HRP980441A2 - 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives - Google Patents

2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives

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HRP980441A2
HRP980441A2 HR60/055,764A HRP980441A HRP980441A2 HR P980441 A2 HRP980441 A2 HR P980441A2 HR P980441 A HRP980441 A HR P980441A HR P980441 A2 HRP980441 A2 HR P980441A2
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fluoro
diseases
piperazin
hydrogen
ylmethyl
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Hans Rollema
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Hans Rollema
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Description

Stanje tehnike izuma State of the art of the invention

Ovaj izum se odnosi na 2-(4-aril ili heteroaril-piperazin-1-ilmetil)-1H-indol derivate koji posjeduju centralnu dopaminergijsku aktivnost. Takvi spojevi su korisni u tretmanu oboljenja centralnog živčanog sustava (CNS). Ovaj izum se također odnosi na postupak korištenja takvih spojeva u tretmanu gornjih oboljenja kod sisavaca, uključujući i ljude, i na za to korisne farmaceutske preparate. This invention relates to 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives possessing central dopaminergic activity. Such compounds are useful in the treatment of diseases of the central nervous system (CNS). This invention also relates to the method of using such compounds in the treatment of the above diseases in mammals, including humans, and to pharmaceutical preparations useful therefor.

Općenito se smatra da su dopamin receptori važni za mnoge funkcije u tijelu životinje. Na primjer, izmijenjene funkcije ovih receptora učestvuju u postanku duševne bolesti, sklonosti lijeku, prisilnim oboljenjima, bipolarnim oboljenjima, viđenju, emesisu, spavanju, hranjenju, učenju, pamćenju, seksualnom ponašanju, regulaciji imunoloških odziva i krvnom tlaku. Kako ovi receptori kontroliraju veliki broj farmakoloških događaja, nisu svi od njih sada poznati, postoji mogućnost da spojevi koji djeluju preferencijalno na D4 dopamin receptor mogu pokazati široki opseg terapeutskih efekata na ljude. Dopamine receptors are generally considered to be important for many functions in the animal's body. For example, altered functions of these receptors are involved in mental illness, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immune responses, and blood pressure. As these receptors control a large number of pharmacological events, not all of which are currently known, it is possible that compounds that act preferentially at the D4 dopamine receptor may exhibit a wide range of therapeutic effects in humans.

2-(4-aril ili heteroaril-piperazin-1-ilmetil)-1H-indol derivati iz ovog izuma, uključujući oblike tautomera, enantiomera i prihvatljivih adicijskih soli kiseline, su centralno djelujući D4 dopamin receptor agonisti i tako su korisni kao pojačavači spoznaje i za tretman CNS oboljenja, takvih kao Parkinson-ovo oboljenje, Alzheimer-ovo oboljenje, abnormalnosti učenja i pamćenja. Druga osobina ovog izuma omogućava primjenu kombinacija spojeva iz ovog izuma zajedno sa D1, D2, D3 ili D5 dopamin receptor agonistima, takvim kao L-dopa i D2 agonisti, u tretmanu CNS oboljenja, takvih kao Parkinson-ovo oboljenje, Alzheimer-ovo oboljenje, oboljenje nedostatka pažnje i abnormalnosti učenja i pamćenja. The 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives of this invention, including forms of tautomers, enantiomers, and acceptable acid addition salts, are centrally acting D4 dopamine receptor agonists and are thus useful as cognitive enhancers and for the treatment of CNS diseases, such as Parkinson's disease, Alzheimer's disease, learning and memory abnormalities. Another feature of this invention enables the use of combinations of compounds from this invention together with D1, D2, D3 or D5 dopamine receptor agonists, such as L-dopa and D2 agonists, in the treatment of CNS diseases, such as Parkinson's disease, Alzheimer's disease, attention deficit disorder and learning and memory abnormalities.

Kratki pregled izuma Brief overview of the invention

Ovaj izum se odnosi na spoj formule This invention relates to a compound of the formula

[image] [image]

ili njegovu farmaceutski prihvatljivu sol, gdje isprekidana linija predstavlja opcionalnu dvostruku vezu; or a pharmaceutically acceptable salt thereof, wherein the dashed line represents an optional double bond;

a je 0 ili 1, gdje kada a je 0, X može formirati opcionalnu dvostruku vezu sa ugljikom susjednim sa V; a is 0 or 1, where when a is 0, X may form an optional double bond with the carbon adjacent to V;

V je CHR10, gdje R10 je vodik ili (C1-C6) alkil; V is CHR 10 , where R 10 is hydrogen or (C 1 -C 6 ) alkyl;

T je dušik ili CH; T is nitrogen or CH;

X je dušik ili CR11, gdje R11 je vodik, (C1-C6) alkil, (C1-C6) alkoksi, hidroksi ili ciano; X is nitrogen or CR 11 , where R 11 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, hydroxy or cyano;

Y i Z su svaki nezavisno dušik ili CR12, gdje R12 je vodik, kloro, bromo, trifluorometil, trifluorometoksi, ciano, (C1-C6) alkoksi ili (C1-C6) alkil; Y and Z are each independently nitrogen or CR 12 , where R 12 is hydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6 ) alkoxy or (C 1 -C 6 ) alkyl;

R1 je vodik, fluoro, kloro, bromo, trifluorometil, trifluorometoksi, ciano ili (C1-C6) alkil; R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or (C 1 -C 6 ) alkyl;

R2, R6, R7, R8 i R9 su svaki nezavisno odabrani od vodika, fluoro, kloro, bromo, trifluorometila, trifluorometoksi, ciano, (C1-C6) alkoksi i (C1-C6) alkila; R 2 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkyl;

R3 i R4 su svaki nezavisno vodik ili (C1-C6) alkil; i R 3 and R 4 are each independently hydrogen or (C 1 -C 6 )alkyl; and

R5 je vodik, (C1-C6) alkoksi, trifluorometil, ciano, (C1-C6) alkil ili R13CO-, gdje R13 je amino, (C1-C6) alkilamino, ((C1-C6) alkil)2amino, (C1-C6) alkil, (C6-C10) aril; R5 is hydrogen, (C1-C6) alkoxy, trifluoromethyl, cyano, (C1-C6) alkyl or R13CO-, where R13 is amino, (C1-C6) alkylamino, ((C1-C6) alkyl)2amino, (C1- C6) alkyl, (C6-C10) aryl;

ili kada a je 1, R1 i R10 mogu biti uzeti zajedno sa ugljikom na koga su vezani radi formiranja spoja formule or when a is 1, R1 and R10 may be taken together with the carbon to which they are attached to form a compound of the formula

[image] [image]

gdje isprekidane linije predstavljaju opcionalne veze; where dashed lines represent optional links;

T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 i R9 su definirani kao gore; T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above;

b je 0 ili 1; i b is 0 or 1; and

A i B su svaki nezavisno CH, CH2, kisik, sumpor, NH ili dušik; A and B are each independently CH, CH 2 , oxygen, sulfur, NH or nitrogen;

pod uvjetom da kada X je dušik, opcionalna dvostruka veza između X i V ne postoji; provided that when X is nitrogen, the optional double bond between X and V does not exist;

pod uvjetom da kada b je 0, opcionalna dvostruka veza između A i B ne postoji; i provided that when b is 0, the optional double bond between A and B does not exist; and

pod uvjetom da kada b je 1, A i B ne mogu oba biti kisik ili sumpor. provided that when b is 1, A and B cannot both be oxygen or sulfur.

Termin "alkil" kako je ovdje korišteno, ako nije drugačije naznačeno, uključuje zasićene monovalentne ugljikovodične radikale koji imaju normalne, razgranate ili ciklične dijelove ili njihove kombinacije. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having normal, branched or cyclic moieties or combinations thereof.

Termin "alkoksi" kako je ovdje korišteno, uključuje O-alkil grupe, gdje "alkil" je definiran kao gore. The term "alkoxy" as used herein includes O-alkyl groups, where "alkyl" is defined as above.

Termina "tretiranje" kako je ovdje korišteno, odnosi se na okretanje, olakšanje, inhibiranje napretka, ili prevenciju oboljenja ili stanja na koji se takav termin primjenjuje, ili jedan ili više simptoma takvih oboljenja ili stanja. Termin "tretman" kako je ovdje korišteno, odnosi se na čin tretiranja, gdje je "tretiranje" definirano kao neposredno gore. The term "treating" as used herein refers to reversing, alleviating, inhibiting the progress of, or preventing the disease or condition to which such term applies, or one or more symptoms of such disease or condition. The term "treatment" as used herein refers to the act of treating, where "treating" is defined as immediately above.

Termin "oboljenja dopamin sustava" kako je ovdje korišteno, odnosi se na tretman oboljenja na koja se može utjecati ili olakšati sa mijenjanjem (npr. povećanje ili smanjenje) dopamin izazvane neurotransmisije. The term "diseases of the dopamine system" as used herein refers to the treatment of disorders that can be affected or alleviated by altering (eg, increasing or decreasing) dopamine-mediated neurotransmission.

Spojevi u skladu sa ovim izumom, budući da su ligandi za dopamin receptor podtipove, specijalno dopamin D4 receptor, unutar tijela, prikladno se primjenjuju u tretmanu oboljenja dopamin sustava. The compounds according to the present invention, since they are ligands for dopamine receptor subtypes, especially the dopamine D4 receptor, within the body, are conveniently used in the treatment of diseases of the dopamine system.

Spojevi formule I mogu imati hiralne centre, te stoga postojati u raznim enantiomernim oblicima. Ovaj izum se odnosi na sve optičke izomere i stereoizomere spojeva formule I i njihove smjese. Compounds of formula I can have chiral centers and therefore exist in various enantiomeric forms. This invention relates to all optical isomers and stereoisomers of compounds of formula I and their mixtures.

Poželjni spojevi formule I uključuju kod kojih gdje X je dušik. Preferred compounds of formula I include wherein X is nitrogen.

Drugi poželjni spojevi formule I uključuju one kod kojih Y i Z su svaki CR12, gdje R12 je vodik ili fluoro. Other preferred compounds of formula I include those wherein Y and Z are each CR 12 , wherein R 12 is hydrogen or fluoro.

Drugi poželjni spojevi formule I uključuju one kod kojih R2 je vodik, fluoro ili kloro. Other preferred compounds of formula I include those wherein R 2 is hydrogen, fluoro or chloro.

Drugi poželjni spojevi formule I uključuju one kod kojih R3, R4 i R5 su vodik. Other preferred compounds of formula I include those wherein R 3 , R 4 and R 5 are hydrogen.

Drugi poželjni spojevi formule I uključuju one kod kojih R7 je fluoro ili kloro. Other preferred compounds of formula I include those wherein R 7 is fluoro or chloro.

Drugi poželjni spojevi formule I uključuju one kod kojih R9 je fluoro, kloro, bromo ili alkoksi. Other preferred compounds of formula I include those wherein R 9 is fluoro, chloro, bromo or alkoxy.

Poželjniji spojevi formule I uključuju one kod kojih X je dušik; Y i Z su svaki CR13, gdje R13 je vodik ili fluoro; R2 je vodik, fluoro ili kloro; More preferred compounds of formula I include those wherein X is nitrogen; Y and Z are each CR 13 , where R 13 is hydrogen or fluoro; R 2 is hydrogen, fluoro or chloro;

R3, R4 i R5 su vodik; R7 je fluoro ili kloro; i R9 je fluoro, kloro, bromo ili alkoksi. R 3 , R 4 and R 5 are hydrogen; R 7 is fluoro or chloro; and R 9 is fluoro, chloro, bromo or alkoxy.

Specifični poželjni spojevi formule I uključuju slijedeće spojeve: Specific preferred compounds of formula I include the following compounds:

2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol; 2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-fluoro-2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol; 5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-fluoro-2-[4-(4-fluoro-fenil)-piperazin-1-ilmetil]-1H-indol; 5-fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-fluoro-2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-indol; 5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;

2-[4-(6-kloro-piridazin-3-il)-piperazin-1-ilmetil]-5-fluoro-1H-indol; 2-[4-(6-chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole;

5-fluoro-2-(4-[5'-fluoro]piridin-2-il-piperazin-1-ilmetil)-1H-indol; 5-fluoro-2-(4-[5'-fluoro]pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;

2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-azaindol; 2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole;

5-fluoro-2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-azaindol; i 5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole; and

2-[4-(4-fluoro-fenil)-piperazin-1-ilmetil]-1H-azaindol. 2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-azaindole.

Ovaj izum se također odnosi na postupak za tretiranje oboljenja dopamin sustava uključujući psihička oboljenja (afektivna duševna bolest, šizofrenija, i šizoafektivna oboljenja), pokretna oboljenja (ekstrapiramidalni sporedni efekti od neuroleptičkih sredstava, neuroleptički maligni sindrom, tardivna diskinezia, Gilles De La Tourette-ov sindrom, Parkinson-ovo oboljenje ili Huntington-ovo oboljenje), želučano-crijevna oboljenja (lučenje želučane kiseline ili emesis), kemijsku zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja (kongestivni otkaz srca i hipertenzija), okularna oboljenja i oboljenja spavanja kod sisavaca, koji obuhvaća unošenje u spomenutog sisavca količine D4 dopamin receptora selektivnog spoja prema formuli I ili njegove farmaceutski prihvatljive soli, koja je efikasna u tretiranju takvog oboljenja. This invention also relates to a method for treating diseases of the dopamine system including psychiatric disorders (affective mental illness, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptics, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal diseases (gastric acid secretion or emesis), chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases (congestive heart failure and hypertension), eye diseases and diseases sleep in mammals, which includes introducing into said mammal an amount of D4 dopamine receptor selective compound according to formula I or its pharmaceutically acceptable salt, which is effective in treating such a disease.

Ovaj izum se također odnosi na postupak za tretiranje oboljenja dopamin sustava uključujući psihička oboljenja (afektivna duševna bolest, šizofrenija, i šizoafektivna oboljenja), pokretna oboljenja (ekstrapiramidalni sporedni efekti od neuroleptičkih sredstava, neuroleptički maligni sindrom, tardivna diskinezia, Gilles De La Tourette-ov sindrom, Parkinson-ovo oboljenje ili Huntington-ovo oboljenje), želučano-crijevna oboljenja (lučenje želučane kiseline ili emesis), kemijsku zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja (kongestivni otkaz srca i hipertenzija), okularna oboljenja i oboljenja spavanja kod sisavaca, koji obuhvaća unošenje u spomenutog sisavca količine D4 dopamin receptora selektivnog spoja prema formuli I ili njegove farmaceutski prihvatljive soli, zajedno sa jednim ili više D1, D2, D3 ili D5 dopamin receptor agonistima, koja je efikasna u tretiranju takvog oboljenja. This invention also relates to a method for treating diseases of the dopamine system including psychiatric disorders (affective mental illness, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptics, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal diseases (gastric acid secretion or emesis), chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases (congestive heart failure and hypertension), eye diseases and diseases sleep in mammals, which comprises introducing into said mammal an amount of D4 dopamine receptor selective compound according to formula I or a pharmaceutically acceptable salt thereof, together with one or more D1, D2, D3 or D5 dopamine receptor agonists, which is effective in treating such a disease.

Ovaj izum se također odnosi na farmaceutski preparat za tretiranje oboljenja dopamin sustavima uključujući psihička oboljenja (afektivna duševna bolest, šizofrenija, i šizoafektivna oboljenja), pokretna oboljenja (ekstrapiramidalni sporedni efekti od neuroleptičkih sredstava, neuroleptički maligni sindrom, tardivna diskinezia, Gilles De La Tourette-ov sindrom, Parkinson-ovo oboljenje ili Huntington-ovo oboljenje), želučano-crijevna oboljenja (lučenje želučane kiseline ili emesis), kemijsku zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja (kongestivni otkaz srca i hipertenzija), okularna oboljenja i oboljenja spavanja kod sisavaca, koji obuhvaća unošenje u spomenutog sisavca količine D4 dopamin receptora selektivnog spoja formule I ili njegove farmaceutski prihvatljive soli, koja je efikasna u tretiranju takvog oboljenja. This invention also relates to a pharmaceutical preparation for the treatment of diseases of the dopamine systems, including mental diseases (affective mental illness, schizophrenia, and schizoaffective diseases), movement disorders (extrapyramidal side effects from neuroleptics, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette- this syndrome, Parkinson's disease or Huntington's disease), gastrointestinal diseases (gastric acid secretion or emesis), chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases (congestive heart failure and hypertension), eye diseases and sleeping disorders in mammals, which includes introducing into said mammal an amount of D4 dopamine receptor selective compound of formula I or its pharmaceutically acceptable salt, which is effective in treating such a disorder.

Ovaj izum se također odnosi na farmaceutski preparat za tretiranje oboljenja dopamin sustava uključujući psihička oboljenja (afektivna duševna bolest, šizofrenija, i šizoafektivna oboljenja), pokretna oboljenja (ekstrapiramidalni sporedni efekti od neuroleptičkih sredstava, neuroleptički maligni sindrom, tardivna diskinezia, Gilles De La Tourette-ov sindrom, Parkinson-ovo oboljenje ili Huntington-ovo oboljenje), želučano-crijevna oboljenja (lučenje želučane kiseline ili emesis), kemijsku zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja (kongestivni otkaz srca i hipertenzija), okularna oboljenja i oboljenja spavanja kod sisavaca, koji obuhvaća unošenje u spomenutog sisavca količine D4 dopamin receptora selektivnog spoja prema formuli I ili njegove farmaceutski prihvatljive soli, zajedno sa jednim ili više D1, D2, D3 ili D5 dopamin receptor agonistima, koja je efikasna u tretiranju takvog oboljenja. This invention also relates to a pharmaceutical preparation for the treatment of diseases of the dopamine system including mental diseases (affective mental illness, schizophrenia, and schizoaffective diseases), movement disorders (extrapyramidal side effects from neuroleptics, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette- this syndrome, Parkinson's disease or Huntington's disease), gastrointestinal diseases (gastric acid secretion or emesis), chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases (congestive heart failure and hypertension), eye diseases and sleeping disorders in mammals, which comprises introducing into said mammal an amount of D4 dopamine receptor selective compound according to formula I or a pharmaceutically acceptable salt thereof, together with one or more D1, D2, D3 or D5 dopamine receptor agonists, which is effective in treating such a disorder.

Detaljni opis izuma Detailed description of the invention

Slijedeće reakcijske sheme ilustriraju dobivanje spojeva iz ovog izuma. Ako nije drugačije naznačeno, T, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, i R8 u reakcijskim shemama i diskusiji koja slijedi definirani su kao gore. The following reaction schemes illustrate the preparation of the compounds of this invention. Unless otherwise indicated, T, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, and R8 in the reaction schemes and discussion that follows are defined as above.

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U reakciji 1 sheme 1, spojevi formule III i IV sprežu se u oblik odgovarajuće formule I sa prvim tretiranjem III sa O-, N-dimetil hidroksilamin hidrokloridom, dicikloheksilkarbodiimidom i bazom, takvom kao trietilamin, u polarnom aprotičnom otapalu, takvom kao metanol klorid. Tako formiran hidroksamid intermedijer reducira se korištenjem redukcijskog sredstva takvog kao litij aluminij hidrid, u polarnom aprotičnom otapalu, takvom kao tetrahidrofuran. Redukcijska aminacija aldehid tako formiranog intermedijera vrši se reagiranjem aldehida sa spojem formule IV u prisustvu natrij triacetoksiborohidrida i polarnog aprotičnog otapala, takvog kao dikloroetan. Reakcijska smjesa je miješana pod inertnom atmosferom, na sobnoj temperaturi tokom perioda vremena između oko 40 sati do oko 56 sati, poželjno oko 48 sati. In reaction 1 of scheme 1, compounds of formula III and IV are coupled to form the corresponding formula I by first treating III with O-, N-dimethyl hydroxylamine hydrochloride, dicyclohexylcarbodiimide and a base, such as triethylamine, in a polar aprotic solvent, such as methanol chloride. The hydroxamide intermediate thus formed is reduced using a reducing agent such as lithium aluminum hydride in a polar aprotic solvent such as tetrahydrofuran. Reductive amination of the aldehyde intermediate thus formed is performed by reacting the aldehyde with the compound of formula IV in the presence of sodium triacetoxyborohydride and a polar aprotic solvent, such as dichloroethane. The reaction mixture was stirred under an inert atmosphere at room temperature for a period of time between about 40 hours to about 56 hours, preferably about 48 hours.

U reakciji 1 sheme 2, spojevi formule VI, gdje L je odlazeća grupa takva kao kloro, bromo, metoksi ili bilo koji aktivni ester derivat takav kao para-nitro fenil ester, hidroksi benzotriazol ester, N-hidroksisukcinimid ester ili hidroksi, i IV sprežu se radi formiranja odgovarajućeg metanona spoja formule III sa reagiranjem VI i IV u prisustvu diizopropiletilamina, larbodiimida ili dehidracijskog sredstva i polarnog aprotičnog otapala, takvog kao metilen klorid, ili u obliku smjese koja sadrži, ako se želi, kombinacije organskih otapala ili vode takvih kao kombinacije cikličnih i acikličnih mono i dialkilamida, (C1-C4) alkoholi, halogenirana otapala, ili aciklični i ciklični alkileteri na temperaturama u opsegu od oko 0 °C do oko 150 °C ili točki ključanja iste smjese otapala. Dodavanje akceptora kiseline takvog kao alkilkarbonat, tercijarni amin ili slični reagens može biti vrlo korisno. In reaction 1 of Scheme 2, compounds of formula VI, where L is a leaving group such as chloro, bromo, methoxy or any active ester derivative such as para-nitro phenyl ester, hydroxy benzotriazole ester, N-hydroxysuccinimide ester or hydroxy, and IV couple is to form the corresponding methanone compound of formula III by reacting VI and IV in the presence of diisopropylethylamine, larbodiimide or a dehydrating agent and a polar aprotic solvent such as methylene chloride, or in the form of a mixture containing, if desired, combinations of organic solvents or water such as combinations of cyclic and acyclic mono and dialkylamides, (C1-C4) alcohols, halogenated solvents, or acyclic and cyclic alkyl ethers at temperatures in the range of about 0 °C to about 150 °C or the boiling point of the same solvent mixture. The addition of an acid acceptor such as an alkylcarbonate, tertiary amine or similar reagent can be very useful.

U reakciji 2 sheme 2, metanon spoj formule V se konvertira u odgovarajući spoj formule I, gdje R3 i R4 su vodik, sa redukcijom V sa redukcijskim sredstvom, takvim kao litij aluminij hidrid ili derivat borana, u prisustvu polarnog aprotičnog otapala, takvog kao tetrahidrofuran, tokom perioda vremena između oko 10 sati do oko 14 sati, poželjno oko 12 sati. In reaction 2 of Scheme 2, the methanone compound of formula V is converted to the corresponding compound of formula I, where R3 and R4 are hydrogen, by reduction of V with a reducing agent, such as lithium aluminum hydride or a borane derivative, in the presence of a polar aprotic solvent, such as tetrahydrofuran , during the time period between about 10 a.m. to about 2 p.m., preferably about 12 p.m.

U svakoj od gornjih reakcija, tlak nije kritičan. Tlakovi u opsegu od oko 0,506625 atmosfera do 3,03975 bara su prikladni, a najprikladniji je atmosferski tlak ambijenta (1,013325 bara). Također, za one reakcije gdje se poželjna temperatura mijenja sa određenim reagiranim spojevima, ne ističe se poželjna temperatura. Za takve reakcije, poželjna temperatura za određene reaktante može se odrediti ispitivanjem reakcije pomoću kromatografije tankog sloja. In each of the above reactions, pressure is not critical. Pressures in the range of about 0.506625 atmospheres to 3.03975 bar are suitable, with ambient atmospheric pressure (1.013325 bar) being the most suitable. Also, for those reactions where the preferred temperature changes with certain reacted compounds, the preferred temperature is not highlighted. For such reactions, the preferred temperature for certain reactants can be determined by examining the reaction using thin layer chromatography.

Novi spojevi formule I i njihovih farmaceutski prihvatljivih soli (u daljnjem tekstu označeni i kao "terapeutski spojevi iz ovog izuma") su korisni kao dopaminergijska sredstva, npr. oni posjeduju sposobnost mijenjanja neurotransmisije izazvane sa dopaminom kod sisavaca, uključujući i ljude. Oni su zato sposobni funkcionirati kao terapeutska sredstva u tretmanu mnoštva stanja kod sisavaca, tretmanu ili prevenciji kojima se može utjecati ili ublažiti sa povećanjem ili smanjenjem neurotransmisije izazvane sa dopaminom. The novel compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as "therapeutic compounds of the present invention") are useful as dopaminergic agents, eg, they possess the ability to alter dopamine-induced neurotransmission in mammals, including humans. They are therefore capable of functioning as therapeutic agents in the treatment, treatment, or prevention of a variety of mammalian conditions that may be affected or alleviated by increasing or decreasing dopamine-induced neurotransmission.

Spojevi formule I koji su bazne prirode sposobni su za formiranje velikog mnoštva soli sa raznim neorganskim i organskim kiselinama. Mada takve soli mogu biti farmaceutski prihvatljive za unošenje u životinje, često se želi u praksi da se početno izolira spoj formule I iz reakcijske smjese kao farmaceutski neprihvatljiva sol, i da se poslije jednostavno konvertira natrag u slobodni bazni spoj tretmanom sa alkalnim reagensom, te daljnjim konvertiranjem slobodne baze u farmaceutski prihvatljivu adicijsku sol kiseline. Adicijske soli kiseline baznih spojeva iz ovog izuma lako se dobivaju reagiranjem baznog spoja sa suštinski ekvivalentnom količinom izabrane neorganske ili organske kiseline u sredini vodenog otapala ili u prikladnom organskom otapalu, takvom kao metanol ili etanol. Poslije pažljivog isparavanja otapala, željena čvrsta sol se lako dobiva. Željena sol kiseline također se može istaložiti iz otopine slobodne baze u organskom otapalu sa dodavanjem u otopinu prikladne neorganske ili organske kiseline. Compounds of formula I which are basic in nature are capable of forming a large number of salts with various inorganic and organic acids. Although such salts may be pharmaceutically acceptable for administration to animals, it is often desired in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert it back to the free base compound by treatment with an alkaline reagent, and further by converting the free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily prepared by reacting the base compound with a substantially equivalent amount of a selected inorganic or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding a suitable inorganic or organic acid to the solution.

Terapeutski spojevi iz ovog izuma mogu se unositi oralno, transdermalno (npr. preko primjene melema), parenteralno ili topikalno. Oralno unošenje je poželjno. Općenito, ovi spojevi se najpoželjnije unose u doziranjima u opsegu od oko 0,1 mg do oko 1.000 mg po danu, ili 1 mg do 1.000 mg po danu u nekim slučajevima, mada se varijacije mogu primijeniti zavisno od težine i stanja osobe koja se tretira i određenog izabranog puta unošenja. U nekim slučajevima, nivoi doziranja ispod donje granice gore spomenutog opsega mogu biti više nego adekvatni, dok u drugim slučajevima još veće doze mogu se koristiti bez izazivanja bilo kakvog štetnog sporednog efekta, pod uvjetom da se takve veće doze prvo podijele u nekoliko malih doza za unošenje tokom dana. The therapeutic compounds of this invention can be administered orally, transdermally (e.g., via the application of an ointment), parenterally, or topically. Oral intake is preferred. Generally, these compounds are most preferably administered in dosages ranging from about 0.1 mg to about 1,000 mg per day, or 1 mg to 1,000 mg per day in some cases, although variations may be employed depending on the weight and condition of the subject being treated. and the specific selected entry path. In some cases, dosage levels below the lower end of the range mentioned above may be more than adequate, while in other cases even higher doses may be used without causing any adverse side effects, provided that such higher doses are first divided into several small doses for intake during the day.

Terapeutski spojevi iz izuma mogu se unositi sami ili u kombinaciji sa farmaceutski prihvatljivim nosačima ili razblaživačima sa jednim od dva puta ranije naznačena, a takvo unošenje može da se vrši pojedinačno ili u više doza. Preciznije, novi terapeutski spojevi iz ovog izuma mogu se unositi u velikom mnoštvu raznih oblika doziranja, npr. oni se mogu kombinirati sa raznim farmaceutski prihvatljivim inertnim nosačima u obliku tableta, kapsula, pastila, pilulica, tvrdih kandia, praškova, sprejeva, krema, melema, supozitorija, želea, gelova, pasti, losiona, pomada, eliksira, sirupa, i slično. Takvi nosači uključuju čvrste razblaživače ili punila, na primjer sterilne vodene sredine i razna netoksična organska otapala. Nadalje, oralni farmaceutski preparati mogu se prikladno zasladiti i/ili začiniti. Therapeutic compounds from the invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents with one of the two routes indicated earlier, and such administration can be done individually or in multiple doses. More specifically, the novel therapeutic compounds of this invention can be administered in a wide variety of dosage forms, e.g., they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, pastilles, pills, hard candies, powders, sprays, creams, salves , suppositories, jellies, gels, pastes, lotions, pomades, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, for example sterile aqueous media and various non-toxic organic solvents. Furthermore, oral pharmaceutical preparations may be suitably sweetened and/or flavored.

Za oralno unošenje, tablete koje sadrže razne ekscipijente takve kao mikrokristalna celuloza, natrij citrat, kalcij karbonat, dikalcij fosfat i glicin mogu se koristiti zajedno sa raznim dezintegratorima takvim kao škrob (poželjno škrob žita, krumpira ili tapioke), alginska kiselina i neki kompleksni silikati, zajedno sa granulacijskim vezivima sličnim polivinilpirolidonumu, sukrozi, želatini i akaciji. Dodatno, sredstva podmazivanja takva kao magnezil stearat, natrij lauril sulfat i talk često su vrlo korisna za potrebe tabletiranja. Čvrsti preparati sličnog tipa mogu se također koristiti kao punila u želatinskim kapsulama, a poželjni materijali u vezi ovog također uključuju laktozu ili mliječni šećer, kao i polietilen glikole velike molekulske težine. Kada se vodene suspenzije i/ili eliksiri žele za oralno unošenje, aktivni sastojak se može kombinirati sa raznim sredstvima zaslađivanja ili začina, materijom za bojenje ili bojama, i, ako se želi, sredstvima emulgiranja i/ili suspendiranja, kao i zajedno sa takvim razblaživačima kao voda, etanol, propilen glikol, glicerin i razne njihove slične kombinacije. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used together with various disintegrants such as starch (preferably wheat, potato or tapioca starch), alginic acid and some complex silicates , together with granulation binders similar to polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid preparations of a similar type may also be used as fillers in gelatin capsules, and preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying and/or suspending agents, as well as together with such diluents. such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

Za parenteralno unošenje mogu se koristiti otopine spojeva iz ovog izuma u ulju sezama ili kikirikija ili u vodenom propilen glikolu. Vodene otopine trebaju se prikladno puferirati ako je potrebno i tekući razblaživač se prvo vraća izotonski. Ove vodene otopine su prikladne za potrebe intravenske injekcije. Uljne otopine su prikladne za potrebe intraartikularne, intramuskularne i potkožne injekcije. Dobivanje svih ovih otopina pod sterilnim uvjetima lako se vrši sa standardnim farmaceutskim tehnikama dobro poznatim stručnjacima. For parenteral administration, solutions of the compounds of this invention in sesame or peanut oil or in aqueous propylene glycol can be used. Aqueous solutions should be suitably buffered if necessary and the liquid diluent first returned isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oil solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Obtaining all of these solutions under sterile conditions is easily accomplished with standard pharmaceutical techniques well known to those skilled in the art.

Dodatno, također je moguće unijeti spojeve iz ovog izuma topikalno kada se tretiraju upalna stanja kože, a ovo se može prikladno uraditi pomoću krema, želea, gelova, pasti, pomada i slično, u skladu sa standardnom farmaceutskom praksom. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin, and this may conveniently be done using creams, jellies, gels, pastes, pomades and the like, in accordance with standard pharmaceutical practice.

Sposobnost spojeva da vežu dopamin receptore sisavaca, i relativna sposobnost spojeva iz ovog izuma da inhibiraju [3H]-spiperon vezivanje na podtipove dopamin D4 receptora čovjeka izražena u klonalnim linijama stanice, mjerena je praćenjem slijedećeg postupka. The ability of compounds to bind mammalian dopamine receptors, and the relative ability of compounds of this invention to inhibit [3H]-spiperone binding to human dopamine D4 receptor subtypes expressed in clonal cell lines, was measured by following the following procedure.

Sposobnost vezivanja D4 receptora Ability to bind D4 receptors

Određivanje sposobnosti vezivanja D4 receptora opisao je Van Tol i dr.: "Nature", 350, str. 610, (1991.). Klonalne linije stanice koje izražavaju ljudski dopamin D4 receptor sakupljene su i homogenizirane (politron) u 50 mM Tris:HCl (pH = 7,4 na 4 °C) puferu koji sadrži 5 mM EDTA, 1,5 mM kalcij klorida (CaCl2), 5 mM magnezil klorida (MgCl2), 5 mM kalij klorida (KCl) i 120 mM natrij klorida (NaCl). Homogenati se centrifugiraju tokom 10-15 minuta na 48.000 g, i rezultirajuće pelete se ponovo suspendiraju u puferu u koncentraciji od 150-250 mg/ml. Za eksperimente zasićenja, 0,75 ml alikvoti od tkiva homogenata se inkubiraju u triplikatu sa povećanjem koncentracije [3H]-spiperona (70,3 Ci/mmol; 10-3.000 pM finalna koncentracija) tokom 30-120 minuta na 22 °C u ukupnom volumenu od 1 ml. Za eksperimente uspoređenja vezivanja, pokusi se iniciraju sa dodavanjem 0,75 ml membrane i inkubiraju se u duplikatu sa označenim koncentracijama liganada uspoređenja (10-14-10-3 M) i/ili [3H]-spiperona (100-300 pM) tokom 60-120 minuta na 22 °C. Pokusi su završeni sa brzim filtriranjem preko Brandell-ovog sakupljača stanica, i filtrima dalje ispitivanim na tritij kako je opisao R. K. Sunahara i dr.: "Nature", 346, str. 76, (1990.). Za sve eksperimente, specifično [3H] spiperon vezivanje je definirano kao ono inhibirano sa 1-10 mM (+)-butaklamola. Podaci vezivanja analizirani su regresijom sa krivulje metodom najmanjeg kvadrata. Spojevi iz primjera su testirani u ovom pokusu, i za sve je nađeno da imaju afinitete vezivanja (Ki) za premještanje [3H]-spiperona manje od 2 mikromolara. Determination of D4 receptor binding capacity was described by Van Tol et al.: "Nature", 350, p. 610, (1991). Clonal cell lines expressing the human dopamine D4 receptor were collected and homogenized (Polytron) in 50 mM Tris:HCl (pH = 7.4 at 4 °C) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCl2), 5 mM magnesium chloride (MgCl2), 5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl). Homogenates are centrifuged for 10-15 minutes at 48,000 g, and the resulting pellets are resuspended in buffer at a concentration of 150-250 mg/ml. For saturation experiments, 0.75 ml aliquots of tissue homogenates are incubated in triplicate with increasing concentrations of [3H]-spiperone (70.3 Ci/mmol; 10-3,000 pM final concentration) for 30-120 minutes at 22 °C in a total volume of 1 ml. For comparison binding experiments, experiments are initiated by adding 0.75 ml of membrane and incubated in duplicate with indicated concentrations of comparison ligands (10-14-10-3 M) and/or [3H]-spiperone (100-300 pM) over 60-120 minutes at 22 °C. The experiments were completed with rapid filtration through a Brandell cell collector, and the filters further examined for tritium as described by R. K. Sunahara et al.: "Nature", 346, p. 76, (1990). For all experiments, specific [3H] spiperone binding was defined as that inhibited by 1-10 mM (+)-butaclamol. Binding data were analyzed by curve regression using the least-squares method. The compounds of the examples were tested in this experiment, and all were found to have binding affinities (Ki) for the displacement of [ 3 H]-spiperone less than 2 micromolar.

Modulacija cAMP formiranja ljudskog D4 receptora Modulation of cAMP formation of the human D4 receptor

Jajne stanice kineskog hrčka (CHO) koje izražavaju ljudski D 4,4 dopamin receptor dobivene su od dr. H. Van Tol-a (Clarke Institute of Psychiatry, Toronto) i razvijene su radi sjedinjavanja u minimalnoj suštinskoj alfa sredini (Gibco) snabdjevenoj sa 2,5 % fetalnim goveđim serumom (koji je bez topline neaktivan), 2,5 % konjskim serumom (koji je na toplini neaktivan), i 500 µg/ml Geneticin. Monoslojevi su razbijeni i stanice su uklonjene sa 5 mM etilendiamintetra octenom kiselinom (EDTA) i ponovo suspendirane u puferu fosfat puferiranog slaništa koji sadrži 5 mM magnezil klorida, 30 mM hidroksietilpiperazin-N-etansulfonske kiseline (HEPES), 300 µM 3-izobutil-1-metil-ksantina (IBMX, inhibitor fosfodiesteraze), i 5,6 mM dekstroze. Stanice (približno 200.000/cijev) izložene su 5 µM forskolinu (aktivator adenilat ciklaze), forskolinu plus test spojevima ili kinpirolu (agonist D4 receptora), ili forskolinu plus kinpirolu plus antagonistu tokom 11 minuta. U eksperimentima sa anatgonistima, stanice su izložene antagonistima 11 minuta prije izazivanja agonista. Utjecaj test spojeva u odsustvu agonist kinpirola korišten je za procjenu aktivnosti agonista. D4 agonisti proizvode inhibiciju cAMP akumulacije koja se može okrenuti sa D4 antagonistima. Reakcija je završena sa dodavanjem 6N perklorne kiseline, i uzorci su neutralizirani sa 5N kalij hidroksidom i 2M Tris puferom. Ciklični AMP nivoi su mjereni korištenjem komercijalno raspoloživog pribora usporednog vezivanja (Amersham). IC50 vrijednosti su računate sa analizom linerane regresije krivulja koncentracija-odziv. Ki vrijednosti su računate korištenjem jednadžbe: Ki=IC50/(1 + (agonist)/(agonist EC50)) (Minneman i Johnson, 1984). Chinese hamster ovary (CHO) cells expressing the human D 4,4 dopamine receptor were obtained from Dr. H. Van Tol (Clarke Institute of Psychiatry, Toronto) and grown to confluence in minimal essential alpha medium (Gibco) supplied with 2.5% fetal bovine serum (which is inactive without heat), 2.5% horse serum (which is inactive with heat), and 500 µg/ml Geneticin. Monolayers were disrupted and cells were removed with 5 mM ethylenediaminetetraacetic acid (EDTA) and resuspended in phosphate buffered saline containing 5 mM magnesium chloride, 30 mM hydroxyethylpiperazine-N-ethanesulfonic acid (HEPES), 300 µM 3-isobutyl-1 -methyl-xanthine (IBMX, phosphodiesterase inhibitor), and 5.6 mM dextrose. Cells (approximately 200,000/tube) were exposed to 5 µM forskolin (an adenylate cyclase activator), forskolin plus test compounds or quinpirole (a D4 receptor agonist), or forskolin plus quinpirole plus an antagonist for 11 minutes. In antagonist experiments, cells were exposed to antagonists for 11 min before agonist challenge. The effect of the test compounds in the absence of the agonist quinpirole was used to evaluate agonist activity. D4 agonists produce inhibition of cAMP accumulation that can be reversed with D4 antagonists. The reaction was terminated with the addition of 6N perchloric acid, and the samples were neutralized with 5N potassium hydroxide and 2M Tris buffer. Cyclic AMP levels were measured using a commercially available comparative binding kit (Amersham). IC50 values were calculated with linear regression analysis of concentration-response curves. Ki values were calculated using the equation: Ki=IC50/(1 + (agonist)/(agonist EC50)) (Minneman and Johnson, 1984).

Ovaj izum je dalje ilustriran sa slijedećim primjerima, ali nije ograničen na njihove detalje. This invention is further illustrated by the following examples, but is not limited to their details.

Primjer 1 Example 1

2-[4-(6-kloro-piridazin-3-il)-piperazin-1-ilmetil]-5-fluoro-1H-indol 2-[4-(6-chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole

Smjesa od 5 gm 5-fluoro-3-indolo karboksilne kiseline, 2,74 gm O-, N-dimetil hidroksilamin hidroklorida, 3,89 ml trietilamina i 5,76 gm dicikloheksilkarbodi imida u 35 ml metilen klorida miješana je na sobnoj temperaturi dok se ne formira žutosmeđi talog. Čvrsti materijal je uklonjen sa filtriranjem, ostatak je koncentriran i pročišćen na SiO2 (25 %) EtOAc u heksanu) i dobiveno je 3,6 gm (64 %) N-O-dimetil 2 indol hidroksamida. A mixture of 5 gm of 5-fluoro-3-indole carboxylic acid, 2.74 gm of O-, N-dimethyl hydroxylamine hydrochloride, 3.89 ml of triethylamine and 5.76 gm of dicyclohexylcarbodiimide in 35 ml of methylene chloride was stirred at room temperature while no yellow-brown precipitate is formed. The solid was removed by filtration, the residue was concentrated and purified on SiO2 (25% EtOAc in hexane) to give 3.6 gm (64%) of N-O-dimethyl 2 indole hydroxamide.

3,9 gm N-O-dimetil 2 indol hidroksilamida je dodano tokom perioda od 5 minuta u hladnu suspenziju (-40 °C) od 0,67 gm LiAlH4 u 30 ml tetahidrofurana. Smjesa je miješana tokom sata (-40 °C->-30 °C), tretirana je sa zasićenom vodenom otopinom natrij sulfata i zagrijana na sobnoj temperaturu. Otapalo je izdvojeno poslije dodavanja čvrstog natrij sulfata i koncentrirano dok nije formiran čvrst talog 2,94 gm 5-fluoro 2-indolkarboksaldehida. 3.9 gm of N-O-dimethyl 2 indole hydroxylamide was added over a period of 5 minutes to a cold suspension (-40 °C) of 0.67 gm LiAlH 4 in 30 ml of cyanohydrofuran. The mixture was stirred for an hour (-40 °C->-30 °C), treated with a saturated aqueous solution of sodium sulfate and warmed to room temperature. The solvent was separated after addition of solid sodium sulfate and concentrated until a solid precipitate of 2.94 gm of 5-fluoro 2-indolecarboxaldehyde was formed.

Smjesa od 0,96 gm 4-(5-kloro-fenil)-piperazina, 1,0 gm 5-fluoro, 2-indolkarboksaldehida i 1,2 gm natrij triacetoksiborohidrida u 50 ml dikloroetana je miješana pod dušikom na sobnoj temperaturi tokom 48 sati. Otapalo je uklonjeno i ostatak je podijeljen između 100 ml EtOAc i 20 ml NaOH (1N). Organski sloj je ispran sa vodom (2 × 20 ml) i slanom vodom (1 × 10 ml) i koncentriran. Ostatak je pročišćen na SiO2 (eluent: 5% metanola u metilen kloridu) radi dobivanja svjetlo smeđeg čvrstog materijala. A mixture of 0.96 gm 4-(5-chloro-phenyl)-piperazine, 1.0 gm 5-fluoro,2-indolecarboxaldehyde and 1.2 gm sodium triacetoxyborohydride in 50 ml dichloroethane was stirred under nitrogen at room temperature for 48 hours. . The solvent was removed and the residue was partitioned between 100 ml EtOAc and 20 ml NaOH (1N). The organic layer was washed with water (2 x 20 ml) and brine (1 x 10 ml) and concentrated. The residue was purified on SiO2 (eluent: 5% methanol in methylene chloride) to give a light brown solid.

t.t.: 204-205 °C). m.p.: 204-205 °C).

Primjer 2 Example 2

(5-fluoro-1H-indol-2-il)-[4-(3-trifluorometil-fenil)-piperazin-1-il]-metanon (5-fluoro-1H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Smjesa od 1,0 mmol 5-fluoro, 2-indol karboksikakidklorida i 230 mg meta-trifluorometilfenilpiperazina i 129 mg diizopropiletilamina u 10 ml metilenklorida držana je na sobnoj temperaturi tokom 12 sati. Voda je dodana, organski sloj je izdvojen, ispran sa vodom, osušen preko natrij sulfata i koncentriran radi dobivanja 296 mg spoja iz naslova. t.t.: 198 °C. A mixture of 1.0 mmol of 5-fluoro, 2-indole carboxycacid chloride and 230 mg of meta-trifluoromethylphenylpiperazine and 129 mg of diisopropylethylamine in 10 ml of methylene chloride was kept at room temperature for 12 hours. Water was added, the organic layer was separated, washed with water, dried over sodium sulfate and concentrated to give 296 mg of the title compound. m.p.: 198 °C.

Primjer 3 Example 3

5-fluoro-2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol 5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole

Otopina od 275 mg (5-fluoro-1H-indol-2-il)-[4-(3-trifluorometil-fenil)-piperazin-1-il]metanona u 5 ml anhidriranog tetrahidrofurana držana je pod atmosferom inertnog plina i tretirana na sobnoj temperaturi sa 2,11 ml 1M otopine litijaluminijhidrida u tetrahidrofuranu. Poslije 12 sati smjesa je tretirana sa 78 µl 15% otopine natrij hidroksida i opet 234 µl vode. Poslije dodavanja magnezilsulfata organski sloj je izdvojen i koncentriran u žuto ulje (240 mg). Ovo ulje je otopljeno u eteru i tretirano sa otopinom etera klorovodične kiseline dok se ne formira talog. Talog je sakupljen, i osušen pod vakuumom. A solution of 275 mg of (5-fluoro-1H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]methanone in 5 ml of anhydrous tetrahydrofuran was kept under an inert gas atmosphere and treated at at room temperature with 2.11 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After 12 hours, the mixture was treated with 78 µl of 15% sodium hydroxide solution and again 234 µl of water. After addition of magnesium sulfate, the organic layer was separated and concentrated to a yellow oil (240 mg). This oil was dissolved in ether and treated with an ether solution of hydrochloric acid until a precipitate formed. The precipitate was collected and dried under vacuum.

Spojevi iz naslova iz primjera 4-89 dobiveni su sa postupcima analognim sa onim dobivenim u primjerima 1-3. The title compounds from Examples 4-89 were obtained by procedures analogous to those obtained in Examples 1-3.

Primjer 4 Example 4

2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol-5-ol 2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indol-5-ol

t.t.: 188-190 °C; HRSMS 375,15. mp: 188-190 °C; HRSMS 375.15.

Primjer 5 Example 5

2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol 2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole

t.t.: 192-194 °C; HRSMS 359,15. mp: 192-194 °C; HRSMS 359.15.

Primjer 6 Example 6

(1H-indol-2-il)-[4-(2-nitro-fenil)-piperazin-1-il]-metanon (1H-indol-2-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone

t.t.: 186-189 °C. m.p.: 186-189 °C.

Primjer 7 Example 7

(5-fluoro-1H-indol-2-il)-[4-(2-nitro-fenil)-piperazin-1-il]-metanon (5-fluoro-1H-indol-2-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone

t.t.: 184-188 °C. m.p.: 184-188 °C.

Primjer 8 Example 8

(5-fluoro-1H-indol-2-il)-[4-(3-trifluorometil-fenil)-piperazin-1-il]-metanon (5-fluoro-1H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

t.t.: 198 °C. m.p.: 198 °C.

Primjer 9 Example 9

3-[4-(1H-indol-2-ilmetil)-piperazin-1-il]-benzo[d]isotiazol 3-[4-(1H-indol-2-ylmethyl)-piperazin-1-yl]-benzo[d]isothiazole

t.t.: 150-152 °C; MRSMS 348,12. mp: 150-152 °C; MRSMS 348,12.

Primjer 10 Example 10

5-fluoro-2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol 5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole

t.t.: 196-197 °C; HRMS 377,148. m.p.: 196-197 °C; HRMS 377,148.

Primjer 11 Example 11

2-(4-naftalen-1-il-piperazin-1-ilmetil)-1H-indol 2-(4-Naphthalen-1-yl-piperazin-1-ylmethyl)-1H-indole

t.t.: 238-239 °C; HRMS 341,19. mp: 238-239 °C; HRMS 341,19.

Primjer 12 Example 12

2-[4-(2-nitro-fenil)-piperazin-1-ilmetil]-1H-indol 2-[4-(2-nitro-phenyl)-piperazin-1-ylmethyl]-1H-indole

t.t.: 210-211 °C; HRMS 336,16. mp: 210-211 °C; HRMS 336,16.

Primjer 13 Example 13

5-fluoro-2-[4-(2-nitro-fenil)-piperazin-1-ilmetil]-1H-indol 5-fluoro-2-[4-(2-nitro-phenyl)-piperazin-1-ylmethyl]-1H-indole

t.t.: 236 °C; HRMS 354,14. m.p.: 236 °C; HRMS 354,14.

Primjer 14 Example 14

5-fluoro-2-(4-naftalen-1-il-piperazin-1-ilmetil)-1H-indol 5-fluoro-2-(4-naphthalen-1-yl-piperazin-1-ylmethyl)-1H-indole

t.t.: 249-250 °C; HRMS 359,18. mp: 249-250 °C; HRMS 359.18.

Primjer 15 Example 15

5-fluoro-2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-indol 5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole

t.t.: 242 °C; HRMS 310,15. m.p.: 242 °C; HRMS 310.15.

Primjer 16 Example 16

5-fluoro-2-[4-(4-fluoro-fenil)-piperazin-1-ilmetil]-1H-indol 5-fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole

t.t.: m.p.:

Primjer 17 Example 17

5-fluoro-1-(4-pirimidin-2-il-piperazin-1-ilmetil)-1H-indol 5-fluoro-1-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-1H-indole

t.t.: 199 °C; HRSMS 311,16. m.p.: 199 °C; HRSMS 311,16.

Primjer 18 Example 18

(5-fluoro-1H-indol-2-il)-(4-piridin-2-il-piperazin-1-il)-metanon (5-fluoro-1H-indol-2-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone

t.t.: 214-218 °C. m.p.: 214-218 °C.

Primjer 19 Example 19

2-(4-piiridin-2-il-piperazin-1-ilmetil)-1H-indol 2-(4-Pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole

t.t.: m.p.:

Primjer 20 Example 20

(1H-indol-2-il)-(4-piridin-2-il-piperazin-1-il)-metanon (1H-indol-2-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone

t.t.: 198-200 °C. mp: 198-200 °C.

Primjer 21 Example 21

2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-indol 2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole

13C NMR (CDCl3, 75 MHz) d 45,29; 53,03; 55,96; 77,44; 101,94; 107,29; 110,91; 113,52; 119,70; 120,28; 121,69; 128,40; 135,53; 136,37; 137,61; 148,00; 159,55. 13 C NMR (CDCl 3 , 75 MHz) d 45.29; 53.03; 55.96; 77.44; 101.94; 107.29; 110.91; 113.52; 119.70; 120.28; 121.69; 128.40; 135.53; 136.37; 137.61; 148.00; 159.55.

13C NMR (CDCl3, 200 MHz) d 2,6 (m, 4H); 3,6 (m, 4H); 3,7 (s, 2H); 6,4 (s, 1H); 6,7 (m, 2H); 7,1-7,6 (m, 4H); 8,2 (m, 1H); 8,7 (br. s, 1H). 13 C NMR (CDCl 3 , 200 MHz) d 2.6 (m, 4H); 3.6 (m, 4H); 3.7 (s, 2H); 6.4 (s, 1H); 6.7 (m, 2H); 7.1-7.6 (m, 4H); 8.2 (m, 1H); 8.7 (no. s, 1H).

GC-MS, tR = 4,468 min., M+ = 292, (M-162) = 130. GC-MS, tR = 4.468 min, M+ = 292, (M-162) = 130.

Primjer 22 Example 22

(2'α, 3'αβ6'αβ)-1-(4-fluoro-fenil)-4-(5'-fenil-1',2',3',3'a,4',6'a-heksahidro-pentalen-2'-il)-piperazin-dihidroklorid (2'α, 3'αβ6'αβ)-1-(4-fluoro-phenyl)-4-(5'-phenyl-1',2',3',3'a,4',6'a- hexahydro-pentalen-2'-yl)-piperazine-dihydrochloride

t.t.: 250-253 °C. m.p.: 250-253 °C.

Analiza izračunata za C24H27FN2 • 2 HCl • 0,75 H2O: C 66,28; H 7,07; N 6,44. Analysis calculated for C24H27FN2 • 2 HCl • 0.75 H2O: C 66.28; H 7.07; N 6.44.

Nađeno: C 66,18; H 6,76; N 6,56. Found: C 66,18; H 6.76; N 6.56.

Primjer 23 Example 23

(2'α, 3'αβ, 5'α, 6'αβ)-5'-[4-(4-fluoro-fenil)-piperazin-1-il]-2'-fenil-oktahidro-pentalen-2'-ol maleat (2'α, 3'αβ, 5'α, 6'αβ)-5'-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2'-phenyl-octahydro-pentalene-2' -ol maleate

t.t.: 206-207,5 °C. m.p.: 206-207.5 °C.

Analiza izračunata za C24H29FN2O • 0,75 C4H4O4 • 0,75 H2O: C 67,41; H 7,02; N 5,82. Analysis calculated for C24H29FN2O • 0.75 C4H4O4 • 0.75 H2O: C 67.41; H 7.02; N 5.82.

Nađeno: C 67,24; H 6,77; N 5,68. Found: C 67.24; H 6.77; N 5.68.

Primjer 24 Example 24

(2'α, 3'αβ, 5'α, 6'αβ)-1-(4-fluoro-fenil)-4-(5'-fenil-oktahidro-pentalen-2'-il)-piperazin dihidroklorid (2'α, 3'αβ, 5'α, 6'αβ)-1-(4-fluoro-phenyl)-4-(5'-phenyl-octahydro-pentalen-2'-yl)-piperazine dihydrochloride

t.t.: 255-256,5 °C. m.p.: 255-256.5 °C.

Analiza izračunata za C24H29FN2O • 2HCl • 0,25 H2O: C 65,23; H 7,18; N 6,34. Analysis calculated for C24H29FN2O • 2HCl • 0.25 H2O: C 65.23; H 7,18; N 6.34.

Nađeno: C 65,40; H 7,02; N 6,38. Found: C 65.40; H 7.02; N 6.38.

Primjer 25 Example 25

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-hidroksi-5'-fenil-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitrilmaleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-hydroxy-5'-phenyl-octahydro-pentalen-2'-yl)-piperazin- 1-yl]-benzonitrile maleate

t.t.: 207-207,5 °C. m.p.: 207-207.5 °C.

Analiza izračunata za C25H28FN3O • C4H4O4: C 66,78; H 6,18; N 8,06. Analysis calculated for C25H28FN3O • C4H4O4: C 66.78; H 6.18; N 8.06.

Nađeno: C 66,64; H 6,06; N 8,14. Found: C 66.64; H 6.06; N 8,14.

Primjer 26 Example 26

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidrospirobenzofuran-1(3H), 2'(1'H)-penten]-5'il)-1 (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydrospirobenzofuran- 1(3H), 2'(1'H)-penten]-5'yl)-1

-piperazinil)-benzonitril maleat -piperazinyl)-benzonitrile maleate

t.t.: 221-221,5 °C. m.p.: 221-221.5 °C.

Analiza izračunata za C26H28FN3O • C4H4O4 • 0,5 H2O: C 66,41; H 6,13; N 7,74. Analysis calculated for C26H28FN3O • C4H4O4 • 0.5 H2O: C 66.41; H 6.13; N 7.74.

Nađeno: C 66,33; H 6,26; N 7,61. Found: C 66.33; H 6.26; N 7.61.

Primjer 27 Example 27

(2'α, 3'αβ, 5'α, 6'αβ)-5'-[4-(2-metoksi-fenil)-piperazin-1-il]-2'-fenil-oktahidro-pentalen-2'-ol maleat (2'α, 3'αβ, 5'α, 6'αβ)-5'-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2'-phenyl-octahydro-pentalene-2' -ol maleate

t.t.: 188-189 °C. m.p.: 188-189 °C.

Analiza izračunata za C25H32N2O2 • C4H4O4: C 68,48; H 7,13; N 5,51. Analysis calculated for C25H32N2O2 • C4H4O4: C 68.48; H 7.13; N 5.51.

Nađeno: C 68,64; H 7,10; N 5,81. Found: C 68.64; H 7.10; N 5.81.

Primjer 28 Example 28

(2'α, 3'αβ, 5'α, 6'αβ)-2-(4-fluoro-fenil)-5'-[4-(5-fluoro-pirimidin-2-il)-piperazin-1-il]-oktahidro-pentalen-2'-ol maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-(4-fluoro-phenyl)-5'-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1- yl]-octahydro-pentalen-2'-ol maleate

t.t.: 219,5-220 °C. m.p.: 219.5-220 °C.

Analiza izračunata za C22H26F2N4O • C4H4O4 • 0,5 H2O: C 59,41; H 5,94; N 10,66. Analysis calculated for C22H26F2N4O • C4H4O4 • 0.5 H2O: C 59.41; H 5.94; N 10.66.

Nađeno: C 59,76; H 5,89; N 10,65. Found: C 59.76; H 5.89; N 10.65.

Primjer 29 Example 29

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-fluoro-fenil)-5'-hidroksi-oktahidro-pentalen-2'-il]-piperazin-1-il} (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-fluoro-phenyl)-5'-hydroxy-octahydro-pentalene-2' -yl]-piperazin-1-yl}

-benzonitril maleat -benzonitrile maleate

t.t.: 204-204,5 °C. m.p.: 204-204.5 °C.

Analiza izračunata za C25H27F2N3O • C4H4O4 • H2O: C 62,47; H 5,97; N 7,54. Analysis calculated for C25H27F2N3O • C4H4O4 • H2O: C 62.47; H 5.97; N 7.54.

Nađeno: C 62,77; H 5,74; N 7,58. Found: C 62.77; H 5.74; N 7.58.

Primjer 30 Example 30

(2'α, 3'αβ, 5'α, 6'αβ)-2'-(4-fluoro-fenil)-5'-[4-(4-fluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-ol maleat (2'α, 3'αβ, 5'α, 6'αβ)-2'-(4-fluoro-phenyl)-5'-[4-(4-fluoro-phenyl)-piperazin-1-yl]- octahydro-pentalen-2'-ol maleate

t.t.: 209-209,5 °C. m.p.: 209-209.5 °C.

Analiza izračunata za C24H28F2N2O • C4H4O4: C 65,36; H 6,27; N 5,54. Analysis calculated for C24H28F2N2O • C4H4O4: C 65.36; H 6.27; N 5.54.

Nađeno: C 65,65; H 6,25; N 5,34. Found: C 65.65; H 6.25; N 5.34.

Primjer 31 Example 31

(2'α, 3'αβ, 6'αβ)-5-fluoro-2-[4-(5'-fenil-1',2',3',3'a,4',6'a-heksahidro-pentalen-2'-il)-piperazin-1-il]-pirimidin maleat (2'α, 3'αβ, 6'αβ)-5-fluoro-2-[4-(5'-phenyl-1',2',3',3'a,4',6'a-hexahydro -pentalen-2'-yl)-piperazin-1-yl]-pyrimidine maleate

t.t.: 202-203 °C. mp: 202-203 °C.

Analiza izračunata za C22H25FN4 • C4H4O4: C 64,99; H 6,08; N 11,66. Analysis calculated for C22H25FN4 • C4H4O4: C 64.99; H 6.08; N 11.66.

Nađeno: C 64,67; H 6,00; N 11,79. Found: C 64.67; H 6.00; N 11.79.

Primjer 32 Example 32

(2'α, 3'αβ, 6'αβ)-2-fluoro-4-[4-(5'-fenil-1',2',3',3'a,4',6'a-hekdahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril maleat (2'α, 3'αβ, 6'αβ)-2-fluoro-4-[4-(5'-phenyl-1',2',3',3'a,4',6'a-hexahydro -pentalen-2'-yl)-piperazin-1-yl]-benzonitrile maleate

t.t.: 172-173 °C. m.p.: 172-173 °C.

Analiza izračunata za C25H26FN3 • C4H4O4: C 69,17; H 6,00; N 8,34. Analysis calculated for C25H26FN3 • C4H4O4: C 69.17; H 6.00; N 8.34.

Nađeno: C 69,06; H 5,88; N 8,57. Found: C 69.06; H 5.88; N 8.57.

Primjer 33 Example 33

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(5'-fenil-oktahidro-pentalen-2'-il)-piperazin-1-il]-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(5'-phenyl-octahydro-pentalen-2'-yl)-piperazin-1-yl]- pyrimidine maleate

t.t.: 211,5-212 °C. m.p.: 211.5-212 °C.

Analiza izračunata za C22H27FN4 • C4H4O4: C 64,72; H 6,48; N 11,61. Analysis calculated for C22H27FN4 • C4H4O4: C 64.72; H 6.48; N 11.61.

Nađeno: C 64,67; H 6,43; N 11,82. Found: C 64.67; H 6.43; N 11.82.

Primjer 34 Example 34

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-fenil-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-phenyl-octahydro-pentalen-2'-yl)-piperazin-1-yl]- benzonitrile maleate

t.t.: 195-196 °C. m.p.: 195-196 °C.

Analiza izračunata za C25H28FN3 • C4H4O4: C 68,89; H 6,38; N 8,31. Analysis calculated for C25H28FN3 • C4H4O4: C 68.89; H 6.38; N 8.31.

Nađeno: C 68,99; H 6,47; N 8,30. Found: C 68.99; H 6.47; N 8.30.

Primjer 35 Example 35

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-trifluorometil-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-trifluoromethyl-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 192-193 °C. m.p.: 192-193 °C.

Analiza izračunata za C26H27F4N3 • C4H4O4: C 62,82; H 5,45; N 7,33. Analysis calculated for C26H27F4N3 • C4H4O4: C 62.82; H 5.45; N 7.33.

Nađeno: C 62,87; H 5,22; N 7,27. Found: C 62.87; H 5.22; N 7.27.

Primjer 36 Example 36

(2'α, 3'αβ, 6'αβ)-2-fluoro-4-{4-[5-(2-metoksi-fenil)-1',2',3',3'a,4',6'a-heksahidro-pentalen-2'-il]-piperazin-1-il} (2'α, 3'αβ, 6'αβ)-2-fluoro-4-{4-[5-(2-methoxy-phenyl)-1',2',3',3'a,4', 6'a-hexahydro-pentalen-2'-yl]-piperazin-1-yl}

-benzonitril maleat -benzonitrile maleate

t.t.: 155-156 °C. mp: 155-156 °C.

Analiza izračunata za C26H28FN3O • C4H4O4 • 0,25 H2O: C 66,96; H 6,09; N 7,81. Analysis calculated for C26H28FN3O • C4H4O4 • 0.25 H2O: C 66.96; H 6.09; N 7.81.

Nađeno: C 67,00; H 6,05; N 7,82. Found: C 67.00; H 6.05; N 7.82.

Primjer 37 Example 37

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-metoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-methoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 176-177 °C. m.p.: 176-177 °C.

Analiza izračunata za C26H30FN3O • C4H4O4 • 0,50 H2O: C 66,16; H 6,48; N 7,71. Analysis calculated for C26H30FN3O • C4H4O4 • 0.50 H2O: C 66.16; H 6.48; N 7.71.

Nađeno: C 66,20; H 6,31; N 7,69. Found: C 66.20; H 6.31; N 7.69.

Primjer 38 Example 38

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(1H-indol-3-il)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(1H-indol-3-yl)-octahydro-pentalen-2'-yl] -piperazin-1-yl}-benzonitrile maleate

t.t.: 226-227 °C. m.p.: 226-227 °C.

Analiza izračunata za C27H29FN4O • C4H4O4: C 68,37; H 6,11; N 10,29. Analysis calculated for C27H29FN4O • C4H4O4: C 68.37; H 6.11; N 10.29.

Nađeno: C 68,17; H 6,24; N 10,20. Found: C 68,17; H 6.24; N 10,20.

Primjer 39 Example 39

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-metansulfonil-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-methanesulfonyl-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 179-180 °C. m.p.: 179-180 °C.

Analiza izračunata za C26H30FN3O2S • C4H4O4 • 0,25 H2O: C 61,25; H 5,91; N 7,14. Analysis calculated for C26H30FN3O2S • C4H4O4 • 0.25 H2O: C 61.25; H 5.91; N 7,14.

Nađeno: C 61,26; H 6,32; N 6,76. Found: C 61.26; H 6.32; N 6.76.

Primjer 40 Example 40

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidrospirobenzofuran-1(3H), 2'(1'H)-pentalen)-5'il]-1 (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydrospirobenzofuran- 1(3H),2'(1'H)-pentalene)-5'yl]-1

-piperazinil)-benzonitril maleat -piperazinyl)-benzonitrile maleate

t.t.: > 260 °C. m.p.: > 260 °C.

Analiza izračunata za C26H28FN3O • CH4O3S: C 63,14; H 6,27; N 8,18. Analysis calculated for C26H28FN3O • CH4O3S: C 63.14; H 6.27; N 8,18.

Nađeno: C 63,12; H 6,66; N 8,00. Found: C 63,12; H 6.66; N 8.00.

Primjer 41 Example 41

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro(2H)-1-benzopiran-2,2'(1'H)-pentalen) (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6' a-hexahydrospiro(2H)-1-benzopyran-2,2'(1'H)-pentalene)

-5'-il]-1-piperazinil)-benzonitril maleat -5'-yl]-1-piperazinyl)-benzonitrile maleate

t.t.: 176-177 °C. m.p.: 176-177 °C.

Analiza izračunata za C27H28FN3O2 • C4H4O4 • 0,50 H2O: C 65,25; H 5,82; N 7,36. Analysis calculated for C27H28FN3O2 • C4H4O4 • 0.50 H2O: C 65.25; H 5.82; N 7.36.

Nađeno: C 65,52; H 6,06; N 7,19. Found: C 65.52; H 6.06; N 7,19.

Primjer 42 Example 42

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro(2H)-1-benzopiran-2,2'(1'H)-pentalen) (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6' a-hexahydrospiro(2H)-1-benzopyran-2,2'(1'H)-pentalene)

-5'-il]-1-piperazinil)-benzonitril maleat -5'-yl]-1-piperazinyl)-benzonitrile maleate

t.t.: 179-180 °C. m.p.: 179-180 °C.

Analiza izračunata za C27H28FN3O2 • C4H4O4: C 66,30; H 5,74; N 7,48. Analysis calculated for C27H28FN3O2 • C4H4O4: C 66.30; H 5.74; N 7.48.

Nađeno: C 66,17; H 6,07; N 7,34. Found: C 66,17; H 6.07; N 7.34.

Primjer 43 Example 43

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-trifluorometoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-trifluoromethoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 126-129 °C. m.p.: 126-129 °C.

NMR DMSO d6 δ 7,70 (t, J=8,5 Hz, 1H); 7,52 (d, J=7,1 Hz, 1H); 7,40-7,25 (m, 3H); 7,09 (d, J=13,6 Hz, 1H); 6,96 (d, J=9,0 Hz, 1H); 6,06 (s, 2H); 3,73-2,90 (br. m, 10H); 2,65-2,54 (m, djelomično pod DMSO, 1H); 2,46-2,18 (m, 4H); 1,63-1,42 (m, 4H). NMR DMSO d6 δ 7.70 (t, J=8.5 Hz, 1H); 7.52 (d, J=7.1 Hz, 1H); 7.40-7.25 (m, 3H); 7.09 (d, J=13.6 Hz, 1H); 6.96 (d, J=9.0 Hz, 1H); 6.06 (s, 2H); 3.73-2.90 (No. m, 10H); 2.65-2.54 (m, partially under DMSO, 1H); 2.46-2.18 (m, 4H); 1.63-1.42 (m, 4H).

Primjer 44 Example 44

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-fluoro-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-fluoro-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 179-180,5 °C. m.p.: 179-180.5 °C.

Analiza izračunata za C25H27F2N3 • C4H4O4: C 66,53; H 5,97; N 8,03. Analysis calculated for C25H27F2N3 • C4H4O4: C 66.53; H 5.97; N 8.03.

Nađeno: C 66,62; H 6,24; N 7,98. Found: C 66.62; H 6.24; N 7.98.

Primjer 45 Example 45

(2'α, 3'αβ, 5'α, 6'αβ)-2-ciano-4-{4-[5'-(2-fluoro-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-cyano-4-{4-[5'-(2-fluoro-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t.: 193-194 °C. m.p.: 193-194 °C.

Analiza izračunata za C26H27FN4 • C4H4O4 • 0,50 H2O: C 66,78; H 5,98; N 10,38. Analysis calculated for C26H27FN4 • C4H4O4 • 0.50 H2O: C 66.78; H 5.98; N 10.38.

Nađeno: C 66,99; H 6,05; N 10,34. Found: C 66.99; H 6.05; N 10.34.

Primjer 46 Example 46

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-piridin-2-il-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril dihidroklorid (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-pyridin-2-yl-octahydro-pentalen-2'-yl)-piperazin-1 -yl]-benzonitrile dihydrochloride

t.t.: 203-206 °C. m.p.: 203-206 °C.

Analiza izračunata za C24H27FN4 • 2HCl • H2O: C 59,88; H 6,49; N 11,63. Analysis calculated for C24H27FN4 • 2HCl • H2O: C 59.88; H 6.49; N 11.63.

Nađeno: C 59,55; H 6,42; N 11,47. Found: C 59.55; H 6.42; N 11.47.

Primjer 47 Example 47

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-{4-[5'-(2-metoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-{4-[5'-(2-methoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-pyrimidine maleate

t.t.: 183-184 °C. mp: 183-184 °C.

Analiza izračunata za C23H29FN4 • C4H4O4 • C4H4O4: C 63,26; H 6,49; N 10,93. Analysis calculated for C23H29FN4 • C4H4O4 • C4H4O4: C 63.26; H 6.49; N 10.93.

Nađeno: C 63,21; H 6,71; N 10,82. Found: C 63.21; H 6.71; N 10.82.

Primjer 48 Example 48

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(6-fluoro-2-okso-2,3-dihidro-benzoimidazol-1-il)-oktahidro-pentalen-2'-il] (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(6-fluoro-2-oxo-2,3-dihydro-benzoimidazole-1- yl)-octahydro-pentalen-2'-yl]

-piperazin-1-il}-benzonitril dimesilat -piperazin-1-yl}-benzonitrile dimesylate

t.t.: 219-222 °C. m.p.: 219-222 °C.

Analiza izračunata za C26H27FN5O • 2 CH4O3S: C 51,29; H 5,38; N 10,68. Analysis calculated for C26H27FN5O • 2 CH4O3S: C 51.29; H 5.38; N 10.68.

Nađeno: C 51,84; H 5,57; N 10,64. Found: C 51.84; H 5.57; N 10.64.

Primjer 49 Example 49

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(6-fluoro-2-metilbenzoimidazol-1-il)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril dimesilat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(6-fluoro-2-methylbenzoimidazol-1-yl)-octahydro-pentalen-2 '-yl]-piperazin-1-yl}-benzonitrile dimesylate

t.t.: > 260 °C. m.p.: > 260 °C.

Analiza izračunata za C27H29F2N5 • 2 CH4O3S• 0,50 H2O: C 52,56; H 5,48; N 10,57. Analysis calculated for C27H29F2N5 • 2 CH4O3S• 0.50 H2O: C 52.56; H 5.48; N 10.57.

Nađeno: C 52,64; H 5,71; N 10,57. Found: C 52.64; H 5.71; N 10.57.

Primjer 50 Example 50

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidrospiro[izobenzofuran-1(3H), 2'(1'H)-pentalen]-5' (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydrospiro[ isobenzofuran-1(3H), 2'(1'H)-pentalene]-5'

-il)-piperazin-1-il]-pirimidin -yl)-piperazin-1-yl]-pyrimidine

t.t. = 186 °C. d.p. = 186 °C.

NMR CDCl3 δ 8,20 (s, 2H); 7,25-7,17 (m, 4H); 7,12-7,09 (m, 1H); 5,00 (s, 2H); 3,79-3,71 (m, 4H); 2,72-2,44 (m, 7H); 2,20-2,13 (m, 2H); 2,17-1,93 (m, 2H); 1,69-1,67 (s, 2H). NMR CDCl3 δ 8.20 (s, 2H); 7.25-7.17 (m, 4H); 7.12-7.09 (m, 1H); 5.00 (s, 2H); 3.79-3.71 (m, 4H); 2.72-2.44 (m, 7H); 2.20-2.13 (m, 2H); 2.17-1.93 (m, 2H); 1.69-1.67 (s, 2H).

Primjer 51 Example 51

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidrospiro[izobenzofuran-1(3H), 2'(1'H)-pentalen]-5' (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydrospiro[ isobenzofuran-1(3H), 2'(1'H)-pentalene]-5'

-il)-piperazin-1-il]-pirimidin -yl)-piperazin-1-yl]-pyrimidine

t.t. = 186-187 °C. d.p. = 186-187 °C.

NMR CDCl3 δ 8,18 (s, 2H); 7,26-7,10 (m, 3H); 7,08-7,06 (m, 1H); 5,00 (s, 2H); 3,78-3,76 (br. s, 4H); 2,78-2,73 (m, 2H); 2,66-2,54 (m, 5H); 2,32-2,22 (m, 4H); 1,74-1,69 (m, 2H); 1,38-1,29 (m, 2H). NMR CDCl3 δ 8.18 (s, 2H); 7.26-7.10 (m, 3H); 7.08-7.06 (m, 1H); 5.00 (s, 2H); 3.78-3.76 (No. s, 4H); 2.78-2.73 (m, 2H); 2.66-2.54 (m, 5H); 2.32-2.22 (m, 4H); 1.74-1.69 (m, 2H); 1.38-1.29 (m, 2H).

Primjer 52 Example 52

(2'α, 3'αβ, 5'α, 6'αβ)-1-fenil-4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro[2H-1-benzopiran-2,2'(1'H)-pentalen]-5'-il) (2'α, 3'αβ, 5'α, 6'αβ)-1-phenyl-4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-hexahydrospiro [2H-1-benzopyran-2,2'(1'H)-pentalene]-5'-yl)

-piperazin maleat - piperazine maleate

t.t. = 200-201 °C. d.p. = 200-201 °C.

Analiza izračunata za C26H30N2O2 • C4H4O4: C 69,48; H 6,61; N 5,40. Analysis calculated for C26H30N2O2 • C4H4O4: C 69.48; H 6.61; N 5.40.

Nađeno: C 69,48; H 6,80; N 5,44. Found: C 69.48; H 6.80; N 5.44.

Primjer 53 Example 53

(2'α, 3'αβ, 5'α, 6'αβ)-1-fenil-4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro[2H-1-benzopiran-2,2'(1'H)-pentalen]-5'-il) (2'α, 3'αβ, 5'α, 6'αβ)-1-phenyl-4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-hexahydrospiro [2H-1-benzopyran-2,2'(1'H)-pentalene]-5'-yl)

-piperazin maleat - piperazine maleate

t.t. = 220-221 °C. d.p. = 220-221 °C.

Analiza izračunata za C26H30N2O2 • C4H4O4: C 69,48; H 6,61; N 5,40. Analysis calculated for C26H30N2O2 • C4H4O4: C 69.48; H 6.61; N 5.40.

Nađeno: C 69,28; H 6,84; N 5,33. Found: C 69.28; H 6.84; N 5.33.

Primjer 54 Example 54

(2'α, 3'αβ, 5'α, 6'αβ)-3-[5'-(4-fenil-piperazin-1-il)-oktahidro-pentalen-2'-il]-1H-indol maleat (2'α, 3'αβ, 5'α, 6'αβ)-3-[5'-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2'-yl]-1H-indole maleate

t.t. = 232-232,5 °C. d.p. = 232-232.5 °C.

Analiza izračunata za C26H31N3 • C4H4O4: C 71,83; H 7,03; N 8,38. Analysis calculated for C26H31N3 • C4H4O4: C 71.83; H 7.03; N 8.38.

Nađeno: C 71,57; H 7,38; N 8,31. Found: C 71.57; H 7.38; N 8.31.

Primjer 55 Example 55

(2'α, 3'αβ, 6'αβ)-1-fenil-4-(5'-fenil-1',2',3',3'a,4',6'a-heksahidro-pentalen-2'-il)-piperazin dimaleat (2'α, 3'αβ, 6'αβ)-1-phenyl-4-(5'-phenyl-1',2',3',3'a,4',6'a-hexahydro-pentalene- 2'-yl)-piperazine dimaleate

t.t. = 156-157 °C. d.p. = 156-157 °C.

Analiza izračunata za C26H30N2O2 • 2C4H4O4: C 66,65; H 6,29; N 4,86. Analysis calculated for C26H30N2O2 • 2C4H4O4: C 66.65; H 6.29; N 4.86.

Nađeno: C 66,27; H 6,57; N 5,00. Found: C 66,27; H 6.57; N 5.00.

Primjer 56 Example 56

(2'α, 3'αβ, 5'α, 6'αβ)-4-(5'-fenil-oktahidro-pentalen-2'-il)-piperazin maleat (2'α, 3'αβ, 5'α, 6'αβ)-4-(5'-phenyl-octahydro-pentalen-2'-yl)-piperazine maleate

t.t. = 217-218 °C. d.p. = 217-218 °C.

Analiza izračunata za C24H30N2O2 • C4H4O4: C 72,70; H 7,41; N 6,06. Analysis calculated for C24H30N2O2 • C4H4O4: C 72.70; H 7.41; N 6.06.

Nađeno: C 72,28; H 7,46; N 6,01. Found: C 72.28; H 7.46; N 6.01.

Primjer 57 Example 57

(2'α, 3'αβ, 5'α, 6'αβ)-6-fluoro-2-metil-1-[5'-(4-fenil-piperazin-1-il)-oktahidro-pentalen-2'-il]-1H-benzoimidazol dimaleat (2'α, 3'αβ, 5'α, 6'αβ)-6-fluoro-2-methyl-1-[5'-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2' -yl]-1H-benzoimidazole dimaleate

t.t. = 203-205 °C. d.p. = 203-205 °C.

Analiza izračunata za C26H31FN4 • 2C4H4O4 • 0,50 H2O: C 61,90; H 6,11; N 8,49. Analysis calculated for C26H31FN4 • 2C4H4O4 • 0.50 H2O: C 61.90; H 6.11; N 8.49.

Nađeno: C 61,96; H 6,01; N 8,58. Found: C 61.96; H 6.01; N 8.58.

Primjer 58 Example 58

(2'α, 3'αβ, 5'α, 6'αβ)-1-[5'-(4-fluoro-fenoksi)-oktahidro-pentalen-2'-il]-4-fenil-piperazin maleat (2'α, 3'αβ, 5'α, 6'αβ)-1-[5'-(4-fluoro-phenoxy)-octahydro-pentalen-2'-yl]-4-phenyl-piperazine maleate

t.t. = 177-178 °C. d.p. = 177-178 °C.

Analiza izračunata za C24H29FN2O • C4H4O4: C 67,72; H 6,70; N 5,64. Analysis calculated for C24H29FN2O • C4H4O4: C 67.72; H 6.70; N 5.64.

Nađeno: C 67,33; H 6,82; N 5,62. Found: C 67.33; H 6.82; N 5.62.

Primjer 59 Example 59

(2'α, 3'αβ, 5'α, 6'αβ)-2-[5'-(4-fenil-piperazin-1-il)-oktahidro-pentalen-2'-il]-izoindol-1,3-dion maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-[5'-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2'-yl]-isoindol-1, 3-dione maleate

t.t. = 235-236 °C. d.p. = 235-236 °C.

Analiza izračunata za C26H29N3O2 • C4H4O4: C 67,78; H 6,26; N 7,90. Analysis calculated for C26H29N3O2 • C4H4O4: C 67.78; H 6.26; N 7.90.

Nađeno: C 67,71; H 6,37; N 7,94. Found: C 67.71; H 6.37; N 7.94.

Primjer 60 Example 60

(2'α, 3'αβ, 5'α, 6'αβ)-N-(2-{5'-[4-(5-fluoro-pirimidin-2-il)-piperazin-1-il]-oktahidro-pentalen-2'-il}-fenil)-acetamid maleat (2'α, 3'αβ, 5'α, 6'αβ)-N-(2-{5'-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro -pentalen-2'-yl}-phenyl)-acetamide maleate

t.t. = 211,5-212 °C. d.p. = 211.5-212 °C.

Analiza izračunata za C24H30FN5O • C4H4O4: C 62,33; H 6,35; N 12,98. Analysis calculated for C24H30FN5O • C4H4O4: C 62.33; H 6.35; N 12.98.

Nađeno: C 62,07; H 6,32; N 12,87. Found: C 62.07; H 6.32; N 12.87.

Primjer 61 Example 61

(2'α, 3'αβ, 5'α, 6'αβ)-N-(2-{5'-[4-(4-ciano-3-fluoro-fenil)-piperazinil-1-il]-oktahidro-pentalen-2'-il}-fenil)-acetamid maleat (2'α, 3'αβ, 5'α, 6'αβ)-N-(2-{5'-[4-(4-cyano-3-fluoro-phenyl)-piperazinyl-1-yl]-octahydro -pentalen-2'-yl}-phenyl)-acetamide maleate

t.t. = 197-199 °C. d.p. = 197-199 °C.

Analiza izračunata za C27H31FN4O • C4H4O4: C 66,18; H 6,27; N 9,96. Analysis calculated for C27H31FN4O • C4H4O4: C 66.18; H 6.27; N 9.96.

Nađeno: C 66,06; H 6,20; N 9,89. Found: C 66.06; H 6.20; N 9.89.

Primjer 62 Example 62

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-okso-2,3-dihidro-benzoimidazol-1-il)-oktahidro-pentalen-2'-il]-piperazin-1 (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro -pentalen-2'-yl]-piperazine-1

-il}-benzonitril mezilat -yl}-benzonitrile mesylate

t.t. > 260 °C. d.p. > 260 °C.

Analiza izračunata za C26H28FN5O • CH4O3S • 0,50 H2O: C 58,89; H 6,04; N 12,72. Analysis calculated for C26H28FN5O • CH4O3S • 0.50 H2O: C 58.89; H 6.04; N 12.72.

Nađeno: C 59,01; H 6,06; N 12,71. Found: C 59.01; H 6.06; N 12.71.

Primjer 63 Example 63

(2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(5-fluoro-pirimidil-2-il)-piperazin-1-il]-oktahidro-pentalen-2'-il}-1,3-dihidro (2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(5-fluoro-pyrimidyl-2-yl)-piperazin-1-yl]-octahydro-pentalene- 2'-yl}-1,3-dihydro

-benzoimidazol-2-on mezilat -benzoimidazol-2-one mesylate

t.t. > 260 °C. d.p. > 260 °C.

Analiza izračunata za C23H27FN6O • CH4O3S: C 55,58; H 6,04; N 16,20. Analysis calculated for C23H27FN6O • CH4O3S: C 55.58; H 6.04; N 16.20.

Nađeno: C 55,48; H 5,87; N 16,41. Found: C 55.48; H 5.87; N 16.41.

Primjer 64 Example 64

(2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(4-ciano-3-fluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-il}-benzamid maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(4-cyano-3-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen- 2'-yl}-benzamide maleate

t.t. = 198,5-200 °C. d.p. = 198.5-200 °C.

Analiza izračunata za C26H29FN4O • C4H4O4 • 0,50 H2O: C 64,62; H 6,15; N 10,05. Analysis calculated for C26H29FN4O • C4H4O4 • 0.50 H2O: C 64.62; H 6.15; N 10.05.

Nađeno: C 64,84; H 6,01; N 10,03. Found: C 64.84; H 6.01; N 10.03.

Primjer 65 Example 65

(2'α, 3'αβ, 5'α, 6'αβ)-N-[5'-(4-fenil-piperazin-1-il)-oktahidro-pentalen-2'-il]-benzamid maleat (2'α, 3'αβ, 5'α, 6'αβ)-N-[5'-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2'-yl]-benzamide maleate

t.t. = 211-212,5 °C. d.p. = 211-212.5 °C.

Analiza izračunata za C25H31N3O • C4H4O4 • 0,25 H2O: C 68,28; H 7,01; N 8,23. Analysis calculated for C25H31N3O • C4H4O4 • 0.25 H2O: C 68.28; H 7.01; N 8,23.

Nađeno: C 68,17; H 6,94; N 8,18. Found: C 68,17; H 6.94; N 8,18.

Primjer 66 Example 66

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-fluoro-fenoksi)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-fluoro-phenoxy)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t. = 192-193 °C. d.p. = 192-193 °C.

Analiza izračunata za C25H27F2N3O • C4H4O4: C 64,55; H 5,79; N 7,79. Analysis calculated for C25H27F2N3O • C4H4O4: C 64.55; H 5.79; N 7.79.

Nađeno: C 64,50; H 5,80; N 7,71. Found: C 64.50; H 5.80; N 7.71.

Primjer 67 Example 67

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-{4-[5'-(4-fluoro-fenoksi)-oktahidro-pentalen-2'-il]-piperazin-1-il}-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-{4-[5'-(4-fluoro-phenoxy)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-pyrimidine maleate

t.t. = 192-194 °C. d.p. = 192-194 °C.

Analiza izračunata za C22H26F2N4O • C4H4O4: C 60,46; H 5,85; N 10,85. Analysis calculated for C22H26F2N4O • C4H4O4: C 60.46; H 5.85; N 10.85.

Nađeno: C 60,30; H 5,82; N 10,78. Found: C 60.30; H 5.82; N 10.78.

Primjer 68 Example 68

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-okso-2,3-dihidro-benzoimidazol-1-il)-oktahidro-pentalen-2'-il]-piperazin-1 (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro -pentalen-2'-yl]-piperazine-1

-il}-benzonitril maleat -yl}-benzonitrile maleate

t.t.: 170-177 °C. m.p.: 170-177 °C.

NMR DMSO d6 δ 10,89 (s, 1H); 7,70 (t, J=8,4 Hz, 1H); 7,30-7,23 (m, 1H); 7,11 (d, J=13,9 Hz, 1H); 7,04-6,94 (m, 4H); 6,06 (s, 2H); 4,97-4,82 (m, 1H); 3,62-2,80 (br. m, 10H); 2,75-2,63 (m, 2H); 2,60-2,50 (m djelomično pod DMSO vrhom, 1H); 2,48-2,36 (m, 2H); 1,60 (dd, J1=12,4 Hz, J2=6,6 Hz, 2H); 1,58-1,34 (m, 2H). NMR DMSO d6 δ 10.89 (s, 1H); 7.70 (t, J=8.4 Hz, 1H); 7.30-7.23 (m, 1H); 7.11 (d, J=13.9 Hz, 1H); 7.04-6.94 (m, 4H); 6.06 (s, 2H); 4.97-4.82 (m, 1H); 3.62-2.80 (No. m, 10H); 2.75-2.63 (m, 2H); 2.60-2.50 (m partially under DMSO peak, 1H); 2.48-2.36 (m, 2H); 1.60 (dd, J1=12.4 Hz, J2=6.6 Hz, 2H); 1.58-1.34 (m, 2H).

Primjer 69 Example 69

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(3-metoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(3-methoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t. = 169-170 °C. d.p. = 169-170 °C.

Analiza izračunata za C26H30FN3O • C4H4O4: C 67,27; H 6,40; N 7,85. Analysis calculated for C26H30FN3O • C4H4O4: C 67.27; H 6.40; N 7.85.

Nađeno: C 67,18; H 6,52; N 7,87. Found: C 67,18; H 6.52; N 7.87.

Primjer 70 Example 70

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-metoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-{4-[5'-(4-methoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-benzonitrile maleate

t.t. = 189-186,5 °C. d.p. = 189-186.5 °C.

Analiza izračunata za C26H30FN3O • C4H4O4 • 0,25 H2O: C 66,71; H 6,44; N 7,78. Analysis calculated for C26H30FN3O • C4H4O4 • 0.25 H2O: C 66.71; H 6.44; N 7.78.

Nađeno: C 66,70; H 6,60; N 7,60. Found: C 66.70; H 6.60; N 7.60.

Primjer 71 Example 71

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-m-tolil-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-m-tolyl-octahydro-pentalen-2'-yl)-piperazin-1-yl ]-benzonitrile maleate

t.t. = 198-198,5 °C. d.p. = 198-198.5 °C.

Analiza izračunata za C26H30FN3O • C4H4O4: C 69,35; H 6,60; N 8,09. Analysis calculated for C26H30FN3O • C4H4O4: C 69.35; H 6.60; N 8.09.

Nađeno: C 69,48; H 6,74; N 8,14. Found: C 69.48; H 6.74; N 8,14.

Primjer 72 Example 72

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-p-tolil-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-p-tolyl-octahydro-pentalen-2'-yl)-piperazin-1-yl ]-benzonitrile maleate

t.t. = 194-195 °C. d.p. = 194-195 °C.

NMR DMSO d6 7,70 (t, J=8,5 Hz, 1H); 7,16-7,09 (m, 5H); 6,96 (d, J=8,7 Hz, 1H); 6,06 (s, 2H); 3,75-2,85 (s, 2H); 3,75-2,85 (m, 11H); 2,55-2,43 (m djelomično pod DMSO vrhom, 1H); 2,40-2,23 (m sa jednostrukim na 2,26, 7H ukupno); 1,63-1,32 (m, 4H). NMR DMSO d6 7.70 (t, J=8.5 Hz, 1H); 7.16-7.09 (m, 5H); 6.96 (d, J=8.7 Hz, 1H); 6.06 (s, 2H); 3.75-2.85 (s, 2H); 3.75-2.85 (m, 11H); 2.55-2.43 (m partially under DMSO peak, 1H); 2.40-2.23 (m with single at 2.26, 7H total); 1.63-1.32 (m, 4H).

Primjer 73 Example 73

(2'α, 3'αβ, 5'α, 6'αβ)-1-[5'-(4-fluoro-fenoksi)-oktahidro-pentalen-2'-il]-4-fenil-piperazin maleat (2'α, 3'αβ, 5'α, 6'αβ)-1-[5'-(4-fluoro-phenoxy)-octahydro-pentalen-2'-yl]-4-phenyl-piperazine maleate

t.t. = 174-175 °C. d.p. = 174-175 °C.

Analiza izračunata za C24H29FN2O • C4H4O4: C 67,72; H 6,70; N 5,64. Analysis calculated for C24H29FN2O • C4H4O4: C 67.72; H 6.70; N 5.64.

Nađeno: C 67,82; H 6,83; N 5,59. Found: C 67.82; H 6.83; N 5.59.

Primjer 74 Example 74

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-o-tolil-oktahidro-pentalen-2'-il)-piperazin-1-il]-benzonitril maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(5'-o-tolyl-octahydro-pentalen-2'-yl)-piperazin-1-yl ]-benzonitrile maleate

t.t. = 198-199 °C. d.p. = 198-199 °C.

Analiza izračunata za C26H30FN3 • C4H4O4: C 69,35; H 6,60; N 8,09. Analysis calculated for C26H30FN3 • C4H4O4: C 69.35; H 6.60; N 8.09.

Nađeno: C 69,13; H 6,69; N 8,12. Found: C 69,13; H 6.69; N 8,12.

Primjer 75 Example 75

(2'α, 3'αβ, 5'α, 6'αβ)-1-fenil-4-[5'-(3-pirolidin-1-ilmetil-fenil)-oktahidro-pentalen-2'-il]-piperaksin dimaleat (2'α, 3'αβ, 5'α, 6'αβ)-1-phenyl-4-[5'-(3-pyrrolidin-1-ylmethyl-phenyl)-octahydro-pentalen-2'-yl]- piperaxine dimaleate

t.t. = 163-164 °C. d.p. = 163-164 °C.

Analiza izračunata za C29H39N3 • 2 C4H4O4: C 67,15; H 7,16; N 6,35. Analysis calculated for C29H39N3 • 2 C4H4O4: C 67.15; H 7.16; N 6.35.

Nađeno: C 66,81; H 7,22; N 6,27. Found: C 66.81; H 7.22; N 6.27.

Primjer 76 Example 76

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidro-3'a, 6'a-dimetilspiro[izobenzofuran-1(3H), 2'(1'H)-pentalen]-5'-il)-1-piperazinil]-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydro- 3'a, 6'a-dimethylspiro[isobenzofuran-1(3H), 2'(1'H)-pentalene]-5'-yl)-1-piperazinyl]-pyrimidine maleate

t.t. = 224,5-225 °C. d.p. = 224.5-225 °C.

Analiza izračunata za C25H31FN4O • C4H4O4 • 0,25 H2O: C 64,13; H 6,59; N 10,32. Analysis calculated for C25H31FN4O • C4H4O4 • 0.25 H2O: C 64.13; H 6.59; N 10.32.

Nađeno: C 64,25; H 6,68; N 10,14. Found: C 64.25; H 6.68; N 10,14.

Primjer 77 Example 77

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-heksahidro-3'a, 6'a-dimetilspiro[izobenzofuran-1(3H), 2'(1'H)-pentalen]-5'-il)-1-piperazinil]-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(3', 3'a, 4', 5', 6', 6'a-hexahydro- 3'a, 6'a-dimethylspiro[isobenzofuran-1(3H), 2'(1'H)-pentalene]-5'-yl)-1-piperazinyl]-pyrimidine maleate

t.t. = 222-223 °C. d.p. = 222-223 °C.

NMR DMSO d6 δ 8,58 (s, 2H); 7,34-7,30 (m, 1H); 7,28-7,25 (m, 3H); 6,04 (s, 2H); 4,94 (s, 2H); 3,65-2,75 (br. m, 9H); 2,20-2,12 (m, 2H); 1,94 (AB kvartet, �v=37,8 Hz, J=13,2 Hz, 4H); 1,54 (br. t, J=11,7 Hz, 2H); 1,21 (s, 6H). NMR DMSO d6 δ 8.58 (s, 2H); 7.34-7.30 (m, 1H); 7.28-7.25 (m, 3H); 6.04 (s, 2H); 4.94 (s, 2H); 3.65-2.75 (No. m, 9H); 2.20-2.12 (m, 2H); 1.94 (AB quartet, �v=37.8 Hz, J=13.2 Hz, 4H); 1.54 (No. t, J=11.7 Hz, 2H); 1.21 (s, 6H).

Primjer 78 Example 78

(2'α, 3'αβ, 5'α, 6'αβ)-4-{4-[5'-(1,3-diokso-1,3-dihidro-izoindol-2-il)-oktahidro-pentalen-2'-il]-piperazin-1-il}-2 (2'α, 3'αβ, 5'α, 6'αβ)-4-{4-[5'-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-octahydro-pentalene -2'-yl]-piperazin-1-yl}-2

-fluoro-benzonitril maleat -fluoro-benzonitrile maleate

t.t. = 224-224,5 °C. d.p. = 224-224.5 °C.

Analiza izračunata za C27H27FN4O2 • C4H4O4: C 64,80; H 5,44; N 9,75. Analysis calculated for C27H27FN4O2 • C4H4O4: C 64.80; H 5.44; N 9.75.

Nađeno: C 64,85; H 5,56; N 9,74. Found: C 64.85; H 5.56; N 9.74.

Primjer 79 Example 79

(2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(5-fluoro-pirimidin-2-il)-piperazin-1-il]-oktahidro-pentalen-2'-il}-izoindol-1,3-dion maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen- 2'-yl}-isoindole-1,3-dione maleate

t.t. = 241,5-224 °C. d.p. = 241.5-224 °C.

Analiza izračunata za C24H26FN5O2 • C4H4O4: C 60,97; H 5,48; N 12,70. Analysis calculated for C24H26FN5O2 • C4H4O4: C 60.97; H 5.48; N 12.70.

Nađeno: C 60,66; H 5,55; N 12,44. Found: C 60.66; H 5.55; N 12.44.

Primjer 80 Example 80

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro[2H-6-fluoro-1-benzopiran-2,2'(1'H) (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6' a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2'(1'H)

-pentalen]-5'-il)-1-piperazinil]-benzonitril maleat -pentalene]-5'-yl)-1-piperazinyl]-benzonitrile maleate

t.t. = 219-220 °C. d.p. = 219-220 °C.

Analiza izračunata za C24H26F2N4O2 • C4H4O4 • 0,50 H2O: C 59,46; H 5,55; N 9,90. Analysis calculated for C24H26F2N4O2 • C4H4O4 • 0.50 H2O: C 59.46; H 5.55; N 9.90.

Nađeno: C 59,86; H 5,70; N 9,40. Found: C 59.86; H 5.70; N 9.40.

Primjer 81 Example 81

(2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6'a-heksahidrospiro[2H-6-fluoro-1-benzopiran-2,2'(1'H) (2'α, 3'αβ, 5'α, 6'αβ)-2-fluoro-4-[4-(3, 3', 3'a, 4, 4', 5', 6', 6' a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2'(1'H)

-pentalen]-5'-il)-1-piperazinil]-benzonitril maleat -pentalene]-5'-yl)-1-piperazinyl]-benzonitrile maleate

t.t. = 216-217 °C. d.p. = 216-217 °C.

Analiza izračunata za C24H26F2N4O2 • C4H4O4: C 60,43; H 5,43; N 10,07. Analysis calculated for C24H26F2N4O2 • C4H4O4: C 60.43; H 5.43; N 10.07.

Nađeno: C 60,39; H 5,47; N 9,90. Found: C 60.39; H 5.47; N 9.90.

Primjer 82 Example 82

(2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(5'-o-tolil-oktahidro-pentalen-2'-il)-piperazin-1-il]-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-fluoro-2-[4-(5'-o-tolyl-octahydro-pentalen-2'-yl)-piperazin-1-yl ]-pyrimidine maleate

t.t. = 204-205 °C. d.p. = 204-205 °C.

Analiza izračunata za C23H29FN4 • C4H4O4: C 65,31; H 6,70; N 11,28. Analysis calculated for C23H29FN4 • C4H4O4: C 65.31; H 6.70; N 11.28.

Nađeno: C 65,38; H 6,77; N 11,32. Found: C 65.38; H 6.77; N 11.32.

Primjer 83 Example 83

(2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(4-fluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-il}-1,3-fihidro-benzoimidazol-2 (2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(4-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2'-yl }-1,3-hydro-benzoimidazole-2

-on maleat - he's maleate

t.t. = 217-218 °C. d.p. = 217-218 °C.

Analiza izračunata za C25H29FN4O • C4H4O4: C 64,91; H 6,20; N 10,44. Analysis calculated for C25H29FN4O • C4H4O4: C 64.91; H 6.20; N 10.44.

Nađeno: C 64,57; H 6,28; N 10,18. Found: C 64.57; H 6.28; N 10,18.

Primjer 84 Example 84

(2'α, 3'αβ, 5'α, 6'αβ)-2-[5'-(4-fenil-piperazin-1-il)-oktahidro-pentalen-2'-iloksi]-1H-benzoimidazol maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-[5'-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2'-yloxy]-1H-benzoimidazole maleate

t.t. = 161-162 °C. d.p. = 161-162 °C.

Analiza izračunata za C25H30N4O • C4H4O4: C 67,16; H 6,61; N 10,80. Analysis calculated for C25H30N4O • C4H4O4: C 67.16; H 6.61; N 10.80.

Nađeno: C 67,05; H 6,66; N 10,59. Found: C 67.05; H 6.66; N 10.59.

Primjer 85 Example 85

(2'α, 3'αβ, 5'α, 6'αβ)-2-kloro-2-{4-[5'-(2-metoksi-fenil)-oktahidro-pentalen-2'-il]-piperazin-1-il}-pirimidin maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-chloro-2-{4-[5'-(2-methoxy-phenyl)-octahydro-pentalen-2'-yl]-piperazine -1-yl}-pyrimidine maleate

t.t. = 199,5-200 °C. d.p. = 199.5-200 °C.

Analiza izračunata za C23H29ClN4O • C4H4O4: C 61,30; H 6,29; N 10,59. Analysis calculated for C23H29ClN4O • C4H4O4: C 61.30; H 6.29; N 10.59.

Nađeno: C 61,05; H 6,31; N 10,83. Found: C 61.05; H 6.31; N 10.83.

Primjer 86 Example 86

(2'α, 3'αβ, 5'α, 6'αβ)-5-kloro-2-[4-(5'-o-tolil-oktahidro-pentalen-2'-il)-piperazin-1-il]-pirimisin maleat (2'α, 3'αβ, 5'α, 6'αβ)-5-chloro-2-[4-(5'-o-tolyl-octahydro-pentalen-2'-yl)-piperazin-1-yl ]-pyrimisin maleate

t.t. = 200-200,5 °C. d.p. = 200-200.5 °C.

Analiza izračunata za C23H29ClN4 • C4H4O4: C 63,21; H 6,48; N 10,92. Analysis calculated for C23H29ClN4 • C4H4O4: C 63.21; H 6.48; N 10.92.

Nađeno: C 62,97; H 6,33; N 11,29. Found: C 62.97; H 6.33; N 11.29.

Primjer 87 Example 87

(2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(3,4-difluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-il}-izoindol-1,3-dion maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2' -yl}-isoindole-1,3-dione maleate

t.t. = 221,5-222 °C. d.p. = 221.5-222 °C.

Analiza izračunata za C26H27F2N3O2 • C4H4O4: C 63,48; H 5,51; N 7,46. Analysis calculated for C26H27F2N3O2 • C4H4O4: C 63.48; H 5.51; N 7.46.

Nađeno: C 63,28; H 5,51; N 7,64. Found: C 63.28; H 5.51; N 7.64.

Primjer 88 Example 88

(2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(4-fluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-il}-izoindol-1,3-dion maleat (2'α, 3'αβ, 5'α, 6'αβ)-2-{5'-[4-(4-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2'-yl }-isoindole-1,3-dione maleate

t.t. = 209-210 °C. d.p. = 209-210 °C.

Analiza izračunata za C26H28FN3O2 • C4H4O4 • 0,50 H2O: C 64,51; H 5,95; N 7,52. Analysis calculated for C26H28FN3O2 • C4H4O4 • 0.50 H2O: C 64.51; H 5.95; N 7.52.

Nađeno: C 64,47; H 5,91; N 7,66. Found: C 64.47; H 5.91; N 7.66.

Primjer 89 Example 89

(2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(3,4-difluoro-fenil)-piperazin-1-il]-oktahidro-pentalen-2'-il}-1,3-dihidro (2'α, 3'αβ, 5'α, 6'αβ)-1-{5'-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2' -yl}-1,3-dihydro

-benzoimidazol-2-on maleat -benzoimidazol-2-one maleate

t.t. = 201-202 °C. d.p. = 201-202 °C.

Analiza izračunata za C25H28F2N4O • C4H4O4 • 0,50 H2O: C 61,80; H 5,90; N 9,94. Analysis calculated for C25H28F2N4O • C4H4O4 • 0.50 H2O: C 61.80; H 5.90; N 9.94.

Nađeno: C 62,10; H 5,80; N 9,56. Found: C 62.10; H 5.80; N 9.56.

Claims (21)

1. Spoj formule [image] ili njegova farmaceutski prihvatljiva sol, naznačen time što isprekidana linija predstavlja opcionalnu dvostruku vezu; a je 0 ili 1, gdje kada a je 0, X može formirati opcionalnu dvostruku vezu sa ugljikom susjednim sa V; V je CHR10, gdje R10 je vodik ili (C1-C6) alkil; T je dušik ili CH; X je dušik ili CR11, gdje R11 je vodik, (C1-C6) alkil, (C1-C6) alkoksi, hidroksi ili ciano; Y i Z su svaki nezavisno dušik ili CR12, gdje R12 je vodik, kloro, bromo, trifluorometil, trifluorometoksi, ciano, (C1-C6) alkoksi ili (C1-C6) alkil; R1 je vodik, fluoro, kloro, bromo, trifluorometil, trifluorometoksi, ciano ili (C1-C6) alkil; R2, R6, R7, R8 i R9 su svaki nezavisno odabrani od vodika, fluoro, kloro, bromo, trifluorometila, trifluorometoksi, ciano, (C1-C6) alkoksi i (C1-C6) alkila; R3 i R4 su svaki nezavisno vodik ili (C1-C6) alkil; i R5 je vodik, (C1-C6) alkoksi, trifluorometil, ciano, (C1-C6) alkil ili R13CO-, gdje R13 je amino, (C1-C6) alkilamino, ((C1-C6) alkil)2amino, (C1-C6) alkil, (C6-C10) aril; ili kada a je 1, R1 i R10 mogu biti uzeti zajedno sa ugljikom na koga su vezani radi formiranja spoja formule [image] gdje isprekidane linije predstavljaju opcionalne veze; T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 i R9 su definirani kao gore; b je 0 ili 1; i A i B su svaki nezavisno CH, CH2, kisik, sumpor, NH ili dušik; pod uvjetom da kada X je dušik, opcionalna dvostruka veza između X i V ne postoji; pod uvjetom da kada b je 0, opcionalna dvostruka veza između A i B ne postoji; i pod uvjetom da kada b je 1, A i B ne mogu oba biti kisik ili sumpor.1. Compound formula [image] or a pharmaceutically acceptable salt thereof, wherein the dashed line represents an optional double bond; a is 0 or 1, where when a is 0, X may form an optional double bond with the carbon adjacent to V; V is CHR 10 , where R 10 is hydrogen or (C 1 -C 6 ) alkyl; T is nitrogen or CH; X is nitrogen or CR 11 , where R 11 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, hydroxy or cyano; Y and Z are each independently nitrogen or CR 12 , where R 12 is hydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6 ) alkoxy or (C 1 -C 6 ) alkyl; R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or (C 1 -C 6 ) alkyl; R 2 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) alkyl; R 3 and R 4 are each independently hydrogen or (C 1 -C 6 )alkyl; and R5 is hydrogen, (C1-C6) alkoxy, trifluoromethyl, cyano, (C1-C6) alkyl or R13CO-, where R13 is amino, (C1-C6) alkylamino, ((C1-C6) alkyl)2amino, (C1- C6) alkyl, (C6-C10) aryl; or when a is 1, R1 and R10 may be taken together with the carbon to which they are attached to form a compound of the formula [image] where dashed lines represent optional links; T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above; b is 0 or 1; and A and B are each independently CH, CH 2 , oxygen, sulfur, NH or nitrogen; provided that when X is nitrogen, the optional double bond between X and V does not exist; provided that when b is 0, the optional double bond between A and B does not exist; and provided that when b is 1, A and B cannot both be oxygen or sulfur. 2. Spoj prema zahtjevu 1, naznačen time što X je dušik.2. A compound according to claim 1, characterized in that X is nitrogen. 3. Spoj prema zahtjevu 1, naznačen time što Y i Z su svaki CR12, gdje R12 je vodik ili fluoro.3. A compound according to claim 1, characterized in that Y and Z are each CR 12 , where R 12 is hydrogen or fluoro. 4. Spoj prema zahtjevu 1, naznačen time što R2je vodik, fluoro ili kloro.4. A compound according to claim 1, characterized in that R2 is hydrogen, fluoro or chloro. 5. Spoj prema zahtjevu 1, naznačen time što R3, R4 i R5 su vodik.5. Compound according to claim 1, characterized in that R3, R4 and R5 are hydrogen. 6. Spoj prema zahtjevu 1, naznačen time što R7 je fluoro ili kloro.6. A compound according to claim 1, characterized in that R7 is fluoro or chloro. 7. Spoj prema zahtjevu 1, naznačen time što R9 je fluoro, kloro, bromo ili alkoksi.7. A compound according to claim 1, characterized in that R9 is fluoro, chloro, bromo or alkoxy. 8. Spoj prema zahtjevu 1, naznačen time što X je dušik; Y i Z su svaki CR12, gdje R12 je vodik ili fluoro; R2 je vodik, fluoro ili kloro; R3, R4 i R5 su vodik; R7 je fluoro ili kloro; i R7 je fluoro, bromo ili alkoksi.8. A compound according to claim 1, characterized in that X is nitrogen; Y and Z are each CR 12 , wherein R 12 is hydrogen or fluoro; R 2 is hydrogen, fluoro or chloro; R 3 , R 4 and R 5 are hydrogen; R 7 is fluoro or chloro; and R 7 is fluoro, bromo or alkoxy. 9. Spoj prema zahtjevu 1, naznačen time što je odabran iz grupe koja sadrži: 2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol; 5-fluoro-2-[4-(3-trifluorometil-fenil)-piperazin-1-ilmetil]-1H-indol; 5-fluoro-2-[4-(4-fluoro-fenil)-piperazin-1-ilmetil]-1H-indol; 5-fluoro-2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-indol; 2-[4-(6-kloro-piridazin-3-il)-piperazin-1-ilmetil]-5-fluoro-1H-indol; 5-fluoro-2-(4-[5'-fluoro]piridin-2-il-piperazin-1-ilmetil)-1H-indol; 2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-azaindol; 5-fluoro-2-(4-piridin-2-il-piperazin-1-ilmetil)-1H-azaindol; i 2-[4-(4-fluoro-fenil)-piperazin-1-ilmetil]-1H-azaindol.9. Compound according to claim 1, characterized in that it is selected from the group containing: 2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole; 5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole; 5-fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole; 5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole; 2-[4-(6-chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole; 5-fluoro-2-(4-[5'-fluoro]pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole; 2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole; 5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole; and 2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-azaindole. 10. Postupak za tretiranje oboljenja dopamin sustava kod sisavaca, naznačen time što obuhvaća unošenje u spomenutog sisavca količine selektivnog D4 dopamin receptora spoja prema zahtjevu 1 ili njegove farmaceutski prihvatljive soli, koja je efikasna u tretiranju takvog oboljenja.10. A method for treating diseases of the dopamine system in mammals, characterized in that it comprises introducing into said mammal an amount of the selective D4 dopamine receptor compound according to claim 1 or its pharmaceutically acceptable salt, which is effective in treating such a disease. 11. Postupak prema zahtjevu 10, naznačen time što oboljenja dopamin sustava uključuju psihička oboljenja, pokretna oboljenja, želučano-crijevna oboljenja, kemijske zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja, okularna oboljenja i oboljenja spavanja.11. The method according to claim 10, characterized in that diseases of the dopamine system include mental diseases, movement disorders, gastrointestinal diseases, chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases, eye diseases and sleep diseases. 12. Postupak za tretiranje oboljenja dopamin sustava kod sisavaca, naznačen time što obuhvaća unošenje u spomenutog sisavca količine selektivnog D4 dopamin receptora spoja prema zahtjevu 1 ili njegove farmaceutski prihvatljive soli, zajedno sa jednim ili više D1, D2, D3 ili D5 dopamin receptor agonistima, koja je efikasna u tretiranju takvog oboljenja.12. A method for treating diseases of the dopamine system in mammals, characterized in that it comprises introducing into said mammal an amount of the selective D4 dopamine receptor compound according to claim 1 or its pharmaceutically acceptable salt, together with one or more D1, D2, D3 or D5 dopamine receptor agonists, which is effective in treating such a disease. 13. Postupak prema zahtjevu 12, naznačen time što oboljenja dopamin sustava uključuju psihička oboljenja, pokretna oboljenja, želučano-crijevna oboljenja, kemijske zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja, okularna oboljenja i oboljenja spavanja.13. The method according to claim 12, characterized in that diseases of the dopamine system include mental diseases, movement disorders, gastrointestinal diseases, chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases, eye diseases and sleep diseases. 14. Postupak prema zahtjevu 11, naznačen time što psihička oboljenja uključuju afektivnu duševnu bolest, šizofreniju, i šizoafektivna oboljenja.14. The method according to claim 11, characterized in that the mental illnesses include affective mental illness, schizophrenia, and schizoaffective illnesses. 15. Postupak prema zahtjevu 11, naznačen time što pokretna oboljenja uključuju ekstrapiramidalne sporedne efekte od neuroleptičkih sredstava, neuroleptički maligni sindrom, tardivnu diskineziu, Gilles De La Tourette-ov sindrom, Parkinson-ovo oboljenje ili Huntington-ovo oboljenje.15. The method according to claim 11, characterized in that the movement disorders include extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease. 16. Postupak prema zahtjevu 11, naznačen time što želučano-crijevna oboljenja uključuju lučenje želučane kiseline ili emesis.16. The method according to claim 11, characterized in that gastrointestinal diseases include secretion of gastric acid or emesis. 17. Postupak prema zahtjevu 11, naznačen time što vaskularna i kardiovaskularna oboljenja uključuju kongestivni otkaz srca i hipertenziju.17. The method according to claim 11, characterized in that vascular and cardiovascular diseases include congestive heart failure and hypertension. 18. Farmaceutski preparat za tretiranje oboljenja dopamin sustava kod sisavaca, naznačen time što obuhvaća unošenje u spomenutog sisavca količine slektivnog D4 dopamin receptora spoja prema zahtjevu 1 ili njegove farmaceutski prihvatljive soli, koja je efikasna u tretiranju takvog oboljenja.18. Pharmaceutical preparation for the treatment of diseases of the dopamine system in mammals, characterized in that it comprises introducing into said mammal an amount of the selective D4 dopamine receptor compound according to claim 1 or its pharmaceutically acceptable salt, which is effective in treating such a disease. 19. Farmaceutski preparat prema zahtjevu 18, naznačen time što oboljenja dopamin sustava uključuju psihička oboljenja, pokretna oboljenja, želučano-crijevna oboljenja, kemijske zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja, okularna oboljenja i oboljenja spavanja.19. Pharmaceutical preparation according to claim 18, characterized in that diseases of the dopamine system include mental diseases, movement disorders, gastrointestinal diseases, chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases, eye diseases and sleep diseases. 20. Farmaceutski preparat za tretiranje oboljenja dopamin sustava kod sisavaca, naznačen time što obuhvaća unošenje u spomenutog sisavca količine selektivnog D4 dopamin receptora spoja prema zahtjevu 1 ili njegove farmaceutski prihvatljive soli, zajedno sa jednim ili više D1, D2, D3 ili D5 dopamin receptor agonistima, koja je efikasna u tretiranju takvog oboljenja.20. A pharmaceutical preparation for treating diseases of the dopamine system in mammals, characterized in that it comprises introducing into said mammal an amount of the selective D4 dopamine receptor compound according to claim 1 or its pharmaceutically acceptable salt, together with one or more D1, D2, D3 or D5 dopamine receptor agonists , which is effective in treating such a disease. 21. Farmaceutski preparat prema zahtjevu 20, naznačen time što oboljenja dopamin sustava uključuju psihička oboljenja, pokretna oboljenja, želučano-crijevna oboljenja, kemijske zloupotrebu, kemijske zavisnosti, zloupotrebu supstance, vaskularna i kardiovaskularna oboljenja, okularna oboljenja i oboljenja spavanja.21. Pharmaceutical preparation according to claim 20, characterized in that diseases of the dopamine system include mental diseases, movement disorders, gastrointestinal diseases, chemical abuse, chemical addictions, substance abuse, vascular and cardiovascular diseases, eye diseases and sleep diseases.
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