Title of Invention

SUBSTITUTED 4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVES AS CANNABINOID MODULATORS

Abstract

Disclosed herein the embodiment of the invention are compounds of formula (I), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutical acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also discloses process of preparing compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutical acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "SUBSTITUTED 4,5-DIHYDRO-lH-PYRAZOLE DERIVATIVES AS CANNABINOID MODULATORS" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India. The following specification describes the invention: ZRC-MC-53-prov FIELD OF INVENTION The present invention relates to compounds of general formula (I), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process of preparing compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis. BACKGROUND & PRIOR ART Cannabinoids are present in Indian hemp Cannabis sativa and have been well known for their medicinal properties for ages. Cannabinoids as a therapeutic agents is however a recent phenomenon. (Williamson E. M. & Evans E. J. Drugs 2000 Dec; 60(6): 1303-14) Research in this area over the last decade have provided very important information on the cannabinoid receptors and their agonists and antagonists. Development of central Cannabinoid receptor ligands with lower lipophilicity.( J. Med. Chem. 2003; 46:642-645) Further cloning and isolation of two different subtypes of cannabinoid receptors – CB1 (central subtype) and CB2 (peripheral subtype) and the first endogenous ligand N-arachidonyl ethanolamine amide(AEA; anadamide (Matsuda LA et. al., Nature 1990; 346:561-4; Devane WA et. al. J. Med. Chem. 1992; 35:2065-9; Munro, S. et. al., Nature 1993, 365, 61-5) have stimulated research in this field. There has also been an increased interest among the different pharmaceutical companies in developing drugs for the treatment of diseases connected with disorders of the cannabinoid systems (Greenberg D. A., Drugs News & Perspectives 1999; 12: 458; Kulkarni S. K. & Ninan, Indian Journal of Pharmacology 2001; 33: 170-184; Piomelli D et. al., Trends Pharmacol Sci. 2000 Jun; 21(6): 218-24). Several compounds which are either CB1 &/or CB2 antagonists have been reported and are under various stages of development for e.g. SR-141716 A(Sanofi), CP-272871 (Pfizer), LY-320135 (Eli Lily), 2 ZRC-MC-53-prov AM-630 (Alexis), SR-144528(Sanofi) etc. Novel compounds which are selective CB1 and/or CB2 antagonists, their preparation and their use in medicine have also been reported in US 5925768, US 6344474, US 6028084, US 5462960, EP 0656354, US 6432984, US 6509367 Bl, US 5624941, EP1230222, EP 122952, FR 2816938, FR 2761266, FR 2800375, EP 0656354, EP 0576357, WO 2006042955, WO 03027076, WO 03026648, WO 03026647, WO 03020217, WO 0158450, WO 0185092, WO 0132663, WO 0132629 which are incorporated as references in their entirety. 1,3,5-Trisubstituted 4,5-Dihydro-lH-Pyrazole derivatives of the following general formula and having CB1 Antagonistic activity has been disclosed in US 20050171179A1. T A. i R2 K8 Synthesis of tricyclic pyrazole derivative (NESS 0327) as CB1 antagonist has been disclosed in J Pharmacology & Experimental Therapeutics, 2003, 306(1), 363-370. Synthesis and activity of tricyclic pyrazole ligands for CB1 & CB2 receptors have been disclosed in Bioorg. Med. Chem., 2003, 11, 251-263. WO 93018038 disclose the compounds of formula wherein 'A' represents H; 'E' is selected from the group H and C1-C3 alkyl; or 'A' and 'E' can be taken together to form-CH2-, -CH2CH2-, -0-, -S-, -S(O)-, -S(0)2-, NR7, -OCH2-, -SCH2-, -N(R7)CH-, substituted –CH2- and substituted -CH2CH2-, where the substitutions are independently selected from 1-2 halogens or 2-methyl; 'X' is selected from the group O and S. 'Y' is selected from the group H; C1-C6 alkyl; benzyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkyl substituted by halogen, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, N02, S(0)rR30, C(0)R30, C(0)2R30, and phenyl optionally substituted by halogen, CN, C1-C2 haloalkyl and C1-C2 haloalkoxy; C3-C6 cycloalkyl; C3-C6 halocycloalkyl; C4-C6 cycloalkylalkyl; CHO; C2-C6 alkylcarbonyl; C2-C6 alkoxycarbonyl; C2-C6 haloalkylcarbonyl; C(0)R33; C(0)2R33; C1-C6 3 ZRC-MC-53-prov alkylthio; C1-C6 haloalkylthio; phenylthio; R11OC(0)N(R12)S-; R,3(R14)NS-; N=CR9R10; OR8 and NR8R9; 'R1' 'R 2' ' R 3' 'R 4' 'R 5' 'R 7' 'R8' 'R '9' R 10' R 11' 'R 12' 'R 13' 'R 14' 'R33' R33, and 'm' 'n' are as defined in the specification for WO 93018038, US 5369121 & WO 9203421 disclose several classes of compounds suitable as insecticides, representative compounds have the following general formula (R2)rf ^N-S02Ph ' Y' is selected from the group H, C1-C6 alkyl, benzyl, C2-C6 alkoxyalkyl, CHO, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 haloalkylcarbonyl, C1-C6 alkylthio, C1-C6 haloalkylthio, phenylthio, R17OC(0)N(R)l8S and SN(R19)R20. 'R2',' R3', 'R5', are as defined in the specification. All these compounds are suitable as arthropodicidal agents useful in agriculture, not suitable for therapeutic use. WO 2006042955 describes pyridine compounds of the following general formula as antagonists of CB-1 receptor R3 CH2-Z R9 Though research in the area of cannabinoids have been going on for more than a decade there are only few medicines available which modulate the cannabinoid receptors and fewer with minor side effects. Recently, the molecule Rimonabant (SR-141716 A, Sanofi) has been approved as a treatment of obesity. Looking at the beneficial effects of cannabinoids, it would be highly desired to develop further compounds which modulate the cannabinoid receptors, having better or comparable absorption, metabolic stability, and exhibiting lesser toxicity. SUMMARY OF INVENTION The present invention describes compounds useful as modulators of cannabinoid receptors. The compounds are defined by the general formula (I) below: 4 ZRC-MC-53-prov 7* R6 (i) The compounds of the present invention mimic the actions of the cannabinoids making them useful for preventing or reversing the symptoms that can be treated with cannabis, some of its derivatives, and synthetic cannabinoids in a human or other mammalian subject. Preferably, the compounds of the present invention are selective antagonists of the cannabis CB1-receptor. OBJECTS OF THE INVENTION The main objective of the present invention thus is to provide compounds of general formula (I), their stereoisomers, tautomeric forms, their regioisomers, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures and their use in medicine. 7* (i) In an embodiment of the present invention is provided a process for the preparation of novel compounds of general formula (I), their stereoisomers, regioisomers and their tautomeric forms, novel intermediates involved in their synthesis, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. In a further embodiment is provided a method of treatment of diseases which can be treated or whose symptoms can be reversed with cannabis or their derivatives both natural and synthetic, by administering a therapeutically effective & non-toxic amount of the compound of formula (I) or their pharmaceutically acceptable compositions to the mammals. DETAILED DESCRIPTION The compounds of the present invention are defined by the general formula (I) below: ZRC-MC-53-prov R I &( R wherein R1 represents H or an alkyl group; R2 is selected from optionally substituted alkyl, aryl, cycloalkyl, fused bicycloalkyl, heterocyclyl, heteroaryl, arylalkyl, heterocyclylalkyl, or heteroarylalkyl groups; X may be selected from the groups CO, SO2; the groups representing R3-R8 may be same or different and are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, or the group (O-SO2)alkyl; The aryl groups may be selected from phenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, biphenyl groups and each of these groups may be optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, alkylthio, thioalkyl, cycloalkyl groups; the "cycloalkyl" group may be selected from a cyclic radical containing three to ten carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; the substituents on the cycloalkyl group may be selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, alkylthio, thioalkyl groups; The "heteroaryl" or "heteroaromatic" group is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups, each of these groups may be optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, cyano, alkylthio, thioalkyl groups; the "heterocyclyl" group may be selected from suitable saturated, partially saturated or unsaturated aromatic or non aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- 6 ZRC-MC-53-prov oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, groups, each of these groups may be optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, aryl, aralkyl, cyano, alkylthio, thioalkyl groups; In a further embodiment the groups, radicals described above may be selected from: - the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, n-butoxy, pentyloxy, hexyloxy, and the like; - the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; - the "alkylthio" group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio; - the group "aralkyl" represents an aryl group as defined above attached to an alkyl group as described above; - the group "heteroaralkyl" and "heterocyclyclakyl" represents heteroaryl and heterocyclyl groups respectively as defined above attached to an alkyl group as defined above. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. 7 ZRC-MC-53-prov Particularly useful compounds may be selected from (±) lH-Indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3-ylmethyl]-amide (+)-lH-Indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3-ylmethyl]-amide (-)-1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-amide (±) N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-4- trifluoromethyl-benzenesulfonamide (+)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-4- trifluoromethyl-benzenesulfonamide (-)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-4- trifluoromethyl-benzenesulfonamide (±) 5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide (+)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyI)-1 -(2,4-dichloro-phenyl)-4,5- dihydro-1 H-pyrazol-3 -ylmethy 1] -amide (-)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-1 H-pyrazol-3 -ylmethy 1] -amide (±) Propane-1-sulfonic acid 4-(2-(2,4-dichloro-phenyl)-5-{[(lH-indole-2-carbonyl)-amino]- methyl}-3,4-dihydro-2H-pyrazol-3-yl)-phenyl ester (+)-Propane-1 -sulfonic acid 4-(2-(2,4-dichloro-phenyl)-5- {[(1 H-indole-2-carbonyl)-amino]- methyl}-3,4-dihydro-2H-pyrazol-3-yl)-phenyl ester (-)-Propane-1 -sulfonic acid 4-(2-(2,4-dichloro-phenyl)-5-{[(1 H-indole-2-carbonyl)-amino]- methyl} -3,4-dihydro-2H-pyrazol-3 -yl)-phenyl ester (±) lH-Indole-2-carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-amide (+)-1 H-Indole-2-carboxylic acid [ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethy 1] -amide (-)-1 H-Indole-2-carboxylic acid [ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art. Referred 8 ZRC-MC-53-prov methods include, but are not limited to those described below, where all symbols are as defined earlier. Scheme 1: Synthesis of compound of general formula (IV) The carboxylic acid derivative of formula (V) may be synthesized as per the methods mentioned in the literature, which may be converted into the acid chloride derivative, using halogenating agents such as thionyl chloride, oxalyl chloride, phosphorous pentachloride and the like at temperatures ranging from 0-110 °C in solvents such as dichloromethane, toluene etc or their mixtures. The acid chloride obtained may further be reacted with ammonia gas at temperature varying from 0- 25 °C in solvents such as chloroform, diethyl ether, dichloromethane to afford amide derivative of formula (V) as solid after usual work up. Synthesis of compound of general formula (III) The amide derivative of formula (V) in dry dimethyl formamide may be treated with a mixture of oxalyl chloride and dimethyl formamide at 0-5 °C to afford cyano derivative of formula (III). Synthesis of compound of general formula (II) The cyano derivative of formula (III) may be reduced using reducing agents such as Lithium aluminum hydride, sodium hydride or by using methods such as hydrogenation etc. at temperature varying from 0- 40 °C in solvents such as diethyl ether, tetrahydrofuran to afford amine derivative of general formula (II). Synthesis of compound of general formula (I) 9 ZRC-MC-53-prov The amine derivative of general formula (II) may be coupled with different suitable substituted/unsubstituted heteroaryl carboxylic acid, sulfonic acid using coupling agents such as DMAP, DCC, HOBt.H20, and EDC. HC1, etc. in presence of organic bases such as TEA, pyridine, etc. in solvents such as tetrahydrofuran, dichloromethane, chloroform, etc. or converting the substituted/unsubstituted heteroaryl carboxylic acid into corresponding acid chloride derivative followed by coupling with the amine derivative of general formula (II) at ambient temperature to afford amide derivative of general formula (I). Alternatively, the amine of general formula (II) may be monoalkylated with suitable alkylating agents such as R1-halides where R1 is as defined earlier, followed by reaction with corresponding suitable carboxylic acids or sulfonyl halides to afford the corresponding compounds of general formula (I). The compound of general formula (I) may be prepared in its racemic form, or as (-)-enantiomer or (+)- enantiomer depending on the use of carboxylic acid of general formula (V) as racemic or in the corresponding optically active form. It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. The compounds of formula (1) may optionally be converted to their suitable pharmaceutically acceptable salts by processes as are known in the art. The novel compounds of the present invention can further be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The compounds of the present invention modulate the CB-1 receptor and are useful in the treatment of obesity, substance dependence, psychotic disorders and the like. Dated this 25th day of July 2006 H. SUBRAMANIAM Subramaniam, Nataraj & Associates Attorneys For the applicants 10

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