Tricyclic pyrazole derivatives as cannabinoid receptor modulators

Abstract

The present invention relates to novel compounds of general formula (I), their regioisomers, tautomeric forms, novel intermediates involved in their synthesis. The present invention also relates to a process of preparing compounds of general formula (I), their regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

1 - 15 . (canceled) 
     
     
         16 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       a tautomeric form, or pharmaceutically acceptable salt thereof, wherein Ar represents a single or fused group selected from the group consisting of aryl, heterocyclyl or heteroaryl group, optionally substituted with one or more groups selected from the group consisting of hydroxy, halo, amino or optionally substituted groups selected from the group consisting of linear or branched alkyl, monosubstituted or disubstituted amino, alkoxy or acyl group wherein the substituted alkyl, monosubstituted or disubstituted amino, alkoxy or acyl group is substituted by one or more of hydroxy, halo, amino, linear or branched alkyl, monosubstituted or disubstituted amino, alkoxy or acyl group;
 a) A represents an optionally substituted heteroaromatic group, and X is selected from the group consisting of —CH 2 —, O, S, SO, SO 2 , or NR′, where R′ represents H or an optionally substituted group selected from linear or branched alkyl and cycloalkyl group and m and n represent integers such that 1≦m+n≦3; 
 b) A represents a substituted aromatic group, and X is selected from the group consisting of O, S, SO, SO 2 , or NR′, where R′ represents H or an optionally substituted group selected from linear or branched alkyl, and cycloalkyl group and m and n represent integers such that 2≦m+n≦3; or 
 c) A represents optionally substituted heterocyclic groups, and X is selected from the group consisting of —CH 2 —, O, S, SO, SO2, or NR′, where R′ represents H or an optionally substituted group selected from linear or branched alkyl and cycloalkyl groups and m and n represent integers such that 1≦m+n≦3; 
 wherein when A is substituted, the one or more substituents are the selected from the group consisting of halogen, hydroxyl, thio, nitro, amino, cyano, or an optionally substituted group selected from linear or branched alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl, and aminoalkyl groups; wherein the substituted alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl and aminoalkyl groups are substituted by one or more of halogen, hydroxyl, thio, nitro, amino, cyano, linear or branched alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl, and aminoalkyl groups; 
 R 1  represents O, S, or the group represented by N-Q, where Q represents H or substituted alkyl; or R 1  represents the group represented by SO 2 R″, where R″ represents H, —OH, halogen or a substituted or unsubstituted group selected from alkyl, aryl, heteroaryl or heterocyclic groups; R 2  is either H or (C 1 -C 6 ) alkyl; R 3  is NR b R c  wherein R b  and R c  are the same or different and are selected from an optionally substituted group selected from alkyl, aralkyl or alkenyl or R b  and R c  together with the nitrogen atom to which they are bonded, form a saturated or unsaturated heterocyclic or heteroaromatic radical. 
 
     
     
         17 . A compound as claimed in  claim 16 , wherein the alkyl group is selected from a linear or branched alkyl group comprising from one to eight carbon atoms. 
     
     
         18 . A compound as claimed in  claim 16 , wherein the aryl group is selected from a monocyclic, bicyclic or tricyclic aryl group. 
     
     
         19 . A compound as claimed in  claim 16 , wherein the aryl group is selected from phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl group. 
     
     
         20 . A compound as claimed in  claim 16 , wherein the heterocyclyl is selected from saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic groups, containing one or more heteroatoms selected from N, O, and S. 
     
     
         21 . A compound as claimed in  claims 16 , wherein the heterocycyl group is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, and thieno piperidinyl groups. 
     
     
         22 . A compound as claimed in  claim 16 , wherein the heteroaryl group is selected from optionally fused mono, bi or tricyclic aromatic heteroaromatic groups containing one or more heteroatoms selected from O, N and S. 
     
     
         23 . A compound as claimed in  claim 16 , wherein the heteroaryl group is selected from the group consisting of pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopylimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, and benzothiazolyl group. 
     
     
         24 . A compound as claimed in  claim 16 , selected from the group consisting of:
 4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo[e]azulene-3-yl]-methylamino-methylene}-benzenesulfonamide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid-(4-hydroxy-piperidin-1-yl-amide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid pyrrolidin-1-yl amide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid morpholine-4-yl-amide and its pharmaceutically acceptable salts;   8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid (4-methyl-piperazine-1-yl)-amide and its pharmaceutically acceptable salts;   8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid pyrrolidin-1-ylamide and its pharmaceutically acceptable salts;   8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid morpholin-4-ylamide and its pharmaceutically acceptable salts;   8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid N′-cyclopropyl-hydrazide and its pharmaceutically acceptable salts;   8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid pyrrolidin-1-ylamide and its pharmaceutically acceptable salts;   1-(4-chloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   1-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza-cyclopenta [e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   8-Chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza-cyclopenta [e]azulene-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide and its pharmaceutically acceptable salts;   8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6,7-dithia-1,2-diaza-cyclopenta[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-indacene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts;   7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-indacene-3-carboxylic acid (hexahydro-cyclopenta [c]pyrrol-2-yl)-amide and its pharmaceutically acceptable salts;   8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-thia-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts; and   8-Bromo-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically acceptable salts.   
     
     
         25 . A pharmaceutical composition which comprises a compound as claimed in  claim 16  and at least one of a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         26 . A pharmaceutical composition which comprises a compound as claimed in  claim 24  and at least one of a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         27 . A method of treatment of a disease associated with cannabinoid receptors by administering a therapeutically recommended amount of the compound as claimed in  claim 16  to a mammal, in need of such treatment. 
     
     
         28 . A method of treatment of a disease associated with cannabinoid receptors by administering a therapeutically recommended amount of the composition as claimed in  claim 24  to a mammal, in need of such treatment. 
     
     
         29 . A method of treatment of a disease associated with cannabinoid receptors by administering a therapeutically recommended amount of the composition as claimed in  claim 25  to a mammal, in need of such treatment. 
     
     
         30 . A method of treatment of a disease associated with cannabinoid receptors by administering a therapeutically recommended amount of the composition as claimed in  claim 26  to a mammal, in need of such treatment. 
     
     
         31 . The method according to  claim 27 , wherein the mammal is a human. 
     
     
         32 . A process for preparing a compound of formula (I) as claimed in  claim 16 , wherein Ar, A, X, R 1 , R 2 , R 3 , m and n are as defined in  claim 16 , comprises the steps of:
 i) converting a compound of formula (2) to compound of formula (4) by reacting with a substituted hydrazine hydrochloride of formula (3),   
       
         
           
           
               
               
           
         
       
       wherein A, X, m and n are as defined in  claim 16  and R is an alkyl group
 ii) hydrolyzing the compound of formula (4) to obtain the acid of formula (5), 
 
       
         
           
           
               
               
           
         
       
       wherein A, X, m and n are as defined in  claim 16 ; and R is an alkyl group;
 iii) converting the compound of formula (5) to compound of formula (I) by treating with suitable substituted amine of formula NR 2 R 3 , where R 2  and R 3  are as defined in  claim 16 , 
 
       
         
           
           
               
               
           
         
         iv) alternatively, converting the compound of formula (5) to a compound of formula (7) by treatment with a compound of formula NH 2 Q, where Q is as defined in  claim 16 , 
       
       
         
           
           
               
               
           
         
         v) converting the compound of formula (7) to compound of formula (8) 
       
       
         
           
           
               
               
           
         
       
       where Ar, A, X, Q, m and n are as defined in  claim 16 ; and
 vi) converting the compound of formula (8) to a compound of formula (I) by treatment with a substituted amine of formula NR 2 R 3 , where R 2  and R 3  are as defined in  claim 16   
 
       
         
           
           
               
               
           
         
       
     
     
         33 . An intermediate of formula (2) 
       
         
           
           
               
               
           
         
         wherein: 
         a) A represents an optionally substituted heteroaromatic group, and X is selected from the group consisting of —CH 2 —, O, S, SO, SO 2 , or NR′, where R′ represents H or a optionally substituted group selected from linear or branched alkyl and cycloalkyl groups and m and n represent integers such that 1≦m+n≦3; 
         b) A represents a substituted aromatic group and X is selected from the group consisting of O, S, SO, SO 2 , or NR′, where R′ represents H or a optionally substituted group selected from linear or branched alkyl, and cycloalkyl group and m and n represents integers such that 2≦m+n≦3; 
         c) A represents an optionally substituted heterocyclic group, and X is selected from the group consisting of —CH 2 —, O, S, SO, SO 2 , or NR, where R′ represents H or an optionally substituted group selected from linear or branched alkyl and cycloalkyl groups and m and n represents integers such that 1≦m+n≦3; or 
         d) A represents an optionally substituted alicyclic group, and X is selected from the group consisting of —CH 2 —, O, S, SO, SO 2 , or NR′, where R′ represents H or an optionally substituted group selected from linear or branched alkyl and cycloalkyl groups and m and n represents integers such that 1≦m+n≦3; and 
         R represents an alkyl group.