nad síranom sodným, zahustia za vysokého vákua a zvyšok sa rozdelí medzi dichlórmetán a vodu. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku. Mierne vlhké tuhé častice od rozpúšťadla sa vyzrážajú v hexáne, tuhá fáza sa oddelí a premyje hexánom. Potom sa vysuší pri 20-25 °C za zníženého tlaku a vzniku t-butyl 4-(piperazín-l-yl)benzonátu. Ďalší produkt sa získá zahustením filtrátu a jeho chromatografiou (silikagél; metanol/dichlórmetán/hydroxid amonný, 3,5/96,5/0,5 až 7/93/0,5), vznikne 4-(piperazín-l-yl)benzoová kyselina, t-butylester (Q-3); MS (m/z) 262; NMR (CDClj) 1,57, 3,01, 3,25, 6,84 a 7,87 δ.A mixture of 4-fluorobenzoic acid, tert-butyl ester (Q-2) (Step 1; 20.5 g, 0.105 mol), piperazine (52.8 g, 0.613 mol) and dimethylacetamide (121 mL) is heated to 155 ° C for 160 minutes. After cooling, the solid was removed by filtration and washed with hexane. The combined filtrates were dried over sodium sulfate, concentrated under high vacuum, and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The slightly wet solids from the solvent precipitate in hexane, the solid phase is separated and washed with hexane. It is then dried at 20-25 ° C under reduced pressure to give t-butyl 4- (piperazin-1-yl) benzonate. Further product is obtained by concentration of the filtrate and its chromatography (silica gel; methanol / dichloromethane / ammonium hydroxide, 3.5 / 96.5 / 0.5 to 7/93 / 0.5) to give 4- (piperazin-1-yl) benzoic acid, t-butyl ester (Q-3); MS (m / z) 262; NMR (CDCl 3) 1.57, 3.01, 3.25, 6.84 and 7.87 δ.

- 1163 .krok: (S)-(-)-4-[4-[2-(6-brómizochróman-1 -y l)etyl ] -1 piperazinyl]benzoová kyselina, terc-butyl ester (V-l)- 1163.step: (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzoic acid, tert-butyl ester (V-1)

Postupom podľa príkladu 84, 3. kroku s drobnými obmenami vzniká z (S)-(-)-2-(6brómizochróman-l-yl)etyl alkoholu (S-l) (Príklad 6, 1. krok; 4,95 g, 0,0193 mol) a 4(piperazín-l-yl)benzoovej kyseliny, t-butylesteru (Q-3) (2. krok; 5,42 g, 0,0206 mol) uvedená zlúčenina, MS (m/z) 500; NMR (CDC1₃) 1,57, 2,02, 2,12, 2,50-2,70, 2,95, 3,32, 3,73, 4,10, 4,79,6,85, 6,97,7,29 a 7,86 δ.Following the procedure of Example 84, Step 3, with minor variations, (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S1) was formed (Example 6, Step 1; 4.95 g, 0, 0193 mol) and 4 (piperazin-1-yl) benzoic acid, t-butyl ester (Q-3) (Step 2; 5.42 g, 0.0206 mol) of the title compound, MS (m / z) 500; NMR (CDCl ₃ ) 1.57, 2.02, 2.12, 2.50-2.70, 2.95, 3.32, 3.73, 4.10, 4.79.6.85, 6 , 97.7.29 and 7.86 δ.

4. krok: (S)-(-)-l-[2-[4-[4-(terc-butyloxykarbonyl)fenyl]-lpiperazinyl]etyl]-N-metylizochróman-6-kaiboxamidStep 4: (S) - (-) - 1- [2- [4- [4- (tert-butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-kaiboxamide

K zmesi (S)-(-)-4-[4-[2-(6-brómizochróman-l-yl)etyl]- 1-piperazinyl] benzoovej kyseliny, terc-butyl esteru (V-l) (3. krok; 2,63 g, 5,25 mmol) v dimetylacetamidu (45 ml), ktorý bol odplynený, sa pod argónovou atmosférou pridá octan paládnatý (0,0616 g, 0,274 mmol), 1,3 bis(difenylfosfíno)propán (0,164 g, 0,396 mmol) a diizopropyletylamín (1,8 ml, 0,0103 mol). Zmes sa odplyní po druhý raz pod argónovou atmosférou. Potom sa zahreje na 60-65 °C za vybublania oxidu uhoľnatého. Za niekoľko minút začne zo zmesi vybublávať tiež metylamín. Po 6,5 hodinovom zahrievaní pri 60-65 °C sa zmes uchová cez noc v chladničke. Potom sa prefiltruje cez kremeninu a k filtrátu sa pridá ďalšia časť octanu paládnatého (0,065 g, 0,290 mmol), l,3-bis(difenylfosfino)propánu (0.162 g, 0,329 mmol) a diizopropyletylénamínu (1,8 ml, 0,0103 mol) a zahrieva 4 hodiny pri 60 °C s prídavkom oxidu uhoľnatého a plynov metylamínu, zmes sa potom ochladí a zahustí za zníženého tlaku. Zvyšok sa rozdeb na dichlórmetán a vodu. Zmiešané organické vrstvy sa premyjú vodou a soľankou, vysušia nad síranom sodným a zahustia za zníženého tlaku. Zvyšok látky sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 2/98 až 4/96). Zmiešané nečisté frakcie sa rechromatografujú (silikagél; metanol/dichlórmetán, 2/98) za vzniku uvedenej zlúčeniny, MS (m/z) 479; NMR (CDClj) 1,56, 2,03, 2,16, 2,48-2,79, 3,01, 3,32, 3,76, 4,14, 4,86, 6,08, 6,84, 7,15, 7,53 a 7,86 δ.To a mixture of (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzoic acid tert -butyl ester (VI) (Step 3; 2) , 63 g, 5.25 mmol) in dimethylacetamide (45 mL) which was degassed was added palladium acetate (0.0616 g, 0.274 mmol), 1.3 bis (diphenylphosphino) propane (0.164 g, 0.396) under argon. mmol) and diisopropylethylamine (1.8 mL, 0.0103 mol). The mixture was degassed a second time under argon. It is then heated to 60-65 ° C with carbon monoxide bubbling. After a few minutes, methylamine also starts to bubble out of the mixture. After heating at 60-65 ° C for 6.5 hours, the mixture was stored in a refrigerator overnight. Then filter through quartz and add a further portion of palladium acetate (0.065 g, 0.290 mmol), 1,3-bis (diphenylphosphino) propane (0.162 g, 0.329 mmol) and diisopropylethyleneaminine (1.8 mL, 0.0103 mol) to the filtrate. and heated at 60 ° C for 4 hours with the addition of carbon monoxide and methylamine gases, then the mixture is cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98 to 4/96). The combined impure fractions were rechromatographed (silica gel; methanol / dichloromethane, 2/98) to give the title compound, MS (m / z) 479; NMR (CDCl 3) 1.56, 2.03, 2.16, 2.48-2.79, 3.01, 3.32, 3.76, 4.14, 4.86, 6.08, 6, 84, 7.15, 7.53 and 7.86 δ.

Príklad 95 ester (+/-)-1 -[2-[4-[4-(metoxyfenyl)-1 -piperazinyljetyl]izochróman-6-ol metylkarbamátu (X-6)Example 95 1- (2-) 4- [4- [4- (Methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-6-ol methylcarbamate ester (+/-) - (X-6)

1. krok: etylester (+/-)-2-(6-hydroxyizochróman-l-yl)octovej kyseliny,Step 1: (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid ethyl ester

- 117 Do ľadom chladenej zmesi 3-hydroxyfenylalkoholu (X-l) (2,9 g, 21 mmol) a etyl 3,3dietoxypropionátu (4,75 g, 25 mmol) v nitrometáne (5 ml) sa pridá éterát fluoridu bóritého (3,44 ml). Po prídavku všetkých zložiek (asi za 5 minút) sa reakcia mieša počas ďalších 60 minút. Zmes sa tak rozdelí na dichlórmetán a vodný amónium chlorid. Organické vrstvy sa vysušia nad síranom sodným a zahustia. Zvyšok látky sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 10/90 až 30/70) za vzniku etylesteru (+/-)-2-(6hydroxyizochróman-l-yl)octovej kyseliny, (X-2), NMR (CDC1₃) 1,28, 2,6-3,0, 3,79, 4,09, 4,21,5,07, 5,19, 6,60 a 6,91 δ.- 117 Boron trifluoride etherate (3.44) is added to an ice-cooled mixture of 3-hydroxyphenyl alcohol (XL) (2.9 g, 21 mmol) and ethyl 3,3-diethoxypropionate (4.75 g, 25 mmol) in nitromethane (5 mL). ml). After addition of all components (about 5 minutes), the reaction is stirred for an additional 60 minutes. The mixture was then partitioned between dichloromethane and aqueous ammonium chloride. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90 to 30/70) to give (+/-) -2- (6-hydroxyisochroman-1-yl) acetic acid ethyl ester, (X-2), NMR (CDCl 3). ₃ ) 1.28, 2.6-3.0, 3.79, 4.09, 4.21.5.07, 5.19, 6.60 and 6.91 δ.

2. krok: (+/-)-2-(6-hydroxyizochróman-l-)octová kyselinaStep 2: (+/-) - 2- (6-hydroxyisochroman-1-) acetic acid

K etylesteru (6-hydroxyizochróman-l-)octovej kyseliny, (X-2) (1. krok; 2,38 g, 10,1 mmol) v etanole (10-15 ml) ša pridá hydroxid sodný (2N, 10 ml). Zmes sa cez noc mieša a etanol sa potom odstráni za zníženého tlaku. Výsledná vodná zmes sa potom zriedi niekoľkými ml soli a okyslí sa kyselinou chlorovodíkovou (3N), zmes sa extrahuje etylesterom ä zahustí. Pre odstránenie prebytočnej východiskovej látky sa zvyšok rozdelí na vodný uhličitan sodný a dichlórmetán. Organická fáza sa odstráni a vodná fáza sa okyslí koncentrovanou kyselinou chlorovodíkovou a potom extrahuje éterom. Éterová vrstva sa vysuší nad síranom horečnatým a zahustí. Koncentrát kryštalizuje zo zmesi THF/hexán/dichlórmetán za vzniku (+/-)-2-(6-hydroxyizochróman-l-yl)octovej kyseliny (X3), NMR (CDCb) 2,1-3,0, 3,81,4,15, 5,2, 6,59, 6,68 a 6,90 δ.To (6-hydroxyisochroman-1-) acetic acid ethyl ester, (X-2) (Step 1; 2.38 g, 10.1 mmol) in ethanol (10-15 mL) was added sodium hydroxide (2N, 10 mL). ). The mixture was stirred overnight and the ethanol was then removed under reduced pressure. The resulting aqueous mixture was then diluted with a few ml of salt and acidified with hydrochloric acid (3N), extracted with ethyl ester and concentrated. To remove excess starting material, the residue was partitioned between aqueous sodium carbonate and dichloromethane. The organic phase is removed and the aqueous phase is acidified with concentrated hydrochloric acid and then extracted with ether. The ether layer was dried over magnesium sulfate and concentrated. The concentrate crystallizes from THF / hexane / dichloromethane to give (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid (X3), NMR (CDCl 3) 2.1-3.0, 3.81, 4.15, 5.2, 6.59, 6.68 and 6.90.

.krok: (+/-)-1 -2-(6-hydroxyizochróman-1 -yl)acetyl-4-(4-metoxy fenyl)piperazínStep: (+/-) -1- 2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine

K zmesi (+/-)-2-(6-hydroxyizochróman-l-yl)octovej kyseliny (X-3) (2. krok; 0,361 g, 1,76 mmol), l-(4-metoxyfenyl)piperazín dihydrochloridu (0,458 g, 1,73 mmol), dichlórmetánu (5 ml) a DMF (0,5 ml) sa pridá trietylamín (0,80 ml, 5,72 mmol) a potom dietylkyanofosfonát (0,29 ml, 1,91 mmol). Po 50 minútovom miešaní sa pridá do zmesi voda a mieša sa 1 hodinu. Zmes sa potom extrahuje dichlórmetánom a organické vrstvy sa oddelia, zmiešajú a premyjú vodným uhličitanom sodným. Organické vrstvy sa vysušia síranom sodným a zahustia. Zvyšok kryštalizuje zo zmesi octan etylnatý-dichlórmetán-metanol za vzniku (+/-)-1 -2-(6-hydroxyizochróman-1 -yl)acetyl-4-(4-metoxyfeny l)piperazínu (X-4),To a mixture of (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid (X-3) (Step 2; 0.361 g, 1.76 mmol), 1- (4-methoxyphenyl) piperazine dihydrochloride ( 0.458 g, 1.73 mmol), dichloromethane (5 mL) and DMF (0.5 mL) were added triethylamine (0.80 mL, 5.72 mmol) followed by diethyl cyanophosphonate (0.29 mL, 1.91 mmol). . After stirring for 50 minutes, water was added to the mixture and stirred for 1 hour. The mixture is then extracted with dichloromethane and the organic layers are separated, mixed and washed with aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue crystallizes from ethyl acetate-dichloromethane-methanol to give (+/-) -1- 2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (X-4),

NMR (DMSO) 2,57-2,63,2,73-2,90, 2,97, 3,64, 3,69,3,95, 5,03,6,51, 6,57,6,8-7,0 a 9,27 δ.NMR (DMSO) 2.57-2.63.2.73-2.90, 2.97, 3.64, 3.69.3.95, 5.03.6.51, 6.57.6, 8-7.0 and 9.27 δ.

- 118 4. krok: (+/-)-l-[2-[4-[4-(metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-ol- 118 Step 4: (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol

Zmes(+/-)-1 -2-(6-hydroxyizochróman-1 -yl)acetyl-4-)4-metoxyfeny 1) piperazínu (X-4) (3. krok; 0,375 g, 0.,98 mmol), metylsulfidu bóranu (0,28 ml, 2,9 mmol) a THF (15 ml) sa mieša cez noc pri 20-25 °C a potom pri 80 °C dve hodiny. Po schladení zmes reaguje s metanolom a zahustí sa za zníženého tlaku. Prídavok metanolu a zahustenie sa opakuje ešte dvakrát a zvyšok sa potom mieša 3 hodiny v zmesi kyselina chlorovodíková/acetón (4N, 1/9, 5 ml). Acetón sa potom odstráni za zníženého tlaku a zvyšok sa rozdelí medzi dichlórmetán a vodný uhličitan sodný. Organické vrstvy sa vysušia síranom sodným a zahustia. Zvyšok kryštalizuje zo zmesi dichlórmetán/hexán za vzniku (+/-)-l-[2-[4-[4-(metoxyfenyl)-lpiperazinyl]etyl]-izochróman-6-ol (X-5), NMR (CDCb) 2,05, 2,21, 2,5-2,7, 2,94, 3,13, 3,70,A mixture of (+/-) -1- 2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (X-4) (Step 3; 0.375 g, 0. 98 mmol) , borane methyl sulfide (0.28 mL, 2.9 mmol) and THF (15 mL) were stirred overnight at 20-25 ° C and then at 80 ° C for two hours. After cooling, the mixture was treated with methanol and concentrated under reduced pressure. The addition of methanol and concentration was repeated two more times, and the residue was then stirred for 3 hours in hydrochloric acid / acetone (4N, 1/9, 5 mL). The acetone was then removed under reduced pressure and the residue was partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue was crystallized from dichloromethane / hexane to give (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-ol (X-5), NMR (CDCl 3) 2.05, 2.21, 2.5-2.7, 2.94, 3.13, 3.70,

3,76,4,10, 4,82, 6,41, 6,57 a 6,80-6,91 δ.3.76.4.10, 4.82, 6.41, 6.57 and 6.80-6.91 δ.

5. krok: ester (+/-)-l-[2-[4-[4-(metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-oI metylkarbamátu (X-6)Step 5: 1- (2-) 4- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol methylcarbamate (X-6) ester

K zmesi (S)-(-)-l-[2-[4-[4-(metoxyfenyl)-l-piperazinyl]etyl]-izochróman-6-ol (X-5) (4. krok; 0,064 g, 0,17 mmol) a DBU (0,032 g, 0,21 mmol) v dichlórmetáne (2 ml) sa pridá metylizokyanát (0,31 ml; 0,52 mmol). Po 1,5 hodinovom miešaní sa zmes rozdelí na dichlórmetán a zriedený hydroxíd sodný. Organické vrstvy sa vysušia síranom sodným a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán 2/98) za vzniku ester metylkarbamátu (+/-)- l-[2-[4-[4-(metoxyfenyl)-l-piperazinyl]etyl]-izochróman6-ol, (X-6), ktorý kryštalizuje zo zmesi éter/hexán. MS (m/z) pri 425; NMR (CDCb) 2,04,To (S) - (-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-ol (X-5) (Step 4; 0.064 g, 0.17 mmol) and DBU (0.032 g, 0.21 mmol) in dichloromethane (2 mL) were added methyl isocyanate (0.31 mL; 0.52 mmol). After stirring for 1.5 hours, the mixture was partitioned between dichloromethane and dilute sodium hydroxide. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-ol methylcarbamate ester, (X-6), which crystallizes from ether / hexane. MS (m / z) at 425; NMR (CDCl3) 2.04,

2,12,2,65,2,90, 3,11, 3,75, 3,77, 4,11,4,83, 4,98, 6,82-6,95 a 7,08 δ.2.12.2.65.2.90, 3.11, 3.75, 3.77, 4.11, 4.83, 4.98, 6.82-6.95 and 7.08 δ.

Príklad 96 (+/-)- l-[2-[4-[4-(aminokarbonyl)fenyl]-l- piperazinyljetyl]N-metylizochrómanyl-6-karboxamidExample 96 (+/-) -1- [2- [4- [4- (Aminocarbonyl) phenyl] -1-piperazinyl-ethyl] N-methylisochromanyl-6-carboxamide

1. krok: (+/-)-l-(2-chlóretyl)izochróman-6-olStep 1: (+/-) - 1- (2-chloroethyl) isochroman-6-ol

K zmesi 3-hydroxyfénylalkoholu (Y-l) (0,074 g, 0,537 mmol) a chloropropionaldehyd dietylacetálu (0,107 g, 0,64 mmol) v nitrometáne (0,5 ml) sa pridá éterát trifluoridu bóritého (0,007 ml, 0,054 mmol). Po 100 minútovom miešaní sa pridá voda a zmes sa rozdelí na dichlórmetán, vodu a soľ. Organické vrstvy sa vysušia síranom sodným a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 10/90) za vzniku (+/-)-1-(2-119chlóretyl)izochróman-6-ol (Y-2), obsahujúci malé množstvo (+/-)-1-(2-etoxyetyl)izochróman6-ol ako nečistoty. Látka sa používá bez ďalšieho prečistenia v 2. kroku, NMR (CDCb) 2,152,38, 2,62, 2,68,2,91, 3,6-3,8,4,10,4,89, 5,08, 6,59, 6,68 a 6,95 δ.To a mixture of 3-hydroxyphenyl alcohol (Y-1) (0.074 g, 0.537 mmol) and chloropropionaldehyde diethyl acetal (0.107 g, 0.64 mmol) in nitromethane (0.5 mL) was added boron trifluoride etherate (0.007 mL, 0.054 mmol). After stirring for 100 minutes, water was added and the mixture was partitioned between dichloromethane, water and salt. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90) to give (+/-) - 1- (2-119-chloroethyl) isochroman-6-ol (Y-2) containing a small amount of (+/-) - 1- (2-ethoxyethyl) isochroman-6-ol as an impurity. The material was used without further purification in Step 2, NMR (CDCl 3) 2.152.38, 2.62, 2.68.2.91, 3.6-3.8, 4, 4.89, 5.08 , 6.59, 6.68 and 6.95 δ.

2. krok: ester trifluórmetán (+/-)-l-(2-chlóretyl)izochróman-6-ol kyseliny sírovejStep 2: Sulfuric acid (+/-) - 1- (2-chloroethyl) isochroman-6-ol ester

K zmesi (+/-)-l-(2-chlóretyl)izochróman-6-ol (Y-2,1. krok; 0,079 g, 0,371 mmol), trietylamínu (0,0413 g, 0,408 mmol), 4-dimetylaminopyridínu (0,0009 g, 0,0074 mmol) a dichlórmetánu (1 ml) schladenej na -78 °C sa pridá anhydrid kyseliny trifluorometán sírovej (0,069 g, 0,408 mmol). Chladiaci kúpeľ sa odstráni a zmes sa pomaly zahreje na 20-25 °C. Po 60 minútovom miešaní sa zmes rozdelí na dichlórmetán a vodný amónium chlorid. Organické vrstvy sa vysušia síranom sodným a zahustia. Zvyšná látka sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 10/90) za vzniku (+/-)-l-(2-chlóretyl)izochróman-6-ol, estem trifluorometán sírovej kyseliny (Y-3), NMR (CDCb ) 2,24, 2,31, 2,73, 2,78, 3,00, 3,67, 3,80, 4,12,4,94 a 7,05-7,18 Ô.To a mixture of (+/-) - 1- (2-chloroethyl) isochroman-6-ol (Y-2.1 step; 0.079 g, 0.371 mmol), triethylamine (0.0413 g, 0.408 mmol), 4-dimethylaminopyridine (0.0009 g, 0.0074 mmol) and dichloromethane (1 mL) cooled to -78 ° C was added sulfuric trifluoromethane anhydride (0.069 g, 0.408 mmol). Remove the cooling bath and slowly warm to 20-25 ° C. After stirring for 60 minutes, the mixture was partitioned between dichloromethane and aqueous ammonium chloride. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90) to give (+/-) -1- (2-chloroethyl) isochroman-6-ol, sulfur trifluoromethane ester (Y-3), NMR (CDCl3). ) 2.24, 2.31, 2.73, 2.78, 3.00, 3.67, 3.80, 4.12, 4.94 and 7.05-7.18.

3. krok: (+/-)-l-(2-chlóretyl)-N-metylizochróman-6-karboxamidStep 3: (+/-) - 1- (2-Chloroethyl) -N-methylisochroman-6-carboxamide

Zmes ester trifluorometán (+/-)-l-(2-chlóretyl)izochróman-6-ol, sírovej kyseliny) Y-3,(+/-) - 1- (2-Chloroethyl) isochroman-6-ol sulfuric acid ester mixture Y-3,

2. krok; 0,291 g, 0,844 mmol) v DMF (1,5 ml) sa odplyní za zníženého tlaku počas piatich minút a potom sa pridá octan paládnatý (0,018 g, 0,084 mmol) a 1,3bis(difenylfosfíno)propán (0,52g, 0,127 mmol). Potom, čo sa pridá diizopropyletylamín (0,29 ml, 1,69 mmol), vyvrie oxid uhoľnatý. Potom začne vrieť metylamín a teplota kúpeľa sa zvýši na 50 °C. Počas 1 hodiny sa opäť pridá plynný metylamín a oxid uhoľnatý a ku koncu tiež octan paládia (0,010 g) a 1,3- bis(difenylfosfmo)propán (0,025 g). Po štyroch hodinách sa zmes ochladí a potom sa rozdelí na éter, vodný ammónium chlorid, amónium chlorid soľanku a soľanku. Organické vrstvy sa vysušia síranom horečnatým a zahustia. Zvyšná látka sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán 2/98) za vzniku (+/-)-1-(2chlóretyl)-N-metylizochróman-6-karboxamidu (Y-4), NMR (CDCb ) 2,20, 2,33, 2,73, 2,79, 2,97, 3,01, 3,65,4,12,4,95, 6,09, 7,14, 7,53 a 7,56 δ.Step 2; 0.291 g, 0.844 mmol) in DMF (1.5 mL) was degassed under reduced pressure for five minutes and then palladium acetate (0.018 g, 0.084 mmol) and 1,3bis (diphenylphosphino) propane (0.52g, 0.127 mmol) were added. ). After addition of diisopropylethylamine (0.29 mL, 1.69 mmol), carbon monoxide boils. Methylamine is then boiled and the bath temperature is raised to 50 ° C. Methylamine gas and carbon monoxide gas were added again over 1 hour, and palladium acetate (0.010 g) and 1,3-bis (diphenylphosphino) propane (0.025 g) were added at the end. After four hours the mixture was cooled and then partitioned between ether, aqueous ammonium chloride, ammonium chloride brine and brine. The organic layers were dried over magnesium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4), NMR (CDCl 3) 2.20, 2.33, 2.73, 2.79, 2.97, 3.01, 3.65.4, 12.4.95, 6.09, 7.14, 7.53 and 7.56 δ.

4. krok: (+/-)-l-[2-[4-[4-(aminokarbonyl)fenyl]-l-piperazinyl]etyl]-Nmetylizochrómanyl-6-karboxamidStep 4: (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide

Zmes (+/-)-1-(2-chlóretyl)-N-metylizochróman-6-karboxamidu (Y-4, 3. krok; 0,0937 g, 0,369 mmol), 4-(piperazín-l-yl)benzamidu (Q-3, príprava 1, 0,114 g, 0,554 mmol),A mixture of (+/-) -1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4, step 3; 0.0937 g, 0.369 mmol) of 4- (piperazin-1-yl) benzamide (Q-3, Preparation 1, 0.114 g, 0.554 mmol),

- 120diizopropyletylamínu (0,0716 g, 0,554 mmol), jodidu sodného (0,007 g) a etylénglykolu (2 ml) sa zahreje na 100 °C počas 6,5 hodiny a potom sa pridá ďalších 0,056 g 4-(piperazín-lyl)benzamidu. Po 24 hodinovom miešaní pri 100 °C sa zmes môže ochladiť (miešaním). Potom sa pridá voda a zmes sa extrahuje dichlórmetánom. Organické vrstvy sa zahustia a zmiešajú s lepkavým zvyškom (z ktorého sa odstránila dekantáciou vodná vrstva). Zmiešaný surový produkt sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán 6/94) za vzniku (+/-)-l-[2-[4-[4-(aminokarbonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochrómanyl-6karboxamidu (Y-5), NMR (CDC1₃ ) 2,05, 2,18, 2,5-2,8, 3,02, 3,32, 3,77, 4,13, 4,88, 4,8-6,0, 6,12,6,89, 7,16, 7,54 a 7,72 Ô.120diisopropylethylamine (0.0716 g, 0.554 mmol), sodium iodide (0.007 g) and ethylene glycol (2 mL) were heated to 100 ° C for 6.5 hours and then an additional 0.056 g of 4- (piperazin-1-yl) benzamide was added. . After stirring at 100 ° C for 24 hours, the mixture can be cooled (with stirring). Water is then added and the mixture is extracted with dichloromethane. The organic layers were concentrated and mixed with a sticky residue (from which the aqueous layer was removed by decantation). The mixed crude product is analyzed by chromatography (silica gel; methanol / dichloromethane 6/94) to give (+/-) -1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N- methyl isochromanyl-6-carboxamide (Y-5), NMR (CDCl ₃ ) 2.05, 2.18, 2.5-2.8, 3.02, 3.32, 3.77, 4.13, 4.88, 4.8-6.0, 6.12.6.89, 7.16, 7.54 and 7.72 Ô.

Príklad 97 (R)-(+)-l-[2-[4-[4-(aminokarbonyl)fenyl]-lpiperazinyl]etyl]-N-metylizochrómanyl-6-karboxamidExample 97 (R) - (+) - 1- [2- [4- [4- (Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide

Rozdelenie(+/-)-1 -[2-[4-[4-(aminokarbonyl)fenyl]-1 -piperazinyl]etyl]-N-metylizochrómanyl-6-karboxamidu (Y-5, príklad 96) na jeho plus a mínus enantioméry, čo sa dosiahne deliacou chromatografiou na kolóne naplnenej chirálnou fázou za použitia zmesi etylalkohol/izopropyl alkohol/trietylamín ako rozpúšťadla v pomere 4/1/0,08 (V/V) a detekcii pri 295 nM. Prvý vrchol patrí (S)-(+)-l-[2-[4-[4-(aminokarbonyl)fenyl]-l-piperaziny ljetyl]N-metylizochrómanyl-6-karboxamidu (Príklad 6), druhý predstavuje (R)-(+)-l-[2-[4-[4(aminokarbonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochromanyl-6-karboxamid (Y-5), MS (m/z) 422.Splitting (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Y-5, Example 96) into its plus a minus enantiomers, which was achieved by chiral phase column chromatography using 4: 1 / 0.08 (v / v) ethyl alcohol / isopropyl alcohol / triethylamine as the solvent and detection at 295 nM. The first peak is (S) - (+) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] N-methylisochromanyl-6-carboxamide (Example 6), the second representing (R) - (+) - 1- [2- [4- [4 (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Y-5), MS (m / z) 422.

Príklad 98 (S)-(-)-1 -[2-[4-[4-(kyanofenyl)-1 -piperazinyl]etyl]-Nmetylizochróman-6-karboxamidExample 98 (S) - (-) - 1- [2- [4- [4- (Cyanophenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

1. krok l-(4-kyanofenyl)piperazínStep 1 1- (4-cyanophenyl) piperazine

Zmes 4-fluórbenzamidu (Q-2, 0,700 g, 5,78 mmol), piperazínu (2,49 g, 28,9 mmol) a vody (5 ml) sa varí pri 100 °C počas 85 minút a potom sa ochladí. Pridá sa voda (5-10 ml) a zmes sa rozdelí na octan etylnatý, vodný uhličitan sodný a soľanka-vodný uhličitan sodný. Organické vrstvy sa vysušia síranom horečnarým a zahustia za vzniku l-(4kyanofenyl)piperazínu, NMR (CDC1₃ ) 1,77,3,02, 3,28, 6,85 a 7,49 δ.A mixture of 4-fluorobenzamide (Q-2, 0.700 g, 5.78 mmol), piperazine (2.49 g, 28.9 mmol) and water (5 mL) was boiled at 100 ° C for 85 minutes and then cooled. Water (5-10 ml) was added and the mixture was partitioned between ethyl acetate, aqueous sodium carbonate and brine-aqueous sodium carbonate. The organic layers were dried over magnesium sulfate and concentrated to give 1- (4-cyanophenyl) piperazine, NMR (CDCl ₃ ) 1.77, 3.02, 3.28, 6.85, and 7.49 δ.

2. krok: (S)-(-)-2-(6-brómizochróman-l-yl)etylalkoholStep 2: (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol

- 121 Bóran-metyl sulfid (3,1 ml, 33,2 mmol) sa pridá do zmesi (S)-(-)-2-(6brómizochróman-l-yl)octovej kyseliny (XI, Príklad 1, 2. krok; 3,0 g, 11 mmol) a THF (40 ml). Dôjde k exotermnej reakcii a vývinu plynu. Po 2,5 hodinovom miešaní sa pro potlačení prebytku bóran-metyl sulfid pomaly pridá metanol. Zmes sa potom zahustí za zníženého tlaku a ku zvyšku sa pridá metanol. Po celkovom prídavku metanolu sa zvyšok rozdelí na dichlórmetán, vodnú HCI a vodný hydrogénuhličitan sodný. Organické vrstvy sa vysušia nad síranom sodným a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán 4/96) za vzniku (S)-(-)-2-(6-brómizochróman-l-yl)etyl alkoholu (S-l), NMR (CDCb ) 2,03,2,20, 2,60-2,70, 3,02, 3,70-3,85, 4,16,4,93, 6,93 a 7,29 δ.- 121 Borane-methyl sulfide (3.1 mL, 33.2 mmol) was added to a mixture of (S) - (-) - 2- (6-bromoisochroman-1-yl) acetic acid (XI, Example 1, Step 2; 3.0 g, 11 mmol) and THF (40 mL). There will be an exothermic reaction and gas evolution. After stirring for 2.5 hours, methanol is slowly added to quench excess borane-methyl sulfide. The mixture was then concentrated under reduced pressure and methanol was added to the residue. After the total addition of methanol, the residue was partitioned between dichloromethane, aqueous HCl and aqueous sodium bicarbonate. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 4/96) to give (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (Sl), NMR (CDCl 3) 2.03.2 , 20, 2.60-2.70, 3.02, 3.70-3.85, 4.16.4.93, 6.93 and 7.29 δ.

3. krok: (S)-(-)-6-bróm-l-(2-brómetyl)izochrómanStep 3: (S) - (-) - 6-Bromo-1- (2-bromomethyl) isochroman

K zmesi trifenylfosfínu (9,60 g, 36,6 mmol), bromidu uhličitému (6,06 g, 18,3 mmol) a dichlórmetánu (25 ml, schladenom na asi 20 °C s ohľadom na exotermnú reakciu, ku ktorej dôjde po zmiešaní reagencií) sa počas 10 minút pridá (S)-(-)-2-(6-brómizochróman-l-yl)etyl alkohol (S-l, 2. krok; 2,35 g, 9,1 mmol) v dichlórmetáne (25 ml). Chladiaci kúpeľ sa odstráni, zmes sa mieša 40 minút a ku koncu sa po kvapkách pridá hexán, až je kvapalina číra. Zmes sa ponechá cez noc v chladničke a potom sa tuhé častice odstránia filtráciou. Tuhá fáza sa premyje éterom. Zmiešané filtráty sa zahustia a zvyšok sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán, 10/90) za vzniku (S)-(-)-6-bróm-l-(2-brómetyl)izochrómanu (T-l), NMR (CDCb ) 2,22-2,46,2,66, 2,71,2,94, 3,51,3,62,4,09,4,84,6,94 a 7,29 δ.To a mixture of triphenylphosphine (9.60 g, 36.6 mmol), carbon tetrabromide (6.06 g, 18.3 mmol) and dichloromethane (25 mL, cooled to about 20 ° C due to the exothermic reaction occurring after (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S1, step 2; 2.35 g, 9.1 mmol) in dichloromethane (25 mL) was added over 10 min. ml). Remove the cooling bath, stir the mixture for 40 minutes and add hexane dropwise to the end until the liquid becomes clear. The mixture was left in the refrigerator overnight and then the solids were removed by filtration. The solid phase is washed with ether. The combined filtrates were concentrated and the residue analyzed by chromatography (silica gel; ethyl acetate / hexane, 10/90) to give (S) - (-) - 6-bromo-1- (2-bromomethyl) isochroman (Tl), NMR (CDCl 3). ) 2,22-2,46,2,66, 2,71,2,94, 3,51,3,62,4,09,4,84,6,94 and 7,29 δ.

4. krok: (S)-(-)-4-[4-[2-(6-brómizochróman-l-yl)etyl]-lpiperazinyl]benzonitrilStep 4: (S) - (-) - 4- [4- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -1-piperazinyl] -benzonitrile

Zmes (S)-(-)-6-bróm-l-(2-brómetyl)izochrómanu (T-l, 3. krok, 1,53 g, 4,79 mmol), 1(4-kyanofenyl)piperazínu (Q-3, 1. krok, 0,987 g, 5,27 mmol), diizopropyletylamínu (0,681 g,A mixture of (S) - (-) - 6-bromo-1- (2-bromomethyl) isochroman (T1, Step 3, 1.53 g, 4.79 mmol), 1- (4-cyanophenyl) piperazine (Q-3) Step 1, 0.987 g, 5.27 mmol), diisopropylethylamine (0.681 g,

5,27 mmol) a etylénglykolu (5 ml) sa zahreje na 95 °C počas 4 hodín a potom cez noc na 2025 °C. Zmes sa rozdelí na dichlórmetán a vodu a organické vrstvy sa vysušia nad síranom sodným a zahustia. Zvyšná látka sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán 2/98) za vzniku (S)-(-)-4-[4-[2-(6-brómizochróman-l-yl)etyl]-lpiperazinyljbenzonitrilu (VI), NMR (CDC1₃) 2,00, 2,12, 2,48-2,72, 2,95, 3,33, 3,73, 4,10,5.27 mmol) and ethylene glycol (5 mL) were heated at 95 ° C for 4 hours and then overnight at 2025 ° C. The mixture was partitioned between dichloromethane and water and the organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzonitrile (VI), NMR (CDCl ₃ ) 2.00, 2.12, 2.48-2.72, 2.95, 3.33, 3.73, 4.10,

4,80, 6,85, 6,96, 7,38 a 7,49 δ.4.80, 6.85, 6.96, 7.38 and 7.49 δ.

krok: (S)-(-)-1 -[2-[4-(4-kyanofenyl)-1 -piperazinylyl)etyl]-Nmetylizochróman-6-karboxamidStep: (S) - (-) - 1- [2- [4- (4-Cyanophenyl) -1-piperazinylyl) ethyl] -N-methylisochroman-6-carboxamide

- 122 Podľa postupu príkladu 6, 4. kroku s drobnými obmenami (S)-(-)-4-[4-[2-(6brómizochróman-l-yl)etyl]-l-piperazinyl]benzonitril (VI, 4. krok, 1,61 g) sa premeňuje na (S)-(-)-l-[2-[4-(4-kyanofenyl)-l-piperazinylyl)etyl]-N-metylizochróman -6-karboxamid (IX), MS (m/z) pri 404; IR (minerálny olej, najvyšší vrchol) 1603, 1635, 2210, 1517 a 1553 cm'¹, NMR (CDCb ) 2,05, 2,18, 2,48-2,78, 3,00, 3,01, 3,34, 3,76, 4,12, 4,88, 6,08, 6,85, 7,15, 7,49,122 Following the procedure of Example 6, Step 4, with small variations of (S) - (-) - 4- [4- [2- (6-Bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzonitrile (VI, Step 4) , 1.61 g) was converted to (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1-piperazinylyl) ethyl] -N-methylisochroman-6-carboxamide (IX), MS (m / z) at 404; IR (mineral oil, highest peak) 1603, 1635, 2210, 1517 and 1553 cm ^-1 , NMR (CDCl 3) 2.05, 2.18, 2.48-2.78, 3.00, 3.01, 3 , 34, 3.76, 4.12, 4.88, 6.08, 6.85, 7.15, 7.49,

7,53 a 7,54 δ.7.53 and 7.54 δ.

Príklad 99 (S)-(-)-1 -[2-[4-(4-aminokarbonyl)fenylj-1 -piperazinylyl]étyl]-NmetyI-N-(fenylmetoxy)izochróman-6-karboxamidExample 99 (S) - (-) - 1- [2- [4- (4-Aminocarbonyl) phenyl] -1-piperazinylyl] ethyl] -Nmethyl-N- (phenylmethoxy) isochroman-6-carboxamide

1. krok: metylester (S)-(-)-l-[2-[(tetrahydropyrán-2-yI)oxy]izochróman-6karboxylovej kyselinyStep 1: (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] isochroman-6-carboxylic acid methyl ester

Zmes metylester (S)-(-)-l-(hydroxyetyl)izochróman-6-karboxylovej kyseliny, (S-2, Príklad 81, 2. krok, 1,36 g, 5,76 mmol), dichlórmetánu (10 ml), monohydrátu p-toluén sulfónovej kyseliny (0,0142 g, 0,0747 mmol) a 3,4-dihydro-2H-pyránu (1,6 ml, 0,0175 mol) sa mieša 45 minút pri 20-25 °C. Zmes sa potom rozdelí na vodný uhličitan sodný a dichlórmetán. Zmiešané organické vrstvy sa vysušia nad síranom sodným a zahustia za zníženého tlaku. Zvyšok sa analyzuje chromatograficky (silikagél; octan etylnatý/hexán 5/95 až 15/85) za vzniku metylesteru (S)-(-)-l-[2-[(tetrahydropyrán-2-yl)oxy]izochróman-6karboxylovej kyseliny, (W-2), NMR (CDC1₃ ) 1,53, 1,69-1,80, 2,04, 2,23, 2,73-2,79, 2,98, 3,51-4,13, 4,60,4,92, 7,18, 7,80 a 7,83 δ.A mixture of (S) - (-) - 1- (hydroxyethyl) isochroman-6-carboxylic acid methyl ester, (S-2, Example 81, Step 2, 1.36 g, 5.76 mmol), dichloromethane (10 mL) , p-toluene sulfonic acid monohydrate (0.0142 g, 0.0747 mmol) and 3,4-dihydro-2H-pyran (1.6 mL, 0.0175 mol) were stirred at 20-25 ° C for 45 min. The mixture was then partitioned between aqueous sodium carbonate and dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; ethyl acetate / hexane 5/95 to 15/85) to give (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] isochroman-6-carboxylic acid methyl ester, (W-2), NMR (CDCl ₃ ) 1.53, 1.69-1.80, 2.04, 2.23, 2.73-2.79, 2.98, 3.51-4.13 , 4.60.4.92, 7.18, 7.80 and 7.83 δ.

2. krok: (S)-(-)-l-[2-[(tetrahydropyrán-2-yl)oxy]etyl]izochróman-6karboxylová kyselinaStep 2: (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid

Zmes, metylesteru (S)-(-)-1 -[2-[(tetrahydropyrán-2-yl)oxy]etyl]izochróman-6karboxylovej kyseliny (W-2, 1. krok, 1,55 g, 4,85 mmol), etanolu (12 ml), hydroxidu sodného (2N, 3,6 ml, 7,2 mmol) a vody (1 ml) sa mieša 6,5 hodiny pri 20-25 °C. Potom sa zmes nechá cez noc v chladničke. Potom sa mieša ďalšie 2,5 hodiny pri 20-25 °C a zahustí za zníženého tlaku. Pridá sa voda (6 ml) a zvyšná zmes sa ochladí v ľadovom kúpeli. pH zmesi sa upraví na pH 5 pomocou kyseliny chlorovodíkovej (4 N) a výsledná suspenzia sa extrahuje dichlórmetánom. Zmiešané organické vrstvy sa vysušia nad síranom horečnatým, zahustia za zníženého tlaku a vznikne (S)-(-)-l-[2-[(tetrahydropyrán-2-yl)oxy]etyl]izochróman-6karboxylová kyselina (W-3), MS (m/z) = 306; NMR (CDCb ) 1,55, 1,70-1,84, 2,08, 2,26, 2,77-2,82, 3,01, 3,54, 3,66-4,17,4,63, 4,96, 7,23 a 7,88 δ.(S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid methyl ester (W-2, Step 1, 1.55 g, 4.85 mmol) ), ethanol (12 mL), sodium hydroxide (2N, 3.6 mL, 7.2 mmol) and water (1 mL) were stirred at 20-25 ° C for 6.5 hours. The mixture was then left in the refrigerator overnight. It is then stirred for an additional 2.5 hours at 20-25 ° C and concentrated under reduced pressure. Water (6 mL) was added and the remaining mixture was cooled in an ice bath. The pH of the mixture was adjusted to pH 5 with 4 N hydrochloric acid, and the resulting suspension was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated under reduced pressure to give (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid (W-3), MS (m / z) = 306; NMR (CDCl 3) 1.55, 1.70-1.84, 2.08, 2.26, 2.77-2.82, 3.01, 3.54, 3.66-4.17.4, 63, 4.96, 7.23 and 7.88 δ.

- 123 3. krok: (S)-(-)-N-metyl-N-(fenylmetoxy)-1 -[2-[(tetrahydropyrán-2yl)oxy]etyl]izochróman-6-karboxamid l,ľ-karbonyldiimidazol (0,064 g, 0,39 mmol) sa pridá k (S)-(-)-l-[2[(tetrahydropyrán-2-yl)oxy]etyl]izochróman-6-karboxylovej kyseline (W-3, 2. krok; 0,109 g, 0,356 mmol) a THF (2 ml). Zmes sa mieša 2 hodiny pri 20-25 °C a potom sa pridá N-metyl, O-benzylhydroxylamín (Tetrahedron Letters, 30, 31-34 (1989), 0,054 g, 0,39 mmol), zmes sa mieša cez noc pri 60 °C. Potom sa zahustí a zvyšok sa rozdelí na dichlórmetán, vodu a vodný uhličitan sodný. Organické vrstvy sa vysušia nad síranom sodným a zahustia. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 2/98) za vzniku (S)-(-)-Nmetyl-N-(fenylmetoxy) -1 -[2-[(tetrahydropyrán-2-yl)oxy]etyl] izochróman-6-karboxamidu (W-4), NMR (CDCb) 1,50-1,65-,1,70-1,90, 2,07, 2,28, 2,67, 2,72, 2,92, 3,36, 3,53, 3,66-3,95,- 123 Step 3: (S) - (-) - N-Methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxamide 1,1'-carbonyldiimidazole ( 0.064 g, 0.39 mmol) is added to (S) - (-) - 1- [2 [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid (W-3, Step 2; 0.109 g, 0.356 mmol) and THF (2 mL). The mixture was stirred at 20-25 ° C for 2 hours and then N-methyl, O-benzylhydroxylamine (Tetrahedron Letters, 30, 31-34 (1989), 0.054 g, 0.39 mmol) was added, the mixture was stirred overnight at 60 ° C. It is then concentrated and the residue is partitioned between dichloromethane, water and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxamide (W-4), NMR (CDCl 3) 1.50-1.65-, 1.70-1.90, 2.07, 2.28, 2.67, 2.72, 2, 92, 3.36, 3.53, 3.66-3.95,

4,02,4,11, 4,62,4,69, 4,92, 7,07-7,14, 7,30, 7,36 a 7,45 δ.4.02, 4.11, 4.62, 4.69, 4.92, 7.07-7.14, 7.30, 7.36 and 7.45 δ.

4. krok:(S)-(-)-l-(2-hydroxyetyl)-N-metyl-N-fenylmetoxy izochróman-6karboxamid (S)-(-)-N-metyl-N-(fenylmetoxy)-l-[2-[(tetrahydropyrán-2-yl)oxy]etyl]izochróman-6karboxamid (W-4, 3. krok; 0,131 g, 0,308 mmol) sa mieša 2 hodiny pri 20-25 °C v zmesi kyselina octová/THF/voda (4/2/1, 5 ml), potom 4 hodiny pri 60 °C, a nechá sa cez noc v chladničke. Rozpúšťadlá sa odstránia a výsledná zmes sa rozdelí na dichlórmetán a vodu. Organické vrstvy sa vysušia nad síranom sodným, zahustia a zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 2/98) za vzniku surového produktu. NMR tejto látky indikuje navyše prítomnosť tetrahydropyranyl (THP)-like protónov, metanolu (2 ml) a hydrátu p-toluénsulfónovej kyseliny (0,006 g). Zmes sa mieša cez noc. Rozpúšťadlo sa odstráni za zníženého tlaku a zvyšok sa rozdelí medzi dichlórmetán a vodný uhličitan sodný. Organické vrstvy sa vysušia síranom sodným a zahustia za vzniku (S)-(-)-l-(2-hydroxyetyl)N-metyl-N-fenylmetoxy-izochróman-6-karboxamidu (W-5), NMR (CDCb ) 2,07, 2,25, 2,64, 2,70, 3,02, 3,38,3,77, 3,86,4,19, 5,01, 7,06, 7,08, 7,31, 7,37 a 7,46 δ.Step 4: (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxy isochroman-6-carboxamide (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxamide (W-4, step 3; 0.131 g, 0.308 mmol) was stirred for 2 hours at 20-25 ° C in acetic acid / THF / water (4/2/1, 5 mL), then 4 hours at 60 ° C, and left in the refrigerator overnight. The solvents were removed and the resulting mixture was partitioned between dichloromethane and water. The organic layers were dried over sodium sulfate, concentrated and the residue analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98) to give the crude product. NMR of this material additionally indicated the presence of tetrahydropyranyl (THP) -like protons, methanol (2 mL) and p-toluenesulfonic acid hydrate (0.006 g). The mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and aqueous sodium carbonate. The organic layers are dried over sodium sulfate and concentrated to give (S) - (-) - 1- (2-hydroxyethyl) N-methyl-N-phenylmethoxy-isochroman-6-carboxamide (W-5), NMR (CDCl 3) 2, 07, 2.25, 2.64, 2.70, 3.02, 3.38.3.77, 3.86.4.19, 5.01, 7.06, 7.08, 7.31, 7.37 and 7.46 δ.

5.krok:(S)-(-)-l-[2-[4-(4-ammokarbonyl)fenyl]-l-piperazinylyl)etyl]-Nmetyl-N-(fenylmetoxy)izochróman-6-karboxamid5th step: (S) - (-) - l- [2- [4- (4-aminocarbonyl) phenyl]-piperazinylyl) ethyl] -N-methyl-N- (phenylmethoxy) isochroman-6-carboxamide

K ľadom chladenej zmesi (S)-(-)-l-(2-hydroxyetyl)-N-metyl-Nfenylmetoxyizochróman-6-karboxamidu (W-5, 4. krok; 0,099 g, 0,290 mmol), diizopropyletylamínu (0,049 g, 0,377 mmol) a 4-dimetylaminopyridínu (0,0018 g, 0,014To an ice-cooled mixture of (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxyisochroman-6-carboxamide (W-5, step 4; 0.099 g, 0.290 mmol), diisopropylethylamine (0.049 g, 0.377 mmol) and 4-dimethylaminopyridine (0.0018 g, 0.014

-124mmol) v dichlórmetáne (1,5 ml) sa pridá metánsulfonyl chlorid (0,043 g, 0,377 mmol) v dichlórmetáne (0,5 ml). Zmes sa mieša 1,5 hodiny a potom sa rozdelí na dichlórmetán a vodný uhličitan sodný. Organické vrstvy sa vysušia nad síranom sodným a zahustia za vzniku metánsuifonátu (W-6). K metánsulfonátu sa pridá 4-(piperazín-l-yl)benzamid) (Q-3, príprava 1, 0,071 g, 0,348 mmol), diizopropyletylamín (0,075 ml, 0,580 mmol) a etylénglykol (0,3 ml). K zmytiu stien nádoby sa použije malé mnnožstvo dichlórmetánu. Zmes sa zahrieva 2,5 hodiny pri 85 °C a potom sa ochladí. Pridá sa voda a zmes sa nechá cez noc v chladničke. Supematant sa potom dekantuje a zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 4/96 až 6/94) za vzniku uvedenej zlúčeniny, NMR (CDC1₃ ) 2,08, 2,20,Methanesulfonyl chloride (0.043 g, 0.377 mmol) in dichloromethane (0.5 mL) was added. The mixture was stirred for 1.5 hours and then partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated to give the methanesulfonate (W-6). To the methanesulfonate was added 4- (piperazin-1-yl) benzamide) (Q-3, Preparation 1, 0.071 g, 0.348 mmol), diisopropylethylamine (0.075 mL, 0.580 mmol) and ethylene glycol (0.3 mL). A small amount of dichloromethane was used to wash the vessel walls. The mixture was heated at 85 ° C for 2.5 hours and then cooled. Water was added and the mixture left in the refrigerator overnight. The supernatant is then decanted and the residue analyzed by chromatography (silica gel; methanol / dichloromethane, 4/96 to 6/94) to give the title compound, NMR (CDCl ₃ ) 2.08, 2.20,

2,5-2,75,2,95, 3,34, 3,37, 3,76,4,13,4,69, 4,89, 5,7,6,89, 7,10, 7,29, 7,47 a 7,72 δ.2.5-2.75.25.95, 3.34, 3.37, 3.76.4, 13.4, 69, 4.89, 5.7, 6.89, 7.10, 7, 29, 7.47 and 7.72 δ.

Príklad 100 (S)-(-)-1 -[2-[4-[4-aminokarbony l)feny 1]-1 -piperazinyl] etyl]-Nhydroxy-N-metylizochróman-6-karboxamidExample 100 (S) - (-) - 1- [2- [4- [4-Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

Zmes (S)-(-)-1 -[2-[4-[4-aminokarbonyl)fenyl]-1 -piperazinyl)etyl]-N-metyl-N(fenylmetoxy)izochróman-6-karboxamidu (W-7, Príklad 99, 5. krok, 0,067 G, 0,13 mmol), paládia na aktívnom uhlí (10 %, 0,0068 G) a metanole (3 ml) sa mieša 1 hodinu pod zhruba jednou atmosférou vodíka a potom sa pridá octan etylnatý (1 ml) na rozpustenie zvyšnej východiskovej látky. Miešanie pokračuje vo vodíkovej atmosfére a po 8 hodinách sa pridá ďalšie paládium na aktívnom uhlí (10 %, 0,0068 g). Až sa spotrebuje východisková látka (asi za 28 hodín), paládium na aktívnom uhlí sa odfiltruje a filtrát sa zahustí. Zvyšok sa analyzuje chromatograficky (silikagél; metanol/dichlórmetán, 8/92 až 15/85) za vzniku (S)-(-)-l-[2-[4[4-aminokarbonyl)fenyl]-l-piperazinyl)etyl]-N-hydroxy-N-metylizochróman-6-karboxamidu (W-8), NMR (DMSO) 1,89, 2,10, 2,45, 2,65-2,70, 2,85, 3,21, 3,66, 4,02, 4,77, 6,90, 6,98, 7,22,7,36, 7,41, 7,68, 7,72 a 9,94 δ.(S) - (-) - 1- [2- [4- [4-Aminocarbonyl) phenyl] -1-piperazinyl) ethyl] -N-methyl-N (phenylmethoxy) isochroman-6-carboxamide (W-7, Example 99, Step 5, 0.067 G, 0.13 mmol), palladium on charcoal (10%, 0.0068 G) and methanol (3 mL) were stirred for 1 hour under about one atmosphere of hydrogen, then ethyl acetate was added. (1 mL) to dissolve the remaining starting material. Stirring was continued under a hydrogen atmosphere and after 8 hours additional palladium on charcoal (10%, 0.0068 g) was added. When the starting material is consumed (about 28 hours), the palladium on charcoal is filtered off and the filtrate is concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 8/92 to 15/85) to give (S) - (-) - 1- [2- [4- [4-aminocarbonyl) phenyl] -1-piperazinyl) ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide (W-8), NMR (DMSO) 1.89, 2.10, 2.45, 2.65-2.70, 2.85, 3.21, 3.66, 4.02, 4.77, 6.90, 6.98, 7.22.7.36, 7.41, 7.68, 7.72 and 9.94 δ.

Príklad 101 (+/-)-l-[2-[4-(4-aminosulfonyl)fenyl]-l-piperazinyl]etyl]-Nmetylizochróman-6-karboxamidExample 101 (+/-) -1- [2- [4- (4-Aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

1. krok: 4-(piperazín-1 -yl)benzénsulfónamidStep 1: 4- (piperazin-1-yl) benzenesulfonamide

Zmes 4-fluórbenzénsulfónamidu (Q-2, 6,95 g) a piperazínu (17,1 g) vo vode (30 ml) sa zahrieva pri 100 °C cez noc. Tuhá časť sa nazhromaždí, premyje vodou a toluénom, vysuší za zníženého tlaku a vznikne 4-(piperazín-l-yl)benzénsulfónamid (Q-3), MS (m/z) = 241; IR (minerálny olej, najvyšší vrchol) 1160, 822, 1332, 608, 1593 a 1137 cm'¹; NMR (DMSO)A mixture of 4-fluorobenzenesulfonamide (Q-2, 6.95 g) and piperazine (17.1 g) in water (30 mL) was heated at 100 ° C overnight. The solid was collected, washed with water and toluene, dried under reduced pressure to give 4- (piperazin-1-yl) benzenesulfonamide (Q-3), MS (m / z) = 241; IR (mineral oil, highest peak) 1160, 822, 1332, 608, 1593 and 1137 cm ^-1 ; NMR (DMSO)

2,81, 3,17, 2,3, 7,01, 7,07 a 7,61 δ.2.81, 3.17, 2.3, 7.01, 7.07 and 7.61 δ.

- 125 2.krok:(+/-)-l-[2-[4-[4-aminosulfonyl)fenyl]-l-piperazinyl]etyl]-Nmetyl izochróman-6-karboxamid- 125 Step 2: (+/-) - 1- [2- [4- [4-Aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide

Postupom podľa príkladu 96 s drobnými obmenami vzniká z (+/-)-l-(2-chlóretyl)-Nmetylizochróman-6-karboxamidu (Y-4, Príklad 96, 3. krok, 0,024 g, 0,095 mmol) a 4(piperazinyl-l-yl)benzénsulfónamidu (Q-3, 1. krok) (+/-)-l-[2-[4-[4-aminosulfonyl)fenyl]-lpiperazinyl]etyl]-N-metylizochróman-6-karboxamid (Y-5), NMR (CDCb) 2,05,2,19,2,5-2,8, 3,01, 3,34, 3,42,3,79, 4,16,4,89, 6,41, 6,91, 7,18, 7,54, 7,56 a 7,76 δ.Following the procedure of Example 96 with minor variations, it was formed from (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4, Example 96, Step 3, 0.024 g, 0.095 mmol) and 4 (piperazinyl). (1-yl) benzenesulfonamide (Q-3, Step 1) (+/-) -1- [2- [4- [4-aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide ( Y-5), NMR (CDCl 3) 2.05.2, 19.2.5-2.8, 3.01, 3.34, 3.42.3.79, 4.16.4.89, 6 , 41, 6.91, 7.18, 7.54, 7.56 and 7.76 δ.

Postupom podľa príkladu 94 (schéma 5) s drobnými obmenami sa za použitia reakčných látok pre odpovedajúce produkty získajú zlúčeniny príkladu 102-104:Following the procedure of Example 94 (Scheme 5) with slight variations, using the reagents for the corresponding products, the compounds of Example 102-104 were obtained:

Príklad 102 (S)-(-)-N-metyl-l-[2-[4-[4-(metylaminokarbonyl)fenyl]-lpiperaziny 1] etyl] izochróman-6-karboxamidExample 102 (S) - (-) - N-Methyl-1- [2- [4- [4- (methylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Príklad 103 (S)-(-)-N-metyl-1 -[2-[4-[4-(dimetylaminokarbonyl)fenyl]-1 piperazinyl]etyl]izochróman-6-karboxamidExample 103 (S) - (-) - N-Methyl-1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Príklad 104 (S)-(-)-N-metyl-1 -[2-[4-[4-(n-propylaminokarbonyl)fenyl]-1 piperazinyl]etyl]izochróman-6-karboxamidExample 104 (S) - (-) - N-Methyl-1- [2- [4- [4- (n-propylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Postupom podľa príkladu 100 s drobnými obmenami sa za použitia reakčných látok pre odpovedajúce produkty získajú zlúčeniny príkladu 105-108:Following the procedure of Example 100 with minor variations, using the reagents for the corresponding products, the compounds of Example 105-108 were obtained:

Príklad 105 (S)-(-)-N-hydroxy-N-metyl-l-[2-[4-[4-(trifluórmetyl)fenyl]-lpiperazinyl]etyl]izochróman-6-karboxamidExample 105 (S) - (-) - N-Hydroxy-N-methyl-1- [2- [4- [4- (trifluoromethyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Príklad 106 (S)-(-)-1 -[2-[4-[4-(chlórfenyl)-1 -piperazinyl]etyl]-N-hydroxy-Nmetylizochróman-6-karboxamidExample 106 (S) - (-) - 1- [2- [4- [4- (Chlorophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

Príklad 107 (S)-(-)-1 -[2-[4-(4-kyanofenyl)-1 -piperazinyl]etyl]-N-hydroxy-Nmetylizochróman-6-karboxamidExample 107 (S) - (-) - 1- [2- [4- (4-Cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

Príklad 108 (S)-(-)-N-hydroxy-N-metyl-1 -[2-[4-[4-(metylkarbonyl)fenyl]-1 piperazinyl]etyl]izochróman-6-karboxamidExample 108 (S) - (-) - N-Hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Postupom podľa schémy DD s drobnými obmenami, známymi odborníkom v tomto obore, vznikajú zlúčeniny príkladu 109 až 120.Following the procedure of Scheme DD with minor variations known to those skilled in the art, the compounds of Example 109-120 are formed.

- 126 Príklad 109 (S)-4-[4-[2-[6-( 1,2,4-triazol-3 -yl)-izochróman-1 -yljetyl]-1 piperazinyljbenzamid- 126 Example 109 (S) -4- [4- [2- [6- (1,2,4-Triazol-3-yl) -isochroman-1-yl-ethyl] -1-piperazinyl] -benzamide

Príklad 110 (S)-4-[4-[2-[6-(2-metyl-l,2,4-triazol-3-yl)-izochróman-ly 1] etyl]-1 -piperazinyljbenzamidExample 110 (S) -4- [4- [2- [6- (2-Methyl-1,2,4-triazol-3-yl) -isochroman-1-yl] -ethyl] -1-piperazinyl] -benzamide

Príklad 111 (S)-4-[4-[2-[6-( 1,2,4-oxadiazol-5-yl)-izochróman-1 -yljetyl]-1 piperazinyl]benzamidExample 111 (S) -4- [4- [2- [6- (1,2,4-Oxadiazol-5-yl) -isochroman-1-yl-ethyl] -1-piperazinyl] -benzamide

Príklad 112 (S)-l-[2-[6-(l,2,4-triazol-3-yl)izochróman-l-yl]etyl-4-[4trifluórmetylfenylj-piperazínExample 112 (S) -1- [2- [6- (1,2,4-Triazol-3-yl) isochroman-1-yl] ethyl-4- [4-trifluoromethylphenyl] piperazine

Príklad 113 (S)-1 -[2-[6-(2-metyl-1,2,4-triazol-3 -yl)-izochróman-1 -y 1] ety 1-4-[4trifluórmetylfenylj-piperazínExample 113 (S) -1- [2- [6- (2-Methyl-1,2,4-triazol-3-yl) -isochroman-1-yl] -ethyl-4- [4-trifluoromethyl-phenyl] -piperazine

Príklad 114 Example 114 (S)-1 - [2-[6-( 1,2,4-oxadiazol-5 -yl)izochróman-1 -yl Jetyl-4-[4- trifluórmetylfenylj-piperazín (S) -1- [2- [6- (1,2,4-Oxadiazol-5-yl) isochroman-1-yl] Jyl-4- [4- trifluórmetylfenylj-piperazine Príklad 115 Example 115 (S)-1 -[4-acetylfeny 1] -4-[2-[6-( 1,2,4-triazol-3-yl)izochróman-1 - yl]etyl]piperazín (S) -1- [4-acetylphenyl] -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1- yl] ethyl] piperazine Príklad 116 Example 116 (S)- l-[4-acetylfenyl]-4-[2-[6-(2-metyl-1,2,4-triazol-3 y l)izochróman-1 -yl]etyl]piperazín (S) -1- [4-acetylphenyl] -4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine Príklad 117 Example 117 (S)-l-[4-acetylfenyl]-4-[2-[6-(l,2,4-oxadiazol-5-yl)izochróman-l- (S) -l- [4-acetylphenyl] -4- [2- [6- (l, 2,4-oxadiazol-5-yl) isochroman-l- Príklad 118 Example 118 yljetylj-piperazín 3 -[ 1 -[2-[4-(4-aminokarbonylfenyl)piperazín-1 yl]etyl]izochróman-6-yl]-N,N-dimetylakrylamid yljetylj-piperazine 3- [1- [2- [4- (4-Aminocarbonylphenyl) piperazin-1-yl] ethyl] isochroman-6-yl] -N, N-dimethylacrylamide Príklad 119 Example 119 3 -[ 1 -[2-[4-(4-trifluórmetylfeny l)piperazín-1 -y 1] etyl] izochróman-6-y 1] N,N-dimetylakrylamid 3- [1- [2- [4- (4-Trifluoromethylphenyl) piperazin-1-yl] ethyl] isochroman-6-yl] N, N-dimethylacrylamide

Príklad 120 3-[l-[2-(4-(4-acetylfenyl)piperazín-l -yl]-etyl]izochróman-6-yl]N,N-dimetylakrylamidExample 120 3- [1- [2- (4- (4-Acetyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] - N, N-dimethylacrylamide

- 127 Vzorce k príkladom (E-č.)- 127 Formulas to Examples (E-No)

OCH,OCH

E-2E-2

E-1E-1

(-)-enantiomér(-) - enantiomer

OABOUT

12801280

Ε-14Ε-14

HgC.HgCl.

'N'N

II

HH

OABOUT

-129--129-

ΟΟ

IIII

-130--130-

- 131 -- 131 -

OCH,OCH

OABOUT

IiIi

OCH,OCH

OABOUT

IIII

• 2 HCI E-39• 2 HCl E-39

-132 --132 -

(-)-enantiomer E-45The (-) enantiomer E-45

E-47E-47

-1330 tl-1330 tl

E-53E-53

E-55E-55

-134HaC-134HaC

E-63E-63

-135--135-

- 1360- 1360

ΟΟ

Ε-79Ε-79

13701370

E-87 _CfE-87 _C f

- 138 -- 138 -

Ε-93Ε-93

ΟΟ

Ε-95Ε-95

-139--139-

-140SCHÉMA A-140SCHEMISTRY A

(VI)(VI)

- 141 SCHÉMA B- 141 SCHEME B

-142SCHÉMAC-142SCHÉMAC

CO₂C₂H₅ CO ₂ C ₂ H ₅

(Π)(Π)

-143(CHglgSi^-143 (CHglgSi ^

Ol-3 θ!Ol-3 θ!

SCHÉMA DSCHEME D

- 144SCHÉMA E- 144SCHEME E

(VI) (XVI) (XVII) (XVIII) (XIX)(VI) (XVI) (XVIII) (XVIII) (XIX)

- 145 SCHÉMA F- 145 SCHEME F

(xxní)(Xxní)

-146SCHÉMAG-146SCHÉMAG

(X) (XXIV) (XXV)(X) (XXIV)

-147SCHÉMAH \ z-147SCHEMMA \ z

(VI) (XXVI) (XXVII) “l-3(VI) (XXVI) (XXVII) '1-3

(XXVIH)(XXVIh)

IIII

Qm —sQm —s

.0.0

Ri r₂ (XXIX)Ri r ₂ (XXIX)

-148SCHÉMAI-148SCHÉMAI

BrCHj (CH_a)_n BrCH 3 (CH _a ) _n

(XXXII)(XXXII)

(ΧΧΧΙΠ) (XXXIV)(XXXIV)

- 149 BrCH₂(CHj)_n 149 BrCH ₂ (CH 3) _n

OABOUT

11' d-SCHjÍCHjJh11 'd-SCHjÍCHjJh

II oII o

SCHÉMA JSCHEME J

NaO — s— CH^oyNaO-s-CH3Oy

(XXXII) (XXXV)(XXXV) XXXV

O,.·ABOUT,.·

Γ~\ f=\^R' (XXXVI) ^R ~ XXX (XXXVI)

IIII

N- SCHjlCHy,, / IIN- SCH 2 CH 3, II

Q, *1-2Q, * 1-2

O·^-© (XXXVn)About · ^- © (XXXVn)

-150 SCHÉMA K-150 SCHEME K

«1 «a (XXXII)«1« and (XXXII)

(XXXVHI)(XXXVHI)

-151 SCHÉMA L o-151 SCHEME L o

-152SCHÉMAM-152SCHÉMAM

(XXXII)(XXXII)

(XLI)(XLI)

(XLH)(XLH)

(XLIU)(Xliu)

-153SCHÉMA N-153SCHÉMA N

(XLI) (XLH) (XLHI)(XLI) (XLH)

++

(XLIV)(XLIV)

- 154 SCHÉMA Ο- 154 SCHEME Ο

(0-3)(0-3)

- 155 SCHÉMA P- 155 SCHEME P

(P-l)(P-L)

(P-2)(P-2)

-156SCHÉMAQ-156SCHÉMAQ

Γ~\Γ ~ \

H—N N-H \_/ (Q-l)H — N N-H / _ / (Q-1)

(Q-2)(Q-2)

(Q-3)(Q-3)

- 157- 157

SCHÉMA RSCHEME R

(R-l) (R-2)(R-2) (R-2)

(R-3)(R-3)

-158SCHÉMA S-158SCHÉMA S

(S-l)(S-I)

OH (S-2) (S-3)OH (S-2)

-159SCHÉMAT-159SCHÉMAT

(IX)(IX)

-160SCHÉMAU-160SCHÉMAU

OH (U-l) (U-2) (U-3) (U-4) (U-5)OH (U-1) (U-2) (U-3) (U-4)

- 161 SCHÉMA VSCHEME V

(V-l) (C,-Cg) alkyl (C^alkyKV-Ž) (V-3) (V-4)(V-1) (C 1 -C 8) alkyl (C 1-6 alkyl-N-Z) (V-3) (V-4)

- 162 SCHÉMA W- 162 SCHEME W

(W-l) (W-2) (W-3) (W-4) (W-5) (W-6) (W-7) (W-8)(W-1) (W-2) (W-3) (W-4) (W-5) (W-6) (W-7) (W-8)

-163SCHÉMAX-163SCHÉMAX

(X-l) (X-2) (X-3) (X-4) (X-5)(X-1) (X-2) (X-3) (X-4) (X-5)

oabout

(X-6) ^Ql-2(X-6) ^Q1-2

- 164$chéma z- $ 164 chemistry z

<2-6)<2-6)

-165SCHÉMAAA-165SCHÉMAAA

.0 (vi) (AA-1) (AA-2).0 (vi) (AA-2) (AA-2)

NsCNSC

(AA-3)(AA-3)

Η₂ΝΗ ₂ Ν

(AA-4)(AA-4)

(AA-5)(AA-5)

- 166SCHÉMA BB- 166CHEMIST BB

(BB-l) (BB-2)(BB-2) (BB-2)

- 167SCHÉMA CC- 167CHEMISTRY CC

(CC-1)(CC-1)

OABOUT

(CC-2) (CC-3)(CC-2)

(K)(C)

- 168SCHÉMA DD- 168CHEMISTRY DD

f 1/f 1 /

- 169-- 169-

Claims (36)

1. 1,6-disubstituovaný izochróman vzorca (I) kde:1. A 1,6-disubstituted isochroman of formula (I) wherein: (I) Wi je dusíkový (-N-) alebo uhlíkový atóm (-CH-); (H)Xije:(I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (H) Xije: (A) -(CH2)ni kde ni je 0 až 3, (B) -CH=CH-;(A) - (CH 2) n 1 wherein n 1 is 0 to 3, (B) -CH = CH-; (ΙΠ) Ri je:(ΙΠ) Ri is: (A) -H, (B) -F,-Cl,-Br,-J, (QCrCgalkyl, (D) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (E) C₂-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (F) C₃-C₈ cykloalkyl, (G) -Ci-C₃ alkyl-C₃-Cg cykloalkyl, (H) -NO₂, (I) -C=N, (J) -CF₃, (K) -O -Ri-i, kde Ru je (1) -H (2) Ci-Cg alkyl, (3) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (5) C₃-Cg cykloalkyl, (6) -Ci-C₃ alkyl -C₃-Cg cykloalkyl, (7) -CF₃, (8) -SO₂-CF₃,(A) -H, (B) -F, -Cl, -Br, -J, (C ₁ -C ₆ alkyl), (D) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (E) C ₂ -C 8 alkynyl containing 1 or 2 triple bonds (ξ), (F) C ₃ -C ₈ cycloalkyl, (G) -C 1 -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (H) -NO ₂ , (I) -C = N, (J) -CF ₃ , (K) -O-R 1 -I, where R 1 is (1) -H (2) C 1 -C 8 alkyl, (3) C ₂ -C 8 alkenyl containing 1 to 3 double bonds ( (4) C ₂ -C 8 alkynyl containing 1 or 2 triple bonds (ξ), (5) C ₃ -C 8 cycloalkyl, (6) -C 1 -C ₃ alkyl -C ₃ -C 8 cycloalkyl, (7) - CF ₃ , (8) -SO ₂ -CF ₃ , - 170 (9) -(ΟΗ₂)η₂-φ, kde η₂ je 0 až 4, a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl,-Br,-I, (b) -ON, (c) -CF₃, (d) CrC₃ alkyl, (g) -O -Rma, kde Rma je -H, Ci-Cé alkyl, -CF₃ alebo -Οί₂-φ, (f) -NRma Rmb , kde Rma a Rmb sú zhodné alebo sa líšia a kde Rmb je -H, C1-C6 alkyl, -CF₃ alebo -0Η₂-φ a kde Rma je definované vyššie, (g) -CO-NRmaR mb, kde Rma a Rmb sú definované vyššie, (h) -SO₂-NRmaRmb , kde Rma a Rmb sú definované vyššie, (i) -NRma-SO₂-Rmb, kde Rma a Rmb sú definované vyššie, (j) -NO₂, (k) -O-SO₂-CF₃, (L) -N(Rm), kde Rm môžu byť zhodné alebo rôzne ako je definované vyššie, (M) -CO -N(Rm)₂ , kde Rm sú zhodné alebo rôzne ako je definované vyššie, (N) -SO₂ -Ri-₃, kde Rm je:- 170 (9) - (ΟΗ ₂ ) η ₂ -φ, where η ₂ is 0 to 4, and where -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b ) -ON, (c) -CF ₃ , (d) C ₁ -C ₃ alkyl, (g) -O-Rma, wherein Rma is -H, C 1 -C 6 alkyl, -CF _3, or -Οί ₂ -φ, (f) -NRma Rmb, wherein Rma and Rmb are the same or different and wherein Rmb is -H, C 1 -C 6 alkyl, -CF _3, or -O ₂ -, and wherein Rma is as defined above, (g) -CO-NRmaR mb, wherein Rma and Rmb are as defined above, (h) -SO ₂ -NRmaRmb wherein Rma and Rmb are as defined above, (i) -NRma-SO ₂ -Rmb wherein Rma and Rmb are as defined above, (j) -NO ₂ (k) -O-SO ₂ -CF ₃ , (L) -N (R m), wherein R m can be the same or different as defined above, (M) -CO -N (R m) ₂ , wherein R m are identical or different, as defined above, (N) _-SO2 -Ri- _3, where R is: (1) -H, (2) -CF₃, (3) -Ci-Cgalkyl, (4) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C₂-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (6) C₃-Cg cykloalkyl, (7) -Ci-C₃ alkyl -C₃-C₈ cykloalkyl, (8) -(CH₂)n₂ -φ, kde n₂ je vyššie definované a -φ je voliteľne substituovaný jedným alebo dvoma:(1) -H, (2) -CF ₃ , (3) -C 1 -C 8 alkyl, (4) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C ₂ -C 8 alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C 8 cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) - (CH ₂ ) n ₂ -φ, where n ₂ is the a -φ defined above is optionally substituted by one or two: (a) -F,-Cl,-Br,-J, (b) -ON, (c) -CF₃, (d) C,-C₃ alkyl, (e) -O-Rma ,kde Rma je -H, Ci-Ce alkyl, -CF₃ alebo -CH₂ -φ,(a) -F, -Cl, -Br, -J, (b) -ON, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Rma, wherein Rma is - H, C 1 -C 6 alkyl, -CF ₃ or -CH ₂ -φ, - 171 (f) -NRi._3ARi-3B, kde Rma a R^b sú zhodné alebo rôzne a kde Ri.₃a je definované vyššie, (g) -CO-NRi.jaRi-sb , kde Rua a Ri.₃b sú definované vyššie, (h) -SO2 -NRj_3a Rub kde Ri-₃a a Ri.₃b sú definované vyššie, (i) -NR i-3A-SO2-R1-3B kde R1.3A a Ri-₃b sú definované vyššie, (j) -NO₂, (k) -O-SO₂ -CF₃, (9) -O-Ri-ia kde Ri.₃a a Ri.₃b sú definované vyššie, (10) -NRi._3a Rub, kde ₃b Ri-₃a a Rub sú definované vyššie, (O) -NRm-SO₂ -Ru, kde Ru a Ru môžu byť zhodné alebo rôzne ako je definované vyššie, (P) -(CH₂)n₂-<J>, kde n₂ je definované vyššie a kde -φ je voliteľne substituovaný jedným alebo dvoma:171 (f) -NR 1. _3A R 1 -B, wherein R 1a and R 1b are the same or different and wherein R 1. ₃ a is as defined above, (g) -CO-NR 1a and R 1 -sb, where Rua and R 1. ₃ b are as defined above, (h) -SO 2 -NR _{3 -3} R 11a where R 13a and R 1. ₃ b are as defined above, (i) -NR i-3A-SO2-R1-3B where R1.3 and managed ₃ b are as defined above, (j) _-NO2, (k) -O-SO ₂ -CF ₃ , (9) -O-R 1 -ia and R 1. ₃ aa Ri. ₃ b are as defined above, (10) -NR 1. Rub _{3a, 3b} wherein Ri- ₃ aa Rub are as defined above, (O) -NRm _-ru-SO2, where R and R may be the same or different, as defined above, (P) - (CH ₂₎ n ₂ - <J>, where n ₂ is as defined above and wherein -φ is optionally substituted by one or two: (1) -F,-Cl,-Br,-J, (2) -C=N, (3) -CF₃, (4) C,-C₆ alkyl, (5) -O-Ri-i, kde Ru je definovaný vyššie, (6) -N(Rm)_2j kde Ru sú zhodné alebo rôzne a sú definované vyššie, (7) -C0-N(Rm)₂, kde Ru sú zhodné alebo rôzne a sú definované vyššie, (8) -SO₂-N(Ru)₂, kde Ru sú zhodné alebo rôzne a sú definované vyššie, (9) -NRu-SO₂ -Rm, kde Ru sú zhodné alebo rôzné a sú definované vyššie, (10) -NO₂, (11) -O-SO₂-CF₃, (Q) -CO -Ru, kde Ru je definovaný vyššie, (R) -CO-O-Qi-₂, kde Qu je definovaný nižšie, (IV) R₂ je zhodné s Ri, R₂ môže byť zhodné alebo sa líšiť od Ri;(1) -F, -Cl, -Br, -J, (2) -C = N, (3) -CF ₃ , (4) C 1 -C ₆ alkyl, (5) -O-R 1, wherein Ru is as defined above, (6) -N (R m) _2j wherein Ru is the same or different and is as defined above, (7) -CO-N (R m) ₂ , where Ru is the same or different and is as defined above, ( 8) -SO ₂ -N (Ru) ₂ , where Ru are the same or different and are as defined above, (9) -NRu-SO ₂ -Rm, where Ru is the same or different, and are as defined above, (10) -NO ₂ , (11) -O-SO ₂ -CF ₃ , (Q) -CO-R 11, where R 11 is as defined above, (R) -CO-O-Q ₁₂ , where Qu is as defined below, (IV) R ₂ is identical to R 1, R ₂ may be the same or different from R 1; (V) Q, je:(V) Q, is: (A) -CO-NQuQi.₂ , kde Qu je (1) -H, (2) Ci-Cg alkyl, (3) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (-),(A) -CO-NQuQi. ₂ , wherein Qu is (1) -H, (2) C 1 -C 8 alkyl, (3) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (-), - 172 (4) Cí-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (5) C₃-C₈ cykloalkyl, (6) -Ci-C₃ alkyl-C₃-Cg cykloalkyl, (7) -CF₃, (8) -SO₂-CF₃, (9) -(ΟΙ₂)η₇-φ, kde n₇ je 0 až 4 a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl, -Br, -J, (b) -CsN, (c) -CF₃, (d) Ci-C₃ alkyl, (e) -O-Qma, kde Qua je -H, Ci-C₆ alkyl, -CF₃ alebo -CFfc-φ, (f) -NQmaQmb, kde Qua a Qi-ib sú zhodné alebo rôzne, a kde Qub je -H, Cj-Có alkyl, -CF₃ alebo -ΟΗ₂-φ, a kde Qua je definované vyššie, (g) -CO-NQma Qi-ib, kde Qua a Qub sú definované vyššie, (h) -SO₂-NQua Qub, kde Qua a Qub sú definované vyššie, (i) -NQua-SO₂ -Qub, kde Qua a Qub sú definované vyššie,172 (4) C 1 -C 8 alkynyl containing 1 or 2 triple bonds (ξ), (5) C ₃ -C ₈ cycloalkyl, (6) -C 1 -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (7) -CF ₃ , (8) -SO ₂ -CF ₃ , (9) - (ΟΙ ₂ ) η ₇ -φ, where n ₇ is 0 to 4 and wherein -φ is optionally substituted with one or two (a) -F, -Cl , -Br, -J, (b) -ČSN, (c) _-CF3, (d) _Ci-C3 alkyl, (e) -O-QMA wherein Qua is H, _Cl-C6 alkyl, - CF ₃ or -CFc-φ, (f) -NQmaQmb, wherein Qua and Qi-ib are the same or different, and wherein Qub is -H, C 1 -C 6 alkyl, -CF _3, or -ΟΗ ₂ -φ, and wherein Qua is as defined above, (g) -CO-NQa and Qi-ib, wherein Qua and Qub are as defined above, (h) -SO ₂ -NQa and Qub, wherein Qua and Qub are as defined above, (i) -NQa-SO ₂ - Qub, where Qua and Qub are as defined above, G)-no₂, (k) -O-SO₂-CF₃, a kde Qi.₂ je (1) -H, (2) Ci-Cg alkyl, (3) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂ -Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C₃-Cg cykloalkyl, (6) -Ci-C₃ alkyl -C₃-Cg cykloalkyl, (7) -CF₃, (8) -(CH₂)n₂ -φ, kde n₂ je vyššie definovaný, a -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl,-Br,-J, (b) -CsN, (c) -CF₃, (d) Ci-Cô alkyl, (e) -O-Qi-_2A, kde Qi._2A jeG) -no ₂ , (k) -O-SO ₂ -CF ₃ , and wherein Q 1. ₂ is (1) -H, (2) C 1 -C 8 alkyl, (3) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C 8 alkynyl containing 1 or 2 triple bonds (= (5) C ₃ -C 8 cycloalkyl, (6) -C 1 -C ₃ alkyl -C ₃ -C 8 cycloalkyl, (7) -CF ₃ , (8) - (CH ₂ ) n ₂ -φ, where n ₂ is as defined above, and -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -CsN, (c) -CF ₃ , (d) C 1 -C 6 alkyl, ( e) O-Qi- _2A, wherein Q. _2A is - 173(i) -H, (ii) Ci-C₆ alkyl, (iii) -CF₃, (iv) -(CH₂ )-φ, (9) -(CH₂ )n₉ -Qi-₂b(CH₂)iiio -Qmc , kde n₉ a n™ sú zhodné alebo rôzne a sú 0 až 4, kde Qmb je -O- alebo -NQmd-, kde Qmd je:- 173 (i) -H, (ii) C 1 -C ₆ alkyl, (iii) -CF ₃ , (iv) - (CH ₂ ) -φ, (9) - (CH ₂ ) n ₉ -Q ₁ b (CH ₂ ) ii 10 -Qmc, where n ₉ and n are the same or different and are 0 to 4, wherein Qmb is -O- or -NQmd-, wherein Qmd is: (a) -H, (b) Ci-Cg alkyl, (c) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby, (e) Cí-Cg cykloalkyl, (f) -C1-C3 alkyl -C₃-Cg cykloalkyl, (g) -cf₃, (h) -(CH₂)nn -φ, kde nn je 0 až 4 a -φ je voliteľne substituovaný jedným alebo dvoma (i) F, -Cl,-Br,-J, (ii)-ON, (iii) -CF₃, (iv) C1-C3 alkyl, (v) -O-Qme, kde Qme je -H, Ci-C₆ alkyl, -CF₃ alebo(a) -H, (b) C 1 -C 8 alkyl, (c) C ₂ -C 8 alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 or 2 triple bonds, (e) C ₁ - ₈ cg cycloalkyl, (f) -C 1 -C 3 alkyl-C ₃ -C cycloalkyl, (g) _-CF3, (h) - (CH ₂₎ -φ nn wherein nn is 0 to 4 and the -φ is optionally substituted with one or two (i) F, -Cl, -Br, -J, (ii) -ON, (iii) -CF ₃ , (iv) C 1 -C 3 alkyl, (v) -O-Qme, wherein Qme is -H , C 1 -C ₆ alkyl, -CF ₃ or -CHj-φ, (vi) -NQme Q1-2F, kde Qme a Qmf sú zhodné alebo rôzne, a kde Qmf je -H, Ci-C₆ alkyl, -CF3 alebo -Οϊ₂-φ, a kde Qme je definované vyššie, (vii) -CO -NQme Q1-2F, kde Qme a Qmf sú definované vyššie, (viii) -SO₂ -NQi.aE Q1-2F, kde Qmf je definované vyššie, (ix) -NQme -SO₂ -Qmf, kde Qme a Qmf sú definované vyššie,-CH-φ, (vi) -NQme Q1-2F where QME and QMF are the same or different, and wherein the QMF-H, _Cl-C6 alkyl, -CF3 or -φ -Οϊ _2, and wherein the defined QME above, (vii) -CO -NQme Q1-2F, wherein Qme and Qmf are as defined above, (viii) -SO ₂ -NQi.aE Q1-2F, wherein Qmf is as defined above, (ix) -NQme -SO ₂ - Qmf, where Qme and Qmf are as defined above, - 174(Χ)-ΝΟ₂, (xi) -Ο -SO₂ -CF3, a kde Q1-2C je zhodné s Q1-2D a Qi.₂c a Qi.₂d môžu byť zhodné alebo rôzne a kde Qm a Q1.2 tvoria spolu s atómom dusíka päť alebo šesť členný kruh, ktorý môže obsahovať ešte ďalší dusíkový alebo kyslíkový atóm;174 (Χ) -ΝΟ ₂ , (xi) -Ο -SO ₂ -CF 3, and wherein Q 1-2C is identical to Q 1-2D and Qi. ₂ ca Qi. _2d may be the same or different, and wherein Q m and Q1.2 together with the nitrogen atom a five or six membered ring which may also contain a further nitrogen or oxygen atom; (B) -SO2 -NQm Qi-í, kde Qm a Qi-₂ sú definované vyššie, (C) -CO -O -Qm , kde Q1.3 je(B) -SO 2 -NQm Qi-1, where Q m and Q _1-2 are as defined above, (C) -CO-O-Qm, where Q 1 -31 is 0)-H, (2) -CF₃, (3) Ci-C₈ alkyl, (4) C2-C8 alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (e), (6) C3-C8 cykloalkyl, (7) -C1-C3 alkyl -C3-C8 cykloalkyl, (8) -(CH₂)n7-<j), kde Π7 je definovaný vyššie a -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl, -Br, -J, (b) -C^N, (c) -CF₃, (d) C1-C3 alkyl, (e) -O-Qma, kde Qma je -H, Ci-Cô alkyl, -CF3 alebo -ΟΗ₂-φ, (f) -NQma Qi-3b, kde Qma a Qmb sú zhodné alebo rôzne a kde Qmb je -H, Ci-Cô alkyl, -CF3 alebo -ΟΗ₂-φ, a kde Qma je definovaný vyššie, (g) -CO-NQma Qi-3b ,kde Qma a Qmb sú definované vyššie,O) -H, (2) -CF ₃ , (3) C 1 -C ₈ alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (e), (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl -C 3 -C 8 cycloalkyl, (8) - (CH ₂ ) n 7 - (j), wherein Π 7 is as defined above, and - φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -C 1 N, (c) -CF ₃ , (d) C 1 -C 3 alkyl, (e) -O -Qma, wherein Qma is -H, C 1 -C 6 alkyl, -CF 3, or -ΟΗ ₂ -φ, (f) -NQma Q 1 -3b, wherein Qma and Qmb are the same or different and wherein Qmb is -H, C 1 -C 6 alkyl, -CF 3, or -ΟΗ ₂ -φ, and wherein Qma is as defined above, (g) -CO-NQma Qi-3b, wherein Qma and Qmb are as defined above, -175(h) -SOí-NQma Qi-3B ,kde Q1-3a a Qmb sú definované vyššie, (i) -NQ1.3A-SO2 -Qmb ,kde Qma a Qmb sú definované vyššie,-175 (h) -SO 1 -NQma Q1-3B, wherein Q1-3a and Qmb are as defined above, (i) -NQ1.3A-SO2 -Qmb wherein Qma and Qmb are as defined above, 0) -no₂ , (k) -O-SO2 -CFj, (D) -CO-Qi-3, kde Q1.3 je definované vyššie, (E) -CO-imidazol, (F) -NQ1-1Q1-2, kde Qm a Qi.₂ sú definované vyššie, (F’) -NQ14-CO-Q1.2 ,kde Qm a Q1-2 sú definované vyššie, (G) -C(Qm)=N-O-Qm, kde Qm je zhodné s Q1.3 a Qm je definované vyššie, Qm aO) -no ₂ , (k) -O-SO 2 -CF 3, (D) -CO-Q 1 -3, wherein Q1.3 is as defined above, (E) -CO-imidazole, (F) -NQ 1-1Q 1 - 2, wherein Qm and Qi. ₂ are as defined above, (F ') -NQ14-CO-Q1.2, where Qm and Q1-2 are as defined above, (G) -C (Qm) = NO-Qm, wherein Qm is identical to Q1.3 and Qm is as defined above, Qm and Qm môže byť zhodné alebo rôzne, (H) -SO2-Q1.3, kde Q m je definované vyššie, (I) -N(Qm)-SO2 -Qm, kde Qm a Qm je definované vyššie, (J) 5-oxadiazol voliteľne substituovaný jedným Qm, kde Qm je:Q m can be identical or different, (H) -SO 2 -Q1.3, where Q m is as defined above, (I) -N (Q m) -SO 2 -Qm, where Q m and Q m are as defined above, (J) 5- oxadiazole optionally substituted with one Qm, wherein Qm is: (1) -H, (2) -F, -Cl,-Br,-J, (3) Ci-C₈ alkyl, (4) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (6) C₃-C₈ cykloalkyl, (7) -C1-C3 alkyl -C₃-C₈ cykloalkyl, (8)-NO₂,(1) -H, (2) -F, -Cl, -Br, -J, (3) C 1 -C ₈ alkyl, (4) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), ( 5) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (ξ), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C 3 alkyl -C ₃ -C ₈ cycloalkyl, (8) -NO ₂ . - 176(9) -ΟΝ, (10) -CF₃, (11) -O-Qi-sa , kde Qi-₅a je:- 176 (9) -ΟΝ, (10) _-CF3, (11) -O-Qi-out Qi- ₅ wherein a is: (a) -H, (b) Ci-Cg alkyl, (c) C₂-Cs alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C2-C8 alkinyl obsahujúci 1 až 2 trojité väzby, (e) C₃-Cs cykloalkyl, (f) -C i-C₃ alkyl-C3-C8 cykloalkyl, (g) -CFa, (h) -SO₂-CF₃, (I) -(CH₂)n7-<|>, kde ruje 0 až 4, (12) -NQi-5aQi-5d, kde Qi-5Aje definované vyššie, Qi-sd je:(a) -H, (b) C 1 -C 8 alkyl, (c) C ₂ -C 8 alkenyl having 1 to 3 double bonds, (d) C 2 -C 8 alkynyl having 1 to 2 triple bonds, (e) C ₃ -C 8 cycloalkyl, (f) -C 1 -C ₃ alkyl-C 3 -C 8 cycloalkyl, (g) -CFa, (h) -SO ₂ -CF ₃ , (I) - (CH ₂ ) n 7 -, wherein r is 0 to 4, (12) -NQi-5aQi-5d, wherein Qi-5A is as defined above, Qi-sd is: (a) -H, (b) Ci-C₈alkyl, (c) C₂-C₈ alkenyl obsahujúci l až 3 dvojité väzby, (d) C₂-C₈ alkinyl obsahujúci 1 až 2 trojité väzby (=), (e) C₃-C₈ cykloalkyl, (f) -Ci-C₃ alkyl - C₃-Cs cykloalkyl, (g) -CF₃, (h) -(Ο1₂)η7-φ, kde Π7 je definované vyššie,(a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 triple bonds (=), (e) C ₃ -C ₈ cycloalkyl, (f) -C 1 -C ₃ alkyl - C ₃ -C 8 cycloalkyl, (g) -CF ₃ , (h) - (Ο ₁₂ ) η 7-, where Π7 is as defined above . - 177 (13) -C0-NQi_5a Qi-sd , kde Qi._5A a Qi-sd sú definované vyššie, (14) -SO2-Q1-5K, kdeQi.siJe (a) -H, (b) -CF₃ , (c) C,-C₈ alkyl, (d) Cí-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (e) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (f) C₃-C₈ cykloalkýl, (g) -Ci-C₃ alkyl -C₃-C₈ cykloalkýl, (h) -(ΟΗ2)η7-φ, kde ηγ je definované vyššie, (15) -NQi.sa -SO2-Q1.5K ,kde Qi-sa a Qi-sk môžu byť zhodné alebo rôzne a sú definované vyššie, (16) -(CH₂)n7-<(>, kde 07 je definované vyššie a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl,-Br,-J, (b) -C=N, (c) -CF₃, (d) Ci-Ce alkyl, (e) -O-Q1.5A, kde Qi-sa je definované vyššie, (f) -NQi-sa Qi-sd, kde Qi-sa a Qi-sd sú vyššie definované, (g) -CO-NQj.sa Qi-sd, kde Qi-sa a Qi-sd sú definované vyššie, (h) -SO2-NQ1.5AQ1-5D, kde Qi-sa a Qi-sd sú definované vyššie,177 (13) -CO-NQi_5a Qi-sd, wherein Qi. _5A-SD and Q are as defined above, (14) -SO 2 Q1-5K, kdeQi.siJe (a) -H, (b) _-CF3, (c) C, -C ₈ alkyl, (d) C C8 alkenyl containing 1 to 3 double bonds (=), (e) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (ξ), (f) C ₃ -C ₈ cycloalkyl, (g) -C 1 -C ₃ alkyl C ₃ -C ₈ cycloalkyl, (h) - (ΟΗ2) η7-φ, wherein ηγ is as defined above, (15) -SO 2 -NQi.sa Q1.5K, wherein Q and Q-is-in may be the same or different and are as defined above, (16) - (CH ₂ ) n 7 - <(>, where 07 is as defined above and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J (b) -C =N, (c) -CF ₃ , (d) C 1 -C 6 alkyl, (e) -O-Q 1.5A, wherein Q 1 -s is as defined above, (f) -NQ 1 -s Q 1 -sd, wherein Q1-sa and Q1-sd are as defined above, (g) -CO-NQ1 and Qi-sd, wherein Q1-sa and Q1-sd are as defined above, (h) -SO2-NQ1.5AQ1- 5D, wherein Q1-sa and Q1-sd are as defined above, - 178 (i) -NQ1-5A-SO2 -Q1-5D ,kde Qi-5a a Qi-sd sú definované vyššie, (j) -NO₂, (k) -O-SO₂-CF₃;178 (i) -NQ1-5A-SO2 -Q1-5D, wherein Q1-5a and Q1-sd are as defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ ; (K) 3-oxadiazol voliteľne substituovaný jedným Q1.5, kde Qm je definované vyššie, (L) triazol voliteľne substituovaný jedným alebo dvoma Q1-5, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je vyššie definované, (M) 5-tiadiazol voliteľne substituovaný jedným Q1-5, kde Q1.5 je definované vyššie, (N) 3-tiadiazoI voliteľne substituovaný jedným Q1.5, kde Qm je definované vyššie, (O) 2-oxazol voliteľne substituovaný jedným alebo dvoma Qm, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (P) 2-tiazol voliteľne substituovaný jedným alebo dvoma Q1.5, ktoré môžu byť zhodné alebo rôzne, kde Qm je definované vyššie, (Q) 2-imidazol voliteľne substituovaný jedným, dvoma alebo troma Qm, ktoré môžu byť zhodné alebo rôzne, kde Q1-5 je definované vyššie, (R) 1-imidazol substituovaný jedným, dvoma alebo troma Q1-5 , ktoré môžu byť zhodné alebo rôzne, kde Qm je vyššie definované, (S) tetrazol voliteľne substituovaný jedným Qm , kde Qm je definované vyššie, (T) cyklobutendión voliteľne substituovaný jedným Qm a jedným Qm, kde Qm a Qm sú definované vyššie, (U) 1-pyrimidinyl voliteľne substituovaný jedným Qm, kde Qm je definované vyššie, (V) 2-pyridinyl voliteľne substituovaný jedným Qm, kde Qm je definované vyššie, (W) 3-pyridinyl voliteľne substituovaný jedným Qm, kde Qm je definované vyššie, (X) 4-pyridinyl voliteľne substituovaný jedným Qm, kde Qm je definované vyššie, (Y) -Zi-CO -Z₂ -Qi.₂, kde Qi.₂ je definované vyššie a Zi je(K) 3-oxadiazole optionally substituted with one Q1.5, wherein Qm is as defined above, (L) triazole optionally substituted with one or two Q1-5, which may be identical or different, wherein Q1.5 is as defined above, (M) 5-thiadiazole optionally substituted with one Q1-5, wherein Q1.5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1.5, wherein Qm is as defined above, (O) 2-oxazole optionally substituted with one or two Qm, which may be identical or different, wherein Q1.5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1.5 which may be identical or different, wherein Qm is as defined above, (Q) 2-imidazole optionally substituted with one, two or three Qm, which may be identical or different, wherein Q1-5 is as defined above, (R) 1-imidazole substituted with one, two or three Qm-5, which may be identical or different, wherein Qm is higher defined, (S) tetrazole optionally substituted (T) cyclobutenedione optionally substituted with one Qm and one Qm, wherein Qm and Qm are as defined above, (U) 1-pyrimidinyl optionally substituted with one Qm, wherein Qm is as defined above, (V) 2-pyridinyl optionally substituted with one Qm where Qm is as defined above, (W) 3-pyridinyl optionally substituted with one Qm where Qm is as defined above, (X) 4-pyridinyl optionally substituted with one Qm where Qm is as defined above, (Y) ) -Z 1 -CO -Z ₂ -Qi. ₂ , wherein Qi. ₂ is as defined above and Z 1 is -O- alebo-O- or -Nqm, kde Qm je definované vyššie, kde Z₂ je-Nqm, wherein Qm is as defined above, wherein Z ₂ is - 179 -O- alebo- 179 -O- or -Nqm, kde Qi-i je definované vyššie, s výhradou, že pokiaľ Xi je -(CH₂)ni -, kde ni je 0 a Qi je:-Nqm, where Q 1 -i is as defined above, provided that when X 1 is - (CH ₂ ) ni -, where ni is 0 and Q 1 is: -CO-NQmQi-₂,-CO-NQmQi- ₂ , -SO₂-NQhQi-2 alebo-SO ₂ -NQhQi-2 or -NQmQi.₂ ,-NQmQi. ₂ , -NQi-i-CO-Qi-₂ potom Qm a Qi.₂ nemôžu byť obidva vybrané z-NQi-i-CO-Qi- ₂ then Q m and Q. ₂ cannot be both selected from -H,-H. -Ci-Cô alkyl,-C 1 -C 6 alkyl, -C3-C7 cykloalkyl,-C3-C7 cycloalkyl, -C1-C3 alkyl -(C3-C7) cykloalkyl a ich farmaceutický prijateľné soli-C 1 -C 3 alkyl - (C 3 -C 7) cycloalkyl and pharmaceutically acceptable salts thereof 2. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde (I) Wi je dusíkový (-N-) alebo uhlíkový atóm (-CH-);The 1,6-disubstituted isochroman (I) according to claim 1, wherein (I) W 1 is a nitrogen (-N-) or carbon atom (-CH-); I I (ĽQXije:I I (LQXije: (A) -(CH₂)ni - kde m je 0 až 3, (B) -CH=CH-, (HI)Ri je:(A) - (CH ₂ ) n 1 - wherein m is 0 to 3, (B) -CH = CH-, (HI) R 1 is: (A) -H, (B) -F,-Cl,-Br,-J, (C) Ci-C₈ alkyl, (D) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (E) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (s), (F) C₃-C₈ cykloalkyl, (G) -C1-C3 alkyl-C₃-C₈ cykloalkyl, (H) -NO₂, (I) -C=N,(A) -H, (B) -F, -Cl, -Br, -J, (C) C 1 -C ₈ alkyl, (D) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), ( E) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (s), (F) C ₃ -C ₈ cycloalkyl, (G) -C 1 -C 3 alkyl-C ₃ -C ₈ cycloalkyl, (H) -NO ₂ , (I) -C =N, - 180(J) -CF₃, (K) -Ο-Rm, kde R_w je:- 180 (J) -CF ₃ , (K) -Ο-R m, where R _w is: (1) -H (2) C,-C₈ alkyl, (3) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C₃-C₈ cykloalkyl, (6) -Ci-C₃ alkyl -C₃-C₈ cykloalkyl, (7) -CF₃, (8) -SO₂-CF₃, (9) -(Οί₂)η₂-φ, kde n₂ je 0 až 4, a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl, -Br, -J, (b) -ON, (c) -CF₃, (d) C_rC₃ alkyl, (e) -O-Rma, kde Rma je -H, Ci-Cď alkyl, -CF₃ alebo -ΰί₂-φ, (f) -NRmaRi-ib, kde Rua a Rm_B sú zhodné alebo rôzne a kde Rub je -H, Ci-C₆ alkyl, -CF₃ alebo -Οί₂-φ, a kde Rma sú definované vyššie, (g) -CO-NRmaRmb, kde Rma a Rmb sú definované vyššie, (h) -SO₂-NRmaRmb, kde Rma a Rmb sú definované vyššie, (i) -NRma-SO₂-Rmb, kde Rma a Rmb sú definované vyššie, (j) -NO₂, (k) -O-SO₂ -CF₃, (L) -N(Rm), kde Rm môže byť zhodné alebo rôzne a je definované vyššie, (M) -C0-N(Rm)₂, kde Rm môže byť zhodné alebo rôzne a je definované vyššie, (N) -SO₂ -Rm, kde Rm je:(1) -H (2) C 1 -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds ( =), (5) C ₃ -C ₈ cycloalkyl, (6) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (7) -CF ₃ , (8) -SO ₂ -CF ₃ , (9) - (Οί ₂ ) η ₂ -φ, where n ₂ is 0 to 4, and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -ON, ( c) _-CF3, (d) C _r C ₃ alkyl, (e) -O-Rmax, where Rmax is H, Cl-Cd alkyl, -CF ₃ or -ΰί ₂ -φ, (f) -NRmaRi- ib, wherein R a and R m _B are identical or different, and wherein R e is -H, C 1 -C ₆ alkyl, -CF _3, or-β ₂ -φ, and wherein R m is as defined above, (g) -CO-NR m R m b, wherein Rma and Rmb are as defined above, (h) -SO ₂ -NRmaRmb, wherein Rma and Rmb are as defined above, (i) -NRma-SO ₂ -Rmb, wherein Rma and Rmb are as defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ , (L) -N (R m), wherein R m can be identical or different and is as defined above, (M) -CO-N (R m) ₂ , wherein R m can be identical or different and is as defined above, ( N) -SO ₂ -R m, where R m is: (1) -H, (2) -CF₃, (3) -C,-C₈ alkyl, (4) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ),(1) -H, (2) -CF ₃ , (3) -C 1 -C ₈ alkyl, (4) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (5) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (ξ), -181(6) C₃-Cs cykloalkyl, (7) -Ci-C₃ alkyl -C₃-C₈ cykloalkyl, (8) -(Φί₂)η₂-φ, kde n₂ je definované vyššie a -φ je voliteľne substituovaný jedným alebo dvoma (a) -F,-Cl,-Br,-J, (b) -C^N, (c) -CF₃, (d) Ci-C₃alkyl, (e) -O-Rua , kde Ri-₃a je -H, Ci-Cô alkyl, -CF₃ alebo -ΟΗ₂-φ, (f) -NRuaRub, kde Ri._3A a Rub sú zhodné alebo rôzne a kde Ri._3B je -H, -Ci-C₆ alkyl, -CF₃ alebo -CH₂ -φ, a kde Ri-_3A je definované vyššie, (g) -CO-NRi-_3ARi-3b,kde Ri-₃a a Ri.₃b sú definované vyššie, (h) -SO₂-NRi._3a Rub kde Rua a Rub sú definované vyššie, (i) -NRi-3a-SO₂ -Rub kde Rua a Rub sú definované vyššie,-181 (6) C ₃ -C 8 cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) - (Φί ₂ ) η ₂ -φ, where n ₂ is as defined above and -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -C 1 N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O -Rua wherein Ri- and ₃ is -H, C-Co alkyl, -CF ₃ or -ΟΗ ₂ -φ, (f) -NRuaRub wherein R. _3A and Rub are the same or different and wherein R 1. _3B is -H, -C ₆ alkyl, -CF ₃ or -CH ₂ -φ, and wherein Ri- _3A is as defined above, (g) CO-NRi- _3A-R 3b, wherein R aa ₃ Ri- . ₃ b are as defined above, (h) -SO ₂ -NR 1. _3a Rub wherein Rua and Rub are as defined above, (i) -NRi-3a-SO ₂ -Rub wherein Rua and Rub are as defined above, 0)-no₂, (k) -O-SO₂ -CF₃, (9) -O-Rma, kde Rua a Rub sú definované vyššie, (10) -NRi-sa Rub, kde ₃b Rua a Rub sú definované vyššie, (O) -NRm-SO₂-Ri-3, kde Ru a Ru môžu byť zhodné alebo rôzne ako je definované vyššie, (P) -(ΟΙ₂)η₂-φ, kde n₂ je definované vyššie, a kde -φ je voliteľne substituovaný jedným alebo dvoma (1) -F,-Cl,-Br,-J, (2) -C^N, (3) -CF₃, (4) Cí-Ce alkyl, (5) -O-Ri-i, kde Ru je definovaný vyššie, (6) -N(Rm)₂, kde Ru sú zhodné alebo rôzne a sú definované vyššie, (7) -C0-N(Ru)₂ ,kde Ru sú zhodné alebo rôzne a sú definované vyššie, (8) -SO₂-N(Rm)2 ,kde Ru sú zhodné alebo rôzne a sú definované vyššie, (9) -NRm-SO₂-Rm, kde Ru sú zhodné alebo rôzne a sú definované vyššie, (10) -NO₂, (11) -O-SO₂ -CF₃;0) _-NO2, (k) -O-SO ₂ -CF _3, (9) -O-Rmax, wherein Rua and Rub are as defined above, (10) -NR-Rub is wherein b ₃ Rua and Rub are as defined above, (O) -NRm-SO ₂ -Ri-3, where Ru and Ru may be the same or different as defined above, (P) - (ΟΙ ₂ ) η ₂ -φ, where n ₂ is as defined above, and wherein -φ is optionally substituted with one or two (1) -F, -Cl, -Br, -J, (2) -C 1 N, (3) -CF ₃ , (4) C 1 -C 6 alkyl, (5) ) -O-R 1 -I, where Ru is as defined above, (6) -N (R m) ₂ , where R a are the same or different and are as defined above, (7) -CO-N (Ru) ₂ , where R a are identical or different and are as defined above, (8) -SO ₂ -N (R m) 2, where R a are identical or different and are as defined above, (9) -NR m -SO ₂ -R m, where R a are identical or different, and are as defined above, (10) -NO ₂ , (11) -O-SO ₂ -CF ₃ ; -182(IV) R₂ je zhodné s Ri, R₂ môže byť zhodné alebo rôzne s Ri;-182 (IV) R ₂ is identical to R 1, R ₂ may be the same or different to R 1; (V) Q, je:(V) Q, is: (A) -CO-NQi-iQi-χ kde Qm je:(A) -CO-NQi-iQi-χ where Qm is: (1) -H, (2) Ci-C₈ alkyl, (3) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (ξ), (5) C₃-C₈ cykloalkyl, (6) -Ct-C₃ alkyl-C₃-C₈ cykloalkyl, (7) -CF₃, (8) -SO₂-CF₃, (9) -(CH₂)n7-<J>, kde ηγ je 0 až 4 a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F,-Cl,-Br,-J, (b) -C^N, (c) -CF₃, (d) Ci-C₃ alkyl, (e) -O-Qma, kde Qma je -H, Ci-Cô alkyl, -CF₃ alebo -Οί₂-φ, (f) -NQmaQmb, kde Qma₃ Qmb sú zhodné alebo rôzne, a kde Qmb je -H, Ci-Cŕ alkyl, -CF₃ alebo -CH₂-<j), a kde Qma je definované vyššie, (g) -CO-NQma Qmb, kde Qma a Qmb sú definované vyššie, (h) -SO₂-NQma Qmb, kde Qma a Qmb sú definované vyššie, (i) -NQma-SO₂-Qmb, kde Qma a Qmb sú definované vyššie, (j) -NO₂, (k) -O-SO₂ -CF₃, a kde Qi-₂ je:(1) -H, (2) C 1 -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds ( ξ), (5) C ₃ -C ₈ cycloalkyl, (6) -C 1 -C ₃ alkyl-C ₃ -C ₈ cycloalkyl, (7) -CF ₃ , (8) -SO ₂ -CF ₃ , (9) - (CH ₂₎ n7 <J>, wherein ηγ is 0 to 4, and wherein the -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -C? N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Qma, wherein Qma is -H, C 1 -C 6 alkyl, -CF ₃ or -ΟΟ ₂ -φ, (f) -NQmaQmb wherein Qma ₃ Qmb are the same or different, and wherein Qmb is -H, C 1 -C 6 alkyl, -CF ₃ or -CH ₂ - (j), and wherein Qma is as defined above, (g) -CO-NQma Qmb, wherein Qma and Qmb are as defined above, (h) -SO ₂ -NQma Qmb, wherein Qma and Qmb are as defined above, (i) -NQma-SO ₂ -Qmb, wherein Qma and Qmb are as defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ , and wherein Q _1-2 is: (1) -H, (2) Ci-C₈ alkyl, (3) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) C₃-C₈ cykloalkyl, (6) -Ci-C₃ alkyl -C₃-C₈ cykloalkyl, (7) -CF₃,(1) -H, (2) C 1 -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds ( =), (5) C ₃ -C ₈ cycloalkyl, (6) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (7) -CF ₃ , - 183(8) -(ΟΗ₂)η₂-φ, kde n₂ je vyššie definovaný, a -φ je voliteľne substituovaný jedným alebo dvoma (a) -F,-CI, -Br,-J, (b) -C=N, (c) -CF₃, (d) Ci-Cô alkyl, (e) -O-Qi._2A, kde Qi._2A je:- 183 (8) - (ΟΗ ₂ ) η ₂ -φ, where n ₂ is as defined above, and -φ is optionally substituted with one or two (a) -F, -CI, -Br, -J, (b) - C = N, (c) -CF ₃ , (d) C 1 -C 6 alkyl, (e) -O-Q 1. _2A where Qi. _2A is: (0 -H, (ii) Ci-Cô alkyl, (iii) -CF₃, (iv) -(CH₂ )-φ, (9) -(CH₂ )n₉ -Qi-2B(CH₂)nio -Qmc , kde n₉ a n₃o sú zhodné alebo rôzne a sú 0 až 4, kde, Qmb je -O- alebo -NQi._2D-, kde Qmd je:(O -H, (ii) C 1 -C 6 alkyl, (iii) -CF ₃ , (iv) - (CH ₂ ) n -, (9) - (CH ₂ ) n ₉ -Q ₁ -B (CH ₂ ) nio -Qmc, where n ₉ and ₃ o are identical or different and are 0 to 4, wherein, Qmb is -O- or -NQi. _2D -, wherein Qmd is: (a) -H, (b) Ci-C₈ alkyl, (c) C2-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby, (e) C₃-C₈ cykloalkyl, (f) -Ci-C₃ alkyl-C₃-C₈ cykloalkyl, (g) -cf₃, (h) -(CH₂)nn -φ, kde nn je 0 až 4 a -φ je voliteľne substituovaný jedným alebo dvoma (i) F,-Cl,-Br,-J, (ii)-C^N, (iii) -CF₃, (iv) Ci-C₃ alkyl (v) -O-Q1-2E, kde Qi.₂e je -H, Ci-C₆ alkyl, -CF₃ alebo -ΟΗ₂-φ (vi) -NQ1-2E Q1-2F, kde Qme a Qi-₂f sú zhodné alebo rôzne, a kde Qmf je -H, Ci-C₃ alkyl, -CF₃ alebo -Ο4₂-φ, a kde Qme je definované vyššie, (vii) -CO -NQi._2E Qi-2f, kde Qi-₂e a Qi-₂f sú definované vyššie,(a) -H, (b) C 1 -C ₈ alkyl, (c) C 2 -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 or 2 triple bonds, (e) C ₃ -C ₈ cycloalkyl, (f) -C-C ₃ alkyl-C ₃ -C ₈ cycloalkyl, (g) _-CF3, (h) - (CH ₂₎ -φ nn wherein nn is 0 to 4 and the - φ is optionally substituted with one or two (i) F, -Cl, -Br, -J, (ii) -C 1 N, (iii) -CF ₃ , (iv) C 1 -C ₃ alkyl (v) -O- Q1-2E, where Qi. E ₂ is H, _Cl-C6 alkyl, _-CF3 or -φ ₂ -ΟΗ (vi) -NQ1-2E Q1-2F where QME and Qi- f ₂ are the same or different, and wherein H is QMF , C 1 -C ₃ alkyl, -CF ₃ or -Ο _{4 2} -φ, and wherein Qme is as defined above, (vii) -CO -NQi. Qi _2E-2F, wherein the Qi- ₂ e and ₂ f Qi- are as defined above, -184(viii) -SO2-NQ1.2E Q1-2F a Q1-2F sú definované vyššie, (ix) -NQ1-2E-SO2-Q1-2F, kde Q1-2E a Qi.₂f sú definované vyššie, (x) -NO₂, (xi) -O-SO2 -CF₃, a kde Qi..₂c je zhodné s Qi.₂d a Qi._2C a Qi._2D môžu byť zhodné alebo rôzne, (B) -SO₂-NQm Qi-₂ ,kde Qu a Qi-₂ sú definované vyššie, (C) -CO-O-Qi-₃ , kde Qi.₃ je:-184 (viii) -SO 2 -NQ1.2E Q1-2F and Q1-2F are as defined above, (ix) -NQ1-2E-SO2-Q1-2F, wherein Q1-2E and Q1. F ₂ are as defined above, (x) _-NO2, (xi) -O-SO2 _-CF3, and wherein Q ₂ .. c is the same as Qi. ₂ da Qi. _2C and Qi. _2D may be the same or different, (B) _-SO2 -NQm Qi- _2, wherein the Qi- Qu and ₂ are as defined above, (C) -CO-O-Qi- _3, wherein Q. ₃ je: (1) -H, (2) -CF₃, (3) Ci-C₈ alkyl, (4) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) Cb-Cg alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (6) C₃-Cg cykloalkyl, (7) -C,-C₃ alkyl-C₃-Cg cykloalkyl, (8) -(CH₂)n₇-^, kde n₇ je definovaný vyššie a -φ je voliteľne substituovaný jedným alebo dvoma (a) -F,-Cl,-Br,-J, (b) -C=N, (c) -CF₃, (d) C,-C₃ alkyl, (e) -O-Q1.3A, kde Qi-₃a je -H, C1-C6 alkyl, -CF₃ alebo -ΟΗ₂-φ, (f) -NQ1-3A Q1-3 b, kde Qi-₃a a Qi-₃b sú zhodné alebo rôzne a kde Qi.₃b je -H, Ci-Ce alkyl, -CF₃ alebo -ΟΗ₂-φ, a kde Qi-₃a je definované vyššie,(1) -H, (2) -CF ₃ , (3) C 1 -C ₈ alkyl, (4) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 1 -C 8 alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C 8 cycloalkyl, (7) -C 1 -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (8) - (CH ₂ ) n ₇ - ^, where n ₇ is as defined above and -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -C = N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl , (e) -O-Q1.3A wherein Qi- ₃ and is H, C 1 -C 6 alkyl, -CF ₃ or -ΟΗ ₂ -φ, (f) -NQ1-3A Q1-3 b wherein Qi- ₃ aa Qi- ₃ b are the same or different, and wherein Q. ₃ b is H, C -C alkyl, -CF ₃ or -φ -ΟΗ _2, and wherein a Qi- ₃ is as defined above, -185(g) -CO -NQi-ía Qi-3b , kde Qi._3A a Qmb sú definované vyššie, (h) -SOí-NQua Qub , kde Qi.₃a a Qmb sú definované vyššie, (i) -NQi.₃a -SO2-Q1-3B , kde Qi.₃a a Qi.₃b sú definované vyššie, (j) -no₂, (k) -O-SO₂-CF₃, (D) -CO-Qi.₃, kde Qm je definované vyššie, (E) -CO-imidazol, (F) -NQmQi-x kde Qm a Qi.₂ sú definované vyššie, (G) -C(Qi.₃)=N-O-Qm, kde Qm je zhodné s Qi.₃ a Q1.3 je definované vyššie, Qi.₃ a Qi 4 môže byť zhodné alebo rôzne, (H) -SO₂-Qi._3> kde Qi.₃ je definované vyššie, (I) -N(Qi.i)-SO₂-Qi-3, kde Qm a Q1.3 je definované vyššie, (J) 5-oxadiazol voliteľne substituovaný jedným Qm, kde Qm je-185 (g) -CO -NQi-1a and Qi-3b, wherein Qi. _3A and Qmb are as defined above, (h) -SO 1 -NQu and Q 1b, where Q 1. ₃ and and Qmb are as defined above, (i) -NQi. ₃ and -SO2-Q1-3B, wherein Qi. ₃ aa Qi. ₃ b are as defined above, (j) _-NO2, (k) -O-SO ₂ -CF _3, (D) -CO-Qi. ₃ , wherein Qm is as defined above, (E) -CO-imidazole, (F) -NQmQi-x wherein Qm and Qi. ₂ are as defined above, (G) -C (Qi. ₃₎ = NO-Q m, wherein Q m is the same as Qi. ₃ and Q1.3 is as defined above, Q1. ₃ and Q 14 may be identical or different, (H) -SO ₂ -Q 1. _3> where Qi. ₃ is as defined above, (I) -N (Qi.i) _-SO2 -Q-3 wherein Q m and Q1.3 is as defined above, (J) 5-oxadiazole optionally substituted by Q m, wherein Q m is 0)-H, (2) -F, -Cl, -Br, -J, (3) C_rC₈ alkyl, (4) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (5) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (6) C₃-C₈ cykloalkyl, (7) -Ci-C₃ alkyl-C₃-C₈ cykloalkyl, (8) -NO₂, (9)-ON,0) H, (2) -F, -Cl, -Br, -J, (3) C _r -C ₈ alkyl, (4) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (5 ) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl-C ₃ -C ₈ cycloalkyl, (8) -NO ₂ (9) -ON -186(10) -CF₃, (11) -0-Qi-5A ,kde Qi-sa je:-186 (10) -CF ₃ , (11) -O-Qi-5A, wherein Qi-sa is: (a) -H, (b) C,-C₈ alkyl, (c) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C₂-C₈ alkinyl obsahujúci 1 až 2 trojité väzby, (e) C3-C8 cykloalkyl, (f) -C1-C3 alkyl-Cí-Cg cykloalkyl, (g) -CFs, (h) -SO₂-CF₃, (I) -(ΟΗ₂)η7-φ, kde n₇ je 0 až 4, (12) -NQi-5aQi-5d, kde Qi-5Aje definované vyššie, Qi-sd je:(a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 triple bonds, (e) ) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl-C 1 -C 8 cycloalkyl, (g) -CF 5, (h) -SO ₂ -CF ₃ , (I) - (ΟΗ ₂ ) η7-φ, where n ₇ is 0 to 4, (12) -NQi-5aQi-5d, wherein Qi-5A is as defined above, Qi-sd is: (a) -H, (b) CrCg alkyl, (c) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby, (d) C^-Cg alkinyl obsahujúci 1 až 2 trojité väzby (=), (e) C₃-Cg cykloalkyl, (f) -Ci-C₃ alkyl-C₃-Cg cykloalkyl, (g) -CF₃, (h) -(CH₂)n7-<|>, kde n₇ je definované vyššie, (13) -CO-NQi._5A Qi-sd ,kde Qi-sa a Qi-sd sú definované vyššie,(a) -H, (b) C 1 -C 8 alkyl, (c) C ₂ -C 8 alkenyl having 1 to 3 double bonds, (d) C 1 -C 6 alkynyl having 1 to 2 triple bonds (=), (e) C ₃ -C 8 cycloalkyl, (f) -C 1 -C ₃ alkyl-C ₃ -C 8 cycloalkyl, (g) -CF ₃ , (h) - (CH ₂ ) n _{7 -} , wherein n ₇ is as defined above, (13) ) -CO-NQi. _5A Qi-sd, wherein Qi-sa and Qi-sd are as defined above, - 187 (14) -SO₂-Qmk, kdeQi.skje (a) -H, (b) -CF₃, (c) Ci-C₈alkyl, (d) C₂-Cs alkenyl obsahujúci 1 až 3 dvojité väzby (=), (e) C2-C8 alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (f) C3-C8 cykloalkyl, (g) -C1-C3 alkyl-C₃-C8 cykloalkyl, (h) -(CH₂)n7-<|), kde n₇ je definované vyššie, (15) -NQi-5a-SO₂ -Q1-5K, kde Qma a Qmk môžu byť zhodné alebo rôzne a sú definované vyššie, (16) -(CH₂)n₇-<j), kde n₇ je definované vyššie a kde -φ je voliteľne substituovaný jedným alebo dvoma (a) -F, -Cl,-Br,-J, (b) -ON, (c) -CF₃, (d) Ci-C₆ alkyl, (e) -O-Q, -5A, kde Qma je definované vyššie, (f) -NQi-5a Qi-5d, kde Qma a Qmd sú definované vyššie, (g) -CO-NQma Qmd , kde Qma a Qmd sú definované vyššie, (h) -SO₂-NQmaQi-5d , kde Qma a Qmd sú definované vyššie, (i)-NQ ma -SO₂ -Qmd ,kde Qma a Qmó sú definované vyššie,187 (14) -SO ₂ -Qmk, wherein Q 1 is (a) -H, (b) -CF ₃ , (c) C 1 -C ₈ alkyl, (d) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (=), (e) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (=), (f) C 3 -C 8 cycloalkyl, (g) -C 1 -C 3 alkyl-C ₃ -C 8 cycloalkyl, (h) - (CH) ₂₎ n7 <|) wherein n ₇ is as defined above, (15) -NQi-5-SO ₂ -Q1-5K wherein qmk QMA and may be the same or different and are as defined above, (16) - (CH ₂ ) n ₇ - (j), wherein n ₇ is as defined above and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -J, (b) -ON, (c) - CF ₃ , (d) C 1 -C ₆ alkyl, (e) -OQ, -5A, wherein Qma is as defined above, (f) -NQi-5 and Qi-5d, wherein Qma and Qmd are as defined above, (g) - CO-NQma Qmd wherein Qma and Qmd are as defined above, (h) -SO ₂ -NQmaQi-5d wherein Qma and Qmd are as defined above, (i) -NQ has -SO ₂ -Qmd where Qma and Qmo are as defined higher, - 188 (j) -NO₂, (k) -0-S0₂ -CF₃;188 (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ ; (K) 3-oxadiazol voliteľne substituovaný jedným Qi.s, kde Q1.5 je definované vyššie, (L) triazol voliteľne substituovaný jedným alebo dvoma Q1.5, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (M) 5-tiadiazol voliteľne substituovaný jedným Q1-5. kde Q1.5 je definované vyššie, (N) 3-tiadiazol voliteľne substituovaný jedným Q1-5, kde Q1-5 je definované vyššie, (O) 2-oxazol voliteľne substituovaný jedným alebo dvoma Qi.s, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (P) 2-tiazol voliteľne substituovaný jedným alebo dvoma Q1.5, ktoré môžu byť zhodné alebo rôzne, kde Q1.5 je definované vyššie, (Q) 2-imidazol voliteľne substituovaný jedným, dvoma alebo troma Q1.5, ktoré môžu byť zhodné alebo rôzne, kde Q1-5 je definované vyššie, (R) 1-imidazol substituovaný jedným, dvoma alebo troma Q1-5, ktoré môžu byť zhodné alebo rôzne, kde Qi.j je definované vyššie, (S) tetrazol voliteľne substituovaný jedným Q1.5, kde Q1-5 je definované vyššie, (T) cyklobuténdión voliteľne substituovaný jedným Q1-1 a jedným Q1.5, kde Qm a Qi. 5 sú definované vyššie, (U) 1-pyrimidinyl voliteľne substituovaný jedným Q1.5, kde Q1.5 je definované vyššie, (V) 2-pyridinyl voliteľne substituovaný jedným Q1.5, kde Q1.5 je definované vyššie, (W) 3-pyridinyl voliteľne substituovaný jedným Q1.5, kde Q1-5 je definované vyššie, (X) 4-pyridinyl voliteľne substituovaný jedným Q1.5, kde Q1-5 je definované vyššie, (Y) -Zi -CO -Z₂ -Qi-₂, kde Qi.₂ je definované vyššie a Zi je -O- alebo(K) 3-oxadiazole optionally substituted with one Q1.s, wherein Q1.5 is as defined above, (L) triazole optionally substituted with one or two Q1.5s, which may be identical or different, wherein Q1.5 is as defined above, ( M) 5-Thiadiazole optionally substituted with one Q1-5. wherein Q1.5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1-5, wherein Q1-5 is as defined above, (O) 2-oxazole optionally substituted with one or two Q1.s, which may be identical or different wherein Q1.5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1.5, which may be identical or different, wherein Q1.5 is as defined above, (Q) 2-imidazole optionally substituted with one, two or three Q1.5, which may be identical or different, wherein Q1-5 is as defined above, (R) 1-imidazole substituted with one, two or three Q1-5, which may be identical or different, wherein Q1.j is defined above, (S) tetrazole optionally substituted with one Q1.5, wherein Q1-5 is as defined above, (T) cyclobutenedione optionally substituted with one Q1-1 and one Q1.5, wherein Qm and Q1. 5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one Q1.5, wherein Q1.5 is as defined above, (V) 2-pyridinyl optionally substituted with one Q1.5, wherein Q1.5 is as defined above, (W) 3-pyridinyl optionally substituted with one Q1.5, where Q1-5 is as defined above, (X) 4-pyridinyl optionally substituted with one Q1.5, where Q1-5 is as defined above, (Y) -Z-CO-Z ₂ - Qi- ₂ , where Qi. ₂ is as defined above and Z 1 is -O- or -Nqm , kde Qi-i je definované vyššie, kde Z₂ je -O- alebo-Nqm, wherein Q 1 -i is as defined above, wherein Z ₂ is -O- or - 189-Nqm , kde qm je definované vyššie s výhradou, že pokiaľ Xi je -(CH₂)ni kde ni a Qi je:- 189-Nqm, where qm is as defined above, with the proviso that when Xi is - (CH ₂ ) ni where ni and Qi is: -CO-NQm Qm,-CO-NQm Qm -SO₂-NQmQi.2 aleboOr _-SO2 -NQmQi.2 -NQmQi-2,-NQmQi-2, -NQm-CO-Qi-2 potom Qm a Qm nemôžu byť obidva vybrané z-NQm-CO-Qi-2 then Qm and Qm cannot both be selected from -H,-H. -Ci-C₆ alkyl,-C 1 -C ₆ alkyl, -C3-C7 cykloalkyl,-C3-C7 cycloalkyl, -C1-C3 alkyl-(C₃-C7) cykloalkyl a ich farmaceutický prijateľné soli.-C 1 -C 3 alkyl- (C ₃ -C 7) cycloalkyl and pharmaceutically acceptable salts thereof. 3. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Wi je dusíkový atóm.The 1,6-disubstituted isochroman (I) according to claim 1, wherein W 1 is a nitrogen atom. 4.1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Wi je uhlíkový atóm.4.1,6-disubstituted isochroman (I) according to claim 1, wherein W 1 is a carbon atom. 5. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Xi je -(CH2)ni -.The 1,6-disubstituted isochroman (I) of claim 1, wherein X 1 is - (CH 2) n 1 -. 6. 1,6-disubstituovaný izochróman (I) podľa nároku 5, kde m je 0 alebo 1.The 1,6-disubstituted isochroman (I) according to claim 5, wherein m is 0 or 1. 7. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Xi je -CH=CH-.The 1,6-disubstituted isochroman (I) of claim 1, wherein X 1 is -CH = CH-. 8. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Ri je -O-Rm, -CF₃, -CO-N(Rm)₂ a -CO-RmThe 1,6-disubstituted isochroman (I) of claim 1, wherein R 1 is -O-R m, -CF ₃ , -CO-N (R m) _2, and -CO-R m. 9. 1,6-disubstituovaný izochróman (I) podľa nároku 7, kde Rm je Ci-C₃ alkyl.The 1,6-disubstituted isochroman (I) of claim 7, wherein R m is C 1 -C ₃ alkyl. 10. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde R₂ je -H.The 1,6-disubstituted isochroman (I) of claim 1, wherein R ₂ is -H. 11. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Qi je vybrané zo skupiny pozostávajúcej z -CO-NQmQi-2, -SO2-NQmQi-2, a -NQmQi-2The 1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is selected from the group consisting of -CO-NQmQi-2, -SO 2 -NQmQi-2, and -NQmQi-2. 12. 1,6-disubstituovaný izochróman (I) podľa nároku 10, kde Qi je -CO-NQmQi-2- 190The 1,6-disubstituted isochroman (I) of claim 10, wherein Q 1 is -CO-NQ m Q 1 -2 -190. 13. 1,6-disubstituovaný izochróman (I) podľa nároku 11, kde farmaceutický prijateľný anión soli je vybraný zo skupiny pozostávajúcej z aniónu kyseliny metánsulfónovej, chlorovodíkovej, bromovodíkovej, sírovej, fosforečnej, dusičnej, benzoovej, citrónovej, vínnej, fúmarovej, maleínovej, CH₃ -(CH₂)n -COOH, kde n je 0 až 4, H00C-(CH₂)„-C00H, kde n je definované vyššie.The 1,6-disubstituted isochroman (I) of claim 11, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic anionic anions. CH ₃ - (CH ₂₎ n COOH where n is 0-4, H00C- _(CH2) "- C00H, wherein n is as defined above. 14. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Ri je (Q)-CO-Rm alebo -CO-OQl-2The 1,6-disubstituted isochroman (I) of claim 1, wherein R 1 is (Q) -CO-R m or -CO-OQ1-2 15. 1,6-disubstituovaný izochróman (I) podľa nároku 14, kde 1,6-disubstituovaným izochrómanom je (S)-(-)-l-[2-[4-(4-trifluóracetylfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid.The 1,6-disubstituted isochroman (I) of claim 14, wherein the 1,6-disubstituted isochroman is (S) - (-) - 1- [2- [4- (4-trifluoroacetylphenyl) -1-piperazinyl] ethyl ] -N-methylisochroman-6-carboxamide. 16. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Qi je (Y)-Zi-CO-Z₂-Qi-₂.The 1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is (Y) -Z 1 -CO-Z ₂ -Q _{1 - 2} . 17. 1,6-disubstituovaný izochróman (I) podľa nároku 16, kde 1,6-disubstituovaný izochróman je vybraný zo skupiny pozostávajúcej z (S)-(-)-6-amino-1 -[2-[4-(4-metoxyfeny l)piperazín-1 -yl]etyl]izochrómanmetyl močovina, (S)-(-)-6-amino-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl]etyl]izochróman tbutylkarbamát a (+/-)- l-[2-[4-(4-metoxyfenyl) -l-piperazinyl]etyl]izochróman-6-ol metyl karbamát ester.The 1,6-disubstituted isochroman (I) of claim 16, wherein the 1,6-disubstituted isochroman is selected from the group consisting of (S) - (-) - 6-amino-1- [2- [4- (4)]. (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] isochromanebutylcarbamate-methoxyphenyl) piperazin-1-yl] ethyl] and (+/-) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol methyl carbamate ester. 18. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Qi je (F’) -NQm -CO-Qi-₂.The 1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is (F ') -NQ m -CO-Q ₁₂ . 19. 1,6-disubstituovaný izochróman (I) podľa nároku 18, kde 1,6-disubstituovaný izochróman je vybraný zo skupiny pozostávajúcej z:The 1,6-disubstituted isochroman (I) of claim 18, wherein the 1,6-disubstituted isochroman is selected from the group consisting of: (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl]etyl]-6-yl]benzamid a (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl]etyl]-6-yl]akrylamid.(S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] benzamide; and (S) - (-) - N - [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acrylamide. 20. 1,6-disubstituovaný izochróman (I) podľa nároku 1, kde Qm a Qi.₂ tvoria spolu s pripojeným dusíkovým atómom 5 a 6 členný kruh.The 1,6-disubstituted isochroman (I) of claim 1, wherein Q m and Q 1. ₂ together with the attached nitrogen atom form a 5 and 6 membered ring. - 19121. 1,6-disubstituovaný izochróman (I) podľa nároku 20, kde 5 a 6 členný kruh je vybraný zo skupiny pozostávajúcej z pyrolidínu, piperidínu, piperazínu a morfolínu.The 1,6-disubstituted isochroman (I) of claim 20, wherein the 5 and 6 membered ring is selected from the group consisting of pyrrolidine, piperidine, piperazine, and morpholine. 22. 1,6-disubstituovaný izochróman (I) podľa nároku 20, ktorým je (+/-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinylyl]etyl]izochróman-6-yl]-4metylpiperazín.The 1,6-disubstituted isochroman (I) of claim 20 which is (+/-) -1- [2- [4- (4-methoxyphenyl) -1-piperazinylyl] ethyl] isochroman-6-yl] - 4-methylpiperazin. 23. 1,6-disubstituovaný izochróman (I) podľa nároku 1, ktorý je vybraný zo skupiny pozostávajúcej z:The 1,6-disubstituted isochroman (I) of claim 1, which is selected from the group consisting of: l-[2-[4-(4-metylsulfonylfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamid, (S)-(-)-l-[2-[4-(4-trifluórmetoxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6karboxamid,1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-trifluoromethoxyphenyl) -1- piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide, 1 -[2-[4-(4-metylsulfonylfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6-karboxamid,1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-allylizochróman-6-karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-allylisochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-propargylizochróman-6-karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargylisochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-(4-metoxy fenylmetyl)-izochróman-6karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (4-methoxyphenylmethyl) -isochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-fenylmetylizochróman-6-karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethylisochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-[(R)-a-mety lfenylmetylj-izochróman6-karboxamid, l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-[(S)-a-metylfenylmetyl]-izochróman6-karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -α-methylphenylmethyl] isochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl)] piperazinyl] ethyl] -N - [(S) -a-methylphenylmethyl] -izochróman6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)~ 1 -piperaziny l]etyl]-N-feny lizochróman-6-karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylisochroman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-feny lmetyl -N-metylizochróman-6karboxamid, l-(4-metoxyfenyl)-4-[2-[6-(5-metyloxazol-2-yl)izochróman-l-yl)etyl]piperazín,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-N-methylisochroman-6-carboxamide, 1- (4-methoxyphenyl) -4- [2- [6- (5) -metyloxazol-2-yl) isochroman-l-yl) ethyl] piperazine, - 192(S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]metánsulfónamid,- 192 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] methanesulfonamide, 1 -(4-metoxyfenyl)-4-[2-(6-metylaminometylizochróman-1 -yl)etyl]piperazín,1- (4-Methoxyphenyl) -4- [2- (6-methylaminomethylisochroman-1-yl) ethyl] piperazine, 1 -(4-metoxyfenyl)-4-[2-(6-dimetylaminometylizochróman-1 -yl)etyl]piperazín, etylester l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6- karboxylovej kyseliny,1- (4-Methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine, 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6 ethyl ester - carboxylic acid, 6-acetyl-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyljety 1] izochróman,6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, 6-formyl- l-[2-[4-(4-metoxyfenyl)-1 -piperazinyl] etyl] izochróman,6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, 2-[izochróman-1 -[2-[4-(4-metoxyfeny l)piperazín-1 -yl]etyl]-6-yl]acetamid,2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide, 2-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl]etyl]-6-yl]-N-metylacetamid, (S)-(-)-3-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]-N,Ndimetylakrylamid, (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(l,2,4-triazol-3-yl)-izochróman-l-yl]etyl]piperazín, (S)-(-)-1 -(4-metoxyfeny 1)-4-(2- [6-(2-metyl-1,2,4-triazol-3 -y l)-izochróman-1 yl]etyl]piperazín, (S)-(-)-1 -(4-metoxyfenyl)-4-[2-[6-(2-fenylmetyl-1,2,4-triazol-3-yl)-izochróman-1 yl]etyl]piperazín, (S)-(-)-l-(4-metoxyfenyl)-4-[2-[6-(l,2,4-oxadiazol-5-yl)-izochróman-lyl]etyl]piperazín,2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide, (S) - (-) - 3- [isochroman-1] - [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N, N-dimethylacrylamide, (S) - (-) - 1- (4-methoxyphenyl) -4- [2] - [6- (1,2,4-triazol-3-yl) -isochroman-1-yl] ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- (2- [6- (2-methyl-1,2,4-triazol-3-yl) -isochroman-1-yl] ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2] - [6- (2-phenylmethyl-1,2,4-triazol-3-yl) -isochroman-1-yl] ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [ 2- [6- (l, 2,4-oxadiazol-5-yl) isochroman-yl] ethyl] piperazine, 1 -(2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-yl]karbonyl]pyrolidín,1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-yl] carbonyl] pyrrolidine, N-(2-hydroxyetyl)-1 -[2-[4-(4-metoxyfeny 1)-1 -piperazinyl]etyl]izochróman-6karboxamid,N- (2-hydroxyethyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1 -(2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-(fenylmetoxy)izochróman-6karboxamid,1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (phenylmethoxy) isochroman-6-carboxamide, - 193(+/-)-N-hydroxy-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid, (S)-(-)-1 -[2-[4-(4-aminokarbonyl)fenyl]-1 -piperaziny l]etyl]-N-metyl-N(fenylmetoxy)izochróman-6-karboxamid, (S)-(-)-1 -[2-[4-(4-aminokarbonyl)fenyl]-1 -piperazinyl] etyl]-N-metyl-Nmetylizochróman-6-karboxamid, (S)-(-)N-hydroxy-N-metyl-1 -[2-[4-(4-trifluórmetyl)fenyl]-1 piperazinyl]etyl]izochróman-6-karboxamid, (S)-(-)-1 -[2-[4-(4-chlorofenyl)-1 -piperazinyl]etyl]-N-hydroxy-N-metylizochróman-6karboxamid, (S)-(-)-1 -[2-[4-(4-kyanofenyl)-1 -piperazinyl]etyl]-N-hydroxy-N-metylizochróman-6karboxamid, (S)-(-)-N-hydroxy-N-metyl-l-[2-[4-[4-(metylkarbonyl)fenyl]-lpiperazinyl]etyl]izochróman-6-karboxamid, (S)-4-[4-[2-[6-( 1,2,4-triazol-3-yl)izochróman-1 -yl] ety 1] -1 -piperazinyljbenzamid, (S)-4-[4-[2-[6-(2-metyl-l ,2,4-triazol-3-yl)izochróman-l -yl]etyl]-l piperazinyljbenzamid, (S)-4-[4-[2-[6-( 1,2,4-oxadiazol-5-yl)izochróman-1 -y 1] ety 1] -1 -piperazinyljbenzamid, (S)-l -[2-[6-(l ,2,4-triazol-3-yl)izochróman-1 -yl]etyl]-4-[4-trifluórmetylfenyl]piperazín, (S)-1 -[2-[6-(2-mety 1-1,2,4-triazol-3 -yl)izochróman-1 -y 1] etyl] -4-[4trifluórmetylfenyljpiperazín, (S)-1 - [2- [6-( 1,2,4-oxadiazol-5-yl)izochróman-1 -y l]etyl]-4-[4trifluórmetylfenyljpiperazín, (S)-1 -[4-acetylfenyl]-4-[2-[6-( 1,2,4-triazol-3 -yl)izochróman-1 -yljetyljpiperazín, (S)-1 -[4-acetylfeny lJ-4-[2-[6-(2-metyl-1,2,4-triazol-3 -yl)izochróman-1 yl]etyl]piperazín,- 193 (+/-) - N-hydroxy-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1 - [ 2- [4- (4-aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl-N (phenylmethoxy) isochroman-6-carboxamide, (S) - (-) - 1- [2- [4] - (4-aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl-N-methylisochroman-6-carboxamide, (S) - (-) N-hydroxy-N-methyl-1- [2- [4- ( 4-Trifluoromethyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N-hydroxy N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide, (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) -4- [4- [2] - [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -1-piperazinyl] benzamide, (S) -4- [4- [2- [6- (2-methyl)] -1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -1-piperazinyl-benzamide, (S) -4- [4- [2- [6- (1,2,4-oxadiazol-5)] -yl) isochroman-1-yl] ethyl] -1-piperazinyl] benzamide, (S) -1- [2- [6- (1,2,4) (Triazol-3-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine, (S) -1- [2- [6- (2-methyl-1,1,2,4-triazole)] -3-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine, (S) -1- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine, (S) -1- [4-acetylphenyl] -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine, (S) ) -1- [4-acetylphenyl] -4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine, - 194 (S)-l-[4-acetylfenyl]-4-[2-[6-(l,2,4-oxadiazol-5-yl)izochróman-l-yl]etyl]piperazín,- 194 (S) -1- [4-acetylphenyl] -4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] piperazine, 3 -[ 1 -[2-[4-(4-aminokarbonylfenyl)piperazín-1 -y 1] ety l]izochróman-6-yl]-N,Ndimetylakryl amid,3- [1- [2- [4- (4-Aminocarbonylphenyl) piperazin-1-yl] ethyl] isochroman-6-yl] -N, N-dimethylacrylamide, 3-[l -[2-[4-(4-trifluórmetylfenyl)piperazín-1 -yl]etyl]izochróman-6-yl]-N,Ndimetylakrylamid,3- [1- [2- [4- (4-Trifluoromethyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide, 3-[ 1 -[2-[4-(4-acetylfeny l)piperazín-1 -yl]-etyl]izochróman-6-yl]-N,Ndimetylakry lamid.3- [1- [2- [4- (4-Acetyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide. 24. Aromatický bicyklický amín vzorca (ABA) (ABA) (I) Wi je dusíkový (-N-) alebo uhlíkový (-CH-) atóm;Aromatic bicyclic amine of formula (ABA) (ABA) (I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (Π) Xi je -(CH₂)ni a ni je 0, (IH)Qije (A) -CO-NQm Qi._2; kde Qm je:(Π) X 1 is - (CH ₂ ) ni and ni is 0, (IH) Q is (A) -CO-NQm Qi. _2; where Qm is: (1) -H, (2) Cj-Cg alkyl, (3) C₂-Cg alkenyl obsahujúci 1 až 3 dvojité väzby (=), (4) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (5) -(CH₂)n7 -φ, kde n₇ je 0 až 4, a kde -φ je voliteľne substituovaný jedným alebo dvoma(1) -H, (2) C 1 -C 8 alkyl, (3) C ₂ -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=) (5) - (CH ₂ ) n ₇ -φ, wherein n ₇ is 0 to 4, and wherein -φ is optionally substituted with one or two - 195(a) -F,-Cl,-Br,-J, (b) -CsN, (c) -CF,, (d) C,-C₃ alkyl, (e) -O-Qma, kde Qma je -H, Ci -Ce alkyl, -CF₃ alebo -(CH)₂ -φ, (f) -NQmaQmb, kde Qma a Qmb sú zhodné alebo rôzne, a kde Qmb je -H, Ci-Cô alkyl, -CF3 alebo -CH₂-<J>, a kde Qma je definované vyššie, (g) -CO-NQma Qmb, kde Qma a Qmb sú definované vyššie, (h) -SO₂-NQma Qmb kde Qma a Qmb sú definované vyššie, (i) -NQma -SO₂ -Qmb kde Qma a Qmb sú definované vyššie, (j) -NO₂, (k) -O-SO₂ -CF3, a kde Qi_₂ je:195 (a) -F, -Cl, -Br, -J, (b) -C 5 N, (c) -C F 1, (d) C 1 -C ₃ alkyl, (e) -O-Qma, wherein Qma is -H, C 1 -C 6 alkyl, -CF ₃ or - (CH) ₂ -φ, (f) -NQma Qmb, wherein Qma and Qmb are the same or different, and wherein Qmb is -H, C 1 -C 6 alkyl, -CF 3 or -CH ₂ - <J>, and wherein Qma is as defined above, (g) -CO-NQma Qmb, wherein Qma and Qmb are as defined above, (h) -SO ₂ -NQma Qmb wherein Qma and Qmb are as defined above, (i) -NQma -SO ₂ -Qmb wherein Qma and Qmb are as defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF 3, and wherein Q ₁₂ is: (6) Ci-C₈ alkyl, (7) C₂-C₈ alkenyl obsahujúci 1 až 3 dvojité väzby (=), (8) C₂-C₈ alkinyl obsahujúci 1 alebo 2 trojité väzby (=), (9) -(ΟΙ₂)π₂-φ, kde n₂ je definované vyššie a -φ je voliteľne substituovaný jedným alebo dvoma:(6) C 1 -C ₈ alkyl, (7) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (8) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (9) - (ΟΙ ₂ ) π ₂ -φ, where n ₂ is as defined above and -φ is optionally substituted by one or two: (a) -F, -Cl,-Br,-J, (b) -C=N, (c) -CF₃, (d) Ci-Cô alkyl, (e) -O-Qi-_2A, kde Qi._2A je(a) -F, -Cl, -Br, -J, (b) -C = N, (c) _-CF3, (d) Ci-Co alkyl, (e) -O-Qi- _{2 A,} wherein Q . _2A is - 196(I) -Η, (ii) Ci-Cô alkyl, (iii) -CF₃, (iv) -(CHxH, (B) -SO2-NQ1.1 Qi-2, kde Qm a Qi.₂ sú definované vyššie, (C) -NQmQi-2, kde Qm a Qi.₂ sú definované vyššie, (D) -NQm-CO-Qi-2, kde Qm a Q1-2 sú definované vyššie, (ΙΠ) Ri je:- 196 (I) -Η, (ii) C 1 -C 6 alkyl, (iii) -CF ₃ , (iv) - (CH x H, (B) -SO 2 -NQ 1, Q 1 -2, wherein Q m and Q 1, ₂ are as defined above, (C) -NQmQi-2, wherein Q m and Q. ₂ are as defined above, (D) -CO--NQm Qi-2, wherein Q m and Q1-2 are as defined above, (ΙΠ) R is: (A) -H, (B) -F,-Cl,-Br,-J, ; (C) Ci-C₈ alkyl, (D) -ON, (E) -CF₃, (F) -O-Rm, kde Rm je:(A) -H, (B) -F, -Cl, -Br, -J,; (C) C 1 -C ₈ alkyl, (D) -ON, (E) -CF ₃ , (F) -O-R m, where R m is: (1) -H, (2) C_rC₈ alkyl, (3) -CF₃, (4) -SO₂-CF₃, (5) -(CH₂)n2-|, kde n₂ je 0 až 4 (G) -N(Rm)2, kde Rm sú zhodné alebo rôzne a sú definované vyššie, (H) -CO-N(Rm)₂, kde Rm sú zhodné alebo rôzne a sú definované vyššie,(1) -H, (2) C _r -C ₈ alkyl, (3) _-CF3, (4) _{-SO2 -CF3,} (5) - (CH ₂₎ n2 |, where n is 0 to ₂ 4 (G) -N (R m) 2, wherein R m are identical or different and are as defined above, (H) -CO-N (R m) ₂ , wherein R m are identical or different and are as defined above, - 197(I) -SO2-R1-3, kde Ru je:- 197 (I) -SO2-R1-3, where Ru is: (1) -cf₃, (2) Ci-Cg alkyl, (3) -Ο-Rua, kde Ri._3A je definované vyššie, (4) -NRi.3aRi-3b , kde Ru_Ä a Rub sú definované vyššie, (J) -CO-Ru, kde Ru je definované vyššie;(1) -cf ₃ , (2) C 1 -C 8 alkyl, (3) -Ο-Rua, wherein R 1. _3A is as defined above, (4) -NRi.3aRi-3 b, where R and _R are as defined above, Rub, (J) -CO-Ru wherein Ru is as defined above; (IV) R₂ je zhodné s Ri, R₂ môže byť zhodné alebo rôzne s Ri; a ich farmaceutický prijateľné soli.(IV) R ₂ is identical to R 1, R ₂ may be the same or different to R 1; and pharmaceutically acceptable salts thereof. 25. Aromatický bicyklický amín (ABA) podľa nároku 24, kde je (-N-).The aromatic bicyclic amine (ABA) of claim 24, wherein it is (-N-). 26. Aromatický bicyklický amín (ABA) podľa nároku 24, kde jeden z Ri a R₂ je -H.The aromatic bicyclic amine (ABA) of claim 24, wherein one of R 1 and R ₂ is -H. 27. Aromatický bicyklický amín (ABA) podľa nároku 24, kde Qi je (A) -CO -NQu Q1-2.The aromatic bicyclic amine (ABA) of claim 24, wherein Q 1 is (A) -CO -NQu Q 1-2. 28. Aromatický bicyklický amín (ABA) podľa nároku 27, kde Qu je -H.The aromatic bicyclic amine (ABA) of claim 27, wherein Qu is -H. 29. Aromatický bicyklický amín (ABA) podľa nároku 27, kde Qu je -CH₃.The aromatic bicyclic amine (ABA) of claim 27, wherein Qu is -CH ₃ . 30. Aromatický bicyklický amín (ABA) podľa nároku 27, kde farmaceutický prijateľný anión soli je vybraný zo skupiny pozostávajúcej z aniónu kyseliny metánsulfónovej, chlorovodíkovej, bromovodíkovej, sírovej, fosforečnej, dusičnej, benzoovej, citrónovej, tertarovej, filmárovej, maleínovej, CH3 -(CH₂)n -COOH, kde n je 0 až 4, HOOC -(CH₂)n COOH, kde n je definované vyššie.The aromatic bicyclic amine (ABA) of claim 27, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic acid, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tertaric, cinematographic, maleic, CH3 - ( CH ₂ ) n -COOH, wherein n is 0 to 4, HOOC - (CH ₂ ) n COOH, wherein n is as defined above. 31. Aromatické bicyklické amíny (ABA) podľa nároku 27, kde substituované aminozlúčeniny sú vybrané zo skupiny pozostávajúcej z (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6-karboxamid, (R) -(+)-l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6- karboxamid, (S) -(-)l-[2-[4-(4-trifluórmetylfenyl]-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid,Aromatic bicyclic amines (ABA) according to claim 27, wherein the substituted amino compounds are selected from the group consisting of (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] - N-methylisochroman-6-carboxamide, (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - ( -) l- [2- [4- (4-trifluoromethyl-phenyl] -l-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, - 198 (S)-(-) l-[2-[4-(4-(aminokarbonyl)fenyl]-1 -piperazinyl]etyl]-N-metylizochróman-6karboxamid,- 198 (S) - (-) 1- [2- [4- (4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1 -[2-[4-(4-etoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, l-[2-[4-(4-propoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid, (S)-(-)-1 -[2-[4-(4-etylfenyl)~ 1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, (S)-(-)-1 -[2-[4-(4-etoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, (S)-(-)-l-[2-[4-(4-fenylmetyloxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid, (R) -(+)-1 -[2-[4-(4-etoxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid,1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1- [2- [4- (4-propoxyphenyl) -1-piperazinyl] ethyl] - N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - ( -) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4) (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-ylmethyl-phenyl-1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide; 6- carboxamide, 1 -[2-[4-(3-trifluórmetylfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-propylizochróman-6-karboxamid,1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] - N-propylizochróman-6-carboxamide, 1 -[2-[4-(4-metoxyfenyl)-l -piperazinyl]etyl]-N-etylizochróman-6-karboxamid, l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]-N-butylizochróman-6-karboxamid, l-[2-[4-(4-chlórfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid, (S) -(-)-l-[2-[4-(4-metoxyfenyl)-l-piperidinyl]etyl]-N-metylizochróman-6-karboxamid, (S)-(-)-1 -[2-[4-(4-hydroxyfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, (S)-(-)-l-[2-[4-(4-trifluórmetánsulfonyloxyfenyl)-l-piperazinyl]etyl]-N-metyl-izochróman-6karboxamid, (S)-(-) 1 -[2-[4-(4-acetylfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6- karboxamid, (S)-(-)-N-metyl-l-[2-[4-(4-propionylfenyl)-l-piperazinyl]etyl]izochróman-6- karboxamid,1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-ethylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] - N-butylisochroman-6-carboxamide, 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide, (S - (-) 1- [2- [4- (4-Acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - N-methyl-1- [2] - [4- (4-Propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, N-metyl-1 - [2-(4-fenyl)-1 -piperidiny 1] etyl] izochróman-6- karboxamid, (+/-)-N-metyl-1 -[2-[4-(2,4-dichlórfenyl)-1 -piperazinyljetyl Jizochróman-6-karboxamid, (+/-)-l-[2-[4-(3-chlór-4-metoxyfenyl)-l-piperazinyl]etyl]-N-metylizochróman-6-karboxamid,N-methyl-1- [2- (4-phenyl) -1-piperidinyl 1] ethyl] isochroman-6-carboxamide, (+/-) - N-methyl-1- [2- [4- (2,4) (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6- (dichlorophenyl) -1-piperazinyl-ethyl] iso-chroman-6-carboxamide carboxamide - 199(S)-(-)-l-[2-[4-[4-(terc-butyloxykarbonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid, (+/-)-l-[2-[4-[4-(aminokarbonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochrómanyl-6karboxamid, (R) -(⁺)^-1 -[2-[4-[4-(aminokarbonyl)fenyl]-1 -piperazinyl]etyl]-N-metylizochrómanyl-6karboxamid, (+/-)-l-[2-[4-[4-(aminosulfonyl)fenyl]-l-piperazinyl]etyl]-N-metylizochróman-6karboxamid, (S) -(-)-N-metyl-1 -[2-[4-[4-(metylaminokarbonyl)fenyl]-1 -piperazinyl]etyl]izochróman-6karboxamid, (S)-(-)-N-metyl-l-[2-[4-[4-(dimetylaminokarbonyl)fenyl]-l-piperazinyl]etyl]izochróman-6karboxamid, (S)-(-)-N-metyl-l-[2-[4-[4-(n-propylaminokarbonyl)fenyl]-l-piperazinyl]etyl]izochróman-6karboxamid.- 199 (S) - (-) - 1- [2- [4- [4- (tert-butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide, (R) - ( ⁺ ) ^- 1- [2- [4- [4- (aminocarbonyl)] phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide, (+/-) -1- [2- [4- [4- (aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman- 6-carboxamide, (S) - (-) - N-methyl-1- [2- [4- [4- (methylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - N -methyl-1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - N-methyl-1- [2- [4- [4- (n-propylamino carbonyl) phenyl] piperazinyl] ethyl] isochroman-6-carboxamide. 32. Aromatický bicyklický amín (ABA) podľa nároku 31, kde substituovanou aminozlúčeninou je (S)-(-)-1 -[2-[4-[4-(trifluórmetylfenyl)-1 -piperazinyl]etyl]-N-metylizochróman-6-karboxamid a (S)-(-)-1 -[2-[4-[4-(aminokarbonyl)fenyl]-1 -piperazinyl]etyl]-N-metylizochróman-6karboxamid.The aromatic bicyclic amine (ABA) of claim 31, wherein the substituted amino compound is (S) - (-) - 1- [2- [4- [4- (trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 6-carboxamide and (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide. 33. Aromatický bicyklický amín (ABA) podľa nároku 27, kde substituovaná aminozlúčenina je vybraná zo skupiny pozostávajúcej zThe aromatic bicyclic amine (ABA) of claim 27, wherein the substituted amino compound is selected from the group consisting of: 1 -[2-[4-(4-chlórfenyl)-1 -piperazinyl]etyl]-N,N-dimetylizochróman-6- karboxamidu a (S)-(-)-l-[2-[4-(4-trifluorometylfenyl)-l-piperazinyl]etyl]-N,N-dimetylizochróman-6karboxamidu.1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide and (S) - (-) - 1- [2- [4- (4- trifluoromethylphenyl) piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide. -20034. Aromatický bicyklický amín (ABA) podľa nároku 24, kde substituovaná aminozlúčenina je volená zo skupiny pozostávajúcej z-20034. The aromatic bicyclic amine (ABA) of claim 24, wherein the substituted amino compound is selected from the group consisting of: 1 -[2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)piperazínu, (S)-(-)-l -2-(6-aminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)piperazínu, (S)-(-)-1 -2-(6-etylaminoizochróman-1 -yl)-etyl]-4-(4-metoxyfenyl)piperazínu, (S)-(-)-1 -(4-metoxyfenyl)-4-[2-(6-propylaminoizochróman-1 -yl)etyl]piperazínu, (S)-(-)-l-(4-metoxyfenyl)-4-[2-(6-metylaminoizochróman-l-yl)etyl]piperazínu, (S)-(-)-1 -(4-metoxyfenyl)-4-[2-(6-dimetylaminoizochróman-1 -yl)etyl]piperazínu a (S)-(-)-l-2-(6-etylmetylaminoizochróman-l-yl)etyl]-4-(4-metoxyfenyl)piperazínu.1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine, (S) - (-) - 1-2- (6-aminoisochroman-1-yl) -ethyl -4- (4-Methoxyphenyl) piperazine, (S) - (-) -1- 2- (6-ethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine, (S) - ( -) - 1- (4-methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl) ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminoisochroman-1-yl) ethyl] piperazine, and (S) - (-) - l-2- (6-etylmetylaminoizochróman-yl) ethyl] -4- (4-methoxyphenyl) piperazine. 35. Aromatický bicyklický amín (ABA) podľa nároku 24, kde substituovaná aminozlúčenina je vybraná zo skupiny pozostávajúcej z (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -yl] etyl]-6-yl]formamidu, (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]acetamidu, (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]propiónamidu, (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]izobutyramidu, (S)-(-)-N-[izochróman-l-[2-[4-(4-metoxyfenyl)piperazín-l-yl]etyl]-6-yl]-N-metylacetamidu a (S)-(-)-N-[izochróman-1 -[2-[4-(4-metoxyfenyl)piperazín-1 -y 1] etyl]-6-y 1] -Nmetylizobutyramidu.The aromatic bicyclic amine (ABA) of claim 24, wherein the substituted amino compound is selected from the group consisting of (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazine-1]. (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] ethyl] -6-yl] formamide (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide, (S) - (-) (S) - (-) - N- [Isochroman-1-yl] -N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] isobutyramide [2- [4- (4-Methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide and (S) - (-) - N- [isochroman-1- [2- [4-] (4-Methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylisobutyramide. 36. Aromatický bicyklický amín je vybraný zo skupiny pozostávajúcej z (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamidu, (R)-(+)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamidu,36. The aromatic bicyclic amine is selected from the group consisting of (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (R) - ( +) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1 -[2-[4-(4-dietylaminofenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamidu,1- [2- [4- (4-diethylaminophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1 -[2-[4-(3 -trifluórmetylfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamidu,1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, -201(S)-(-)-l-[2-[4-(4-trifluórmetylfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu, l-[2-[4-(4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu,-201 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) - piperazinyl] ethyl] isochroman-6-carboxamide, 1 - [2-[4-feny lpiperaziny 1] etyl] izochróman-6-karboxamidu,1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide, 1 -[2-[4-(4-hydroxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamidu, (+/-)-l-[2-(4-fenyl-l-piperidinyl)etyl]izochróman-6-karboxamidu, (+/-)-l-[2-[4-(2,4-dichlorofenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu, l-[2-[4-(3-chlór-4-metoxyfenyl)-l-piperazinyl]etyl]izochróman-6-karboxamidu.1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman- 6-carboxamide, (+/-) - 1- [2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4- (3-chloro) 4-methoxyphenyl) piperazinyl] ethyl] isochroman-6-carboxamide. 37. Aromatický bicyklický amín podľa nároku 36, ktorým je (S)-(-)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamid, (R)-(+)-1 -[2-[4-(4-metoxyfenyl)-1 -piperazinyl]etyl]izochróman-6-karboxamid.The aromatic bicyclic amine of claim 36 which is (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (R) - ( +) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide. 38. Aromatický bicyklický amín podľa nároku 36, kde farmaceutický prijateľný anión soli je vybraný zo skupiny pozostávajúcej z aniónu kyseliny metánsulfónovej, chlorovodíkovej, bromovodíkovej, sírovej, fosforečnej, dusičnej, benzoovej, citrónovej, vínnej, fumarovej, maleínovej, CH₃ -(CH₂)„ -COOH, kde n je 0 až 4, HOOC-(CH₂)„ -COOH, kde n je definované vyššie.The aromatic bicyclic amine of claim 36, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic acid, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartar, fumaric, maleic, CH ₃ - (CH ₂₎ ) "-COOH where n is 0 thru 4, HOOC- _(CH2)" COOH, wherein n is as defined above.