Title of Invention

4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVES

Abstract

The present invention relates to a group of novel 4,5-dihydro-1H-pyrazole derivatives which are potent antagonists of the cannabis CB \- receptor. The compounds have general formula (I) wherein Rand R\ are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1,2 or 3 substituents Y or Rand/or R<sub>1</sub> represents hydrogen, hydroxy C<sub>4</sub>-<sub>3</sub> alkoxy,acetyloxy or propionyloxy,Aa represents one of the groups (i),(ii),(iii),(iv) or (v), Bb represents sulfonyl or carbonyl, R<sub>3</sub3 represents benzyl, phenyl,thienyl or pyridyl which may be substituted with 1,2 or 3 substituents Y or R<sub>3</sub> represents C<sub>1</sub>-<sub>8</sub> branched or unb.ranched alkyl or C<sub>3</sub>-<sub>8</sub> cycloalkyl, or R<sub>3</sub>, represents naphtyl.

Full Text

4,5-Dihvdro-1H-pvrazole derivatives having CB,-antaqonistic activity The present invention relates to a group of novel 4,5-dihydro~1 H-pyrazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component. The above mentioned 4,5-dihydro-1 H-pyrazoles are potent Cannabis-1 (CB,) receptor antagonists with utility for the treatment of psychiatric and neurological disorders. Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB, and CBZ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, LA.; Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CB, receptors in the brain, in combination with the strictly peripheral localisation of the CB2 receptor, makes the CB, receptor a very interesting molecular target for CNS-directed drug discovery in the areas of both psychiatric and neurological disorders (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. in CPNS Investigational Drugs 1999, 1, 587. Greenberg, D.A. Drug News Perspect. 1999, 12, 458). Hitherto, three types of distinct CB, receptor antagonists are known. Sanofi disclosed their diarylpyrazoie congeners as selective CB, receptor antagonists. A representative example is SR-141716A, which is currently undergoing Phase ll clinical development for psychotic disorders (Dutta, A.K.; Sard, H.; Ryan, W.; Razdan, R.K.; Compton, D.R.; Martin, B.R. Med. Chem. Res. 1994, 5, 54. Ian, R.; Liu, Q.; Fan, P.: Lin, S.; Fernando, S.R.; McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43). Aminoalkylindoies have been disclosed as CB, receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a CB, receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y. Burkey, T.H.; Makriyannis, A.; Consroe, p.; Roeske, W.R.; Yamamura, H.I. Lite Sc. 1997, 61, PL115). More recently, researchers from Eli Lilly described aryf-aroyl substituted benzofurans as selective CB, receptor antagonists (e.g. LY-320135) (Felder, C.C.; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie. K.P.; Fahey. K.J.; Cullinan, G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M. J. Pharmacol. Exp. Thar. 1998, 284, 291). Recently, 3-alkyl-5,5'-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J.H., Lambert, D.M. Biorg. Med.Chem. Left 1999, 9, 2233). Interestingly, many CB, receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R.S.; Burkey, T.H.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Eur. J. Pharmacol. 1997, 334, R1). Recent reviews provide a nice overview of the current status in the cannabinoid research area (Mechoulam, R.; Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199. Lambert, D.M. Curt. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998,359,1). It has now surprisingly been found that the novel 4,5-dihydro-1H-pyrazole derivatives of the formula (]), wherein - R and R, are the same or different and represent phenyl," thtenyl or pyridyl which groups may be substituted with 1, 2 or 3 substituents Y, which can be the same or different, from the group C^-alkyi or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, n'ttro, amino, mono- or dlalkyl (CjJ-amino, mono- or dialkyl (C,j)-amido, (C,J-alkyl sulfonyl, dimethylsuifamido, C1-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano. carbamoyl, sulfamoyl and acetyl, or R and/or R, represent naphtyi, - Ra represents hydrogen, hydroxy, C3-alkoxy, acetyloxy or propionyloxy, - Aa represent one of the groups 0), II). W, flv) or (v) wherein - R« and R$ independently of each other represent hydrogen or C,^ branched or unbranched alkyl or CM cycloaikyl or R« represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that Rs represents hydrogen - Re represents hydrogen or C,^ unbranched alkyl - 6b represents sutfonyl or carbonyl, - R3 represents benzyt, phenyl, thienyl or pyridyl which may be substituted with 1, 2 or 3 substituents Y, which can be the same or different, or R3 represents C,^ branched or unbranched alkyl or C^cycloaikyl, or R3 represents naphtyl are potent and selective antagonists of the cannabis CBrreceptor. Due to the potent CB, antagonistic activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral iscbaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders. The affinity of the compounds of the invention for cannabinoid CB, receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CB, receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting. The cannabinoid CB, antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB, receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB, receptors by CB, receptor agonists (e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB, receptor-mediated response can be antagonised by CB, receptor antagonists such as the compounds of the invention. At least one centre of chirality is present (at the C* position of the 4,5-dihydro-1 H-pyrazole moiety) in the compounds of the formula (I). The invention relates both to racemates, mixtures of diastereorners and the individual stereoisomers of the compounds having formula (I). The invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I) wherein Aa has the meaning (i) or (a) as described herein above. The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances andtor liquid or solid carrier materials. The compounds of the invention having formula (III) (vide infra), wherein R2 represents hydrogen can be obtained according to methods known, for example: a) EP 0021506; b) DE 2529689. A suitable synthesis for the compounds according to the present invention is the following: Synthesis route A (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above). Step 1 of route A Reaction of a compound having formula (II) wherein R2 represents a hydroxy group. This reaction is preferably carried out in a polar solvent, such as for example ethanol. Compounds having formula (III) wherein R2 represents a hydroxy group and wherein R and R, have the meaning as described herein above for compound (I) are new. Step 2 of route A Reaction of a compound having formula (III) with a compound having formula (IVa) or a compound having formula (IVb) wherein R7 represents a lower alkyl group, such as for example 2-methyl-2-thiopseudourea, or with a suitable salt form thereof in the presence of a base. This reaction gives a 4,5-dihydro-1H-pyrazole-1-carboxamidine derivative having formula (V) wherein Aa has the meaning Alternatively, a compound having formula (111) is reacted with a so-called guanylating agent Examples of such guanylating agents are 1H-pyrazole-1-carboxamidine and its salts (for example the hydrochloride salt) and 3,5-dimethyl-1H-pyrazo!e-1-carboxamidine and its salts (for example the nitrate salt) and the like. This reaction gives a carboxamidine derivative having formula (V). Alternatively, a compound having formula (III) is reacted with a so-called protected guanylating agent Examples of such protected guanylating agents are N-(benzyloxycarbonyl)-lH-pyrazole-1-carboxamidine, N-(ten*-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and N,N'-bis-(fert-butoxycarbpnyl)-1H-pyrazole-1-carboxamidine and the like. This reaction gives after deprotection a compound having formula (V). Step 3 of route A The compound having formula (V) is reacted with an optionally substituted compound of the formula R3-SOp( or R3-COX, wherein R3 has the above mentioned meaning and X represents a halogen atom. This reaction is preferably carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitriie. This reaction gives compound (I) wherein Bb represents a sulfonyl group or a carbonyl group, respectively. Synthesis route.A1 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A1 React/on of a compound having formula ((II) Steo 2 of route A1 Reaction of a compound having formula (VII) with an amine in the presence of a mercury(ll) salt, such as for example HgCI2l gives a compound having formula (i) wherein Aa has the meaning (i) or (ii) as described herein above. This reaction is preferably carried out in a polar organic solvent, such as for example acetonttrile. Synthesis route A2 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A2 Reaction of a compound having formula III wherein R7 represents a lower alkyl group, for example methyl. This reaction is preferably carried out in an inert organic solvent, such as for example 1,4-dioxane. This reaction gives a 4,5-dihydropyrazole-1-carboxamide derivative having formula (IX). Compounds having formula (IX) wherein R, R1f R2, R3 and Bb have the meaning as described herein above for compound (I) are new. Step 2 of route A2 Reaction of a compound having formula (IX) with a halogenating agent, such as for example PCl6, gives a 4,5-dihydropyrazole-1-carboximidoyl halogenide derivative having formula (X) wherein R8 represents a halogen atom, such as for example chloro. This reaction is preferably carried out in an inert organic solvent, such as for example chlorabenzene. Compounds having formula (X) wherein R, R,, R2, R3 and Bb have the meaning as described herein above for compound (1) and wherein RB represents a halogen atom are new. Step 3 of route A2 Reaction of a compound having formula (X) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above. This reaction is preferably carried out in an inert organic solvent, such as for example dichloramethane. Synthesis route A3 (for compounds having formula (J), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A3 Reaction of a compound having formula III wherein R8 represents a halogen atom, such as for example chloro. This reaction is preferably carried out in an inert organic solvent, such as for example chlorobenzene. Compounds having formula (X) wherein R, R,, R2, R3 and Bb have the-meaning as described herein above for compound (I) and wherein R6 represents 'a halogen atom are new. Step 3 of route A2 Reaction of a compound having formula (X) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above. This reaction is preferably carried out in an inert organic solvent, such as for example dichioromethane. Synthesis route A3 (for compounds having formula (1), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A3 Reaction of a compound having formula III with a dithioimidocarbonic ester derivative having formula (XI). wherein R, represents a C1-3 alkyl group. Compounds having formula (XII) wherein R, R„ R2, R3 and Bb have the meaning as described herein above for compound (I) and wherein R6 represents a C1-6 alkyl group are new. Step 2 of route A3 Reaction of a compound having formula (XII) with an amine gives a compound having formula (!) wherein Aa has the meaning (i) or (ii) as described herein above. This reaction is preferably carried out in a polar organic solvent, such as for example methanol. Synthesis route B (for compounds having formula (1), wherein Aa has the meaning (iii) or (iv) as described herein above) Step 1 of route B Reaction of a compound having formula (III) with a compound having formula (XIII), or a compound having formula (XIV), respectively wherein R^ has the above mentioned meaning, Z represents a so-called leaving group and Prot represents a so-called protective group, such as tert-butoxycarbonyl, benzyloxycarbony! and the like, These reactions give compounds having formula (XVII) wherein Aa has the meaning (v) as described herein above. Compounds having formula (XVII) wherein R, R, and R2 have the meaning as described herein above for compound (!) and wherein Aa has the meaning (v) as described herein above and wherein Prat represents a so-called protective group are new. Subsequent removal of the so-called protective group according to known methods (see for example: T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, Inc., New York, 1999) gives compounds (V), wherein Aa has the meaning (v) as described herein above). Compounds having formula (V) wherein R, R1 and R2 have the meaning as described herein above for compound (I) and wherein Aa has the meaning (v) as described herein above are new. Step 2 of route C The compound having formula (V), wherein Aa has the meaning (v) as described herein above, is reacted with an optionally substituted compound of the formula R3-SOzX or R3-COX, wherein R3 has the above mentioned meaning and X is halogen. This reaction preferably is carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as aceton'rtrile. This reaction gives compound (I) wherein Bb represents a sulfonyl group or carbonyl group respectively. Alternatively, the above mentioned compound having formula (V) can be reacted with a compound of the formula R3-COOH via formation of an active ester or in the presence of a so-called coupling reagent The preparation of the compounds is illustrated in the following examples. Example I 3-(4-ChlorophenyI)-4,5-dfhydro-4-hydroxy-4-phenyl-1H-pyrazoie 2-(4-Chiorobenzoyl)-2-phenyloxirane (112 gram, 0.43 mol) is dissolved in ethanol (650 ml) at 35 °C. To the resulting stirred solution is added N2H4.HzO (42 ml) and the formed 3-(4-chlorophenyl)4.5-diriydro-4-hydroxy-4-phenyl-1H-pyrazoie slowly precipitates. After standing for 16 hours the crystalline material is collected by filtration and successively washed with ethanol, water and ethanol and subsequently dried to give 3-(4-chlorophenyl)-4.5-dihydro-4-hydroxy-*-phenyl-1H-pyrazole (92 gram, 78 % yield). Melting point: 195-196 °C. Example II 3-(4-Chlorophenyl)-4,5-dihydro-N-{{4-fluorophenyl)sulfonyl)-4-phenyl-1H-pyrazole-1 -carboxamidine Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (5.13 gram, 20.0 mmol), 2-methyl-2-thiopseudourea hydroiodide (5.00 gram, 23.0 mmol) and pyridine (10 ml) is heated at 110 °C for 1 hour. After one night standing at room temperature diethyl ether is added and the precipitate is collected by filtration. This precipitate is washed three times with diethyl ether portions to afford a solid (9 gram). Melting point: -230 °C. This solid is dissolved in methanol (20 ml). To the resulting solution is successively added a 2N sodium hydroxide solution (12 ml) and water (200 ml). The formed precipitate is collected by filtration, washed two times with diethyl ether and successively with diisopropyl ether. The resulting solid is dried in vacuo to yield 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (5.1 gram, 88 % yield). Melting point: 187-189°C. Part B: To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.50 gram, 1.68 mmol) and 4-fluorophenylsulfonyl chloride (0.34 gram, 1.75 mmol) in acetonitrite (10 ml) is added N,N-dimethyl-4-aminopyridine (0.020 gram, 0.175 mmol) and triethyiamine (1 ml). The resulting solution is stirred at room temperature for 30 minutes. After addition of a 2N sodium hydroxide solution and extraction with ethylacetate (400 ml), the ethylacetate layer is concentrated in vacuo. The resulting crude residue is further purified by means of flash chromatography (petroleum ether/diethyl ether = 1/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo affords solid 3-(4-dilorophenyt)-4,5-dihydro-N-((4-ftuorophenyl)sulfonyl)-4-phenyl-1H-pyrazole-1-carboxamidine (0.55 gram, 72 % yield). Melting point: 214-215 °C In an analogous manner the compounds having formula (I) listed below have been prepared: 4,5-Dihydro-N-((4-fluorophenyl)sulfonyl)-3-(4-methoxyphenyl)-4-(4-methoxy- phenyl)-1H-pyrazole-1-carboxamidine: Melting point 155-156 °C 4,5-Dihydro-3-{4-methoxyphenyl)-4-(4-methoxyphenyl)-N-((4-methoxy- phenyl)sulfonyl)-1H-pyrazole-1-carboxamidine: Melting point 148-150 °C 3-{4-Chloraphenyl)-4,5-dihydro-4-phenyl-N-{(2,4,6-trimethylpheny!)sulfonyl)-lH-pyrazole-1-carboxamidine: Melting point 221-222 °C 3-(4-Chloropheny I )-4.5-dihydro-N-((4-fiuoraphenyl )sulfony IH-hydroxy-4-phenyl-1H-pyra20le-1-carboxamidine: Melting point: 227-228 DC Example III 3-(4-Chlorophenyl)-4,5-dihydro-N-{1-naphtoyl)-4-phenyl-1H-pyrazole-1- carboxamidine To a stirred mixture of 3-{4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.75 gram, 2.50 mmol) and 1-naphtoyl chloride (0.4 ml, 2.70 mmol) in acetonitrile (15 ml) is added triethylamine (1ml). The resulting mixture is stirred at room temperature for 1 hour. After addition of a 2N sodium hydroxide solution and extraction with ethylacetate, the ethylacetate layer is concentrated in vacuo. The resulting crude residue is further purified by means of flash chromatography (petroleum ether/diethyl ether = 3/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo affords 3-(4-chlorophenyl)-4,5-dihydro-N-(1-naphtoyl)-4-phenyl-1H-pyra2ole-1-carboxamidine ( 0.94 gram, 83 % yield). Melting point: 206-207 °C In an analogous manner the compound having formula (I) listed below has been prepared: 3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-N-(2-pyridoyl)-1H-pyrazole-1-carboxamidine. Melting point 118 °C (decomposition) Example IV N1,N1-Dimethyl-N2(4-chlorophenyl)sulfonyl)-3-(4-chlorophenyI)-4,5-dihydro-4-phenyI-1 H-pyrazoIe-1 -carboxamidine Part A: A stirred mixture of 3-(4-chlorophenyl)-4.5-dihydro-4-phenyl-1H-pyra2ole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbon!c acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) is heated at reflux temperature for 20 hours. An additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyra2ole (12.0 gram, 46.8 mmol) is added and the resulting mixture is heated at reflux temperature for another 16 hours. After concentration in vacuo, dichloromethane is added and the resulting solution is washed twice with water and dried over anhydrous Na2So4 After filtration and evaporation in vacuo the residue is further purified by flash chromatography (diethyl ether/ petroleum ether = 1/1 (v/v)) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)suifonyl)-4,5-dihydro-4-phenyl-1H- pyrazole-1-carboximidothioic acid methyl ester (12.S gram, 80% yield based on [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester) as an amorphous solid. Part B: To a stirred mixture of 3-{4-chlorophenyl)-N-{(4-chlorophenyl)sulfonyl)-4)5-dihydrc-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) is added dimethylamine {10 ml) and dichloromethahe (75 ml) and the resulting solution is stirred at room temperature for 6 hours. Evaporation in vacuo and subsequent flash chromatographic purification (diethyl ether/ petroleum ether = 1/1 (v/v), followed by diethyl ether) gives a solid which is further purified by recrystallisation from diisopropyi ether to yield N1,N1-dimethyl-N2-((4-chloro-phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1-carboxamidine (2.63 gram, 63 % yield). Melting point: 182 °C. In an analogous manner the compounds having formula (I) listed below have been prepared: N-Methyl-N'-((4-chlorophenyl)sulfonyl>-3-(4-chlorophenyl)-4,5-dihydro^-(3-pyridyl)-1H-pyrazole-1-carboxarnidine. Melting point: 101-105 °C. N-Methyl-N'-((4-chlorophenyl)suffonyl>-3-(4-chlorophenylH.5-d'hydro-4-(4-pyridyl}-1H-pyrazole-1-carboxarnidine. Melting point: 112-115 °C. N1,Nt-Dimethyi-N3-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-pheny!-1H-pyrazole-1-carboxamidine. Melting point: Amorphous. N-Emyl-N'-((4-chloraphenyl)sulfonyl)-3-(4-chlorophenyl" phenyl-1H-pyrazole-1-carboxamidine. Melting point: 183-185 °C. Example V N-Methyl-N'-(3-{trifluoromethyl)ben2oyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine Part A: To 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5.13 gram, 20.0 mmol) in acetonitrile (80 ml) is added 3-{trifluoromethyJ)benzoylisothio-cyanate (4.62 gram, 20.0 mmol) at 0 °C and the resulting mixture is stirred for 1 hour. The formed yellow precipitate is collected by filtration and washed with a small portion of acetonitrile and water, respectively, and subsequently dried in vacuo to give 3-(4-chlorophenyl-4-5hydro-4-prrenyl-N-({3-trifluorornethyl) benzoyl)-! H-pyrazole-1-thiocarboxamtde (8.26 gram, 85 % yield). Melting point: 180-182 °C. Part B: To a stirred suspension of 3-{4-chlorophenylH,5-dihydro-4-phenyl-N-((3-trifluoromethyl)benzoyl)-lH-pyrazole-1-thiocarboxamide (4.88 gram, 10.0 mmol) in acetonitrile (50 ml) is added cold methylamine (5 ml) to give a green solution. After addition of a solution of HgCI2 (3.0 gram, 11 mmol) in 25 ml acetonitrile, the resulting mixture is stirred for three hours. The precipitate is removed by filtration over hyflo and the filtrate is collected and concentrated in vacuo. After addition of ethylacetate and 0.5 N NaOH, the ethylacetate layer is collected, washed with saturated aqueous NaCI solution and dried over anhydrous NazS04, filtered and concentrated in vacuo. Chromatography (dichloromethane/acetone = 9/1 (v/v)) gives N-methyl-N'-(3-(trifluoro-methyl)benzoyl)-3-(4-chlorophenyl)-4.5-dihydro-4-phenyMH-pyrazole-1-carboxamidine (0.99 gram, 20 % yield) as a foam. Melting point: Amorphous. R, (Silicagei: Dichloromethane/acetone - 9/1 (v/v)) = 0.3. Example VI N-Methyl-N'-((4-chloropheny!)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1H-pyrazole-1-carboxamidine Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1,4-dioxane (20 ml) is added 3-(4-chtorophenyl)-4.5-dihydro-4-phenyl-1H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1N HCI and water, dried over anhydrous Na2S04, filtered and concentrated in vacuo to a volume of 20 ml. Methyi-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-fe/f-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyi)-4.5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide (4.75 gram, 76 % yield) Melting point: 211-214 °C. Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide (3.67 gram, 7.75 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4-chlorophenyi)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyt-1H-pyrazole-1-carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give Part B: To a stirred suspension of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-N-((3-trifluoromethyl)ben2oyl)-1H-pyrazole-1-thiocarboxamide (4.88 gram, 10.0 mmol) in acetonitrile (50 ml) is added cold methylamine (5 ml) to give a green solution. After addition of a solution of HgCI2 (3.0 gram, 11 mmol) in 25 ml acetonitrile, the resulting mixture is stirred for three hours. The precipitate is removed by filtration over hyflo and the filtrate is collected and concentrated in vacuo. After addition of ethylacetate and 0.5 N NaOH, the ethylacetate layer is collected, washed with saturated aqueous NaCI solution and dried over anhydrous Na2S04, filtered and concentrated in vacuo. Chromatography (dichloromethane/acetone = 9/1 (v/v)) gives N-methyl-N'-(3-(trifiuoro-methyl)ben2oyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.99 gram, 20 % yield) as a foam. Melting point: Amorphous. Rf (Silicagel: Dichloromethane/acetone = 9/1 (v/v)) = 0.3. Example VI N-Methyl-N'-{(4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyMH-pyrazole-1-carboxamidine Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS; 34643-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4.5-dihydro-4-phenyl-1H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1N HCl and water, dried over anhydrous Na2S04, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-buty! ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-terf-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl>-4.5-dihydro-4-phenyl-1H-pyrazote-1-carboxamide (4.75 gram, 76 % yield) Melting point: 211-214 °C. Part B: A mixture of 3-(4-chlorophenyl}-N-((4-chlorophenyl)sulfonyl)-4.5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide (3.67 gram, 7.75 mmol) and phosphorus pentachioride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-({4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4.5-dihydro-4-phenyl-1H-pyrazole-1-carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N((4-chlorophenyl)sulfonyl)-3-(4-chlorophenylH.5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C (dec). In an analogous manner the compounds having fonnula (I) listed below have been prepared: N-Methy(-N'-((3-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl - IH-pyrazole-i-carboxamidine. Melting point: 156-160 °C. N-Methyl-N'-{(4-chlorophenyl)sulfonyl)-3-(5-chloro-2-thienyl)-4,5-dihydro-4-phenyl- 1H-pyrazple-1-carboxamidine. Melting point: Amorphous N-Propyf-N'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H- pyrazole-1-cartoxamidine. Melting point: 129-138 °C. N-(2-Propyl)-N'-{{4-fluorophenyl)sulfonyl>3-(4-chlorophenyl)-4,5Hdihydro-4-phenyl- 1H-pyrazole-1-carboxamidine. Melting point: 110-112 "C. N-Methyl-N'-({2-propyl)sulfonyl)-3-(4-chtorophenyl)-4,5-dihydro-4-phenyl-1H- pyrazole-1-carboxamidine. Melting point: Amorphous. N-(2-Propyl)-N'-((4-chlorophenyl)sulfonyI)-3-(4-pyridyl)-4.5-dihydro-4-phenyl-1l-l- pyrazole-1-carboxamidine. Melting point: Amorphous. N '-Ethy l-N 1-methy l-N2-{(4-chloraphenyi)sulfonyl)-3-{4-chloropheny l)-4,5-d ihyd ro-4- phenyl-1H-pyrazole-1-carboxamidtne. Melting paint: 184 °C. N^Ethyl-N1methyl-N2Ct^fluorophenyOsuifonyl)3-4chlorophenyl-4-5-dihydro- phenyl-1H-pyrazole-1-carboxamidine. Melting point: 173-176 °C. N1,N1-Dimethyl-N2-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 195-196 DC. N1,N1-Dimethyl-N2-((3-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1H-pyrazole-1-carboxamidine. Melting point: 195-198 °C. N1,N1-Dimethyi-N2-((3-methoxyphenyl)sutfonyl)-3-(4-chlorophenyl)-4,5-dihydrc-4- phenyl-1H-pyrazole-1-carboxamidine. Melting point 204-206 °C. N-Ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H- pyrazole-1-carboxamidine. Melting point: Amorphous. N-Dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenylH,5-dihydro-4- phenyl-1H-pyrazole-1-carboxamidine. Melting point: 155-159 °C. N-Methyl-N'-((4-(trifluoromethyi)phenyl)sulfonyl)-3-{4-chlorophenyl)-4,5-dihydro-4- phenyl-1H-pyrazole-1-carboxamidine. Melting point: Amorphous. N\N1-Dimethyl-N2-((2-methylphenyl)suifonyl)-3-(4-chlorophenyl)-4.5-dihydro-4- phenyl-1H-pyrazole-1-carboxamidine. Melting point:148-151 °C. N-Methyl-N'-((2,4-difluorophenyi)sulfonyl)-3-(4-chlorophenylH.5- phenyl-1H-pyrazole-1-carboxamidine. Melting point: 85 °C. N-H4-cnioropneny[)sulfonyl)-3-(4-chlorophenyl)-4,5-diriydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: Amorphous. N-(2,2,2-Trifluoroethyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-415-dihydrc-4-phenyl-1 H-pyrazole-1-carboxamidine. Melting point: Amorphous. N-(2-Pyridyl)-N'-((4-chIorophenyl)sulfonyl)-3-{4-chloraphenyl)-4.5-dihydro-4-phenyl -1H-pyrazole-1-carboxamidine. Melting point: 142-146 °C. N-(4-Pyridy l>N X(4-chlorophenyl )sulfonyl)-3-(4-ch lorophenyl>4.5-dihydro-4-phenyI -1H-pyrazole-1-carboxamidine. Melting point: 204-206 °C. N-Phenyl-N'-((4-chlorophenyl)suifonyl)-3-(4-chlorophenyi)-4,5-dihydro-4-phenyl -1H-pyrazole-1-cart>oxamidine. Melting point: 158-160 °C. Example VII 3-(4-CWorophenyt)-1-[3-((4-chlorQphenyl)sulfonyl)butanoyl]-4,5-dihydro-4-phenyl-1 H-pyrazole To a stirred mixture of 3-((4-chlorophenyl)sulfonyl)butyric acid (1.85 gram, 7.00 mmol), diisopropylethylamine (3 ml) and 1-ethyl-3-{3-dimethylaminopropyl)carbodiirnide hydrochloride (1.50 gram, 15.7 mmol) was added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazole (3.00 gram, 11.7 mmol) and the resulting mixture was stirred for 16 hours at room temperature. After concentration in vacuo the resulting residue was purified by flash chromatography (petroleum ether/ diethyl ether = 1/2 (v/v), followed by diethyl ether) to give 3-(4-chlorophenyl)-1-[3-((4-chlorophenyl)sulfontyl)butanoy[]-4,5-dihydro-4-phenyl-1H-pyrazole (3.69 gram, 63 % yield) as a diastereomeric mixture. Melting point: amorphous In an analogous manner the compounds having formula (I) listed below have been prepared: 3-(4-Ch!orophenyl)-1-[3-(phenylsulfonyi)propanoyl]-4,5-dihydro-4-pheny[-lH-pyrazole. Melting point: 122-123 °C. 3-(4-Chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)propanoyll-4,5-dihydro-4-phenyl-1 H-pyrazole. Melting point: 178-181 °C. Example VIII 3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-{{3-(trifIuoromethyl)phenyl)-sulf orryl)ethy IJ-1 H-pyrazole To a stirred mixture of 3-(4-chlorophenyl)-4.5-dihydro-4-phenyl-1H-pyrazole (1.7 gram, 6.60 mmol) and collidine (2 ml) in acetonitnle (25 ml) is slowly added a solution of 2-((3-(trifluoromethyl)phenyl)sulfonyI)ethyl chloride (1.5 gram, 5.50 mmol) in acetonitnle (20 ml) and the resulting solution is heated at reflux temperature for 16 hours. After concentration in vacuo the residue is dissolved in ethylacetate and washed with aqueous sodium hydrogencarbonate solution. The resulting ethylacetate layer is successively washed with 1N hydrochloric acid solution and aqueous sodium hydrogencarbonate solution. Subsequent flash chromatographic purification (petroleum ether/ diethyl ether = 1/2 (v/v)) gives an oil which is crystallised from diisopropyl ether to afford 3-(4-chlorophenylH.^dihydro-4-phenyl-1-[2-((3-{trifluoromethyl)phenyl)sulfonyl)ethyl]-1 H-pyrazole (0.52 gram, 19 % yield). Melting point 118-119 °C. In an analogous manner the compounds having formula (I) listed below have been prepared: 3-(4-Chlorophenyl)-1-[2-(benzylsulfonyl)ethyl]-4,5-dihydro-4-phenyl-1H-pyra20le. Melting point 161 °C. 3-(4-Chlorophenyl)-1-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-phenyl-1H-pyrazote. Melting point: Amorphous 3-(4-Chlorophenyl)-1-[2-({4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-hydroxy-4-phenyl-1 H-pyrazole. Melting point: 127-128 °C. Example IX N-[2-(3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazol-1-yl)ethyl]-3- (trifluoromethyl)benzenesulfonamide Part A: A stirred solution of 3-{4-chlorophenyl)-4,5-dihydro~4-phenyl-1 H-pyrazole (5.00 gram, 19.5 mmol) and N-(ferf-butoxycarbonyl)aziridine (2.00 gram, 14.0 mmol) in toluene (100 ml) is heated at reflux temperature for 16 hours. After concentration in vacuo the residue is purified by flash chromatography (petroleum ether/ diethyl ether = 3/1 (v/v)), followed by petroleum ether/ diethyl ether = 1/1 (v/v)). After concentration in vacuo the remaining oily residue is crystallised from diisopropyl ether to afford 1-[2-(((ert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4.5-dihydro-4-phenyl-1 H-pyrazole (1.91 gram, 34 %). Repeated crystallisations from the mother liquor afforded an additional amount of crystalline 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyi)-4,5-dihydrc-4-phenyl-1 H-pyrazole (1.19 gram). Part B: To a solution of 1-[2- concentrated in vacuo to afford 1-(2-aminoethyI)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl-lH-pyrazole (1.44 gram, quantitative yield) as an oil. Part C: To a solution of 1-{2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (0.56 gram, 1.87 mmol) and diisopropylethylamine in acetonitriie (20 ml) is added 3-(trifiuoromethyl)phenylsulfonyl chloride (0.35 ml, 2.18 mmol) and the resulting solution is stirred at room temperature for 20 minutes. After concentration in vacuo the residue is dissofved in ethylacetate and washed with 2N sodium hydroxide solution. The ethylacetate layer is concentrated in vacuo. The resulting oil is crystallised from a small amount of diisopropyl ether to afford crystalline N-[2-(3-(4-chlorophenyl)-4.5-dihydro-4-Phenyl-1H-pyrazol-1-yl)ethyrj-3-viifluoromethyObenzenesulfonamide (0.44 gram, 46 % yield). Melting point: 94-96 °C. we claim* 1. A compound of formula (I) wherein - R and R, are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2 or 3 substituents Y, which can be the same or different, from the group C1.3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifiuoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1.2)-aminol mono- or dialkyl (C1-2-amido, (C,^)-alkyl sulfonyl, dimethylsulfamido, C1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R1 represent naphtyl, - R2 represents hydrogen, hydroxy, C^-alkoxy, acetyloxy or propionyloxy, - Aa represents one of the groups (i), (ii), (iii), (iv) or (v) wherein - R4 and R6 independently of each other represent hydrogen or C1-8 branched or unbranched alkyL or C63-6 cycloalkyl or R4 represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that R5 represents hydrogen - R5 represents hydrogen or C1-3 unbranched alkyl - Bb represents sulfonyl or carbonyl, - R3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2 or 3 substituents Y, which can be the same or different, or R3 represents CM branched or unbranched alkyf or CM cycloalkyl, or R3 represents naphtyi and tautomers, prodrugs and salts thereof. 2. A compound having formula (I) as chimed in claim 1, wherein R is the group 4-chlorophenyl, R, is phenyl, R2 is hydrogen, Aa is the group (i) wherein R, is hydrogen and Rj is methyl, Bb is sulfonyl, and R3 represents 4-chlorophenyl, and salts thereof. 3. A pharmaceutical composition containing at least one compound as claimed in 1 as an active component. 4. A method of preparing pharmaceutical compositions characterized in that a compound as claimed in claim 1 is brought in a form suitable for administration. 5. Process for the preparation of compounds having formula I, characterized in that a) a compound is prepared wherein R, R1-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (i) or (H) as defined in claim 1 by 1) reacting a compound having formula (II) with hydrazine or hydrazine hydrate to obtain a compound having formula (III), which is reacted with a compound having formula (IVa) of (IVb) to give a compound having formula (V), which is reacted with a compound of the formula RJ-SOJX- or R3-COX, wherein X is halogen, or 2) reacting a compound having formula (III) with a thioisocyanate of the formula (VI) to produce a compound of the formula (VII), which Is reacted with an amine in the presence of a mercury (II) salt; or 3) reacting a compound having formula (111) with a compound of the formula (VIII) to give a compound of the formula (IX) which is reacted with a halogenating agent to give a compound having formula (X) which is reacted with an amine, or 4) reacting a compound having formula (III) with a compound of the formula (XI) to give a compound having formula (XII) which is reacted with an amine, or b) a compound is prepared wherein R, R,-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (iii) or (iv) as defined in claim 1 by reacting a compound of the formula (III) with a compound of the formula (XIII) of (XIV), or c) a compound is prepared wherein R, R,-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (v) as defined in claim 1, by reacting a compound having formula (III) with a compound having formula (XV) or (XVI) to give a compound having formula (XVII), which is deprotected to give a compound having formula (V), which is reacted with a compound having formula R3-SOpc or R3-COX wherein X is halogen or with a compound of the formula R3-COOH. wherein Aa has the meaning (i), (ii) or (v) as given in claim 1 and wherein R, R, and R2 have the meanings given in claim 1. 8. A compound of formula (VII) wherein R, R,, R2 R3 and Bb have the meanings given in claim 1 and wherein R4 represents a halogen atom. 11. A compound of formula (XII) wherein R, R, and Rz have the meanings given in claim 1 and wherein Aa has the meaning (v) as given in claim 1 and wherein Prot represents a so-called protective group. 13. A method of treating psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as Parkinson's disease, dementia, distonia, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, ischaemia, pain and other CNS-diseases involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used. 14. A method of treating gastrointestinal disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used. 15. A method of treating cardiovascular disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used. 16. A method of treating gastrointestinal disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used. 17. A method of treating cardiovascular disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used. 16. A compound of formula (I), substantially as hereinabove described and exemplified.

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