WO2008075118A1

WO2008075118A1 - Novel cb1 antagonists and their preparation

Info

Publication number: WO2008075118A1
Application number: PCT/HU2007/000126
Authority: WO
Inventors: János Fischer; Attila SZEMZÖ; György SZABÓ; Péter ERDÉLYI; Balázs VARGA; István Gyertyán; Judit Szikra; Mónika VASTAG
Original assignee: Richter Gedeon Nyrt.
Priority date: 2006-12-19
Filing date: 2007-12-19
Publication date: 2008-06-26
Also published as: HU0600925D0; HUP0600925A2; HUP0600925A3

Abstract

The invention relates to new compounds of general formula (I) acting as CB1 antagonists and to their preparation. The compounds according to this invention can be used for the treatment of obesity, behavioral addictions, psychiatric and metabolic disorders.

Description

Novel CBl antagonists and their preparation

Introduction

The present invention relates to new compounds of general formula (I) acting as CBl antagonists and to their preparation. The compounds according to this invention can be used for the treatment of obesity, behavioral addictions, psychiatric and metabolic disorders.

Background of the invention

Terpenoids of Cannabis sativa have been used for several thousand years as folk medicines, but their use has been banned since 1930s because of their addictive potential. A new era started in 1990s in the pharmacology of cannabionoids when the endocannabinoid system has been discovered. Identification of the receptors CBl (1990) and CB2 (1992) made it possible to develop selective agonists and antagonists and to study the endocannabinoid system (Howlett et al., 2002).

Rimonabant, a diaryl-pyrazole derivative, has been published in the patent EP 576 357 as the first potent and selective CBl antagonist. In animal models the CBl antagonists and inverse agonists are effective in the treatment of depression, anxiety, schizophrenia, nicotine, alcohol- and cocaine addiction, obesity, metabolic syndrome and related disorders, such as dyslipidemia and type II diabetes etc.

The molecules of diaryl-pyrazole structure are important among the CBl antagonists under development (Muccioli et al.: Current Medicinal Chemistry (2005), 12, 1361-94). The majority of the published CBl antagonists belong to this structural group. Their activity and medicinal application have been proven in clinical tests. The first and best known representative of this class, the above mentioned rimonabant (Acomplia^®) was active and well tolerated in clinical trials of obese patients and average weight loss of 3.4 kg and 6.6 kg have observed at one year treatment in doses of 5 mg and 20 mg, resp. (LF Van Gaal et al, RIO- Europe Study (2005), Lancet, 365, 1389-1397). Treatment of diseases e.g. obesity, connected to potential field of application of CBl antagonists often needs lifelong drug therapy. Because of high comorbidity in this condition application of several drugs at the same time is very common in clinical practice therefore there is a high risk of drug interaction incidents.

Therefore obvious need emerged for introduction of medication having good pharmacokinetic parameters resulting in less drug-drug interactions.

Compounds metabolized intensively before entering systemic circulation (first-pass effect) are highly prone to drug-drug interactions. A compound that metabolized in 80% can evoke pharmacological effect by only the remaining 20% that reaches the circulation. A coadministered enzyme inhibitor can multiply the plasma level of an enzyme substrate so much that it can reach toxic concentration. Therefore, higher metabolic stability means less capability for drug-drug interactions. High metabolic stability not only results in less capability to drug-drug interactions but it has additional advantages considering drug safety. (See: Venkatakrishnan K. et.al.: Drug metabolism and drug interactions: application and clinical value of in vitro models. Current Drug Metabolism 4, 423-459, 2003). Lower dose of a metabolically stable compound is needed to evoke the desired pharmacological effects; besides, less accumulation of metabolites occurs as well. Metabolisms of several xenobiotics results in formation of toxic metabolites.

Tremendous information is available on the mechanisms of action of diaryl-pyrazoles but their pharmacokinetic is under investigation. Only one reference has been published on the metabolism of diaryl-pyrazoles (Zhang et al., 2001); therefore, it was reasonable to study the in vitro metabolism of rimonabant. Our results showed, that in human, rat and mouse liver microsomes the rimonabant has weak/moderate metabolic stability (mouse=35%; rat=37%; human=52%).

Accordingly, potent and in vivo effective but higher metabolic stability diaryl- pyrazole analogues may bring remarkable improvement in the effectiveness of therapies recently used. Summary of the invention

The present invention relates to new compounds of formula (I),

a.)

-N (CH₂), m

b.)

— N O

c.)

wherein

• n is an integer from 0 to 3,

• X and Y are each independently hydrogen, halogen, or C₁-C₅ alkyl group,

• R₁ and R₂ are each independently hydrogen, halogen, C₁-C4 alkyl group or C₁- C₄ alkylmercapto group,

• R₃ is hydrogen, C₁-C₄ alkyl group or C₁-C₄ alkoxy group, • R4 is a cycloalkyl ring having about 3 to about 6 members ring, optionally substituted with a hydroxy group or a group having formula a.), b.) and c.) where

• m is an integer from 4 to 6, • Z is hydrogen, halogen, C₁-C₄ alkyl, hydroxy, trifluoromethyl or methoxymethyl group, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof.

The invention also relates to the process of their synthesis as well as the pharmaceutical composition containing the same and the use for diseases or disorders associated with cannabinoid system e.g. psychiatric disorders such as schizophrenia (Weiser and Noy; Dialogues in Clinical Neuroscience Vol.7 No.l. 2005), depression (Witkin; Trends Pharmacol Sci. 2005 Dec 26(12):609-17) anxiety, (Griebel; Biol Psychiatry. 2005 Feb 1 57(3):261-7.), Huntington's chorea (Lastres-Becket; Neuroreport. 2003 May 6 14(6):813-6.), Alzheimer's disease (Mazzola Eur J Pharmacol. 2003 Sep 23 477(3):219-25.), metabolic syndrome and related disorders such as obesity and being overweight (van Gaal; Lancet. 2005 Apr 16-22 365(9468): 1389-97), dyslipidemia (Despres; N Engl J Med. 2005 Nov 17 353(20):2121-34.), type II diabetes (Despres; N Engl J Med. 2005 Nov 17 353(20):2121-34.) or atherosclerosis (Gomaraschi; IDrugs. 2005 JuI 8(7):555-9.), dependence and addictive disorders such as nicotine, cocaine, opioid, alcohol, methamphetamine dependence (Fattore; Brain Res Brain Res Rev. 2006 JuI 11), social dependence, such as pathological gambling or every other diseases in which cannabinoid system plays a special role e.g. different type of cancers (Sarnataro; MoI Pharmacol. 2006 Oct 70(4): 1298-306. Epub 2006 JuI 5.), cirrhosis (Gabbay; Liver Int. 2005 Oct 25 (5):921-6.) or hemorrhagia (Cainazzo; Eur J Pharmacol. 2002 Apr 19 441(l-2):91-7). Detailed description of the invention

The present invention relates to new compounds of formula (I),

a.)

-N (CH₂) ^r,m

b.)

— N O

c.)

wherein

• n is an integer from 0 to 3,

• X and Y are each independently hydrogen, halogen, or C₁-C₅ alkyl group,

• R₁ and R₂ are each independently hydrogen, halogen, C₁-C₄ alkyl group or C₁- C₄ alkylmercapto group,

• R₃ is hydrogen, CpC₄ alkyl group or Ci -C₄ alkoxy group, • R₄ is a cycloalkyl ring having about 3 to about 6 members ring, optionally substituted with a hydroxy group or a group having formula a.), b.) and c.) where

• m is an integer from 4 to 6, • Z is hydrogen, halogen, C₁-C₄ alkyl, hydroxy, trifluoromethyl or methoxymethyl group, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof. .The invention also relates to the process of the synthesis of compounds of formula (I). In compounds of formula (I) the meaning of halogen is fluoro, chloro, bromo and iodo atom, in the meaning OfR₁ and R₂ preferably fluoro, chloro and bromo atom.

In compounds of formula (I) the meaning of the alkyl group or the alkyl group at the alkoxy group is methyl, ethyl, n-propyl, n-butyl or its branched isomers such as isopropyl, tert-butyl, sec-butyl etc.

Synthesis of compounds of formula (I)

The synthesis of compounds of formula (I) can be shown on Scheme 1.

The reaction of compound of formula (II), wherein the meaning of X, Y and n is the same as mentioned before and compound of formula (III), wherein the meaning of R₃ is the same as mentioned before in the presence of AlCl₃ give compound of formula (IV), wherein X, Y, n and R₃ is the same as mentioned before, which is reacted with imidazol-1-yl-oxo- acetic acid ethyl ester in the presence of lithium bis(trimethylsilyl)amide to yield the diketon esters (V), wherein the meaning of X, Y, n and R₃ is the same as mentioned before, then reacting the obtained compound of formula (V) with the appropriate substituted phenyl hydrazine hydrochloride (VI), wherein the meaning of R₁ and R₂ is the same as mentioned before to give compounds of formula (VII), wherein the meaning of X, Y, n, R₁, R₂ and R₃ is the same as mentioned before, then hydrolyzing the ester groups of compounds of formula (VII) with KOH to give compounds having formula (VIII) wherein the meaning of X, Y, n, R₁, R₂ and R₃ is the same as mentioned before, which is reacted with oxalyl chloride, then reacted with compounds of formula (IX), wherein the meaning of R₄ is the same as above mentioned to yield compounds of formula (I).

The invention also relates to the process of their synthesis as well as the pharmaceutical composition containing the same and the use for diseases or disorders associated with cannabinoid system e.g. psychiatric disorders such as schizophrenia (Weiser and Noy; Dialogues in Clinical Neuroscience Vol.7 No.l. 2005), depression (Witkin; Trends Pharmacol Sci. 2005 Dec 26(12):609-17) anxiety, (Griebel; Biol Psychiatry. 2005 Feb 1 57(3):261-7.), Huntington's chorea (Lastres-Becket; Neuroreport. 2003 May 6 14(6):813-6.), Alzheimer's disease (Mazzola Eur J Pharmacol. 2003 Sep 23 477(3):219-25.), metabolic syndrome and related disorders such as obesity and being overweight (van Gaal; Lancet. 2005 Apr 16-22 365(9468): 1389-97), dyslipidemia (Despres; N Engl J Med. 2005 Nov 17 353(20):2121-34.), type II diabetes (Despres; N Engl J Med. 2005 Nov 17 353(20):2121-34.) or atherosclerosis (Gomaraschi; IDrugs. 2005 JuI 8(7):555-9.), dependence and addictive disorders such as nicotine, cocaine, opioid, alcohol, methamphetamine dependence (Fattore; Brain Res Brain Res Rev. 2006 JuI 11), social dependence, such as pathological gambling or every other diseases in which cannabinoid system plays a special role e.g. different type of cancers (Samataro; MoI Pharmacol. 2006 Oct 70(4): 1298-306. Epub 2006 JuI 5.), cirrhosis (Gabbay; Liver Int. 2005 Oct 25(5):921-6.) or hemorrhagia (Cainazzo; Eur J Pharmacol. 2002 Apr l9 441(l-2):91-7).

Compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof may be administered by any convenient method, for example by oral, parenteral buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

Pharmaceutical compositions containing compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

Liquid formulations of compounds of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof generally consist of a suspension or solution of a compound of formula (I) in an appropriate liquid carrier(s), for example an aqueous solvent, such as water, ethanol or glycerin or a non-aqueous solvent, such as polyethylene glycol or an oil. The pharmaceutical composition can also contain a suspending agent, preservative, flavoring and coloring agents.

A composition in the solid form of tablet can be prepared using any suitable pharmaceutical carrier(s), which are commonly used in practice, such as magnesium stearate, starch, lactose, saccharose, cellulose etc.

A composition in the solid form of capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

Compositions of the present invention for nasal administration containing the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. The aerosol dosages form can also take the form of a pump- atomizer. Compositions containing the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth or gelatine and glycerine etc. Composition of the present invention containing the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. Composition of the present invention containing the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches.

The compositions of the present invention containing the compound of formula (I) and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof are preferably in the unit dose form, such as tablet, capsule or ampoule.

The compounds of formula (I) of our invention are in vitro and in vivo effective CBl antagonists and their metabolic stability better than the common diaryl-pyrazoles stability, so the compositions containing the compounds of formula (I) as active ingredient are effective in lower dose and has lower capability for drug-drug interactions because of their higher metabolic stability than the known CBl antagonists till now. Biological evaluation

The in vitro CBl affinity of compounds of formula (I) was measured on [³H]SR- 141716A radioligand binding assay, their metabolic stability assessed using human, rat and mouse liver microsomes and their in vivo efficacy was determined by CBl agonist induced hypothermia test.

1. In vitro [³H]SR-Hl 716A radioligand binding at CBl receptors

For the evaluation of in vitro CBl affinities of compounds radioligand binding assay using [³H]SR- 141716A binding to rat cerebellum membrane preparation was employed. The assay was set up according to the methods of Thomas et al. (1998) and Devane et al. (1988). Aliquots of 200 μg rat brain membrane preparation were incubated at 30°C for 60 min in the presence of 0.04 nM [³H]SR-141716A in a thermostated shaker. Incubation was stopped by rapid vacuum filtration, filters were washed then radioactivity remaining on the filters was detected by scintillation spectrometry. Nonspecific binding was determined in the presence of 1 μM unlabelled SR-141716A. Data were analyzed and IC_5O values calculated using sigmoid fitting with the software Origin 6.0 then equilibrium inhibition coefficients (Kj) calculated using the Cheng-Prusoff equation (Cheng and Prusoff, 1973).

References:

Cheng Y. and Prusoff W.H. Biochem Pharmacol 22(23): 3099-3108, 1973 Devane W.A., Dysarz F.A., Johnson M.R., Melvin L.S. and Howlett M.C. MoI Pharmacol 34 (5): 605-613, 1988

Thomas B.F., Gilliam A.F., Burch D.F., Roche MJ. and Seltzmand H.H. JPET 285 (1): 285- 292, 1998)

10 2. In vitro metabolic stability in rat, human and mouse liver microsomes

Microsomes: Rat liver microsomes (Gedeon Richter, pool of 10); human liver microsomes (Xenotech, USA; pool of 50), CD-I mouse liver microsomes (Gedeon Richter, pool of 10).

Method: Metabolic stability of the test compounds was assessed using liver microsomes (see: Houston J.B.: Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance Biochemical Pharmacology 47, 1469-1479, 1994).

Metabolic stabilities were determined by incubation of test compounds with liver microsomes under first order reaction conditions. Consumption of test compound was monitored in time and unchanged test compound was quantified using high performance liquid chromatography. Intrinsic clearance (CLj_nO ^was calculated from the consumption-time curves by determination of the actual rate of enzyme reaction under first order conditions.

Metabolic bioavailability (F_M) was calculated comparing the intrinsic clearance to the hepatic blood flow. The metabolic bioavailability obtained is the highest possible bioavailability of the test compounds that is limited by the rate of liver metabolism.

Calculation of Metabolic Bioavailability: F_M = (1 - E_H) x 100; E_H = CL_int / (CL_int + HBF) where CL_int = V_max / K_n, or if [S] « K_n, than CL_int = v / [S] CLi_nt = intrinsic clearance; F_M = metabolic bioavailability; EH = hepatic extraction ratio; V_max ⁼ maximal rate of enzyme reaction; K_n, = affinity constant of a substrate; [S] = substrate concentration; v = actual rate of enzyme reaction under first order conditions; HBF = hepatic blood flow

3. In vivo CBl agonist induced hypothermia

CDl mice weighted ~30g was treated orally with various doses of the test compounds (pretreatment time = 60 min, n=8/group). 15 minutes hence, CBl agonist (WIN 55,212-2, 3 mg/kg, pretreatment time = 45 min) was given

and after 45 minutes, body temperatures was measured rectally. From the mean body temperatures of the different groups, inhibition percentage" was calculated (see below), and the results were plotted as the

11 dependent variable of the logarithm of the dose. ED50 values were calculated using linear regression (Microcal Origin 6.0, linear plot).

Calculation of the inhibition percentages: inh%=100x(Mx-Ma)/(Mc-Ma); where Mx = mean body temperature of a group treated with a dose of the test compound and later with the agonist; Ma = mean body temperature of the group treated with the vehicle of the test compound and later with the agonist; Mc = mean body temperature of the group treated with vehicle of the test compound and later with the vehicle of the agonist.

Biological results

The CBl affinity of compounds of formula (I) on radioligand binding assay were the same (Ki=5.6 nM) or better (2.7 nM < Ki < 62 nM) as compared to rimonabant as main reference.

The results of in vitro metabolic stability tests are summarized in Table 1.

Table 1

12 The results show, that rimonabant has weak/moderate metabolic stability. The metabolic stability of examples (1-4) covered by general structure (I) improved in parallel to the increasing size of cycloalkyl rings and reached the highest possible value of 99% in example 4.

Results of the hypothermia test show that compounds of formula (I) are in vivo potent CBl antagonist compounds. The obtained results show that oral efficacy of compounds of formula (I) are the same (ED50=0.41mg/kg) or better (3 mg/kg > ED50 > 0.1 mg/kg) as compared to rimonabant.

Examples

The invention is illustrated by the following not limiting examples. Example 1.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-l-fr-pyrazole- 3-carboxamide

a.:

1 -(4-cyclopropylphenyl)propan- 1 -one

To a stirred suspension of AlCl₃ (33.3 g, 0.25 mol) in trichloroethylene (50 ml) propionyl chloride (0.25 mol, 19.4 ml) was added dropwise at 0-5 °C. After stirring for 0.5 h the reaction mixture was cooled to -50 °C and cyclopropylbenzene (25 g, 0.21 mol) was added dropwise. The obtained mixture was stirred for 1 h at -50 °C then poured into a mixture of ice (250 g) and cc. HCl (30 ml). The organic layer was washed with NaHCO₃ (10% solution in water), dried over anh. MgSO₄ and evaporated in vacuo. The residue was purified by column chromatography using dichloromethane/hexane as eluent. Yield: 14 g (38%)

13 b.:

4-(4-cvclopropylphenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester

In a -70 ⁰C solution of lithium bis(trimethylsilyl)amide (91 ml, 91 mmol) in methyl t-butyl ether (223 ml) under argon atmosphere l-(4-cyclopropylphenyl)propan-l-one (14 g, 0.08 mol) dissolved in methyl t-butyl ether (116 ml) was added. The reaction mixture was allowed to warm to -10 °C then imidazol-1-yl-oxo-acetic acid ethyl ester (13.5 g, 0.08 mol) dissolved in methyl t-butyl ether (70 ml) was added. The so obtained mixture was stirred for 16 h at ambient temperature then a mixture of cc. HCl (50 ml) and water (50 ml) was added. The organic layer was separated and dried over anh. MgSO₄. The obtained crystalline product was used in the next step without further purification. Yield: 19.7 g (90%) c:

5-(4-cvclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-l-H-pyrazole-3-carboxylic acid ethyl ester To a stirred solution of 4-(4-cyclopropylphenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (19.7 g, 0.072 mol) in ethanol (230 ml) 2,4-dichlorophenylhydrazine hydrochloride (15.4 g, 0.072 mol) was added at ambient temperature, followed by addition of a mixture of cc. HCl (10 ml) and water (10 ml). The obtained suspension was refluxed for 3 h, then concentrated in vacuo. The residue was purified by column chromatography using dichloromethane as eluent. Yield: 9.3 g (31%)

d.:

5-(4-cyclopropylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- 1 -H-pyrazole-S-carboxylic acid To a stirred suspension of 5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-l-H- pyrazole-3-carboxylic acid ethyl ester (9.3 g, 0.022 mol) in methanol (28 ml) KOΗ (2.9 g, 0.051 mol) dissolved in water (28 ml) was added. The obtained suspension was refluxed for 2 h, then acidified with 3 M HCl. The precipitated product was collected by filtration and washed with water. Yield: 8.9 g (96%)

14 e.:

5-(4-cyclopropylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-iV-piperidin- 1 - yl- 1 -H-p yrazole-3 - carboxamide

To a stirred suspension of 5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-l-H- pyrazole-3-carboxylic acid (8.9 g, 0.021 mol) and DMF (0.36 ml) in dichloromethane (278 ml) oxalyl chloride (3.8 ml, 0.043 mol) was added dropwise with cooling. The mixture was stirred for 2 h at room temperature then evaporated in vacuo and dissolved in dichloromethane (80 ml). The so obtained solution was added dropwise to a stirred mixture of N-amino-piperidine (3.4 ml, 0.032 mol) and triethyl amine (4.5 ml, 0.032 mol) in dichloromethane (150 ml) at 0-5°C. The resulting mixture was allowed to warm to ambient temperature and stirred for 14-16 h then evaporated in vacuo. The residue was purified by column chromatography using dichloromethane/ethyl acetate as eluent. Yield: 8.6 g (80%)

Example 2.

5-(4-cyclobutylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-l-fl-pyrazole- 3-carboxamide hydrochloride

This compound was synthesized according to the method described in example 1 using 4- cyclobutylbenzene in step ,,a", which can be prepared by a known method starting from commercially available 2-phenyl-l,4-butanediol (W. F. BAILEY, P. R. GAGNIER, and J. J. PATRICIA., Journal of Organic Chemistry 49, (12) 2098-2107 (1984). 1U NMR(DMSO): 1.90-2.01 m (1Η); 1.99-2.11 m (2Η); 2.21-2.29 m (IH); 2.27 s (3H); 3.28- 3.41 m (4H); 3.44-3.55 m (IH); 7.13-7.18 m (2H); 7.23-7.27 m (2H); 7.59 d (IH); 7.77 d (IH); 7.79 d (IH)

15 Example 3.

5-(4-cyclopentylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-l-H-pyrazole-

3-carboxamide

This compound was synthesized according to the method described in example 1 using 4- cyclopentylbenzene in step ,,a", which can be prepared by the reaction of cyclopentanol and benzene (W. F. BAILEY, P. R. GAGNIER, and J. J. PATRICIA., Journal of Organic Chemistry 49, (12) 2098-2107 (1984).

¹H NMR(DMSO): 1.44-1.56 m (4H); 1.57-1.67 m (2H); 1.70-1.79 m (2H); 1.84-1.92 m (4H); 1.95-2.04 m (2H); 2.30 s (3H); 2.89-3.01 m (IH); 3.39-3.51 m (4H); 7.13-7.18 m (2H); 7.26- 7.30 m (2H); 7.59 dd (IH); 7.78 d (IH); 7.79 d (IH); 11.60 br s (IH)

Example 4. 5-(4-cyclohexylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-l-J9^r-pyrazole- 3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 4-cyclohexylbenzene in step ,,a".

1H NMR(DMSO): 1.16-1.26 m (IH); 1.29-1.41 m (4H); 1.46-1.56 m (2H); 1.64-1.73 m (IH); 1.73-1.81 m (4H); 1.82-1.88 m (4H); 2.28 s (3H); 2.43-2.50 m (IH); 3.34-3.48 m (4H); 7.12- 7.17 m (2H); 7.21-7.28 m (2H); 7.58 dd (IH); 7.76 d (IH); 7.79 d (IH); 11.38 br s (IH)

16 Example 5.

5-(4-cyclohexylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-iV-morpholin-l-yl-l-H^r-pyrazole-

3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 4-aminomorpholine in step ,,e".

¹H NMR(DMSO): 0.63-0.70 m (2H); 0.90-0.98 m (2H); 1.81-1.92m (IH); 2.21 s (3H); 2.81-

2.87 m (4H); 3.61-3.68 m (4H); 7.06 m (4H); 7.56 dd (IH); 7.71 d (IH); 7.75 d (IH); 9.25 s

(IH)

Example 6.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-pyrrolidine-l-yl-l-/f- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 1-aminopyrrolidine in step ,,e".

¹H NMR(DMSO): 0.63-0.71 m (2H); 0.90-0.99 m (2H); 1.68-1.78 m (2H); 1.81-1.93m (IH);

2.21 s (3H); 2.83-2.95 m (4H); 7.05 m (4H); 7.55 dd (IH); 7.71 d (IH); 7.74 d (IH); 9.03 s

(IH)

17 Example 7.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyI-Λ'-hexahydro- cyclopenta[c]pyrrole-2-yl-l-//-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 3-amino-3-azabicyclo[3.3.0]octane in step ,,e". 1H NMR(DMSO): 0.63-0.71 m (2H); 0.90-0.97 m (2H); 1.36-1.51 m (3H); 1.54-1.74 m (3H); 1.81-1.93 m (IH); 2.20 s (3H); 2.45-2.54 m (2H); 2.54-2.60 m (2H); 3.01-3.09 m (2H); 7.05 m (4H); 7.55 dd (IH); 7.69 d (IH); 7.74 d (IH); 8.88 s (IH)

Example 8.

5-(4-cyclopentylphenyl)-l-(2,4-dichIorophenyl)-4-methyl-N-morpholin-l-yl-l-H- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 3 using commercially available 4-aminomorpholine in step ,,e".

¹H NMR(DMSO): 1.47-1.57 m (2H); 1.60-1.70 m (2H); 1.71-1.82 m (2H); 1.98-2.06 m (2H); 2.29 s (3H); 2.91-3.02 m (IH); 3.08-3.18 m (4H); 3.78-3.85 m (4H); 7.07-7.11 m (2H); 7.20- 7.23 m (2H); 7.49 dd (IH); 7.61 d (IH); 7.62 d (IH); 10.14 br s (IH)

18 Example 9.

5-(4-cyclopentylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-7V-hexahydro- cyclopenta [c] py rrole-2-yl- l-//-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 3 using commercially available 3-amino-3-azabicyclo[3.3.0]octane in step ,,e". 1H NMR(DMSO): 1.42-1.80 m (12H); 1.95-2.05 m (2H); 2.28 s (3H); 2.80-2.89 m (2H); 2.89-3.01 m (IH); 3.17-3.28 m (2H); 3.96-4.04 m (2H); 7.13-7.17 m (2H); 7.25-7.30 m (2H); 7.61 dd (IH); 7.78 d (IH); 7.81 d (IH)

Example 10.

5-(4-cyclopentylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-Λ'-pyrrolidine-l-yl-l-H- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 3 using commercially available 1-aminopyrrolidine in step ,,e".

¹H NMR(DMSO): 1.42-1.53 m (2H); 1.57-1.67 m (2H); 1.68-1.78 m (2H); 1.94-2.02 m (2H); 2.04-2.13 m (4H); 2.28 s (3H); 2.91-3.00 m (IH); 3.69-3.76 m (4H); 7.13-7.19 m (2H); 7.25- 7.29 m (2H); 7.62 dd (IH); 7.77 d (IH); 7.78 d (IH)

19 Example 11.

5-(4-cyclophexylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-morpholin-l-yl-l-ZT- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 4 using commercially available 4-aminomorpholine in step ,,e".

¹H NMR(DMSO): 1.17-1.27 m (IH); 1.33-1.41 m (4H); 1.68-1.75 m (IH); 1.77-1.85 m (4H); 2.27 s (3H); 2.42-2.51 m (IH); 2.88-2.95 m (4H); 3.69-3.75 m (4H); 7.05-7.08 m (2H); 7.13- 7.18 m (2H); 7.44 dd (IH); 7.54-7.57 m (2H); 9.02 s (IH)

Example 12.

5-(4-cyclohexylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-iV-hexahydro- cyclopenta[c]pyrrole-2-yl-l-/?-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 4 using commercially available 3-amino-3-azabicyclo[3.3.0]octane in step ,,e". 1H NMR(DMSO): 1.14-1.26 m (IH); 1.26-1.40 m (4H); 1.53-1.81 m (HH); 2.27 s (3H); 2.44-2.52 m (IH); 2.80-2.93 m (2H); 3.17-3.29 m (2H); 3.96-4.06 m (2H); 7.12-7.18 m (2H); 7.22-7.28 m (2H); 7.60 dd (IH); 7.77 d (IH); 7.80 d (IH)

20 Example 13.

5-[4-(2,2-dichlorocyclopropyl)-phenyl]-l-(2,4-dichlorophenyl)-4-methyl-N-pyperidine-l- yl-l-//-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 2,2-dichloro-cyclopropylbenzene in step ,,a".

¹H NMR(DMSO): 1.27-1.37 m (2H); 1.52-1.65 m (4H); 2.00-2.20 m (2H); 2.28 s (3H); 2.75- 2.82 m (4H); 3.96-4.04 m (2H); 7.16-7.22 m (2H); 7.28-7.34 m (2H); 7.55 dd (IH); 7.72 d (IH); 7.73 d (IH); 9.02 s (IH)

Example 14.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-iV-piperidiii-l-yl-l-Z-^r-pyrazole-3- carboxamide hydrochloride

This compound was synthesized according to the method described in example 1 using acetyl chloride in step ,,a".

¹H NMR(DMSO): 0.64-0.69 m (2H); 0.91-0.98 m (2H); 1.42-1.51 m (2H); 1.76-1.83 m (4H); 1.84-1.92 m (IH); 3.25-3.35 m (4H); 7.03-7.08 m (2H); 7.10-7.15 m (2H); 7.24 s (IH); 7.65 dd (IH); 7.81 d (IH); 7.87 d (IH); 11.21 s (IH)

21 Example 15.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-Λ'-pyrrolidine-l-yl-l-H-pyrazole-3- carboxaniide hydrochloride

This compound was synthesized according to the method described in example 14 using commercially available l-aminopyrrolidine in step ,,e".

¹H NMR(DMSO): 0.63-0.70 m (2H); 0.92-0.98 m (2H); 1.85-1.93 m (IH); 1.95-2.05 m (4H); 3.47-3.63 m (4H); 7.01-7.08 m (2H); 7.11-7.15 m (2H); 7.28 br s (IH); 7.66 dd (IH); 7.81 d (IH); 7.88 d (IH); 11.8O s (IH)

Example 16.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-ethyl-iV-piperidin-l-yl-l-JEr-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using butyryl chloride in step ,,a".

¹H NMR(DMSO): 0.64-0.69 m (2H); 0.91-0.97 m (2H); 1.07 t (3H); 1.30-1.38 m (2H); 1.52- 1.65 m (4H); 1.82-1.92 m (IH); 2.62 q (2H); 2.74-2.81 m (4H); 7.03-7.09 m (4H); 7.51 dd (IH); 7.71 d (IH); 7.73 d (IH); 9.01 s (IH)

22 Example 17.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-ethyl-A^Lmorpholin-l-yl-l-ZT-pyrazole-

3-carboxamide

This compound was synthesized according to the method described in example 16 using commercially available 4-aminomorpholine in step ,,e".

¹H NMR(DMSO): 0.64-0.67 m (2H); 0.91-0.98 m (2H); 1.07 t (3H); 1.82-1.92 m (IH); 2.62 q (2H); 2.80-2.88 m (4H); 3.60-3.69 m (4H); 7.04-7.10 m (4H); 7.54 dd (IH); 7.72 d (IH); 7.74 d (IH); 9.28 s (IH)

Example 18.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-ethyl-iV-pyrrolidin-l-yl-l-H-pyrazole-

3-carboxamide

This compound was synthesized according to the method described in example 16 using commercially available 1-aminopyrrolidine in step ,,e".

¹H NMR(DMSO): 0.64-0.67 m (2H); 0.91-0.97 m (2H); 1.07 t (3H); 1.71-1.79 m (4H); 1.82- 1.92 m (IH); 2.62 q (2H); 2.85-2.94 m (4H); 7.03-7.09 m (4H); 7.53 dd (IH); 7.70 d (IH); 7.73 d (IH); 9.03 s (IH)

23 Example 19.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-ethyl-iV-hexahydro- cyclopenta[c]pyrrole-2-yl-l-17-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 16 using commercially available 3-amino-3-azabicyclo[3.3.0]octane in step ,,e". 1H NMR(DMSO): 0.63-0.69 m (2H); 0.91-0.97 m (2H); 1.06 t (3H); 1.36-1.52 m (3H); 1.54- 1.74 m (3H); 1.82-1.92 m (IH); 2.54-2.64 m (4H); 3.01-3.07 m (2H); 7.02-7.09 m (4H); 7.53 dd (IH); 7.70 d (IH); 7.74 d (IH); 8.90 s (IH)

Example 20.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methoxy-iV-piperidin-l-yl-l-H- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 starting from 2-methoxy-l-(4-cyclopropylphenyl)-ethanone (step "b").

¹H NMR (500 MHz, DMSO-J₆, 25 ⁰C) δ 9.03 (s, IH); 7.78 (d, J - 2.3 Hz, IH); 7.75 (d, J = 8.5 Hz, IH); 7.59 (dd, J = 8.5, 2.3 Hz, IH); 7.13-7.02 (m, 4H); 3.75 (s, 3H); 2.84-2.73 (m, 4H); 1.91-1.82 (m, IH); 1.63-1.52 (m, 4H); 1.39-1.29 (m, 2H); 0.97-0.90 (m, 2H); 0.70-0.63 (m, 2H) ppm.

24 Example 21.

5-(4-cyclopropylphenyl)-l-(2-chlorophenyl)-4-methyl-N-piperidin-l-yl-lH-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 2-chloro-phenylhydrazine hydrochloride in step ,,c". 1H NMR(CDCB): 0.64-0.69 m (2H); 0.92-0.99 m (2H); 1.38-1.47 m (2H); 1.71-1.79 m (4H); 1.79-1.87 m (IH); 2.37 s (3H); 2.83-2.89 m (4H); 6.93-7.02 m (4H); 7.25-7.35 m (3H); 7.37- 7.7.43 m (IH); 7.68 s (IH)

Example 22.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-((lR,2R)-2-hydroxy- cyclohexyl)-l//-pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available tran.s-2-amino-cyclohexanol in step ,,e".

25 ¹H NMR(DMSO): 0.63-0.68 m (2H); 0.90-0.96 m (2H); 1.13-1.30 m (4H); 1.56-1.65 m (2H); 1.82-1.92 m (3H); 2.22 s (3H); 3.35-3.43 m (IH); 3.52-3.61 m (IH); 4.58 d (IH); 7.05 m (4H); 7.54 dd (IH); 7.68 d (IH); 7.68 s (IH); 7.74 d (IH)

Example 23.

5-(4-cyclopropylphenyl)-l-(2-chlorophenyl)-4-methyl-N-pyrrolidin-l-yl-lJ9^r-pyrazole-3- carboxamide hydrochloride

This compound was synthesized according to the method described in example 22 using commercially available 1-aminopyrrolidine in step ,,e".

¹H NMR(CDCl₃): 0.64-0.69 m (2H); 0.93-0.99 m (2H); 1.79-1.87 m (IH); 2.23-2.31 m (4H); 2.33 s (3H); 3.86-3.93 m (4H); 6.94-7.03 m (4H); 7.29-7.41 m (4H); 9.50 br s (IH)

Example 24.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-(3-hydroxy-piperidin)-l-yl- l//-pyrazole-3-carboxamide hydrochloride

This compound was synthesized according to the method described in example 1 using 3- hydroxy-1-aminopiperidine in step ,,e".

26 ¹H NMR(CDCl₃): 0.64-0.72 m (2H); 0.93-1.01 m (2H); 1.65-1.96 m (4H); 2.30 s (3H); 2.33- 2.44 m (IH); 3.61-4.12 m (4H); 4.34-4.43 m (IH); 6.92-7.01 m (4H); 7.24-7.38 m (4H); 10.29 br s (IH)

Example 25.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-(4-hydroxy-piperidin)-l-yl- l//-pyrazole-3-carboxamide hydrochloride

This compound was synthesized according to the method described in example 1 using 4- hydroxy-1-aminopiperidine in step ,,e".

¹H NMR(DMSO): 0.65-0.69 m (2H); 0.91-0.97 m (2H); 1.44-1.55 m (2H); 1.70-1.78 m (2H); 1.83-1.91 m (IH); 2.20 s (3H); 2.66-2.74 m (2H); 2.88-2.91 m (2H); 3.44-3.51 m (2H); 4.59 d (IH); 7.04 m (4H); 7.55 dd (IH); 7.70 d (IH); 7.74 d (IH); 8.99 br s (IH)

Example 26.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-cyclohexyl-l/-^r-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available cyclohexylamine in step ,,e".

27 ¹H NMR(DMSO): 0.64-0.70 m (2H); 0.90-0.98 m (2H); 1.20-1.41 m (6H); 1.54-1.81 m (4H); 1.83-1.91 m (IH); 2.21 s (3H); 3.70-3.81 m (IH); 7.06 m (4H); 7.55 dd (IH); 7.71 d (IH); 7.75 d (IH); 7.84 d (IH)

Example 27.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-cyclopentyl-lH-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available cyclopenylamine in step ,,e".

¹H NMR(DMSO): 0.64-0.69 m (2H); 0.91-0.97 m (2H); 1.46-1.72 m (7H); 1.76-1.92 m (3H);

2.22 s (3H); 4.17-4.28 m (IH); 7.06 m (4H); 7.56 dd (IH); 7.70 d (IH); 7.75 d (IH); 7.94 d

(IH)

Example 28.

5-(4-cyclopropylphenyl)-l-(2-chloro-4-bromophenyl)-4-methyl-N-piperidin-l-yl-lZT- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 4-bromo-2-chloro-phenylhydrazine hydrochloride in step ,,c".

28 ¹H NMR(CDCl₃): 0.65-0.73 m (2H); 0.93-1.01 m (2H); 1.39-1.46 m (2H); 1.70-1.78 m (4H); 1.79-1.87 m (IH); 2.35 s (3H); 2.81-2.91 m (4H); 6.99 m (4H); 7.18 d (IH); 7.41 dd (IH); 7.57 d (IH); 7.63 s (IH)

Example 29.

5-(4-cyclopropylphenyl)-l-(2-bromo-4-chlorophenyl)-4-methyl-N-piperidin-l-yl-lH- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 2-bromo-4-chloro-phenylhydrazine hydrochloride in step ,,c". 1H NMR(CDCl₃): 0.66-0.71 m (2H); 0.94-1.01 m (2H); 1.37-1.46 m (2H); 1.71-1.79 m (4H); 1.80-1.88 m (IH); 2.36 s (3H); 2.82-2.89 m (4H); 6.96-7.02 m (4H); 7.22 d (IH); 7.30 dd (IH); 7.6O d (IH); 7.65 s (IH)

Example 30.

5-(4-cyclopropylphenyl)-l-(2-chloro-4-fluorophenyl)-4-methyl-N-piperidin-l-yl-l/f- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 4-fluoro-2-chloro-phenylhydrazine hydrochloride in step ,,c".

29 ¹H NMR(DMSO): 0.64-0.72 m (2H); 0.90-0.98 m (2H); 1.29-1.38 m (2H); 1.52-1.62 m (4H); 1.84-1.90 m (IH); 2.20 s (3H); 2.74-2.81 m (4H); 7.03-7.09 m (4H); 7.35 ddd (IH); 7.57 dd (IH); 7.75 dd (IH); 8.99 s (IH)

Example 31.

5-(4-cyclopropylphenyl)-l-(2-fluoro-4-chlorophenyl)-4-methyl-N-piperidin-l-yl-liϊ- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 2-fluoro-4-chloro-phenylhydrazine hydrochloride in step ,,c". 1H NMR(CDCl₃): 0.63-0.73 m (2H); 0.95-1.03 m (2H); 1.39-1.46 m (2H); 1.72-1.79 m (4H); 1.80-1.88 m (IH); 2.35 s (3H); 2.82-2.91 m (4H); 6.96-7.03 m (4H); 7.08 dd (IH); 7.17 dd (IH); 7.31 dd (IH); 7.65 s (IH)

Example 32.

5-(4-cyclopropylphenyl)-l-(2,4-difluorophenyl)-4-methyl-N-piperidin-l-yl-lH-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 2,4-difluoro-phenylhydrazine hydrochloride in step ,,c".

30 ¹H NMR(DMSO): 0.65-0.70 m (2H); 0.91-0.98 m (2H); 1.28-1.37 m (2H); 1.54-1.63 m (4H); 1.84-1.92 m (IH); 2.19 s (3H); 2.72-2.82 m (4H); 7.03-7.08 m (4H); 7.19-7.25 m (IH); 7.35- 7.42 m (IH); 1.66-1.11 m (IH); 9.02 s (IH)

Example 33.

5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-azepan-l-yl-l-/T-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available 1-aminohomopiperidine in step ,,e".

¹H NMR(DMSO): 0.64-0.72 m (2H); 0.91-0.98 m (2H); 1.53-1.59 m (4H); 1.60-1.69 m (4H); 1.84-1.92 m (IH); 2.20 s (3H); 2.95-3.03 m (4H); 7.05 m (4H); 7.55 dd (IH); 7.69 d (IH); 7.75 d (IH); 9.26 s (IH)

Example 34.

5-(4-cydopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-cyclopropyl-lH-pyrazole-3- carboxamide

This compound was synthesized according to the method described in example 1 using commercially available cyclopropylamine in step ,,e".

31 ¹H NMR(DMSO): 0.58-0.70 m (6H); 0.90-0.98 m (2H); 1.83-1.92 m (IH); 2.22 s (3H); 2.79- 2.87 m (IH); 7.06 m (4H); 7.54 dd (IH); 7.68 d (IH); 7.75 d (IH); 8.18 d (IH)

Example 35.

5-(4-methyl-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-iV-piperidin-l-yl-l-iy- pyrazole-3-carboxamide

This compound was synthesized according to the method described in example 1 using methyl-cyclopropylbenzene in step ,,a", which can be prepared by a known method starting from commercially available methylstyrene (S. E. DENMARK and J. P. EDWARDS, Journal of Organic Chemistry 56, (25) 6974-6981 (1991).

¹H NMR(DMSO): 0.70-0.78m (IH); 0.83-0.89 m (IH); 1.00-1.08 m (IH); 1.12 s (3H); 1.30-

1.39 m (2H); 1.52-1.63 m (5H); 2.19 s (3H); 2.74-2.82 m (4H); 6.99-7.07 m (4H); 7.55 dd (IH); 7.71 d (IH); 7.74 d (IH); 9.00 s (IH)

Example 36.

5-(4-methyl-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-iV-pyrrolidin-l-yl-l-/-^r- pyrazoIe-3-carboxamide

This compound was synthesized according to the method described in example 35 using commercially available 1 -amino-pyrrolidine in step ,,e".

32 ¹H NMR(DMSO): 0.70-0.78m (IH); 0.83-0.89 m (IH); 1.00-1.09 m (IH); 1.12 s (3H); 1.53- 1.62 m (IH); 1.69-1.79 m (4H); 2.20 s (3H); 2.84-2.93 m (4H); 6.99-7.07 m (4H); 7.55 dd (IH); 7.70 d (IH); 7.75 d (IH); 9.03 s (IH)

33

Claims

CLAIMS:

1. New compounds of formula (I),

a.)

-N (CH₂) 'm

b.)

— N O

c.)

wherein

• n is an integer from 0 to 3,

• X and Y are each independently hydrogen, halogen, or C₁-C₅ alkyl group,

• R₃ is hydrogen, Cj-C₄ alkyl group or C₁-C₄ alkoxy group,

34 • R₄ is a cycloalkyl ring having about 3 to about 6 members ring, optionally substituted with a hydroxy group or a group having formula a.), b.) and c.) where

2. 5-(4-cyclopropylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-iV-pyrrolidine- 1 -yl- 1 -H- pyrazole-3 -carboxamide,

5-(4-cyclopropylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-N-piperidin- 1 -yl- 1 -H-pyrazole-3 - carboxamide

5-(4-cyclobutylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-iV-piperidin- 1 -yl- 1 -H-pyrazole-3 - carboxamide

5-(4-cyclopentylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-7V-piperidin- 1 -yl- 1 -H-pyrazole-3 - carboxamide

5-(4-cyclohexylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-N-piperidin- 1 -yl- 1 -H-pyrazole-3 - carboxamide

3. Process for the synthesis of compounds of claims 1-2, characterized by a) reacting compound of formula (II), wherein the meaning of X, Y and n is the same as mentioned before with compound of formula (III), wherein the meaning of R₃ is the same as mentioned before to give compound of formula (IV), wherein X, Y, n and R₃ is the same as mentioned before, b) which is reacted with imidazol-1-yl-oxo-acetic acid ethyl ester in the presence of lithium bis(trimethylsilyl)amide to yield the diketon esters (V), wherein the meaning of X, Y, n and R₃ is the same as mentioned before, c) then reacting the obtained compound of formula (V) with the appropriate substituted phenyl hydrazine hydrochloride (VI), wherein the meaning of Ri and

R₂ is the same as mentioned before to give compounds of formula(VIi), wherein the meaning of X, Y, n, Ri, R₂ and R₃ is the same as mentioned before,

35 d) then hydrolyzing the ester groups of compounds of formula (VII) with KOH to give compounds having formula (VIII) as defined in claim 1 , e) which is reacted with oxalyl chloride, then reacted with compounds of formula (IX), wherein the meaning of R₄ is the same as above mentioned to yield compounds of formula (I).

4. Pharmaceutical composition containing a compound of claims 1-2 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof as well as one or more pharmaceutically acceptable adjuvant and auxiliary material.

5. Use of a compound of claims 1-2 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof for manufacturing a pharmaceutical composition for treating and/or preventing condition requiring influence on cannabinoid receptor.

6. A use according to claim 5, wherein the cannabinoid receptor is cannabinoid CBl receptor.

7. Method of treating and/or preventing condition requiring influence on cannabinoid receptor, characterized by administering to a mammal to be treated - including human - effective amount/amounts of a compound of claims 1-2 and/or geometric isomers and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof.

8. A method according to claim 7, wherein the cannabinoid receptor is cannabinoid CBl receptor.

36