WO2008062424A2 - Substituted 4,5-dihydro-1h-pyrazole derivatives as cannabinoid modulators - Google Patents

Substituted 4,5-dihydro-1h-pyrazole derivatives as cannabinoid modulators Download PDF

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WO2008062424A2
WO2008062424A2 PCT/IN2007/000320 IN2007000320W WO2008062424A2 WO 2008062424 A2 WO2008062424 A2 WO 2008062424A2 IN 2007000320 W IN2007000320 W IN 2007000320W WO 2008062424 A2 WO2008062424 A2 WO 2008062424A2
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phenyl
dihydro
pyrazol
dichloro
ylmethyl
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WO2008062424A3 (en
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Brijesh K. Srivastava
Braj Bhushan Lohray
Vidya Bhushan Lohray
Pankaj Ramanbhai Patel
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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. and 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).
  • Novel compounds which are selective CBl 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.
  • 'A' represents H; ⁇ ' is selected from the group H and C 1 -C 3 alkyl; or 'A' and ⁇ ' can be taken together to form-CH 2 -, -CH 2 CH 2 -, -O-, -S-, -S(O)-, -S(O) 2 -, NR 7 , - OCH 2 -, -SCH 2 -, -N(R 7 )CH-, substituted -CH 2 - and substituted -CH 2 CH 2 -, 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; C 1 -C 6 alkyl; benzyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 1 -C 6 alkyl substituted by halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalk
  • 'Y' is selected from the group H, C 1 -C 6 alkyl, benzyl, C 2 -C 6 alkoxyalkyl, CHO, C 2 -C 6 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, phenylthio, R 17 OC(O)N(R) 18 S and SN(R 19 )R 20 .
  • 'R 2 ',' R 3 ', 'R 5 ' are as defined in the specification.
  • WO 2006042955 describes pyridine compounds of the following general formula as antagonists of CB-I receptor
  • FR 2888236 discloses preparation of N-[(l,5-diphenyl-lH-pyrazol-3- yl)methyl] sulfonamide derivatives and their therapeutic application as CBl cannabinoid receptor antagonists.
  • 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.
  • the compounds of the present invention are selective antagonists of the cannabis CB 1 -receptor.
  • 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 and non-toxic amount of the compound of formula (I) or their pharmaceutically acceptable compositions to the mammals.
  • R 1 represents H or an alkyl group
  • R 2 is selected from - C 1 -C 12 straight or branched alkyl chain optionally substituted by halogen, hydroxy, nitro, nitrile groups; optionally substituted aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, heterocyclylalkyl, or heteroarylalkyl groups
  • X may be selected from the groups CO, SO 2, CN, CS;
  • 'Ra' and 'Rb' may be same or different and at each occurrence may be independently selected from from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, or the group (O-SO 2 )alkyl groups;
  • 'n' and 'm' independently represents an integer from 0-4; in a preferred embodiment the substituent Ra is present in the para position of 'A'.
  • 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 preferably 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, alkylthi
  • 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, w-propyl, iso-piopyl, «-butyl, sec-butyl, tert-bntyl, arnyl, r-amyl, «-pentyl, n- hexyl, and the like;
  • 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, z ' s ⁇ -propoxy, ra-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like;
  • haloalkyl 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;
  • haloalkoxy 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;
  • alkylthio 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;
  • aralkyl represents an aryl group as defined above attached to an alkyl group as described above;
  • heteroaryl 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.
  • Particularly useful compounds may be selected from but not limited to
  • (+)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro-1 H-pyrazol-3-ylmethyl]-amide;
  • (+)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
  • (+)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro- phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide; (-)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro- ⁇ henyl)-
  • (+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide; ( ⁇ )-Cyclohexane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
  • (+)-He ⁇ tanoic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3-yl-methyl amide;
  • the carboxylic acid derivative of formula (V) synthesized according to the process known in the prior art 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 0 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 0 C in solvents such as chloroform, diethyl ether, dichloromethane and the like or their mixtures to obtain amide derivative of formula (IV).
  • amide derivative of formula (V) in suitable solvent such as dry dimethyl formamide may be treated with a mixture of oxalyl chloride and dimethyl formamide at
  • the cyano derivative of formula (III) may be reduced using reducing agents such as lithium aluminum hydride, sodium hydride or by hydrogenation at temperature varying from 0-40 0 C in solvents such as diethyl ether, tetrahydrofuran and the like to give amine derivative of general formula (II).
  • reducing agents such as lithium aluminum hydride, sodium hydride or by hydrogenation at temperature varying from 0-40 0 C in solvents such as diethyl ether, tetrahydrofuran and the like to give amine derivative of general formula (II).
  • the amine derivative of general formula (II) may be coupled with suitable substituted/unsubstituted heteroaryl carboxylic acids, sulfonic acids, as desired, using coupling agents such as dimethyl amino pyridine (DMAP), dicyclohexyl carbodimide (DCC), hydroxy benzotriazole (HOBLH 2 O) etc. in presence of suitable organic bases such as triethyl amine (TEA), pyridine and the like, in suitable solvents such as tetrahydrofuran, dichloromethane, chloroform and the like or mixtures thereof.
  • DMAP dimethyl amino pyridine
  • DCC dicyclohexyl carbodimide
  • HBLH 2 O hydroxy benzotriazole
  • suitable organic bases such as triethyl amine (TEA), pyridine and the like
  • suitable solvents such as tetrahydrofuran, dichloromethane, chloroform and the like or mixtures thereof.
  • substituted/unsubstituted heteroaryl carboxylic acid may be converted into their corresponding acid chloride derivatives, followed by coupling with the amine derivative of general formula (II) at ambient temperature to give amide derivative of general formula (I).
  • the amine of general formula (II) may be monoalkylated with suitable alkylating agents such as R ⁇ halides where R 1 is as defined earlier, followed by reaction with corresponding suitable carboxylic acids or sulfonyl halides to afford the corresponding compounds of general formula (I).
  • suitable alkylating agents such as R ⁇ halides where R 1 is as defined earlier
  • 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-I receptor and are useful in the treatment of obesity, substance dependence, psychotic disorders and the like.
  • (+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)- 4,5-dihydro- 1 H-pyrazol-3-yl-methyl] -amide
  • Step 1 (+)-5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-carboxylic acid amide
  • (+)-5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH pyrazol-3 -carboxylic acid 9 g, 24.3 mmol
  • oxalyl chloride 2.5 mL, 29.2 mmol
  • the temperature of the reaction mixture increased to 30 0 C.
  • the reaction mixture was concentrated under reduced pressure and the resulting oil was diluted with dry dichloromethane and the solution was cooled to temperature -20 0 C.
  • reaction mixture increased to 30 0 C and the reaction mixture was poured in IN HCl and extracted with ethyl acetate. Ethyl acetate layer was separated, washed with water. The organic layer was seperated, dried over anhydrous Na 2 SO 4 and solvents were evaporated on a rotary evaporator under reduced pressure.
  • the solid obtained was further triturated in petroleum ether and di-isopropyl ether (80 mL: 20 mL). The solid obtained was filtered under reduced pressure and dried to obtain (+)-5-(4-chloro-phenyl)- 1 -(2 5 4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 - carbonitrile as light yellow solid (3.9 g, 63.0 %).
  • (+)-5-(4-chloro- ⁇ henyl)-l-(2,4-dichloro- ⁇ henyl)-4,5- dihydro-1 H-pyrazol-3 -carbonitrile (3.5 g, 9.98 mmol) in diethyl ether (70 mL) was added at the same temperature.
  • the reaction mixture was stirred at this temperature for about 60-90 minutes.
  • the reaction mixture was quenched by mixture of ice and sodium sulfate till evalution of hydrogen gas stops.
  • the suspension was filtered through bed of hy-flow, filtrate was collected and washed with water.
  • (+)-5- (4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-yl-methyl amine (1.7 g, 4.7 mmol) was added followed by addition of triethylamine (1.3 niL, 9.5 mmol).
  • the reaction mixture was stirred at ambient temperature for few minutes.
  • the TLC was checked using 5% MeOH in CHCI 3 as a mobile phase.
  • the reaction mixture was poured in water and extracted with dichloromethane.
  • the dichloromethane layer was separated, dried over anhydrous Na 2 SO 4 and solvents were evaporated on a rotatory evaporator under reduced pressure to get crude brown oil.
  • (+)-Heptanoic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide
  • Table 1 Effect of representative compounds on the WIN-55212-2 inhibition of forskolin-induced cAMP accumulation in hCB ⁇ CHO cells at concentration of 10 DM.
  • Table 2 Effect of representative compounds on the intake of 5 % sucrose solution in animal model.

Abstract

Disclosed herein in the embodiment of the invention are 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 discloses 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.

Description

SUBSTITUTED 4,5-DIHYDRO-lH-PYRAZOLE DERIVATIVES AS CANNABINOID MODULATORS
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.
Figure imgf000002_0001
BACKGROUND AND 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. and 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; anandamide (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 and Perspectives 1999; 12: 458; Kulkarni S. K. and 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 and/or CB2 antagonists have been reported and are under various stages of development for e.g. SR-141716 A(Sanofϊ), CP-272871(Pfizer), LY-320135 (Eli LiIy)5 AM-630 (Alexis), SR-144528(Sanofi MK-0364 (Merck), SLV-319 (Solvay) etc. Novel compounds which are selective CBl 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 CBl Antagonistic activity has been disclosed in US 20050171179Al.
Figure imgf000003_0001
Synthesis of tricyclic pyrazole derivative (NESS 0327) as CBl antagonist has been disclosed in J Pharmacology and Experimental Therapeutics, 2003, 306(1), 363- 370. Synthesis and activity of tricyclic pyrazole ligands for CBl and CB2 receptors have been disclosed in Bioorg. Med. Chem., 2003, 11 , 251 -263. WO 93018038 disclose the compounds of formula
Figure imgf000003_0002
wherein 'A' represents H; Ε' is selected from the group H and C1-C3 alkyl; or 'A' and Ε' can be taken together to form-CH2-, -CH2CH2-, -O-, -S-, -S(O)-, -S(O)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, NO2, S(O)rR30, C(O)R30, C(O)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(O)R33; C(O)2R33; C1-C6 alkylthio; Ci-C6 haloalkylthio; phenylthio; Ru0C(0)N(RI2)S-; R13(R14)NS-; N=CR9R10; OR8 and NR8R9; 'R1', 'R2',' R3', 'R4', 'R 5', 'R7', 'R8', 'R9', 'R 10', R 11', R 12', 'R 13', 'R 14', 'R30', 'R33' and 'm' 'n'are as defined in the specification for WO 93018038
US 5369121 and WO 9203421 disclose several classes of compounds suitable as insecticides, representative compounds have the following general formula
Figure imgf000004_0001
'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(O)N(R)18S 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-I receptor
Figure imgf000004_0002
In a similar context, preparation of N-[(4,5-diphenyl-l,3-alkyl-2- thiophenyl)methyl] amine derivatives as antagonists of CBl cannabinoid receptors and their therapeutic application has been disclosed in WO 2006070106 describes compounds of the following general formula.
Figure imgf000005_0001
Likewise, preparation of N-[(4,5-diphenyl-2-thiophenyl)methyl]sulfonamide derivatives as antagonists of CBl cannabinoid receptors and their therapeutic application has been disclosed in WO 2006077320 describes compounds of the following general formula.
Figure imgf000005_0002
Similarly, preparation of l,5-diaryl-3-aminomethylpyrrole derivatives as antagonists of CBl cannabinoid receptors and their therapeutic application has been disclosed in WO 2006087476 describes compounds of the following general formula.
Figure imgf000005_0003
, Preparation of iV-[(4,5-diphenylpyrimidin-2-yl)methy] amine derivatives and their therapeutic application as cannabinoid receptor antagonists is also disclosed in FR 2888237, WO 2007 006928.
Figure imgf000005_0004
Il Similarly, FR 2888236 discloses preparation of N-[(l,5-diphenyl-lH-pyrazol-3- yl)methyl] sulfonamide derivatives and their therapeutic application as CBl cannabinoid receptor antagonists.
Figure imgf000006_0001
I
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:
Figure imgf000006_0002
O
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.
EMBODIMENTS OF THE INVENTION
In an embodiment of the present invention is provides 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. In an embodiment of the present invention is also provided a process for the
preparation
Figure imgf000007_0001
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 and 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 represented by the general formula (I) below:
Figure imgf000007_0002
wherein 'A' represents 5-6 membered aromatic, heteroaromatic or heterocyclic groups optionally containing one or more substitutions defined by 'Ra'. R1 represents H or an alkyl group; R2 is selected from - C1-C12 straight or branched alkyl chain optionally substituted by halogen, hydroxy, nitro, nitrile groups; optionally substituted aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, heterocyclylalkyl, or heteroarylalkyl groups; X may be selected from the groups CO, SO2, CN, CS; 'Ra' and 'Rb' may be same or different and at each occurrence may be independently selected from from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, or the group (O-SO2)alkyl groups;
'n' and 'm' independently represents an integer from 0-4; in a preferred embodiment the substituent Ra is present in the para position of 'A'.
In a preferred embodiment, 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 preferably 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 "lieteroaryl" or "heteroaromatic" group may be preferably 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, quinazυlinyl, 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 preferably 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-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, behzopyranonyl, 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, w-propyl, iso-piopyl, «-butyl, sec-butyl, tert-bntyl, arnyl, r-amyl, «-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, z'sø-propoxy, ra-butoxy, t-butoxy, iso-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.
Particularly useful compounds may be selected from but not limited to
(+)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro-1 H-pyrazol-3-ylmethyl]-amide;
(+)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
(-)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 - dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-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-phenyl)-l-(2,4-dichloro- phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide; (-)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-l H-Indole-2-carboxylic acid [l-(2,4-dichloiO-phenyl)-5-(4-methoxy-phenyl)-4:>5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
•(+)- 1 H-lndole-2-carboxylic acid [ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro-1 H-pyrazol-3 -ylmethyl] -amide;
(-)-l H-Indole-2-carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
(+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-Cyclohexane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3(4-flurophenyl)-acrylamide; (±)-iV-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl]-3(4-methoxy-phenyl)-acrylamide;
(d=)-iV-[5-(4-Bromo-phenyl)-l-(254-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -4-chlorobenzamide; (±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-(3-chloro-phenyl)-acrylamide;
(±)-iV-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-cyclohexyl-acrylamide;
(±)-Piperidine- 1 -carboxylic acid[5-(4-bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
(±)-l-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-cylohexyl thiourea;
(±)-5-Chlorothiophene-2-carboxylic acid — [5-(4-bromo-phenyl)-l -(2,4-dichloro- phenyl)-4,5-dihydro- 1 H-pyrazol-3-ylmethyl]-amide; (±)-N- [5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl]-2-methoxy-benzamide;
(±)-N-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl] -3 -chlorobenzamide;
(±)-/V-[5-(4-Bromo-phenyl)-l-(2,4-diGhloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-(5-trifluoromethyl-pyridin-2-yloxy)-butyramide;
(±)-5-Chloro- 1 H-indole-3 -carboxylic acid [5-(4-bromo-phenyl)-l -(2,4-dichloro- phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
(±)-lH-Indole-3-carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide; (±)-N-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl] -3 -trifluoromethyl-benzamide;
(±)-Heptanoic acid-[5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide;
(±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide;
(±)-N-[5-(4-Chloro-ρhenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide;
(±)-2-Propyl-pentanoic acid-[5-(4-bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl] -amide; (±)-2-Propyl-pentanoic acid-[5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl]-amide;
(±)-lH-Indole-2-carboxylic acid [l,5-bis-(4-chloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-amide; (±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-Cyclohexanecarboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3-ylmethyl]-amide;
(±)-4-Chloro-N-[l -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- 1 H- pyrazol-3-ylmethyl]-benzamide;
(±)-4-tert-Butyl-iV-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide;
(±)-4-Chloro-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-benzenesulfonamide; (±)-N-[l-(2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-(4-fluoro-phenyl)-acrylamide;
(±)- 1 -Cyclohexyl-3 -[ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -urea;
(±)-Λ/-[l-(2,4-πichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 -(4-methoxy-phenyl)-acrylamide;
(±)-3-(4-Chloro-phenyl)-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylrnethyl]-acrylamide;
(±)-5-Chloro-thiophene-2-carboxylic acid [ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy- phenyl)-4,5-dihydro-lH-pyrazol-3-yhnethyl]-amide; (±)-l-Cyclohexyl-3-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -thiourea;
(±)-Heρtanoic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl]-amide;
(±)-Cyclopentanecarboxylic acid [1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
(±)-Adamantane- 1 -carboxylic acid [1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyi]-amide;
(±)-4-Chloro-iV-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-2-nitro-benzamide; (-)-Cyclohexanecarboxylic acid [5-(4-chloro-phenyl)-l -(2,4-dicb.loro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
(-)-Heptanoic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- IH- pyrazol-3 -ylmethyl] -amide; (±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-trifluoromethoxy-benzenesulfonamide;
(±)-Cyclohexanecarboxylic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl]-amide;
(±)-5-Chloro-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 (l,5-diphenyl-4,5-dihydro-lH-pyrazol-3-ylmethyl)- amide;
(±)-Isoquinoline-3-carboxylic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3-ylmethyl]-amide; (±)-Quinoline-8-sulfonic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amϊde;
(±)-5-Chloro-thiophene-2-sulfonic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-
4,5-dihydro- 1 H-pyrazol-3 -ylmethyl]-amide;
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-4,5-dihydro-lH-pyrazol-3- ylmethylJ-4-trifluoromethyl-benzamide;
(±)-Cyclopropane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichlo'ro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide;
(±)-2-Oxo-2H-chromene-3 -carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-Cyclobutane carboxylic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-l-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-455-dihydro-lH-pyrazol-3- ylmethyl]-3 -cyclohexyl-urea;
(±)-2-Chloro-8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid [5-(4-chloro- phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-2-Chloro-N-[5-(4-chloro-ρhenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-
3-ylmethyl]-benzarnide; (±)-3-Chloro-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-
3 -ylmethylj-benzamide;
(±)-4-Chloro-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-
3 -y lmethy 1] -benzamide ; (±)- 1 -[5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl]-3-cyclohexyl-thiourea;
(±)-4-(4-Chloro-phenoxy)-iV-[5-(4-chloro-plienyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-butyramide;
(±)-5-Bromo-furan-2-carboxylic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -y lmethy 1] -amide;
(±)-2,6-Dichloro-iV-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-benzamide;
(±)-2-{[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -carbamoyl} -pyrrolidine- 1-carboxylic acid tert-butyl ester; (±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-hydroxy-benzamide;
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-cyano-butyramide;
(+)-Heρtanoic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3-yl-methyl amide;
(±)-Cyclobutane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro-1 H-ρyrazol-3-ylmethyl]-amide;
(±)-2-Piopyl-pentanoic acid [l-(2,4-dichloro-phcnyϊ)-5-(4-mcthoxy-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-Heptanoic acid [5-(4-chloro-ph.enyl)-l-(2?4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide; ' (-)-2-Propyl-pentanoic acid [5-(4-chloro-phenyl)-l-(254-dichloro-phenyl)- 4,5-dihydro- lH-pyrazol-3-ylmethyl]-amide;
(±)-5-Chloro- 1 H-indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro- phenyl)- 4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide;
(±)-Cyclopentane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)- 4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-Cyclohexane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methyl-thien-2-yl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethy 1] -amide;
(±)-2-Propyl-pentanoic acid [5-[4-(5-chloro-pentyl)-phenyl]-l-(2,4-dichloro-phenyl)-
4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide; (±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)-l-phenyl-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide;
(±)-lH-Indole-2-carboxylic acid [l-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl] -amide;
(±)-N-[5-(4-Chloro-phenyl> 1 -(2,4-dichloro-phenyl)-455-dihydro- 1 H-pyrazol-3- ylmethyl]-C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-l-yl)-methanesulfonamide; (±)- 1 -[5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl] -3 -(3 ,4-dichloro-phenyl)-urea;
(±)-Benzo[l,3]dioxole-5-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide; (±)-iV-[5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl] -isonicotinamide;
(±)-JV-[5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl]-nicotinamide;
(±)-4-tert-Butyl-N-[5-(4-chloro-ρhenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide;
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide;
(±)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -phenyl-4,5-dihydro- 1 H- pyrazol-3-yhiiethyl]-aniide; 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 methods include, but are not limited to those described below, where all symbols are as defined earlier. Scheme 1:
Figure imgf000016_0001
Synthesis of compound of general formula (IV) The carboxylic acid derivative of formula (V) synthesized according to the process known in the prior art, 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 0C 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 0C in solvents such as chloroform, diethyl ether, dichloromethane and the like or their mixtures to obtain amide derivative of formula (IV).
Synthesis of compound of general formula (III)
The amide derivative of formula (V) in suitable solvent such as dry dimethyl formamide may be treated with a mixture of oxalyl chloride and dimethyl formamide at
0-5 0C to give 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 hydrogenation at temperature varying from 0-40 0C in solvents such as diethyl ether, tetrahydrofuran and the like to give amine derivative of general formula (II).
Synthesis of compound of general formula (I)
The amine derivative of general formula (II) may be coupled with suitable substituted/unsubstituted heteroaryl carboxylic acids, sulfonic acids, as desired, using coupling agents such as dimethyl amino pyridine (DMAP), dicyclohexyl carbodimide (DCC), hydroxy benzotriazole (HOBLH2O) etc. in presence of suitable organic bases such as triethyl amine (TEA), pyridine and the like, in suitable solvents such as tetrahydrofuran, dichloromethane, chloroform and the like or mixtures thereof. In an alternate embodiment, the substituted/unsubstituted heteroaryl carboxylic acid may be converted into their corresponding acid chloride derivatives, followed by coupling with the amine derivative of general formula (II) at ambient temperature to give amide derivative of general formula (I).
Alternatively, the amine of general formula (II) may be monoalkylated with suitable alkylating agents such as R^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-I receptor and are useful in the treatment of obesity, substance dependence, psychotic disorders and the like.
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. IH NMR spectral data given in the examples (vide infra) are recorded using a 300 MHz spectrometer (Bruker AVANCE-300) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is DMSO-dβ usmg tetramethyl silane as the internal standard. EXAMPLE 1
(+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)- 4,5-dihydro- 1 H-pyrazol-3-yl-methyl] -amide Step 1: (+)-5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-carboxylic acid amide
To solution of (+)-5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH pyrazol-3 -carboxylic acid (9 g, 24.3 mmol) in dry dichloromethane was added dropwise oxalyl chloride (2.5 mL, 29.2 mmol) at -20 0C under N2 and the reaction mixture was stirred for 10-20 minutes. The temperature of the reaction mixture increased to 30 0C. The reaction mixture was concentrated under reduced pressure and the resulting oil was diluted with dry dichloromethane and the solution was cooled to temperature -20 0C. To this, dry ammonia gas was passed over 30-60 minutes and the reaction mixture was diluted with water and dichloromethane. The dichloromethane layer was separated and washed with water. The organic layer was seperated, dried over anhydrous Na2SO4 and solvents were evaporated on a rotary evaporator under reduced pressure. The solid obtained was further triturated in petroleum ether, filtered on a Buchner funnel under suction and dried to afford (+)-5-(4-chloro-phenyl)-l-(2,4- dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-carboxylic acid amide as light yellow solid (6.6 g, 73.53 %). 1H NMR (300 MHz, DMSO): δ 7.69 (s, IH)3 7.45 (m, 2H), 7.37 (s, IH), 7.26 (m, 3H), 7.13 (d, J= 8.4 Hz, 2H), 5.83 (dd, J= 11.7 and 5.7 Hz, IH), 3.63 (dd, J= 18.0 and 11.9 Hz, IH), 3.03 (dd, J= 18.0 and 5.8 Hz, IH); ESI-MS: 368 [M+H]+. Step 2: (+)-5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- carbonitrile
To stirred dry DMF cooled under N2 was added oxalyl chloride (3.3 mL,38.7 mmol) dropwise and the resulting yellow suspension was stirred under cold temperature for few minutes. To this was added a solution of (+)-5-(4-chloro-phenyl)- l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-carboxylic acid amide (6.5 g, 17.6 mmol) in dry DMF and the reaction mixture was stirred at this temperature for about 60-90 minutes. Pyridine (5 mL, 75.1 mmol) was added to the reaction mixture at temperature below 0 0C. The temperature of the reaction mixture increased to 30 0C and the reaction mixture was poured in IN HCl and extracted with ethyl acetate. Ethyl acetate layer was separated, washed with water. The organic layer was seperated, dried over anhydrous Na2SO4 and solvents were evaporated on a rotary evaporator under reduced pressure.
The solid obtained was further triturated in petroleum ether and di-isopropyl ether (80 mL: 20 mL). The solid obtained was filtered under reduced pressure and dried to obtain (+)-5-(4-chloro-phenyl)- 1 -(254-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 - carbonitrile as light yellow solid (3.9 g, 63.0 %). 1H NMR (300 MHz, CDCl3): δ 7.23 (t, J= 3.8 Hz5 2H); 7.18 (d, J= 2.2 Hz, 2H), 7.06 (m, 3H), 5.89 (dd, J= 12.6 and 5.9 Hz, IH), 4.04 (bs, 4H)5 3.71 (dd, J= 17.5 and 12.6 Hz, IH)5 3.21 (dd,J= 17.5 and 5.9 Hz5 IH); ESI-MS: 350 [M+H]+. Step 3:
(+)-5 -(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 -yl-methyl amine Dry diethyl ether (200 mL) was stirred using a magnetic stirrer was cooled to -5 to 0 0C under N2 and to this lithium alluminium hydride (0.758 g, 19.9 mmol) was added at temperature -10 to -15 0C under N2. The suspension was cooled to temperature -30 to -35 0C. To this solution of (+)-5-(4-chloro-ρhenyl)-l-(2,4-dichloro-ρhenyl)-4,5- dihydro-1 H-pyrazol-3 -carbonitrile (3.5 g, 9.98 mmol) in diethyl ether (70 mL) was added at the same temperature. The reaction mixture was stirred at this temperature for about 60-90 minutes. The reaction mixture was quenched by mixture of ice and sodium sulfate till evalution of hydrogen gas stops. The suspension was filtered through bed of hy-flow, filtrate was collected and washed with water. The organic layer was separated, dried over anhydrous Na2SO4 and solvents were evaporated on a rotary evaporator under reduced pressure to obtain (+)-5-(4-chloro-phenyl)-l-(254-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-yl-methyl amine as light yellow oil (1.8 g, 50.84 %). 1H NMR (300 MHz, DMSO-^6): δ 7.33 (t, J = 4.2 Hz, 2H); 7.24 (d, J = 8.4 Hz, 2H), 7.17 (m. 3H), 5.59 (dd, J= 10.9 and 4.7 Hz, IH), 3.56 (s, 2H), 3.48 (dd, J= 13.7 and 6.8 Hz, IH), 3.08 (s, 2H)3 2.95 (dd, J= 17.8 and 4.9 Hz, IH); ESI-MS: 354 [M+H]+. Step 4: (+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3-yl-methyl]-amide
To a stirred solution of cyclohexane carboxylic acid (0.602 g, 4.7 mmol) in dichloromethane was added 1-hydroxybenzotriazole hydrate (1.294 g, 9.5 mmol), [1- (3-dimethylaminopropyl)-3-ethylcarbodiimide] hydrochloride (1.376 g, 7.1 mmol) and the reaction was stirred for few minutes at ambient temperature. To this mixture, (+)-5- (4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3-yl-methyl amine (1.7 g, 4.7 mmol) was added followed by addition of triethylamine (1.3 niL, 9.5 mmol). The reaction mixture was stirred at ambient temperature for few minutes. The TLC was checked using 5% MeOH in CHCI3 as a mobile phase. The reaction mixture was poured in water and extracted with dichloromethane. The dichloromethane layer was separated, dried over anhydrous Na2SO4 and solvents were evaporated on a rotatory evaporator under reduced pressure to get crude brown oil. The crude oil was purified through flash column-chromatography using silica gel of 230-400 mesh as a stationary phase and petroleum ether: EtOAc (6: 4) as an eluent. The fractions were pooled and solvents were evaporated on a rotatory evaporator under reduced pressure to obtain an oil. The oil was triturated in petroleum ether to afford the final compound (+)- Cyclohexane carboxylic acid [5~(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-yl-methyl] -amide as white solid (1.1 g, 49%). 1H-NMR: 8.14 (t, J= 5.6 Hz, IH), 7.35 (d, J= 2.27 Hz, IH), 7.25 (d, J= 1.5 Hz, IH), 7.21 (t, J= 2.9 Hz, IH), 7.18 (d, J = 2.38 Hz, IH), 7.13 (d, J = 8.4 Hz, IH), 7.06 (s, IH), 5.59 (dd, J = 11.04 and 4.72 Hz, IH), 4.04 (d, J = 4.17 Hz, 2H), 3.4Q (dd, J = 17.66 and 11.04 Hz, IH), 2.80 (dd, J= 17.66 and 4.78 Hz, IH), 2.15 (m, IH), 1.65 (m, 4H)5 1.33 (t, 2H), 1.24 (d, 2H), 1.02 (d, 2H)
The following compounds were prepared as per the process similar to that disclosed in the above example. Suitable modifications, alterations which may be required are well within the scope of a person skilled in the art. . EXAMPLE 2
(±)- 1 H-indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3-ylmethyl] -amide
1H-NMR : 11.63 (bs, -NH gr.), 8.94 (bs5 -NH gr.), 7.61 (d, J = 7.5 Hz, IH)5 7.43-7.37 (m, 2H), 7.31-7.25 (m, 2H)5 7.22-7.15 (m, 6H)5 7.02(t, J= 7.6 Hz5 IH)5 5.63-5.59 (m,
IH)5 4.33-4.29 (m, 2H)5 1.9-1.8 (m, 2H)
EXAMPLE 3
(+)- 1 H-indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide 1H-NMR : 11.67 (s, IH)5 8.98 (t, J = 5.6 Hz, IH)5 7.62 (d, J= 7.56 Hz5 IH)5 7.61 (t, J
= 9.3 Hz5 2H)5 7.23 (m, 8H)5 7.04 (t5 J= 7.14 Hz5 IH)5 5.64 (dd, J= 11.10 and 4.56 Hz5
IH)5 4.33 (bs5 2H)5 3.53 (dd, J= 17.58 and 11.31 Hz ,1H)5 2.90 (dd, J= 17.55 and 4.48
Hz5 2H)
EXAMPLE 4 (-)-l H-indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3-ylmethyl]-amide
1H-NMR: 11.65 (s, IH)5 8.96 (s, IH), 7.61 (d, J= 7.92 Hz5 IH), 7.61 (d, J = 7.92 Hz5
IH)5 7.41 (t, J= 9.19 Hz, IH), 7.30 (d, J= 8.73 Hz, 2H)5 7.23 (m. 6H)5 7.03 (t, J= 7.33
Hz5 IH)5 5.63 (dd5 J = 11.01 and 4.74 Hz5 IH)5 4.33(bs, IH)5 3.52(dd5 J=17.43 and 11.37, IH), 2.90 (dd, J= 17.58 and 4.56, 2H)
EXAMPLE 5
(+)-N-[5-(4-Chloro-phenyl)-l-(2,4-dicliloiO-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-trifluoromethoxy-benzenesulfonamide
1H-NMR: 8.33 (bs, -NH gr.), 7.96 (d, J= 8.76 Hz, 2H), 7.60 (d, J= 8.27 Hz, 2H), 7.35 (d, J= 2.11 Hz, IH), 7.23 (d, J= 8.39 Hz5 2H), 7.14 (d, J= 8.0 Hz5 2H)5 7.0(d, J= 8.44
Hz5 2H), 5.54-5.48 (dd, J= 11.0 and 5.37 Hz, IH)5 3.88 (d, J= 5.43 Hz, 2H), 3.38-3.31
(bs, IH)5 2.80-2.73(dd5 J= 17.65 and 5.34 Hz, IH)
EXAMPLE 6
(±)-2-Propyl-pentanoic acid [5-[4-(5-chloro;rpentyl)-phenyl]-l-(254-dichloro-phenyl)- 4,5-dihydro- 1 H-pyrazol-3rylmethyl]-amide
1H-NMR: 7.19 (d, J= 1.8 Hz, IH)5 7.13 (d, J= 1.8 Hz5 IH), 7.01-6.95 (m, 5H)5 6.0 (bs5
IH)5 5.56-5.53 (m, IH), 4.31-4.22 (m, IH)5 4.18-4.11 (m, IH)5 3.49 (t, J= 5.1 Hz5 2H)5 3.45-3.41 (m, IH), 3.04-2.98 (m, IH), 2.50 (t, J= 5.7 Hz, 2H)3 2.10-2.02 (m, 3H), 1.76-
1.73 (m, 2H)3 1.64-1.60 (m, 3H)3 1.56-1.53 (m, 2H), 1.42-1.30 (m, HH)
EXAMPLE 7
(-)-2-Propyl-pentanoic acid [5-(4-chloro-phenyl)- 1 -(234-dichloro-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-amide
1H-NMR: 8.28 (t, J= 5.6 Hz3 IH)3 7.35 (d, J = 2.4 Hz3 IH)3 7.32 (d, J = 8.8 Hz3 ' IH),
7.21 (dd, J = 14 and 8.4 Hz3 2H), 7.18 (d, J = 2.4 Hz3 IH)3 7.13 (d3 J = 8.4 Hz3 2H),
5.63 (dd, J= 11.2 and 4.4 Hz3 IH)3 4.06 (d, J= 5.6 Hz3 2H)3 3.4 (dd, J = 17.6 and 6.4
Hz3 IH)3 2.8 (dd, J= 17.6 and 4.4 Hz, IH), 2.17 (m, IH), 1.43 (m, 2H)3 1.21 (m, 6H), 0.77 (m, 6H)
EXAMPLE 8
(±)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro- phenyl)-4,5-dihydro- 1 H-pyrazol-3-ylmethyl] -amide
1H-NMR: 9.0 (bs, -NH gr.), 7.69 (d, J = 4.0 Hz, IH), 7.28-7.17 (m, 6H), 7.12 (t, J = 7.62 Hz, IH), 6.89 (t, J= 6.95 Hz, IH)3 5.60 (dd, J= 10.96 and 5.68 Hz3 IH)3 4.26 (bs,
2H), 3.47 (dd, J= 17.37 and 11.10 Hz, IH), 2.85 (dd, J= 17.65 and 5.80 Hz, IH)
EXAMPLE 9
(±)-Cyclobutane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide 1H-NMR: 8.09 (t, IH)3 7.34 (d, J= 2.0 Hz3 IH)3 7.26 (d, J- 8.8 Hz3 IH)3 7.17 (dd, J=
8.8 and 2.4 Hz, IH)3 7.03 (d, J= 8.8 Hz3 2H)3 6.71 (d, J= 8.8 Hz3 2H)3 5.53 (dd3 J= 8.4 and 3.3 Hz3 IH)3 4.06 (bs, 2H), 3.62 (s, 3H)3 3.36 (dd, J= 17.56 and 8.78 Hz, IH), 3.06
(m, IH), 2.80 (dd, J= 17.60 and 4.2 Hz3 IH)3 2.04 (m, 4H)3 2.01 (m, 2H)
EXAMPLE 10 (±)-2-Propyl-pentanoic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-435- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.29 (t, IH), 7.34 (d, J= 2:4 Hz3 IH)3 7.28 (d, J= 8.8 Hz3 IH)3 7.16 (dd, J=
8.8 and 2.4 Hz, IH), 7.03 (d, J= 8.4 Hz, 2H), 6.70 (d, J= 8.4 Hz, 2H), 5.55 (dd, J= 8.4 and 3.3 Hz, IH), 4.07 (d, 2H)3 3.62 (s, 3H), 3.37 (dd, J = 13.2 and 8.4 Hz3 IH)3 2.82 (dd3 J= 13.2 and 3.3 Hz, IH), 2.21 (t, IH)3 1.45 (t, 2H), 1.23 (t, 6H), 0.80 (t, 6H)
EXAMPLE 11
(+)- 1 H-indole-2-carboxyiic acid [ 1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide 1H-NMR: 8.94 (t, IH), 7.61 (d, J= 7.81 Hz, IH), 7.59 (d, J= 8.05 Hz, IH)5 7.34 (d, J= 8.07 Hz, IH), 7.29 (d, J= 8.73 Hz, IH), 7.17 (t, J= 2.37 Hz, IH), 7.04 (t, J= 7.02 Hz, IH), 6.70 (d, J- 8.4 Hz, 2H), 5.58 (dd, J= 10.90 and 4.36 Hz, IH), 4.31 (bs, 2H), 3.60 (s, 3H), 3.47 (dd, J= 17.82 and 6.42 Hz, IH), 2.86 (dd, J= 18.15 and 4.89 Hz, IH). EXAMPLE 12
(+)-Heptanoic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide
1H NMR (300 MHz, DMSO-J6): δ 8.2 (t, J= 5.6 Hz, IH), 7.3 (d, J= 2.4 Hz, IH), 7.28 (d, J = 8.8 Hz, IH)5 7.23 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 2.4 Hz5 2H), 7.16 (dd, J = 13.2 and 2.4 Hz, 2H), 5.6 (dd, J= 10.8 and 4.4 Hz5 IH), 4.0 (t, J = 7.6 Hz, 2H)5 3.4 (m, IH)5 2.8 (dd, J= 17.6 and 4.8 Hz, IH), 2.1 (t, J- 7.4 Hz5 2H)5 1.4 (t, J= 6.8 Hz, 2H), 1.1 (t, J= 7.2 Hz, 6H), 0.8 (s, 3H). EXAMPLE 13 (±)-Cyclohexane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.13 (t, J= 5.66 Hz5 IH)5 7.38-7.35 (m, 3H)5 7.28 (d, J= 8.77 Hz, IH), 7.20 (dd, J= 8.76 and 2.33 Hz, IH)5 7.07 (d, J= 8.36 Hz, 2H), 5.57 (dd, J= 11.03 and 4.76 Hz, IH), 4.04 (d, J= 5.50 Hz5 2H), 3.42 (dd, J= 17.71 and 11.03 Hz, IH), 2.78 (dd, J= 17.72 and 4.75 Hz, IH), 2.13 (t, IH)5 1.67-1.60 (m5 4H)5 1.37-1.25 (t5 2H), 1.21-1.17 (m, 2H)
EXAMPLE 14
(d=)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 (4-flurophenyl)-acrylamide
1H-NMR: 8.53 (t5 J= 5.65 Hz5 IH)5 7.6 (m, 2H), 7.42 (d, J= 15.8 Hz, 2H)5 7.37 (m5 3H), 7.22 (m, 4H)5 7.10 (d, J= 8.36 Hz, 2H)5 6.63 (d, J= 15.8 Hz, 2H)5 5.60 (dd, J = 11.02 and 5.03 Hz, IH), 4.21 (d, J = 5.52 Hz5 2H), 3.47 (dd, J = 17.7 and 11.26 Hz, IH), 2.8 (dd, J= 17.6 and 5.09 Hz, IH) EXAMPLE 15 (±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-455-dihydro-lH-pyrazol-3- ylmethyl]-3-(4-methoxy-phenyl)-acrylamide
1H-NMR: 8.4 (s, IH), 7.52 (d, J= 8.62 Hz, 2H)5 7.40 (m5 3H), 7.39 (d, J= 15.35 Hz5 IH)5 7.30 (d5 J= 8.78 Hz, IH)5 7.21 (dd5 J= 8.75 and 2.27 Hz, IH)5 7.10 (d, J= 8.35 Hz, 2H), 6.97 (d, J= 8.61 Hz, 2H)5 6.52 (d5 J= 15.74 Hz5 IH)5 5.59 (dd, J= 11.02 and 5.07 Hz3 IH), 4.20 (d, J= 5.25 Hz, 2H)5 3.77 (s, 3H), 3.43 (dd, J = 17.5 and 6.3 Hz , IH)5 2.85 (dd, J= 17.45 and 4.95 Hz, IH).
EXAMPLE 16
(d=)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-chlorobenzamide
1H-NMR: 9.02 (s, IH), 7.88 (d, J= 8.21 Hz, 2H), 7.55 (d, J= 8.22 Hz, 2H), 7.38 (d, J=
7.08 Hz, 3H), 7.24 (m, 2H), 7.10 (d, J= 7.95 Hz, 2H), 5.59 (d, J= 5.88 Hz5 IH), 4.28 (s, IH), 3.47 (t, J= 14.4 Hz, IH)5 2.82 (t, J= 5.8 Hz, IH)
EXAMPLE 17 (±)-7V-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 -(3 -chloro-phenyl)-acrylamide
1H-NMR: 8.56 (s, 1H),7.65 (s, IH), 7.54 (d, J= 4.07 Hz5 IH), 7.41 (m, 6H), 7.30 (d, J
= 8.77 Hz5IH), 7.21- (m, IH)5 7.1 (d, J= 8.3 Hz, 2H), 6.74 (d, J= 15.8 Hz5 IH)5 5.6 (dd,
J= 10.63 and 4.69 Hz5 IH), 4.22 (d, J= 5.22 Hz, 2H)5 3.47 (dd, J= 17.6 and 11.12 Hz, IH), 2.8 (dd, J= 17.6 and 5.1Hz , IH)
EXAMPLE 18
(±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 -cyclohexyl-acrylamide
1H-NMR: 8.33(s5 IH)5 7.38 (d5 J= 8.3 Hz, 2H), 7.29 (d, J= 8.7 Hz5 IH), 7.20 (d, J = 8.7 Hz, IH), 7.08 (d, J= 8.1 Hz, 2H)5 6.62 (m, IH), 5.88 (d, J= 15.4 Hz, IH)5 5.57 (t, J
= 5.4 Hz, IH), 4.12 (d, J= 4.8 Hz, 2H)5 3.43 (t, J= 8.7 Hz ,1H), 2.80 (dd, J= 17.6 and
4.68 Hz5 IH)5 1.67 (d5 J= 10.9 Hz5 4H), 1.27-1.12 (m, 4H)5 1.08-1.05 (m, 2H)
EXAMPLE 19
(±)-Piperidine-l-carboxylic acid[5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR; 8.16 (s5 IH), 7.42 (d, J = 8.75 Hz5 3H), 7.27 (m, 2H), 7.12 (d, J = 8.0 Hz,
2H), 5.64 (dd, J = 10.8 and 5.8 Hz, IH), 4.2 (s, 2H), 3.55 (dd, J = 17.2 and 10.8 Hz,
IH)5 2.92 (dd, J= 17.2 and 5.4 Hz, IH)5 1.59 (bs, 4H), 1.25 (s, 4H), 1.02 (d, J= 6.0 Hz,
2H). EXAMPLE 20
(±)-l-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-cylohexyl thiourea 1H-NMR: 7.61(bs, 2H), 7.34(m, 4H), 7.21 (t, J = 5.4 Hz, IH), 7.12 (d5 J= 8.3 Hz, 2H), 5.59 (dd, J= 11.0 and 4.7 Hz, IH)5 4.44 (s, 2H), 4.02 (d, J= 9.6 Hz, IH)5 3.46 (dd, J = 17 and 10.6 Hz5 IH), 2.84 (dd, J= 17.5 and 12.9 Hz, IH)5 1.82 (s, 2H)5 1.62 (s, 2H) EXAMPLE 21 (±)-5-Chlorothiophene-2-carboxylic acid -[5-(4-Bromo-phenyl)-l-(254-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR: 9.05 (t, J= 5.5 Hz5 IH)5 7.6 (d, J= 4.04 Hz, IH)5 7.37 (m, 3H)5 7.26 (d5 J = 8.7 Hz5 IH)5 7.2 (m, 2H)5 7.10 (d, J= 8.3 Hz, 2H)5 5.59 (dd5 J= 10.9 and 5.05 Hz, IH)5 4.01 (m, 2H)5 3.47 (dd, J= 17.5 and 11.2 Hz, IH)5 2.85 (dd, J= 17.6 and 5.1 Hz, IH) EXAMPLE 22
(±)-N-[5-(4-Bromo-phenyl)-l-(254-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -2-methoxy-benzamide
1H-NMR:- 8.7 (t5 J= 5.2 Hz5 IH)5 7.75 (m, IH), 7.47 (m, IH)5 7.37 (m, 3H)5 7.32 (d, J = 8.7 Hz5 IH), 7.22 (m, IH)5 7.13 (t, J= 6.6 Hz, 3H)5 7.03 (t, J= 7.5 Hz, IH)5 5.62 (dd, J =10.9 and 4.7 Hz, IH)5 4.3 (d, J= 5.23 Hz, 2H)5 3.82 (m, 3H), 3.49 (dd, J= 17.8 and 11.1 Hz5 IH), 2.91 (dd, J= 17.6 and 4.8 Hz , IH) EXAMPLE 23
(±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-chlorobenzamide 1H-NMR: 9.0 (t, J= 5.5 Hz; IH), 7.9 (d, J= 1.5 Hz5 IH)5 7.83 (d, J= 7.7 Hz5 IH)5 7.62 (d, J= 8.7 Hz5 IH), 7.50 (t, J= 7.8 Hz, IH)5 7.37 (m, 3H), 7.28 (d, J= 8.7 Hz5 IH)5 7.2 (m, IH), 7.1 (d, J= 8.4 Hz, 2H)5 5.59 (dd, J= 10.9 and 4.9 Hz, IH), 4.28 (t, J= 4.8 Hz, 2H), 3.49 (dd, J= 17.9 and 11.3 Hz, IH), 2.86 (dd, J= 17.6 and 5.1 Hz , IH) EXAMPLE 24 (±)-N-r5-(4-Bromo-phenyl)-l-(254-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-4-(5-trifluoromethyl-pyridin-2-yloxy)-butyramide
1H-NMR: 8.31 (s, 2H), 7.63 (m, IH), 7.36 (d, J= 8.3 Hz5 3H), 7.26 (d, J= 8.7 Hz, IH), 7.17 (m, IH), 7.07 (d, J= 8.3 Hz, 2H)5 6.50 (d, J= 9.5 Hz, IH), 5.57 (dd, J= 10.9 and 4.8 Hz, IH), 4.04 (t, J= 8.5 Hz, 2H)5 3.93 (t, J= 7.06 Hz, 2H)5 3.42 (dd, J= 17.7 and 11.2 Hz, IH), 2.82 (dd, J= 17.7 and 4.9 Hz, IH), 2.15 (t, J= 7.5 Hz, 2H), 1.9 (m, 2H) EXAMPLE 25
(±)-5-Chloro- 1 H-indole-2-carboxylic acid [5-(4-bromo-phenyl)- 1 -(2,4-dichloro- phenyl)-455-dihydro- 1 H-pyrazol-3-ylmethyl] -amide 1H-NMR: 11.8 (s, IH), 9.08 (t, J = 5.5 Hz, IH), 7.7 (s, IH), 7.4 (d, J = 8.7 Hz, IH), 7.30 (m, 3H), 7.27 (s, IH), 7.20 (m, 3H), 7.10 (d, J = 8.28 Hz, 2H), 5.6 (dd, J= 10.9 and 4.9 Hz, IH), 4.31 (t, J- 11.4 Hz, 2H), 3.48 (dd, J= 17.5 and 6.5 Hz, IH), 2.88 (dd, J= 17.7 and 4.9 Hz, I xH) EXAMPLE 26
(±)- 1 H-Indole-2-carboxylic acid [5-(4-bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 11.6 (s, IH)5 8.9 (d, J- 5.7 Hz5 IH)5 7.6 (d, J= 7.9 Hz, IH)5 7.4 (t, J= 13.2
Hz, 2H), 7.36 (d, J= 3.0 Hz5 2H)5 7.3 (d, J= 8.7 Hz, IH)5 7.19 (m, 2H), 7.14 (d, J= 5.7 Hz5 2H)5 7.20 (s5 IH)5 7.02 (t, J= 7.3 Hz, IH), 5.6 (dd, J= 10.9 and 4.8 Hz5 IH)5 4.3 (t,
J = 5.9 Hz, 2H)5 3.51 (dd, J = 17.9 and 11.4 Hz5 IH)5 2.89 (dd, J = 17.4 and 4.8 Hz5
IH)
EXAMPLE 27
(±)-N-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 -trifluoromethyl-benzamide
1H-NMR: 9.17 (t5 J= 5.5 Hz5 IH), 8.05 (d, J= 8.13 Hz5 2H), 7.8 (d, J= 8.2 Hz5 2H),
7.3 (d, J= 8.25 Hz, 3H), 7.28 (d, J = 8.76 Hz, IH)5 7.2 (m, IH)5 7.1 (d, J= 8.34 Hz,
2H), 5.6 (dd, J=10.9 and 5.01 Hz, IH), 4.3 (t, J= 4.3 Hz5 2H), 3.50 (dd, J= 17.8 and
11.3 Hz5 IH)5 2.88 (dd, J= 17.6 and 5.04 Hz, IH) EXAMPLE 28
(±)-Heptanoic acid- [5 -(4-bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H- pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.23 (t, J= 5.4 Hz, IH), 7.38 (s, IH), 7.35 (s, 2H), 7.28 (d, J= 8.7 Hz, IH),
7.19 (m5 IH)5 7.07 (d, J= 8.3 Hz5 2H)5 5.59 (dd, J= 10.9 and 4.6 Hz5 IH)5 4.05 (d5 J= 5.5 Hz5 2H)5 3.42 (dd5 J= 17.5 and 11.1 Hz5 IH)5 2.8 (dd, J = 17.6 and 4.6 Hz5 IH)5
2.10 (t, J= 7.2 Hz5 IH)5 1.45 (d, J = 6.3 Hz5 IH)5 1.18 (bs5 6H)5 0.80 (d, J= 6.0 Hz5
3H)
EXAMPLE 29
(±)-iV-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide
1H-NMR: 8.27 (t, J= 5.6 Hz5 IH)5 8.0 (d, J= 0.8 Hz5 IH)5 7.9 (dd5 J= 8.8 and 2.4 Hz5
IH)5 7.3 (m, 3H), 7.22 (d, J= 8.8 Hz5 IH)5 7.17 (dd, J= 8.8 and 2.4 Hz5 IH), 7.0 (m,
3H), 5.5 (dd, J= 11.2 and 4.8 Hz, IH), 4.0 (t, J= 5.2 Hz5 2H), 3.29 (d, J= 11.2 Hz5
IH)5 2.72 (dd, J= 18.0 and 4.8 Hz5 IH), 1.6 (d5 J= 4.0 Hz5 6H) EXAMPLE 30
(±)-7V-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide
1H-NMR: 8.28 (t, J= 5.6 Hz5 IH), 8.09 (d, J- 0.4 Hz, IH)5 7.96 (dd, J = 8.8 and 2.8 s 5 Hz, IH), 7.33 (d, J= 2.4 Hz, IH), 7.19 (d, J= 8.4 Hz5 IH)5 7.16 (m, 3H)5 7.09 (m, 2H),
7.01 (d, J= 8.8 Hz5 IH)5 5.54 (dd, J= 11.2 and 4.8 Hz5 IH)5 4.05 (t, J= 6.0 Hz5 2H)5
3.29 (d, J= 11.2 Hz5 IH)5 2.72 (dd, J= 18.0 and 4.8 Hz5 IH)5 1.60 (d5 J= 4.0 Hz5 6H)
EXAMPLE 31
(±)-2-Propyl-pentanoic acid-[5-(4-bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 10 lH-pyrazol-3-ylniethyl] -amide
1H-NMR: 8.27 (t, J= 5.6 Hz, IH)5 7.34 (t5 J= 5.8 Hz, 3H), 7.30 (d, J= 6.6 Hz, IH)5
7.24-7.17 (m, 3H)5 7.13 (d, J= 6.3 Hz5 2H)5 5.63 (dd, J= 10.8 and 4.4 Hz5 IH), 4.05 (d,
J = 5.6 Hz5 2H)5 3.42 (dd5 J = 17.6 and 11.2 Hz5 IH)5 2.79 (dd, J = 17.6 and 4.4 Hz5
IH)5 2.1 (m5 IH), 1.25-1.13 (m, 8H)5 0.84-0.78 (m, 6H) 15 EXAMPLE 32
(±)-2-Propyl-pentanoic acid-[5-(4-chloro-phenyl)- 1 -(254-dichloro-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.28 (t, J= 5.6 Hz5 IH)5 7.34 (d5 J= 2.4 Hz5 IH), 7.3 (d, J= 8.8 Hz5 IH)5 7.2
(m, 3H)5 7.13 (d, J= 8.4 Hz5 2H)5 5.63 (dd, J= 10.8 and 4.4 Hz, IH)5 4.0 (d, J= 5.6 0 Hz, 2H), 3.42 (dd, J = 17.6 and 11.2 Hz5 IH)5 2.79 (dd5 J= 17.6 and 4.4 Hz5 IH)5 2.1
(m, IH)5 1.18 (m, 8H)5 0.8 (m, 7H)
EXAMPLE 33
(±)-Cyclopentane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)- 4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide 5 1H-NMR : 8.15(t5 J= 5.6 Hz5 IH), 7.36(t5 J= 5.6 Hz5 3H), 7.28 (d5 J= 8.8 Hz, IH)5 7.2
(dd, J= 8.8 and 2.4 Hz5 IH)5 7.08 (d, J= 8.4 Hz, 2H)5 5.58 (dd, J= 11.2 and 4.8 Hz5
IH)5 4.05 (t, J= 4.6 Hz5 2H), 3.41(dd, J= 17.6 and 11.2 Hz, IH), 2.79 (dd, J= 17.6 and
4.8 Hz5 IH)5 2.58 t, J= 5.6 Hz5 IH), 1.7 (t, J= 7.2 Hz, 2H), 1.5 (s, 4H)5 1.46 (d, J= 4.4
Hz5 2H) 0 EXAMPLE 34
(±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR:- 8.27 (t, J = 5.6 Hz5 IH)5 7.35 (d, J = 2.39 Hz, IH)5 7.30 (d, J = 8.78 Hz,
IH)5 7.2 (m5 3H)5 7.13 (d, J= 8.38 Hz5 IH)5 5.61 (dd5 J= 11.08 and 4.5 Hz, IH)5 4.05 (d, J = 5.55 Hz, 2H), 3.41 (dd5 J= 17.56 and 11.05 Hz3 IH), 2.80 (dd, J = 17.55 and
4.56 Hz, IH), 2.59 (t, J= 4.55 Hz, IH), 1.72 (t, J= 7.19 Hz, 2H), 1.5 (bs, 4H), 1.47 (m,
2H)
EXAMPLE 35 (±)-Cyclohexanecarboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR :- 8.26 (t, J = 5.6 Hz, IH)5 7.33 (d, J = 2.01 Hz, IH), 7.25 (d, J = 7.91 Hz,
IH), 7.16 (d, J = 8.63 Hz, IH), 7.03 (d, J = 8.47 Hz, 2H), 6.69 (d, J= 8.48 Hz, IH ),
5.51 (dd, J= 11.10 and 4.09 Hz, IH), 4.03 (bs, 2H), 3.63 (s, 3H), 3.32 (dd, J = 17.59 and 11.10 Hz, IH), 2.78 (dd, J= 17.59 and 4.08 Hz, IH), 2.14 (m, IH), 1.68-1.65 (bd,
4H), 1.34-1.27 (bs, 4H), 1.20 (m, 2H)
EXAMPLE 36
(±)-4-Chloro-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide 1H-NMR :- 9.02 (t, IH), 7.88 (d, J= 8.50 Hz, 2H), 7.56 (d, J= 8.45 Hz, 2H), 7.35 (d, J
= 2.18 Hz, IH), 7.26 (d, J= 8.73 Hz, IH), 7.05 (d, J= 8.50 Hz, IH), 6.70 (d, J= 8.50
Hz, 2H), 5.55 (dd, J= 10.98 and 4.45 Hz, IH), 4.28 (m, 2H), 3.62 (s, 3H), 3.40 (dd, J=
17.71 and 11.01 Hz, IH), 2.82 (dd, J= 17.71 and 4.43 Hz, IH)
EXAMPLE 37 (±)-Heptanoic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-amide
1H-NMR:- 8.24 (t, J = 5.35 Hz, IH), 7.34 (d, J = 2.10 Hz, IH), 7.25 (d, J = 8.8 Hz,
IH), 7.16(d, J = 8.82 Hz, IH), 7.03 (d, J = 8.55 Hz, 2H), 6.71 (d, J= 8.55 Hz, 2H),
5.54 (dd, J= 11.12 and 4.60 Hz, IH), 4.04 (bs, 2H), 3.63 (s, 3H), 3.45 (dd, J= 17.56 and 11.10 Hz, IH), 2.78 (dd, J = 17.59 and 4.50 Hz, IH), 2.10 (t, 2H), 1.48 (m, 2H),
1.18 (bs, 6H), 0.80 (t, 3H)
EXAMPLE 38
(-)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide 1H-NMR:- 8.16(t, J= 5.64 Hz, IH), 7.35 (d, J= 2.23 Hz, IH), 7.28-7.17 (m, 4H), 7.13
(d, J= 8.45 Hz, IH), 5.59 (dd, J= 10.96 and 4.34 Hz, IH), 4.04 (d, J= 4.94 Hz, 2H),
3.38 (dd,J= 17.56 and 10.68 Hz, IH), 2.78(dd,J= 17.56 and4.71 Hz, IH), 2,13 (t,J=
11.11 Hz, IH), 1.67-1.60 (bd, 4H), 1.37-1.25 (bd, 4H), 1.16(bs, 2H) EXAMPLE 39
(±)-Cyclohexane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methyl-thien-2-yl)-4,5- dihydro- 1 H-pyrazol-3-ylmethyl] -amide
1H-NMR:- 8.17 (t, J=5.7 Hz, IH), 7.43 (d, J=2.0 Hz, IH)3 7.20 (m, 2H), 6.6(d, J=5.1 ,5 Hz, IH)5 6.45(d, J=2.26 Hz IH), 4.06(t, J=5.1 Hz, 2H), 2.85 (dd, J=3.4 Hz and 17.44
Hz, 2H), 2.19(t, J=12.6 Hz, 3H)3 2.12 (s3 IH)3 1.69(d, J=10.61 Hz, 4H), 1.40 (m, 2H)3
1.02(d, J=6.1 Hz, 4H)
EXAMPLE 40
(±)-5-Chloro- 1 H-indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-0 phenyl)- 4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR:- 11.84 (bs, -NH gr., IH), 9.01 (bs, -NH gr., IH), 7.70 (s, IH), 7.42 (d3 J =
8.70 Hz, IH)3 7.35 (d3 J= 2.19 Hz3 IH), 7.27 (s, IH)3 7.25-7.14 (s, IH), 5.61 (dd, J =
11.01 and4.98 Hz, IH)34.31 (bs, 2H)33.51 (dd,J= 17.61 and 11.19 Hz, IH), 2.89 (dd,
J= 17.7 and 4.98 Hz, IH) 5 EXAMPLE 41
(±)-Cyclopentanecarboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.23 (t, IH)3 7.34 (d, J= 2.19 Hz3 IH), 7.27 (d, J= 8.7 Hz3 IH), 7.18 (dd, J
8.76 and 2.29 Hz, IH)3 7.03 (d, J= 8.57 Hz, 2H), 6.71 (d, J= 8.57 Hz3 2H), 5.56 (dd, J0 = 10.91 and 4.26 Hz, IH)3 4.10 (bs, 2H), 3.62(s, 3H), 3.41 (dd, J= 17.73 and 10.91 Hz3
IH)3 2.82 (dd, J= 17.73 and 4.29 Hz3 IH), 2.59 (m, IH), 1.71(bs, 4H), 1.47(bs3 4H)
EXAMPLE 42
(±)-Cyclohexanecarboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide 5 1H-NMR: 8.13 (bs, -NH gr, IH)3 7.35 (d, J= 2.19 Hz3 IH), 7.29-7.20 (m, 4H), 7.18-
7.12 (m, 2H), 5.58 (dd, J= 11.01 and 4.68 Hz, IH)3 4.04 (d, J= 4.0 Hz, 2H), 3.45-3.35
(dd,J= 17.65 and 11.05 Hz, IH), 2.82-2.75 (dd, J= 17.67 and 4.70 Hz, IH)32.13 (t3J
= 11.08 Hz, IH), 1.68-1.60 (bs, 4H)3 137-1.09 (bs, 6H)
EXAMPLE 43 0 (±)-2,6-Dichloro-N-[5-(4-chloro-phenyl)- 1 -(2,4-dichloro-ρhenyl)74,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -benzamide
1H-NMR: 8.97 (t, J= 4.25 Hz, IH)3 7.68 (d, J = 1.2 Hz, IH), 7.51-7.46 (m, 2H), 7.36
(d, J = 1.8 Hz3 IH), 7.32 (d, J = 6.6 Hz, IH)3 7.26-7.21 (m, 2H)3 7.20-7.16 (m, 3H), 5.66-5.62 (dd, J= 8.4 and 3.6 Hz5 IH), 4.25 (d, J= 4.5 Hz, 2H), 3.57-3.49 (dd, J= 13.2 and 8.4 Hz5 IH)5 2.97-2.92 (dd, J= 13.2 and 3.9 Hz5 IH) EXAMPLE 44
(±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)- 1 -phenyl-455-dihydro- 1 H- pyrazol-3-ylmethyl]-amide
1H-NMR: 8.16 (t, J = 5.34 Hz5 IH)5 7.38 (d5 J = 8.31 Hz5 2H), 7.28 (d, J = 8.22 Hz5 2H)5 7.10 (t, J= 7.68 Hz5 2H)5 6.82 (d, J= 8.07 Hz5 2H)5 6.67 (t, J= 7.23 Hz, IH)5 5.23 (dd, J = 11.85 and 6.87 Hz5 IH)5 4.03 (d, J = 5.49 Hz5 2H)5 3.46 (dd, J = 17.76 and 12.12 Hz, IH), 2.58 (dd, J= 17.97 and 6.93 Hz, IH), 2.57 (s, IH), 1.70 (bs, 2H)5 1.59 (bs, 4H), 1.47 (bs, 2H) EXAMPLE 45
(±)-lH-Indole-2-carboxylic acid [l-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-amide 1H-NMR: 11.59 (s, IH), 8.95 (t, J= 5.48 Hz5 IH)5 7.62 (d, J= 7.95 Hz, IH)5 7.43 (d, J = 8.25 Hz, IH), 7.29 (d, J= 8.07 Hz, IH), 7.21-7.14 (m, 7H)5 7.10 (d, J= 7.59 Hz5 IH)5 7.03 (t5 J= 7.33 Hz5 IH)5 6.90 (t, J= 7.7 Hz, IH), 5.61 (dd, J= 10.95 and 5.31 Hz5 IH)5 4.SS (bs, IH)5 3.50 (dd, J= 17.55 and 11.19 Hz, IH)5 2.90 (dd5 J= 17.55 and 5.28 Hz5 IH) EXAMPLE 46 (±)-N-[5-(4-Chloro-phenyl)-l-(254-dichloro-phenyl)-455-dihydro-lH-pyrazol-3- ylmethyl]-C-(757-dimethyl-2-oxo-bicyclo[2.2.1]hept-l-yl)-methanesulfonamide 1H-NMR: 7.61 (d, J= 3.33 Hz5 IH)5 7.36 (d, J= 2.11 Hz, IH)5 7.28 (m, 2H), 7.26 (d, J = 2.83 Hz, IH), 7.20-7,16 (m, 3H), 5.63 (dd, J = 6.17 and 3.12 Hz, IH), 4.06 (d, J = 5.21 Hz, 2H), 3.51-3.43 (m, IH)5 3.38 (s, IH), 3.02 (dd, J= 14.65 and 12.37 Hz, IH), 2.91 (dd, J= 14.65 and 4.94 Hz, IH), 2.36-2.31 (bd, 2H)5 2.03-1.88 (m, 3H), 1.54 (m, IH), 1.40 (m, IH), 1.00 (d5 J= 3.24 Hz5 3H), 0.77 (d, J= 3.98 Hz, 3H) EXAMPLE 47
(±)-N-[5-(4-Chloro-phenyl)-l-(254-dichloro-ρhenyl)-4,5-dihydro-lH-ρyrazol-3- ylmethyl]-C-(757-dimethyl-2-oxo-bicyclo[2.2.1]hept-l-yl)-methanesulfonamide 1H-NMR: 8.30 (t, J = 5.76 Hz ,1H), 7.84 (d, J = 8.50 Hz5 2H)5 7.68 (d5 J = 8.49 Hz5 2H)5 7.24-7.20 (m, 3H), 7.13-7.06 (m, 4H), 6.91-6.86 (m, IH), 5.46 (dd, J= 11.06 and 6.05 Hz5 IH)5 3.87 (d, J= 5.60 Hz5 2H), 3.29 (dd, J= 17.65 andl l.24 Hz5 IH), 2.72 (dd, J= 17.52 and 6.06 Hz, IH) EXAMPLE 48
(±)- 1 - [5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3- ylmethyl]-3-(3,4-dichloro-phenyl)-urea
1H-NMR: 9.08 (s, IH), 7.84 (d, J= 2.20 Hz, IH), 7.45 (d, J= 8.79 Hz3 IH), 7.36 (d, J= 2.10 Hz, IH), 7.32-7.25 (m, 2H), 7.22-7.14 (m, 2H), 7.08 (d, J = 8.91 Hz, 2H), 6.72 (t,
J= 5.28 Hz, IH), 5.61 (dd, J= 10.92 and 4.8 Hz, IH), 4.11 (d, J= 5.08 Hz, 2H), 3.47
(dd, J= 17.62 and 11.18 Hz, IH), 2.88 (dd, J= 17.62 and 4.83 Hz, IH)
EXAMPLE 49
(±)-Benzo[l,3]dioxole-5-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)- 4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
1H-NMR: 8.76 (t, J= 5.40 Hz, IH), 7.47 (d, J= 8.20Hz, IH), 7.40 (s, IH), 7.35 (d, J=
2.05 Hz, IH), 7.29 (s, IH)5 7.27-7.14 (m, 5H), 6.98 (d, J= 8.11 Hz, IH), 6.08 (s, 2H),
5.59 (dd, J= 10.95 and 4.87 Hz, IH), 4.26 (t, J= 5.37 Hz ,2H), 3.47 (dd, J= 17.65 and
11.21 Hz, IH), 2.85 (dd, J= 17.68 and 4.89 Hz, IH) EXAMPLE 50
(±)-iV-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -isonicotinamide
1H-NMR: 9.23 (t, J = 5.53 Hz, IH), 8.73 (d, J = 5.72 Hz, IH), 7.77 (d, J = 5.76 Hz,
2H), 7.36 (d, J = 2.10 Hz, IH), 7.29-7.23 (m, 3H), 7.21-7.15 (m, 3H), 5.61 (dd, J = 10.99 and 5.04 Hz5 IH)5 4.31 (t, J = 4.76 Hz ,2H), 3.50 (dd, J= 16.50 and 11.14 Hz,
IH), 2.88 (dd, J= 17.68 and 5.05 Hz, III)
EXAMPLE 51
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -nicotinamide 1H-NMR: 9.13 (t, IH), 9.02 (d, J= 1.47 Hz, IH), 8.70 (dd, J= 4.74, 1.29 Hz, IH), 8.20
(d, J= 7.97 Hz, IH), 7.52 (m, IH), 7.36 (d, J= 2.19 Hz, IH), 7.27-7.23 (m, 3H)5 7.21-
7.15 (m, 3H), 5.61 (dd, J= 11.01 and 5.07 Hz, IH), 4.31 (t, J= 5.43 Hz ,2H), 3.51 (dd,
J= 17.69 and 11.23 Hz, IH), 2.90 (dd, J= 17.68 and 5.08 Hz, IH)
EXAMPLE 52 (±)-4-tert-Butyl-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-benzaniide
1H-NMR: 8.84 (t, J = 5.47 Hz, IH)5 7.80 (d, J = 8.21 Hz, 2H), 7.47 (d, J = 8.23 Hz5
2H), 7.35 (d, J= 1.97 Hz5 IH)5 7.28 (d, J= 8.77 Hz5 IH), 7.24-7.14 (m, 5H), 5.60 (dd, J = 10.93 and 4.83 Hz5 IH), 4.28 (t, J= 5.34 Hz ,2H), 3.47 (dd, J= 17.62 and 11.10 Hz5
IH), 2.84 (dd, J= 17.69 and 4.80 Hz, IH), 1.28 (s, 9H)
EXAMPLE 53
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -2-(4-trifluoromethyl-phenyl)-acetamide
1H-NMR: 8.61 (t, J = 5.49 Hz, IH), 7.58 (d, J = 8.08 Hz, 2H), 7.48 (d, J = 7.99 Hz,
2H), 7.35 (d, J = 2.00 Hz5 IH), 7.21 (dd, J = 8.63, 2.28 Hz5 2H)5 7.15 (dd, J = 8.77,
2.09 Hz, IH), 7.09 (d, J= 8.34 Hz, 2H), 5.57 (dd, J= 11.31 and 4.97 Hz, IH), 4.08 (d J
= 5.52 Hz, 2H), 3.58 (s, 2H), 3.38 (dd, J= 17.73 and 11.27 Hz5 IH)5 2.74 (dd5 J= 17.66 and 4.72 Hz, IH)
EXAMPLE 54
(±)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -phenyl-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -amide
1H-NMR: 11.59 (s, IH), 8.87 (t, IH)5 7.60 (d, J= 7.92 Hz5 IH), 7.38 (m, 3H), 7.28 (d, J = 8.31 Hz, 2H), 7.07 (m, 5H), 6.83 (d, J= 7.92 Hz, 2H), 6.66 (t, J= 7.11 Hz, IH), 5.23
(dd, J= 11.7 and 7.17 Hz5 IH), 4.28 (d, J= 5.22 Hz, 2H), 3.55 (dd, J= 17.79 and 12.24
Hz, IH), 2.66 (dd, J= 17.85 and 6.99 Hz, IH)
EXAMPLE 55
(±)-4-(4-Chloro-phenoxy)-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro- lH-pyrazol-3-ylmethyl]-butyramide
1H-NMR: 8.31 (t, J= 4.2 Hz5 IH)5 7.33 (d, J= 1.8 Hz, IH)5 7.26-7.22 (m, 4H), 7.17-
7.12 (m, 3H)5 6.95-6.94 (m, 2H), 6.85-6.83 (m, IH)5 5.58-5.54 (dd, J = 8.1 and 3.6 Hz5
IH), 4.05 (d, J= 3.3 Hz, 2H), 3.98-3.94 (t, J= 4.8 Hz5 2H)5 3.41-3.36 (dd, J =13.2 and 4.5 Hz5 IH)5 2.83-2.78 (dd, J= 13.2 and 4.5 Hz, IH)5 2.3 (t, J = 5.6 Hz, 2H), 1.93 (t, J= 5.1 Hz, 2H)
EXAMPLE 56
(±)-5-Bromo-furan-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
1H-NMR: 8.86 (t, J= 4.35 Hz, IH), 7.35 (d, J= 1.8 Hz5 IH)5 7.27-7.20 (m, 3H), 7.19- 7.15 (m, 4H), 6.76 (d, J= 2.7 Hz5 IH), 5.61-5.57 (dd, J =8.1 and 3.9 Hz, IH), 4.22 (d, J
= 3.45 Hz, 2H), 3.50-3.43 (dd, J= 13.2 and 8.4 Hz5 IH), 2.87 (dd, J= 13.2 and 3.9 Hz5
IH) EXAMPLE 57
(±)-2,6-Dichloro-N-[5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3-ylmethyI]-benzamide
1H-NMR: 8.97 (t, J= 4.25 Hz5 IH)5 7.68 (d, J = 1.2 Hz, IH), 7.51-7.46 (m, 2H)5 7.36
(d, J = 1.8 Hz, IH), 7.32 (d, J = 6.6 Hz5 IH), 7.26-7.21 (m5 2H)5 7.20-7.16 (m, 3H),
5.66-5.62 (dd, J= 8.4 and 3.6 Hz5 IH)5 4.25 (d, J= 4.5 Hz, 2H), 3.57-3.49 (dd, J= 13.2 and 8.4 Hz5 IH), 2.97-2.92 (dd, J= 13.2 and 3.9 Hz5 IH)
Biological activity
In vitro study:
Compounds of the present invention in the cAMP accumulation model, antagonizes the WIN-55, 212-2 inhibition of forskolin-induced cAMP accumulation in !1CB1-CHO cells
(Table 1) [JPharmacol. Exp. Ther., 1998, 284, 291-297].
Table 1: Effect of representative compounds on the WIN-55212-2 inhibition of forskolin-induced cAMP accumulation in hCB^CHO cells at concentration of 10 DM.
Figure imgf000033_0001
Figure imgf000034_0001
In vivo study:
In a mouse vas deferens preparation, representative compounds cause rightward shift of the WIN-55212-2 concentration-response curve (Eur. J. Pharm. 1995, 284, 241- 247). Representative compounds of the present invention have shown decrease in sucrose solution intake in rat model (Table 2) [Psychopharmacology, 1997, 132, 104- 106].
Table 2: Effect of representative compounds on the intake of 5 % sucrose solution in animal model.
Figure imgf000034_0002
* formula for calculation :
[Total consumption — Mean total consumption of control]
X lOO [Mean total consumption by control]
number of animals in a group = 6.
No significant adverse effects were observed for any of the mentioned compounds of invention.

Claims

We claim:
1. Compounds of general formula (I),
Figure imgf000035_0001
(I) wherein
'A' represents 5-6 membered aromatic, heteroaromatic or heterocyclic groups optionally containing one or more substitutions defined by 'Ra'; R1 represents H or an alkyl group; R2 is selected from
- C1-C12 straight or branched alkyl chain optionally substituted by halogen, hydroxy, nitro, nitrile groups; optionally substituted aryl, cycloalkyl, heterocyclyl, heteroaryl, arylalkyl, heterocyclylalkyl, or heteroarylalkyl groups; X is selected from the groups CO, SO2, CN, CS;
'Ra' and 'Rb' can be same or different and at each occurrence may be independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, or the group (O-SO2)alkyl groups;
'n' and 'm' independently represents an integer from 0-4.
2. A compound as claimed in claim 1, wherein the substituent 'Ra' is present in the para position of ' A' .
3. A compound as claimed in claim 1 wherein the aryl groups is selected from phenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, biphenyl groups.
4. A compound as claimed in claim 1, wherein the "cycloalkyl" group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups.
5. A compound as claimed in claim 1 wherein the "heteroaryl" group is 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.
6. A compound as claimed in claim 1 wherein the "heterocyclyl" group are selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2- oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomoφholinyl, 2-oxomoφholinyl, 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.
7. A compound as claimed in one or more preceding claims wherein the substituents on R2 are selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, alkylthio, thioalkyl, cycloalkyl groups, the substituents on the cycloalkyl group may be selected from hydrogen, halogen, alkyl, alkoxy,. hydroxyl, haloalkyl, haloalkoxy, cyano, alkylthio, thioalkyl groups.
8. A compound as claimed in any preceding claims selected from (±)-lH-Indole-2-carboxylic acid [5-(4-chloro-phenyi)-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)- 1 -(2,4-dichloro-ρhenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
■ (+)-7V-[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)- 1 -(2,4-dichloro-ρhenyl)-4,5-dihydro- 1 H-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-phenyl)-l -(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (-)-5-Chloro-thiophene-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro- phenyl)-455-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(+)- 1 H-Indole-2-carboxylic acid [1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (+)-lH-Indole-2-carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro- 1 H-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 -ylmethyl] -amide
(+)-Cyclohexane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-Cyclohexane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-ΛL[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 (4-flurophenyl)-acrylamide (±)-iV-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl] -3 (4-methoxy-phenyl)-acrylamide
(±)-iV-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 - ylmethyl] -4-Chlorobenzamide
(±)-N-[5-(4-Bromo-phenyl)-l-(254-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -3 -(3 -Chloro-phenyl)-acrylamide
(±)-JV-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl] -3 -cyclohexyl-acrylamide
(±)-Piperidine-l -carboxylic acid[5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-455- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide (±)- 1 -[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 - ylmethyl] -3 -cylohexyl thiourea
(±)-5-Chlorothiophene-2-carboxylic acid -[5-(4-bromo-phenyl)- 1 -(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-iV-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-455-dihydro-lH-pyrazol-3- ylmethyl]-2-methoxy-benzamide
(±)-N-[5-(4-Bromo-ρhenyl)-l-(2?4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-chlorobenzamide (±)-N- [5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3 - ylmethyl]-4-(5-trifluoromethyl-pyridin-2-yloxy)-butyramide
(±)-5-Chloro-lH-indole-3-carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (±)-lH-Indole-3-carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-N-[5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H-pyrazol-3- ylmethyl] -3 -trifluoromethyl-benzamide
(±)-Heptanoic acid-[5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide
(±)-iV-[5-(4-Bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide
(±)-iV-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide (±)-2-Propyl-pentanoic acid-[5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-2-Propyl-pentanoic acid-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)- lH-Indole-2-carboxylic acid [1 ,5-bis-(4-chloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -amide
(±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-Cyclohexanecarboxylic acid [1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (±)-4-Chloro-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-benzamide
(±)-4-tert-Butyl-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl] -benzamide
(±)-4-Chloro-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-ρhenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzenesulfonamide
(±)-N-[l-(254-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3 -(4-fluoro-phenyl)-acrylamide
(±)-l-Cyclohexyl-3-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethy 1] -urea (±)-7V-[l-(2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-(4-methoxy-phenyl)-acrylamide
(±)-3-(4-Chloro-phenyl)-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -acrylamide (±)-5-Chloro-thiophene-2-carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy- phenyl)-4, 5 -dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-l-Cyclohexyl-3-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-
1 H-pyrazol-3 -ylmethyl] -thiourea
(±)-Heptanoic acid [1 -(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-Cyclopentanecarboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-Adamantane-l-carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (±)-4-Chloro-N-[l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -2-nitro-benzamide
(-)-Cyclohexanecarboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(-)-Heptanoic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -amide
(±)-7V-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-4,5-dihydro-lH-ρyrazol-3- ylmethyl]-4-trifluoromethoxy-benzenesulfonamide
(±)-Cyclohexanecarboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide (±)-5-Chloro-lH-indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-lH-Indole-2-carboxylic acid (l,5-diphenyl-4,5-dihydro-lH-pyrazol-3- ylmethyl)-amide
(±)-Isoquinoline-3-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)- 4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-Quinoline-8-sulfonic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide (±)-5-Chloro-thiophene-2-sulfonic acid [5-(4-chloro-phenyl)- 1 -(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-benzamide (±)-Cyclopropane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-2-Oxo-2H-chromene-3-carboxylic acid [5-(4-chloro-phenyl)- 1 -(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-Cyclobutane carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)- 1 -[5-(4-Chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5 -dihydro- 1 H-pyrazol-3 - ylmethyl] -3 -cyclohexyl-urea
(±)-2-Chloro-8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid [5-(4-chloro- phenyl)-l-(2,4-dichloro-pheήyl)-4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (±)-2-Chloro-N-[5-(4-chloro-phenyl)- 1 -(2,4-dichloro-phenyl)-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -benzamide
(±)-3-Chloro-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide
(±)-4-Chloro-iV-[5-(4-chloro-phenyl)-l-(254-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3-ylmethyl]-benzamide
(±)-l-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethy 1] -3 -cyclohexyl-thiourea
(±)-4-(4-Chloro-phenoxy)-iV-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -butyramide (±)-5-Bromo-furan-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-
4,5-dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-2,6-Dichloro-iV-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-455-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide
(±)-2-{[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-ρyrazol-3- ylmethylj-carbamoyty-pyrrolidine-r-carboxylic acid tert-butyl ester
(±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -4-hydroxy-benzamide (±)-iV-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-ρyrazol-3- ylrnethyl]-4-cyano-butyramide
(+)-Heptanoic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3-yl-methyl amide (±)-Cyclobutane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-
455-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-2-Prόpyl-pentanoic acid [l-(2,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-Heptanoic acid [5-(4-chloro-phenyl)-l -(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -amide
(-)-2-Propyl-pentanoic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)- 4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide
(±)-5-Chloro-lH-indole-2-carboxylic acid [5-(4-chloro-phenyl)-l-(2,4-dichloro- phenyl)- 4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide (±)-Cyclopentane carboxylic acid [5-(4-bromo-phenyl)-l-(2,4-dichloro-phenyl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-Cyclohexane carboxylic acid [l-(2,4-dichloro-phenyl)-5-(4-methyl-thien-2-yl)-
4,5-dihydro-lH-pyrazol-3-ylmethyl]-amide
(±)-2-Propyl-pentanoic acid [5-[4-(5-chloro-pentyl)-phenyl]-l-(2,4-dichloro- phenyl)-4,5-dihydro-lH-pyrazol-3-ylmelhyl]-amide
(±)-Cyclopentanecarboxylic acid [5-(4-chloro-phenyl)-l -phenyl-4,5-dihydro-lH- pyrazol-3 -ylmethyl]-amide
(±)-lH-Indole-2-carboxylic acid [l-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4,5- dihydro- 1 H-pyrazol-3 -ylmethyl] -amide (±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-l-yl)-methanesulfonamide
(±)-l-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-ρhenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-3-(3,4-dichloro-phenyl)-urea
(±)-Benzo[l,3]dioxole-5-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] -isonicotinamide (±)-N-[5-(4-Chloro-phenyl)-l-(2:>4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl] -nicotinamide
(±)-4-tert-Butyl-N-[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH- pyrazol-3 -ylmethyl] -benzamide (±)-N-[5-(4-Chloro-phenyl)-l-(2,4-dichloro-phenyl)-4,5-dihydro-lH-pyrazol-3- ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide
(±)- 1 H-Indole-2-carboxylic acid [5-(4-chloro-phenyl)- 1 -phenyl-4,5-dihydro- 1 H- pyrazol-3 -ylmethyl] -amide
9. A pharmaceutical composition which comprises compounds of formula (I)5 as claimed in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients.
10. A method of preventing or treating diseases caused by CB1 cannabinoid receptors comprising administering an effective, non-toxic amount of compound of formula (I) or suitable pharmaceutical composition as defined in any preceding claims to a patient in need thereof.
11. The method according to any preceding claims, wherein the disease is obesity, substance dependence, psychotic disorders, wherein CB1 cannabinoid receptor is the underlying pathophysiologal mechanism.
12. A medicine for treating/reducing any of the disease conditions described in any preceding claims which comprises administering a compound of formula (I), as defined in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients to a patient in need thereof.
13. Use of compounds of formula (I), their pharmaceutical compositions and medicines containing them as defined in any previous claims as a medicament suitable for the treatment of diseases mentioned in any of the aforesaid claims.
14. A process for preparing compounds of formula (I) as claimed in claim 1, comprising: i) converting carboxylic acid derivative of formula (V) into the acid chloride derivative by halogenating agents selected from thionyl chloride, oxalyl chloride, phosphorous pentachloride or mixtures thereof and further reacting with ammonia to obtain amide derivative of formula (IV), wherein all symbols are as defined earlier,
Figure imgf000043_0001
ii) reacting amide derivative of formula (IV) with a mixture of oxalyl chloride and dimethyl formamide to give cyano derivative of formula (III);
Figure imgf000043_0002
ϋi) converting cyano derivative of formula (III) amine derivative of general formula (II).
Figure imgf000043_0003
(III) (H) iv) coupling amine derivative of formula (II) with suitable substituted/unsubstituted heteroaryl carboxylic acid, sulfonic acid using coupling agents selected from DMAP, DCC, HOBt.H2O, EDC. HCl to obtain amide derivative of formula (I).
Figure imgf000043_0004
alternatively," monoalkylating amine of general formula (II) with suitable alkylating agents selected from Ri-halides wherein R1 is as defined earlier, followed by reaction with suitable carboxylic acids or sulfonyl halides to give the compounds of formula (I).
15. A compound of formula (II)
Figure imgf000044_0001
(II) wherein
'A' represents 5-6 membered aromatic, heteroaromatic or heterocyclic groups optionally containing one or more substitutions defined by Ra; 'Ra' and 'Rb' at each occurrence may be independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, or the group (O-Sθ2)alkyl groups; 'n' and 'm' independently represents an integer from 0-4.
PCT/IN2007/000320 2006-07-31 2007-07-27 Substituted 4,5-dihydro-1h-pyrazole derivatives as cannabinoid modulators WO2008062424A2 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2864958A1 (en) * 2004-01-12 2005-07-15 Sanofi Synthelabo New 1,5-diphenyl-3-sulfonamidomethyl-1H-pyrazole derivatives are cannabinoid receptor antagonists used for treating e.g. eating disorders, gastrointestinal disorders, inflammation and immunological disorders
WO2005077911A1 (en) * 2004-02-17 2005-08-25 Laboratorios Del Dr. Esteve S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
EP1602656A1 (en) * 2004-05-24 2005-12-07 NEUROSCIENZE PHARMANESS S.C. a R.L. Pyrazole derivatives having affinity for cb1 and/or cb2 receptors
WO2008043544A1 (en) * 2006-10-11 2008-04-17 Laboratorios Del Dr. Esteve, S.A. Sulfonamide substituted pyrazoline compounds, their preparation and use as cb1 modulators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2864958A1 (en) * 2004-01-12 2005-07-15 Sanofi Synthelabo New 1,5-diphenyl-3-sulfonamidomethyl-1H-pyrazole derivatives are cannabinoid receptor antagonists used for treating e.g. eating disorders, gastrointestinal disorders, inflammation and immunological disorders
WO2005077911A1 (en) * 2004-02-17 2005-08-25 Laboratorios Del Dr. Esteve S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
EP1602656A1 (en) * 2004-05-24 2005-12-07 NEUROSCIENZE PHARMANESS S.C. a R.L. Pyrazole derivatives having affinity for cb1 and/or cb2 receptors
WO2008043544A1 (en) * 2006-10-11 2008-04-17 Laboratorios Del Dr. Esteve, S.A. Sulfonamide substituted pyrazoline compounds, their preparation and use as cb1 modulators

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