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AU2002333853A1 - 4,5-dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity - Google Patents

4,5-dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity

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AU2002333853A1
AU2002333853A1 AU2002333853A AU2002333853A AU2002333853A1 AU 2002333853 A1 AU2002333853 A1 AU 2002333853A1 AU 2002333853 A AU2002333853 A AU 2002333853A AU 2002333853 A AU2002333853 A AU 2002333853A AU 2002333853 A1 AU2002333853 A1 AU 2002333853A1
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Arnoldus H.J. Herremans
Cornelis G. Kruse
Josephus H.M. Lange
Jacobus Tipker
Herman H. Van Stuivenberg
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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4,5-Dihvdro-1 H-pyrazole derivatives having potent CBi-antagonistic activity
The present invention relates to a group of novel 4,5-dihydro-1H-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 cannabinoid (CBi) 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 (CBi and CB2) stimulated the search for novel cannabinoid receptor antagonists (Munro, S. et al., Nature 1993, 365, 61. Matsuda, L.A. and Bonner, T.l. 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 CBi receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CBT 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 SR141716A, but less potent and less CBi receptor subtype- selective than SR141716A (Meschler, J.P. er al., Biochem. Pharmacol. 2000, 60, 1315). Aminoalkylindoles have been disclosed as CB-, receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a moderately active CBi receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K. ef al., Life Sc. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CBi receptor antagonists (e.g. LY-320135) (Felder, CO et al., J. Pharmacol. Exp. Ther. 1998, 284, 291). 3-Alkyl-5,5'-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M. et al., Biorg. Med.Chem. Lett. 1999, 9, 2233). Aventis Pharma claimed diarylmethyleneazetidine analogs as CB-i receptor antagonists (Mignani, S. et al., Patent FR 2783246, 2000; Chem. Abstr. 2000, 32, 236982). Tricyclic pyrazoles were claimed by Sanofi-Synthelabo as CBi antagonists (Barth, F. ef al., Patent WO 0132663, 2001 ; Chem. Abstr. 2001, 134, 340504). Interestingly, many CBi receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R.S. et al., Eur. J. Pharmacol. 1997, 334, R1). Reviews provide a nice overview of the cannabinoid research area (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199. Lambert, D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R. ef al., Eur. J. Pharmacol. 1998, 359, 1. Williamson, E.M. and Evans, F.J. 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. Op//?. 77?er. Patents 2000, 70, 1529. Pertwee, R. G. Givf 2001, 48, 859).
It has now surprisingly been found that potent and selective antagonism of cannabinoid-CB! receptors is present in the novel 4,5-dihydro-1H-pyrazole derivatives of the formula (la) or (lb), prodrugs thereof, tautomers thereof and salts thereof
(|a) (lb)
wherein
- R and Ri 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, thfluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2)-amino, mono- or dialkyl (C1-2)-amido, (C1-3)-alkyl sulfonyl, dimethylsulfamido, C1-3- alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R-i represent naphtyl, - R2 represents hydrogen, hydroxy, C1-3-alkoxy, acetyloxy or propionyloxy,
- R3 represents a hydrogen atom or a branched or unbranched C1-8 alkyl group or a C3- cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group,
- R represents a hydrogen atom or a branched or unbranched C1-8 alkyl, C3.8 cycloalkyl, C2-10 heteroalkyl, C3-8 nonaromatic heterocycloalkyl or C4-10 nonaromatic heterocycloalkyl-alkyl 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 C6-9 cycloalkenylalkyl 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 cycloalkenylalkyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino 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 NR8R9with the proviso that R3 represents a hydrogen atom or a methyl group and wherein R8 and R9 are the same or different and represent C1-4 alkyl or C2.4 trifluoroalkyl or R8 and R9 - together with the nitrogen atom to which they are 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 are bonded - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring 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 C1- alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1 H-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 more 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 cycloalkyl group or C3-8 cycloalkenyl group which may contain one or more 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 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 R5 and R6 - together with the nitrogen atom to which they are 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), dialkylamino group
(Cι-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 centre of chirality is present (at the C4 position of the 4,5-dihydro-1 H- 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- 1 H-pyrazole moiety as represented by the formulas (1 a*) and (1 b*):
(1 a*) (1 b*)
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 CBi 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, 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, O 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 CBi receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CBi 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 CBT antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CBi receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CBi receptors by CBi 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 CBi receptor-mediated response can be antagonised by CB-i receptor antagonists such as the compounds of the invention.
Intermediates having formula (II) (see below) can be obtained according to methods known, for example: a) Francotte, E.; Tong, Z. Chem. Abstr. 126, 213598; b)
Rempfler, 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. Agric. Food Chem. 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.
Suitable synthetic routes for the compounds of the invention are the following:
Synthetic route A
Step 1 : reaction of a compound having formula (III)
with a compound having formula (IV).
I o=s=o
I (iv) R^ ^R«
This reaction is preferably carried out in an organic solvent, such as for example dichloromethane, and yields a compound having formula (V) wherein R, R-i, R2, R5 and R6 have the meaning as described above for compound (la), and which are new.
(V)
Step 2: reaction of a compound having formula (V) with a compound R7-X, wherein X represents a leaving group, for example an iodide group, and R7 has the meaning as described above for (lb) gives a compound having formula (lb).
(lb)
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)
(V)
with an amine having formula HNR3R4 wherein R3 and R4 have the meanings as described above in the presence of a mercury(II) salt, for example HgCI2, 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 HNR5R6
o=s=o (VI)
I Cl
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) are new.
Step 2: reaction of a compound having formula (VII) with a halogenating agent, such as for example PCI5, gives a compound having formula (Vlll)
wherein R10 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 (Vlll) wherein R, R.,, R2, R5 and R6 have the meanings as described above for compound (la) and wherein R10 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 (Vlll) 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
Step 1 : reaction of a compound having formula (III)
with a compound having formula (IX)
gives a compound having formula (lb), (see e.g. Chem. Ber. 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-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine
Part A: To a stirred solution of ((ethyl)propylamino)sulfonyl isothiocyanate (5.98 gram, 25.4 mmol) in dry dichloromethane in a nitrogen atmosphere 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- (((ethyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1 H-pyra-zole-1-thiocarboxamide (6.57 gram, 56 % yield). Melting point: 144-146 °C.
Part B: To a stirred suspension of 3-(4-chlorophenyl)-N-(((ethyl)propyl- amino)sulfonyl)-4-phenyl-4,5-dihydro-1 H-pyrazole-1 -thiocarboxamide (2.32 gram, 5 mmol) in acetonitrile (20 mL) is added cold methylamine (4 mL). To the resulting solution is added a solution of HgCI2 (1.5 gram) in acetonitrile (10 mL). The resulting black suspension is stirred for four hours. The precipitate is removed by filtration. The filtrate is concentrated in vacuo, dissolved in dichloromethane and successively washed with aqueous 0.5 N NaOH solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is crystallized from diethyl ether to give 3-(4-chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro- 1H-pyrazole-1-carboxamidine (1.78 gram, 77 % yield). Melting point (MP): 129-131 °C.
In an analogous manner the compounds having formula (la) listed below have been prepared:
2. 3-(4-Chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1-carboxamidine. MP: 112-115 °C. 3. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1-carboxamidine. MP: 104-106 °C.
4. 3-(4-Chlorophenyl)-N-(2-hydroxyethyl)-N'-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1-carboxamidine. MS (ESI+): 490 (MH+).
5. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(morpholin-4-yl)ethyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine. MS (ESI+): 547 (MH+))
6. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-(morpholin-4-yl)ethyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine. Amorphous.
7. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(dimethylamino)ethyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine.MS (ESI+): 505 (MH+)). 8. 3-(4-Chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((dimethylamino)sulfo-nyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine. Amorphous.
9. 3-(4-Chlorophenyl)-N-(2-(piperidin-1-yl)ethyl)-N'-((piperidin-1-yl)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine. MS (ESI+): 557 (MH+)).
10. 3-(4-Chlorophenyl)-N-(2-(morfolin-4-yl)ethyl)-N'-((piperidin-1 -yl)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine. MS (ESI+): 559 (MH+)); MP:
174-176 °C. 11. 3-(4-Chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-((dimethylamino)sulfo-nyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous.
12. 3-(4-Chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((dimethylamino)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous.
13. 3-(4-Chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((diethylamino)sulfo-nyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1-carboxamidine.MS(ESI+):519 (MH+). 14. 3-(4-Chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((diethylamino)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine hemifumarate. MP: 182-185 °C.
15. 3-(4-Chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-((piperidin-1 -yl)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous. 16. 3-(4-Chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((pyrrolidin-1 -yl)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous.
17. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(1 -methylpiperidin-4-yl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous.
18. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 123-126 °C.
19. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1 H- pyrazole-1 -carboxamidine. Amorphous. Rf ~ 0.4 (diethyl ether).
20. 3-(4-Chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-Methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 129-131 °C. 21. 3-(4-Chlorophenyl)-N-methyl-N'-((pyrrolidin-1 -yl)sulfonyl)-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. Amorphous. Rf ~ 0.3 (MTBE).
22. 3-(4-Chlorophenyl)-N-methyl-N'-(((methyl)propylamino)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 132-134 °C.
23. 3-(4-Chlorophenyl)-N,N-dimethyl-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous. Rf ~ 0.25 (MTBE).
24. 3-(4-Chlorophenyl)-N-methyl-N'-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 175-177 °C.
25. 3-(4-Chlorophenyl)-N'-((hexahydro-1 H-azepin-1 -yl)sulfonyl)-N-methyl-4-phenyl- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous. 26. 3-(4-Chlorophenyl)-N'-((dipropylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 141-142 °C.
27. 3-(4-Chlorophenyl)-N'-(((isopropyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 134-136 °C.
28. 3-(4-Chlorophenyl)-N-methyl-N'-((octahydroazocin-1-yl)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 165-168 °C.
29. 3-(4-Chlorophenyl)-N-ethyl-N'-((piperidin-1 -yl)sulfonyl)-4-phenyl-4,5-dihydro-1 H- pyrazole-1 -carboxamidine. Amorphous.
30. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 166-168 °C.
Example 31
3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-propyl-4-phenyl-4,5-dihydro-
1 H-pyrazole-1 -carboxamidine
Part A: To a stirred solution of chlorosulfonyl isocyanate (1.73 mL, 20 mmol) in dry dichloromethane (20 mL) is very slowly added a solution of 3-(4-chlorophenyl)-4- phenyl-4,5-dihydro-1H-pyrazole (5.13 gram, 20 mmol) in dry dichloromethane (125 mL) at - 5 °C. After stirring for 30 minutes the reaction mixture is allowed to attain room temperature 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-1 H-pyrazole- - carboxamide (4.75 g, 58 %). MP: 210-212 °C.
Part B: A mixture of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5- dihydro-1 H-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 temperature for 1 hour. After thorough concentration in vacuo, the formed 3-(4- chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1 H-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 mixture 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-1 H-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-1 H-pyrazole-1 -carboxamidine. MP: 128-131 °C. 33. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-N-(2,2,2- trifluoroethyl)-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 158-159 °C. 34. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methoxy-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 170-172 °C.
Example 35
3-(4-Chlorophenyl)-N-((piperidin-1-yI)sulfonyl)-4-phenyl-4,5-dihydro-1H- pyrazoIe-1 -carboximidothioic acid methyl ester
Part A: To a stirred solution of (piperidin-1 -yl)sulfonyl isothiocyanate (54.77 g, 266 mmol) in dry dichloromethane (900 mL) in a nitrogen atmosphere is added 3-(4- chlorophenyl)-4-phenyl-4,5-dihydro-1 H-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 Na2SO4, 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-1 H-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-1 H-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-1 H-pyrazole-1 -carboximidothioic acid methyl ester (27.9 gram, 90% yield). MP: 192-194 °C.
In an analogous manner the compounds having formula (lb) listed below have been prepared:
36. 3-(4-Chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1 H- pyrazole-1 -carboximidothioic acid methyl ester. MP: 159-160 °C.
37. 3-(4-Chlorophenyl)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1 H-pyrazole- 1 -carboximidothioic acid methyl ester. MP: 141-143 °C.
38. 3-(4-Chlorophenyl)-4-phenyl-N-((1 ,2,3,4-tetrahydroisoquinolin-2-yl)sulfonyl) -4,5- dihydro-1 H-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- 1 H-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-1 H-pyrazole-1 -carboximidothioic acid methyl ester. Amorphous.
43. 3-(4-Chlorophenyl)-N-((dimethylamino)sulfonyl)-4-(3-(trifluoromethyl) phenyl)-4,5- dihydro-1 H-pyrazole-1 -carboximidothioic acid methyl ester. Amorphous.
44. 3-(4-Chlorophenyl)-N-(((ethyl)methylamino)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro- 1 H-pyrazole-1 -carboximidothioic acid methyl ester.MP:133-136 °C.
45. 3-(4-Chlorophenyl)-N-((piperidin-1 -yl)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1 H- pyrazole-1 -carboximidothioic acid methyl ester. MP: 182-185 °C. 46. 3-(4-Chlorophenyl)-N-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1 H- 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- 1 H-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-1 H- pyrazole-1 -carboximidothioic acid methyl ester. MP: 196-198°C.
49. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-((dimethylamino)sulfonyl)-4,5-dihydro- 1 H-pyrazole-1 -carboximidothioic acid methyl ester. MP:181-183°C.
50. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N-((morpholin-4-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboximidothioic acid methyl ester. MP:231-233°C. 51. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N-((piperidin-1 -yl)sulfonyl)-4,5-dihydro- 1 H-pyrazole-1 -carboximidothioic acid methyl ester. MP:221-225°C. 52. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N-((dimethylamino)sulfonyl)-4,5- dihydro-1 H-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-1 H-pyrazole-1 -carboximidothioic acid methyl ester. MP: 216-217 °C.
54. 3-(5-Chlorothien-2-yl)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1 H- pyrazole-1 -carboximidothioic acid methyl ester. Amorphous.
lb
Example 55
3-(4-Chlorophenyl)-N-methyl-4-phenyl-N'-((piperidin-1-yl)sulfonyI)-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine To a cooled mixture (< 0 °C) of 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboximidothioic acid methyl ester (10.0 gram, 21 mmol) in methanol (75 mL) is added cold methylamine (15 mL). The resulting mixture
! is allowed to attain room temperature and stirred for 3 hours at 50 °C. After cooling to room temperature the mixture is concentrated in vacuo, dissolved in dichloromethane, washed twice with water, dried over Na2SO , filtered and concentrated in vacuo. Subsequent flash chromatography (EtOAc/MeOH/NH4OH (25 % aq.) = 95/5/0.5 (v/v)), followed by recrystallisation from diisopropyl ether gives 3- (4-chlorophenyl)-N-methyl-4-phenyl-N'-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H- pyrazole-1 -carboxamidine (7.87 gram, 81 % yield) as a white solid. MP: 175-177 °C.
In an analogous manner the compounds having formula (la) listed below - including those in table 1 - have been prepared: 56. 3-(4-Chlorophenyl)-N-cyclopropyl-4-phenyl-N'-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 142-144 °C.
57. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-hydroxy-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 180-182 °C.
58. 3-(5-Chlorothien-2-yl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 122-123 °C. 59. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 169-170 °C.
60. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(1-methylpiperidin-4-yl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 144-146 °C.
61. 3-(4-Chlorophenyl)-N-cyclopropyl-N'-((diethylamino)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 150-151 °C.
62. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-ethyl-4-phenyl-4,5-dihydro-1 H- pyrazole-1 -carboxamidine. MP: 116-119 °C.
63. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N,N-dimethyl-4-hydroxy-4-phenyl- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 135-137 °C. 64. N'-((Diethylamino)sulfonyl)-N,N-dimethyl-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 159-160 °C.
65. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboxamidine. MP: 81-85 °C.
66. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-ethyl,N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous.
67. 3-(4-Chlorophenyl)-N-ethyl,N-methyl-N'-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 178 °C.
68. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-ethyl-4-hydroxy-4-phenyl-4,5- dihydro-1 H-pyra∑ole-1 -carboxamidine. MP: 162-165 °C. 69. 3-(4-Chlorophenyl)-N-methyl-N'-((1 ,2,3,4-tetrahydroisoquinolin-2-yl)sulfo-nyl)-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. Amorphous. 70. 3-(4-Chlorophenyl)-N'-(((ethyl)phenylamino)sulfonyl)-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 145-147 °C. 71. N'-((Diethylamino)sulfonyl)-3-(4-chlorophenyl)-N-methyl-4-(pyridin-4-yl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 109-111 °C.
72. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 157-159 °C. 73. 3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 85-89 °C.
74. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-4-yl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 178-182 °C.
75. 3-(4-Chlorophenyl)-N-methyl-N'-((piperidin-1-yl)sulfonyl)-4-(3-(trifluoro- methyl)phenyl)-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 168-170 °C.
76. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(3-(trifluoro- methyl)phenyl)-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 65-68 °C.
77. 3-(4-Chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 125-128 °C. 78. 3-(4-Chlorophenyl)-N-methyl-N'-((piperidin-1 -yl)sulfonyl)-4-(pyridin-3-yl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 174-177 °C.
79. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N-methyl-N'-((morpholin-4-yl)sulfonyl)- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 223-235 °C.
80. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 214-216 °C.
81. 3-(4-Chlorophenyl)-4-(2,6-difluorophenyl)-N-methyl-N'-((piperidin-1-yl)sulfonyl)- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 260-263 °C.
82. 3-(4-Chlorophenyl)-4-(3-fluorophenyl)-N-methyl-N'-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 170 °C. 83. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-methyl-N'-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 223-225 °C.
84. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(2-fluorophenyl)-N-methyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 173-175 °C.
85. 3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(3-fluorophenyl)-N-methyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 110 °C.
86. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-methyl-N'-((morpholin-4-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 165-168 °C.
87. 3-(4-Chlorophenyl)-N'-((1 , 1 -dioxidothiomorpholin-4-yl)sulfonyl)-N-methyl-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine. MP: 268-271 °C. 88. 3-(4-Chlorophenyl)-N'-((4-hydroxypiperidin-1 -yl)sulfonyl)-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine. MP: 80 °C.
Table 1
93: 4-Methylpiperazin-1-yl Dimethylamino 191-193
Example 94 3-(4-ChIorophenyl)-N-((4-methylpiperazin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboximidothioic acid methyl ester
Part A: A stirred mixture of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.21 gram, 11.3 mmol), [(4-methylpiperazin-1-yl)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 temperature the mixture is concentrated in vacuo, water is added and the resulting mixture is extracted with dichloromethane. The dichloromethane extract is washed twice with water, dried over Na2SO4, filtered and concentrated in vacuo. Subsequent flash chromatographic purification gives 3-(4-chlorophenyl)-N-((4-methylpiperazin-1 -yl)sulfonyl)-4-phenyl- 4,5-dihydro-1 H-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-1 H-pyrazole-1 -carboximidothioic acid methyl ester.
MP: 158 °C.
96. N-((Diethylamino)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1 H-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)methylamino)sulfonyl)-4-phenyl- 4, 5-dihydro-1 H-pyrazole-1 -carboximidothioic acid methyl ester. Oil. Rf ~ 0.15
(methanol/dichloromethane = 5/95 (v/v)).
99. 3-(4-Chlorophenyl)-N-((4-methyl-1 ,4-diazepan-1-yl)sulfonyl)-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboximidothioic acid methyl ester. Amorphous. Rf ~ 0.10 (methanol/dichloromethane = 5/95 (v/v)).
Example 100
(-)-(4S)-3-(4-ChlorophenyI)-N-methyl-4-phenyl-N'-((piperϊdin-1-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine
(-)-(4S)-3-(4-Chlorophenyl)-N-methyl-4-phenyl-N'-((piperidin-1-yl)sulfonyl)-4,5- dihydro-1 H-pyrazole-1 -carboxamidine (3.8 gram, 8.3 ol)) ([ 25 D] = -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-1 H-pyrazole-1 -carboxamidine (7.87 gram, 17.1 mmol) using a chiral stationary phase Chiralpak AD. The mobile phase consisted of methanol/diethylamine = 999/1 (v/v).
In an analogous manner the optically pure compounds listed below have been prepared from the corresponding racemates:
101. (-)-(4S)-3-(4-Chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1 -carboxamidine (Chiral stationary phase: Chiralcel OD). Mobile phase consisted of hexane/2-propanol = 80/20 (v/v). ([α25 D] = -147 °, c = 0.01 , MeOH). Amorphous.
102. (-)-(4S)-3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of methanol/diethylamine = 999/1 (v/v). ([«25 D] = -171 °, c = 0.005, MeOH). Amorphous. 103. (-)-(4S)-3-(4-Chlorophenyl)-N-methyl-N'-((morpholin-4-yl)sulfonyl)-4-phenyl- 4,5-dihydro-1 H-pyrazole-1 -carboxamidine. ([α25 D] = -144 °, c = 0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous.

Claims (9)

Claims
1. Compounds of the general formulas (la) or (lb)
(la) (lb)
wherein
- R and Ri 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 dialkyl (C1-2)-amino, mono- or dialkyl (C1-2)-amido, (C1-3)-alkyl sulfonyl, dimethylsulfamido, C1-3- alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R-i represent naphtyl, - R2 represents hydrogen, hydroxy, C1-3-alkoxy, acetyloxy or propionyloxy,
- R3 represents a hydrogen atom or a branched or unbranched C1-8 alkyl group or a C3-7 cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group,
- R4 represents a hydrogen atom or a branched or unbranched C1-8 alkyl, C3-8 cycloalkyl, C2-10 heteroalkyl, C3-8 nonaromatic heterocycloalkyl or C -10 nonaromatic heterocycloalkyl-alkyl 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 C6-9 cycloalkenylalkyl group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or -SO2- group which C -8 alkoxy, C3-8 alkenyl, C5-8 cycloalkenyl or C6-9 cycloalkenylalkyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino 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 NR8R9with the proviso that R3 represents a hydrogen atom or a methyl group and wherein R8 and R9 are the same or different and represent C1-4 alkyl or C2-4 trifluoroalkyl or R8 and R9 - together with the nitrogen atom to which they are 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 R - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to
10 ring 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 C1-4 alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1 H-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 more 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 cycloalkyl group or C3-8 cycloalkenyl group which may contain one or more 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 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
R5 and R6 - together with the nitrogen atom to which they are 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), 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. and tautomers, stereoisomers, prodrugs and salts thereof.
2. Pharmaceutical compositions containing a pharmacologically active amount of at least one compound as claimed in claim 1 as an active component.
3. Method of preparing pharmaceutical compositions as claimed in claim 2 characterized in that a compound as claimed in claim 1 is brought in a form suitable for administration.
4. Process for the preparation of compounds having formula (lb), characterized in that a compound is prepared wherein R, R1-2, R5-Re and R7 have the meanings given in claim 1 by
1) reacting a compound having formula (111) with a compound having formula (IV) to give a compound of the formula (V) which is reacted with a compound of the formula R7-X, or
2) reacting a compound having formula (III) with a compound having formula (IX).
5. Process for the preparation of compounds having formula (la), characterized in that a compound is prepared wherein R and RrR6 have the meanings given in claim 1 by
1) reacting a compound having formula (lb), with an amine of the formula
HNR3R , or
2) reacting a compound having formula (V) with an amine of the formula HNR3R4 in the presence of a mercury (II) salt, or
3) reacting a compound having formula (III) with a compound of the formula (VI) to give a compound of the formula (VII) which is reacted with a halogenating agent to give a compound of the formula (Vlll) which is reacted with an amine of the formula HNR3R4.
6. Compounds of the general formula (V)
wherein R, R1 t R2, R5 and R6 have the meanings given in claim 1.
7. Compounds of the general formula (VII)
wherein R, R-,, R2, R5 and R6 have the meanings given in claim 1.
8. Compounds of the general formula (Vlll)
wherein R, R-i, R2, R5 and R6 have the meanings given in claim 1 and wherein R10 represents a halogen atom.
9. Use of a compound as claimed in claim 1 for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission.
0. Use as claimed in claim 9 characterised in that said disorders are 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.
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Families Citing this family (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6974810B2 (en) * 2001-09-21 2005-12-13 Solvay Pharmaceuticals B.V. 4,5-Dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity
EP1496838B1 (en) 2002-03-12 2010-11-03 Merck Sharp & Dohme Corp. Substituted amides
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US20050239859A2 (en) * 2003-09-03 2005-10-27 Solvay Pharmaceuticals Gmbh Novel medical uses of 4,5-dihydro-1h-pyrazole derivatives having cb1- antagonistic activity
CN1956949A (en) * 2003-09-18 2007-05-02 默克公司 Substituted sulfonamides
AR046132A1 (en) * 2003-10-24 2005-11-23 Solvay Pharm Gmbh PHARMACEUTICAL COMPOSITION CONTAINING AT LEAST ONE COMPOUND WITH RECEIVER ACTIVITY OF CB1, OR A PROFARMACO, TAUTOMERO OR SALT OF THE SAME, AS A SUITABLE ACTIVE COMPONENT FOR THE TREATMENT AND / OR PROFILAXIS OF DISEASES RELATED TO THE RECEIVER CB1 IN PATIENTS OR YOUTH PATIENTS THE TREATMENT
EP1753413A2 (en) * 2003-10-24 2007-02-21 Solvay Pharmaceuticals GmbH Novel medical uses of compounds showing cb sb 1/sb -antagonistic activity and combination treatment involving said compounds
US20050124660A1 (en) * 2003-10-27 2005-06-09 Jochen Antel Novel medical uses of compounds showing CB1-antagonistic activity and combination treatment involving said compounds
US20050143441A1 (en) * 2003-10-27 2005-06-30 Jochen Antel Novel medical combination treatment of obesity involving 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
TW200522944A (en) 2003-12-23 2005-07-16 Lilly Co Eli CB1 modulator compounds
BRPI0507005A (en) * 2004-01-30 2007-06-05 Solvay Pharm Bv compounds, pharmaceutical compositions, use of a compound, and method of preparing a pharmaceutical composition
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
TW200602314A (en) 2004-05-28 2006-01-16 Tanabe Seiyaku Co A novel pyrrolidine compound and a process for preparing the same
EA011307B1 (en) 2004-07-12 2009-02-27 Кадила Хелзкэр Лимитед Tricyclic pyrazole derivatives as cannabinoid receptor modulators
US20060025448A1 (en) 2004-07-22 2006-02-02 Cadila Healthcare Limited Hair growth stimulators
AU2005298692A1 (en) 2004-10-25 2006-05-04 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of diabetes mellitus type I, obesity and related conditions
SG163577A1 (en) * 2004-12-03 2010-08-30 Schering Corp Substituted piperazines as cb1 antagonists
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
AU2006253842A1 (en) 2005-06-02 2006-12-07 Glenmark Pharmaceuticals S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
BRPI0613505A2 (en) 2005-06-30 2011-01-11 Prosidion Ltd gpcr agonists
EP1743890A1 (en) * 2005-07-15 2007-01-17 Laboratorios Del Dr. Esteve, S.A. 4,5-Dihydro-1H-pyrazole derivatives, their preparation and use as medicaments
EP1928463A2 (en) * 2005-08-17 2008-06-11 Solvay Pharmaceuticals GmbH Method of using potassium channel inhibiting compounds
US7897601B2 (en) * 2006-01-18 2011-03-01 Intervet, Inc. Cannabinoid receptor modulators
US7482470B2 (en) * 2006-05-05 2009-01-27 Jenrin Discovery, Inc. Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes
US7964728B2 (en) 2006-07-06 2011-06-21 Solvay Pharmaceuticals B.V. Azaindole derivatives with a combination of partial nicotinic acetyl-choline receptor agonism and dopamine reuptake inhibition
TWI428334B (en) 2006-09-22 2014-03-01 Abbvie Bahamas Ltd Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists
US7923026B2 (en) 2006-10-20 2011-04-12 Solvay Pharmaceuticals B.V. Embedded micellar nanoparticles
EP2083799A1 (en) * 2006-10-20 2009-08-05 Solvay Pharmaceuticals B.V. Micellar nanoparticles of chemical substances
AR064735A1 (en) 2007-01-04 2009-04-22 Prosidion Ltd GPCR AGONISTS AND PHARMACEUTICAL COMPOSITION BASED ON THE COMPOUND
US20100048632A1 (en) 2007-01-04 2010-02-25 Matthew Colin Thor Fyfe Piperidine GPCR Agonists
WO2008081208A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
CL2008000017A1 (en) 2007-01-04 2008-08-01 Prosidion Ltd COMPOUNDS DERIVED FROM NITROGEN AND OXYGEN HETEROCICLES, GPCR AGONISTS; PHARMACEUTICAL COMPOSITION THAT INCLUDES SUCH COMPOUND; AND USE OF THE COMPOUND FOR THE TREATMENT OF OBESITY, DIABETES, METABOLIC SYNDROME, HYPERLIPIDEMIA, TOLERANCE
GB0700122D0 (en) 2007-01-04 2007-02-14 Prosidion Ltd GPCR agonists
US20100197564A1 (en) * 2007-04-19 2010-08-05 Schering Corporation Diaryl morpholines as cb1 modulators
CA2688161C (en) 2007-06-04 2020-10-20 Kunwar Shailubhai Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
CN101318931B (en) * 2007-06-04 2010-05-19 上海阳帆医药科技有限公司 Diaryl substituted pyrazole derivative, preparation method and application thereof
KR20100020998A (en) * 2007-06-15 2010-02-23 솔베이 파마슈티칼스 비. 브이 4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators
US8410135B2 (en) 2007-06-15 2013-04-02 Solvay Pharmaceuticals B.V. 4,5 dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators
WO2009005646A2 (en) * 2007-06-28 2009-01-08 Schering Corporation Substituted piperazines as cb1 antagonists
JP2010531874A (en) * 2007-06-28 2010-09-30 インターベット インターナショナル ベー． フェー． Substituted piperazines as CB1 antagonists
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
GB0720390D0 (en) 2007-10-18 2007-11-28 Prosidion Ltd G-Protein coupled receptor agonists
GB0720389D0 (en) 2007-10-18 2008-11-12 Prosidion Ltd G-Protein Coupled Receptor Agonists
US7655685B2 (en) * 2007-11-02 2010-02-02 Jenrin Discovery, Inc. Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes
CA2705132C (en) 2007-11-30 2017-09-26 Alltranz Inc. Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same
AR070898A1 (en) * 2008-03-18 2010-05-12 Solvay Pharm Bv ARILSULFONIL PIRAZOLIN CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS
EP2328910B1 (en) 2008-06-04 2014-08-06 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
AR071995A1 (en) * 2008-06-16 2010-07-28 Solvay Pharm Bv DERIVATIVES OF 3,4-DIARIL-4,5-DIHIDRO-1H-PIRAZOL-1-CARBOXAMIDINE REPLACED WITH FLUOR having CBTA ANTAGONIST ACTIVITY, PREPARATION PROCESSES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP3241839B1 (en) 2008-07-16 2019-09-04 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
TW201010981A (en) * 2008-08-01 2010-03-16 Solvay Pharm Bv Synthesis of 3,4-diaryl-4,5-dihydro-(1H)-pyrazole-1-carboxamidine derivatives
EP2348857B1 (en) 2008-10-22 2016-02-24 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
AU2009309037A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010079241A1 (en) 2009-01-12 2010-07-15 Fundacion Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion Use of antagonists and/or inverse agonists of cb1 receptors for the preparation of drugs that increase motor neuron excitability
WO2011044370A1 (en) 2009-10-07 2011-04-14 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes
AR079935A1 (en) * 2010-01-29 2012-02-29 Abbott Healthcare Products Bv SYNTHESIS OF DERIVATIVES OF PIRAZOLIN CARBOXAMIDINA REPLACED
JP2013520502A (en) 2010-02-25 2013-06-06 メルク・シャープ・エンド・ドーム・コーポレイション Novel cyclic benzimidazole derivatives that are useful anti-diabetic drugs
EP2582709B1 (en) 2010-06-18 2018-01-24 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
AU2011329636B2 (en) 2010-11-18 2016-05-19 Jenrin Discovery Cannabinoid receptor antagonists-inverse agonists useful for treating metabolic disorders, including obesity and diabetes
JP5728099B2 (en) 2011-02-25 2015-06-03 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Novel cyclic azabenzimidazole derivatives useful as antidiabetic agents
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
US8809325B2 (en) 2011-03-08 2014-08-19 Sanofi Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof
CN103459383B (en) * 2011-09-30 2016-06-22 财团法人国家卫生研究院 pyrazole compound
US8680131B2 (en) 2012-07-25 2014-03-25 Jenrin Discovery, Inc. Cannabinoid receptor antagonists/inverse agonists useful for treating disease conditions, including metabolic disorders and cancers
RU2015106909A (en) 2012-08-02 2016-09-27 Мерк Шарп И Доум Корп. ANTI-DIABETIC TRICYCLIC COMPOUNDS
IN2015DN03733A (en) 2012-11-13 2015-09-18 Us Health
US11155521B2 (en) 2012-11-13 2021-10-26 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor mediating compounds
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
EP2970119B1 (en) 2013-03-14 2021-11-03 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
HK1220611A1 (en) 2013-03-15 2017-05-12 Bausch Health Ireland Limited Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
CN113388007A (en) 2013-06-05 2021-09-14 博士医疗爱尔兰有限公司 Ultra-pure agonists of guanylate cyclase C, methods of making and using the same
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10329259B2 (en) * 2014-05-09 2019-06-25 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Pyrazole derivatives and their use as cannabinoid receptor mediators
EP3551176A4 (en) 2016-12-06 2020-06-24 Merck Sharp & Dohme Corp. ANTIDIABETIC HETEROCYCLIC COMPOUNDS
WO2022128050A1 (en) 2020-12-14 2022-06-23 Symrise Ag Medicament for fighting inflammation and pain
WO2022245627A1 (en) * 2021-05-17 2022-11-24 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A facile and odor-free approach to convert sulfonyl urea derivatives to chalcogenide sulfonyl urea derivatives
WO2023108036A1 (en) * 2021-12-10 2023-06-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor modulating compounds

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL158178B (en) * 1974-07-12 1978-10-16 Philips Nv METHOD OF PREPARING INSECTICIDE PREPARATIONS CONTAINING A PYRAZOLINE DERIVATIVE, SO PREPARED PREPARATIONS, AND METHOD OF PREPARING PYRAZOLINE DERIVATIVES WITH INSECTICIDE ACTION.
JPH03173887A (en) * 1989-03-27 1991-07-29 Nissan Chem Ind Ltd Sultamsulfonamide and herbicide
FR2713225B1 (en) * 1993-12-02 1996-03-01 Sanofi Sa Substituted N-piperidino-3-pyrazolecarboxamide.
FR2692575B1 (en) * 1992-06-23 1995-06-30 Sanofi Elf NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2789079B3 (en) 1999-02-01 2001-03-02 Sanofi Synthelabo PYRAZOLECARBOXYLIC ACID DERIVATIVE, ITS PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CN1205188C (en) 2000-03-23 2005-06-08 索尔瓦药物有限公司 4,5-dihydro-1h-pyrazole derivatives having cbi-antagonistic activity
US6974810B2 (en) * 2001-09-21 2005-12-13 Solvay Pharmaceuticals B.V. 4,5-Dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity
US20050143441A1 (en) 2003-10-27 2005-06-30 Jochen Antel Novel medical combination treatment of obesity involving 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
US20050124660A1 (en) 2003-10-27 2005-06-09 Jochen Antel Novel medical uses of compounds showing CB1-antagonistic activity and combination treatment involving said compounds

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