Title of Invention

PYROZOLE DERIVATIVES AND PROCESS FOR PREPARING THE SAME

Abstract

The present invention relates to a group of novel 4,5-dihydro-lH-pyrazole derivatives which are potent cannabinoid (CB<SUB>1</SUB>) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (la) or (lb) wherein the symbols have the meanings given in the specification. The invention also relates to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.

Full Text

The present invention relates to a group of novel pyrazole derivatives to methods for the preparation of these compounds, and to pharmaceutical compositions containing one ore more of these compounds as an active component. The above mentioned 4,5-dihydro-1H-pyra2oles are potent cannabinoid (CB1) receptor antagonists with utility for the treatment of disorders involving cannabinoid neurotransmission. Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries (Mechoulam, R. and 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 (CB1 and CB2) stimulated the search for novel cannabinoid receptor antagonists (Munro, S. et ai, Nature 1993, 365, 61. Matsuda, L.A. and 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 (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. Pertwee, R.G., Progress in Neurobiology 2001, 63, 569). Hitherto, several CB1 receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB1 receptor antagonists. A representative example is SR-141716A (Dutta, A.K. et al., Med. Chem. Res, 1994, 5, 54. Lan, R. et aL, J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E.M, et al, CNS Drug Rev. 1999, 5, 43). CP-272871 is a pyrazole derivative, like SRI 41716A, but less potent and less CB1 receptor subtype-selective than SR141716A (Meschler, J.P. et ai, Biochem. PharmacoL 2000, 60, 1315). Aminoalkylindoles have been disclosed as CB-j receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a moderately active CB1 receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K. et al., Life So. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB1 receptor antagonists (e.g. LY-320135) (Felder, C.C. et ai, J. Pharmacol Exp. Then 1998, 284, 291). 3-Alkyl-5,5'-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M. et ai, Biorg. Med. Chem. Lett. 1999, 9, 2233). Aventis Pharma claimed diarylmethyleneazetidine analogs as CB1 receptor antagonists (Mignani, S. et ai. Patent PR 2783246. 2000; Chem. Abstr. 2000. 132, 236982). Tricyclic pyrazoles were claimed by Sanofi-Synthelabo as CB1 antagonists (Barth, F, et ai, Patent WO 0132663, 2001; Chem. Abstr. 2001, 134, 340504). Interestingly, many CB1 receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R.S. e^ a/., Eur. J. Pliarmacol. 1997, 334, R1). Reviews provide a nice overview of the cannabinoid research area (Mechoulam, R. ef a/.. Prog, Med, Ciiem. 1998, 35, 199. Lambert, D.M. Cum Med. Cliem, 1999, 6, 635. Mechoulam, R. et al., Eur J. Pharmacol. 1998, 359, 1. Williamson, E.M. and Evans, FJ. Drugs 2000, 60, 1303. Pertwee, R.G. Addiction Biology 2000, 5, 37. Robson, P. Br. J. Psychiatry 2001, 178, 107. Pertwee, R. G. Prog, Neurobiol. 2001, 63, 569. Goya, P and Jagerovic, N. Exp. Opin, Then Patents 2000, 10, 1529. Pertwee, R. G. Gut 2001, 48, 859). It has now surprisingly been found that potent and selective antagonism of cannabinoid-CB1 receptors is present in the novel 4,5-dihydro-1 H-pyrazole derivatives of the formula (la) or (lb), prodrugs thereof, tautomers thereof and salts thereof wherein - R and R1 independently 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, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyi (C1-2)-amino, mono- or dialkyi (C1-2)-arnido, (C1-3)-alkyl sulfonyl, dimethylsulfamido, C1-3-alkoxycarbonyl. carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R1 represent naphtyl, R2 represents hydrogen, hydroxy, C1-3-alkoxy, acetyloxy or propionyloxy, R3 represents a hydrogen atom or a branched or unbranched C1-8B alkyl group or a C3_7 cycloalkyi group which alkyl group or cycloalkyi group may be substituted with a hydroxy group, R4 represents a hydrogen atom or a branched or unbranched C1_8 alkyl, C3-8 cycloalkyi, C2-10 heteroalkyi, C3-8 nonaromatic heterocycloalkyi or C4.10 nonaromatic heterocycloalkyl-alkyi moiety which moieties may contain one or more heteroatoms from the group (O, N, S), which moieties may be substituted with a keto group, trifluoromethyl group, C1-3 alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R4 represents an amino, hydroxy, phenoxy or benzyloxy group or R4 represents a branched or unbranched C1-8 alkoxy, C3-8 alkenyl, C5.8 cycloalkenyl or C5-8 cycloalkenylalkyi group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or "SO2" group which C1-8 alkoxy, C3-8 alkenyl, C5-8 cycloalkenyl or C6-9 cycloalkenylalkyi groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkyjamino group or a fluoro atom, or R4 represents a phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the aromatic rings may be substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or R4 represents a group NR6R9 with the proviso that R3 represents a hydrogen atom or a methyl group and wherein Rs and Rg aR6 the same or different and represent C1-4 alkyl or C2-4 trifluoroalkyl or Rs and Rg - together with the nitrogen atom to which they aR6 bonded - form a saturated or un-saturated heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or -SO2- group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a C1-4 alkyl group or R3 and R4 - together with the nitrogen atom to which they aR6 bonded - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic moiety may contain one or moR6 atoms from the group (O, N, S) or a keto group or -SOa- group, which moiety may be substituted with a C1-4 alkyl, hydroxyalkyi, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyi, dialkylaminoalkyi, monoalkylamino, dialkylamino, aminoalkyi, azetidinyl, pyrrolidinyl, piperidinylor hexahydro-1H-azepinyl group, R5 and R6 independently of each other represent a hydrogen atom or a branched or unbranched C1_8 alkyl or alkenyl group which groups may contain one or moR6 heteroatoms from the group (O, N, S), a keto group or a "-SO2- group and which groups may be substituted with a hydroxy or amino group, or R5 and R6 independently of each other represent a C3-8 cycloalkyi group or C3-8 cycloalkenyl group which may contain one or moR6 ring heteroatoms from the group (O, N, S) or the -SO2- group and which groups may be substituted with a hydroxy group, alkyl (C1.3), the -SO2- group, the keto group, amino group, monoalkylamino group (C1_3) or dialkylamino group (C1.3), or R5 represents a naphtyl group or a phenyl group which phenyl group may be substituted with 1, 2 or 3 substituents Y wherein Y has the meaning as described hereinabove, with the proviso that R6 represents a hydrogen atom, or a branched or unbranched alkyl group (C1-5) which alkyl group may contain one or moR6 heteroatoms from the group (O, N, S) or the -SO2- group and which alkyl group may be substituted with a hydroxy, keto or amino group, or R5 and R6 - together with the nitrogen atom to which they aR6 bonded - form a monocyclic, bicyclic or tricyclic alkyl or alkenyl group which may contain ring heteroatoms from the group (O, N, S), the keto or the SO2 group and which monocyclic, bicyclic or tricyclic alkyl or alkenyl group may be substituted with a hydroxy group, alkyl (C1_3) group, SO2 group, keto group, amino group, monoalkylamino group (C1-3)r dialkylamino group (C1_3), pyrrolidinyl group or piperidinyl group, which monocyclic, bicyclic or tricyclic alkyl or alkenyl group may contain an annelated phenyl group which annelated phenyl group may be substituted with 1 or 2 substituents Y, wherein Y has the meaning as described herein above. - R7 represents branched or unbranched C1_3 alkyl. At least one centR6 of chirality is present (at the C4 position of the 4,5-dihydro-1H-pyrazole moiety) in the compounds of the formula (la) and (lb). The invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (la) or (lb). Particular compounds of interest of formula (la) or (lb) have the absolute stereoconfiguration at the C4 position of the 4,5-dihydro-1H-pyrazole moiety as represented by the formulas (1a*) and (1b*): The invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (la) or (lb). The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials. Due to the potent CB1 antagonistic activity the compounds according to the invention aR6 suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders. The affinity of the compounds of the invention for cannabinoid CB1 receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB1 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 CB1 antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB1 receptors aR6 stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB1 receptors by CB1 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 CB1 receptor-mediated response can be antagonised by CB1 receptor antagonists such as the compounds of the invention. Intermediates having formula (11) (see below) can be obtained according to methods known, for example: a) Francotte, E.; Tong, Z. Chem, Abstr. 126, 213598; b) Rempfier, H. and Kunz, W. Chem. Abstr. 113, 40432; c) Rempfler, H. and Kunz, W. Chem, Abstr. 107,217473. Intermediates having formula (III) wherein R2 represents hydrogen (see below) can be obtained according to methods known, for example: a) EP 0021506; b) DE 2529689, c) Grosscurt. A.C. et al., J. Agn'a FoodChem. 1979, 27, (2), 406. Intermediates having formula (III) wherein R2 represents a hydroxy group can be obtained by reacting a compound having formula (II) with hydrazine or hydrazine hydrate This reaction, preferably carried out in an organic solvent such as ethanol, yields a compound having formula (III) wherein R2 represents a hydroxy group. This reaction is preferably carried out in the presence of a base, for example triethylamine. Step 3: reaction of a compound having formula (lb) with an amine having formula HNR3R4 wherein R3 and R4 have the meanings as described above, analogous to the method described in Synth. Commun. 1996, 26, (23), 4299. This reaction gives a compound having formula (la). Synthetic route A1 Step 1: Reaction of a compound having formula (V) with an amine having formula HNR3R4 wherein R3 and R4 have the meanings as described above in the presence of a mercury(ll) salt, for example HgCl2, gives a compound having formula (la). This reaction is preferably carried out in an organic solvent, such as for example acetonitrile, analogous to the method described in Synth, Commun, 1996, 26, (23), 4299. Synthetic route A2 Step 1: reaction of a compound having formula (III) with a isocyanate derivative having formula (VI), followed by treatment with an amine HNRsRe This reaction is preferably carried out in an organic solvent like dichloromethane, and yields a compound having formula (VII). Compounds having formula (VII) wherein R, Ri, R2, R5 and R6 have the meaning as described herein above for compound (la) aR6 new. Step 2: reaction of a compound having formula (VII) with a halogenating agent, such as for example PCI5, gives a compound having formula (VIII) wherein Rio represents a halogen atom, for example a chloro atom. This reaction is preferably carried out in an organic solvent such as chlorobenzene. Compounds having formula (VIII) wherein R, Ri, R2, R5 and R6 have the meanings as described above for compound (la) and wherein Rio represents a halogen atom, are new. Step 3: reaction, preferably carried out in an inert organic solvent such as dichloromethane, of a compound having formula (Vill) with an amine having formula HNR3R4 wherein R3 and R4 have the meanings as described above gives a compound having formula (la). Synthetic route A3 gives a compound having formula (lb), (see e.g. Chem. Ben 1966, 99, 2885 and Chem, Ztg. 1984, 108, (12), 404). The preparation of the compounds is illustrated in the following examples. Example 1 3-(4-Chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyi-4-phenyl-4,5-dihydro-1 H-py razole-l -carboxamidine Part A: To a stirred solution of ((ethyl)propylamino)sulfonyl isothiocyanate (5.98 gram, 25.4 mmol) in dry dichloromethane in a nitrogen atmospheR6 is added of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (6.52 gram, 25.4 mmol). After stirring for 90 minutes the resulting solution is concentrated in vacuo and purified by column chromatography (CH2CI2, silicagel, Rf --0.45). The resulting solid is recrystallized from diethyl ether to give 3-(4-chlorophenyl)-N- room temperatuR6 and stirred for another 2 hours. After cooling to 0 °C liquid dimethylamine (5 mL) is added and the resulting solution is stirred for another hour at 0 °C and for 2 hours at room temperature. The solution is washed with water, filtered over hyflo and concentrated in vacuo. Flash chromatography (MTBE. Rf - 0.3) gives 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (4.75 g, 58 %). MP: 210-212 °C. Part B: A mixtuR6 of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.47 gram, 3.62 mmol) and phosphorus pentachloride (0.80 gram. 3-84 mmol) in chlorobenzene (20 mL) is heated at reflux temperatuR6 for 1 hour. After thorough concentration in vacuo, the formed 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyI-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride is suspended in dry dichloromethane and reacted with cold n-propylamine (1.0 mL) at 0 °C. After stirring for 1 hour, the mixtuR6 is dissolved in ethyl acetate and washed with water and concentrated in vacuo. The residue is purified by column chromatography (dichloromethane/acetone = 19/1 (v/v), Rf - 0.35) to give an oil (0.82 g). Crystallisation from diethyl ether, followed by recrystallisation from ethanol gives 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-N"propyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (0.38 gram, 23 % yield). MP: 127-129'C. In an analogous manner the compounds having formula (la) listed below have been prepared; 32. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-fluoroethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 128-131 °C. 33. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-N-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 158-159 °C. 34. 3-(4-Chlorophenyl)-N-((dimethylamino)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP; 170-172 °C. Example 35 3-(4-Chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester Part A: To a stirred solution of (piperidin-l-yl)sulfonyl isothiocyanate (54.77 g, 266 mmol) in dry dichloromethane (900 mL) in a nitrogen atmospheR6 is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (68.3 gram, 266 mmol). After stirring for 16 hours an additional amount of dichloromethane is added. The resulting solution is twice washed with water, dried over Na2S04, and concentrated in vacuo. After addition of MTBE, the residue crystallizes. The crystalline material is collected and washed with MTBE to give 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1 -yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (77.6 gram, 63 % yield). Part B: To a stirred solution of 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (30 gram, 64.9 mmol) in acetone (1 L) is added triethylamine (18.0 mL, 130 mmol). To the resulting yellow solution is added methyl iodide (9.12 g, 64 mmol) and the resulting solution is stirred for 16 hours at room temperature. The formed precipitate is removed by filtration. The filtrate is washed with water, concentrated in vacuo to give a yellow solid. Recrystallisation from MTBE gives 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (27.9 gram, 90% yield). MP: 192-194 °C. In an analogous manner the compounds having fomiula (lb) listed below have been prepared: 36. 3-(4-Chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 159-160 °C. 37. 3-(4-Chlorophenyl)-N-((diethylamino)sulfonyl)"4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 141-143 °C. 38. 3-(4-ChlorophenyI)-4-phenyl-N-((1,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl) -4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 143-145 °C. 39. 3-(4-Chlorophenyl)-N-(((ethyl)phenylamino)sulfonyl)-4-phenyl-4,5-dihydrO"1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 143-146 °C. 40. 3-(4-Chlorophenyl)-N-((diethylamino)sulfonyl)-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. Amorphous. 41.3-(4-Chlorophenyl)-N-((diethylamino)sulfonyl)-4-(pyridin-4-yl)-4,5-dihydro-1 H-pyrazole-1-carboximidothioic acid methyl ester. Amorphous. 42. 3-(4-Chlorophenyl)-N-((piperidin-1"yl)sulfonyl)-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. Amorphous. 43. 3-(4-Chlorophenyl)-N-((dimethylamino)sulfonyl)-4-(3-(trifluoromethyl) phenyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. Amorphous. 44. 3-(4-Chiorophenyl)-N-(((ethyl)methylamino)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester.MP:133-136 ^'C. 45. 3-(4-Chlorophenyl)-N-((piperidin-1 -yI)sulfonyl)-4-(pyridin-3-yi)-4,5-dihydro-1 H-pyrazole-1-carboximidothioic acid methyl ester. MP: 182-185 °C. 46. 3-(4-ChlorophenyI)-N-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 202-204 °C. 47. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-((morpholin-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP:205-207°C. 48. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)"-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP:196-198°C. 49. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-((dimethylamino)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP:181-183°C. 50. 3-(4-ChIorophenyl)-4-(2,6-difluorophenyl)-N-((morpholin-4-yl)suifonyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioicacid methyl ester. MP:231-233°C. 51. 3-(4-ChIorophenyl)-4-(2,6-difluorophenyl)-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP:221-225°C. 52. 3-(4"Chlorophenyl)-4-{2,6-difluorophenyl)-N-((dimethylamino)suiTonyi)--4.D-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP:181-185°C. 53. 3-(4"Chlorophenyl)-N-((1,1 -dioxidothiomorpholin"4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 216-217 °C, 54. 3-(5-Chlorothien-2-yI)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H- pyrazole-1-carboximidothioic acid methyl ester. Amorphous. Example 94 3-(4-Chlorophenyl)-N-((4-methylpiperazin-1-yI)sulfonyl)-4-Phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester Part A: A stirred mixtuR6 of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.21 gram, 11.3mmol), [(4-methylplperazin-1-yi)sulfonyl]dithioimido-carbonic acid dimethyl ester (3.08 gram, 12.0 mmol) and pyridine (25 mL) is heated at 100 °C for 24 hours in a nitrogen atmosphere. After cooling to room temperatuR6 the mixtuR6 is concentrated in vacuo, water is added and the resulting mixtuR6 is extracted with dichloromethane. The dichloromethane extract is washed twice with water, dried over Na2S04, filtered and concentrated in vacuo. Subsequent flash chromatographic purification gives 3-(4-chlorophenyl)-N-((4-methylpiperazJn-1 -yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (4.24 gram, 76 % yield) as an amorphous solid. (Rf ~ 0.1, EtOAc/methanol = 95/5 (v/v)). In an analogous manner the compounds having formula (lb) listed below have been prepared: 95.3-(4-Chlorophenyl)-N-(((2-(dimethylamino)ethyl)ethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester. MP: 158°C. 96. N-((Diethylamino)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole- 1-carboximidothioic acid methyl ester. Amorphous. Rf ~ 0.4 (MTBE). 97. 3-(4-Chlorophenyl)-N-(([1.4']bipiperidin-1 '-yl)sulfonyl)-4-phenyl-4,5-dihydro-1 H- pyrazole-1-carboximidothioic acid methyl ester. MP: 245 °C. 98. 3-(4-Chlorophenyl)-N-(((1-methylpiperidin-4-yl)methyIamino)sulfonyl)-4-phenyl- 4,5-dihydro-IH-pyrazole-l-carboximidothioic acid methyl ester. Oil. Rf ~ 0.15 (methanol/dichloromethane = 5/95 (v/v)), 99. 3-(4-ChlorophenyI)-N-((4-methyl-1,4-diazepan-1 -yl)sulfonyl)-4-phenyi-4,5- dihydro-1H-pyrazole-1-carboximidothioicacid methyl ester. Amorphous. Rf'-' 0.10 (methanol/dichloromethane = 5/95 (v/v)). Example 100 (-)-(4S)-3-(4-ChlorophenyI)-N-methyl-4-phenyl-N'-((piperidin-1-yl)sulfonyl)-4,5" dihydro-1H-pyrazole-1-carboxamidine (-)-(4S)-3-(4-Chlorophenyl)-N-methyl-4-phenyl-N'-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1H-pyrazole-1-carboxamidine (3-8 gram, 8.3 mol)) ([a25o] = -139 °, c = 0.006, MeOH) was obtained as an amorphous solid via chiral chromatographic separation of racemic 3-(4-chlorophenyl)-N-methyl-4-phenyl-N*-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1H-pyra2o!e-1-carboxamidine (7.87 gram, 17.1 mmol) using a chiral stationary phase Chiralpak AD. The mobile phase consisted of methanoi/diethylamine = 999/1 (v/v). In an analogous manner the optically puR6 compounds listed below have been prepared from the corresponding racemates: (-)-(4S)-3-(4-Chlorophenyl)"N'-((diethylamino)sulfonyl)-N'methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (Chiral stationary phase: Chiralcel OD). Mobile phase consisted of hexane/2-propanol = 80/20 (v/v). {[a25o] = -147 °, c = 0.01, MeOH). Amorphous. (-)-(4S)-3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyra2ole-1-carboxamidine (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of methanol/diethylamine = 999/1 (v/v). ([a25o] = -171 °, c = 0.005, MeOH). Amorphous. (-)-(4S)-3-(4-Chlorophenyl)-N-methyl-N'-((morpholin-4-yl)sulfony!)-4-phenyl- 4,5-dihydro-1H-pyrazoIe-1-carboxamidine. {a25D] = -144 ^ c = 0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous. wherein X represents - N(R3) (R4) or S R? - R and R1 independently represent phenyl, thienyl or pyR1dyl 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, tR1fluoromethyl. tR1fluoromethylthio, tR1fluoromethoxy, nitro, amino, mono- or dialkyi (C1-2)-amino, mono- or dialkyi (C1-2)-amido, (C1-2)-alkyl sulfonyl, dimethylsulfamido, C1-3-alkoxycarbonyl, carboxyl, tR1fluoromethylsulfonyl, cyano. carbamoyl, sulfamoyi and acetyl, or R and/or R1 represent naphtyl, - R2 represents hydrogen, hydroxy. Ct-3-alkoxy. acetyloxy or propjonyloxy, - R3 represents a hydrogen atom or a branched or unbranched C1-8 alky! group or a C3-7 cycloalkyi group which alkyl group or cycloalkyi group may be substituted with a hydroxy group, - R4 represents a hydrogen atom or a branched or unbranched C1-8 alkyl, C3-8 cycloalkyi. C2-10 heteroalkyi, C3-8 nonaromalic heterocycloalkyi or C4-10 nonaromatic heterocycloalkyl-alkyi moiety which moieties may contain one or more heteroatoms from the group (O. N. S). which moieties may be substituted with a keto group, tR1fluoromethyl group, C1.3 alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R4 represents an amino, hydroxy, phenoxy or benzyloxy group or R4 represents a branched or unbranched C1-8 alkoxy. C3-8 alkenyl, C5-8 cycloalkenyl or C6-9 cycloalkenylalkyi group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or -SO2- group which C1-8alkoxy, C3-6 alkenyl. C5-8cycloalkenyl or C6-9 cycloalkenylalkyi groups may be substituted with a hydroxy group, a tR1fluoromethyl group, an amino group, a monoalkylamino group or dialkylamino group or a fluoro atom, or R4 represents a phenyl, benzyl, pyR1dyl. thienyl, pyR1dylmethyl or phenethyl group wherein the aromatic R1ngs may be substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or RA represents a group NRgRgWith the proviso that R3 represents a hydrogen atom or a methy! group and wherein RB and Rg are the same or different and represent Ci^ alkyl or C2-4 tR1fluoroalkyi or Rg and Rg - together with the nitrogen atom to which they are bonded - form a saturated or un-saturated heterocyclic moiety having 4 to 8 R1ng atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or -SO2- group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a CM alkyl group or R3 and R4 - together with the nitrogen atom to which they are bonded - fomn a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 R1ng atoms, which heterocyclic moiety may contain one or more atoms from the group (O, N, S) or a keto group or -SO2- group, which moiety may be substituted with a Ci^ alkyl, hydroxyalkyi, phenyl, thienyl, pyR1dyl, amino, monoalkylaminoalkyi, dialkylaminoalkyl. monoaikylamino, dialkylamino, aminoalkyi, azetidinyl, pyrrolldinyl, pipeR1dinyl or hexahydro-1 H-azepinyl group, - R5 and Re independently of each other represent a hydrogen atom or a branched or unbranched Ci^ alkyl or alkenyl group which grcups may contain one or more heteroatoms from the group (O, N, S), a keto group or a -SOr group and which groups may be substituted with a hydroxy or amino group, or R5 and Re independently of each other represent a Ca-e cydoalkyl group or Ca^ cycloalkenyl group which may contain one or more R1ng heteroatoms from the group (O, N, S) or the -SOr group and which groups may be substituted with a hydroxy group, alkyl (C1-3)> the -SOr group, the keto group, amino group, monoaikylamino group (C1-3) or dialkylamino group (C1.3). or R5 represents a naphtyl group or a phenyl group which phenyl group may be substituted with 1, 2 or 3 substituents Y wherein Y has the meaning as descR1bed hereinabove, with the proviso that R6 represents a hydrogen atom, or a branched or unbranched alkyl group (C1-5) which alkyl group may contain one or more heteroatoms from the group (O, N. S) or the -SO2' group and which alkyl group may be substituted with a hydroxy, keto or amino group, or Rs and Re - together with the nitrogen atom to which they are bonded - fomn a monocyclic, bicyclic or tR1cyclic alkyl or alkenyl group which may contain R1ng heteroatoms from the group (O, N. S), the keto or the SO2 group and which monocyclic, bicyclic or tR1cyclic alkyl or alkenyl group may be substituted with a hydroxy group, alkyl (C1-3) group, SO2 group, keto group, amino group, monoaikylamino group (C1-3). dialkylamino group (C1-3). pyrrolldinyl group or pipeR1dinyl group, which monocyclic, bicyclic or tR1cyclic alkyl or alkenyl group may contain an annelated phenyl group which annelated phenyl group may be substituted with 1 or 2 substituents Y, wherein Y has the meaning as descR1bed herein above, - R7 represents branched or unbranched C1-3 alkyl. and tautomers, stereoisomers, and salts thereof. 2, A pharmaceutical composition containing the compound as claimed in claim 1 as an active component along with auxiliary substances and / or liquid or solid carR1er mateR1als. 3. A process for prepaR1ng the compound as claimed in claim 1 having the formula (lb), wherein the compound is prepared having the meaning of R, R,1-2, R5-R6 and R7 as given in claim 1, by 1) reacting in an organic solvent, a compound having fomiula (III) with a compound having formula (IV) to give a compound of the formula (V) which, in the presence of a base, is reacted with a compound of the formula R7-X, wherein X represents a leaving group such as an iodide group, or 2) reacting a compound having formula (III) with a compound having formula (IX) 4. A process for prepaR1ng the compound as claimed in claim 1 having the formula (la), wherein the compound is prepared having the meaning of R and R1-R6 as given in claim 1, by 1) reacting a compound having formula (lb), with an amine of the formula HNR3R4, or 2) reacting a compound having formula (V) with an amine of the formula HNR3R4 in the presence of a Hg+ salt, or 3) reacting a compound having formula (III) with a compound of the formula (VI) followed by treatment in an organic solvent with an amine HNR5R6 to give a compound of the formula (VII) which in an organic solvent is reacted with a halogenating agent such as PCI5 to give a compound of the formula (VIII) which in an inert organic solvent is reacted with an amine of the formula HNR3R4. 5. An intemediate of the compound as claimed in claim 1, represented by the general formula wherein R, R1, R2, R5 and R6 have the meanings given in claim 1 and wherein Y is sulphur, oxygen or halogen atom.

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575-chenp-2004 abstract duplicate.pdf

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575-chenp-2004 description (complete) duplicate.pdf

575-chenp-2004-abstract.pdf

575-chenp-2004-claims.pdf

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575-chenp-2004-correspondnece-po.pdf

575-chenp-2004-description(complete).pdf

575-chenp-2004-form 1.pdf

575-chenp-2004-form 26.pdf

575-chenp-2004-form 3.pdf

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