HRP970020A2

HRP970020A2 - Therapeutic agents

Info

Publication number: HRP970020A2
Authority: HR
Inventors: Bruce Jeremy Sargent
Original assignee: Bruce Jeremy Sargent
Priority date: 1997-01-10
Filing date: 1997-01-10
Publication date: 1998-10-31

Description

Predloženi izum odnosi se na nove heteroaril-karboksamidne spojeve koji pokazuju afinitet prema 5-HT1a i/ili α1 i/ili α2 i/ili D2 receptorima, na postupke za njihovu pripravu, na farmaceutske sastave koji ih sadrže i na njihovu upotrebu za liječenje poremećaja središnjeg živčanog sustava, na primjer depresije, anksioznosti, psihoze (na primjer šizofrenije), tardive diskinezije, Parkinsonove bolesti, debljine, hipertenzije, Touretteovog sindroma, seksualne disfunkcije, odvikavanja od druga, zloupotrebe droga, spoznajnih poremećaja, Alzheimerove bolesti, senilne demencije, opsesivno-nasilnog ponašanja, napada panike, socijalnih fobija, poremećaja uzimanja hrane i anoreksije, kardiovaskularnih i cerebrovaskularnih poremećaja, diabetesa mellitusa koji nije ovisan o inzulinu, hiperglikemije, opstipacije, aritmije, poremećaja neuroedokrinog sistema, stresa, hipetrofije prostate i spastičnosti. The proposed invention relates to new heteroaryl-carboxamide compounds that show affinity for 5-HT1a and/or α1 and/or α2 and/or D2 receptors, to methods for their preparation, to pharmaceutical compositions containing them and to their use for the treatment of disorders central nervous system, for example depression, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, withdrawal from friends, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive -violent behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostate hypertrophy and spasticity.

Predloženim izumom osigurani su spojevi formule I The proposed invention provides compounds of formula I

[image] [image]

uključiv njihove farmaceutski prihvatljive soli, u kojima including their pharmaceutically acceptable salts, in which

A je metilen ili O; A is methylene or O;

B je metilen ili O; B is methylene or O;

g je 0, 1, 2, 3 ili 4; g is 0, 1, 2, 3 or 4;

R1 predstavlja R1 represents

a) halogen; a) halogen;

b) alkilnu skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; b) an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens;

c) alkoksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; c) an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens;

d) alkiltio skupina koja ima po potrebi supstituirana s jednim ili više halogenih; d) an alkylthio group which is optionally substituted with one or more halogens;

e) hidroksi; e) hydroxy;

f) aciloksi skupina koja ima 1 do 3 ugljikova atoma; f) an acyloxy group having 1 to 3 carbon atoms;

g) hidroksimetil; g) hydroxymethyl;

h) cijano; h) cyano;

i) alkanoilnu skupinu koja ima 1 do 6 ugljikovih atoma; i) an alkanoyl group having 1 to 6 carbon atoms;

j) alkoksikarbonilnu skupinu koja ima 2 do 6 ugljikovih atoma; j) an alkoxycarbonyl group having 2 to 6 carbon atoms;

k) karbamoilnu skupinu ili karbamoilmetilnu skupinu od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; k) carbamoyl group or carbamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms;

l) sulfamoilnu ili sulfamoilmetilnu skupinu od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; ili l) sulfamoyl or sulfamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; or

m) alkilsulfoniloksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; m) an alkylsulfonyloxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens;

n) furilnu skupinu; n) furyl group;

o) amimo skupinu po potrebi supstituirana s jednom ili dvije alkilne skupine kojih svaka ima 1 do 3 ugljikova atoma; ili dvije susjedne R1 skupine zajedno s ugljikovim atomom kojeg dodiruju tvore benzenski prsten, pri čemu, ako je g 2, 3 ili 4, supstituenti predstavljeni sa R1 mogu biti jednaki ili različiti; o) an amimo group optionally substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; or two adjacent R1 groups together with the carbon atom they touch form a benzene ring, wherein, if g is 2, 3 or 4, the substituents represented by R1 may be the same or different;

R2 je H, alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, ili alkoksi skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; R 2 is H, an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens, or an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens;

R3 i R4 koji su jednaki ili različiti, jesu H, ili alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; R3 and R4, which are the same or different, are H, or an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens;

U je alkilneksi lanac koji ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više alkilenskih skupina od kojih svaki ima 1 do 3 ugljikova atoma; U is an alkylnexy chain having 1 to 3 carbon atoms optionally substituted with one or more alkylene groups each having 1 to 3 carbon atoms;

Q predstavlja dvovalentnu skupinu formula IIa, IIb ili IIc Q represents a divalent group of formulas IIa, IIb or IIc

[image] [image]

u kojima in which

V je veza ili alkilenski lanac koji ima 1 do 3 ugljikova toma po potrebi supstituirana s jednim ili više alkilenskih skupina od kojih svaka ima 1 do 3 ugljikova atoma; V is a bond or alkylene chain having 1 to 3 carbon atoms optionally substituted with one or more alkylene groups each having 1 to 3 carbon atoms;

V' je alkilenski lanac koji ima 2 do 5 ugljikovih atoma po potrebi supstituirana s jednim ili više alkilnih skupina od kojih svaka ima 1 do 3 ugljikova atoma; V' is an alkylene chain having 2 to 5 carbon atoms optionally substituted with one or more alkyl groups each having 1 to 3 carbon atoms;

X je alkelinski lanac koji ima 0 do 2 ugljikova atoma, a X' je alkelinski lanac koji ima 1 do 4 ugljikova atoma, pod uvjetom da broj ugljikovih atoma u X i X' iznosi 3 ili 4; X is an alkylene chain having 0 to 2 carbon atoms, and X' is an alkylene chain having 1 to 4 carbon atoms, provided that the number of carbon atoms in X and X' is 3 or 4;

R5 je H ili alkilna skupina koja ima 1 do 3 ugljikova atoma; i R5 is H or an alkyl group having 1 to 3 carbon atoms; and

T predstavlja skupinu CO.HET u kojoj HET je 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-tienil, 2- ili 3-furil, 2-, 3- ili 7-benzo[b]tienil, 2-, 3- ili 4-piperidil, 3-, 4- ili 5-pirazolil, 4- ili 5-triazolil, 5-tetrazolil, 2-, 3-, 4- ili 8-kinolil, 2- ili 4- kinazolil, 3-, 4- ili 5-izoksazolil ili 2-, 4- ili 5-oksazolil, 3-, 4- ili 5-izotiazolil ili 2-, 4- ili 5-tiazolil, od kojih svako po potrebi može biti supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine T represents the group CO.HET where HET is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 7-benzo[b]thienyl, 2-, 3- or 4-piperidyl, 3-, 4- or 5-pyrazolyl, 4- or 5-triazolyl, 5-tetrazolyl, 2-, 3-, 4- or 8- quinolyl, 2- or 4-quinazolyl, 3-, 4- or 5-isoxazolyl or 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl, from each of which, if necessary, can be substituted with one or more substituents selected from the group they comprise

a) halogen, a) halogen,

b) alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, b) an alkyl group having 1 to 3 carbon atoms, optionally substituted with one or more halogens,

c) alkoksi skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, c) an alkoxy group having 1 to 3 carbon atoms, optionally substituted with one or more halogens,

d) alkiltio skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, d) an alkylthio group having 1 to 3 carbon atoms, optionally substituted with one or more halogens,

e) hidroksi, e) hydroxy,

f) aciloksi skupina koja ima 1 do 3 ugljikova atoma, f) an acyloxy group having 1 to 3 carbon atoms,

g) hidroksimetil, g) hydroxymethyl,

h) cijano, h) cyano,

i) alkanoilna skupina koja ima 1 do 6 ugljikovih atoma, i) an alkanoyl group having 1 to 6 carbon atoms,

j) alkoksikarbonilna skupina koja ima 2 do 6 ugljikovih atoma, j) alkoxycarbonyl group having 2 to 6 carbon atoms,

k) karbamoilna skupina ili karbamoilmetilna skupina od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; k) carbamoyl group or carbamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms;

l) sulfamoilna ili sulfamoilmetilna skupina od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; l) sulfamoyl or sulfamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms;

m) amino skupina po potrebi supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 5 ugljikova atoma; m) an amino group optionally substituted with one or two alkyl groups, each of which has 1 to 5 carbon atoms;

n) 1-pirolil ili n) 1-pyrrolyl or

o) 1-pirolidinil ili piperidino. o) 1-pyrrolidinyl or piperidino.

U spojevima formule I, kojima se daje prednost, A je O. In preferred compounds of formula I, A is O.

U spojevima formule I, kojima se daje prednost, B je O. In preferred compounds of formula I, B is O.

U spojevima formule I, kojima se daje veću prednost, obadva A i B su O. In more preferred compounds of formula I, both A and B are O.

U spojevima formule I, kojima se daje prednost, g je 0, 1 ili 2. In preferred compounds of formula I, g is 0, 1 or 2.

U spojevima formule I, kojima se daje prednost, u kojima g je 1 ili 2, R1 predstavlja halogen (na primjer fluor, klor ili brom), alkilnu skupinu koja ima 1 do 3 ugljikova toma po potrebi supstituirana s jednim ili više halogenih, alkoksi skupinu od kojih svaka ima 1 do 3 ugljikova atoma, alkansulfoniloksi skupinu koja ima 1 do 3 ugljikova toma po potrebi supstituirana s jednim ili više halogenih, ili hidroksi. U spojevima formule I, kojima se daje veću prednost, u kojima g je 1 ili R1 predstavlja brom, klor, fluor, trifluormetil, trifluormetansulfoniloksi, meitl ili metoksi. In preferred compounds of formula I, in which g is 1 or 2, R 1 represents a halogen (for example fluorine, chlorine or bromine), an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens, alkoxy group each having 1 to 3 carbon atoms, an alkanesulfonyloxy group having 1 to 3 carbon atoms optionally substituted with one or more halogen, or hydroxy. In more preferred compounds of formula I, wherein g is 1 or R 1 represents bromine, chlorine, fluorine, trifluoromethyl, trifluoromethanesulfonyloxy, methyl or methoxy.

U spojevima formule I, kojima se daje prednost, R2 je H ili alkilna skupina koja ima 1 do 3 ugljikova atoma. U spojevima formule I, kojima se daje veću prednost, R2 je H. In preferred compounds of formula I, R 2 is H or an alkyl group having 1 to 3 carbon atoms. In more preferred compounds of formula I, R 2 is H.

U spojevima formule I, kojima se daje prednost, R3 i R4 koji mogu biti jednaki ili različiti, jesu H ili metil. U spojevima formule I, kojima se daje veću prednost, obadva, R3 i R4 su H. In preferred compounds of formula I, R 3 and R 4 , which may be the same or different, are H or methyl. In more preferred compounds of formula I, both R 3 and R 4 are H.

U spojevima formule I, kojima se daje prednost, U je metilen. In preferred compounds of formula I, U is methylene.

U spojevima formule I, kojima se daje prednost, u kojima Q je skupina formule IIa ili IIc, V je metilen ili etilen, obadva, X i X' su etilen. In preferred compounds of formula I, wherein Q is a group of formula IIa or IIc, V is methylene or ethylene, X and X' are both ethylene.

U spojevima formule I, kojima se daje prednost, u kojima Q je skupina formule IIb, V' je alkilenski lanac koji ima 2 do 4 ugljikova atoma. In preferred compounds of formula I in which Q is a group of formula IIb, V' is an alkylene chain having 2 to 4 carbon atoms.

U spojevima formule I, kojima se daje veću prednost, Q je skupina formule IIa ili IIc, a V' je metilen. In more preferred compounds of formula I, Q is a group of formula IIa or IIc and V' is methylene.

U spojevima formule I, kojima se daje prednost, R5 je H ili metil. U spojevima formule I, kojima se daje veću prednost, R5 je H. In preferred compounds of formula I, R 5 is H or methyl. In more preferred compounds of formula I, R5 is H.

U spojevima formule I, kojima se daje prednost, HET je 2-, 3- ili 4-piridil, 8-kinolinil, ili 2-tienil, od kojih svaki po potrebi može biti supstituiran s jednim ili više supstituenata odabranih između metila, metoksi, trifluor-metila, halogenog, metiltio, 1-pirolila, ili amino skupine po potrebi supstituirane s jednom ili više alkilnih skupina od kojih svaka ima 1 do 3 ugljikova atoma. U spojevima formule I, kojima se daje veću prednost, HET je 2-piridil, 3-piridil, 8-kinolinil, ili 2-tienil, od kojih svaki po potrebi može biti supstituiran s amino skupinom metilom, metoksi, 1-pirolilom, trifluormetilom, s metiltio ili s bromom. U spojevima formule I, kojima se daje najveću prednost, HET je 2-piridil, ili 3-piridil, po potrebi supstituiran s amino skupinom. In preferred compounds of formula I, HET is 2-, 3- or 4-pyridyl, 8-quinolinyl, or 2-thienyl, each of which may optionally be substituted with one or more substituents selected from methyl, methoxy, trifluoromethyl, halogen, methylthio, 1-pyrrolyl, or amino groups optionally substituted with one or more alkyl groups each having 1 to 3 carbon atoms. In more preferred compounds of formula I, HET is 2-pyridyl, 3-pyridyl, 8-quinolinyl, or 2-thienyl, each of which may optionally be substituted with an amino group by methyl, methoxy, 1-pyrrolyl, trifluoromethyl , with methylthio or with bromine. In the most preferred compounds of formula I, HET is 2-pyridyl, or 3-pyridyl, optionally substituted with an amino group.

U spojevima formule I, kojima se daje prednost obadva, A i B su O, g je 1 ili 2; R1 predstavlja halogen (na primjer fluor, klor ili brom), alkilnu skupinu s jednim ili više halogenih, alkoksi skupina koja ima 1 do 3 ugljikova atoma, alkilsulfoniloksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, ili hidroksi; R2 je H ili alkilna skupina koja ima 1 do 3 ugljikova atoma: R3 i R4, koji mogu biti jednaki ili različiti, jesu H ili metil; U je metilen; Q je skupina formule IIa ili IIc, V je metilen; R5 je H ili metil; obadva, X i X' su etilen; i HET je 2-, 3- ili 4-piridil, 8-kinolinil, ili 2-tienil, od kojih svako po potrebi može biti supstituiran s jednim ili više supstituenata odabranih između metila, metoksi, trifluormetila, halogenog, metiltio, 1-pirolila, ili amino skupine po potrebi supstituirane s jednom ili dvije alkilne skupine, od kojih svaka ima 1 do 3 ugljikova atoma. In compounds of formula I, both of which are preferred, A and B are O, g is 1 or 2; R1 represents a halogen (for example fluorine, chlorine or bromine), an alkyl group with one or more halogens, an alkoxy group having 1 to 3 carbon atoms, an alkylsulfonyloxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens, or hydroxy; R 2 is H or an alkyl group having 1 to 3 carbon atoms: R 3 and R 4 , which may be the same or different, are H or methyl; U is methylene; Q is a group of formula IIa or IIc, V is methylene; R 5 is H or methyl; both X and X' are ethylene; and HET is 2-, 3- or 4-pyridyl, 8-quinolinyl, or 2-thienyl, each of which may optionally be substituted with one or more substituents selected from methyl, methoxy, trifluoromethyl, halogen, methylthio, 1-pyrrolyl , or amino groups optionally substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms.

Podrazumijeva se, da svaka spomenuta skupina, koja sadrži lanac od tri ili više atoma, označava skupinu u kojoj lanac može biti ravan ili razgranat. Na primjer, alkilna skupina može uključiti propil koji uključuje n-propil i izopropil, i butil koji uključuje n-butil, sek.butil, izobutil i terc.butil Pojam "halo", kako se ovdje rabi, označava fluor, klor, brom i jod. It is understood that each mentioned group, which contains a chain of three or more atoms, denotes a group in which the chain can be straight or branched. For example, an alkyl group can include propyl including n-propyl and isopropyl, and butyl including n-butyl, sec-butyl, isobutyl and tert-butyl. The term "halo", as used herein, means fluorine, chlorine, bromine and iodine.

Spojevi formule I mogu postojati kao soli s farmaceutski prihvatljivim kiselinama. Primjeri takovih soli uključuju hidrokloride, hidrobromide, sulfate, metansulfate, nitrate, maleate, acetate, citrate, fumarate, tartarate [npr. (+)-tartarate, (-)-tartarate ili njihove smjese, uključiv njihove racemične smjese], sukcinate, benzoate i soli s amino kiselinama kao što je glutaminska kiselina. Spojevi formule I i njihove soli mogu postojati u obliku solvata (na primjer hidrata). The compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures thereof], succinates, benzoates and salts with amino acids such as glutamic acid. The compounds of formula I and their salts can exist in the form of solvates (for example hydrates).

Neki spojevi formule I imaju jedno ili više kiralnih središta, i postoje u različitim optičkim aktivnim oblicima. Ako spoj formule I ima jedno kiralno središte, spojevi mogu postojati u dva enantiomerna oblika i predloženi izum uključuje obadva enantiomera i smjese enantiomera. Enantiomeri se mogu rastaviti metodama poznatim u struci, na primjer, tvorbom diastereomernih soli koje se mogu rastaviti, na primjer kristalizacijom; tvorbom diastereomernih derivata ili kompleksa koji se mogu rastaviti, na primjer kristalizacijom, plinsko-tekućinskom ili tekućinskom kromatografijom; selektivnom reakcijom jednog enantiomera s enantiomer-specifičnim regentom, na primjer, enzimskom esterifikacijom; ili plinsko-tekućinskom ili tekućinskom kromatografijom u kiralnom okruženju, na primjer, na kiralnoj podlozi, na primjer silika gelu s graničnim kiralnim ligandom ili u prisutnosti kiralnog otapala. Podrazumijeva se, da tamo gdje se želi, enantiomer se pretvara u drugi kemijski entitet jednim od gore spomenutih postupaka odvajanja, i potreban je slijedeći postupak daljnji za oslobađanje željenog enantiomernog oblika. Alternativno, specifični enantiomeri mogu se sintetizirati asimetričnom sintezom upotrebom optički aktivnih reagenata, supstrata, katalizatora ili otapala, ili pretvorbom jednog enantiomera u drugi pomoću asimetrične transformacije. Some compounds of formula I have one or more chiral centers, and exist in different optically active forms. If the compound of formula I has one chiral center, the compounds can exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. Enantiomers can be resolved by methods known in the art, for example, by forming diastereomeric salts that can be resolved, for example by crystallization; by the formation of diastereomeric derivatives or complexes that can be resolved, for example by crystallization, gas-liquid or liquid chromatography; by selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic esterification; or by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support, for example silica gel with a capping chiral ligand or in the presence of a chiral solvent. It is understood that where desired, the enantiomer is converted to another chemical entity by one of the above-mentioned separation procedures, and a further procedure is required to release the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.

Ako spoj formule I sadrži više od jednog kiralnog središta, on može postojati u diastereomernim oblicima. Diastereomerni parovi mogu se rastaviti metodama poznatim u struci, na primjer kromatografijom ili kristalizacijom, a pojedinačni enantiomeri unutar svakog para mogu se rastaviti kako je gore spomenuto. Predloženi izum uključuje svaki diastereomer spojeva formule I i njihove smjese. If a compound of formula I contains more than one chiral center, it may exist in diastereomeric forms. Diastereomeric pairs can be resolved by methods known in the art, for example by chromatography or crystallization, and the individual enantiomers within each pair can be resolved as mentioned above. The proposed invention includes each diastereomer of the compounds of formula I and mixtures thereof.

Neki spojevi formule I i njihove soli mogu postojati u više nego jednom kristaliničnom obliku i predloženi izum uključuje svaki kristalinični oblik i njihove mješavine. Neki spojevi formule I i njihove soli mogu postojati u obliku solvata, na primjer hidrata, i predloženi izum uključuje svaki solvat i njihove mješavine. Some compounds of formula I and salts thereof may exist in more than one crystalline form and the present invention includes each crystalline form and mixtures thereof. Some compounds of formula I and salts thereof may exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Posebni spojevi formule I jesu: Special compounds of formula I are:

2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-2-karboksamid; N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide;

2-amino-N-{[1-(7-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}kinolin-8-karboksamid; N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide;

N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide;

2-amino-N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-2-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide;

2-amino-N-{[1-(8-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-metilpiridin-3-karboksamid; 2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-methylpyridine-3-carboxamide;

3-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}tiofen-2-karboksamid; 3-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide;

3-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}ziofen-2-karboksamid; 3-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide;

1-(2-aminonikotinoil)-4-[N-7-klor-1,4-benzodioksan-2-ilmetil)aminometilpiperidin; 1-(2-aminonicotinoyl)-4-[N-7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethylpiperidine;

2-amino-N-{[1-(8-tetrafluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-tetrafluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}kinolin-8-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide;

N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-metilpiridin-2-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-methylpyridine-2-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metoksipiridin-3-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxypyridine-3-carboxamide;

2-amino-N-{[1-(7,8-difluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7,8-difluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-trifluormetansulfoniloksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

4-[N-(7-klor-1,4-benzodioksan-2-ilmetil)aminometil]-1-(2-piridilkarbonil)-piperidin; 4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-pyridylcarbonyl)-piperidine;

N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-metil-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-methyl-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}6-(1-pyrrolyl)pyridine-3-carboxamide;

N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide;

5-brom-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-bromo-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-metilpiridin-3-karboksamid; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-methylpyridine-3-carboxamide;

N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide;

N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-2(metiltio)piridin-3-karboksamid; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-2-(methylthio)pyridine-3-carboxamide;

5-brom-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-bromo-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide;

N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide;

5-brom-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-bromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-(metiltio)piridin-3-karboksamid; N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-(methylthio)pyridine-3-carboxamide;

N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-metil-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-methyl-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

6-(1-pirolil)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 6-(1-pyrrolyl)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-(metiltio)-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-(methylthio)-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

5-brom-N-{[1-(trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-bromo-N-{[1-(trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide;

N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-(metiltio)piridin-3-karboksamid; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-(methylthio)pyridine-3-carboxamide;

5-brom-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-bromo-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

i njihove farmaceutski prihvatljive soli u obliku pojedinačnih enantiomera, racemata, ili drugih smjesa enantiomera. and their pharmaceutically acceptable salts in the form of single enantiomers, racemates, or other mixtures of enantiomers.

Posebni enantiomerni oblici spojeva formule I uključuju: Specific enantiomeric forms of compounds of formula I include:

(S)-2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(8-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

S)-2-amino-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; S)-2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(7-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-2-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide;

(S)-2-amino-N-{[1-(8-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-metilpiridin-3-karboksamid; (S)-2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-methylpyridine-3-carboxamide;

(S)-2-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}tiofen-2-karboksamid; (S)-2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-metilpiridin-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-methylpyridinecarboxamide;

(S)-2-amino-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}kinolin-8-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide;

(S)-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-metoksipiridin-3-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-methoxypyridine-3-carboxamide;

(S)-2-amino-N-{[1-(7,8-difluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(7,8-difluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-amino-N-{[1-(8-trifluormetansulfoniloksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-amino-N-{[1-(8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; (S)-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide;

(S)-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metiltop}-2-(metiltio)piridin-3-karboksamid; (S)-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyltop}-2-(methylthio)pyridine-3-carboxamide;

(S)-5-brom-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-5-bromo-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; (S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide;

(S)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirrolil)piridin-3-karboksamid; (S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridin-3-carboxamide;

(S)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-2(metiltio)piridin-3-karboksamid; (S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-2-(methylthio)pyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide;

(S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide;

(S)-5-bromN-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-5-bromoN-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; (S)-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide;

(S)-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2metil-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2methyl-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-6-(1-pirolil)-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-6-(1-pyrrolyl)-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-2-metiltio)-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-2-methylthio)-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-5-brom-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-5-bromo-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

(S)-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-8-(1-pirolil)piridin-3-karboksamid; (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-8-(1-pyrrolyl)pyridine-3-carboxamide;

(S)-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide;

(S)-5-brom-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; (S)-5-bromo-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

i njihove farmaceutski prihvatljive soli. and their pharmaceutically acceptable salts.

Predloženi izum također uključuje farmaceutske sastave koji sadrže terapeutski učinkovitu količinu spoja formule I ili njegove soli zajedno s farmaceutski prihvatljivim sredstvom za razređenje ili nosačem. The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a salt thereof together with a pharmaceutically acceptable diluent or carrier.

Kako se ovdje rabi, pojam "aktivni spoj" označava spoj formule I ili njegovu sol. U terapeutskoj upotrebi aktivan spoj može se dati oralno, rektalno, parenteralno ili topički, ponajprije oralno. As used herein, the term "active compound" refers to a compound of formula I or a salt thereof. In therapeutic use, the active compound can be administered orally, rectally, parenterally or topically, preferably orally.

Stoga, terapeutski sastavi ovog izuma mogu imati oblik bilo kojeg od poznatih farmaceutskih sastava za oralno, rektalno, parenteralno ili topičko davanje. Farmaceutski prihvatljivi nosači prikladni za upotrebu u takovim sastavima dobro su poznati u farmaciji. Sastavi prema izumu mogu sadržavati maseno od 0,1 do 99% aktivnog spoja. Sastavi prema izumu općenito se pripremaju u obliku jedinične doze. Ponajprije, jedinična doza aktivnog sastojka je 1-500 mg. Pomoćna sredstva upotrebljena u pripravi tih sastava su pomoćna sredstva poznata u farmaciji. Therefore, the therapeutic compositions of this invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. Compositions according to the invention can contain from 0.1 to 99% by mass of the active compound. The compositions of the invention are generally prepared in unit dose form. Preferably, the unit dose of the active ingredient is 1-500 mg. The auxiliaries used in the preparation of these compositions are the auxiliaries known in pharmacy.

Prema izumu sastavima za oralno davanje daje se prednost i oni su poznati farmaceutski oblici za takovo davanje, na primjer tablete, kapsule, sirupi i vodene ili uljne suspenzije. Pomoćna sredstva koja se upotrebljavaju za pripravu tih sastava poznata su u farmaciji. Tablete se mogu pripremiti miješanjem aktivnog spoja s inertnim sredstvom za razređenje kao što je kalcijev fosfat u prisutnosti sredstva za razgradnju, na primjer kukuruznog škroba, i lubrikanta, na primjer magnezijevog stearata, i tabletiranjem smjese poznatim metodama. Tablete mogu biti formulirane na način poznat u struci tako da potpomažu otpuštanje spojeva ovog izuma. Takove tablete, po želji, mogu biti opremljene s vanjskim prevlakama poznatim metodama, na primjer upotrebom celuloznog acetat-ftalata. Slično, kapsule, na primjer tvrde ili meke želatinske kapsule, koje sadrže aktivan spoj sa ili bez dodatka pomoćnih sredstava, mogu se pripremiti na konvencionalan način i, po želji, mogu se na poznat način opremiti s vanjskim prevlakama. Svaka tableta i kapsula može obično sadržavati do 1 do 500 mg aktivnog spoja. Drugi sastavi za oralno davanje uključuju, na primjer vodene suspenzije aktivnog spoja u vodenoj sredini u prisutnosti netoksičnog sredstva za tvorbu suspenzije, kao što je natrijeva karboksimetil-celuloza, i uljne suspenzije koje sadrže spoj prema izumu u prikladnom biljnom ulju, na primjer arahidovom ulju. According to the invention compositions for oral administration are preferred and are known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The auxiliaries used for the preparation of these compositions are known in pharmacy. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of a disintegrant, for example corn starch, and a lubricant, for example magnesium stearate, and tableting the mixture by known methods. Tablets may be formulated in a manner known in the art to facilitate the release of the compounds of this invention. Such tablets may, if desired, be provided with outer coatings by known methods, for example using cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without the addition of excipients can be prepared in a conventional manner and, if desired, can be provided with outer coatings in a known manner. Each tablet and capsule may typically contain up to 1 to 500 mg of active compound. Other compositions for oral administration include, for example, aqueous suspensions of the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethyl cellulose, and oil suspensions containing the compound of the invention in a suitable vegetable oil, for example arachis oil.

Aktivni spoj može biti formuliran u granule sa ili bez dodatka pomoćnih tvari. Pacijent može granule progutati izravno ili se one prije gutanja mogu dodati k prikladnom tekućem nosaču (na primjer vodi). Granule mogu sadržavati sredstva za razgradnju (na primjer, farmaceutski prihvatljiv par koji kipi, stvoren od kiseline i karbonatne ili bikarbonatne soli) da se olakša disperziju u tekućoj sredini. The active compound can be formulated into granules with or without the addition of excipients. The granules can be swallowed directly by the patient or they can be added to a suitable liquid carrier (eg water) before swallowing. Granules may contain disintegrating agents (for example, a pharmaceutically acceptable effervescent vapor formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in a liquid medium.

Sastavi ovog izuma prikladni za rektalno davanje su poznati farmaceutski oblici za takovo davanje, na primjer, čepići s kakao maslacem i/ili polietilen glikolnim osnovama. Compositions of the present invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with cocoa butter and/or polyethylene glycol bases.

Sastavi ovog izuma prikladni za parenteralno davanje su poznati farmaceutski oblici, na primjer sterilne suspenzije ili sterilne otopine u prikladnim otapalima. The compositions of this invention suitable for parenteral administration are known pharmaceutical forms, for example sterile suspensions or sterile solutions in suitable solvents.

Sastavi za topičko davanje mogu sadržavati matricu u kojoj su dispergirani farmaceutski aktivni spojevi ovog izuma tako da se spojevi drže u dodiru s kožom i da se tako spojevi daju transdermalno. Prikladni transdermalni sastav može se pripremiti miješanjem farmaceutski aktivnog spoja s topičkim vehiklom, kao što je mineralno ulje, petrolej i/ili vosak, na primjer parafinski vosak ili pčelinji vosak, zajedno s jakim transdermalnim ubrzivačem, kao što je dimetil sulfoksid ili propilen glikol. Amternativno, aktivni spojevi mogu se po želji dispergirati u farmaceutski prihvatljivu osnovu za kremu ili pomast. Količina aktivnog spoja sadržana j topičkoj formulaciji treba biti takova da se isporuči terapeutski učinkovitu količinu spoja tijekom vremena predviđenog za dražeje topičke formulacije na koži. Compositions for topical administration may contain a matrix in which the pharmaceutically active compounds of this invention are dispersed so that the compounds are kept in contact with the skin and thus the compounds are administered transdermally. A suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as mineral oil, petroleum and/or a wax, for example paraffin wax or beeswax, together with a strong transdermal accelerator, such as dimethyl sulfoxide or propylene glycol. Alternatively, the active compounds may optionally be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical formulation should be such as to deliver a therapeutically effective amount of the compound over the time provided for more expensive topical formulations on the skin.

Spojevi ovog izuma mogu se također dati kontuiranom infuzijom, iz vanjskog izvora, na primjer intravenskom infuzijom ili iz izvora spoja smještenog u tijelu. Unutarnji izvor uključuje ugrađene spremnike koji sadrže spoj koji se treba infuzirati i koji se trajno oslobađa, na primjer putem osmoze, i implantate koji mogu biti (a) tekućina, kao što je suspenzija ili otopina spoja koji se infuzira u farmaceutski prihvatljivom ulju, na primjer u obliku u vodi vrlo sklonog topivog derivata, kao što je sol dodekanoata ili (b) u obliku ugrađene podloge za spoj koji se infuzira, na primjer sintetičke smole ili materijala sličnog vosku. Podloga može biti jednostruko tijelo koje sadrži cijeli spoj ili nizovi od nekoliko tijela, od koji svako sadrži dio spoja koji se isporučuje. Količina aktivnog spoja prisutna u unutarnjem izvoru mora biti takova da se terapeutski učinkovita količina spoja oslobodi tijekom drugog vremenskog perioda. The compounds of this invention may also be administered by continuous infusion, from an external source, for example by intravenous infusion or from a source of the compound located in the body. An internal source includes embedded reservoirs containing the compound to be infused and which is released permanently, for example by osmosis, and implants which can be (a) a liquid, such as a suspension or solution of the compound to be infused in a pharmaceutically acceptable oil, for example in the form of a highly water-soluble derivative, such as a dodecanoate salt, or (b) in the form of an incorporated support for the compound to be infused, for example a synthetic resin or wax-like material. The substrate can be a single body containing the entire compound or an array of several bodies, each containing a portion of the compound being delivered. The amount of active compound present in the internal source must be such that a therapeutically effective amount of the compound is released over a second time period.

U nekim formulacijama može biti korisno upotrijebiti spojeve ovog izuma u obliku vrlo malih čestica, kao što su na primjer one koje se dobiju snažnim mljevenjem tekućine. In some formulations, it may be advantageous to use the compounds of this invention in the form of very small particles, such as for example those obtained by vigorous liquid milling.

U sastavima ovog izuma aktivan spoj po želji može biti sjedinjen s drugim kompatibilnim farmakološki aktivnim sastojcima. In the compositions of this invention, the active compound can optionally be combined with other compatible pharmacologically active ingredients.

Spojevi formule I ili njihove soli ili farmaceutski sastavi koji sadrže njihovu terapuetski učinkovitu količinu, mogu se upotrijebiti za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive, diskinazije, Parkinsonove bolesti, debljine, hipertenzije, Touretteovog sindroma, seksualne disfunkcije, odvikavanja od druga, zloupotrebe droga, spoznajnih poremećaja, Alzheimerove bolesti, senilne demencije, opsesivno-nasilnog ponašanja, napada panike, socijalnih fobija, poremećaja uzimanja hrane i anoreksije, kardiovaskularnih i cerebrovaskularnih poremećaja, diabetesa mellitusa koji nije ovisan o inzulinu, hiperglikemije, opstipacije, aritmije, poremećaja neuroedokrinog sistema, stresa, hipetrofije prostate i spastičnosti kod ljudi. Budući da se precizna količina datog aktivnog spoja kod takovih liječenja ovisiti o brojnim faktorima, na primjer starosti pacijenta, težini uvjeta i minuloj medicinskoj povijesti i uvijek se kreće unutar pouzdane procijene liječnika, količina datog aktivnog spoja po danu je u rasponu od 1 do 1000 mg, ponajprije 5 do 500 mg data u jednostrukim ili pojedinačnim dozama odjednom ili više puta tijekom dana. The compounds of formula I or their salts or pharmaceutical compositions containing a therapeutically effective amount thereof can be used to treat depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, withdrawal from the second, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-violent behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia , disorders of the neuroendocrine system, stress, prostate hypertrophy and spasticity in humans. Since the precise amount of a given active compound in such treatments depends on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always ranges within the reliable judgment of the physician, the amount of the given active compound per day is in the range of 1 to 1000 mg , preferably 5 to 500 mg given in single or individual doses at once or several times during the day.

Ponajprije spojevi formule I ili njihove soli ili farmaceutski sastavi koji sadrže njihovu terapeutski učinkovitu količinu upotrebljavaju se za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive, diskinazije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa i hipertrofije prostate kod sisavaca, posebno ljudskih bića. In particular, the compounds of formula I or their salts or pharmaceutical compositions containing a therapeutically effective amount thereof are used for the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks , social phobias, cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy in mammals, especially human beings.

Daljnji aspekt ovog izuma osigurava upotrebu spoja formule I, ili njihove soli, za proizvodnju lijeka za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive diskinazije, Parkinsonove bolesti, debljine, hipertenzije, Touretteovog sindroma, seksualne disfunkcije, odvikavanja od druga, zloupotrebe droga, spoznajnih poremećaja, Alzheimerove bolesti, senilne demencije, opsesivno-nasilnog ponašanja, napada panike, socijalnih fobija, poremećaja uzimanja hrane i anoreksije, kardiovaskularnih i cerebrovaskularnih poremećaja, diabetesa mellitusa koji nije ovisan o inzulinu, hiperglikemije, opstipacije, aritmije, poremećaja neuroedokrinog sistema, stresa, hipetrofije prostate i spastičnosti kod sisavaca, posebno ljudskih bića. A further aspect of the present invention provides the use of a compound of formula I, or a salt thereof, for the manufacture of a medicament for the treatment of depression, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug withdrawal, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-violent behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine disorders system, stress, prostate hypertrophy and spasticity in mammals, especially human beings.

Ponajprije spojevi formule I, ili njihove soli, upotrebljavaju se za proizvodnju lijeka za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive diskinazije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa i hipertrofije prostate. In particular, the compounds of formula I, or their salts, are used for the production of a drug for the treatment of depression, anxiety, psychoses (for example, schizophrenia), tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy.

Predloženi izum također osigurava metodu za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive diskinazije, Parkinsonove bolesti, debljine, hipertenzije, Touretteovog sindroma, seksualne disfunkcije, odvikavanja od druga, zloupotrebe droga, spoznajnih poremećaja, Alzheimerove bolesti, senilne demencije, opsesivno-nasilnog ponašanja, napada panike, socijalnih fobija, poremećaja uzimanja hrane i anoreksije, kardiovaskularnih i cerebrovaskularnih poremećaja, diabetesa mellitusa koji nije ovisan o inzulinu, hiperglikemije, opstipacije, aritmije, poremećaja neuroedokrinog sistema, stresa, hipetrofije prostate i spastičnosti koja uključuje davanje terapeutski učinkovite količine spoja formule I sisavcu, posebno ljudskom biću koje je to potrebno. The proposed invention also provides a method for the treatment of depression, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug withdrawal, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-violent behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, hypertrophy of the prostate and spasticity, which includes the administration of therapeutic effective amounts of a compound of formula I to a mammal, especially a human being in need thereof.

Ponajprije to je metoda za liječenje depresije, anksioznosti, psihoza (na primjer šizofrenije), tardive diskinazije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa i hipertrofije prostate. It is primarily a method for treating depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy.

Sad će biti opisan postupak za pripravu spojeva formule I. Ti postupci čine daljnji aspekt predloženog izuma. Postupci se ponajprije provode pod atmosferskim tlakom. A process for the preparation of compounds of formula I will now be described. These processes form a further aspect of the proposed invention. Procedures are primarily carried out under atmospheric pressure.

Spojevi formule I u kojima Q je skupina formule IIa i u kojima R5 je H, a V je (CH2)n+1 gdje n je 0, 1 ili 2, mogu se pripremiti reakcijom spoja formule III Compounds of formula I in which Q is a group of formula IIa and in which R5 is H and V is (CH2)n+1 where n is 0, 1 or 2 can be prepared by reacting a compound of formula III

[image] [image]

sa spojem formule IV with a compound of formula IV

[image] [image]

zatim reakcijom intermedijarnog imina s redukcijskim sredstvom, na primjer natrijevim borhidridom. then by reacting the intermediate imine with a reducing agent, for example sodium borohydride.

Spojevi formule I u kojima Q je skupina formula IIa i u kojima R5 je H, a V (CH2)n+1 gdje n je 0, 1 ili 2, mogu se pripremiti reakcijom spoja formule III sa spojem formule V Compounds of formula I in which Q is a group of formula IIa and in which R5 is H and V is (CH2)n+1 where n is 0, 1 or 2, can be prepared by reacting a compound of formula III with a compound of formula V

[image] [image]

u kojem Y je otpusna skupina, na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti prikladnog otapala, po potrebi u prisutnosti baze, na primjer kalijevog karbonata. wherein Y is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a suitable solvent, optionally in the presence of a base, for example potassium carbonate.

Spojevi formule I u kojima Q je skupina formula IIa i u kojima R5 je H, a V (CH2)n+1 gdje n je 0, 1 ili 2, mogu se pripremiti reakcijom spoja formule III sa spojem formule VI Compounds of formula I in which Q is a group of formula IIa and in which R5 is H and V is (CH2)n+1 where n is 0, 1 or 2, can be prepared by reacting a compound of formula III with a compound of formula VI

[image] [image]

sa spojem formule VII with a compound of formula VII

[image] [image]

u kojoj Z je otpusna skupina, na primjer na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti prikladnog otapala, po potrebi u prisutnosti baze, na primjer kalijevog karbonata. wherein Z is a leaving group, for example for example toluene-4-sulfonyloxy, optionally in the presence of a suitable solvent, optionally in the presence of a base, for example potassium carbonate.

Spojevi formule I u kojima Q je skupina formula IIa i u kojima R5 je H, a V (CH2)n+1 gdje n je 0, 1 ili 2, mogu se pripremiti reakcijom spoja formule III sa spojem formule VIII Compounds of formula I in which Q is a group of formula IIa and in which R5 is H and V is (CH2)n+1 where n is 0, 1 or 2, can be prepared by reacting a compound of formula III with a compound of formula VIII

[image] [image]

sa spojem formule VI, zatim redukcijom intermedijarnog imina s prikladnim redukcijskim sredstvom, na primjer natrijevim borhidridom. with a compound of formula VI, followed by reduction of the intermediate imine with a suitable reducing agent, for example sodium borohydride.

Spojevi formule I u kojima R5 je alkilna skupina, mogu se pripremiti alkilacijom spoja formule I, u kojem R5 je H, sa, na primjer, formaldehidom i mravljom kiselinom, ili aldehidom i redukcijskim sredstvom kao što je natrijev cijanoborhidrid. Compounds of formula I wherein R 5 is an alkyl group can be prepared by alkylating a compound of formula I wherein R 5 is H with, for example, formaldehyde and formic acid, or an aldehyde and a reducing agent such as sodium cyanoborohydride.

Spojevi formule III u kojima U je (CH2)n+1 gdje n je 0, 1 ili 2, mogu se pripremiti redukcijom spoja formule IX Compounds of formula III in which U is (CH2)n+1 where n is 0, 1 or 2 can be prepared by reduction of a compound of formula IX

[image] [image]

s redukcijskim sredstvom kao što je litij aluminijev hidrid. with a reducing agent such as lithium aluminum hydride.

Spojevi formule IX u kojima obadva, A i B su O, mogu se pripremiti reakcijom spoja formule X Compounds of formula IX in which both A and B are O can be prepared by reacting compounds of formula X

[image] [image]

s vicinalno disupstituiranim nitrilnim spojem formule XI with a vicinally disubstituted nitrile compound of formula XI

[image] [image]

u kojem Y je otpusna kao što je halogen, na primjer brom, u prisutnosti baze, kao na primjer kalijevog karbonata. wherein Y is free such as a halogen, for example bromine, in the presence of a base, such as potassium carbonate.

Spojevi formule III mogu se pripremiti iz spoja formule XII Compounds of formula III can be prepared from compounds of formula XII

[image] [image]

u kojoj E zajedno s dušikovim atomom kojeg dodiruje je ciklički imid, na primjer ftalimid, kiselo ili bazično kataliziranom hidrolizom, ili s reagentom za cijepanje, kao na primjer hidrazin hidratom. wherein E together with the nitrogen atom to which it contacts is a cyclic imide, for example phthalimide, by acid- or base-catalyzed hydrolysis, or with a cleavage reagent, such as hydrazine hydrate.

Spojevi formule XII u kojoj E zajedno s dušikovim atomom kojeg dodiruje je ciklički imid, na primjer ftalimid, mogu se pripremiti reakcijom spoja formule VII, u kojoj Z je otpusna skupina, na primjer toluen-4-sulfoniloksi, s kalijevim ftalimidom. Compounds of formula XII in which E together with the nitrogen atom to which it contacts is a cyclic imide, for example phthalimide, can be prepared by reacting a compound of formula VII, in which Z is a leaving group, for example toluene-4-sulfonyloxy, with potassium phthalimide.

Spojevi formule III, u kojoj U je metilen, mogu se pripremiti redukcijom spoja formule XIII Compounds of formula III, in which U is methylene, can be prepared by reduction of compounds of formula XIII

[image] [image]

s prikladnim redukcijskim sredstvom, na primjer litij aluminijevim hidridom. with a suitable reducing agent, for example lithium aluminum hydride.

Spojevi formule XIII mogu se pripremiti reakcijom spoja formule XIV Compounds of formula XIII can be prepared by reacting compounds of formula XIV

[image] [image]

u kojem m je 0, a L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, s amonijakom. wherein m is 0 and L is an alkyl group having 1 to 6 carbon atoms, with ammonia.

Spojevi formule IV mogu se pripremiti reakcijom spojeva formule XV Compounds of formula IV can be prepared by reacting compounds of formula XV

[image] [image]

u kojem R6 je alkilna skupina koja ima 1 do 4 ugljikova atoma, s redukcijskim sredstvom, kao na primjer natrijevim bis(2-metoksietoksi)aluminijevim hidridom u otapalu, na primjer toluenu. wherein R 6 is an alkyl group having 1 to 4 carbon atoms, with a reducing agent, such as sodium bis(2-methoxyethoxy)aluminum hydride in a solvent, for example toluene.

Spojevi formule V mogu se pripremiti reakcijom spoja formule XVI Compounds of formula V can be prepared by reacting compounds of formula XVI

[image] [image]

sa sredstvom za alkilaciju formule X-CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola, u prisutnosti prikladnog otapala kao što je diklormetan. with an alkylating agent of the formula X-CO.HET, where X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, for example triethylamine, or an amide bond-forming agent, for example carbonyl diimidazole, in the presence a suitable solvent such as dichloromethane.

Spojevi formule IV mogu se pripremiti oksidacijom spoja formule XVII Compounds of formula IV can be prepared by oxidation of compounds of formula XVII

[image] [image]

s prikladnim oksidacijskim sredstvom, na primjer oksalil klorid/dimetil sulfoksidom. with a suitable oxidizing agent, for example oxalyl chloride/dimethyl sulfoxide.

Spojevi formule V, u kojima Y je toluen-4-sulfoniloksi, mogu se pripremiti reakcijom spoja formule XVII sa sredstvom za tosilaciju, na primjer toluen-4-sulfonil kloridom. Compounds of formula V, wherein Y is toluene-4-sulfonyloxy, can be prepared by reacting a compound of formula XVII with a tosylating agent, for example toluene-4-sulfonyl chloride.

Spojevi formule XVII mogu se pripremiti reakcijom spoja formule XVIII Compounds of formula XVII can be prepared by reacting compounds of formula XVIII

[image] [image]

Spojevi formule XVIII mogu se pripremiti redukcijom spoja formule XVI, u kojoj R6 je alkoksi skupina koja ima 1 do 4 ugljikova atoma, s redukcijskim sredstvom, na primjer s litij aluminijevim hidridom. Compounds of formula XVIII can be prepared by reducing a compound of formula XVI, wherein R 6 is an alkoxy group having 1 to 4 carbon atoms, with a reducing agent, for example with lithium aluminum hydride.

Spojevi formule VI mogu se pripremiti reakcijom spoja formule XIX Compounds of formula VI can be prepared by reacting compounds of formula XIX

[image] [image]

u kojoj D je zaštitna skupina, na primjer 5-brom-2-hidroksibenziliden, sa sredstvom za acilaciju formule X-CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazol, u prikladnom otapalu kao što je diklormetan, zatim uklanjanjem zaštitne skupine, na primjer kiselo kataliziranom hidrolizom. in which D is a protecting group, for example 5-bromo-2-hydroxybenzylidene, with an acylating agent of the formula X-CO.HET, in which X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, on for example triethylamine, or an amide bond-forming agent, for example carbonyl diimidazole, in a suitable solvent such as dichloromethane, followed by removal of the protecting group, for example by acid-catalyzed hydrolysis.

Spojevi formule XIX mogu se pripremiti reakcijom spoja formule XX Compounds of formula XIX can be prepared by reacting compounds of formula XX

[image] [image]

sa zaštitnim sredstvom, na primjer 5-brom-2-hidroksibenzaldehidom. with a protecting agent, for example 5-bromo-2-hydroxybenzaldehyde.

Spojevi formule XX mogu se pripremiti redukcijom spoja formule XVI, u kojoj R6 je NH2, s redukcijskim sredstvom na primjer litij aluminijevim hidridom. Compounds of formula XX can be prepared by reducing a compound of formula XVI, wherein R 6 is NH 2 , with a reducing agent for example lithium aluminum hydride.

Spojevi formule VII, u kojoj Z je toluen-4-sulfoniloksi mogu se pripremiti reakcijom spoja formule XXI Compounds of formula VII, in which Z is toluene-4-sulfonyloxy, can be prepared by reacting compounds of formula XXI

[image] [image]

s toluen-4-sulfonil kloridom, po potrebi u prisutnosti baze, na primjer piridina. with toluene-4-sulfonyl chloride, if necessary in the presence of a base, for example pyridine.

Spojevi formule XXI, u kojima U je (CH2)n+1 mogu se pripremiti redukcijom spoja formule XIV, u kojoj L je alkilna skupina koja ima 1 do 4 ugljikova atoma i m je 0, 1 ili 2, s redukcijsim sredstvom kao što e litij aluminijev hidrid. Compounds of formula XXI, wherein U is (CH2)n+1 can be prepared by reducing a compound of formula XIV, wherein L is an alkyl group having 1 to 4 carbon atoms and m is 0, 1 or 2, with a reducing agent such as lithium aluminum hydride.

Spojevi formule XXI, u kojoj obadva, A i B su -O-, R2, R3 i R4 svi su H, a U je metilen, mogu se pripremiti reakcijom spoja formule XXII Compounds of formula XXI, in which A and B are both -O-, R2, R3 and R4 are all H, and U is methylene, can be prepared by reacting the compound of formula XXII

[image] [image]

u kojoj Z je otpusna skupina, na primjer klor ili toluen-4-sulfonil oksi, sa spojem formule X u prikladnom otapalu, na primjer vodi ili dimetilformamidu, u prisutnosti baze, na primjer natrijevog hidroksida. Ako se upotrebljava enatiomerno čist oblik spoja formule XXII, na primjer (R)-glicidil-4-toluensulfonat, može se pripremiti (S)-enetiomer spoja formule XXI. wherein Z is a leaving group, for example chlorine or toluene-4-sulphonyloxy, with a compound of formula X in a suitable solvent, for example water or dimethylformamide, in the presence of a base, for example sodium hydroxide. If an enantiomerically pure form of the compound of formula XXII is used, for example (R)-glycidyl-4-toluenesulfonate, the (S)-enetiomer of the compound of formula XXI can be prepared.

Spojevi formule XXI, u kojoj obadva A i B su -O-, U je metilen, R2, R3 i R4 svi su H, a R1 je alkoksi skupina koja ima 1 do 3 ugljikova atoma, mogu se pripremiti alkilacijom odgovarajućeg spoja formule XXI, u kojoj R1 je hidroksi, reakcijom sa sredstvom za alkilaciju, na primjer s metil jodidom, u prisutnosti baze, na primjer natrijevog hidroksida. Compounds of formula XXI, in which both A and B are -O-, U is methylene, R2, R3 and R4 are all H, and R1 is an alkoxy group having 1 to 3 carbon atoms, can be prepared by alkylating the corresponding compound of formula XXI, wherein R 1 is hydroxy, by reaction with an alkylating agent, for example methyl iodide, in the presence of a base, for example sodium hydroxide.

Spojevi formule XXI, u kojoj obadva, A i B su -O-, U je metilen, R2, R3 i R4 svi su H, mogu se pripremiti ciklizacijom spoja formule XXIII Compounds of formula XXI, wherein A and B are both -O-, U is methylene, R2, R3 and R4 are all H, can be prepared by cyclization of a compound of formula XXIII

[image] [image]

u kojoj R je H ili alkilna skupina koja ima 1 do 4 ugljikova atoma, upotrebom baze, na primjer natrijevog metoksida. wherein R is H or an alkyl group having 1 to 4 carbon atoms, using a base, for example sodium methoxide.

Spojevi formule XXIII mogu se pripremiti oksidacijom spoja formule XIV Compounds of formula XXIII can be prepared by oxidation of compounds of formula XIV

[image] [image]

s peroksi kiselinom, na primjer 3-klorperoksibenzojevom kiselinom. with a peroxy acid, for example 3-chloroperoxybenzoic acid.

Spojevi formule XXIV mogu se pripremiti alkilacijom spojeva formule XXV Compounds of formula XXIV can be prepared by alkylation of compounds of formula XXV

[image] [image]

sa spojevima formule XXII, u kojoj Z je otpusna skupina, na primjer klor ili toluen-4-sulfoniloksi, u prikladnom otapalu, na primjer dimetilformamidu, u prisutnosti baze, na primjer kalijevog karbonata. with compounds of formula XXII, in which Z is a leaving group, for example chlorine or toluene-4-sulfonyloxy, in a suitable solvent, for example dimethylformamide, in the presence of a base, for example potassium carbonate.

Spojevi formule XXI, u kojoj obadva, A i B su -O-, U je metilen, R2, R3 i R4 svi su H, mogu se pripremiti reakcijom spoja formule XXVI Compounds of formula XXI, in which A and B are both -O-, U is methylene, R2, R3 and R4 are all H, can be prepared by reacting compounds of formula XXVI

[image] [image]

s reagentom prikladnim za pretvorbu karbonilnih spojeva u epokside, na primjer s dimetilsulfoksonijevim metilidom. with a reagent suitable for the conversion of carbonyl compounds to epoxides, for example with dimethylsulfoxonium methylide.

Spojevi formule XXVI mogu se pripremiti reakcijom spoja formule X s halometil ketonom, na primjer ClCH2COR2, u prisutnosti baze, na primjer kalijevog karbonata. Compounds of formula XXVI can be prepared by reacting a compound of formula X with a halomethyl ketone, for example ClCH2COR2, in the presence of a base, for example potassium carbonate.

Spojevi formule XXI, u kojima A i U su metilen, B je -O- i R2 je H, mogu se pripremiti redukcijom spoja formule XXVII Compounds of formula XXI, in which A and U are methylene, B is -O- and R2 is H, can be prepared by reduction of a compound of formula XXVII

[image] [image]

s redukcijskim sredstvom, na primjer boran-dimetil sulfoksidnim kompleksom. with a reducing agent, for example borane-dimethyl sulfoxide complex.

Spojevi formule XXVII mogu se pripremiti redukcijom spoja formule XXVIII Compounds of formula XXVII can be prepared by reduction of compounds of formula XXVIII

[image] [image]

u kojoj L je H, s redukcijskim sredstvom, na primjer s vodikom u prisutnosti katalizatora paladija na ugljenu. wherein L is H, with a reducing agent, for example with hydrogen in the presence of a palladium-on-charcoal catalyst.

Spojevi formule XXVIII, u kojoj L je H, mogu se pripremiti kiselo ili lužnato kataliziranom hidrolizom spoja formule XXVIII, u kojoj L je alkilna skupina koja ima 1 do 6 ugljikovih atoma. Compounds of formula XXVIII, wherein L is H, can be prepared by acid or base catalyzed hydrolysis of compounds of formula XXVIII, wherein L is an alkyl group having 1 to 6 carbon atoms.

Spojevi formule XXVIII, u kojoj L je alkilna skupina, mogu se pripremiti reakcijom spoja formule XXIX Compounds of formula XXVIII, in which L is an alkyl group, can be prepared by reacting compounds of formula XXIX

[image] [image]

sa spojem formule XXX with a compound of formula XXX

[image] [image]

u kojoj L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, u prisutnosti baze, na primjer kompleksa 1,4-diazabiciklo [2.2.2]oktana (DABCO). wherein L is an alkyl group having 1 to 6 carbon atoms, in the presence of a base, for example 1,4-diazabicyclo[2.2.2]octane (DABCO) complex.

Spojevi formule XXIX mogu se pripremiti reakcijom spoja formule XXXI Compounds of formula XXIX can be prepared by reacting compounds of formula XXXI

[image] [image]

u kojoj M je O-zaštitna skupina, na primjer 1-etoksietilna skupina, sa sredstvom za metalaciju, na primjer n-butil-litijem, zatim sa sredstvom za formulaciju, na primjer s dimetilformamidom. wherein M is an O-protecting group, for example a 1-ethoxyethyl group, with a metallating agent, for example n-butyllithium, then with a formulating agent, for example dimethylformamide.

Spojevi formule XXI, u kojoj A, B i U su metilen i R2, R3 i R4 su H, mogu se pripremiti redukcijom spoja formule XXXII Compounds of formula XXI, wherein A, B and U are methylene and R2, R3 and R4 are H, can be prepared by reduction of a compound of formula XXXII

[image] [image]

s redukcijskim sredstvom, na primjer boran-dimetil sulfidnim kompleksom. with a reducing agent, for example a borane-dimethyl sulfide complex.

Spojevi formule XXXII mogu se pripremiti Birchovom redukcijom spoja formule XXXIII Compounds of formula XXXII can be prepared by Birch reduction of compounds of formula XXXIII

[image] [image]

sa, na primjer, litijem u tekućem amonijaku. with, for example, lithium in liquid ammonia.

Spojevi formule XXXIII mogu se pripremiti reakcijom spoja formule XXXIV Compounds of formula XXXIII can be prepared by reacting compounds of formula XXXIV

[image] [image]

sa sredstvom za metalaciju, na primjer n-butil-litijem, zatim s ugljičnim dioksidom, zatim zakiseljavanjem intermedijarne soli karboksilne kiseline. with a metallating agent, for example n-butyllithium, then with carbon dioxide, then by acidifying the intermediate carboxylic acid salt.

Spojevi formule VIII mogu se pripremiti oksidacijom spoja formule XXI, u kojoj U je metilen, s prikladnim oksidacijskim sredstvom, na primjer piridijevim klorokromatom, ili redukcijom spoja formule XIV, u kojoj m je 0, s prikladnim redukcijskim sredstvom, na primjer bis(2-metoksietoksi)aluminijevim hidridom u otapalu, na primjer toluenu. Compounds of formula VIII may be prepared by oxidation of a compound of formula XXI, wherein U is methylene, with a suitable oxidizing agent, for example pyridium chlorochromate, or by reduction of a compound of formula XIV, wherein m is 0, with a suitable reducing agent, for example bis(2- methoxyethoxy)aluminum hydride in a solvent, for example toluene.

Spojevi formule XIV, u kojoj obadva, A i B su -O-, mogu se pripremiti reakcijom spoja formule XXXV Compounds of formula XIV, in which both A and B are -O-, can be prepared by reacting compounds of formula XXXV

[image] [image]

u kojoj Y je otpusna skupina, na primjer brom, a L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, sa spojem formule X, u prisutnosti baze, na primjer kalijevog karbonata. wherein Y is a leaving group, for example bromine, and L is an alkyl group having 1 to 6 carbon atoms, with a compound of formula X, in the presence of a base, for example potassium carbonate.

Spojevi formule XIV, u kojoj A je metilen, B je -O-, m je 0, R2 je H i L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, mogu se pripremiti redukcijom spoja formule XXVIII, u kojoj L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, s prikladnim redukcijskim sredstvom, na primjer vodikom, u prisutnosti katalizatora paladija na ugljenu. Compounds of formula XIV, in which A is methylene, B is -O-, m is 0, R2 is H and L is an alkyl group having 1 to 6 carbon atoms, can be prepared by reduction of a compound of formula XXVIII, in which L is an alkyl group having 1 to 6 carbon atoms, with a suitable reducing agent, for example hydrogen, in the presence of a palladium-on-charcoal catalyst.

Spojevi formule XIV, u kojoj obadva, A i B su metilen, m je 0, R2 je H i L je alkilna skupina koja ima 1 do 6 ugljikovih atoma, mogu se pripremiti esterifikacijom spoja formule XXXII s alkoholom formule LOH, po potrebi u prisutnosti kiselog ili bazičnog katalizatora. Compounds of formula XIV, in which A and B are both methylene, m is 0, R2 is H and L is an alkyl group having 1 to 6 carbon atoms, can be prepared by esterification of a compound of formula XXXII with an alcohol of formula LOH, optionally in the presence acid or basic catalyst.

Spojevi formule I, u kojoj Q je skupina formule IIa, mogu se pripremiti reakcijom spoja formule XXXVI Compounds of formula I, in which Q is a group of formula IIa, can be prepared by reacting a compound of formula XXXVI

[image] [image]

u kojoj D’ je H, sa spojem formule VII u kojoj Z je otpusna skupina, na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti baze, na primjer kalijevog karbonata i po potrebi u prisutnosti otapala, na primjer acetonitrila. wherein D' is H, with a compound of formula VII wherein Z is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate and optionally in the presence of a solvent, for example acetonitrile.

Spojevi formule XXXVI u kojoj D’ je H, mogu se pripremiti deprotekcijom spoja formule XXXVI, u kojoj D’ je zaštitna skupina, na primjer terc.butilkarbonil, na primjer kiselom hidrolizom u prisutnosti kiseline, na primjer trifluoroctene kiseline. Compounds of formula XXXVI in which D' is H can be prepared by deprotection of a compound of formula XXXVI in which D' is a protecting group, for example tert-butylcarbonyl, for example by acid hydrolysis in the presence of an acid, for example trifluoroacetic acid.

Spojevi formule XXXVI, u kojoj D’ je zaštitna skupina, mogu se pripremiti reakcijom spoja formule XXXVII Compounds of formula XXXVI, in which D' is a protecting group, can be prepared by reacting compounds of formula XXXVII

[image] [image]

u kojoj D’ je zaštitna skupina, na primjer terc.butilkarbonil, sa spojem formule X.CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola, u prikladnom otapalu kao što je diklormetan. in which D' is a protecting group, for example tert.butylcarbonyl, with a compound of the formula X.CO.HET, in which X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, for example triethylamine, or an agent which forms an amide bond, for example a diimidazole carbonyl, in a suitable solvent such as dichloromethane.

Spojevi formule XXXVI, u kojoj D’ je zaštitna skupina, a HET ima formulu XXXVIII Compounds of formula XXXVI, in which D' is a protecting group and HET is of formula XXXVIII

[image] [image]

u kojoj Y upotpunjuje heteroaromatski prsten, a R je H ili alkil, mogu se pripremiti reakcijom spoja formule XXXVII sa spojem formule XXXIX in which Y completes the heteroaromatic ring and R is H or alkyl, can be prepared by reacting the compound of formula XXXVII with the compound of formula XXXIX

[image] [image]

u kojoj Y upotpunjuje heteroaromatski prsten, a R je H ili alkilna skupina, u otapalu, na primjer 1,2-dimetoksietan. in which Y completes a heteroaromatic ring and R is H or an alkyl group, in a solvent, for example 1,2-dimethoxyethane.

Spojevi formule I, u kojoj Q je skupina formule IIb, mogu se pripremiti reakcijom spoja formule XL Compounds of formula I, wherein Q is a group of formula IIb, can be prepared by reacting a compound of formula XL

[image] [image]

sa sredstvom za aciliranje formule X-CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola, u prikladnom otapalu kao što je diklormetan. with an acylating agent of the formula X-CO.HET, where X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, for example triethylamine, or an amide bond-forming agent, for example carbonyl diimidazole, in a suitable a solvent such as dichloromethane.

Spojevi formule I, u kojoj Q je skupina formule IIb, mogu se pripremiti reakcijom spoja formule VII, u kojoj Z je otpusna skupina, na primejr toluen-4-sulfoniloksi, sa spojem formule XLI Compounds of formula I, in which Q is a group of formula IIb, can be prepared by reacting a compound of formula VII, in which Z is a leaving group, for example toluene-4-sulfonyloxy, with a compound of formula XLI

R5NH-V’-NH.T XLI R5NH-V'-NH.T XLI

po potrebi u prisutnosti baze, na primjer kalijevog karbonata. if necessary in the presence of a base, for example potassium carbonate.

Spoejvi formule XL mogu se pripremiti iz spoja formule XLII Compounds of formula XL can be prepared from compounds of formula XLII

[image] [image]

u kojoj E zajedno s dušikovim atomom kojeg dodiruje tvori ciklički imid, na primjer ftalimid, kiselo ili bazično kataliziranom hidrolizom ili cijepanjem s reagentom, na primjer hidrazin hidratom. in which E together with the nitrogen atom it contacts forms a cyclic imide, for example phthalimide, by acid- or base-catalyzed hydrolysis or cleavage with a reagent, for example hydrazine hydrate.

Spojevi formule XLII, u kojoj E zajedno s dušikovim atomom kojeg dodiruje je ftalimid, a R5 je H, mogu se pripremiti reakcijom spoja formule III s haloalkil ftalimidom, na primjer N-(3-brompropil)ftalimidom, po potrebi u prisutnosti baze, na primjer kalijevog karbonata. Compounds of formula XLII, in which E together with the nitrogen atom to which it contacts is phthalimide, and R5 is H, can be prepared by reacting a compound of formula III with a haloalkyl phthalimide, for example N-(3-bromopropyl)phthalimide, optionally in the presence of a base, at example of potassium carbonate.

Spojevi formule I, u kojoj Q je skupina formule IIb, mogu se pripremiti reakcijom spoja formule XLIII Compounds of formula I, in which Q is a group of formula IIb, can be prepared by reacting a compound of formula XLIII

[image] [image]

u kojoj D’ je h, sa spojem formule VII, u kojoj Z je otpusna skupina, na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti baze, na primjer kalijevog karbonata, i po potrebi u otapalu, na primjer acetonitrilu. wherein D' is h, with a compound of formula VII wherein Z is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, and optionally in a solvent, for example acetonitrile.

Spojevi formule XLIII, u kojoj D’ je H, mogu se pripremiti deprotekcijom spoja formule XLIII, u kojoj D’ je zaštitna skupina, na primjer terc.butoksikarbonil, na primjer kiselom hidrolizom u prisutnosti kiseline, na primjer trifluoroctene kiseline. Compounds of formula XLIII, in which D' is H, can be prepared by deprotection of a compound of formula XLIII, in which D' is a protecting group, for example tert.butoxycarbonyl, for example by acid hydrolysis in the presence of an acid, for example trifluoroacetic acid.

Spojevi formule XLIII, u kojoj D’ je zaštitna skupina, mogu se pripremiti reakcijom spoja formule XLIV Compounds of formula XLIII, in which D' is a protecting group, can be prepared by reacting a compound of formula XLIV

[image] [image]

u kojoj D’ je zaštitna skupina, na primjer terc.butoksikarbonil, sa spojem formule X.CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola, u prikladnom otapalu kao što je diklormetan. in which D' is a protecting group, for example tert.butoxycarbonyl, with a compound of the formula X.CO.HET, in which X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, for example triethylamine, or an agent which forms an amide bond, for example a diimidazole carbonyl, in a suitable solvent such as dichloromethane.

Spojevi formule XLIII, u kojoj D’ je zaštitna skupina, a HET ima formulu XXXVII, u kojoj Y upotpunjuje heteroaromatski prsten, a R je H, mogu se pripremiti reakcijom spoja formule XLIV sa spojem formule XXXIX, u kojoj Y upotpunjuje heteroaromatski prsten, a R je H ili alkilna skupina, u otapalu, na primjer 1,2-dimetoksietanu. Compounds of formula XLIII, in which D' is a protecting group and HET has formula XXXVII, in which Y completes a heteroaromatic ring and R is H, can be prepared by reacting a compound of formula XLIV with a compound of formula XXXIX, in which Y completes a heteroaromatic ring, and R is H or an alkyl group, in a solvent, for example 1,2-dimethoxyethane.

Spojevi formule I, u kojoj Q je skupina formule IIc, mogu se pripremiti reakcijom spoja formule XLV Compounds of formula I, wherein Q is a group of formula IIc, can be prepared by reacting a compound of formula XLV

[image] [image]

Spojevi formule XLV, u kojoj D’ je H, mogu se pripremiti deprotekcijom spoja formule XLV, u kojoj D’ je zaštitna skupina, na primjer terc.butoksikarbonil, na primjer kiselom hidrolizom u prisutnosti kiseline, na primjer trifluoroctene kiseline. Compounds of formula XLV, wherein D' is H, may be prepared by deprotection of a compound of formula XLV, wherein D' is a protecting group, for example tert.butoxycarbonyl, for example by acid hydrolysis in the presence of an acid, for example trifluoroacetic acid.

Spojevi formule XLV, u kojoj D’ je zaštitna skupina, mogu se pripremiti reakcijom spoja formule XLVI Compounds of formula XLV, in which D' is a protecting group, can be prepared by reacting compounds of formula XLVI

[image] [image]

Spojevi formule XLV, u kojoj D’ je zaštitna skupina i HET ima formulu XXXVIII, u kojoj Y upotpunjuje heteroaromatski prsten, a R je H ili alkil, mogu se pripremiti reakcijom spoja formule XLVI sa spojem formule XXXIX, u kojoj Y upotpunjuje heteroaromatski prsten, a R je H ili alkil, u otpalu, na primjer 1,2- dimetoksietanu. Compounds of formula XLV, in which D' is a protecting group and HET is of formula XXXVIII, in which Y completes a heteroaromatic ring and R is H or alkyl, can be prepared by reacting a compound of formula XLVI with a compound of formula XXXIX, in which Y completes a heteroaromatic ring, and R is H or alkyl, in solvent, for example 1,2-dimethoxyethane.

Spojevi formule I, u kojoj D’ je skupina formule IIc, mogu se pripremiti reakcijom spoja formule XLVII Compounds of formula I, in which D' is a group of formula IIc, can be prepared by reacting a compound of formula XLVII

[image] [image]

sa spojem formule XXXIX, na primjer pirido[2,3-d][1,3]-oksazin-2,4(1H)-dionom, po potrebi u prisutnosti otapala, na primjer 1,2-dimetoksietana. with a compound of formula XXXIX, for example pyrido[2,3-d][1,3]-oxazin-2,4(1H)-dione, optionally in the presence of a solvent, for example 1,2-dimethoxyethane.

Spojevi formule XLVII, u kojoj R55 je H, mogu se pripremiti iz spojeva formule XLVIII Compounds of formula XLVII, wherein R55 is H, can be prepared from compounds of formula XLVIII

[image] [image]

u kojoj D je zaštitna skupina, na primjer 5-brom-2-hidroksibenziliden, kiselo ili bazično kataliziranom hidrolizom. wherein D is a protecting group, for example 5-bromo-2-hydroxybenzylidene, by acid or base catalyzed hydrolysis.

Spojevi formule XLVIII mogu se pripremiti reakcijom spoja formule XLIX Compounds of formula XLVIII can be prepared by reacting compounds of formula XLIX

[image] [image]

u kojoj D je zaštitna skupina, na primjer 5-brom-2-hidroksibenziliden, sa spojem formule VII, po potrebi u prisutnosti baze, na primjer trietilamina. wherein D is a protecting group, for example 5-bromo-2-hydroxybenzylidene, with a compound of formula VII, optionally in the presence of a base, for example triethylamine.

Spojevi formule XLIX mogu se pripremiti reakcijom spoja formule L Compounds of formula XLIX can be prepared by reacting compounds of formula L

[image] [image]

sa zaštitnim sredstvom, na primjer 5-brom-2-hidroksi-benzaldehidom. with a protecting agent, for example 5-bromo-2-hydroxy-benzaldehyde.

Spojevi formule I u kojoj Q je skupina formule IIc, također se mogu pripremiti reakcijom spoja formule XLVII sa sredstvom za aciliranje formule X-CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer tietilamina ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola ili N,N-diizopropil-karbodiimida, u prikaldnom otapalu kao što je diklormetan. Compounds of formula I wherein Q is a group of formula IIc may also be prepared by reacting a compound of formula XLVII with an acylating agent of formula X-CO.HET, wherein X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base , for example thiethylamine or an amide bond forming agent, for example carbonyl diimidazole or N,N-diisopropylcarbodiimide, in a suitable solvent such as dichloromethane.

Sposobnost spojeva formule I za interakciju s receptorima 5-hidroksitriptamina (5-HT) bila je dokazana slijedećim ispitivanjem kojim se određuje sposobnost spojeva da inhibiraju ligand obilježen tricijem koji se veže na 5-HT receptore in vitro i posebno na 5-HT1A receptore. The ability of the compounds of formula I to interact with 5-hydroxytryptamine (5-HT) receptors was demonstrated by the following assay determining the ability of the compounds to inhibit tritium-labeled ligand binding to 5-HT receptors in vitro and specifically to 5-HT1A receptors.

Hipokamplano tkivo iz mozga štakora Sprague-Dawley (Charles River; raspon težine 150-250 g) homogenizirano je u ledeno hladnom 50 mM Tris-HCl puferu (pH 7,7 mjerenom pri 25°C, 1:40 masa/volumen) i centrifugirano 10 minuta pri 4°C i 30.000 g. Talog je ponovno homogeniziran i istom puferu, inkubiran 10 minuta pri 37°C i centrifugiran 10 minuta pri 4°C i 30.000 g. Konačni talog je ponovno suspendiran u 50 mM Tris-HCl puferu (pH 7,7) koji je sadržavao 4 mM CaCL2, 0,1% L-askorbinske kiseline i 10 µM parfilin hidroklorida (ekvivalent za 6,25 mg mokre mase tkiva/ml) i upotrebljen je neposredno za ispitivanje vezanja. Alikvota (400 µl; ekvivalent za 2,5 mg mokre mase tkiva/cjevčici) te suspenzije dodani su u cjevčice koje su sadržavale ligand (50 µl : 2 nM) i destiliranu vodu (50 µl ukupno vezanje) ili 5-HT (50 µl; 10 µM; nespecifično vezanje) ili ispitani spoj (50 µl; jednostruke koncentracije od 10-6 M ili 10 koncentracija u rasponu od 10-11 do 10-3 M). Ligand je bio ([3H]8-hidroksi-2-(dipropil-amino)tetralin ([3H]8-OH-DPAT) i smjesa je inkubirana 30 minuta pri 25°C prije nego je inkubacija bila prekinuta brzom filtracijom. Hippocampal tissue from the brains of Sprague-Dawley rats (Charles River; weight range 150-250 g) was homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7 measured at 25°C, 1:40 mass/volume) and centrifuged 10 minutes at 4°C and 30,000 g. The precipitate was homogenized again in the same buffer, incubated for 10 minutes at 37°C and centrifuged for 10 minutes at 4°C and 30,000 g. The final precipitate was resuspended in 50 mM Tris-HCl buffer ( pH 7.7) containing 4 mM CaCL2, 0.1% L-ascorbic acid and 10 µM parfilin hydrochloride (equivalent to 6.25 mg wet tissue weight/ml) and was used directly for the binding assay. An aliquot (400 µl; equivalent to 2.5 mg wet tissue mass/tube) of this suspension was added to tubes containing ligand (50 µl : 2 nM) and distilled water (50 µl total binding) or 5-HT (50 µl ; 10 µM; non-specific binding) or the test compound (50 µl; single concentrations of 10-6 M or 10 concentrations ranging from 10-11 to 10-3 M). The ligand was ([3H]8-hydroxy-2-(dipropyl-amino)tetralin ([3H]8-OH-DPAT) and the mixture was incubated for 30 min at 25°C before the incubation was terminated by rapid filtration.

Filteri su isprani s ledeno hladnim puferom Tris-HCl i osušeni. Označeni filtri ugurani su u vijale, dodana je scintilacijska tekućina i radioaktivnost je određena scintilacijskim brojenjem u tekućini. Postotak premještanja specifičnog vezanja liganda obilježenog tricijem izračunat je za jednostruku koncentraciju (10-6M) ispitnog spoja. Krivulje premještanja izrađene su za one spojeve koji su premjestili ≥50% specifičnog vezanja liganda obilježenog tricijem od 10-6 M upotrebom raspona koncentracija spoja. Iz krivulje je dobivena koncentracija koja daje 50% inhibicije specifičnog vezanja (IC50). Filters were washed with ice-cold Tris-HCl buffer and dried. Labeled filters were inserted into vials, scintillation fluid was added, and radioactivity was determined by scintillation counting in the fluid. The percentage of displacement of the specific binding of the tritium-labeled ligand was calculated for a single concentration (10-6M) of the test compound. Displacement curves were generated for those compounds that displaced ≥50% of the specific binding of the 10-6 M tritium-labeled ligand using a range of compound concentrations. The concentration giving 50% inhibition of specific binding (IC50) was obtained from the curve.

Koeficijent inhibicije Ki izračunat je zatim pomoću formule The inhibition coefficient Ki was then calculated using the formula

[image] [image]

u kojoj [ligand] je koncentracija upotrebljenog liganda obilježenog tricijem, a KD je konstanta ravnoteže disocijacije za ligand. where [ligand] is the concentration of tritium-labeled ligand used and KD is the dissociation equilibrium constant for the ligand.

Sposobnost spojeva formule I za interakciju sa stranama koje vežu adrenoreceptor pokazana je pomoću sposobnosti spojeva da inhibiraju vezanje liganda obilježenog tricijem in vitro i posebno α1-adrenoreceptora. The ability of the compounds of formula I to interact with adrenoreceptor binding sites is demonstrated by the ability of the compounds to inhibit tritium-labeled ligand binding in vitro and specifically to α1-adrenoreceptors.

Neoštećeno kortikalno tkivo iz mozga mužjaka Charles River CD štakora, težine između 150 i 250 g, homogenizirano je u ledenoj hladnoj 50 mM tris-HCl, pH 7,6 (pri 25°C, 1:40 masa/volumen) i centrifugirano 10 minuta pri 4°C i 30.000 g. Supernatant je centrifugiran 10 minuta pri 4°C i 30.000 g. Talog je ponovno suspendira u 50 mM tris-HCl, pH 7,6 (1:40 masa/volumen) i centrifugiran 10 minuta pri 4°C i 30.000 g. Konačni talog je ponovno suspendiran u 50 mM tris-HCl puferu (pH 7,6) (ekvivalent za 12,5 mg mokre mase tkiva/ml) i neposredno upotrebljen za ispitivanje vezanja. Alikvoti (400 µl; ekvivalent za 5 mg mokre mase tkiva/cjevčici) te suspenzije dodani su zatim u cjevčice koje su sadržavale ligand (50 µl : 0,1 nM) i destiliranu vodu (50 µl ukupno vezanje) ili fentolamin (50 µl; 5 µM; nespecifično vezanje) ili ispitani spoj (50 µl; jednostruke koncentracije od 10-6 M ili 10 koncentracija u rasponu od 10-11 do 10-3 M). Ligand je bio ([7-metoksi-3H]prazozin i mješavina je inkubirana 30 minuta pri 30°C prije završetka inkubacije pomoću brze filtracije. Intact cortical tissue from the brains of male Charles River CD rats, weighing between 150 and 250 g, was homogenized in ice-cold 50 mM Tris-HCl, pH 7.6 (at 25°C, 1:40 mass/volume) and centrifuged for 10 minutes. at 4°C and 30,000 g. The supernatant was centrifuged for 10 minutes at 4°C and 30,000 g. The pellet was resuspended in 50 mM Tris-HCl, pH 7.6 (1:40 mass/volume) and centrifuged for 10 minutes at 4 °C and 30,000 g. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.6) (equivalent to 12.5 mg tissue wet weight/ml) and used immediately for the binding assay. Aliquots (400 µl; equivalent to 5 mg wet tissue mass/tube) of this suspension were then added to tubes containing ligand (50 µl : 0.1 nM) and distilled water (50 µl total binding) or phentolamine (50 µl; 5 µM; non-specific binding) or the test compound (50 µl; single concentrations of 10-6 M or 10 concentrations ranging from 10-11 to 10-3 M). The ligand was ([7-methoxy-3H]prazosin) and the mixture was incubated for 30 min at 30°C before terminating the incubation by rapid filtration.

Filtri su isprani s ledeno hladnim puferom Tris-HCl i osušeni. Zatim su filtri ugurani u vijale, dodana je scintilacijska tekućina i radioaktivnost je određena scintilacijskim brojenjem u tekućini. Postotak premještanja specifičnog vezanja liganda obilježenog tricijem izračunat je za jednostruku koncentraciju (10-6M) ispitnog spoja. Krivulje premještanja izrađene su za one spojeve koji su premjestili ≥50% specifičnog vezanja liganda obilježenog tricijem od 10-6 M upotrebom raspona koncentracija spoja. Iz krivulje je dobivena koncentracija koja daje 50% inhibicije specifičnog vezanja (IC50). Filters were washed with ice-cold Tris-HCl buffer and dried. Filters were then inserted into vials, scintillation liquid was added and radioactivity was determined by scintillation counting in the liquid. The percentage of displacement of the specific binding of the tritium-labeled ligand was calculated for a single concentration (10-6M) of the test compound. Displacement curves were generated for those compounds that displaced ≥50% of the specific binding of the 10-6 M tritium-labeled ligand using a range of compound concentrations. The concentration giving 50% inhibition of specific binding (IC50) was obtained from the curve.

Konstanta inhibicije Ki izračunata je zatim pomoću formule The inhibition constant Ki was then calculated using the formula

[image] [image]

Sposobnost spojeva formule I za interakciju sa stranom vezenja α2-adrenoreceptora dokazana slijedećim određivanjem sposobnosti spojeva da inhibiraju vezanje liganda obilježenog tricijem na α2-adrenoreceptore in vitro, a posebno na α2A-adrenoceptore. The ability of the compounds of formula I to interact with the binding site of α2-adrenoreceptors was demonstrated by the following determination of the ability of the compounds to inhibit the binding of a tritium-labeled ligand to α2-adrenoreceptors in vitro, and especially to α2A-adrenoceptors.

Humani cerebralni korteks, dobiven post-mortem, homogeniziran je u ledenoj hladnoj 0,25 M saharozi (1:30 masa/volumen) i centrifugiran je 12 minuta pri 4°C i 1000 g. Supernatant je odložen na ledu, a talog je ponovno homogeniziran u 0,25 M saharozi (1:15 masa/volumen) i centrifugiran 12 minuta pri 4°C i 850 g. Sjedinjeni supernatanti razrijeđeni su s 5 mM Tris-HCl (ph 7,5) koja je sadržavala 5 mM etilendiamin tetraoctenu kiselinu (EDTA), ponovno namješteni na pH 7,5 (pri 25°C) i 1M natrijevim hidroksidom na 1:80 (masa/volumen) i centrifugirani 10 minuta pri 11000 g i pri 4°C. Dobiveni talog ponovno je suspendira u 50 mM Tris-HCl (pH 7,5) koja je sadržavala 5,68 mM L-askorbinske kiseline i 0,5 mM EDTA, ponovno namješten na pH 7,5 (pri 25°C) s 1M natrijevim hidroksidom na 1:80 (masa/volumen) i centrifugiran 10 minuta pri 11000 g. Talog je odložen pri -80°C. Na dan ispitivanja talog je otopljen, ponovno suspendiran u 50 mM Tris-HCl (pH 7,5) koja je sadržavala 5,68 mM L-askorbinske kiseline i 5 mM EDTA na 1:80 masa/volumen i centrifugiran 10 minuta pri 11000 g. Konačni talog ponovno je suspendiran u 50 mM Tris-HCl (pH 7,5) koji je sadržavao 5,68 mM L-askorbinske kiseline i 5 mM EDTA (evkivalent za 25 mg mokre mase tkiva). Human cerebral cortex, obtained post-mortem, was homogenized in ice-cold 0.25 M sucrose (1:30 mass/volume) and centrifuged for 12 minutes at 4°C and 1000 g. The supernatant was stored on ice, and the pellet was again homogenized in 0.25 M sucrose (1:15 mass/volume) and centrifuged for 12 minutes at 4°C and 850 g. The combined supernatants were diluted with 5 mM Tris-HCl (pH 7.5) containing 5 mM ethylenediamine tetraacetene. acid (EDTA), re-adjusted to pH 7.5 (at 25°C) and 1M sodium hydroxide at 1:80 (w/v) and centrifuged for 10 minutes at 11000 g and at 4°C. The resulting precipitate was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 0.5 mM EDTA, again adjusted to pH 7.5 (at 25°C) with 1M with sodium hydroxide at 1:80 (mass/volume) and centrifuged for 10 minutes at 11000 g. The precipitate was stored at -80°C. On the day of the test, the pellet was dissolved, resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 5 mM EDTA at 1:80 mass/volume and centrifuged for 10 minutes at 11,000 g The final pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 5 mM EDTA (equivalent to 25 mg wet tissue mass).

Alikvoti /400 µl; ekvivalent za 10 mg mokre mase tkiva/cjevčici) te suspenzije dodani su u cjevčice koje su sadržavale ligand 8(50 µl, 0,2 nM) i destiliranu vodu (50 µl; ukupno vezanje) ili fentolamin (50 µl, 50 µM; nespecifično vezanje) ili ispitni spoj (50 µl jednostruke koncentracije od 10-6 M ili u 10 koncentracija u rasponu od 1’-11 do 10-3 M). Ligand je bio RX 821002 (2-(2-metoksi-1,4-[6,7 (n)-3H]benzodioksan-2-il)-2-imidazolin) obilježen tricijem i smjesa je inkubirana 75 minuta pri 0°C prije nego je inkubacija prekinuta brzom filtracijom. Aliquots /400 µl; equivalent to 10 mg wet tissue weight/tube) and suspensions were added to tubes containing ligand 8 (50 µl, 0.2 nM) and distilled water (50 µl; total binding) or phentolamine (50 µl, 50 µM; nonspecific binding) or the test compound (50 µl of a single concentration of 10-6 M or in 10 concentrations ranging from 1'-11 to 10-3 M). The ligand was tritium-labeled RX 821002 (2-(2-methoxy-1,4-[6,7 (n)-3H]benzodioxan-2-yl)-2-imidazoline) and the mixture was incubated for 75 minutes at 0°C. before incubation was terminated by rapid filtration.

Filtri su isprani s ledeno hladnim puferom Tris-HCl i osušeni. Filtri su ugurani u vijale, dodana je scintilacijska tekućina i radioaktivnost je određena scintilacijskim brojenjem u tekućini. Postotak premještanja specifičnog vezanja liganda obilježenog tricijem izračunat je za jednostruku koncentraciju (10-6M) ispitnog spoja. Krivulje premještanja izrađene su za one spojeve koji su premjestili ≥50% specifičnog vezanja liganda obilježenog tricijem kod 10-6 M upotrebom raspona koncentracija spoja. Iz krivulje je dobivena koncentracija koja daje 50% inhibicije specifičnog vezanja (IC50). Filters were washed with ice-cold Tris-HCl buffer and dried. Filters were pushed into vials, scintillation liquid was added and radioactivity was determined by scintillation counting in the liquid. The percentage of displacement of the specific binding of the tritium-labeled ligand was calculated for a single concentration (10-6M) of the test compound. Displacement curves were generated for those compounds that displaced ≥50% of the specific binding of the tritium-labeled ligand at 10-6 M using a range of compound concentrations. The concentration giving 50% inhibition of specific binding (IC50) was obtained from the curve.

[image] [image]

Sposobnost spojeva formule I za interakciju sa stranama koje vežu adrenoceptor pokazana je pomoću sposobnosti spojeva da inhibiraju vezanje liganda obilježenog tricijem in vitro i posebno α2D-adrenoceptore. The ability of the compounds of formula I to interact with adrenoceptor binding sites is demonstrated by the ability of the compounds to inhibit tritium-labeled ligand binding in vitro and specifically α2D-adrenoceptors.

Prednje kortikalno tkivo iz mozga mužjaka Charles River CD štakora, težine između 150 i 250 g, homogenizirano je u ledeno hladnoj 0,25 M saharozi (1:30 masa/volumen) i centrifugirano 12 minuta g pri 4°c i 1000. Supernatant je odložen na ledu i talog je ponovno homogeniziran u 0,25 M saharozi (1:15 masa/volumen) i centrifugiran 12 minuta s 850 g pri 4°C. Sjedinjeni supernatanti razrijeđeni su s 5 mM Tris-HCl (pH 7,5) koja je sadržavala 5 mM etilendiamin tetraoctenu kiselinu (EDTA), ponovno namješteni na pH 7,5 (pri 25°C) s 1M natrijevim hidrksidom na 1:80 (masa/volumen) i centrifugirani 10 minuta pri 4°C i 30000 g. Dobiveni talog ponovno je suspendiran u 50 mM Tris-HCl (pH 7,5) koja je sadržavala 5,68 mM L-askorbinske kiseline i 0,5 mM EDTA, ponovno namješteni na pH 7,5 (pri 25°C) s 1M natrijevim hidroksidom, i ponovno centrifugiran 10 minuta pri 30000 g. Konačni talog ponovno je suspendiran u 50 mM Tris-HCl (pH 7,5) koja je sadržavala 5,68 mM L-askorbinske kiseline i 5 mM EDTA (ekvivalent za 12,5 mg mokre mase tkiva/ml) i odmah je korišten za ispitivanje vezanja. Alikvoti (400 µl; ekvivalent za 5 mg mokre mase tkiva/cjevčici) te suspenzije dodani su u cjevčice koje su sadržavale ligand (50 µl, 1 nM) i destiliranu vodu (50 µl; ukupno vezanje) ili fentolamin (50 µl, 5 µM; nespecifično vezanje) ili ispitni spoj (50 µl; jednostruke koncentracije od 10-6 M ili 10 koncentracija u rasponu od 10-11 do 10-3 M). Ligand je bio idazoksan obilježen tricijem (2-(1,4-[6,7(n)-3H]-benzodioksan-2-il)-2-imidazolin hidroklorid) i smjesa je inkubirana 75 minuta pri 0°C prije nego je inkubacija prekinuta brzom filtracijom. Frontal cortical tissue from the brains of male Charles River CD rats, weighing between 150 and 250 g, was homogenized in ice-cold 0.25 M sucrose (1:30 mass/volume) and centrifuged for 12 minutes at 4°C and 1000 g. The supernatant was discarded. on ice and the pellet was homogenized again in 0.25 M sucrose (1:15 mass/volume) and centrifuged for 12 minutes at 850 g at 4°C. Pooled supernatants were diluted with 5 mM Tris-HCl (pH 7.5) containing 5 mM ethylenediaminetetraacetic acid (EDTA), re-adjusted to pH 7.5 (at 25°C) with 1M sodium hydroxide at 1:80 ( mass/volume) and centrifuged for 10 minutes at 4°C and 30000 g. The resulting precipitate was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 0.5 mM EDTA , re-adjusted to pH 7.5 (at 25°C) with 1 M sodium hydroxide, and centrifuged again for 10 min at 30,000 g. The final pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5, 68 mM L-ascorbic acid and 5 mM EDTA (equivalent to 12.5 mg wet tissue weight/ml) and was immediately used for the binding assay. Aliquots (400 µl; equivalent to 5 mg wet tissue weight/tube) of this suspension were added to tubes containing ligand (50 µl, 1 nM) and distilled water (50 µl; total binding) or phentolamine (50 µl, 5 µM) ; non-specific binding) or test compound (50 µl; single concentrations of 10-6 M or 10 concentrations ranging from 10-11 to 10-3 M). The ligand was tritiated idazoxane (2-(1,4-[6,7(n)-3H]-benzodioxan-2-yl)-2-imidazoline hydrochloride) and the mixture was incubated for 75 minutes at 0°C before incubation terminated by rapid filtration.

Filtri su isprani s ledeno hladnim puferom Tris-HCl i osušeni. Označene pločice filtar papira ugurane su u vijale, dodana je scintilacijska tekućina i radioaktivnost je određena scintilacijskim brojenjem u tekućini. Postotak premještanja specifičnog vezanja liganda obilježenog tricijem izračunat je za jednostruku koncentraciju (10-6 M) ispitnog spoja. Krivulje premještanja izrađene su za one spojeve koji su premjestili ≥50% specifičnog vezanja liganda obilježenog tricijem kod 10-6 M upotrebom raspona koncentracija spoja. Iz krivulje je dobivena koncentracija koja daje 50% inhibicije specifičnog vezanja (IC50). Filters were washed with ice-cold Tris-HCl buffer and dried. Labeled strips of filter paper were inserted into vials, scintillation liquid was added and radioactivity was determined by scintillation counting in the liquid. The percentage of displacement of the specific binding of the tritium-labeled ligand was calculated for a single concentration (10-6 M) of the test compound. Displacement curves were generated for those compounds that displaced ≥50% of the specific binding of the tritium-labeled ligand at 10-6 M using a range of compound concentrations. The concentration giving 50% inhibition of specific binding (IC50) was obtained from the curve.

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Sposobnost spojeva formule I za interakciju sa receptorima dopamina bila je dokazana slijedećim određivanjem sposobnosti spoja da inhibiraju vezanje liganda obilježenog tricijem na dopamin in vitro a posebno na D2 receptore dopamina. The ability of the compounds of formula I to interact with dopamine receptors was demonstrated by the following determination of the ability of the compound to inhibit the binding of a tritium-labeled ligand to dopamine in vitro and especially to D2 dopamine receptors.

Trakasto tkivo iz mozga štakora Charles River CD, raspona težine između 140-250 g, homogenizirano je u 50 mM ledeno hladnog pufera Tris-HCl (pH 7,7 mjereno pri 25°C) i centrifugirano 10 minuta pri 40000 g. Talog je ponovno suspendiran u puferu Tris soli (50 mM Tris-HCl pufer koji sadrži 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 i 1 mM MgCl2 s dodatkom 6 mM askorbinske kiseline; pH 7,7 mjereno pri 25°C), i opet je centrifugiran 10 minuta pri 40000 g. Konačni talog odložen je pri -80°C. Prije svakog ispitivanja talog ponovno je supendiran u Tris soli (ekvivalent za 2 mg mokre mase tkiva/ml). Alikvoti (720 µl; ekvivalent za 1,44 mg mokre mase tkiva/cjevčici) te suspenziji dodani su u cjevčice koje su sadržavale ligand (40 µl, 1 nM) i pufer Tris soli (40 µl, 10 nM; nespecifično vezanje) ili isitni spoj (40 µl; jednostruke koncentracije od 10-6 M ili u 6 koncentracija u rasponu od 10-11 do 10-11 do 10-4 M). Ligand je bio (S)-sulpirid obilježen tricijem i smjesa je inkubirana 40 minuta pri 4ºC prije nego je inkubacija prekinuta brzom filtracijom. Striated tissue from the brain of Charles River CD rats, weighing between 140-250 g, was homogenized in 50 mM ice-cold Tris-HCl buffer (pH 7.7 measured at 25°C) and centrifuged for 10 minutes at 40,000 g. The pellet was again suspended in Tris salt buffer (50 mM Tris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2 supplemented with 6 mM ascorbic acid; pH 7.7 measured at 25°C), and again centrifuged for 10 minutes at 40000 g. The final precipitate was stored at -80°C. Before each test, the pellet was resuspended in Tris salt (equivalent to 2 mg wet tissue weight/ml). Aliquots (720 µl; equivalent to 1.44 mg wet tissue weight/tube) of this suspension were added to tubes containing ligand (40 µl, 1 nM) and Tris salt buffer (40 µl, 10 nM; non-specific binding) or istin compound (40 µl; single concentrations of 10-6 M or in 6 concentrations ranging from 10-11 to 10-11 to 10-4 M). The ligand was tritiated (S)-sulpiride and the mixture was incubated for 40 min at 4ºC before the incubation was terminated by rapid filtration.

Filteri su isprani s ledeno hladnim puferom Tris-HCl i osušeni. Filteri su ugurani u vijale, dodana je scintilacijska tekućina i filteri su odloženi pribl. 20 sati prije brojenja scintilacijskomspektrofotometrijom. Postotak premještanja specifičnog vezanja liganda obilježenog tricijem izračunat je za jednostruku koncentraciju (10-6M) ispitnog spoja. Krivulje premještanja izrađene su za one spojeve koji su premjestili ≥50% specifičnog vezanja liganda obilježenog tricijem kod 10-6 M upotrebom raspona koncentracija spoja. Iz krivulje je dobivena koncentracija koja daje 50% inhibicije specifičnog vezanja (IC50). Filters were washed with ice-cold Tris-HCl buffer and dried. Filters were pushed into vials, scintillation fluid was added and filters were set aside for approx. 20 hours before counting by scintillation spectrophotometry. The percentage of displacement of the specific binding of the tritium-labeled ligand was calculated for a single concentration (10-6M) of the test compound. Displacement curves were generated for those compounds that displaced ≥50% of the specific binding of the tritium-labeled ligand at 10-6 M using a range of compound concentrations. The concentration giving 50% inhibition of specific binding (IC50) was obtained from the curve.

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Ki vrijednost (nM), dobivena u gornjim ispitivanjima za vezanje 5-HT1A, α1, α2A, α2D i D2 navedene su u donjoj tablici I za svaki krajnji proizvod iz primjera 1 do 52. The Ki value (nM) obtained in the above assays for binding to 5-HT1A, α1, α2A, α2D and D2 are listed in Table I below for each end product of Examples 1 through 52.

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Znak % u tablici 1 označava % premještanja odgovarajućeg radioaktivno liganda kod 10-6M. The sign % in table 1 indicates % displacement of the corresponding radioactive ligand at 10-6M.

Izum se ilustrira pomoću slijedećih primjera koji se daju samo kao primjeri. Krajnji proizvod svakog od ovih primjera bio je karakteriziran pomoću jednog ili više slijedećih postupaka: plinsko-tekućinskom kromatografijom; visokoučinskom tekućinskom kromatografijom; elementarnom analizom, spektroskopijom nuklearne magnetske rezonancije i infracrvenom spektroskopijom. The invention is illustrated by the following examples, which are given by way of example only. The final product of each of these examples was characterized by one or more of the following procedures: gas-liquid chromatography; by high-performance liquid chromatography; elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

Primjer 1 Example 1

Mješavinu od (R)-glicidil 4-toluensulfonata (10,0 g), 5-klor-2-hidroksibenzaldehida (8,92 g) i kalijevog karbonata (7,87 g) u dimetilformamidu (200 ml) miješa se i grije 5 sati pri 60ºC, zatim se ostavi stajati 18 sati. Doda se (200 ml) vode i dobivenu smjese se ekstrahira s eterom (3 x 150 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (3 x 150 ml), osuše preko magnezijevog sulfata i otapalo se ispari. Uljni ostatak se podijeli kroamtografijom na silika gelu s 25:1 i zatim s 10:1 mješavinom petrol etera (vrelište 40.60ºC) i etil acetata i dobije se (R)-5-klor-2-(2,3-epoksipropoksi)benzaldehid (8,1 g) onečišćen s ≈10% nepoznate nečistoće, koji se upotrebljava bez daljnjeg čišćenja. A mixture of (R)-glycidyl 4-toluenesulfonate (10.0 g), 5-chloro-2-hydroxybenzaldehyde (8.92 g) and potassium carbonate (7.87 g) in dimethylformamide (200 ml) was stirred and heated for 5 hours at 60ºC, then left to stand for 18 hours. Water (200 ml) was added and the resulting mixture was extracted with ether (3 x 150 ml). The combined extracts are washed with brine (3 x 150 ml), dried over magnesium sulfate and the solvent is evaporated. The oily residue is fractionated by silica gel chromatography with a 25:1 and then a 10:1 mixture of petroleum ether (b.p. 40.60ºC) and ethyl acetate to give (R)-5-chloro-2-(2,3-epoxypropoxy)benzaldehyde (8.1 g) contaminated with ≈10% unknown impurity, which is used without further cleaning.

Smjesu proizvoda iz prethodne reakcije (8,1 g) i 3-klorperoksibenzojeve kiseline (85%; 9,2 g) u diklormetanu (100 ml) grije se 20 sati pod refluksom i zatim se ohladi na ledenoj vodi. Talog se odfiltrira i filtrat se ispere sa zasićenom vodenom otopinom natrijevog metabisulfita (100 ml), zasićenom vodenom otopinom natrijevog bikarbonata (2 x 100 ml) i s otopinom soli (100 ml) i zatim se osuši preko magnezijevog sulfata. Otapalo se ispari i dobije se (R)-5-klor-2-(2,3-epoksipropoksi)fenil format (7,98 g), koji sadrži ≈10% nepoznate nečistoće, kao narančasto ulje, koje je upotrebljeno bez daljnjeg čišćenja. A mixture of the product from the previous reaction (8.1 g) and 3-chloroperoxybenzoic acid (85%; 9.2 g) in dichloromethane (100 ml) was heated under reflux for 20 hours and then cooled in ice water. The precipitate was filtered off and the filtrate was washed with saturated aqueous sodium metabisulfite (100 ml), saturated aqueous sodium bicarbonate (2 x 100 ml) and brine (100 ml) and then dried over magnesium sulfate. The solvent was evaporated to give (R)-5-chloro-2-(2,3-epoxypropoxy)phenyl formate (7.98 g), containing ≈10% of an unknown impurity, as an orange oil, which was used without further purification .

Metalni natrij (0,25 g) otopi se u metanolu (20 ml) u atmosferi dušika i kap po kap doda se otopinu proizvoda iz prethodne reakcije (2,0 g) u metanolu (30 ml). Dob8venu smjesu miješa se 1 sat i zatim se grije 2 sata pod refluksom i pusti stajati 18 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se podijeli između etera (100 ml) i vode (100 ml). Eterski sloj se ispere s vodom (100 ml) i osuši preko magnezijevog sulfata. Otapalo se ispari i dobije se (S)-7-klor-1,4-benzodioksan-2-ilmetanol kao žuto ulje (1,67 g). Sodium metal (0.25 g) was dissolved in methanol (20 ml) under a nitrogen atmosphere and added dropwise to a solution of the product from the previous reaction (2.0 g) in methanol (30 ml). The resulting mixture is stirred for 1 hour and then heated for 2 hours under reflux and left to stand for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ether (100 ml) and water (100 ml). The ether layer is washed with water (100 ml) and dried over magnesium sulfate. The solvent was evaporated to give (S)-7-chloro-1,4-benzodioxan-2-ylmethanol as a yellow oil (1.67 g).

4-toluensulfonil klorid (5,9 g) doda se k otopini (S)-7-klor-1,4-benzodioksan-2-ilmetanola (6,0 g; pripremljenog gore opisanom metodom) u piridinu (40 ml) i smjesu se miješa 4 sata. Doda se još 4-toluensulfonil klorida (250 mg), miješa se još 2 sata, zatim se doda daljnji obrok 4-toluensulfonil klorida (250 mg) i nastavi se miejšati još 1 sat. Smjesu se prelije u vodu (200 ml) i ekstrahira s etilacetatom (2 x 200 ml). Sjedinjeni ekstrakti se isperu s klorovodičnom kiselinom (2M; 2 x 200 ml), zasićenom vodenom otopinom natrijevog bikarbonata (2 x 200 ml) i s otopinom soli (200 ml). Zatim se osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu i ostatak se prekristalizira iz etera. Dobije se (R)-7-klor-1,4-benzodioksan-2-ilmetanol 4-toluensulfonat (7,00 g), talište 90-91ºC. 4-toluenesulfonyl chloride (5.9 g) was added to a solution of (S)-7-chloro-1,4-benzodioxan-2-ylmethanol (6.0 g; prepared by the method described above) in pyridine (40 ml) and the mixture is stirred for 4 hours. More 4-toluenesulfonyl chloride (250 mg) was added, stirring was continued for 2 hours, then a further portion of 4-toluenesulfonyl chloride (250 mg) was added and stirring was continued for another 1 hour. The mixture is poured into water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with hydrochloric acid (2M; 2 x 200 ml), saturated aqueous sodium bicarbonate (2 x 200 ml) and brine (200 ml). Then it is dried over magnesium sulfate. The solvent is removed in vacuo and the residue is recrystallized from ether. (R)-7-chloro-1,4-benzodioxan-2-ylmethanol 4-toluenesulfonate (7.00 g), melting point 90-91ºC is obtained.

Mješavinu od 5-brom-2-hidroksibenzaldehida (170 g) i 4-(aminometil)piperidina (96,9 g) u etanolu (2,5 l) miješa se 3 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i dobije se 4-brom-2-[N-4-piperidilmetil)-iminometil]fenol (267 g) kao žuta čvrsta tvar, talište 35-38ºC. A mixture of 5-bromo-2-hydroxybenzaldehyde (170 g) and 4-(aminomethyl)piperidine (96.9 g) in ethanol (2.5 L) was stirred for 3 hours at room temperature. The solvent was removed in vacuo to give 4-bromo-2-[N-4-piperidylmethyl)-iminomethyl]phenol (267 g) as a yellow solid, mp 35-38ºC.

Smjesu od proizvoda iz prethodne reakcije (6,87 g), (R)-7-klor-1,4-benzodioksan-2-ilmetanol 4-toluensulfonata (4,1 g) i kalijevog karbonata (1,6 g) u acetonitrilu (160 ml) grije se 18 sati pod refluksom. Nakon hlađenja i filtriranja otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom na silika gelu u s 1:2 mješavinom etil acetata i petrol etera (vrelište 60-80ºC) i zatim sa čistim etil acetatom. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-4-brom-2-{N-[1-(7-klor-1,4-benzodioksan-2-ilmetil)piperid-4-ilmetil]iminometil}fenol (4,0 g kao žuto ulje. A mixture of the product from the previous reaction (6.87 g), (R)-7-chloro-1,4-benzodioxan-2-ylmethanol 4-toluenesulfonate (4.1 g) and potassium carbonate (1.6 g) in acetonitrile (160 ml) is heated under reflux for 18 hours. After cooling and filtering, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel with a 1:2 mixture of ethyl acetate and petroleum ether (boiling point 60-80ºC) and then with pure ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-4-bromo-2-{N-[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperid-4-ylmethyl]iminomethyl}phenol (4.0 g as a yellow oil) is obtained .

Proizvod iz prethodne reakcije (4, 0 g) u mejšavini vodene otopine kalijevog hidrogen sulfata (1M; 30 ml) i industrijskog metiliranog špirita (5 ml) grije se 5 minuta pri 70ºC i zatim se miješa 1 sat pri sobnoj temperaturi. Smjesu se ispere s eterom (3 x 50 ml) i zatim se doda zasićenu vodenu otopinu natrijevog karbonata da se dobije pH 11. Mješavinu se ekstrahira s diklormetanom (3 x 50 ml), sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se /S)-4-(aminometil)-1-7-klor-1,4-benzodioksan-2-ilmetil)piperidin (1,94 g) kao bezbojno ulje. The product from the previous reaction (4.0 g) in a mixture of an aqueous solution of potassium hydrogen sulfate (1M; 30 ml) and industrial methylated spirit (5 ml) is heated for 5 minutes at 70ºC and then stirred for 1 hour at room temperature. The mixture was washed with ether (3 x 50 ml) and then saturated aqueous sodium carbonate was added to give a pH of 11. The mixture was extracted with dichloromethane (3 x 50 ml), the combined extracts were dried over magnesium sulfate and the solvent was evaporated. (S)-4-(aminomethyl)-1-7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (1.94 g) was obtained as a colorless oil.

Smjesu proizvoda iz prethodne reakcije (1,0 g) i pirido[2,3-d]oksazin-2,4-(1H)-diona (0,55 g) u 1,2-dimetoksietanu (30 ml) grije se pod refluksom 16 sati. Otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom na silika gelu s 97.3 i zatim s 95:5 mješavinom diklormetana i metanola: Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Ostatak se triturira s eterom. Dobije se (S)-(-)-2-amino-N{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (0,80 g), talište 150-152ºC, [α]D-50,65º (c=0,918, MeOH). A mixture of the product from the previous reaction (1.0 g) and pyrido[2,3-d]oxazin-2,4-(1H)-dione (0.55 g) in 1,2-dimethoxyethane (30 ml) is heated under by reflux for 16 hours. The solvent was removed in vacuo and the residue was purified by vacuum chromatography on silica gel with 97.3 and then with a 95:5 mixture of dichloromethane and methanol: The appropriate fractions were combined and the solvent was removed in vacuo. The residue is triturated with ether. (S)-(-)-2-amino-N{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (0, 80 g), mp 150-152ºC, [α]D-50.65º (c=0.918, MeOH).

Primjer 2 Example 2

Mješavinu 2-klor-6-hidroksibenzaldehida (4,4 g), (R)-glicidil 4-toluensulfonata (5,0 g) i kalijevog karbonata (3,9 g) u dimetilformamidu (120 ml) miješa se i grije 5 sati pri 60°C. zatim se ostavit stajati 18 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, doda se (60 ml) vode i smjesu se ekstrahira s eterom (3 x 100 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Ostatak se očisti kromatografijom na silika gelu s 1:1 mješavinom petrol etera (vrelište 60 - 80°C) i dilormetana, i zatim s 19:1 mješavinom diklormetana i industrijskog metiliranog špirita. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (R)-5-klor-6(2,3-epoksipropoksi)-benzaldehida (2,8 g), talište 62-64°C. A mixture of 2-chloro-6-hydroxybenzaldehyde (4.4 g), (R)-glycidyl 4-toluenesulfonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) is stirred and heated for 5 hours at 60°C. then let it stand for 18 hours at room temperature. The solvent was removed in vacuo, water (60 ml) was added and the mixture was extracted with ether (3 x 100 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated. The residue is purified by chromatography on silica gel with a 1:1 mixture of petroleum ether (boiling point 60-80°C) and dichloromethane, and then with a 19:1 mixture of dichloromethane and industrial methylated spirit. The appropriate fractions were combined and the solvent was removed in vacuo. (R)-5-chloro-6(2,3-epoxypropoxy)-benzaldehyde (2.8 g) is obtained, melting point 62-64°C.

Otopinu proizvoda iz prethodne reakcije (2,8 g) i 3-klorperoksibenzojeve kiseline (85%; 4,8 g) u diklormetanu (200 ml) grije se 18 sati pod refluksom . Doda se još 3-klorperoksibenzojeve kiseline (4,8 g) i grijanje pod refluksom se nastavi još 6 sati. Smjesu se ispere sa zasićenom vodenom otopinom natrijevog bikarbonata (3 x 200 ml) i zatim se osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu i dobije se (R)-2-klor-6-(2,3-epoksipropoksi)fenil format (2,8 g), kao žuto ulje. A solution of the product from the previous reaction (2.8 g) and 3-chloroperoxybenzoic acid (85%; 4.8 g) in dichloromethane (200 ml) is heated under reflux for 18 hours. More 3-chloroperoxybenzoic acid (4.8 g) is added and heating under reflux is continued for another 6 hours. The mixture is washed with a saturated aqueous solution of sodium bicarbonate (3 x 200 ml) and then dried over magnesium sulfate. The solvent was removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)phenyl formate (2.8 g) as a yellow oil.

Otopinu 4-toluensulfonnil klorida (1,7 g) u piridinu (10 ml) doda se kap po kap k otopini proizvoda iz prethodne reakcije (1,63 g) u piridinu (30 ml) i smjesu se miješa 4 sata pri sobnoj temperaturi i zatim se grije 30 minuta pri 50°C. Ohlađenu otopinu se prelije u klorovodičnu kiselinu (5 M; 50 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu i dobije se (R)-8-klor-1,4-benzodioksa-2-ilmetil4-toluensulfonat (2,33 g) kao narančasto ulje. A solution of 4-toluenesulfonyl chloride (1.7 g) in pyridine (10 ml) was added dropwise to a solution of the product from the previous reaction (1.63 g) in pyridine (30 ml) and the mixture was stirred for 4 hours at room temperature and then it is heated for 30 minutes at 50°C. The cooled solution is poured into hydrochloric acid (5 M; 50 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give (R)-8-chloro-1,4-benzodioxa-2-ylmethyl-4-toluenesulfonate (2.33 g) as an orange oil.

Mješavinu od 4-(aminometil)-1-(terc.butoksikarbonil)-piridina (2,0 g) i pirido[2,3-d]oksazin-2,4-(1H)-diona (1,53 g) u 1,2-dimetoksietanu (30 ml) miješa se 3 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s diklormetanom i zatim s mješavinom 19:1 diklormetana i industrijskog metiliranog špirita. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se 2-amino-N-[1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamid (1,7 g). A mixture of 4-(aminomethyl)-1-(tert.butoxycarbonyl)-pyridine (2.0 g) and pyrido[2,3-d]oxazin-2,4-(1H)-dione (1.53 g) in 1,2-dimethoxyethane (30 ml) was stirred for 3 hours at room temperature. The solvent was removed in vacuo and the residue was purified by vacuum chromatography on silica gel eluting with dichloromethane and then with a 19:1 mixture of dichloromethane and industrial methylated spirit. The appropriate fractions were combined and the solvent was removed in vacuo. 2-Amino-N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (1.7 g) is obtained.

Trifluoroctenu kiselinu (9 ml) doda se k otopini 2-amino-N-[1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamida (2,2 g; pripremljen na isti način kako je gore opisano) u diklormetanu (50 ml) i mješavinu se miješa 1 sat pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i dobije se sirov 2-amino-N-(4-piperidilmetil)-piridin-3-karboksamid trifluoracetat. Trifluoroacetic acid (9 ml) was added to a solution of 2-amino-N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.2 g; prepared in the same manner as described above) in dichloromethane (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo to give crude 2-amino-N-(4-piperidylmethyl)-pyridine-3-carboxamide trifluoroacetate.

Mješavinu materijala, (R)-8-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonata (2,3 g) i kalijevog karbonata (3,6 g) u acetonitrilu se odstrani u vakuumu, k ostatku se doda voda (50 ml) i smjesu se ekstrahira s diklormetanom (2 x 30 ml). Sjedinjeni organski dio se ekstrahira s klorovodičnom kiselinom (2,5 M; 2 x 30 ml), zatim se sjedinjeni ekstrakti zaluže s vodenom otopinom natrijevog hidroksida (5M) i ekstrahiraju s diklormetanom (2 x 30 ml). Sjedinjeni organski do se osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s 9:1 mejšavinom diklormetana i metanola. Odgovarajuće organske frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-2-amino-N{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (1,0 g), talište 62-70ºC, [α]D-35,47º (c=0,888, MeOH). A mixture of materials, (R)-8-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (2.3 g) and potassium carbonate (3.6 g) in acetonitrile was removed in vacuo, water was added to the residue (50 ml) and the mixture was extracted with dichloromethane (2 x 30 ml). The combined organic portion was extracted with hydrochloric acid (2.5 M; 2 x 30 ml), then the combined extracts were basified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (2 x 30 ml). The combined organics were dried over magnesium sulfate and the solvent was removed in vacuo. The residue is purified by vacuum chromatography on silica gel, eluting with a 9:1 mixture of dichloromethane and methanol. The appropriate organic fractions were combined and the solvent was removed in vacuo. (S)-2-amino-N{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (1.0 g) is obtained, mp 62-70ºC, [α]D-35.47º (c=0.888, MeOH).

Primjer 3 Example 3

Otopinu butil-litija u heksanu (2,5 M; 15,9 ml) doda se uz miješanje k otopini 3-fluoranisola (5,0 g u suhom tetrahidrofuranu (100 ml) pri -78°C i smjesa se miješa 30 minuta pri sobnoj temperaturi. Doda se suhi dimetilformamid (3,1 ml) i smjesa se miješa i pusti zagrijati na sobnu temperaturu tijekom jednog sata. Doda se vodu (150 ml) i smjesu se ekstrahira s etil acetatom (3 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (100 ml), osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Destilacijom ostatka pod smanjenim tlakom dobije se 2-fluor-6-metoksibenzaldehid (4,6 g) kao ulje, vrelište 120°C pod 10,66 mbara. A solution of butyllithium in hexane (2.5 M; 15.9 ml) was added with stirring to a solution of 3-fluoroanisole (5.0 g in dry tetrahydrofuran (100 ml)) at -78°C and the mixture was stirred for 30 minutes at room temperature. dry dimethylformamide (3.1 ml) was added and the mixture was stirred and allowed to warm to room temperature for one hour. Water (150 ml) was added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate and the solvent was removed in vacuo Distillation of the residue under reduced pressure gave 2-fluoro-6-methoxybenzaldehyde (4.6 g) as an oil, boiling point 120°C under 10, 66 mbars.

Otopinu borovog tirbomida u diklormetanu (1M; 20,25 ml) doda se kap po kap uz miješanje k otopini 2-fluor-6-metoksibenzaldehida (4,66 g, pripremljen kako je gore opisano) u diklormetanu (40 ml) pri -78°C. Smjesu se pusti zagrijavati na sobnu temperaturu, zatim se doda vodu (150 ml) i smjesu se ekstrahira s diklormetanom (3 x 100 ml). Sjedinjeni ekstrakti se isperu s vodom (100 ml), zatim s otopinom soli (100 ml) i otapalo se ispari. Destilacijom ostatka pod smanjenim tlakom dobije se 2-fluor-6-hidroksibenzaldehid (2,0 g) onečišćen sa 7% početnog metoksi spoja, kao ulje, vrelište 60°C pod 4,66 mbara, koji se upotrebljava bez daljnjeg čišćenja. A solution of boron tribomide in dichloromethane (1M; 20.25 ml) was added dropwise with stirring to a solution of 2-fluoro-6-methoxybenzaldehyde (4.66 g, prepared as described above) in dichloromethane (40 ml) at -78 °C. The mixture was allowed to warm to room temperature, then water (150 ml) was added and the mixture was extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with water (100 ml), then with brine (100 ml) and the solvent was evaporated. Distillation of the residue under reduced pressure gives 2-fluoro-6-hydroxybenzaldehyde (2.0 g) contaminated with 7% of the initial methoxy compound, as an oil, boiling point 60°C under 4.66 mbar, which is used without further purification.

Mješavinu proizvoda iz prethodne reakcije (1,7 g), (R)-glicil 4-toluensulfonata (2,1 g) i kalijevog karbonata (1,68 g) u dimetilformamidu (50 ml) miješa se i grije 5 sati pri 60°C. Nakon miješanja 18 sati pri sobnoj temperaturi smjesa se prelije u vodu (150 ml) i a ztim se ekstrahira s etilacetatom (3 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (100 ml) i osuše preko magneziejvog sulfata. Otapalo se ostrani u vakuumu i uljasti ostatak se pusti kroz kolonu silika gela ispirući s mješavinom 1:2 etil acetata i petrol etera (vrelište 60-80°C). Otapalo se odstrani u vakuumu. Dobije se (R)-2-(2,3-epksipropoksi)-6-fluorbenzaldehid (,071 g) kao ulje. The mixture of the product from the previous reaction (1.7 g), (R)-glycyl 4-toluenesulfonate (2.1 g) and potassium carbonate (1.68 g) in dimethylformamide (50 ml) is stirred and heated for 5 hours at 60° C. After stirring for 18 hours at room temperature, the mixture is poured into water (150 ml) and then extracted with ethyl acetate (3 x 100 ml). The combined extracts are washed with salt solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the oily residue was passed through a silica gel column, washing with a 1:2 mixture of ethyl acetate and petroleum ether (boiling point 60-80°C). The solvent was removed in vacuo. (R)-2-(2,3-epoxypropoxy)-6-fluorobenzaldehyde (.071 g) was obtained as an oil.

Mješavinu proizvoda iz prethodne reakcije (0,71 g) i 3-klorperbenzojeve kiseline (85%; 0,87 g) u diklormetanu (100 ml) grije se 3 dana pod refluksom. Doda se slijedeći obrok 3-klorperbenzojeve kiseline (0,87 g) i grijanje pdo refluksom nastavi se još 18 sati. Smjesu se prelije u zasićenu vodenu otopinu natrijevog karbonata (250 ml) i ekstrahira se s diklormetanom (3 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (100 ml), zatim se osuše preko magnezijevog sulfata i otapalo se ispari u vakuumu. Dobije se (R)-2-(2,3-epksipropoksi)-6-fluorfenil format (0,34 g) kao ulje. A mixture of the product from the previous reaction (0.71 g) and 3-chloroperbenzoic acid (85%; 0.87 g) in dichloromethane (100 ml) was heated under reflux for 3 days. The next portion of 3-chloroperbenzoic acid (0.87 g) is added and heating under reflux is continued for another 18 hours. The mixture was poured into saturated aqueous sodium carbonate solution (250 ml) and extracted with dichloromethane (3 x 100 ml). The combined extracts are washed with brine (100 ml), then dried over magnesium sulfate and the solvent is evaporated in vacuo. (R)-2-(2,3-epoxypropoxy)-6-fluorophenyl formate (0.34 g) was obtained as an oil.

Metalni natrij (0,89 g) otopi se u metanolu (100 ml) i kap po kap doda se otopinu (R)-2-(2,3-epksipropoksi)-6-fluorfenil formata (6,56 g, pripremljenog kako je gore opisano) u metanolu (100 ml). Smjesu se miješa jedan sat pri sobnoj temperaturi i zatim još dva sata pod refluksom, pusti se stajati 3 dana, i zatim se grije još 4 sata pod refluksom. Otapalo se odstrani u vakuumu, doda se vodu (100 ml) i mješavinu se ekstrahira s etil acetatom (4 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (100 ml), zatim se osuše preko magnezijevog sulfata i otapalo se ispari u vakuumu. Dobije se sirov (S)-8-fluor-1,4-benzodioksan-2-ilmetanol (3,85 g) koji se upotrebljava bez daljnjeg čišćenja. Sodium metal (0.89 g) was dissolved in methanol (100 mL) and added dropwise to a solution of (R)-2-(2,3-epoxypropoxy)-6-fluorophenyl formate (6.56 g, prepared as described above) in methanol (100 ml). The mixture is stirred for one hour at room temperature and then for another two hours under reflux, let stand for 3 days, and then heated for another 4 hours under reflux. The solvent was removed in vacuo, water (100 ml) was added and the mixture was extracted with ethyl acetate (4 x 100 ml). The combined extracts are washed with brine (100 ml), then dried over magnesium sulfate and the solvent is evaporated in vacuo. Crude (S)-8-fluoro-1,4-benzodioxan-2-ylmethanol (3.85 g) is obtained, which is used without further purification.

K otopini sirovog proizvoda iz prethodne reakcije (3,85 g) u piridinu (50 ml) doda se 4-toluensulfonil klorid (4,1 g) i smjesu se miješa 18 sati prije nego se prelije u klorovodičnu kiselinu (5M; 100 ml). Smjesu se ekstrahira s etil acetatom (3 x 100 ml) i smejdinjeni ekstrakti se isperu s otopinom soli (100 ml) i zatim se osuše preko magnezijevog sulfata. otapalo se odstrani u vakuumu. Dobije se sirov (R)-8-fluor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (4,1 g) kao polučvrsta tvar, koja se upotrebljava bez daljnejg čišćenja. To a solution of the crude product from the previous reaction (3.85 g) in pyridine (50 ml) was added 4-toluenesulfonyl chloride (4.1 g) and the mixture was stirred for 18 hours before being poured into hydrochloric acid (5M; 100 ml) . The mixture was extracted with ethyl acetate (3 x 100 ml) and the brown extracts were washed with brine (100 ml) and then dried over magnesium sulfate. the solvent was removed in vacuo. Crude (R)-8-fluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (4.1 g) is obtained as a semi-solid, which is used without further purification.

Smjesu sirovog 2-amino-N-(4-piperidilmetil)piridin-3-karboksamida (7,21 g; pripremljen je kako je opisano u primjer 2), kalijevog karbonata (4,15 g) i (R)-8-fluor-1,4-benzodioksan-2-ilmetil toluen-4-sulfonata (2 g) u acetonitrilu (100 ml) grije se 16 sati pod refluksom. Nakon hlađenja i filtracije otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom na silika gelu s čistim etil acetatom. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se čvrstu tvar (1,5 g). Tu čvrstu tvar (0,78 g) se osuši u vakuumu i smrvi. Dobije se (S)-2-amino-N{[1-(8-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid 0,5 hidrat 0,15 etil acetat, solvat (610 mg), talište 115-116°C, [α]D-39,09º (c=0,967, MeOH). A mixture of crude 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide (7.21 g; prepared as described in Example 2), potassium carbonate (4.15 g) and (R)-8-fluoro -1,4-benzodioxan-2-ylmethyl toluene-4-sulfonate (2 g) in acetonitrile (100 ml) is heated under reflux for 16 hours. After cooling and filtration, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel with pure ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. A solid (1.5 g) is obtained. This solid (0.78 g) was dried in vacuo and crushed. (S)-2-amino-N{[1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide 0.5 hydrate 0.15 ethyl acetate, solvate (610 mg), mp 115-116°C, [α]D-39.09º (c=0.967, MeOH).

Primjer 4 Example 4

Uz miješanje smjesu od 1,4benzodioksan-2-ilmetil toluen-4-sulfonata (0,82 g), 2-amino-N-(4-piperidilmetil) piridin-3-karboksamid trifluoracetata (0,905 g); pripremljen kako je opisano u primjer 2) i kalijevog karbonata (1,4 g) u acetonitirlu (50 ml) grije se 6 sati pod refluksom. Nakon hlađenja otapalo se odstrani u vakuumu, k ostatku se doda vodu (60 ml) i proizvod se ekstrahira s diklormetanom (2 x 30 ml). Ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se ulje. Ulje se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom ):1 i zatim 1:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se ulje. K dobivenoj bijeloj čvrstoj tvari doda se etersku maleinsku kiselinu (20 ml). Čvrstu tvar se skupi filtracijom, ispere s eterom i otapalo se odstrani u vakuumu. Dobije se 2-amino-N{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid 0,5 maleat (95 mg), talište 104-106°C. With stirring a mixture of 1,4benzodioxan-2-ylmethyl toluene-4-sulfonate (0.82 g), 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate (0.905 g); prepared as described in example 2) and potassium carbonate (1.4 g) in acetonitrile (50 ml) is heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo, water (60 ml) was added to the residue and the product was extracted with dichloromethane (2 x 30 ml). The extracts were dried over magnesium sulfate and the solvent was removed in vacuo. Oil is obtained. The oil is purified by vacuum chromatography on silica gel eluting with a mixture of ):1 and then 1:1 dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. Oil is obtained. Maleic acid ether (20 ml) was added to the obtained white solid. The solid was collected by filtration, washed with ether and the solvent was removed in vacuo. 2-amino-N{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide 0.5 maleate (95 mg) is obtained, melting point 104-106°C .

Primjer 5 Example 5

Smjesu od 2-hidroksi-5-metilbenzaldehida (7,1 g), (R)-glicidil 4-toluensulfonata (11,9 g) i kalijevog karboanta (7,25 g) u bezvodnom 1,2-dimetoksietanu (150 ml) miješa se i grije 5 sati pri 60°C. Pusti se stajati 18 sati pri sobnoj temperaturi, zatim se grije još 8 sati pri 60°C i zatim se pusti hladiti 18 sati. Otapalo se odstrani u vakuumu i ostatak se podijeli između vode (250 ml) i etera (250 ml). Mješavinu se filtrira kroz Cellite, eterski sloj se odvoji, ispere s vodom i osuši preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 1:1 etera i petrol etera (vrelište 40-60°C). Odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se (R)-2-(2,3-epoksipropoksi)-5-metilbenzaldehid (8,91 g) kao ulje. A mixture of 2-hydroxy-5-methylbenzaldehyde (7.1 g), (R)-glycidyl 4-toluenesulfonate (11.9 g) and potassium carbonate (7.25 g) in anhydrous 1,2-dimethoxyethane (150 ml) it is mixed and heated for 5 hours at 60°C. Let it stand for 18 hours at room temperature, then heat it for another 8 hours at 60°C and then let it cool for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water (250 ml) and ether (250 ml). The mixture is filtered through Cellite, the ether layer is separated, washed with water and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by vacuum chromatography on silica gel, eluting with a 1:1 mixture of ether and petroleum ether (boiling point 40-60°C). The appropriate fractions are combined and the solvent is evaporated. (R)-2-(2,3-epoxypropoxy)-5-methylbenzaldehyde (8.91 g) was obtained as an oil.

otopinu iz proizvoda prethodne reakcije (8,91 i 3-klorperbenzojeve kiseline (86%; 19,6 g) u diklormetanu (250 ml) miješa se 18 sati pri sobnoj temperaturi. Otopinu se ispere s razrijeđenom otopinom natrijevog hidrogenkarbonata (2 x 200 ml), zatim s vodom i osuši preko magnezijevog sulfata. Otapalo se ispari i dobiveni sirov (R)-2-(2,3-epoksipropoksi)-5-metilfenil fromat (14,0 g), koji još uvijek sadrži nešto 3-klorbenzojeve kiseline, upotrbljen je bez daljnjeg čišćenja. the solution from the product of the previous reaction (8.91 and 3-chloroperbenzoic acid (86%; 19.6 g) in dichloromethane (250 ml) was stirred for 18 hours at room temperature. The solution was washed with a dilute solution of sodium bicarbonate (2 x 200 ml ), then with water and dried over magnesium sulfate. The solvent was evaporated to give crude (R)-2-(2,3-epoxypropoxy)-5-methylphenyl formate (14.0 g), which still contains some 3-chlorobenzoic acid, it was used without further cleaning.

Sirov proizvod iz prethodne reakcije (14,0 g) otopi se u vodenoj otopini natrijevog hidroksida (2,5 M; 100 ml) i smjesu se miješa 1,5 sata pri 95-100°C. Hladnu otopinu se ekstrahira s diklormetanom (2 x 200 ml), sjedinjeni ekstrakt se osuši preko magnezijevog sulfata i otapalo se ispari. Ostatak se očisti kromatografijom na silika gelu, ispirući s mješavinom 1:1 etera i petrol etera (vrelište 40-60°C). Odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se (S)-7-metil-1,4-benzodioksan-2-ilmetanol (4,71 g) kao ulje. The crude product from the previous reaction (14.0 g) was dissolved in an aqueous solution of sodium hydroxide (2.5 M; 100 ml) and the mixture was stirred for 1.5 hours at 95-100°C. The cold solution was extracted with dichloromethane (2 x 200 ml), the combined extract was dried over magnesium sulfate and the solvent was evaporated. The residue is purified by chromatography on silica gel, washing with a 1:1 mixture of ether and petroleum ether (boiling point 40-60°C). The appropriate fractions are combined and the solvent is evaporated. (S)-7-methyl-1,4-benzodioxan-2-ylmethanol (4.71 g) was obtained as an oil.

Otopinu 4-toluensulfonil klorida (5,5 g) i bezvodnog piridina (50 ml) doda se kap po kap k otopini proizvoda iz prethodne reakcije (4,7 g) u bezvodnom piridinu (50 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi i zatim 2 sata pri 50°C. Smjesu se prelije na led, zakiseli s klorovodičnom kiselinom (5M), zatim ekstrahira s diklormetnaom (2 x200 ml). Sjedinjeni ekstrakti se isperu sa zasićenom otopinom soli, zatim se osuše preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti kromatografijom na silika gelu ispirući s mješavinom 1:1 etera i petrol etera (vrelište 40.60°C)- Odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se (R)-7-metil-1,4-benzodioksan-2-ilmetil 4-toluen-sulfonat (4,53 g) kao čvrsta tvar. A solution of 4-toluenesulfonyl chloride (5.5 g) and anhydrous pyridine (50 ml) was added dropwise to a solution of the product from the previous reaction (4.7 g) in anhydrous pyridine (50 ml) and the mixture was stirred for 2 hours at room temperature temperature and then 2 hours at 50°C. The mixture is poured onto ice, acidified with hydrochloric acid (5M), then extracted with dichloromethane (2 x 200 ml). The combined extracts are washed with saturated salt solution, then dried over magnesium sulfate. The solvent is evaporated and the residue is purified by chromatography on silica gel, eluting with a 1:1 mixture of ether and petroleum ether (boiling point 40.60°C) - The corresponding fractions are combined and the solvent is evaporated. (R)-7-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (4.53 g) was obtained as a solid.

Trifluoroctenu kiselinu (5 ml) doda se k otopini 2-amino-N-[(1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamida (0,92 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (10 ml), zatim se smjesu miješa 2 sata pri sobnoj temperaturi i otapali se odstrani u vakuumu. Tako proizveden sirov 2-amino-N-[(4-piperidil)metil]piridin-3-karboksamid triluoracetat otopi se u bezvodnom acetonitrilu (10 ml) i doda se kalijev karbonat (1,5 g) zatim se otopina (R)-7-metil-1,4-benzo-dioksan-2-ilmetil 4-toluensulfonata (0,9 g) u bezvodnom aacetonitirlu (5 ml). Smjesu se grije 18 sati pod refluksom, zatim se prelije na vodu i ekstrahira s eterom (2 x 100 ml). Sjedinjeni ekstrakti se isperu s vodom, zatim ekstrahiraju s klorovodičnom kiselinom (1M; 50 ml). Kiseli ekstrakti se isperu s eterom (100 ml), zatim se zaluže s natrijevim hidrogen karbonatom i ekstrahiraju s eterom (2 x 100 ml). Ti ekstrakti se sjedine, isperu s vodom i osuše preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i ispare. Dobije se (S)-2-amino-N{[1-(1-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid kao bezbojna čvrsta tvar (0,36 g), talište 143-146°C, [α]D-46,23º (c=0,53, MeOH). Trifluoroacetic acid (5 ml) was added to a solution of 2-amino-N-[(1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (0.92 g; prepared as described in Example 2) in dichloromethane (10 ml), then the mixture was stirred for 2 hours at room temperature and the solvents were removed in vacuo. The thus produced crude 2-amino-N-[(4-piperidyl)methyl]pyridine-3-carboxamide trifluoroacetate was dissolved in anhydrous acetonitrile (10 ml) and potassium carbonate (1.5 g) was added, then the solution of (R)- 7-methyl-1,4-benzo-dioxan-2-ylmethyl 4-toluenesulfonate (0.9 g) in anhydrous acetonitrile (5 ml). The mixture is heated under reflux for 18 hours, then poured onto water and extracted with ether (2 x 100 ml). The combined extracts were washed with water, then extracted with hydrochloric acid (1M; 50 ml). The acid extracts were washed with ether (100 ml), then basified with sodium hydrogen carbonate and extracted with ether (2 x 100 ml). These extracts are combined, washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by vacuum chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol. The appropriate fractions are combined and evaporated. (S)-2-amino-N{[1-(1-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide was obtained as a colorless solid (0, 36 g), mp 143-146°C, [α]D-46.23º (c=0.53, MeOH).

Primjer 6 Example 6

Smjesu piridin-2-karboksilne kiseline (2,7 g) i 4-(aminometil-1-terc.butoksikarbonilpiperidina (5,0 g) u suhom ksilenu (50 ml) grije se šest sati pod refluksom s Dean i Starkovim separatorom vode. Ohlađenu otopinu se razrijedi s etil acetatom (150 ml, ispere s vodenom otopinom oksalne kiseline (2M; 2 x 100 ml), zatim s vodenom otopinom natrijevog hidrogen karbonata (5M; 2 x 100 ml) i osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu. Dobije se N-[(1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamid (2,53 g) kao ulje. A mixture of pyridine-2-carboxylic acid (2.7 g) and 4-(aminomethyl-1-tert.butoxycarbonylpiperidine (5.0 g) in dry xylene (50 ml) was heated under reflux for six hours with a Dean and Stark water separator. The cooled solution was diluted with ethyl acetate (150 ml, washed with an aqueous solution of oxalic acid (2M; 2 x 100 ml), then with an aqueous solution of sodium hydrogen carbonate (5M; 2 x 100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give N-[(1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.53 g) as an oil.

Trifluoroctenu kiselinu (16 ml) doda se otopini proizvoda iz prethodne reakcije (2, 5 g) u diklormetanu (50 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se otopi u acetonitrilu (25 ml). Doda se kalijev karbonat (7,0 g) i 1,4 benzodioksan-2-ilmetil 4-toluensulfonat (2,4 g) i smjesu se grije 18 sati pod refluksom, zatim se ohladi i prelije u vodu. Dobivenu smjesu se ekstrahira s diklormetanom (2 x 100 ml) i sjedinjeni ekstrakti se isperu s vodom i zatim osuše preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s etil acetatom. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se N{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-2-karboksamid (2,43 g) kao bezbojna čvrsta tvar, talište 95-97°C. Trifluoroacetic acid (16 ml) was added to a solution of the product from the previous reaction (2.5 g) in dichloromethane (50 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in acetonitrile (25 ml). Potassium carbonate (7.0 g) and 1,4 benzodioxan-2-ylmethyl 4-toluenesulfonate (2.4 g) were added and the mixture was heated for 18 hours under reflux, then cooled and poured into water. The resulting mixture was extracted with dichloromethane (2 x 100 ml) and the combined extracts were washed with water and then dried over magnesium sulfate. The solvent is evaporated and the residue is purified by vacuum chromatography over silica gel, eluting with ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. N{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-2-carboxamide (2.43 g) is obtained as a colorless solid, mp 95-97°C.

Primjer 7 Example 7

Smjesa od 2-hidroksi-5-metoksibenzaldehida (6,65 g), (R)-glicil 4-toluensulfonata (10,0 g) i kalijevog karbonata (6,1 g) u suhom dimetilformamidu (100 ml) miješa se i grije pet sati pri 60°C. otapalo se odstrani u vakuumu, k ostatku se doda vodu i smjesu se ekstrahira u s eterom (2 x 200 ml). Sjedinjeni ekstrakti se isperu s vodom i osuše preko magnezijevog sulfata. otapalo se ispari i ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 2:1 etera i petrol etera (vrelište 40-60°C). Odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se (R)-2-(2,3-epoksipropoksi)-5-metoksibenzaldehid (7,25 g) kao bistro ulje. A mixture of 2-hydroxy-5-methoxybenzaldehyde (6.65 g), (R)-glycyl 4-toluenesulfonate (10.0 g) and potassium carbonate (6.1 g) in dry dimethylformamide (100 ml) is stirred and heated five hours at 60°C. the solvent is removed in vacuo, water is added to the residue and the mixture is extracted with ether (2 x 200 ml). The combined extracts are washed with water and dried over magnesium sulfate. the solvent is evaporated and the residue is purified by vacuum chromatography over silica gel, eluting with a 2:1 mixture of ether and petroleum ether (boiling point 40-60°C). The appropriate fractions are combined and the solvent is evaporated. (R)-2-(2,3-epoxypropoxy)-5-methoxybenzaldehyde (7.25 g) was obtained as a clear oil.

Otopinu iz proizvoda prethodne reakcije (7,25 g) i 3-klorperbenzojeve kiseline (86%; 14,85 g) u diklormetanu (200 ml) miješa se 18 sati pri sobnoj temperaturi. Doda se vodu (200 ml), organski sloj se odvoji, ispere s otopinom natrijevog hidrogen-karbonata (5M; 3 x 200 ml) zatim s vodom i osuši preko magnezijevog sulfata. otapalo se ispari i dobije se (R)-2-(2,3-epoksipropoksi)-5-metoksi-fenil format (7,1 g) kao bistro ulje. A solution of the product of the previous reaction (7.25 g) and 3-chloroperbenzoic acid (86%; 14.85 g) in dichloromethane (200 ml) was stirred for 18 hours at room temperature. Water (200 ml) is added, the organic layer is separated, washed with sodium hydrogen carbonate solution (5M; 3 x 200 ml), then with water and dried over magnesium sulfate. the solvent was evaporated to give (R)-2-(2,3-epoxypropoxy)-5-methoxy-phenyl formate (7.1 g) as a clear oil.

Otopinu iz proizvoda prethodne reakcije (71,g) u vodenoj otopini natrijevog hidroksida (2,5 M; 100 ml) grije se 1,5 sata pri 95-100°C. Ohlađenu smjesu se ekstrahira s eterom (2 x 200 ml) i sjedinjeni ekstrakti se osuše preko magnezijevog sulfata. otapalo se ispari i dobije se (S)-7-metoksi-1,4-benzodioksan-2-ilmetanol (3,64 g) kao čvrsta tvar. A solution of the product of the previous reaction (71.g) in an aqueous solution of sodium hydroxide (2.5 M; 100 ml) is heated for 1.5 hours at 95-100°C. The cooled mixture was extracted with ether (2 x 200 ml) and the combined extracts were dried over magnesium sulfate. the solvent was evaporated to give (S)-7-methoxy-1,4-benzodioxan-2-ylmethanol (3.64 g) as a solid.

Otopinu 4-toluensulfonil klorida (3,54 g) u bezvodnom piridinu (35 ml) doda se kap po kap k otopini proizvoda iz prethodne reakcije (3,64 g) u bezvodnom piridinu (60 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi i zatim se prelije na led. Smjesu se zakiseli s klorovodičnom kiselinom (5M), zatim se ektrahira s diklormetanom (200 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata. Otpalo se ispari i dobije se (R)-7-metoksi-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (5,1 g) kao čvrsta bezbojna tvar. A solution of 4-toluenesulfonyl chloride (3.54 g) in anhydrous pyridine (35 ml) was added dropwise to a solution of the product from the previous reaction (3.64 g) in anhydrous pyridine (60 ml) and the mixture was stirred for 18 hours at room temperature. temperature and then poured over ice. The mixture was acidified with hydrochloric acid (5M), then extracted with dichloromethane (200 ml). The combined extracts are dried over magnesium sulfate. The residue was evaporated to give (R)-7-methoxy-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (5.1 g) as a colorless solid.

Trifluoroctenu kiselinu (10 ml) doda se k otopini 2-amino-N-[(1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamida (2,5 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (10 ml), zatim se smjesu miješa 2 sata pri sobnoj temperaturi i otapalo se odstrani u vakuumu. Ostatak se otopi u bezvodnom acetonitrilu(75 ml), doda se kalijev karbonat (15 g) i proizvod iz prethodne reakcije (2,5 g). Smjesu se grije 20 sati pod refluksom. Ohlađenu smjesu se prelije na vodu (200 ml) i ekstrahira s diklormetanom (2 x 200 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata. otapalo se ispari i ostatak se očisti kromatografijom na silika gelu ispirući s etilacetatom i zatim s mješavinom 9:1 etil acetata i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Ostatak se prekristalizira iz etanol acetata i dobije se (S)-2-amino-N{[1-(7-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (1,15 g), talište 156-158°C, [α]D-46,5º (c=0,505, MeOH). Trifluoroacetic acid (10 ml) was added to a solution of 2-amino-N-[(1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.5 g; prepared as described in Example 2) in dichloromethane (10 ml), then the mixture was stirred for 2 hours at room temperature and the solvent was removed in vacuo. The residue is dissolved in anhydrous acetonitrile (75 ml), potassium carbonate (15 g) and the product from the previous reaction (2.5 g) are added. The mixture is heated under reflux for 20 hours. The cooled mixture is poured onto water (200 ml) and extracted with dichloromethane (2 x 200 ml). The combined extracts are dried over magnesium sulfate. the solvent is evaporated and the residue is purified by chromatography on silica gel eluting with ethyl acetate and then with a 9:1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. The residue is recrystallized from ethanol acetate to give (S)-2-amino-N{[1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (1.15 g), mp 156-158°C, [α]D-46.5° (c=0.505, MeOH).

Primjer 8 Example 8

Kinolin-8-karboksilnu kiselinu (0,74 g) i tionil klorid (10 ml) miješaju se i griju 2 sata pri 50°C. Suvišak tionil klorida se odstrani u vakuumu i ostatak se ponovno suspendira u diklormetanu (20 ml). Doda se otopinu 4-(aminometil)-1-terc.butoksikarbonilpiperidina (0,98 g) u diklormetanu (10 ml) i smjesu se miješa 4 sata pri sobnoj temperaturi i prelije u vodenu otopinu natrijevog hidrogen karbonata (1M; 50 ml). organski sloj se odvoji i ispere s vodenom otopinom oksalne kiseline (2M; 2 x 50 ml), zatim se osuši preko magnezijevog sulfata. otapalo se ispari i dobije se N-[1-terc.butoksikarbonil-4-piperidil)metil]-kinolin-8-karboksamid (0,59 g) kao bezbojna čvrsta tvar. Quinoline-8-carboxylic acid (0.74 g) and thionyl chloride (10 ml) are mixed and heated for 2 hours at 50°C. Excess thionyl chloride was removed in vacuo and the residue resuspended in dichloromethane (20 ml). It was added to a solution of 4-(aminomethyl)-1-tert.butoxycarbonylpiperidine (0.98 g) in dichloromethane (10 ml) and the mixture was stirred for 4 hours at room temperature and poured into an aqueous solution of sodium hydrogen carbonate (1M; 50 ml). the organic layer is separated and washed with an aqueous solution of oxalic acid (2M; 2 x 50 ml), then dried over magnesium sulfate. the solvent was evaporated to give N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-quinoline-8-carboxamide (0.59 g) as a colorless solid.

Trifluoroctenu kiselinu (5 ml) doda se k otopini N-[1-terc.butoksikarbonil-4-piperidil)metil]-kinolin-8-karboksamida (1,11 g; pripremljen kako je gore opisano) u diklormetanu (20 ml) i smjesu se miješa 2 sata pod refluksom, zatim se ohladi i otapalo se odstrani u vakuumu. Ostatak se otopi u bezvodnom acetonitrilu (50 ml, doda se kalijev karbonat (3,0 g) i 1,4-benzodioksan-2-ilmetil 4-toluensulfonat (0,92 g) i smjesu se grije 20 sati pod refluksom. Ohlađenu smjesu se prelije na vodu (100 ml) i ekstrahira s diklormetanom (2 x 100 ml). Sjedinjeni ekstrakti se isperu s vodom i osuše preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s etil acetatom. odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se ulje koje se ponovo otpi u metanolu (10 ml) i doda se fumarnu kiselinu (0,4 g). Otapalo se odstrani u vakuumu i dobije se N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}kinolin-8-karboksamid 2,5 fumarat (1,12 g), talište 117-120°C (omekšava se pri 78°C). Trifluoroacetic acid (5 ml) was added to a solution of N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-quinoline-8-carboxamide (1.11 g; prepared as described above) in dichloromethane (20 ml) and the mixture is stirred for 2 hours under reflux, then it is cooled and the solvent is removed in vacuo. The residue is dissolved in anhydrous acetonitrile (50 ml, potassium carbonate (3.0 g) and 1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (0.92 g) are added, and the mixture is heated under reflux for 20 hours. The cooled mixture is poured into water (100 ml) and extracted with dichloromethane (2 x 100 ml). The combined extracts are washed with water and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by vacuum chromatography on silica gel eluting with ethyl acetate. the appropriate fractions were combined and the solvent was removed in vacuo to give an oil which was redissolved in methanol (10 ml) and fumaric acid (0.4 g) was added. The solvent was removed in vacuo to give N-{[1-(1 ,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}quinoline-8-carboxamide 2,5 fumarate (1.12 g), melting point 117-120°C (softens at 78°C).

Primjer 9 Example 9

Mješavinu 2-klor-6-hidroksibenzaldehida (4,4 g), (R)-glicidil 4-toluensulfoanta (5,0 g) i kalijevog karbonata (3,9 g) u dimetilformamidu (120 ml) miješa se i grije 5 sati pri 60°C i zatim se pusti hladiti tijekom 18 sati. Otapalo se odstrani u vakuumu, k ostatku se doda vodu (60 ml) i smjesu se ekstrahira s eterom (3 x 100 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Preostalo ulje se očisti vakuumskom kromatografijom na silika gelu s 1:1 mješavinom petrol etera (vrelište 40-60°C) i diklormetana, zatim s čistim diklormetanom i zatim s mješavinom 19:1 diklormetana industrijskog metiliranog špirita. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (R)-2-klor-6-(2,3-epoksipropoksi)benzaldehid kao blijedo žuta čvrsta tvar (2,8 g). Inače, potpuno očišćene frakcije daju materijal koji se ponovno podvrgava kromatografiji čime se dobije drugi dobitak (0,5 g). A mixture of 2-chloro-6-hydroxybenzaldehyde (4.4 g), (R)-glycidyl 4-toluenesulfonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) is stirred and heated for 5 hours at 60°C and then allowed to cool for 18 hours. The solvent was removed in vacuo, water (60 ml) was added to the residue and the mixture was extracted with ether (3 x 100 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated. The remaining oil is purified by vacuum chromatography on silica gel with a 1:1 mixture of petroleum ether (boiling point 40-60°C) and dichloromethane, then with pure dichloromethane and then with a 19:1 mixture of dichloromethane industrial methylated spirit. The appropriate fractions were combined and the solvent was removed in vacuo. (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde was obtained as a pale yellow solid (2.8 g). Otherwise, the completely purified fractions yield material that is again subjected to chromatography to obtain a second yield (0.5 g).

otopinu iz proizvoda prethodne reakcije (2,8 g) i 3-klorperbenzojeve kiseline (6%; 4,8 g) u diklormetanu (200 ml) miješa se 18 sati pod refluksom. Doda se još 3-klorperbenzojeve kiseline (86%; 4,8 g) i otopina se grije još 6 sati pod refluksom. Smjesu se ispere sa zasićenom vodenom otopinom natrijevog hidrogen-karbonata (3 x 200 ml), osuši preko magnezijevog sulfata i otapalo se ispari- Dobije se (R)-2-klor-6-(2,3-epoksipropoksi)fenil format (2,8 g) kao žuta čvrsta tvar. a solution of the product of the previous reaction (2.8 g) and 3-chloroperbenzoic acid (6%; 4.8 g) in dichloromethane (200 ml) was stirred for 18 hours under reflux. More 3-chloroperbenzoic acid (86%; 4.8 g) is added and the solution is heated under reflux for another 6 hours. The mixture is washed with saturated aqueous sodium hydrogen carbonate solution (3 x 200 ml), dried over magnesium sulfate and the solvent is evaporated. (R)-2-chloro-6-(2,3-epoxypropoxy)phenyl formate (2 .8 g) as a yellow solid.

Otopinu iz proizvoda prethodne reakcije (2,8 g) u vodenoj otopini natrijevog hidroksida (2,5 M; 20 ml) grije se 1,5 sata pod refluksom. Ohlađenu smjesu se ekstrahira s diklormetanom (2 x 20 ml), sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se (S)-8-klor-1,4-benzodioksan-2-ilmetanol (1,63 g) kao žuto ulje. A solution of the product of the previous reaction (2.8 g) in aqueous sodium hydroxide solution (2.5 M; 20 ml) is heated under reflux for 1.5 hours. The cooled mixture is extracted with dichloromethane (2 x 20 ml), the combined extracts are dried over magnesium sulfate and the solvent is evaporated. (S)-8-chloro-1,4-benzodioxan-2-ylmethanol (1.63 g) was obtained as a yellow oil.

Otopinu 4-toluensulfonil klorida (3,15 g) u suhom piridinu (15 ml) doda se k otopini (S)-8-klor-1,4-benzodioksan-2-ilmetanola (3,32 g, pripremljen kako je gore opisano) u suhom piridinu (40 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi i zatim se prelije na led. Smjesu se zakiseli s klorovodičnom kiselinom na pH 4. Smjesu se zatim ekstrahira s diklormetanom (2 x 200 ml). Sjedinjeni ekstrakti se isperu s otopinom soli i osuše preko magnezijevog sulfata. Otapalo se ispari i dobije se (R)-8-klor-1,4-benzodioksan-2-ilmetanol 4-toluensulfonat (5,21 g) kao blijedo žuta čvrsta tvar. A solution of 4-toluenesulfonyl chloride (3.15 g) in dry pyridine (15 ml) was added to a solution of (S)-8-chloro-1,4-benzodioxan-2-ylmethanol (3.32 g, prepared as described above ) in dry pyridine (40 ml) and the mixture was stirred for 18 hours at room temperature and then poured onto ice. The mixture was acidified with hydrochloric acid to pH 4. The mixture was then extracted with dichloromethane (2 x 200 ml). The combined extracts are washed with salt solution and dried over magnesium sulfate. The solvent was evaporated to give (R)-8-chloro-1,4-benzodioxan-2-ylmethanol 4-toluenesulfonate (5.21 g) as a pale yellow solid.

Mješavinu proizvoda iz prethodne reakcije (2,5 g) N-benzilien-1-(4-piperidinil)metilamina (1,42 g) i kalijevog karbonata (2,0 g) u suhom acetonitrilu (50 ml) miješa se i grije pod refluksom 24 sata. Ohlađenu smjesu se prelije u vodu (100 ml), zatim se ekstrahira s diklormetanom (2 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli i zatim osuše preko magnezijevog sulfata. otapalo se ispari i ostatak se odvoji od polaznog materijala prolaskom kroz kolonu silika gela ispirući s eterom. Otapalo se ispari i dobije se djelomično očišćen (S)-N-benziliden-[(1-8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metilamin (1,72 g) kao čvrsta tvar krem boje. A mixture of the product from the previous reaction (2.5 g), N-benzylene-1-(4-piperidinyl)methylamine (1.42 g) and potassium carbonate (2.0 g) in dry acetonitrile (50 ml) was stirred and heated under by reflux for 24 hours. The cooled mixture was poured into water (100 ml), then extracted with dichloromethane (2 x 100 ml). The combined extracts are washed with salt solution and then dried over magnesium sulfate. the solvent is evaporated and the residue is separated from the starting material by passing through a silica gel column, washing with ether. The solvent was evaporated to give partially purified (S)-N-benzylidene-[(1-8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine (1.72 g) as a cream solid colors.

Proizvod iz prethodne reakcije (1,7 g) miješa se s vodenom otopinom kalijevog hidrogen sulfata (1M; 100 ml) tijekom 2 sata pri sobnoj temperaturi. Otopinu se ispere s eterom (100 ml), zaluži se s vodenom otopinom natrijevog hidroksida (5M) i ekstrahira se s diklormetanom (2 x 200 ml). Sjedinjeni ekstrakti se isperu s vodom (100 ml) i zatim se osuše preko magnezijevog sulfata. otapalo se ispari i dobije se (S)-4-(aminometil)-1-(8-klor-1,4-benzodioksan-2-ilmetil)piperidin (0,65 g) kao ulje. The product from the previous reaction (1.7 g) was mixed with an aqueous solution of potassium hydrogen sulfate (1M; 100 ml) for 2 hours at room temperature. The solution was washed with ether (100 ml), basified with aqueous sodium hydroxide (5M) and extracted with dichloromethane (2 x 200 ml). The combined extracts were washed with water (100 ml) and then dried over magnesium sulfate. the solvent was evaporated to give (S)-4-(aminomethyl)-1-(8-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.65 g) as an oil.

K otopini 2-metilpiperidin-3-karboksilne kisleine (0,3 g) u diklormetanu (20 ml) doda se trietilamin (0,22 g) i zatim etil kloroformat (0,24 g) i smjesu se miješa 18 sati pri sobnoj temperaturi. zatim se kap po kap doda otopinu proizvoda iz prethodne reakcije (0,65 g) u diklormetanu (10 ml) i miješa se 24 sata pri sobnoj temperaturi. zatim se ispere s vodom (100 ml) i osuši preko magnezijevog sulfata. otapalo se ispari i ostatak se očisti vakuumskom kroamtografijom preko silikagela ispirući s mješavinom 15:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine, otapalo se ispari u vakuumu i dobije se (S)-N{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metilpiridin-3-karboksamid (0,37 g), kao čvrsta tvar, talište 147-149°C, [α]D-37,9º (c=1,0035, metanol). Triethylamine (0.22 g) and then ethyl chloroformate (0.24 g) were added to a solution of 2-methylpiperidine-3-carboxylic acid (0.3 g) in dichloromethane (20 ml) and the mixture was stirred for 18 hours at room temperature. . then a solution of the product from the previous reaction (0.65 g) in dichloromethane (10 ml) was added drop by drop and stirred for 24 hours at room temperature. then it is washed with water (100 ml) and dried over magnesium sulfate. the solvent is evaporated and the residue is purified by vacuum chromatography over silica gel eluting with a 15:1 mixture of dichloromethane and methanol. The corresponding fractions are combined, the solvent is evaporated in vacuo to give (S)-N{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methylpyridin- 3-Carboxamide (0.37 g), as a solid, mp 147-149°C, [α]D-37.9º (c=1.0035, methanol).

Primjer 10 Example 10

Epiklorhidrin (38 g) doda se uz miješanje k otopini 5’-fluor-2’-hidroksiacetofenona (20,9 g) u etanilu (20 ml). Zatim se doda otopinu kalijevog hidroksida (9,5 g) u etanolu (30 ml) i vodu (5 ml) i miješanje se zatim nastavi još jedan sat. Otapalo se odstrani u vakuumu i ostatak se prelije u vodu i ekstrahira s etilacetatom. Sjedinjeni ekstrakti se isperu s otopinom soli i osuše preko magnezijevog sulfata. otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom preko silika gela ispirući s mješavinom 9:1, zatim 3:2 petrol etera (vrelište 40-60°C) i etilacetata. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se 2’-(2,3-epoksipropoksi)-5’-fluoracetofenon (4,68 g) kao ulje. Epichlorohydrin (38 g) was added with stirring to a solution of 5'-fluoro-2'-hydroxyacetophenone (20.9 g) in ethanol (20 ml). A solution of potassium hydroxide (9.5 g) in ethanol (30 ml) and water (5 ml) was then added and stirring was then continued for another hour. The solvent was removed in vacuo and the residue was poured into water and extracted with ethyl acetate. The combined extracts are washed with salt solution and dried over magnesium sulfate. the solvent is removed in vacuo and the residue is purified by chromatography over silica gel, eluting with a mixture of 9:1, then 3:2 petroleum ether (boiling point 40-60°C) and ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. 2'-(2,3-epoxypropoxy)-5'-fluoroacetophenone (4.68 g) was obtained as an oil.

otopinu iz proizvoda prethodne reakcije (4,68 g) i 3-klorperbenzojeve kiseline (80%; 5,86 g) u kloroformu (50 ml) miješa se 18 sati pod refluksom. Nakon hlađenja smjesu se ispere sa zasićenom vodenom otopinom natrijevog hidrogen-karbonata, zatim s otopinom soli i otapalo se ispari u vakuumu. Dobije se sirov 2-(2,3-epoksipropoks)-5-fluorfenil acetat (4,44 g) koji se koristi bez daljnjeg čišćenja. a solution of the product of the previous reaction (4.68 g) and 3-chloroperbenzoic acid (80%; 5.86 g) in chloroform (50 ml) was stirred under reflux for 18 hours. After cooling, the mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate, then with a salt solution and the solvent is evaporated in a vacuum. Crude 2-(2,3-epoxypropoxy)-5-fluorophenyl acetate (4.44 g) was obtained which was used without further purification.

Sirov proizvod iz prethodne reakcije (4,0 g) i vodena otopina natrijevog hidroksida (10%; 7,3 ml) grije se 5 sati pod refluksom. Ohlađenu smjesu se prelije u vodu ekstrahira s etilacetatom. Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se 7-fluor-1,4-benzodioksan-2-ilmetanol (2,0 g). The crude product from the previous reaction (4.0 g) and an aqueous solution of sodium hydroxide (10%; 7.3 ml) were heated under reflux for 5 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulfate and the solvent is evaporated. 7-Fluoro-1,4-benzodioxan-2-ylmethanol (2.0 g) is obtained.

Otopinu 4-toluensulfonil klorida (2,14 g) doda se k otopini proizvoda iz prethodne reakcije (2,0 g) u piridinu (50 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi. Zatim se prelije u smjesu leda i razrijeđene solne kiseline i zatim se ekstrahira s etil acetatom. Sjedinjeni ekstrakti se isperu s otopinom soli preko magnezijevog sulfata. otpalo se ispari i dobije se proizvod onečišćen sa značajnom količinom polaznog materijala. Taj sirov proizvod reagira s daljnjom količinom 4-toluensulfonil klorida (2,14 g) u piridinu (50 ml), kao gore i obradi se kao gore da se dobije nečist proizvod koji se očisti vakuumskom kromatografijom na silika gelu ispirući s 20:1 mješavinom diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se 7-fluor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (0,78 g) kao bistro ulje. A solution of 4-toluenesulfonyl chloride (2.14 g) was added to a solution of the product from the previous reaction (2.0 g) in pyridine (50 ml) and the mixture was stirred for 18 hours at room temperature. It is then poured into a mixture of ice and dilute hydrochloric acid and then extracted with ethyl acetate. The combined extracts are washed with salt solution over magnesium sulfate. the waste is evaporated and a product contaminated with a significant amount of starting material is obtained. This crude product was reacted with a further amount of 4-toluenesulfonyl chloride (2.14 g) in pyridine (50 ml) as above and worked up as above to give the impure product which was purified by vacuum chromatography on silica gel eluting with a 20:1 mixt. dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. 7-Fluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (0.78 g) was obtained as a clear oil.

Trifluoroctenu kiselinu (5 ml) doda se k otopini 2-amino-N-[1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamida (0,78 g; pripremljenog na isti način kako je opisano u primjeru 2) u diklormetanu (25 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, a ostatak se otopi ponovno u acetonitrilu (20 ml). K toj otopini doda se kalijev karbonat (3,0 g) i otopinu proizvoda iz prethodne reakcije (0,75 g) u acetonitrilu (10 ml), zatim se smjesu miješa i grije 18 sati pod refluksom. Ohlađenu smjesu se filtrira i dobivenu čvrstu tvar se ispere s diklormetanom (100 ml). Trifluoroacetic acid (5 ml) was added to a solution of 2-amino-N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (0.78 g; prepared in the same manner as described in Example 2 ) in dichloromethane (25 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo, and the residue was redissolved in acetonitrile (20 ml). Potassium carbonate (3.0 g) and a solution of the product from the previous reaction (0.75 g) in acetonitrile (10 ml) were added to this solution, then the mixture was stirred and heated for 18 hours under reflux. The cooled mixture was filtered and the resulting solid was washed with dichloromethane (100 ml).

Filtrat i eluati se sjedine, isperu s vodom (2 x 10 ml) i osuše preko magnezijevog sulfata. Otapalo se odstrani u silika gelu ispirući s mješavinom 25:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se 2-amino-N{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metilpiridin-3-karboksamid (0,56 g) kao bezbojna čvrsta tvar, talište 141-143°C. The filtrate and eluates are combined, washed with water (2 x 10 ml) and dried over magnesium sulfate. The solvent was removed in silica gel by washing with a mixture of 25:1 dichloromethane and methanol. The corresponding fractions were combined, the solvent was removed in vacuo to give 2-amino-N{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methylpyridin- 3-Carboxamide (0.56 g) as a colorless solid, mp 141-143°C.

Primjer 11 Example 11

Trifluoroctenu kiselinu (10 ml) doda se k otopini 2-amino-N-[1-terc.butoksikarbonil-4-piperidil)metil]-piridin-3-karboksamida (2,5 g; pripremljenog na isti način kako je opisano u primjeru 2) u diklormetanu (50 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi. otapalo se odstrani u vakuumu, a ostatak se otopi u acetonitrilu (50 ml). K toj otopini doda se kalijev karbonat (3,0 g) i otopinu 8-metoksi-1,4-benzodioksan-2-ilmetil 4-toluensulfonata (2,5 g; pripremljen kako je opisano u WO 95/07274) u acetonitirlu (20 ml). Dobivenu suspenziju miješa se i grije 20 sati pod refluksom, ohladi, i zatim prelije u vodu (100 ml) i smjesu se ekstrahira s diklormetanom (2 x 100 ml). Sjedinjeni ekstrakti se isperu s vodom (100 ml), osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se ulje. Proizvod se očisti vakuumskom kromatografijom na silika gelu s mješavinom 9:1 etilacetata i metanola kao protočnim sredstvom. Odgovarajuće frakcije s sjedine, otapalo se odstrani u vakuumu i dobije se 2-amino-N{[1-(8-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metilpiridin-3-karboksamid 0,4 etil acetat solvat 0,5 hidrat (1,55 g), talište 57-60°C. Trifluoroacetic acid (10 ml) was added to a solution of 2-amino-N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-pyridine-3-carboxamide (2.5 g; prepared in the same manner as described in Example 2) in dichloromethane (50 ml) and the mixture was stirred for 2 hours at room temperature. the solvent was removed in vacuo and the residue was dissolved in acetonitrile (50 ml). To this solution was added potassium carbonate (3.0 g) and a solution of 8-methoxy-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (2.5 g; prepared as described in WO 95/07274) in acetonitrile ( 20 ml). The obtained suspension was stirred and heated for 20 hours under reflux, cooled, and then poured into water (100 ml) and the mixture was extracted with dichloromethane (2 x 100 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulfate and the solvent is evaporated. Oil is obtained. The product is purified by vacuum chromatography on silica gel with a 9:1 mixture of ethyl acetate and methanol as eluant. The corresponding fractions were combined, the solvent was removed in vacuo to give 2-amino-N{[1-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methylpyridin- 3-carboxamide 0.4 ethyl acetate solvate 0.5 hydrate (1.55 g), melting point 57-60°C.

Primjer 12 Example 12

Trifluoroctenu kiselinu (25 ml) doda se k otopini N-[1-terc.butoksikarbonil-4-piperidil)metil]-piridin-2-karboksamida (5,2 g) u diklormetanu (50 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi. Otapala se odstrane u acetonitrilu (50 ml). Doda se kalijev karbonat (25 g) i (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (6,0 g; pripremljen kako je opisano u primjeru 1) i smjesu se miješa i grije 24 sata pod refluksom. Ohlađenu smjesu se filtrira i otapalo se odstrani u vakuumu. Ostatak se otopi u etil acetatu, ispere s vodam i osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 20:1 etil acetata i metanola. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se (S)-N{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (4,42 g), talište 110-112°C, [α]D-47,7º (c=1,005, metanol). Trifluoroacetic acid (25 ml) was added to a solution of N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-pyridine-2-carboxamide (5.2 g) in dichloromethane (50 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed in acetonitrile (50 ml). Potassium carbonate (25 g) and (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (6.0 g; prepared as described in Example 1) were added and the mixture was stirred and heated to 24 hour under reflux. The cooled mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by vacuum chromatography on silica gel eluting with a 20:1 mixture of ethyl acetate and methanol. The corresponding fractions were combined, the solvent was removed in vacuo to give (S)-N{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (4.42 g), mp 110-112°C, [α]D-47.7º (c=1.005, methanol).

Primjer 13 Example 13

Mješavinu 2-benziloksi-3-hidroksibenzaldehida (60,0 g), (R)-glicidil 4-toluensulfonata (60,0 g) i kalijevog karbonata (74 g) u suhom dimetilformamidu (600 ml) miješa se i grije 14 sati pri 60°C. nakon hlađenja otapalo se odstrani u vakuumu, doda se vodu (250 ml) i smjesu se ekstrahira s etil eterom (2 x 200 ml), zatim s etil acetatom (2 x 400 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (2 x 500 ml) i osuše preko magnezijevog sulfata. otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom na silika gelu, prethodnom asporpcijom na silika gelu najprije s isparavanjem iz otopine u diklormetanu, zatim ispiranje s 3:1 mješavinom petrol etera (vrelište 40-60°C) i etera. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (R)-benziloksi-3-(2,3-epoksipropoksi)benzaldehid (14,22 g). Daljnji dobitak proizvoda (33,37 g) dobije se ekstrakcijom silika gela korištenog za kromatografiju s eterom (6 x 500 ml), zatim koncentracijom sjedinjenih ekstrakata na volumen od pribl. 500 ml i hlađenjem preko noći, filtracijom, zatim ispiranjem taloga s mješavinom 1:1 petrol etera (vrelište 40-60°C) i etera. Otapalo se odstrani iz filtrata u vakuumu i ostatak se očisti vakuumskom kromatografijom gore opisanom metodom. Dobije se treći dio proizvoda od (9,68 g). ukupni dobitak proizvoda je 57,27 g. A mixture of 2-benzyloxy-3-hydroxybenzaldehyde (60.0 g), (R)-glycidyl 4-toluenesulfonate (60.0 g) and potassium carbonate (74 g) in dry dimethylformamide (600 ml) was stirred and heated for 14 hours at 60°C. after cooling, the solvent is removed in vacuo, water (250 ml) is added and the mixture is extracted with ethyl ether (2 x 200 ml), then with ethyl acetate (2 x 400 ml). The combined extracts are washed with salt solution (2 x 500 ml) and dried over magnesium sulfate. the solvent is removed in vacuum and the residue is purified by vacuum chromatography on silica gel, prior adsorption on silica gel first with evaporation from the solution in dichloromethane, then washing with a 3:1 mixture of petroleum ether (boiling point 40-60°C) and ether. The appropriate fractions were combined and the solvent was removed in vacuo. (R)-Benzyloxy-3-(2,3-epoxypropoxy)benzaldehyde (14.22 g) is obtained. Further product gain (33.37 g) is obtained by extracting the silica gel used for chromatography with ether (6 x 500 ml), then by concentrating the combined extracts to a volume of approx. 500 ml and cooling overnight, filtration, then washing the precipitate with a 1:1 mixture of petroleum ether (boiling point 40-60°C) and ether. The solvent was removed from the filtrate in vacuo and the residue was purified by vacuum chromatography using the method described above. The third part of the product is obtained (9.68 g). the total product gain is 57.27 g.

Sjedinjeni proizvod iz prethodne reakcije (57,27 g), paladij na ugljenu (10%; 2,75 g), cikloheksan (81,4 ml) i etil acetat (2 litre) grije se i miješa zajedno 24 sata pod refluksom u atmosferi dušika. otapalo se ispari i ostatak se otopi u etil acetatu (1 1), zatim se filtrira kroz filterski umetak Cellite. otapalo se odstrani u vakuumu i dobije se narančasto ulje, koje se otopi u mješavini etanola (500 ml), vode (500 ml) i trietilamina (55,2 ml). Mješavinu se miješa i grije 3 sata pod refluksom. Nakon hlađenja etanol se odstrani u vakuumu, a preostalu vodenu smjesu ekstrahira se s etil acetatom (2 x 250 ml). Sjedinjeni ekstrakti se isperu s klorovodičnom kiselinom (1 M; 2 x 250 ml), zatim s vodom i osuše preko magnezijevog sulfata. otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s 3:1, zatim s 1:1 mješavinom petrol etera (vrelište 40-60°C) i etil acetata. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-hidroksimetil-1,4-benzodioksan-8-karboksaldehid (8,02 g). The combined product of the previous reaction (57.27 g), palladium on carbon (10%; 2.75 g), cyclohexane (81.4 mL), and ethyl acetate (2 L) were heated and stirred together for 24 hours under reflux under atmosphere nitrogen. the solvent is evaporated and the residue is dissolved in ethyl acetate (1 1), then filtered through a Cellite filter insert. the solvent was removed in vacuo to give an orange oil, which was dissolved in a mixture of ethanol (500 ml), water (500 ml) and triethylamine (55.2 ml). The mixture is stirred and heated for 3 hours under reflux. After cooling, the ethanol is removed in vacuo, and the remaining aqueous mixture is extracted with ethyl acetate (2 x 250 ml). The combined extracts are washed with hydrochloric acid (1 M; 2 x 250 ml), then with water and dried over magnesium sulfate. the solvent is removed in vacuo and the residue is purified by vacuum chromatography over silica gel, washing with a 3:1, then with a 1:1 mixture of petroleum ether (boiling point 40-60°C) and ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-hydroxymethyl-1,4-benzodioxane-8-carboxaldehyde (8.02 g) is obtained.

Mješavinu proizvoda iz prethodne reakcije (2,0 g), kalijevog karbonata (0,16 g), hidrazin hidrata (1,0 ml) i etan-1,2-diola (50 ml) miješa se i grije 1 sat pod refluksom. Suvišak hidrazin hidrata se odstrani destilacijom kad se dosegne unutarnju temperaturu 0d 185ºC, zatim se preostalu smjesu grije daljnja 2 sata pod refluksom, ohladi i prelije u vodu. Mješavinu se ekstrahira s etil acetatom (100 ml) i sjedinjeni ekstrakti se isperu s razrijeđenom solnom kiselinom (100 ml), zatim sa zasićenom vodenom otopinom natrijevog hidrogen karbonata (100 ml) i osuše preko magnezijevog sulfata. otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom preko silika gela ispirući s 20:1 mješavinom diklormetana i metanola. Dobije se (S)-8-metil-1,4-benzodioksan-2-ilmetanol (0,9 g). A mixture of the product from the previous reaction (2.0 g), potassium carbonate (0.16 g), hydrazine hydrate (1.0 ml) and ethane-1,2-diol (50 ml) was stirred and heated under reflux for 1 hour. Excess hydrazine hydrate is removed by distillation when an internal temperature of 0d 185ºC is reached, then the remaining mixture is heated for another 2 hours under reflux, cooled and poured into water. The mixture was extracted with ethyl acetate (100 ml) and the combined extracts were washed with dilute hydrochloric acid (100 ml), then with saturated aqueous sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. the solvent was removed in vacuo and the residue was purified by chromatography over silica gel eluting with a 20:1 mixture of dichloromethane and methanol. (S)-8-methyl-1,4-benzodioxan-2-ylmethanol (0.9 g) is obtained.

Otopinu 4-toluensulfonil klorida (0,96 g) u suhom piridinu (10 ml) doda se k ledeno hladnoj otopini proizvoda iz prethodne reakcije (0,9 g) u suhom piridinu (40 ml) i smjesu se miješa i pusti zagrijati na sobnu temperaturu tijekom 18 sati, a zatim se prelije na led. Smjesu se zakiseli s razrijeđenom klorovodičnom kiselinom i zatim ekstrahira s eterom (2 x 200 ml). Sjedinjeni ekstrakti se isperu s vodom i osuše preko magnezijevog sulfata. Otapalo se ispari i ostatak se očisti kromatografijom preko silika gela ispirući s 4:1 mješavinom petrol etera (vrelište 40-60ºC) i etera. Odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se (R)-8-meitl-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (0,91 g). A solution of 4-toluenesulfonyl chloride (0.96 g) in dry pyridine (10 ml) was added to an ice-cold solution of the product from the previous reaction (0.9 g) in dry pyridine (40 ml) and the mixture was stirred and allowed to warm to room temperature. temperature for 18 hours, and then poured over ice. The mixture was acidified with dilute hydrochloric acid and then extracted with ether (2 x 200 ml). The combined extracts are washed with water and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by chromatography over silica gel eluting with a 4:1 mixture of petroleum ether (boiling point 40-60ºC) and ether. The appropriate fractions are combined and the solvent is evaporated. (R)-8-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (0.91 g) is obtained.

Trifluoroctenu kiselinu (5 ml) doda se k otopini N-[1-terc.butoksikarbonil-4-piperidil)metil]-piridin-2-karboksamida (0,9 g) u diklormetanu (30 ml) i smjesu se miješa 2 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, a ostatak se otopi u suhom acetonitrilu (20 ml). K toj otopini doda se kalijev karbonat (2,0 g i proizvod iz prethodne reakcije (0,85 g) i smjesu se miješa i grije 24 sata pod refluksom. Ohlađenu otopinu se filtrira i filtrat se podijeli između diklormetana (100 ml) i vode (100 ml). Organski sloj se ispere s vodom, zatim se osuši preko magnezijevog sulfata i otapalo se ispari u vakuumu. Ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 9:1 diklormetana i metanola kao protočnim sredstvom. Odgovarajuće frakcije se sjedine, otapalo se ispari u dobije se (S)-N-{[1-(8-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (0,42 g), talište 56-58°C, [α]D (c=0,869, metanol). Trifluoroacetic acid (5 ml) was added to a solution of N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-pyridine-2-carboxamide (0.9 g) in dichloromethane (30 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo, and the residue was dissolved in dry acetonitrile (20 ml). To this solution was added potassium carbonate (2.0 g and the product of the previous reaction (0.85 g) and the mixture was stirred and heated under reflux for 24 hours. The cooled solution was filtered and the filtrate was partitioned between dichloromethane (100 ml) and water ( 100 ml). The organic layer is washed with water, then dried over magnesium sulfate and the solvent is evaporated in vacuo. The residue is purified by vacuum chromatography on silica gel eluting with a 9:1 mixture of dichloromethane and methanol as eluant. The appropriate fractions are combined, the solvent is evaporated to give (S)-N-{[1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (0.42 g) , melting point 56-58°C, [α]D (c=0.869, methanol).

Primjer 14 Example 14

Smjesu od 6-metilpiridin-2,3-dikarbonske kiseline (19,75 g) i acetanhidrida (51 ml) miješa se i grije 5 sati na uljnoj kupelji (temperatura kupelji 110ºC). otapalo se odstrani u vakuumu i doda se mješavinu od 2:1 diklormetana i etera, čime se dobije tamno smeđu čvrstu tvar. otopinu te čvrste tvari u dklormetanu propusti se kroz filtersku kolonu silika gela ispirući s diklormetanom, i zatim se otapalo ispari. Dobije se djelomično očišćen acetanhidrid 6-metilpiridin-2,3-dikarbonske kiseline (12,1 g). A mixture of 6-methylpyridine-2,3-dicarboxylic acid (19.75 g) and acetic anhydride (51 ml) is stirred and heated for 5 hours in an oil bath (bath temperature 110ºC). the solvent was removed in vacuo and a 2:1 mixture of dichloromethane and ether was added to give a dark brown solid. a solution of that solid in dichloromethane is passed through a silica gel filter column, washing with dichloromethane, and then the solvent is evaporated. Partially purified 6-methylpyridine-2,3-dicarboxylic acid acetic anhydride (12.1 g) is obtained.

K otopini proizvoda iz prethodne reakcije (2,0 g) u etanolu bez klorofrma (10 ml) doda se trimetilsilil azid (1,633 ml) u atmosferi dušika. Dobije se mliječnu suspenziju koja se razbistri grijanjem tijekom 10 minuta. Nakon 1 sata pri sobnoj temperaturi smjesu se grije jedan sat pri 95-100ºC, ohladi se i doda etanol (0,72 ml). Smjesu se ohladi na ledu i istaloži se žuta čvrsta tvar 7-metilpirido[2,3-d]oksazin-2,4-(1H)-dion (1,2 g). To a solution of the product from the previous reaction (2.0 g) in ethanol without chloroform (10 ml) was added trimethylsilyl azide (1.633 ml) under a nitrogen atmosphere. A milky suspension is obtained, which is clarified by heating for 10 minutes. After 1 hour at room temperature, the mixture is heated for one hour at 95-100ºC, cooled and ethanol (0.72 ml) is added. The mixture was cooled on ice and a yellow solid 7-methylpyrido[2,3-d]oxazin-2,4-(1H)-dione (1.2 g) precipitated.

Mješavinu proizvoda iz prethodne reakcije (0,35 g) i [1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil-amina (0,58 g) u 1,2-dimetoksietanu (15 ml) miješa se 24 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s 95:5 mješavinom dikormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-6-metilpiridin-3-karboksamid (0,3 g), talište 160-163°C, [α]D -50,7º (c=0,036, metanol). A mixture of the product from the previous reaction (0.35 g) and [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl-amine (0.58 g) in 1,2-dimethoxyethane (15 ml) is stirred for 24 hours at room temperature. The solvent was removed in vacuo and the residue was purified by vacuum chromatography on silica gel eluting with a 95:5 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-6-methylpyridine-3-carboxamide (0, 3 g), melting point 160-163°C, [α]D -50.7º (c=0.036, methanol).

Primjer 15 Example 15

Trifluoroctenu kiselinu (8 ml) doda se k otopini N-[1-terc.butoksikarbonil-4-piperidil)metil]-piridin-2-karboksamida (1,0 g) u diklormetanu (50 ml) i smjesu se miješa 1 sat pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, a ostatak se otopi u suhom acetonitrilu (50 ml). K toj otopini doda se kalijev karbonat (1,5 g) i (R)-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (0,89 g) i smjesu se miješa i grije 4 sata pod refluksom. Otapalo se odstrani pod refluksom i ostatak se podijeli između vode (40 ml) i diklormetana (40 ml). organsku fazu se ekstrahira s klorovodičnom kiselinom (2M, 40 ml), zatim se ekstrakti zaluže s vodenom otopinom natrijevog hidroksida (5M) i ekstrahiraju s diklormetanom (3 x 20 ml). Sjedinjeni ekstrakti se osuše preko magnezijeva sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 9:1 dikormetana i industrijskog metiliranog špirita. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se ulje koje se obradi s eterskom otopinom maleinske kiseline. Skupi se dobivenu sol, ali se je pokazalo da je ona vrlo higroskopna i zbog toga je uzeta u vodenu otopinu natrijevog hidroksida (2M) i smjesa je ekstrahirana s diklormetanom. Estrakti su osušeni preko magnezijevog sulfata i otapalo je odstranjeno u vakuumu. Dobije se (S)-2-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (0,18 g), kao bezbojna pjena, talište 102-105°C, [α]D -29,36ºC (c=0,6845, metanol). Trifluoroacetic acid (8 ml) was added to a solution of N-[1-tert.butoxycarbonyl-4-piperidyl)methyl]-pyridine-2-carboxamide (1.0 g) in dichloromethane (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo, and the residue was dissolved in dry acetonitrile (50 ml). Potassium carbonate (1.5 g) and (R)-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (0.89 g) were added to this solution and the mixture was stirred and heated for 4 hours under reflux. The solvent was removed under reflux and the residue was partitioned between water (40 ml) and dichloromethane (40 ml). the organic phase is extracted with hydrochloric acid (2M, 40 ml), then the extracts are basified with aqueous sodium hydroxide solution (5M) and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by vacuum chromatography on silica gel, eluting with a 9:1 mixture of dicormethane and industrial methylated spirit. The corresponding fractions are combined, the solvent is removed in vacuo and an oil is obtained which is treated with an ethereal solution of maleic acid. The resulting salt was collected but proved to be very hygroscopic and was therefore taken up in aqueous sodium hydroxide (2M) and the mixture was extracted with dichloromethane. The extracts were dried over magnesium sulfate and the solvent was removed in vacuo. (S)-2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (0.18 g) is obtained as a colorless foam , melting point 102-105°C, [α]D -29.36ºC (c=0.6845, methanol).

Primjer 16 Example 16

Otopinu 2H-tieno[3,2-d][1,3]oksazin-2,4(1H)-diona (3,1 g) i 4-(aminometil)-terc.butoksikarbonilpiperidina (3,9 g) u 1,2-dimetoksietanu (50 ml) miješa se 5 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s eterom. odgovarajuće frakcije se sjedine i otapalo se ispari. Dobije se 3-amino-N-(1-terc.butoksikarbonil-4-piperidilmetil)tiofen-2-karboksamid kao bezbojna čvrsta tvar (2,57 g) A solution of 2H-thieno[3,2-d][1,3]oxazin-2,4(1H)-dione (3.1 g) and 4-(aminomethyl)-tert.butoxycarbonylpiperidine (3.9 g) in 1 ,2-dimethoxyethane (50 ml) was stirred for 5 hours at room temperature. The solvent was removed in vacuo and the residue was purified by vacuum chromatography over silica gel, eluting with ether. the appropriate fractions are combined and the solvent is evaporated. 3-Amino-N-(1-tert.butoxycarbonyl-4-piperidylmethyl)thiophene-2-carboxamide is obtained as a colorless solid (2.57 g).

Trifluoroctenu kiselinu (10 ml) doda se k suspenziji proizvoda iz prethodne reakcije (2,0 g) u diklormetanu i smjesu se miješa 18 sati pri sobnoj temperaturi. otpalo se odstrani u vakuumu, a ostatak se otopi u acetonitrilu 8100 ml). K toj otopini doda se kalijev karbona (3,1 g), trietilamin (2 ml) i 1,4-benzodioksan-2-ilmetil 4-toluensulfonat (1,8 g). Smjesu se miješa i grije 6 sati pod refluksom. Doda se još trietilamina (4 ml) i nastavi se miješati pod refluksom još 6 sati. Ohlađenu smjesu se filtrira i otapalo se odstrani u vakuumu. Ostatak se otopi u diklormetanu, ispere s vodom (2 x 50 ml), osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s mješavinom 19:1 diklormetana i industrijskom metaliranog špirita. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se ulje koje se trituira s eterom. Dobije se 3-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}tiofen-2-karboksamid (0,22 g) kao čvrsta tvar, talište 144-146ºC. Trifluoroacetic acid (10 ml) was added to a suspension of the product from the previous reaction (2.0 g) in dichloromethane and the mixture was stirred for 18 hours at room temperature. the residue is removed under vacuum, and the residue is dissolved in acetonitrile (8100 ml). Potassium carbonate (3.1 g), triethylamine (2 ml) and 1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1.8 g) were added to this solution. The mixture is stirred and heated for 6 hours under reflux. Add more triethylamine (4 ml) and continue stirring under reflux for another 6 hours. The cooled mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in dichloromethane, washed with water (2 x 50 ml), dried over magnesium sulfate and the solvent is removed in vacuo. The residue is purified by vacuum chromatography on silica gel, eluting with a 19:1 mixture of dichloromethane and industrial metalized spirit. The appropriate fractions are combined, the solvent is removed in vacuo to give an oil which is triturated with ether. 3-Amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}thiophene-2-carboxamide (0.22 g) is obtained as a solid, mp 144-146ºC .

Primjer 17 Example 17

Trifluoroctenu kiselinu (10 ml) doda se k suspenziji se 3-amino-N-(1-terc.butoksikarbonil-4-piperidilmetil) tiofen-2-karboksamida (3,8 g) u dikormetanu (100 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi. otapalo se odstrani u vakuumu, a ostatak se otopi u acetonitrilu (100 ml) K toj otopini doda se kalijev karbonat (1,4 g) trietilamin (4 ml) i (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-tolue-sulfonat (3,5 g). Smjesu se miješa i grije 3 dana pod reluksom. Smjesu se ohladi i filtrira i otapalo se odstrani u vakuumu. Dobije se ulje koje se otopi u diklormetanu (100 ml) i ispere se s vodom (2 x 50 ml). Tu otopinu se osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s diklormetnaom, zatim s mješavinom od 19:1 diklormetana i industrijskog metaliranog špirita. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se blijedo žutu čvrstu tvar koju se trituira s eterom. Dobije se (S)-3-amino-N-{[1-(7-klor-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}tiofen-2-karboksamid (100 mg) kao blijedo žuta čvrsta tvar, talište 200-202ºC, [α]D -30ºC (c=0,224, etanol). Trifluoroacetic acid (10 ml) was added to a suspension of 3-amino-N-(1-tert.butoxycarbonyl-4-piperidylmethyl)thiophene-2-carboxamide (3.8 g) in dichloromethane (100 ml) and the mixture was stirred for 18 hours at room temperature. The solvent is removed in vacuo, and the residue is dissolved in acetonitrile (100 ml). Potassium carbonate (1.4 g), triethylamine (4 ml) and (R)-7-chloro-1,4-benzodioxane-2 are added to this solution. -ylmethyl 4-toluenesulfonate (3.5 g). The mixture is mixed and heated for 3 days under relux. The mixture was cooled and filtered and the solvent was removed in vacuo. An oil is obtained which is dissolved in dichloromethane (100 ml) and washed with water (2 x 50 ml). This solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by vacuum chromatography on silica gel, eluting with dichloromethane, then with a 19:1 mixture of dichloromethane and industrial metalized spirit. The appropriate fractions were combined, the solvent was removed in vacuo to give a pale yellow solid which was triturated with ether. (S)-3-amino-N-{[1-(7-chloro-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}thiophene-2-carboxamide (100 mg) is obtained as pale yellow solid, mp 200-202ºC, [α]D -30ºC (c=0.224, ethanol).

Primjer 18 Example 18

Trietiamin 0,47 ml) doda se k suspenziji 2-metilpiridin-3-karboksilne kiseline (0,46 g) u diklormetanu i smjesu se ohladi u ledenoj vodi. Uz miješanje doda se etil kloroformat (0,33 ml) i smjesu se pusti zagrijati na sobnu temperaturu tijekom 18 sati. Doda se (S)-4-(aminometil)-1-(7-klor-1,4-benzodioksan-2-ilmetil)-piperidin (1,0 g) i miješanje se nastavi tijekom 24 sata. Otapalo se ispari i ostatak se trituira s vodom, skupi se filtracijom i očistiti vakuumskom kromatografijom preko silika gela ispirući s 3:1, zatim s 2:1, zatim s 1:1 mješavinom etil acetata i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se još uvijek nečist proizvod. Ponovljenom vakuumskom kromatografijom preko silika gela ispirući s mješavinom 10:1 diklormetana i metanola, zatim s 18:1:1 mješavinom diklormetana, metanola i trietilamina, zatim uklanjanjem otapala u vakuumu iz odgovarajućih frakcija, dobije se (S)-N-{[1-(7-klor-(1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metilpiridin-3-karboksamid (330 mg) kao bezbojna čvrsta tvar, talište 133-136ºC, [α]D-46,6ºC (c=0,837, metanol). Triethiamine 0.47 ml) was added to a suspension of 2-methylpyridine-3-carboxylic acid (0.46 g) in dichloromethane and the mixture was cooled in ice water. Ethyl chloroformate (0.33 ml) was added with stirring and the mixture was allowed to warm to room temperature for 18 hours. (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-piperidine (1.0 g) was added and stirring was continued for 24 hours. The solvent is evaporated and the residue is triturated with water, collected by filtration and purified by vacuum chromatography over silica gel, washing with 3:1, then with 2:1, then with 1:1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. A still impure product is obtained. Repeated vacuum chromatography over silica gel, washing with a 10:1 mixture of dichloromethane and methanol, then with a 18:1:1 mixture of dichloromethane, methanol and triethylamine, then by removing the solvent in a vacuum from the corresponding fractions, gives (S)-N-{[1 -(7-chloro-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methylpyridine-3-carboxamide (330 mg) as a colorless solid, melting point 133-136ºC, [α] D-46.6ºC (c=0.837, methanol).

Primjer 19 Example 19

Otopinu 2-klorpiridin-3-karboksilne kiseline (4,09 g) i 1-metilmorfolina (2,7 ml) u diklormetanu (100 ml) miješa se u atmosferi dušika pri -5ºC i kap po kap doda se etil kloroformat (2,4 ml). Nakon 10 minuta doda se N-benziliden-1-(4-piridil)metilamin (5,0 g) u diklormetanu (25 ml) i miješanje se nastavi 2 sata pri -5ºC i zatim 18 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu i ostatak se miješa 5 sati s otopinom kalijevog hidrogen sulfata (1 M; 250 ml). Mješavinu se filtrira i filtrat se ispere s diklormetanom (2 x 150 ml), zaluži se s vodenom otopinom natrijevog hidroksida (5 M) i ekstrahira se s diklormetanom (3 x 150 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se 4-(aminometil)-1-(2-klor-3-piridilkarbonil)-piperidina (4,81 g) onečišćen s nešto 1-metilmorfolina. Taj materijal upotrebljava se u slijedećoj reakciji bez daljnjeg čišćenja. A solution of 2-chloropyridine-3-carboxylic acid (4.09 g) and 1-methylmorpholine (2.7 ml) in dichloromethane (100 ml) was stirred under a nitrogen atmosphere at -5ºC and ethyl chloroformate (2, 4 ml). After 10 minutes N-benzylidene-1-(4-pyridyl)methylamine (5.0 g) in dichloromethane (25 ml) was added and stirring was continued for 2 hours at -5ºC and then for 18 hours at room temperature. The solvent was removed in vacuo and the residue was stirred for 5 hours with a solution of potassium hydrogen sulfate (1 M; 250 ml). The mixture was filtered and the filtrate was washed with dichloromethane (2 x 150 ml), basified with aqueous sodium hydroxide (5 M) and extracted with dichloromethane (3 x 150 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated. 4-(Aminomethyl)-1-(2-chloro-3-pyridylcarbonyl)-piperidine (4.81 g) contaminated with some 1-methylmorpholine is obtained. This material is used in the next reaction without further purification.

Smjesu sirovog proizvoda iz prethodne reakcije (4,75 g), kalijevog karbonata (12,93 g) i (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonata (6,64 g) u suhom acetonitrilu (10 ml) miješa se i grije 48 sati pod refluksom. Smjesu se ohladi i filtrira i otapalo se odstrani u vakuumu. Dobije se ulje koje se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 15:1 diklormetana i industrijskog metiliranog špirita. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-4-[N-(7-klor-1,4-benzodioksan-2-ilmetil)aminometil]-1-(2-klornikotinoil)-piperidin etan solvat (2,49 g) kao guma. A mixture of the crude product from the previous reaction (4.75 g), potassium carbonate (12.93 g) and (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (6.64 g) in dry of acetonitrile (10 ml) is stirred and heated for 48 hours under reflux. The mixture was cooled and filtered and the solvent was removed in vacuo. An oil is obtained which is purified by vacuum chromatography over silica gel, washing with a 15:1 mixture of dichloromethane and industrial methylated spirits. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-chloronicotinoyl)-piperidine ethane solvate (2.49 g) was obtained as a gum.

Mješavinu proizvoda iz prethodne reakcije (2,49 g), industrijskog metilirajućeg špirita (10 ml), vodene otopine amonijaka (spec. gustoće 0,88; 100 ml) i praha od bakrene žice (0,5 g) miješa se i grije u tlačnoj posudi pri 150ºC tijekom 18 sati. Nakon hlađenja doda se diklormetan (400 ml) i vodu (400 ml) i smjesu se filtrira kroz Cellite, ispere s vodom (4 x 50 ml) i zatim s diklormetanom (4 x 50 ml). Slojevi filtrata se odvoje i vodeni sloj se ekstrahira s diklormetanom (400 ml). Sjedinjeni organski ekstrakti se osuše preko magnezijevog sulfata, zatim se otapalo ispari, nakon čega ostane crveno ulje koje se očisti vakuumskom kromatografijom preko silika gela ispirući s 9:1 mješavinom diklormetana i etanola. Odgovarajuće frakcije se sjedine i otapalo se ispari u vakuumu. Dobije se proizvod kao crvena guma koji se otopi u vrućem etanolu (20 ml) i doda se vruću otopinu fumarne kiseline (340 mg) i etanola (5 ml). Otapalo se odstrani u vakuumu i ostatak se triturira s eterom. Dobije se racemični 1-(2-aminonikotinoil)-4-[N-(7-klor-1,4-benodioksan-2-ilmetil)aminometil]piridin 1,6-fumarat 0,7 hidrat 0,7 etanol solvat (0,85), talište 110ºC, [α]D -0ºC. A mixture of the product from the previous reaction (2.49 g), industrial methylating spirit (10 ml), aqueous ammonia solution (spec. density 0.88; 100 ml) and copper wire powder (0.5 g) is stirred and heated in pressure vessel at 150ºC for 18 hours. After cooling, dichloromethane (400 ml) and water (400 ml) were added and the mixture was filtered through Cellite, washed with water (4 x 50 ml) and then with dichloromethane (4 x 50 ml). The filtrate layers were separated and the aqueous layer was extracted with dichloromethane (400 mL). The combined organic extracts are dried over magnesium sulfate, then the solvent is evaporated, after which a red oil remains, which is purified by vacuum chromatography over silica gel, eluting with a 9:1 mixture of dichloromethane and ethanol. The appropriate fractions are combined and the solvent is evaporated in vacuo. The product is obtained as a red gum which is dissolved in hot ethanol (20 ml) and a hot solution of fumaric acid (340 mg) and ethanol (5 ml) is added. The solvent is removed in vacuo and the residue is triturated with ether. Racemic 1-(2-aminonicotinoyl)-4-[N-(7-chloro-1,4-benodioxan-2-ylmethyl)aminomethyl]pyridine 1,6-fumarate 0.7 hydrate 0.7 ethanol solvate (0 .85), melting point 110ºC, [α]D -0ºC.

Primjer 20 Example 20

Mješavinu 2-fluor-6-trifluormetilbenzaldehida (25 g) i vodenog natrijevog hidroksida (0,5 M; 866 ml) miješa se i grije 43 sata pri 80ºC u atmosferi dušika. Nakon hlađenja otopinu se ispere s eterom (2 x 350 ml), zakiseli s koncentriranom klorovodičnom kiselinom, zatim se ekstrahira s eterom (2 x 500 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s 95:5 mješavinom diklormetana i metanola. Odgovarajući ekstrakti se sjedine, otapalo se odstrani u vakuumu i dobije se 2-hidroksi-6-trifluormetilbenzaldehid (6,2 g) kao ulje. A mixture of 2-fluoro-6-trifluoromethylbenzaldehyde (25 g) and aqueous sodium hydroxide (0.5 M; 866 ml) was stirred and heated for 43 hours at 80°C under a nitrogen atmosphere. After cooling, the solution is washed with ether (2 x 350 ml), acidified with concentrated hydrochloric acid, then extracted with ether (2 x 500 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated in vacuo. The residue was purified by vacuum chromatography over silica gel eluting with a 95:5 mixture of dichloromethane and methanol. The appropriate extracts were combined, the solvent removed in vacuo to give 2-hydroxy-6-trifluoromethylbenzaldehyde (6.2 g) as an oil.

Smjesu proizvoda iz prethodne reakcije (5,95 g), (R)-glicidil 4-toluensulfonata (6,05 g) i kalijevog karbonata (4,3 g) u dimetilformamidu (150 ml) miješa se i grije 24 sata pri 60ºC. Ohlađenu otopinu se prelije u ledenu vodu (600 ml) i ekstrahira se s eterom (3 x 300 ml). Sjedinjeni organski ekstrakti isperu se s otopinom soli (2 x 400 ml), osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se čvrstu tvar (7,0 g) koju se prekristalizira iz etera (30 ml). Dobije se (R)-2-(2,3-epoksipropoksi)-6-trifluormetilbenzaldehid (5,4 g) kao čvrsta tvar. A mixture of the product from the previous reaction (5.95 g), (R)-glycidyl 4-toluenesulfonate (6.05 g) and potassium carbonate (4.3 g) in dimethylformamide (150 ml) is stirred and heated for 24 hours at 60ºC. The cooled solution was poured into ice water (600 ml) and extracted with ether (3 x 300 ml). The combined organic extracts were washed with brine (2 x 400 ml), dried over magnesium sulfate and the solvent was removed in vacuo. A solid (7.0 g) is obtained, which is recrystallized from ether (30 ml). (R)-2-(2,3-epoxypropoxy)-6-trifluoromethylbenzaldehyde (5.4 g) was obtained as a solid.

Mješavinu proizvoda iz prethodne reakcije (5,4 g) i 3-klorperbenzojeve kiseline (57%, 13,84 g) u kloroformu (300 ml) miješa se i grije 18 sati pod refluksom, zatim se pusti stajati 3 dana pri sobnoj temperaturi prije nego se prelije u zasićenu vodenu otopinu natrijevog hidrogen karbonata (400 ml). Mješavinu se ekstrahira s diklormetanom (200 ml), organsku fazu se ispere s vodenom otopinom natrijevog bikarbonata (3 x 400 ml), zatim se osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se sirov 2-(2,3-epoksipropoksi)-6-trifluormetilfenil format (6,26 g) kao žuta čvrsta tvar. A mixture of the product from the previous reaction (5.4 g) and 3-chloroperbenzoic acid (57%, 13.84 g) in chloroform (300 ml) is stirred and heated for 18 hours under reflux, then allowed to stand for 3 days at room temperature before rather, it is poured into a saturated aqueous solution of sodium hydrogen carbonate (400 ml). The mixture is extracted with dichloromethane (200 ml), the organic phase is washed with aqueous sodium bicarbonate solution (3 x 400 ml), then dried over magnesium sulfate and the solvent is removed in vacuo. The crude 2-(2,3-epoxypropoxy)-6-trifluoromethylphenyl formate (6.26 g) was obtained as a yellow solid.

Otopinu sirovog proizvoda iz prethodne reakcije (6,26 g) u metanolu (75 ml) doda se kap po kap k otopini natrijevog metoksida pripremljenom otapanjem metalnog natrija (0,69 g) u metanolu (75 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi. Zatim se pusti stajati 24 sata. Otapalo se ispari u vakuumu, a ostatak se doda k vodi (300 ml). Mješavinu se ekstrahira s etil acetatom (3 x 200 ml), sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se smeđe ulje koje se očisti vakuumskom kromatografijom preko silika gela ispirući s 1:1 mješavinom petrol etera (vrelište 40-60ºC) i etil acetata. Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-8-trifluormetil-1,4-benzodioksan-2-ilmetanol (1,80 g) kao žuto ulje. A solution of the crude product from the previous reaction (6.26 g) in methanol (75 ml) was added dropwise to the sodium methoxide solution prepared by dissolving sodium metal (0.69 g) in methanol (75 ml) and the mixture was stirred for 18 hours at room temperature. Then let it stand for 24 hours. The solvent is evaporated in vacuo and the residue is added to water (300 ml). The mixture was extracted with ethyl acetate (3 x 200 ml), the combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. A brown oil is obtained, which is purified by vacuum chromatography over silica gel, washing with a 1:1 mixture of petroleum ether (boiling point 40-60ºC) and ethyl acetate. The appropriate extracts were combined and the solvent was removed in vacuo. (S)-8-trifluoromethyl-1,4-benzodioxan-2-ylmethanol (1.80 g) was obtained as a yellow oil.

4-toluensulfonil klorid (1,29 g) doda se k otopini proizvoda i prethodne reakcije (1,26 g) u suhom piridinu (50 ml) pri -10ºC u atmosferi dušika i smjesu se pusti zagrijati na sobnu temperaturu uz miješanje tijekom 18 sati. Doda se još 4-toluensulfonil klorida (0,7 g) i nastavi se miješati još 3 dana, zatim se smjesu prelije u razrijeđenu klorovodičnu kiselinu (200 ml) i ekstrahira s etil acetatom (2 x 300 ml). Sjedinjeni ekstrakti se isperu s razrijeđenom solnom kiselinom ( 2 x 200 ml), osuše preko magnezijevog sulfonata i otapalo se odstrani u vakuumu. Dobije se (R)-8-trifluormetil-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (1,27 g). 4-toluenesulfonyl chloride (1.29 g) was added to a solution of the product and the previous reaction (1.26 g) in dry pyridine (50 ml) at -10ºC under a nitrogen atmosphere and the mixture was allowed to warm to room temperature with stirring for 18 hours . More 4-toluenesulfonyl chloride (0.7 g) is added and stirring is continued for another 3 days, then the mixture is poured into dilute hydrochloric acid (200 ml) and extracted with ethyl acetate (2 x 300 ml). The combined extracts are washed with diluted hydrochloric acid (2 x 200 ml), dried over magnesium sulfonate and the solvent is removed in vacuo. (R)-8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1.27 g) is obtained.

Trifluoroctenu kiselinu (15 ml) doda se k otopini 2-amino-N-[(1-tercbutoksikarbonil-4-piperidil)metil]piridin-3-karboksiamida (1,5 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (15 ml), zatim se smjesu miješa 3 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, a ostatak se otopi u acetonitrilu (100 ml). K toj otopini doda se kalijev karbonat (4,5 g) i proizvod iz prethodne reakcije (1,27 g), i smjesu se miješa i grije 72 sata pod refluksom. Ohlađenu smjesu se filtrira i čvrstu tvar se ispere s etil acetatom (200 ml). Filtrat se ispari u vakuumu, a ostatak se očisti vakuumskom kromatografijom na silika gelu ispirući s 3:1 mješavinom etil acetata i metanola. Odgovarajuće frakcije se sjedine, otapalo se odstrani u vakuumu i dobije se (S)-2-amino-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (870 mg) kao bezbojna čvrsta tvar, talište 101-103ºC, [α]D -16,2ºC (c=0,56, diklormetan). Trifluoroacetic acid (15 ml) was added to a solution of 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (1.5 g; prepared as described in Example 2) in dichloromethane ( 15 ml), then the mixture is stirred for 3 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in acetonitrile (100 ml). Potassium carbonate (4.5 g) and the product from the previous reaction (1.27 g) were added to this solution, and the mixture was stirred and heated for 72 hours under reflux. The cooled mixture was filtered and the solid was washed with ethyl acetate (200 ml). The filtrate is evaporated in vacuo, and the residue is purified by vacuum chromatography on silica gel, eluting with a 3:1 mixture of ethyl acetate and methanol. The corresponding fractions were combined, the solvent was removed in vacuo to give (S)-2-amino-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl} pyridine-3-carboxamide (870 mg) as a colorless solid, mp 101-103ºC, [α]D -16.2ºC (c=0.56, dichloromethane).

Primjer 21 Example 21

Mješavinu 5-brom-hidroksibenzaldehida (68,75 g), (R)-glicidil 4-toluensulfonata (65 g) i kalijevog karbonata (47,3 g) u suhom dimetilformamidu (1,5 l) miješa se i grije u atmosferi dušika 24 sata pri 60ºC, zatim se ohladi i pusti stajati pri sobnoj temperaturi 24 sata. Smjesu se prelije u vodu (2 l) i zatim se ekstrahira s eterom (4 x 400 ml). Sjedinjeni organski ekstrakti se isperu s otopinom soli (4 x 500 ml), osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se ulje koje se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 4:1 petrol etera (vrelište 60-80ºC) i etil acetata. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu, dobije se ulje koje se trituira s eterom (150 ml). Dobije se (R)-5-brom-2-(2,3-epoksipropoksi)benzaldehid (43,3 g) kao bezbojna čvrsta tvar. A mixture of 5-bromo-hydroxybenzaldehyde (68.75 g), (R)-glycidyl 4-toluenesulfonate (65 g) and potassium carbonate (47.3 g) in dry dimethylformamide (1.5 L) was stirred and heated under a nitrogen atmosphere. 24 hours at 60ºC, then cool and let stand at room temperature for 24 hours. The mixture is poured into water (2 L) and then extracted with ether (4 x 400 ml). The combined organic extracts were washed with brine (4 x 500 ml), dried over magnesium sulfate and the solvent was removed in vacuo. An oil is obtained which is purified by vacuum chromatography over silica gel, washing with a 4:1 mixture of petroleum ether (boiling point 60-80ºC) and ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo to give an oil which was triturated with ether (150 ml). (R)-5-bromo-2-(2,3-epoxypropoxy)benzaldehyde (43.3 g) was obtained as a colorless solid.

Otopinu proizvoda iz prethodne reakcije (42,6 g) i 3-klorperbenzojeve kiseline (86%, 69,4 g) u kloroformu (1,5 g) rije se 24 sata pod refluksom, zatim se pusti stajati 48 sati pri sobnoj temperaturi. otopinu se ispere s vodom (5 x 300 ml), sa zasićenom vodenom otopinom natrijevog bikarbonata (600 ml) i s otopinom soli (2 x 500 ml), zatim se osuši preko magnezijevog sulfonata i otapalo se odstrani u vakuumu. Dobije se sirov (R)-5-brom-(2,3-epoksipropoksi)fenil format (47,8 g) kao žuto ulje koje kristalizira stajanjem. A solution of the product from the previous reaction (42.6 g) and 3-chloroperbenzoic acid (86%, 69.4 g) in chloroform (1.5 g) was dissolved for 24 hours under reflux, then allowed to stand for 48 hours at room temperature. the solution is washed with water (5 x 300 ml), with a saturated aqueous solution of sodium bicarbonate (600 ml) and with a salt solution (2 x 500 ml), then it is dried over magnesium sulfonate and the solvent is removed in vacuo. The crude (R)-5-bromo-(2,3-epoxypropoxy)phenyl formate (47.8 g) is obtained as a yellow oil which crystallizes on standing.

Otopinu sirovog proizvoda iz prethodne reakcije (47,6 g) u metanolu (400 ml) doda se kap po kap k otopini natrijevog metoksida pripremljenog otapanjem metalnog natrija (5,3 g) u metanolu (400 ml) i smjesu se miješa 18 sati pri sobnoj temperaturi. Zatim se otapalo odstrani u vakuumu, k ostatku se doda vodu (800 ml) i smjesu se ekstrahira s etil acetatom (4 x 500 ml), sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se smeđe ulje koje se očisti vakuumskom kromatografijom preko silika gela ispirući s 5:1 mješavinom petrol etera (vrelište 60-80ºC) i etil acetata. Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-7-brom-1,4-benzodioksan-2-ilmetanol (29,2 g) kao narančasto ulje. A solution of the crude product from the previous reaction (47.6 g) in methanol (400 ml) was added drop by drop to a solution of sodium methoxide prepared by dissolving metallic sodium (5.3 g) in methanol (400 ml) and the mixture was stirred for 18 hours at room temperature. Then the solvent was removed in vacuo, water (800 ml) was added to the residue and the mixture was extracted with ethyl acetate (4 x 500 ml), the combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. A brown oil is obtained, which is purified by vacuum chromatography over silica gel, washing with a 5:1 mixture of petroleum ether (boiling point 60-80ºC) and ethyl acetate. The appropriate extracts were combined and the solvent was removed in vacuo. (S)-7-bromo-1,4-benzodioxan-2-ylmethanol (29.2 g) was obtained as an orange oil.

4-toluensulfonil klorid (7,63 g) doda se k ledeno hladnoj otopini proizvoda iz prethodne reakcije (7,0 g) u piridinu (50 ml) i smjesu se miješa 20 sati pri sobnoj temperaturi, zatim se smjesu prelije u klorovodičnu kiselinu (1 M; 200 ml) i ekstrahira s etil acetatom (3 x 200 ml). Sjedinjeni ekstrakti se isperu s klorovodičnom kiselinom (1 M; 200 ml) osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se prekristalizira iz mješavine 3:1 etera i etil acetata. Dobije se (R)-7-brom-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (6,9 g) kao bezbojna čvrsta tvar. 4-toluenesulfonyl chloride (7.63 g) is added to an ice-cold solution of the product from the previous reaction (7.0 g) in pyridine (50 ml) and the mixture is stirred for 20 hours at room temperature, then the mixture is poured into hydrochloric acid ( 1 M; 200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined extracts were washed with hydrochloric acid (1 M; 200 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The residue is recrystallized from a 3:1 mixture of ether and ethyl acetate. (R)-7-bromo-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (6.9 g) was obtained as a colorless solid.

Trifluoroctenu kiselinu (17 ml) doda se k otopini 2-amino-N[(1-terc.butoksikarbonil-4-piperidil)metil]piridin-3-karboksamid (2,5 g; pripremljen kako je opisano u primjeru 2) u diklormetanu 817 ml), zatim se smjesu miješa 2 sata pri sobnoj temperaturi. otapalo se odstrani u vakuumu, a ostatak se otopi u acetonitrilu (170 ml). Doda se kalijev karbonat (7,6 g) i proizvod iz prethodne reakcije (2,21 g), i smjesu se miješa i grije 24 sata pod refluksom i zatim pusti stajati 36 sati pri sobnoj temperaturi prije nego se prelije u vodenu otopinu natrijevog hidroksida (5 M; 300 ml). Mješavinu se ekstrahira s etil acetatom (100 ml) i organsku fazu se ispere s klorovodičnom kiselinom (1 M; 2 x 300 ml). Sjedinjeni kiseli ekstrakti se zaluže s vodenom otopinom natrijevog hidroksida (5 M; 200 ml) i mješavinu se ekstrahira s etil acetatom (3 x 200 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se bezbojnu čvrstu tvar (1,3 g) koju se prekristalizira iz mješavine 5:1 etil acetata i petrol etera (vrelište 40-60ºC) (7 ml). Dobije se (S)-2-amino-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metilpiridin-3-karboksamid (0,82 mg), talište 158-160ºC, [α]D -25,5ºC (c=79, dikormetan). Trifluoroacetic acid (17 ml) was added to a solution of 2-amino-N[(1-tert.butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.5 g; prepared as described in Example 2) in dichloromethane 817 ml), then the mixture is stirred for 2 hours at room temperature. the solvent was removed in vacuo and the residue was dissolved in acetonitrile (170 ml). Potassium carbonate (7.6 g) and the product from the previous reaction (2.21 g) were added, and the mixture was stirred and heated under reflux for 24 hours and then allowed to stand for 36 hours at room temperature before being poured into aqueous sodium hydroxide solution (5 M; 300 ml). The mixture was extracted with ethyl acetate (100 ml) and the organic phase was washed with hydrochloric acid (1 M; 2 x 300 ml). The combined acid extracts were basified with aqueous sodium hydroxide solution (5 M; 200 ml) and the mixture was extracted with ethyl acetate (3 x 200 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. A colorless solid (1.3 g) is obtained which is recrystallized from a 5:1 mixture of ethyl acetate and petroleum ether (bp 40-60ºC) (7 ml). (S)-2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methylpyridine-3-carboxamide (0, 82 mg), melting point 158-160ºC, [α]D -25.5ºC (c=79, dicormethane).

Primjer 22 Example 22

Otopinu 3-piridilkarbonil klorid hidroklorida (3,87 g) u diklormetanu (100 ml) doda se suspenziji 4-(amino-metil)-1-terc.butoksikarbonilpiperidina (5,0 g) i kalijevog karbonata (10 g) u diklormetanu (100 ml), i smjesu se miješa 2 sata pri sobnoj temperaturi prije nego se izlije u vodu (500 ml). Organski sloj se ispere s vodom(250 ml), osuši preko magnezijevog sulfata i otapalo se ispari. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 2:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se N-[(1-terc.butoksikarbonil-4-piperidil)-metil]piridin-3-karboksamid (3,22 g) kao narančasto ulje. To a solution of 3-pyridylcarbonyl chloride hydrochloride (3.87 g) in dichloromethane (100 ml) was added a suspension of 4-(amino-methyl)-1-tert.butoxycarbonylpiperidine (5.0 g) and potassium carbonate (10 g) in dichloromethane ( 100 ml), and the mixture was stirred for 2 hours at room temperature before being poured into water (500 ml). The organic layer is washed with water (250 ml), dried over magnesium sulfate and the solvent is evaporated. The residue was purified by vacuum chromatography over silica gel, eluting with a 2:1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]pyridine-3-carboxamide (3.22 g) was obtained as an orange oil.

Trifluoroctenu kiselinu (10 ml) doda se k otopini proizvoda iz prethodne reakcije (0,95 g) u diklormetanu (25 ml) i zatim se smjesu miješa 2 sata. Otapalo se odstrani u vakuumu, a ostatak se otopi u suhom acetonitrilu (25 ml) Doda se kalijev karbonat (5,0 g) i (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (1,0g i smjesu se miješa i grije 24 sata pod refluksom. Ohlađenu smjesu se filtrira i filtrat se ispari u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (0,75 mg), talište 172-4ºC, [α]D -48ºC (c=0,9945, metanol). Trifluoroacetic acid (10 ml) was added to a solution of the product from the previous reaction (0.95 g) in dichloromethane (25 ml) and the mixture was then stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in dry acetonitrile (25 ml) Potassium carbonate (5.0 g) and (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1 .0g and the mixture was stirred and heated for 24 hours under reflux. The cooled mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by vacuum chromatography over silica gel eluting with a 20:1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed. (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (0.75 mg) is obtained, melting point 172-4ºC, [α]D -48ºC (c=0.9945, methanol).

Primjer 23 Example 23

Trifluoroctenu kiselinu (10 ml) doda se k otopini N-[(1-terc.butoksikarbonil-4-piperidil)-metil]piridin-8-karboksamida (1,51 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (50 ml), zatim se smjesu miješa 2 sata u acetonitrilu (30 ml). Doda se kalijev karbonat (3,0 g) i (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (1,51 g) i smjesu se miješa i grije 24 sata pod refluksom. Smjesu se filtrira i otapalo se odstrani u vakuumu. ostatak se otopi u diklormetanu i otopinu se ispere s vodom (2 x 50 ml), i zatim se osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 100:1 i zatim sa 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil} kinolin-3-karboksamid (1,33 mg), talište 51-54ºC, [α]D -39,7ºC (c=0,7230, metanol). Trifluoroacetic acid (10 ml) was added to a solution of N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]pyridine-8-carboxamide (1.51 g; prepared as described in Example 2) in dichloromethane (50 ml), then the mixture was stirred for 2 hours in acetonitrile (30 ml). Potassium carbonate (3.0 g) and (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1.51 g) were added and the mixture was stirred and heated under reflux for 24 hours. The mixture is filtered and the solvent is removed in vacuo. the residue was dissolved in dichloromethane and the solution was washed with water (2 x 50 ml), and then dried over magnesium sulfate and the solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, eluting with a mixture of 100:1 and then with 20:1 dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}quinoline-3-carboxamide (1.33 mg), melting point 51- 54ºC, [α]D -39.7ºC (c=0.7230, methanol).

Primjer 24 Example 24

Trifluoroctenu kiselinu (10 ml) doda se k otopini N-[(1-terc.butoksikarbonil-4-piperidil)-metil]piridin-8-karboksamida (1,56 g); u diklormetanu (50 ml), zatim se smjesu miješa 2 sata i zatim se otapalo odstrani u vakuumu, a ostatak se otopi u acetonitrilu (10 ml).Doda se kalijev karbonat (5,0 g) i zatim se otopinu (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonata (1,7 g) u suhom actonitrilu (15 ml) i smjesu se miješa i grije 6 sati pod refluksom. Ohlađenu smjesu se prelije u vodu i zatim ekstrahira s diklormetanom (2 x 100 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (100 ml) i osuše preko magnezijevog sulfata. Otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (1,04 mg), kao bezbojna čvrsta tvar, talište 52-54ºC, [α]D -35,3ºC (c=1,024, metanol). Trifluoroacetic acid (10 ml) was added to a solution of N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]pyridine-8-carboxamide (1.56 g); in dichloromethane (50 ml), then the mixture was stirred for 2 hours and then the solvent was removed in vacuo, and the residue was dissolved in acetonitrile (10 ml). Potassium carbonate (5.0 g) was added and then (R)- 7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1.7 g) in dry actonitrile (15 ml) and the mixture is stirred and heated under reflux for 6 hours. The cooled mixture was poured into water and then extracted with dichloromethane (2 x 100 ml). The combined extracts are washed with brine (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, eluting with a 20:1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (1.04 mg) is obtained as a colorless solid substance, mp 52-54ºC, [α]D -35.3ºC (c=1.024, methanol).

Primjer 25 Example 25

Mješavinu (S)-4-(aminometil)-1-(7-klor-1,4-benzodioksan-2-ilmetil)piridina (0,57 g) i 6-metilpridin-2-karboksilne kiseline (,027 g) u ksilenu (50 ml) grije se 6 sati pod separatorom vode po Dean i Starku. Otapalo se odstrani u vakuumu, a ostatak se otopi u diklormetanu. Otopinu se ispere s vodom (2 x 100 ml), i osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se ulje (0,15 g) koje se otopi u metanolu (10 ml) i zatim doda furmarnu kiselinu (,0,04 g). Otapalo se odstrani u vakuumu i dobije se (S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-2-karboksamid difumarat (0,19 mg), kao čvrsta tvar bež boje, talište 81-3ºC, [α]D -39,6ºC (c=0,389, metanol). A mixture of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)pyridine (0.57 g) and 6-methylpyridine-2-carboxylic acid (.027 g) in xylene (50 ml) is heated for 6 hours under a water separator according to Dean and Stark. The solvent is removed in vacuo, and the residue is dissolved in dichloromethane. The solution is washed with water (2 x 100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, eluting with a 20:1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. An oil (0.15 g) is obtained, which is dissolved in methanol (10 ml) and then furmaric acid (0.04 g) is added. The solvent was removed in vacuo to give (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-2-carboxamide difumarate (0, 19 mg), as a beige solid, melting point 81-3ºC, [α]D -39.6ºC (c=0.389, methanol).

Primjer 26 Example 26

2-metoksipiridin-3-karboksilnu kiselinu (4,86 g) doda se u obrocima k tionil kloridu (50 ml) i zatim se smjesu miješa i grije 2 sata pod refluksom. Nakon hlađenja suvišak tionil klorida se odstrani u vakuumu, a ostatak se otopi u diklormetanu (100 ml). Doda se otopinu 4-(aminometil)-1-terc.butoksikarbonilpiperidina (7,3 g) u diklormetanu (100 ml) i smjesu se miješa 4 sata pri sobnoj temperaturi. Zatim se prelije u vodu (200 ml). Organsku fazu se ispere s vodom (100 ml), vodenom otopinom oksalne kiseline (2 M; 2 x 100 ml), klorovodičnom kiselinom (1 M; 100 ml), vodenom otopinom natrijevog hidrogen karbonata (2 M; 2 x 150 ml), zatim s vodom, i osuši se preko magnezijevog sulfata. Otapalo se odstrani u vakuumu, a ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 1:1 etil acetata i petrol etera (vrelište 60-80°C). Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se N-[(1-terc.butoksikarbonil-4-piperidil)-metil]-2-metoksipiridin-3-karboksamid (2,06 g). 2-Methoxypyridine-3-carboxylic acid (4.86 g) was added portionwise to thionyl chloride (50 ml) and the mixture was then stirred and heated under reflux for 2 hours. After cooling, the excess thionyl chloride is removed in vacuo, and the residue is dissolved in dichloromethane (100 ml). A solution of 4-(aminomethyl)-1-tert.butoxycarbonylpiperidine (7.3 g) in dichloromethane (100 ml) was added and the mixture was stirred for 4 hours at room temperature. Then it is poured into water (200 ml). The organic phase is washed with water (100 ml), aqueous oxalic acid solution (2 M; 2 x 100 ml), hydrochloric acid (1 M; 100 ml), aqueous sodium hydrogen carbonate solution (2 M; 2 x 150 ml), then with water, and dried over magnesium sulfate. The solvent is removed in a vacuum, and the residue is purified by vacuum chromatography over silica gel, washing with a 1:1 mixture of ethyl acetate and petroleum ether (boiling point 60-80°C). The appropriate fractions were combined and the solvent was removed in vacuo. N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]-2-methoxypyridine-3-carboxamide (2.06 g) was obtained.

Trifluoroctenu kiselinu (10 ml) doda se k otopini proizvoda iz prethodne reakcije (2,06 g) u diklormetanu (25 ml), zatim se smjesu miješa 2,5 sata i zatim se otapalo odstrani u vakuumu, a ostatak se otopi u suhom acetonitrilu (50 ml). Doda se kalijev karbonat (12 g) zatim se otopinu (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensulfonata (2,33 g) u suhom acetonitrilu (15 ml) i smjesu se miješa i grije 24 sata pod refluksom. Ohlađenu smjesu se filtrira i otapalo se odstrani u vakuumu. Ostatak se otopi u diklormetanu (200 ml), zatim se otopinu ispere s vodom (2 x 200 ml) i osuši preko magnezijevog sulfata. Otapalo se odstrani u vakuumu, a ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 20:1 diklormetana i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}-2-metoksipiridin-3-karboksamid 0,6 hidroklorid 0,9 hidrat (1,21 mg), kao čvrsta tvar, talište 72-75ºC, [α]D -47,3ºC (c=0,226, metanol). Trifluoroacetic acid (10 ml) was added to a solution of the product from the previous reaction (2.06 g) in dichloromethane (25 ml), then the mixture was stirred for 2.5 hours and then the solvent was removed in vacuo, and the residue was dissolved in dry acetonitrile (50 ml). Potassium carbonate (12 g) is added, then (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (2.33 g) is dissolved in dry acetonitrile (15 ml) and the mixture is stirred and heated 24 hours under reflux. The cooled mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in dichloromethane (200 ml), then the solution is washed with water (2 x 200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by vacuum chromatography over silica gel, washing with a 20:1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. Obtained (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-2-methoxypyridine-3-carboxamide 0.6 hydrochloride 0.9 hydrate (1.21 mg), as a solid, mp 72-75ºC, [α]D -47.3ºC (c=0.226, methanol).

Primjer 27 Example 27

Iz otopine butil-litija u heksanu (2,4 M; 55,6 ml) otapalo se ispari u vakuumu pri sobnoj temperaturi i dobije se viskozno ulje koje se u atmosferi dušika ohladi na -78°C i polako se doda prethodno ohlađenu otopinu kalijevog terc.butoksida (15,6 g) u tetrahidrofuranu (280 ml). Zatim se kap po kap doda 3,4-difluoranisol (20,0 g), održavajući temperaturu reakcije ispod -60°C. Dobije se smeđu otopinu. Miješa se 2 sata pri -78°C, doda se suhi dimetilformamid (10,8 ml) i smjesu se pusti zagrijati na sobnu temperaturu tijekom 18 sati. Doda se vodu (200 ml) i smjesu se ekstrahira s eterom (3 x 300 ml). Sjedinjeni ekstrakti se isperu s vodenom otopinom litijevog klorida (40%; 100 ml) i osuše preko magnezijevog sulfata. otapalo se ispari i dobije se narančasto ulje (23 g) koje se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 9:1 petrol etera (vrelište 40-60°C) i etil acetata. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se 2,3-difluor-6-metoksi-benzaldehid (10,1 g) kao žuta čvrsta tvar. From a solution of butyllithium in hexane (2.4 M; 55.6 ml), the solvent is evaporated in a vacuum at room temperature and a viscous oil is obtained, which is cooled to -78°C in a nitrogen atmosphere and slowly added to a previously cooled solution of potassium of tert.butoxide (15.6 g) in tetrahydrofuran (280 ml). Then 3,4-difluoroanisole (20.0 g) was added dropwise, keeping the reaction temperature below -60°C. A brown solution is obtained. It is stirred for 2 hours at -78°C, dry dimethylformamide (10.8 ml) is added and the mixture is allowed to warm to room temperature for 18 hours. Water (200 ml) was added and the mixture was extracted with ether (3 x 300 ml). The combined extracts are washed with an aqueous solution of lithium chloride (40%; 100 ml) and dried over magnesium sulfate. the solvent is evaporated and an orange oil (23 g) is obtained which is purified by vacuum chromatography over silica gel eluting with a 9:1 mixture of petroleum ether (boiling point 40-60°C) and ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo. 2,3-difluoro-6-methoxy-benzaldehyde (10.1 g) was obtained as a yellow solid.

Otopinu bor tribromida u diklormetanu (1,0 M; 197,4 ml) doda se k otopini 2,3-difluor-6-metoksibenzaldehida (10,4 g; pripremljen kako je gore opisano) u diklormetanu (100 ml), u atmosferi dušika uz miješanje pri temperaturi ispod -20°C. Dobivenu otopinu se pusti preko noći zagrijati na sobnu temperaturi, zatim se doda metanol (200 ml) i zatim vodu (100 ml). Smjesu se grije 2 sata pri 40°C. Vodeni sloj se odvoji i ekstrahira s diklormetanom (2 x 300 ml). Sjedinjene organske otopine se ekstrahiraju s vodenom otopinom natrijevog hidroksida (1 M; 3 x 400 ml) i sjedinjeni ekstrakti se zakisele s koncentriranom klorovodičnom kiselinom, zatim se ekstrahiraju s etil acetatom (3 x 300 ml). Ti sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se 2,3-difluor-6-hidroksibenzaldehid (8,12 g) kao čvrsta tvar. A solution of boron tribromide in dichloromethane (1.0 M; 197.4 mL) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (10.4 g; prepared as described above) in dichloromethane (100 mL), under an atmosphere of nitrogen with stirring at a temperature below -20°C. The resulting solution is allowed to warm overnight at room temperature, then methanol (200 ml) and then water (100 ml) are added. The mixture is heated for 2 hours at 40°C. The aqueous layer was separated and extracted with dichloromethane (2 x 300 ml). The combined organic solutions were extracted with aqueous sodium hydroxide (1 M; 3 x 400 ml) and the combined extracts were acidified with concentrated hydrochloric acid, then extracted with ethyl acetate (3 x 300 ml). These combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. 2,3-difluoro-6-hydroxybenzaldehyde (8.12 g) was obtained as a solid.

Mješavinu proizvoda iz prethodne reakcije (8,1 g), (R)-glicidil 4-toluensulfonata (11,4 g) i kalijevog karbonata (7,03 g) u dimetilformamidu (250 ml) miješa se i grije u atmosferi dušika 3 dana pri 60°C. Doda se vodu (300 ml) i zatim se ekstrahira s eterom (3 x 400ml). Sjedinjeni organski ekstrakti se isperu s vodenom otopinom litijevog klorida (40%; 200 ml), vodom (200 ml) i osuše preko magnezijevog sulfata. otapalo se ispari i dobije se ulje kojem se doda mješavinu 1:1 etera i petrol etera (vrelište 40-60°C) čime se dobije narančastu otopinu koju se odvoji dekantiranjem od tamno smeđeg ulja. Otapalo se odstrani u vakuumu, a iz narančaste otopine dobije se (R)-6-(2,3-epoksipropoksi)-2,3-difluorbenzaldehid (9,0 g) kao ulje. A mixture of the product from the previous reaction (8.1 g), (R)-glycidyl 4-toluenesulfonate (11.4 g) and potassium carbonate (7.03 g) in dimethylformamide (250 ml) was stirred and heated under a nitrogen atmosphere for 3 days at 60°C. Add water (300 ml) and then extract with ether (3 x 400 ml). The combined organic extracts were washed with an aqueous solution of lithium chloride (40%; 200 ml), water (200 ml) and dried over magnesium sulfate. the solvent is evaporated and an oil is obtained to which a 1:1 mixture of ether and petroleum ether (boiling point 40-60°C) is added, resulting in an orange solution which is separated by decantation from the dark brown oil. The solvent was removed in vacuo and the orange solution gave (R)-6-(2,3-epoxypropoxy)-2,3-difluorobenzaldehyde (9.0 g) as an oil.

Otopinu proizvoda iz prethodne reakcije (9,0 g) i 3-klorperbenzoeve kiseline (57%), 26,47 g) u kloroformu (500 ml) grije se 18 sati pod refluksom. Doda se zasićenu vodenu otopinu natrijevog hidrogen karbonata (300 ml) i diklormetan (500 ml). Organski sloj se odvoji i ispere sa zasićenom vodenom otopinom natrijevog hidrogen karbonata (3 x 300 ml), otopinom soli (300 ml) i osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Dobije se sirov (R)-6-2,3-epoksipropoksi)-2,3-difluorfenil format (11,9 g) kao čvrsta tvar. A solution of the product from the previous reaction (9.0 g) and 3-chloroperbenzoic acid (57%), 26.47 g) in chloroform (500 ml) is heated under reflux for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (300 ml) and dichloromethane (500 ml) were added. The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate solution (3 x 300 ml), brine (300 ml) and dried over magnesium sulfate and the solvent is removed in vacuo. The crude (R)-6-2,3-epoxypropoxy)-2,3-difluorophenyl formate (11.9 g) was obtained as a solid.

Otopinu sirovog proizvoda iz prethodne reakcije (11,9 g) u metanolu (140 ml) doda se kap po kap u atmosferu dušika uz miješanje k otopini natrijevog metoksida pripremljenog otapanjem metalnog natrija (1,22 g) u metnaolu (140 ml) i otopinu se pusti stajati 18 sati pri sobnoj temperaturi. Zatim se otapalo odstrani u vakuumu, k ostatku se doda vodu (500 ml) i zatim se smjesu ekstrahira s etil acetatom (3 x 400 ml). Sjedinjeni ekstrakti se isperu s otopinom soli (300 ml), osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom prelo silika gela ispirući s 1:1 mješavinom etil acetata i petrol etera (vrelište 40-60°C). Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-7,8-difluor-1,4-benzodioksan-2-ilmetanol (0,7 g) kao ulje. A solution of the crude product from the previous reaction (11.9 g) in methanol (140 ml) was added dropwise under a nitrogen atmosphere with stirring to a solution of sodium methoxide prepared by dissolving metallic sodium (1.22 g) in methanol (140 ml) and the solution let stand for 18 hours at room temperature. The solvent was then removed in vacuo, water (500 ml) was added to the residue and the mixture was then extracted with ethyl acetate (3 x 400 ml). The combined extracts were washed with brine (300 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The residue is purified by vacuum chromatography on prelo silica gel, washing with a 1:1 mixture of ethyl acetate and petroleum ether (boiling point 40-60°C). The appropriate extracts were combined and the solvent was removed in vacuo. (S)-7,8-difluoro-1,4-benzodioxan-2-ylmethanol (0.7 g) was obtained as an oil.

4-toluensulfonil klorid (0,74 g) u diklormetanu (10 ml) doda se kap po kap k otopini proizvoda iz prethodne reakcije (0,7 g) i 4-(dimetilamino)piridina (0,52 g) u diklormetanu (10 ml) pri 0°C u atmosferi dušika. Otopina se miješa 2 sata pri 0°C, zatim 1 sat pri sobnoj temperaturi. Zatim se doda vodu (50 ml) i smjesu se ekstrahira s diklormetanom (3 x 100 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se ispari. Dobije se (R)-7,8-difluor-1,4-benzodioksan-2-ilmetil 4-toluensulfonat (1,1 g) kao žuto ulje koje kristalizira stajanjem. 4-toluenesulfonyl chloride (0.74 g) in dichloromethane (10 ml) was added dropwise to a solution of the product from the previous reaction (0.7 g) and 4-(dimethylamino)pyridine (0.52 g) in dichloromethane (10 ml) at 0°C in a nitrogen atmosphere. The solution is stirred for 2 hours at 0°C, then for 1 hour at room temperature. Water (50 ml) was then added and the mixture was extracted with dichloromethane (3 x 100 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated. (R)-7,8-difluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (1.1 g) is obtained as a yellow oil which crystallizes on standing.

Trifluoroctenu kiselinu (10 ml) doda se k otopini 2-amino-N-[(1-terc.butoksikarbonil-4-piperidil)-metil]piridin-3-karboksamida (1,48 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (10 ml), zatim se smjesu miješa 5 sati pri sobnoj temperaturi. Otapalo se odstrani u vakuumu, a ostatku se doda kalijev karbonat (4,3 g), kalijev jodid (10 ml) i proizvod iz prethodne reakcije (1,1 g) u acetonitrilu (100 ml), i smjesu se miješa i grije 16 sati pod refluksom. Iz ohlađene smjese otapalo se odstrani u vakuumu i ostatak se podijeli između zasićene vodene otopine natrijevog hidrogen karbonata (300 ml) i etilacetata (300 ml). Vodeni sloj se dalje ekstrahira s etilacetatom (3 x300 ml) i sjedinjeni organski ekstrakti se isperu sa zasićenom otopinom soli (400 ml) i osuše preko magnezijevog sulfata. Otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 9:1 etil acetata i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-2-amino-N-{[1-(7,8-difluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil} piridin-3-karboksamid 0,2 etilacetat solvat kao čvrsta tvar žućkaste boje (0,47 mg), talište 127-128ºC, [α]D-25,8ºC (c=80, diklormetan). Trifluoroacetic acid (10 ml) was added to a solution of 2-amino-N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]pyridine-3-carboxamide (1.48 g; prepared as described in Example 2) in dichloromethane (10 ml), then the mixture was stirred for 5 hours at room temperature. The solvent was removed in vacuo, and potassium carbonate (4.3 g), potassium iodide (10 ml) and the product from the previous reaction (1.1 g) in acetonitrile (100 ml) were added to the residue, and the mixture was stirred and heated to 16 hours under reflux. The solvent was removed from the cooled mixture in vacuo and the residue was partitioned between a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and ethyl acetate (300 ml). The aqueous layer was further extracted with ethyl acetate (3 x 300 ml) and the combined organic extracts were washed with brine (400 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-2-amino-N-{[1-(7,8-difluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl} pyridine-3-carboxamide 0.2 ethyl acetate is obtained solvate as a yellowish solid (0.47 mg), mp 127-128ºC, [α]D-25.8ºC (c=80, dichloromethane).

Primjer 28 Example 28

Mješavinu pirogalol karbonata (8,2 g), (S)-epiklorhidrina (5,0 g) i suhog piridina (0,2 ml) u suhom etil acetatu (50 ml) grije se 2 sata pod refluksom. Otapalo se odstrani u vakuumu, doda se vodu (30 ml) i smjesu se grije 30 minuta pod refluksom. Kap po kap doda se kalijev hidroksid (10 g) u vodu (20 ml) i smjesu se grije u atmosferi dušika 30 minuta pod refluksom. Ohlađenu smjesu se razrijedi s vodom (100 ml), zakiseli s klorovodičnom kiselinom (5 M), zatim se ekstrahira s etil acetatom (3 x 200 ml). Sjedinjeni ekstrakti se isperu s vodom (2 x 100 ml) i osuše preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s 1:1 mješavinom etil acetata i petrol etera (vrelište 60-80°C), zatim samo s etil acetatom. Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-8-hiroksi-1,4-benzodioksan-2-ilmetanol (0,8 g). A mixture of pyrogallol carbonate (8.2 g), (S)-epichlorohydrin (5.0 g) and dry pyridine (0.2 ml) in dry ethyl acetate (50 ml) was heated under reflux for 2 hours. The solvent was removed in vacuo, water (30 ml) was added and the mixture was heated under reflux for 30 minutes. Potassium hydroxide (10 g) was added dropwise to water (20 ml) and the mixture was heated under a nitrogen atmosphere for 30 minutes under reflux. The cooled mixture is diluted with water (100 ml), acidified with hydrochloric acid (5 M), then extracted with ethyl acetate (3 x 200 ml). The combined extracts were washed with water (2 x 100 ml) and dried over magnesium sulfate and the solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, washing with a 1:1 mixture of ethyl acetate and petroleum ether (boiling point 60-80°C), then only with ethyl acetate. The appropriate extracts were combined and the solvent was removed in vacuo. This gives (S)-8-hydroxy-1,4-benzodioxan-2-ylmethanol (0.8 g).

Anhidrid trifluormetansulfonske kiseline (2,48 g) doda se kap po kap u atmosferi dušika uz miješanje k otopini proizvoda iz prethodne reakcije (0,8 g) i 4-(dimetilamino)piridina (0,64 g) u diklormetanu (50 ml) pri 0°C. Smjesu se pusti zagrijati na sobnu temperaturu i miješanje se nastavi 18 sati. Zatim se ispere s vodom (100 ml) i osuši preko magnezijevog sulfata. otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s diklormetnaom. Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se (R)-8-(trifluormetansulfoniloksi-1,4-benzodioksan-2-ilmetil trifluormetansulfonat (1,10 g). Trifluoromethanesulfonic acid anhydride (2.48 g) was added dropwise under a nitrogen atmosphere with stirring to a solution of the product from the previous reaction (0.8 g) and 4-(dimethylamino)pyridine (0.64 g) in dichloromethane (50 ml). at 0°C. Allow the mixture to warm to room temperature and continue mixing for 18 hours. Then it is washed with water (100 ml) and dried over magnesium sulfate. the solvent was removed in vacuo. The residue is purified by vacuum chromatography over silica gel, washing with dichloromethane. The appropriate extracts were combined and the solvent was removed in vacuo. (R)-8-(trifluoromethanesulfonyloxy-1,4-benzodioxan-2-ylmethyl trifluoromethanesulfonate (1.10 g) is obtained.

Trifluoroctenu kiselinu (5 ml) doda se k otopini 2-amino-N-[(1-terc.butoksikarbonil-4-piperidil)-metil]piridin-3-karboksamida (0,9 g; pripremljen kako je opisano u primjeru 2) u diklormetanu (25 ml), zatim se smjesu miješa 2 sata pri sobnoj temperaturi. Otapalo se odstrani u vakuumu. Ostatak se otopi u suhom acetonitrilu (25 ml), doda se kalijev karbonat (5,o g), zatim otopinu proizvoda iz prethodne reakcije (1,03 g) u suhom acetonitrilu (10 ml). Smjesu se miješa i grije 1,5 sata pod refluksom, ohladi, filtrira i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući mješavinom 20:1 etil acetata i metanola. Odgovarajuće frakcije se sjedine i otapalo se odstrani u vakuumu. Dobije se (S)-2-amino-N-{[1-(8-trifluormetansulfoniloksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]-metil}piridin-3-karboksamid (0,17 g) kao bezbojna čvrsta tvar, talište 52-55ºC, [α]D -21,9ºC (c=0,2925 rmetanol). Trifluoroacetic acid (5 ml) was added to a solution of 2-amino-N-[(1-tert.butoxycarbonyl-4-piperidyl)-methyl]pyridine-3-carboxamide (0.9 g; prepared as described in Example 2) in dichloromethane (25 ml), then the mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo. The residue is dissolved in dry acetonitrile (25 ml), potassium carbonate (5.0 g) is added, followed by a solution of the product from the previous reaction (1.03 g) in dry acetonitrile (10 ml). The mixture is stirred and heated for 1.5 hours under reflux, cooled, filtered and the solvent is removed in vacuo. The residue is purified by vacuum chromatography over silica gel, eluting with a 20:1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. (S)-2-amino-N-{[1-(8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}pyridine-3-carboxamide (0.17 g) is obtained as a colorless solid, melting point 52-55ºC, [α]D -21.9ºC (c=0.2925 rmethanol).

Primjer 29 Example 29

N,N’-karbonil diimidazola (6,58 g) doda se k suspenziji piridin-2-karboksilne kiseline (5,0 g) u diklormetanu (75 ml) i miješa se u atmosferi dušika pri sobnoj temperaturi. Miješanje se nastavi sve dok prestane razvijanje plina (pribl. 2 sata) i tada se dodan N-benziliden-1-(4-piperidil)metilamin (8,2 g) i reakcijsku smjesu miješa se 18 sati. Otapalo se ispari i dobije se viskozno žuto ulje, koje se zatim miješa 18 sati s vodenom otopinom kalijevog hidrogen sulfata (1 M; 200 ml), Smjesu se ispere s diklormetanom (2 x 250 ml) i s vodenom otopinom natrijevog hidroksida (5 M) namjesti se pH 14. Zatim se ekstrahira s diklormetanom (3 x 250 ml). Sjedinjeni ekstrakti se osuše preko magnezijevog sulfata i otapalo se odstrani u vakuum. Dobije se 4-(aminometil)-1-(2-piridilkarbonil)-piperidin (5,2 g) kao viskozno žuto ulje. N,N'-carbonyl diimidazole (6.58 g) was added to a suspension of pyridine-2-carboxylic acid (5.0 g) in dichloromethane (75 ml) and stirred under nitrogen at room temperature. Stirring was continued until gas evolution ceased (approx. 2 hours) at which time N-benzylidene-1-(4-piperidyl)methylamine (8.2 g) was added and the reaction mixture was stirred for 18 hours. The solvent is evaporated and a viscous yellow oil is obtained, which is then mixed for 18 hours with an aqueous solution of potassium hydrogen sulfate (1 M; 200 ml), the mixture is washed with dichloromethane (2 x 250 ml) and with an aqueous solution of sodium hydroxide (5 M) the pH is adjusted to 14. It is then extracted with dichloromethane (3 x 250 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. 4-(Aminomethyl)-1-(2-pyridylcarbonyl)-piperidine (5.2 g) was obtained as a viscous yellow oil.

Mješavinu proizvoda iz prethodne reakcije (3,0 g), (R)-7-klor-1,4-benzodioksan-2-ilmetil 4-toluensullfonata (4,86 g), kalijevog jodida (200 mg) i kalijevog karbonata (9,45 g) u suhom acetonitrilu miješa se i grije 18 sati pod refluksom. Smjesu se ohladi i filtrira i otapalo se odstrani u vakuumu. Ostatak se očisti vakuumskom kromatografijom preko silika gela ispirući s mješavinom 20:1 diklormetana i industrijskog metiliranog špirita. Odgovarajući ekstrakti se sjedine i otapalo se odstrani u vakuumu. Dobije se žuto ulje (2,87 g), koje se otopi u vrućem etanolu (10 ml) i pomiješa s otopinom fumarne kiseline (0,76 g) u vrućem etanolu (10 ml). Otapalo se odstrani u vakuumu i ostatak se triturira s eterom (250 ml). Dobije se 4-[N-(7-klor-1,4-benzodioksan-2-ilmetil)-aminometil]-1-(2-piridilkarbonil)piperidin 1,2 fumarat 0,5 hidrat 0,4 etanol solvat kao čvrsta tvar, talište pribl. 55°C, [α]D -42,9ºC (c=0,8135, rmetanol). A mixture of the product from the previous reaction (3.0 g), (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (4.86 g), potassium iodide (200 mg) and potassium carbonate (9 .45 g) in dry acetonitrile is mixed and heated for 18 hours under reflux. The mixture was cooled and filtered and the solvent was removed in vacuo. The residue was purified by vacuum chromatography over silica gel eluting with a 20:1 mixture of dichloromethane and industrial methylated spirit. The appropriate extracts were combined and the solvent was removed in vacuo. A yellow oil (2.87 g) was obtained, which was dissolved in hot ethanol (10 ml) and mixed with a solution of fumaric acid (0.76 g) in hot ethanol (10 ml). The solvent was removed in vacuo and the residue was triturated with ether (250 ml). 4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)-aminomethyl]-1-(2-pyridylcarbonyl)piperidine 1,2 fumarate 0.5 hydrate 0.4 ethanol solvate is obtained as a solid , melting point approx. 55°C, [α]D -42.9ºC (c=0.8135, rmethanol).

Primjer 30 - 52 Example 30 - 52

Slijedeći spojevi formule I dobiveni su metodom opisanom u pojedinostima u nastavku The following compounds of formula I were prepared by the method described in detail below

[image] [image]

Kao polazni materijal bilo je upotrebljeno 6 različitih spojeva formule XLVII (g je 1; A je O, B je O; U je metilen; X je etilen; V je metilen; R5 je H; i R1 je 7-metil, 7-brom, 7-klor, 7-fluor, 8-trifluormetil ili 8-klor) i 5 različitih spojeva formule R-HET-CO2H (HET je 3-piridil i R je H, 2-metil, 6-(1-pirolil), 2-metiltio ili 5-brom. 6 different compounds of formula XLVII were used as starting material (g is 1; A is O, B is O; U is methylene; X is ethylene; V is methylene; R5 is H; and R1 is 7-methyl, 7-bromo , 7-chloro, 7-fluoro, 8-trifluoromethyl or 8-chloro) and 5 different compounds of the formula R-HET-CO2H (HET is 3-pyridyl and R is H, 2-methyl, 6-(1-pyrrolyl), 2-methylthio or 5-bromo.

Spoj formule R-HET-CO2H (0,1 mmol) odvagne se u reakcijsku vijalu od 2 ml. Spoj formule XLVII (0,1 mmol) otopi se u suhom diklormetanu (0,5 ml) i doda u vijalu. Zatim se doda N,N’-diizopropilkarbodiimid (0,1 mmol) i smjesu se miješa u atmosferi dušika 5,5 sati pri 20°C. Otapalo se odstrani izlaganjem vijale smanjenom pritisku u vakuumskom egzikatoru tijekom 20 minuta. Doda se digol (1 ml) i miješanje se nastavi dok se reakcijski ostatak ponovno otopi/resuspendira (koncentracija 0,1 M). 20µl tog materijala doda se k digolu (1,98 ml). Dobije se otopinu koja je ispitana s obzirom na svojstvo afiniteta vezanja receptora za 5HTA1, α1 i D2 receptore. The compound of the formula R-HET-CO2H (0.1 mmol) is weighed into a 2 ml reaction vial. The compound of formula XLVII (0.1 mmol) was dissolved in dry dichloromethane (0.5 ml) and added to the vial. N,N'-diisopropylcarbodiimide (0.1 mmol) was then added and the mixture was stirred under a nitrogen atmosphere for 5.5 hours at 20°C. The solvent was removed by exposing the vial to reduced pressure in a vacuum desiccator for 20 minutes. Digol (1 ml) was added and stirring was continued until the reaction residue was redissolved/resuspended (concentration 0.1 M). 20 µl of this material is added to digol (1.98 ml). A solution is obtained which has been tested with respect to the property of receptor binding affinity for 5HTA1, α1 and D2 receptors.

Primjer 53 Example 53

Upotreba spojeva predloženog izuma u proizvodnji farmaceutskih sredstava prikazana je slijedećim opisom. U opisu pojam “aktivan sastojak” označava spoj prema izumu, i to posebno bilo koji spoj koji je krajnji proizvod jednog od prethodnih primjera. The use of the compounds of the proposed invention in the production of pharmaceutical agents is shown in the following description. In the description, the term "active ingredient" means a compound according to the invention, and in particular any compound that is the end product of one of the previous examples.

a) Kapsule a) Capsules

Kod priprave kapsula 10 masenih dijelova aktivnog spoja i 240 masenih dijelova laktoze smrvi se i pomiješa. Smjesu se puni u kapsule od tvrde želatine, pri čemu svaka kapsula sadrži jediničnu dozu dijela jedinične doze aktivnog spoja. When preparing capsules, 10 mass parts of the active compound and 240 mass parts of lactose are crushed and mixed. The mixture is filled into capsules made of hard gelatin, where each capsule contains a unit dose of part of a unit dose of the active compound.

b) Tablete b) Tablets

Tablete se pripremaju od slijedećih sastojaka. Tablets are prepared from the following ingredients.

Maseni udio Mass fraction

aktivni sastojak 10 active ingredient 10

laktoza 190 lactose 190

kukuruzni škrob 22 corn starch 22

polivinilpirolidon 10 polyvinylpyrrolidone 10

magnezijev stearat 3 magnesium stearate 3

Aktivni spoj, laktoza i nešto škroba se smrvi, pomiješa i dobivenu smjesu se granulira s otopinom polivinilpirolidona u etanolu. Suhe granule se pomiješaju s magnezijevim stearatom i ostatkom škroba. Smjesu se zatim preša u stroju za izradu tableta i dobiju se tablete od kojih svaka sadrži jediničnu dozu ili dio jedinične doze aktivnog spoja. The active compound, lactose and some starch are crushed, mixed and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granules are mixed with magnesium stearate and the rest of the starch. The mixture is then pressed in a tablet machine to form tablets, each of which contains a unit dose or part of a unit dose of the active compound.

c) Tablete s vanjskom prevlakom c) Tablets with outer coating

Tablete se pripreme gore opisanom metodom (b). Tablete se izvana prevlače na uobičajen način upotrebom otopine od 20% celuloznog acetat ftalata i 3%-tnog dietilftalata u etanol:diklormetanu (1:1). Tablets are prepared by method (b) described above. The tablets are externally coated in the usual way using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).

d) Čepići d) Suppositories

Kod priprave čepića 100 masenih dijelova aktivnog spoja umiješa se u 1300 masenih dijelova trigliceridne osnovne mase za čepiće i smjesu se oblikuje u čepiće od kojih svaki sadrži terapeutski učinkovitu količinu aktivnog sastojka. When preparing suppositories, 100 parts by mass of the active compound are mixed with 1300 parts by mass of triglyceride base mass for suppositories and the mixture is formed into suppositories, each of which contains a therapeutically effective amount of the active ingredient.

Claims

1. Spojevi formule I [image] uključiv njihove farmaceutski prihvatljive soli, naznačeni time, da A je metilen ili O; B je metilen ili O; g je 0, 1, 2, 3 ili 4; R1 predstavlja a) halogen; b) alkilnu skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; c) alkoksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; d) alkiltio skupina koja ima po potrebi supstituirana s jednim ili više halogenih; e) hidroksi; f) aciloksi skupina koja ima 1 do 3 ugljikova atoma; g) hidroksimetil; h) cijano; i) alkanoilnu skupinu koja ima 1 do 6 ugljikovih atoma; j) alkoksikarbonilnu skupinu koja ima 2 do 6 ugljikovih atoma; k) karbamoilnu skupinu ili karbamoilmetilnu skupinu od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; l) sulfamoilnu ili sulfamoilmetilnu skupinu od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; ili m) alkilsulfoniloksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; n) furilnu skupinu; o) amimo skupinu po potrebi supstituirana s jednom ili dvije alkilne skupine kojih svaka ima 1 do 3 ugljikova atoma; ili dvije susjedne R1 skupine zajedno s ugljikovim atomom kojeg dodiruju tvore benzenski prsten, pri čemu, ako je g 2, 3 ili 4, supstituenti predstavljeni sa R1 mogu biti jednaki ili različiti: R2 je H, alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, ili alkoksi skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; R3 i R4 koji su jednaki ili različiti, jesu H, ili alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih; U je alkilneksi lanac koji ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više alkilenskih skupina od kojih svaki ima 1 do 3 ugljikova atoma; Q predstavlja dvovalentnu skupinu formula IIa, IIb ili IIc [image] u kojima V je veza ili alkilenski lanac koji ima 1 do 3 ugljikova toma po potrebi supstituirana s jednim ili više alkilenskih skupina od kojih svaka ima 1 do 3 ugljikova atoma; V' je alkilenski lanac koji ima 2 do 5 ugljikovih atoma po potrebi supstituirana s jednim ili više alkilnih skupina od kojih svaka ima 1 do 3 ugljikova atoma; X je alkelinski lanac koji ima O do 2 ugljikova atoma, a X' je alkelinski lanac koji ima 1 do 4 ugljikova atoma, pod uvjetom da broj ugljikovih atoma u X i X' iznosi 3 ili 4; R5 je H ili alkilna skupina koja ima 1 do 3 ugljikova atoma; i T predstavlja skupinu CO.HET u kojoj HET je 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-tienil, 2- ili 3-furil, 2-, 3- ili 7-benzo[b]tienil, 2-, 3- ili 4-piperidil, 3-, 4- ili 5-pirazolil, 4- ili 5-triazolil, 5-tetrazolil, 2-, 3-, 4- ili 8-kinolil, 2- ili 4- kinazolil, 3-, 4- ili 5-izoksazolil ili 2-, 4- ili 5-oksazolil, 3-, 4- ili 5-izotiazolil ili 2-, 4- ili 5-tiazolil, od kojih svako po potrebi može biti supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine a) halogen, b) alkilna skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, c) alkoksi skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, d) alkiltio skupina koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, e) hidroksi, f) aciloksi skupina koja ima 1 do 3 ugljikova atoma, g) hidroksimetil, h) cijano, i) alkanoilna skupina koja ima 1 do 6 ugljikovih atoma, j) alkoksikarbonilna skupina koja ima 2 do 6 ugljikovih atoma, k) karbamoilna skupina ili karbamoilmetilna skupina od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; l) sulfamoilna ili sulfamoilmetilna skupina od kojih je svaka po potrebi N-supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 3 ugljikova atoma; m) amino skupina po potrebi supstituirana s jednom ili dvije alkilne skupine od kojih svaka ima 1 do 5 ugljikova atoma; n) 1-pirolil ili o) 1-pirolidinil ili piperidino.1. Compounds of formula I [image] including their pharmaceutically acceptable salts, indicated that A is methylene or O; B is methylene or O; g is 0, 1, 2, 3 or 4; R1 represents a) halogen; b) an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens; c) an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens; d) an alkylthio group which is optionally substituted with one or more halogens; e) hydroxy; f) an acyloxy group having 1 to 3 carbon atoms; g) hydroxymethyl; h) cyano; i) an alkanoyl group having 1 to 6 carbon atoms; j) an alkoxycarbonyl group having 2 to 6 carbon atoms; k) a carbamoyl group or a carbamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; l) sulfamoyl or sulfamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; or m) an alkylsulfonyloxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens; n) furyl group; o) an amimo group optionally substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; or two adjacent R1 groups together with the carbon atom they touch form a benzene ring, whereby, if g is 2, 3 or 4, the substituents represented by R1 may be the same or different: R 2 is H, an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens, or an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens; R3 and R4, which are the same or different, are H, or an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogens; U is an alkylnexy chain having 1 to 3 carbon atoms optionally substituted with one or more alkylene groups each having 1 to 3 carbon atoms; Q represents a divalent group of formulas IIa, IIb or IIc [image] in which V is a bond or alkylene chain having 1 to 3 carbon atoms optionally substituted with one or more alkylene groups each having 1 to 3 carbon atoms; V' is an alkylene chain having 2 to 5 carbon atoms optionally substituted with one or more alkyl groups each having 1 to 3 carbon atoms; X is an alkylene chain having 0 to 2 carbon atoms, and X' is an alkylene chain having 1 to 4 carbon atoms, provided that the number of carbon atoms in X and X' is 3 or 4; R5 is H or an alkyl group having 1 to 3 carbon atoms; and T represents the group CO.HET where HET is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 7-benzo[b]thienyl, 2-, 3- or 4-piperidyl, 3-, 4- or 5-pyrazolyl, 4- or 5-triazolyl, 5-tetrazolyl, 2-, 3-, 4- or 8- quinolyl, 2- or 4-quinazolyl, 3-, 4- or 5-isoxazolyl or 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl, from each of which, if necessary, can be substituted with one or more substituents selected from the group they comprise a) halogen, b) an alkyl group having 1 to 3 carbon atoms, optionally substituted with one or more halogens, c) an alkoxy group having 1 to 3 carbon atoms, optionally substituted with one or more halogens, d) an alkylthio group having 1 to 3 carbon atoms, optionally substituted with one or more halogens, e) hydroxy, f) an acyloxy group having 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) an alkanoyl group having 1 to 6 carbon atoms, j) alkoxycarbonyl group having 2 to 6 carbon atoms, k) carbamoyl group or carbamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; l) sulfamoyl or sulfamoylmethyl group, each of which is optionally N-substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms; m) an amino group optionally substituted with one or two alkyl groups, each of which has 1 to 5 carbon atoms; n) 1-pyrrolyl or o) 1-pyrrolidinyl or piperidino.

2. Spojevi formule I prema zahtjevu 1, naznačeni time, da obadva, A i B su O; g je 1 ili 2; R1 predstavlja halogen (na primjer fluor, klor ili brom), alkilnu skupinu s jednim ili više halogenih, alkoksi skupina koja ima 1 do 3 ugljikova atoma, alkilsulfoniloksi skupinu koja ima 1 do 3 ugljikova atoma po potrebi supstituirana s jednim ili više halogenih, ili hidroksi; R2 je H ili alkilna skupina koja ima 1 do 3 ugljikova atoma: R3 i R4, koji mogu biti jednaki ili različiti, jesu H ili metil; U je metilen; Q je skupina formule IIa ili IIc, V je metilen; R5 je H ili metil; obadva, X i X' su etilen; i HET je 2-, 3- ili 4-piridil, 8-kinolinil, ili 2-tienil, od kojih svako po potrebi može biti supstituiran s jednim ili više supstituenata odabranih između metila, metoksi, trifluormetila, halogenog, metiltio, 1-pirolila, ili amino skupine po potrebi supstituirane s jednom ili dvije alkilne skupine, od kojih svaka ima 1 do 3 ugljikova atoma.2. Compounds of formula I according to claim 1, characterized in that both A and B are O; g is 1 or 2; R1 represents a halogen (for example fluorine, chlorine or bromine), an alkyl group with one or more halogens, an alkoxy group having 1 to 3 carbon atoms, an alkylsulfonyloxy group having 1 to 3 carbon atoms optionally substituted with one or more halogens, or hydroxy; R 2 is H or an alkyl group having 1 to 3 carbon atoms: R 3 and R 4 , which may be the same or different, are H or methyl; U is methylene; Q is a group of formula IIa or IIc, V is methylene; R 5 is H or methyl; both X and X' are ethylene; and HET is 2-, 3- or 4-pyridyl, 8-quinolinyl, or 2-thienyl, each of which may optionally be substituted with one or more substituents selected from methyl, methoxy, trifluoromethyl, halogen, methylthio, 1-pyrrolyl , or amino groups optionally substituted with one or two alkyl groups, each of which has 1 to 3 carbon atoms.

3. Spojevi formule I prema zahtjevu 1 ili 2, naznačeni time, da HET je 2-piridil, 3-piridil, 8-kinolinil, ili 2-tienil od kojih svaki po potrebi može biti supstituiran s amino skupinom, metilom metoksi, 1- pirolilom, tirfluormetilom, metiltio ili s bromom.3. Compounds of formula I according to claim 1 or 2, characterized in that HET is 2-pyridyl, 3-pyridyl, 8-quinolinyl, or 2-thienyl, each of which can be substituted with an amino group, methyl methoxy, 1- pyrrolyl, trifluoromethyl, methylthio or with bromine.

4. Spojevi formule I prema bilo kojem od prethodnih zahtjeva, naznačeni time, da HET je 2-piridil, ili 3-pridil po potrebi supstituiran s amino skupinom.4. Compounds of formula I according to any of the preceding claims, characterized in that HET is 2-pyridyl, or 3-pyridyl optionally substituted with an amino group.

5. Spojevi formule I prema zahtjevu 1, naznačeni time, da su odabrani iz skupine koju čine: 2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-2-karboksamid; 2-amino-N-{[1-(7-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}kinolin-8-karboksamid; N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; 2-amino-N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-metoksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-2-karboksamid; 2-amino-N-{[1-(8-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-metilpiridin-3-karboksamid; 3-amino-N-{[1-(1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}tiofen-2-karboksamid; 3-amino-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}ziofen-2-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metilpiridin-3-karboksamid; 1-(2-aminonikotinoil)-4-[N-7-klor-1,4-benzodioksan-2-ilmetil)aminometilpiperidin; 2-amino-N-{[1-(8-tetrafluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}kinolin-8-karboksamid; N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-metilpiridin-2-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-metoksipiridin-3-karboksamid; 2-amino-N-{[1-(7,8-difluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-amino-N-{[1-(8-trifluormetansulfoniloksi-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 4-[N-(7-klor-1,4-benzodioksan-2-ilmetil)aminometil]-1-(2-piridilkarbonil)-piperidin; N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-metil-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; 5-brom-N-{[1-(7-metil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-metilpiridin-3-karboksamid; N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-2(metiltio)piridin-3-karboksamid; 5-brom-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-2-(metiltio)piridin-3-karboksamid; 5-brom-N-{[1-(7-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(7-fluor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-(metiltio)piridin-3-karboksamid; N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-metil-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 6-(1-pirolil)-N-{[1-(7-brom-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 2-(metiltio)-N-{[1-(8-trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; 5-brom-N-{[1-(trifluormetil-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}-6-(1-pirolil)piridin-3-karboksamid; N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}2-(metiltio)piridin-3-karboksamid; 5-brom-N-{[1-(8-klor-1,4-benzodioksan-2-ilmetil)-4-piperidil]metil}piridin-3-karboksamid; i njihove farmaceutski prihvatljive soli u obliku pojedinačnih enantiomera, racemata, ili drugih smjesa enantiomera.5. Compounds of formula I according to claim 1, characterized in that they are selected from the group consisting of: 2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide; 2-amino-N-{[1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide; 2-amino-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide; 2-amino-N-{[1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-methylpyridine-3-carboxamide; 3-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide; 3-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide; 1-(2-aminonicotinoyl)-4-[N-7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethylpiperidine; 2-amino-N-{[1-(8-tetrafluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-methylpyridine-2-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxypyridine-3-carboxamide; 2-amino-N-{[1-(7,8-difluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-amino-N-{[1-(8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-pyridylcarbonyl)-piperidine; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-methyl-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}6-(1-pyrrolyl)pyridine-3-carboxamide; N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide; 5-bromo-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-methylpyridine-3-carboxamide; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide; N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-2-(methylthio)pyridine-3-carboxamide; 5-bromo-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide; N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-(methylthio)pyridine-3-carboxamide; 5-bromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-(methylthio)pyridine-3-carboxamide; N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-methyl-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 6-(1-pyrrolyl)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 2-(methylthio)-N-{[1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; 5-bromo-N-{[1-(trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6-(1-pyrrolyl)pyridine-3-carboxamide; N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2-(methylthio)pyridine-3-carboxamide; 5-bromo-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide; and their pharmaceutically acceptable salts in the form of single enantiomers, racemates, or other mixtures of enantiomers.

6. Sastav, naznačen time, da uključuje terapeutski učinkovitu količinu spoja formule I prema zahtjevu 1 ili njihove soli zajedno s farmaceutski prihvatljivim sredstvom za razređenje ili nosačem.6. A composition characterized in that it includes a therapeutically effective amount of a compound of formula I according to claim 1 or a salt thereof together with a pharmaceutically acceptable diluent or carrier.

7. Spojevi formule I prema zahtjevu 1, naznačeni time, da se upotrebljavaju za liječenje depresije, anksioznosti, psihoza, tardive diskinezije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa ili hipertrofije prostate i spastičnosti sisavaca, osobito kod ljudi.7. Compounds of formula I according to claim 1, characterized in that they are used for the treatment of depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress or prostatic hypertrophy and spasticity in mammals, especially in humans.

8. Spojevi formule I prema zahtjevu 7, naznačeni time, da se upotrebljavaju za liječenje šizofrenije.8. Compounds of formula I according to claim 7, characterized in that they are used for the treatment of schizophrenia.

9. Upotreba spojeva formule I prema zahtjevu 1, naznačena time, da se oni koriste za proizvodnju lijeka za liječenje depresije, anksioznosti, psihoza, tardive diskinezije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa ili hipertrofije prostate i spastičnosti sisavaca, osobito kod ljudi.9. The use of compounds of formula I according to claim 1, characterized by the fact that they are used for the production of a drug for the treatment of depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress or prostatic hypertrophy and mammalian spasticity, especially in humans.

10. Metoda liječenja depresije, anksioznosti, psihoza, tardive diskinezije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa ili hipertrofije prostate kod ljudi, depresije, anksioznosti, psihoza, tardive diskinezije, Parkinsonove bolesti, hipertenzije, Touretteovog sindroma, opsesivno-nasilnog ponašanja, napada panika, socijalnih fobija, kardiovaskularnih i cerebrovaskularnih poremećaja, stresa ili hipertrofije prostate i spastičnosti sisavaca, osobito kod ljudi naznačena time, da uključuje davanje terapeutski učinkovite količine spoja formule I sisavcu, osobito ljudskom biću kojem je to potrebno.10. Method of treating depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-violent behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress or prostate hypertrophy in humans, depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, obsessive-compulsive behavior, panic attacks, social phobias, cardiovascular and cerebrovascular disorders, stress or prostatic hypertrophy and mammalian spasticity, particularly in humans characterized by the administration of a therapeutically effective amount of a compound of formula I a mammal, especially a human being who needs it.

11. Metoda prema zahtjevu 10, naznačena time, da se primjenjuje za liječenje šizofrenije.11. The method according to claim 10, characterized in that it is used for the treatment of schizophrenia.

12. Postupak za pripravu spojeva formule I prema zahtjevu 1, u kojoj Q je skupina formule IIa, naznačena time, da uključuje reakciju spoja formule XXXVI [image] u kojoj D’ je H, sa spojem formule VII, u kojoj Z je otpusna skupina, na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti baze, na primjer kalijevog karbonata, i po potrebi u prisutnosti otapala, na primjer acetonitrila.12. Process for the preparation of compounds of formula I according to claim 1, in which Q is a group of formula IIa, characterized in that it includes the reaction of a compound of formula XXXVI [image] wherein D' is H, with a compound of formula VII wherein Z is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, and optionally in the presence of a solvent, for example acetonitrile.

13. Postupak za pripravu spojeva formule I prema zahtjevu 1, u kojoj Q je skupina formule IIc, naznačena time, da uključuje reakciju spoja formule XLV [image] u kojoj D’ je H, sa spojem formule VII, u kojoj Z je otpusna skupina, na primjer toluen-4-sulfoniloksi, po potrebi u prisutnosti baze, na primjer kalijevog karbonata, i po potrebi u otapalu, na primjer acetonitrilu.13. Process for the preparation of compounds of formula I according to claim 1, in which Q is a group of formula IIc, characterized in that it includes the reaction of a compound of formula XLV [image] wherein D' is H, with a compound of formula VII wherein Z is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, and optionally in a solvent, for example acetonitrile.

14. Postupak za pripravu spojeva formule I prema zahtjevu 1, u kojoj Q je skupina formule IIc, naznačena time, da uključuje reakciju spoja formule XLVII [image] a) sa spojem formule XXXIX, na primjer pirido[2,3-d]-[1,3]oksazin-2,4(1H)-dionom, po potrebi u prisutnosti otapala, na primjer 1,2-dimetoksietana; ili b) sa sredstvom za aciliranje formule X-CO.HET, u kojoj X je otpusna skupina, na primjer halogen, alkoksi, hidroksi ili alkoksikarbonil, u prisutnosti baze, na primjer trietilamina, ili sredstva koje tvori amidnu vezu, na primjer karbonil diimidazola, ili N,N-diizopropil-karbodiimida, u prikladnom otapalu kao što je diklormetan.14. Process for the preparation of compounds of formula I according to claim 1, in which Q is a group of formula IIc, characterized in that it includes the reaction of a compound of formula XLVII [image] a) with a compound of formula XXXIX, for example pyrido[2,3-d]-[1,3]oxazin-2,4(1H)-dione, if necessary in the presence of a solvent, for example 1,2-dimethoxyethane; or b) with an acylating agent of the formula X-CO.HET, in which X is a leaving group, for example halogen, alkoxy, hydroxy or alkoxycarbonyl, in the presence of a base, for example triethylamine, or an agent that forms an amide bond, for example carbonyl diimidazole, or N,N-diisopropylcarbodiimide, in a suitable solvent such as dichloromethane.