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WO2001070700A1 - 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity - Google Patents

4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity Download PDF

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Publication number
WO2001070700A1
WO2001070700A1 PCT/EP2001/003247 EP0103247W WO0170700A1 WO 2001070700 A1 WO2001070700 A1 WO 2001070700A1 EP 0103247 W EP0103247 W EP 0103247W WO 0170700 A1 WO0170700 A1 WO 0170700A1
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Prior art keywords
formula
compound
chlorophenyl
phenyl
dihydro
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PCT/EP2001/003247
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French (fr)
Inventor
Josephus H. M. Lange
Cornelis G. Kruse
Jacobus Tipker
Martinus T. M. Tulp
Bernardus J. Van Vliet
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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Priority to DK01915398T priority Critical patent/DK1268435T3/en
Priority to HU0204519A priority patent/HUP0204519A3/en
Priority to MXPA02009258A priority patent/MXPA02009258A/en
Priority to JP2001568910A priority patent/JP2004500401A/en
Priority to HK03104555.6A priority patent/HK1052349B/en
Priority to SK1352-2002A priority patent/SK287074B6/en
Priority to UA2002108258A priority patent/UA74367C2/en
Priority to IL15145201A priority patent/IL151452A0/en
Priority to DE60124685T priority patent/DE60124685T2/en
Priority to AU4250101A priority patent/AU4250101A/en
Priority to SI200130668T priority patent/SI1268435T1/en
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to AU2001242501A priority patent/AU2001242501B2/en
Priority to EP01915398A priority patent/EP1268435B1/en
Priority to BR0109457-2A priority patent/BR0109457A/en
Priority to CA002401832A priority patent/CA2401832C/en
Priority to DZ013335A priority patent/DZ3335A1/en
Publication of WO2001070700A1 publication Critical patent/WO2001070700A1/en
Priority to IL151452A priority patent/IL151452A/en
Priority to NO20024531A priority patent/NO324173B1/en
Anticipated expiration legal-status Critical
Priority to CY20071100124T priority patent/CY1105967T1/en
Ceased legal-status Critical Current

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a group of novel 4,5-dihydro-l H-pyrazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
  • 4,5-dihydro-1 H-pyrazoles are potent Cannabis-1 (CB,) receptor antagonists with utility for the treatment of psychiatric and neurological disorders.
  • Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB T and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61.
  • Aminoalkylindoles have been disclosed as CB, receptor antagonists.
  • a representative example is lodopravadoline (AM-630), which was introduced in
  • AM-630 is a CB ! receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Life Sc. 1997, 61, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB ! receptor antagonists (e.g. LY-320135) (Felder, CO; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan, G.J.;
  • R and R are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, from the group C ⁇ -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1 - 2 )-amino, mono- or dialkyl (C ⁇ -amido, (C ⁇ -alkyl sulfonyl, dimethylsulfamido, C ⁇ -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R ⁇ represent naphtyl,
  • R 2 represents hydrogen, hydroxy, C 1 . 3 -alkoxy, acetyloxy or propionyloxy,
  • - Aa represents one of the groups (i), (ii), (iii), (iv) or (v)
  • R 4 and R 5 independently of each other represent hydrogen or C ⁇ branched or unbranched alkyl or C 3 ⁇ cycloalkyl or R 4 represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that R 5 represents hydrogen
  • R 6 represents hydrogen or C ⁇ unbranched alkyl
  • Bb represents sulfonyl or carbonyl
  • R 3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, or R 3 represents C ⁇ branched or unbranched alkyl or C 3-8 cycloalkyl, or R 3 represents naphtyl
  • the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders.
  • psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders.
  • the affinity of the compounds of the invention for cannabinoid CB, receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CB ! receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
  • the cannabinoid CB, antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB ! receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB, receptors by CB, receptor agonists (e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB, receptor-mediated response can be antagonised by CB, receptor antagonists such as the compounds of the invention.
  • At least one centre of chirality is present (at the C 4 position of the 4,5-dihydro-1 H- pyrazole moiety) in the compounds of the formula (I).
  • the invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I).
  • the invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
  • a suitable synthesis for the compounds according to the present invention is the following:
  • R 7 represents a lower alkyl group, such as for example 2-methyl-2- thiopseudourea, or with a suitable salt form thereof in the presence of a base.
  • This reaction gives a 4,5-dihydro-1 H-pyrazole-1-carboxamidine derivative having formula (V) (V)
  • Aa has the meaning (i) or (ii) as described herein above.
  • Compounds having formula (V) wherein Aa has the meaning (i) or (ii) as described herein above and wherein R, R, and R 2 have the meaning as described herein above for compound (I) are new.
  • guanylating agent 1 H-pyrazole-1 - carboxamidine and its salts (for example the hydrochloride salt) and 3,5-dimethyl-
  • a compound having formula (III) is reacted with a so-called protected guanylating agent.
  • protected guanylating agents are N-
  • the compound having formula (V) is reacted with an optionally substituted compound of the formula R 3 -SO 2 X or R 3 -COX, wherein R 3 has the above mentioned meaning and X represents a halogen atom.
  • This reaction is preferably carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile.
  • a base such as triethylamine
  • aprotic solvent such as acetonitrile
  • This reaction is preferably carried out in an inert organic solvent, such as for example acetonitrile.
  • This reaction is preferably carried out in a polar organic solvent, such as for example acetonitrile.
  • R 7 represents a lower alkyl group, for example methyl.
  • This reaction is preferably carried out in an inert organic solvent, such as for example 1 ,4-dioxane.
  • R 8 represents a halogen atom, such as for example chloro.
  • This reaction is preferably carried out in an inert organic solvent, such as for example chlorobenzene.
  • This reaction is preferably carried out in an inert organic solvent, such as for example dichloromethane.
  • R 9 represents a C, ⁇ alkyl group.
  • This reaction is preferably carried out in a polar organic solvent, such as for example acetonitrile.
  • R 9 represents a C,. 3 alkyl group.
  • Compounds having formula (XII) wherein R, R,, R 2 , R 3 and Bb have the meaning as described herein above for compound (I) and wherein R 9 represents a C,. 3 alkyl group are new.
  • Step 2 of route A3 Reaction of a compound having formula (XII) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
  • This reaction is preferably carried out in a polar organic solvent, such as for example methanol.
  • R 3 -SO 2 X or R 3 -COX wherein R 3 has the above mentioned meaning and X is halogen.
  • This reaction preferably is carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile.
  • a base such as triethylamine
  • aprotic solvent such as acetonitrile.
  • This reaction gives compound (I) wherein Bb represents a sulfonyl group or carbonyl group respectively.
  • the above mentioned compound having formula (V) can be reacted with a compound of the formula R 3 -COOH via formation of an active ester or in the presence of a so-called coupling reagent.
  • Part A A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (5.13 gram, 20.0 mmol), 2-methyl-2-thiopseudourea hydroiodide (5.00 gram, 23.0 mmol) and pyridine (10 ml) is heated at 110 °C for 1 hour. After one night standing at room temperature diethyl ether is added and the precipitate is collected by filtration. This precipitate is washed three times with diethyl ether portions to afford a solid (9 gram). Melting point: -230 °C. This solid is dissolved in methanol (20 ml).
  • Part B To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine (0.50 gram, 1.68 mmol) and 4-fluorophenylsulfonyl chloride (0.34 gram, 1.75 mmol) in acetonitrile (10 ml) is added N,N-dimethyl-4- aminopyridine (0.020 gram, 0.175 mmol) and triethylamine (1 ml). The resulting solution is stirred at room temperature for 30 minutes.
  • Part A A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) is heated at reflux temperature for 20 hours.
  • Part B To a stirred mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) is added dimethylamine (10 ml) and dichloromethahe (75 ml) and the resulting solution is stirred at room temperature for 6 hours.
  • the formed crystals are collected by filtration and recrystallised from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamide (4.75 gram, 76 % yield) Melting point: 211-214 °C.
  • Part B A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7.75 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour.
  • N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 - carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo.
  • N-Methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine Melting point: Amorphous. N 1 ,N -Dimethyl-N 2 -((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point:148-151 °C.
  • Part A A stirred solution of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole
  • Part B To a solution of 1-[2-((te/t-butoxycarbonyl)amino)ethyl]-3-(4- chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (1.91 gram, 4.8 mmol) in dichloromethane (50 ml) is added trifluoroacetic acid (5 ml) and the resulting solution is stirred at room temperature for 5 hours. After concentration in vacuo the residue is dissolved in ethylacetate and washed with 2N sodium hydroxide solution.
  • Part C To a solution of 1-(2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole (0.56 gram, 1.87 mmol) and diisopropylethylamine in acetonitrile (20 ml) is added 3-(trifluoromethyl)phenylsulfonyl chloride (0.35 ml, 2.18 mmol) and the resulting solution is stirred at room temperature for 20 minutes. After concentration in vacuo the residue is dissolved in ethylacetate and washed with 2N sodium hydroxide solution. The ethylacetate layer is concentrated in vacuo.

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Abstract

The present invention relates to a group of novel 4,5-dihydro-1H-pyrazole derivatives which are potent antagonists of the cannabis CB1-receptor. The compounds have general formula (I) wherein R and R1 are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2 or 3 substituents Y or R and/or R1 represent naphtyl, R2 represents hydrogen, hydroxy, C1-3-alkoxy, acetyloxy or propionyloxy, Aa represents one of the groups (i), (ii), (iii), (iv) or (v), Bb represents sulfonyl or carbonyl, R3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2 or 3 substituents Y or R3 represents C1-8 branched or unbranched alkyl or C3-8 cycloalkyl, or R3 represents naphtyl.

Description

4,5-Dihvdro-1 H-pyrazole derivatives having CB^-antaqonistic activity
The present invention relates to a group of novel 4,5-dihydro-l H-pyrazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.
The above mentioned 4,5-dihydro-1 H-pyrazoles are potent Cannabis-1 (CB,) receptor antagonists with utility for the treatment of psychiatric and neurological disorders.
Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CBT and CB2) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.; Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CBT receptors in the brain, in combination with the strictly peripheral localisation of the CB2 receptor, makes the CB, receptor a very interesting molecular target for CNS-directed drug discovery in the areas of both psychiatric and neurological disorders (Consroe, P.
Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1, 587. Greenberg, D.A. Drug News Perspect. 1999, 12, 458). Hitherto, three types of distinct CB, receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB, receptor antagonists. A representative example is SR-141716A, which is currently undergoing Phase II clinical development for psychotic disorders (Dutta, A.K.; Sard, H.; Ryan, W.; Razdan, R.K.; Compton, D.R.; Martin, B.R. Med. Chem. Res.
1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43).
Aminoalkylindoles have been disclosed as CB, receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in
1995. AM-630 is a CB! receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Life Sc. 1997, 61, PL115). More recently, researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB! receptor antagonists (e.g. LY-320135) (Felder, CO; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan, G.J.;
Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284, 291 ). Recently, 3-alkyl-5,5'- diphenylimidazolidTnediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J.H., Lambert, D.M. Biorg. Med.Chem. Lett. 1999, 9,
2233). Interestingly, many CB, receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R.S.; Burkey, T.H.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Eur. J. Pharmacol. 1997, 334, R1). Recent reviews provide a nice overview of the current status in the cannabinoid research area (Mechoulam, R.; Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199.
Lambert, D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998, 359, 1 ).
It has now surprisingly been found that the novel 4,5-dihydro-l H-pyrazole derivatives of the formula (I), prodrugs thereof, tautomers thereof and salts thereof
Figure imgf000003_0001
wherein - R and R, are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, from the group C^-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2)-amino, mono- or dialkyl (C^-amido, (C^-alkyl sulfonyl, dimethylsulfamido, C^-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R^ represent naphtyl,
- R2 represents hydrogen, hydroxy, C1.3-alkoxy, acetyloxy or propionyloxy,
- Aa represents one of the groups (i), (ii), (iii), (iv) or (v)
Figure imgf000004_0001
(i) (ϋ) (iii) (iv) (v)
wherein
R4 and R5 independently of each other represent hydrogen or C^ branched or unbranched alkyl or C3^ cycloalkyl or R4 represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that R5 represents hydrogen R6 represents hydrogen or C^ unbranched alkyl
Bb represents sulfonyl or carbonyl,
R3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, or R3 represents C^ branched or unbranched alkyl or C3-8 cycloalkyl, or R3 represents naphtyl
are potent and selective antagonists of the cannabis CB^receptor.
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 and appetite disorders, obesity, neurological disorders such as dementia, distonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, as well as for the treatment of pain disorders and other CNS-diseases involving cannabinoid neurotransmission, and in the treatment of gastrointestinal disorders and cardiovascular disorders.
The affinity of the compounds of the invention for cannabinoid CB, receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CB! receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
The cannabinoid CB, antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB! receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB, receptors by CB, receptor agonists (e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB, receptor-mediated response can be antagonised by CB, receptor antagonists such as the compounds of the invention.
At least one centre of chirality is present (at the C4 position of the 4,5-dihydro-1 H- pyrazole moiety) in the compounds of the formula (I). The invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I).
The invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
The compounds of the invention having formula (III) (vide infra), wherein R2 represents hydrogen can be obtained according to methods known, for example: a) EP 0021506; b) DE 2529689.
A suitable synthesis for the compounds according to the present invention is the following:
Synthesis route A (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above). Step 1 of route A
Reaction of a compound having formula (II)
Figure imgf000006_0001
(ii)
with hydrazine or hydrazine hydrate. This reaction gives a compound having formula (III)
Figure imgf000006_0002
wherein R2 represents a hydroxy group. This reaction is preferably carried out in a polar solvent, such as for example ethanol. Compounds having formula (III) wherein R2 represents a hydroxy group and wherein R and R, have the meaning as described herein above for compound (I) are new.
Step 2 of route A Reaction of a compound having formula (III) with a compound having formula
(IVa) or a compound having formula (IVb)
R4
R^ ^R5 H ^R5
(IVa) (IVb)
wherein R7 represents a lower alkyl group, such as for example 2-methyl-2- thiopseudourea, or with a suitable salt form thereof in the presence of a base. This reaction gives a 4,5-dihydro-1 H-pyrazole-1-carboxamidine derivative having formula (V) (V)
Figure imgf000007_0001
wherein Aa has the meaning (i) or (ii) as described herein above. Compounds having formula (V) wherein Aa has the meaning (i) or (ii) as described herein above and wherein R, R, and R2 have the meaning as described herein above for compound (I) are new.
Alternatively, a compound having formula (III) is reacted with a so-called guanylating agent. Examples of such guanylating agents are 1 H-pyrazole-1 - carboxamidine and its salts (for example the hydrochloride salt) and 3,5-dimethyl-
1 H-pyrazole-1-carboxamidine and its salts (for example the nitrate salt) and the like. This reaction gives a carboxamidine derivative having formula (V).
Alternatively, a compound having formula (III) is reacted with a so-called protected guanylating agent. Examples of such protected guanylating agents are N-
(benzyloxycarbonyl)-l H-pyrazole-1 -carboxamidine, N-(te/f-butoxycarbonyl)-1 H- pyrazole-1 -carboxamidine and N,N'-bis-(tetf-butoxycarbonyl)-1 H-pyrazole-1 - carboxamidine and the like. This reaction gives after deprotection a compound having formula (V).
Step 3 of route A
The compound having formula (V) is reacted with an optionally substituted compound of the formula R3-SO2X or R3-COX, wherein R3 has the above mentioned meaning and X represents a halogen atom. This reaction is preferably carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile. This reaction gives compound (I) wherein Bb represents a sulfonyl group or a carbonyl group, respectively.
Synthesis route A1 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A1
Reaction of a compound having formula (III)
Figure imgf000008_0001
(Hi)
with a thioisocyanate derivative having formula (VI) .
NCS
Bb (VI)
I R3
This reaction is preferably carried out in an inert organic solvent, such as for example acetonitrile.
This reaction gives a thiocarboxamide derivative having formula (VII). Compounds having formula (VII) wherein R, R,, R2, R3 and Bb have the meaning as described herein above for compound (I) are new.
Figure imgf000008_0002
Step 2 of route A1
Reaction of a compound having formula (VII) with an amine in the presence of a mercury(ll) salt, such as for example HgCI2, gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
This reaction is preferably carried out in a polar organic solvent, such as for example acetonitrile.
Synthesis route A2 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above) Step 1 of route A2
Reaction of a compound having formula III
Figure imgf000009_0001
with a carbamate ester derivative having formula (VIII).
Figure imgf000009_0002
wherein R7 represents a lower alkyl group, for example methyl. This reaction is preferably carried out in an inert organic solvent, such as for example 1 ,4-dioxane.
This reaction gives a 4,5-dihydropyrazole-1-carboxamide derivative having formula (IX). Compounds having formula (IX) wherein R, R,, R2, R3 and Bb have the meaning as described herein above for compound (I) are new.
Figure imgf000009_0003
Step 2 of route A2
Reaction of a compound having formula (IX) with a halogenating agent, such as for example PCI5, gives a 4,5-dihydropyrazole-1-carboximidoyl halogenide derivative having formula (X)
Figure imgf000010_0001
wherein R8 represents a halogen atom, such as for example chloro. This reaction is preferably carried out in an inert organic solvent, such as for example chlorobenzene.
Compounds having formula (X) wherein R, R,, R2, R3 and Bb have the meaning as described herein above for compound (I) and wherein R8 represents a halogen atom are new.
Step 3 of route A2
Reaction of a compound having formula (X) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
This reaction is preferably carried out in an inert organic solvent, such as for example dichloromethane.
Synthesis route A3 (for compounds having formula (I), wherein Aa has the meaning (i) or (ii) as described herein above)
Step 1 of route A3
Reaction of a compound having formula
Figure imgf000010_0002
with a dithioimidocarbonic ester derivative having formula (XI)
Figure imgf000011_0001
wherein R9 represents a C,^ alkyl group.
This reaction is preferably carried out in a polar organic solvent, such as for example acetonitrile.
This reaction gives a carboximidothioic ester derivative having formula (XII).
Figure imgf000011_0002
wherein R9 represents a C,.3 alkyl group. Compounds having formula (XII) wherein R, R,, R2, R3 and Bb have the meaning as described herein above for compound (I) and wherein R9 represents a C,.3 alkyl group are new.
Step 2 of route A3 Reaction of a compound having formula (XII) with an amine gives a compound having formula (I) wherein Aa has the meaning (i) or (ii) as described herein above.
This reaction is preferably carried out in a polar organic solvent, such as for example methanol.
Synthesis route B (for compounds having formula (I), wherein Aa has the meaning
(iii) or (iv) as described herein above)
Step 1 of route B
Reaction of a compound having formula (III)
Figure imgf000011_0003
with a compound having formula (XIII), or a compound having formula (XIV), respectively
Figure imgf000012_0001
(Xiii) (XIV)
wherein Bb, R3 and R6 have the above mentioned meanings and Z represents a so-called leaving group.
These reactions give compounds having formula (I), wherein Aa has the meaning (iii) or (iv), respectively.
Synthesis route C (for compounds having formula (I), wherein Aa has the meaning
(v) as described herein above) Step 1 of route C Reaction of a compound having formula (III)
Figure imgf000012_0002
with an aziridine derivative having formula (XV), or a compound having formula (XVI), respectively
e ^f
N I NH Prot Prot (XV) (XVI)
wherein R6 has the above mentioned meaning, Z represents a so-called leaving group and Prot represents a so-called protective group, such as tert- butoxycarbonyl, benzyloxycarbonyl and the like. These reactions give compounds having formula (XVII)
Figure imgf000013_0001
(XVII)
wherein Aa has the meaning (v) as described herein above. Compounds having formula (XVII) wherein R, R, and R2 have the meaning as described herein above for compound (I) and wherein Aa has the meaning (v) as described herein above and wherein Prot represents a so-called protective group are new. Subsequent removal of the so-called protective group according to known methods (see for example: T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, Inc., New York, 1999) gives compounds (V), wherein Aa has the meaning (v) as described herein above).
Compounds having formula (V) wherein R, R, and R2 have the meaning as described herein above for compound (I) and wherein Aa has the meaning (v) as described herein above are new.
Step 2 of route C
The compound having formula (V), wherein Aa has the meaning (v) as described herein above, is reacted with an optionally substituted compound of the formula
R3-SO2X or R3-COX, wherein R3 has the above mentioned meaning and X is halogen. This reaction preferably is carried out in the presence of a base, such as triethylamine in an aprotic solvent, such as acetonitrile. This reaction gives compound (I) wherein Bb represents a sulfonyl group or carbonyl group respectively.
Alternatively, the above mentioned compound having formula (V) can be reacted with a compound of the formula R3-COOH via formation of an active ester or in the presence of a so-called coupling reagent.
The preparation of the compounds is illustrated in the following examples.
Example I 3-(4-Chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole 2-(4-Chlorobenzoyl)-2-phenyloxirane (112 gram, 0.43 mol) is dissolved in ethanol
(650 ml) at 35 °C. To the resulting stirred solution is added N2H4.H2O (42 ml) and the formed 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1 H-pyrazole slowly precipitates. After standing for 16 hours the crystalline material is collected by filtration and successively washed with ethanol, water and ethanol and subsequently dried to give 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1 H- pyrazole (92 gram, 78 % yield). Melting point: 195-196 °C.
Example II 3-(4-Chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl-1 H- pyrazole-1 -carboxamidine
Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (5.13 gram, 20.0 mmol), 2-methyl-2-thiopseudourea hydroiodide (5.00 gram, 23.0 mmol) and pyridine (10 ml) is heated at 110 °C for 1 hour. After one night standing at room temperature diethyl ether is added and the precipitate is collected by filtration. This precipitate is washed three times with diethyl ether portions to afford a solid (9 gram). Melting point: -230 °C. This solid is dissolved in methanol (20 ml). To the resulting solution is successively added a 2N sodium hydroxide solution (12 ml) and water (200 ml). The formed precipitate is collected by filtration, washed two times with diethyl ether and successively with diisopropyl ether. The resulting solid is dried in vacuo to yield 3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamidine (5.1 gram, 88 % yield). Melting point: 187- 189 °C.
Part B: To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine (0.50 gram, 1.68 mmol) and 4-fluorophenylsulfonyl chloride (0.34 gram, 1.75 mmol) in acetonitrile (10 ml) is added N,N-dimethyl-4- aminopyridine (0.020 gram, 0.175 mmol) and triethylamine (1 ml). The resulting solution is stirred at room temperature for 30 minutes. After addition of a 2N sodium hydroxide solution and extraction with ethylacetate (400 ml), the ethylacetate layer is concentrated in vacuo. The resulting crude residue is further purified by means of flash chromatography (petroleum ether/diethyl ether = 1/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo affords solid 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl-1 H-pyrazole- 1 -carboxamidine (0.55 gram, 72 % yield). Melting point: 214-215 °C
In an analogous manner the compounds having formula (I) listed below have been prepared:
4,5-Dihydro-N-((4-fluorophenyl)sulfonyl)-3-(4-methoxyphenyl)-4-(4-methoxy- phenyl)-1 H-pyrazole-1 -carboxamidine: Melting point: 155-156 °C
4,5-Dihydro-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-N-((4-methoxy- phenyl)sulfonyl)-1 H-pyrazole-1 -carboxamidine: Melting point: 148-150 °C 3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-N-((2,4,6-trimethylphenyl)sulfonyl)-1 H- pyrazole-1 -carboxamidine: Melting point: 221-222 °C
3-(4-Chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-hydroxy-4-phenyl-
1 H-pyrazole-1 -carboxamidine: Melting point: 227-228 °C
Example III
3-(4-Chlorophenyl)-4,5-dihydro-N-(1 -naphtoyl)-4-phenyl-1 H-pyrazole-1 - carboxamidine
To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 - carboxamidine (0.75 gram, 2.50 mmol) and 1-naphtoyl chloride (0.4 ml, 2.70 mmol) in acetonitrile (15 ml) is added triethylamine (1 ml). The resulting mixture is stirred at room temperature for 1 hour. After addition of a 2N sodium hydroxide solution and extraction with ethylacetate, the ethylacetate layer is concentrated in vacuo. The resulting crude residue is further purified by means of flash chromatography (petroleum ether/diethyl ether = 3/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo affords 3-(4-chlorophenyl)-4,5- dihydro-N-(1-naphtoyl)-4-phenyl-1 H-pyrazole-1-carboxamidine ( 0.94 gram, 83 % yield). Melting point: 206-207 °C
In an analogous manner the compound having formula (I) listed below has been prepared:
3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-N-(2-pyridoyl)-1 H-pyrazole-1- carboxamidine. Melting point: 118 °C (decomposition)
Example IV
N1,N1-Dimethyl-N2-((4-chIorophenyi)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamidine
Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) is heated at reflux temperature for 20 hours. An additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol) is added and the resulting mixture is heated at reflux temperature for another 16 hours. After concentration in vacuo, dichloromethane is added and the resulting solution is washed twice with water and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo the residue is further purified by flash chromatography (diethyl ether/ petroleum ether = 1/1 (v/v)) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1-carboximidothioic acid methyl ester (12.5 gram, 80% yield based on [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester) as an amorphous solid.
Part B: To a stirred mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) is added dimethylamine (10 ml) and dichloromethahe (75 ml) and the resulting solution is stirred at room temperature for 6 hours. Evaporation in vacuo and subsequent flash chromatographic purification (diethyl ether/ petroleum ether = 1/1 (v/v), followed by diethyl ether) gives a solid which is further purified by recrystallisation from diisopropyl ether to yield N1,N1-dimethyl-N2-((4-chloro-phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole- 1 -carboxamidine (2.63 gram, 63 % yield). Melting point: 182 °C.
In an analogous manner the compounds having formula (I) listed below have been prepared:
N-Methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(3- pyridyl)-1 H-pyrazole-1 -carboxamidine. Melting point: 101-105 °C. N-Methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(4- pyridyl)-1 H-pyrazole-1 -carboxamidine. Melting point: 112-115 °C. N1,N1-Dimethyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- hydroxy-4-phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: Amorphous. N-Ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 183-185 °C.
Example V
N-Methyl-N -(3-(trifluoromethyl)benzoyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine Part A: To 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (5.13 gram, 20.0 mmol) in acetonitrile (80 ml) is added 3-(trifluoromethyl)benzoylisothio-cyanate (4.62 gram, 20.0 mmol) at 0 °C and the resulting mixture is stirred for 1 hour. The formed yellow precipitate is collected by filtration and washed with a small portion of acetonitrile and water, respectively, and subsequently dried in vacuo to give 3- (4-chlorophenyl)-4,5-dihydro-4-phenyI-N-((3-trifluoromethyl) benzoyl)-1 H-pyrazole-
1 -thiocarboxamide (8.26 gram, 85 % yield). Melting point: 180-182 °C. Part B: To a stirred suspension of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-N-((3- trifluoromethyl)benzoyl)-1 H-pyrazole-1 -thiocarboxamide (4.88 gram, 10.0 mmol) in acetonitrile (50 ml) is added cold methylamine (5 ml) to give a green solution. After addition of a solution of HgCI2 (3.0 gram, 11 mmol) in 25 ml acetonitrile, the resulting mixture is stirred for three hours. The precipitate is removed by filtration over hyflo and the filtrate is collected and concentrated in vacuo. After addition of ethylacetate and 0.5 N NaOH, the ethylacetate layer is collected, washed with saturated aqueous NaCI solution and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Chromatography (dichloromethane/acetone = 9/1 (v/v)) gives N-methyl-N'-(3-(trifluoro-methyl)benzoyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine (0.99 gram, 20 % yield) as a foam. Melting point: Amorphous. Rf (Silicagel: Dichloromethane/acetone = 9/1 (v/v)) = 0.3.
Example VI N-Methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine
Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1 ,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCI and water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamide (4.75 gram, 76 % yield) Melting point: 211-214 °C.
Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7.75 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 - carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C (dec).
In an analogous manner the compounds having formula (I) listed below have been prepared:
N-Methyl-N'-((3-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl -
1 H-pyrazole- -carboxamidine. Melting point: 156-160 °C.
N-Methyl-N'-((4-chlorophenyl)sulfonyl)-3-(5-chloro-2-thienyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine. Melting point: Amorphous
N-Propyl-N'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine. Melting point: 129-138 °C.
N-(2-Propyl)-N'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-
1 H-pyrazole-1 -carboxamidine. Melting point: 110-112 °C. N-Methyl-N'-((2-propyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine. Melting point: Amorphous.
N-(2-Propyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine. Melting point: Amorphous.
N1-Ethyl-N1-methyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 184 °C.
N1-Ethyl-N1-methyl-N2-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 173-176 °C.
N1,N1-Dimethyl-N2-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 195-196 °C. N1,N1-Dimethyl-N2-((3-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 195-198 °C.
N1,N1-Dimethyl-N2-((3-methoxyphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 204-206 °C.
N-Ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1 -carboxamidine. Melting point: Amorphous.
N-Dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 155-159 °C.
N-Methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: Amorphous. N1,N -Dimethyl-N2-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point:148-151 °C.
N-Methyl-N'-((2,4-difluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: 85 °C. N-Acetamido-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: Amorphous. N-(2,2,2-Trifluoroethyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine. Melting point: Amorphous. N-(2-Pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl
-1 H-pyrazole-1 -carboxamidine. Melting point: 142-146 °C.
N-(4-Pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl -1 H-pyrazole-1 -carboxamidine. Melting point: 204-206 °C.
N-Phenyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl - 1 H-pyrazole-1 -carboxamidine. Melting point: 158-160 °C.
Example VII
3-(4-Chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro-4- phenyl-1 H-pyrazole To a stirred mixture of 3-((4-chlorophenyl)sulfonyl)butyric acid (1.85 gram, 7.00 mmol), diisopropylethylamine (3 ml) and 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.50 gram, 15.7 mmol) was added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazole (3.00 gram, 11.7 mmol) and the resulting mixture was stirred for 16 hours at room temperature. After concentration in vacuo the resulting residue was purified by flash chromatography (petroleum ether/ diethyl ether = 1/2 (v/v), followed by diethyl ether) to give 3-(4-chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5- dihydro-4-phenyl-1 H-pyrazole (3.69 gram, 63 % yield) as a diastereomeric mixture. Melting point: amorphous
In an analogous manner the compounds having formula (I) listed below have been prepared:
3-(4-Chlorophenyl)-1-[3-(phenylsulfonyl)propanoyl]-4,5-dihydro-4-phenyl-1 H- pyrazole. Melting point: 122-123 °C. 3-(4-Chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)propanoyl]-4,5-dihydro-4- phenyl-1 H-pyrazole. Melting point: 178-181 °C.
Example VIII
3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)- sulfonyl)ethyl]-1 H-pyrazole
To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (1.7 gram, 6.60 mmol) and collidine (2 ml) in acetonitrile (25 ml) is slowly added a solution of 2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl chloride (1.5 gram, 5.50 mmol) in acetonitrile (20 ml) and the resulting solution is heated at reflux temperature for 16 hours. After concentration in vacuo the residue is dissolved in ethylacetate and washed with aqueous sodium hydrogencarbonate solution. The resulting ethylacetate layer is successively washed with 1 N hydrochloric acid solution and aqueous sodium hydrogencarbonate solution. Subsequent flash chromatographic purification (petroleum ether/ diethyl ether =
1/2 (v/v)) gives an oil which is crystallised from diisopropyl ether to afford 3-(4- chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl]- 1 H-pyrazole (0.52 gram, 19 % yield). Melting point: 118-119 °C.
In an analogous manner the compounds having formula (I) listed below have been prepared:
3-(4-Chlorophenyl)-1-[2-(benzylsulfonyl)ethyl]-4,5-dihydro-4-phenyl-1 H-pyrazole.
Melting point: 161 °C.
3-(4-Chlorophenyl)-1-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-phenyl-1 H- pyrazole. Melting point: Amorphous
3-(4-Chlorophenyl)-1-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-hydroxy-4- phenyl-1 H-pyrazole. Melting point: 127-128 °C.
Example IX
N-[2-(3-(4-Chlorophenyl)-4,5-di ydro-4-phenyl-1H-pyrazol-1-yl)ethyl]-3-
(trifluoromethyl)benzenesulfonamide
Part A: A stirred solution of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole
(5.00 gram, 19.5 mmol) and N-(terf-butoxycarbonyl)aziridine (2.00 gram, 14.0 mmol) in toluene (100 ml) is heated at reflux temperature for 16 hours. After concentration in vacuo the residue is purified by flash chromatography (petroleum ether/ diethyl ether = 3/1 (v/v)), followed by petroleum ether/ diethyl ether = 1/1
(v/v)). After concentration in vacuo the remaining oily residue is crystallised from diisopropyl ether to afford 1-[2-((terf-butoxycarbonyl)amino)ethyl]-3-(4- chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (1.91 gram, 34 %). Repeated crystallisations from the mother liquor afforded an additional amount of crystalline
1-[2-((tert.-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-
1 H-pyrazole (1.19 gram).
Part B: To a solution of 1-[2-((te/t-butoxycarbonyl)amino)ethyl]-3-(4- chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (1.91 gram, 4.8 mmol) in dichloromethane (50 ml) is added trifluoroacetic acid (5 ml) and the resulting solution is stirred at room temperature for 5 hours. After concentration in vacuo the residue is dissolved in ethylacetate and washed with 2N sodium hydroxide solution. The ethyl acetate layer is dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(2-aminoethyl)-3-(4-chlorophenyl)- 4,5-dihydro- 4-phenyl-1 H-pyrazole (1.44 gram, quantitative yield) as an oil. Part C: To a solution of 1-(2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole (0.56 gram, 1.87 mmol) and diisopropylethylamine in acetonitrile (20 ml) is added 3-(trifluoromethyl)phenylsulfonyl chloride (0.35 ml, 2.18 mmol) and the resulting solution is stirred at room temperature for 20 minutes. After concentration in vacuo the residue is dissolved in ethylacetate and washed with 2N sodium hydroxide solution. The ethylacetate layer is concentrated in vacuo. The resulting oil is crystallised from a small amount of diisopropyl ether to afford crystalline N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazol-1 -yl)ethyl]-3-
(trifluoromethyl)benzenesulfonamide (0.44 gram, 46 % yield). Melting point: 94-96 °C.

Claims

Claims
1. A compound of formula (I)
Figure imgf000022_0001
wherein
- R and R, are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, from the group C,.3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C^-amino, mono- or dialkyl (C,.2)-amido, (C,.3)-alkyl sulfonyl, dimethylsulfamido, C,.3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R, represent naphtyl, - R2 represents hydrogen, hydroxy, C,.3-alkoxy, acetyloxy or propionyloxy,
- Aa represents one of the groups (i), (ii), (iii), (iv) or (v)
Figure imgf000022_0002
(i) (ii) (iii) (iv) (v)
wherein
R4 and R5 independently of each other represent hydrogen or C,^ branched or unbranched alkyl or C3-a cycloalkyl or R4 represents acetamido or dimethylamino or 2,2,2-trifluoroethyl or phenyl or pyridyl with the proviso that R5 represents hydrogen
R6 represents hydrogen or C,.3 unbranched alkyl - Bb represents sulfonyl or carbonyl, - R3 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with
1 , 2 or 3 substituents Y, which can be the same or different, or R3 represents C,-8 branched or unbranched alkyl or C3-3 cycloalkyl, or R3 represents naphtyl and tautomers, prodrugs and salts thereof.
2. A compound having formula (I) as claimed in claim 1 , wherein R is the group
4-chlorophenyl, R, is phenyl, R2 is hydrogen, Aa is the group (i) wherein R4 is hydrogen and R5 is methyl, Bb is sulfonyl, and R3 represents 4-chlorophenyl, and salts thereof.
3. A pharmaceutical composition containing at least one compound as claimed in
1 as an active component.
4. A method of preparing pharmaceutical compositions characterized in that a compound as claimed in claim 1 is brought in a form suitable for administration.
5. Process for the preparation of compounds having formula I, characterized in that
a) a compound is prepared wherein R, R,-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (i) or (ii) as defined in claim 1 by
1 ) reacting a compound having formula (II) with hydrazine or hydrazine hydrate to obtain a compound having formula (III), which is reacted with a compound having formula (IVa) of (IVb) to give a compound having formula (V), which is reacted with a compound of the formula R3-SO2X or R3-COX, wherein X is halogen, or
2) reacting a compound having formula (III) with a thioisocyanate of the formula (VI) to produce a compound of the formula (VII), which is reacted with an amine in the presence of a mercury (II) salt, or
3) reacting a compound having formula (III) with a compound of the formula (VIII) to give a compound of the formula (IX) which is reacted with a halogenating agent to give a compound having formula (X) which is reacted with an amine, or
4) reacting a compound having formula (III) with a compound of the formula
(XI) to give a compound having formula (XII) which is reacted with an amine, or
b) a compound is prepared wherein R, R,-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (iii) or (iv) as defined in claim 1 by reacting a compound of the formula (III) with a compound of the formula (XIII) of (XIV), or c) a compound is prepared wherein R, R,-R3 and Bb have the meanings given in claim 1 and Aa is a group of the formula (v) as defined in claim 1 , by reacting a compound having formula (III) with a compound having formula (XV) or
(XVI) to give a compound having formula (XVII), which is deprotected to give a compound having formula (V), which is reacted with a compound having formula R3-SO2X or R3-COX wherein X is halogen or with a compound of the formula R3-COOH.
6. A compound of formula (III)
R / Ri
»l N
H (HI)
wherein R2 represents a hydroxy group and wherein R and R, have the meanings given in claim 1.
7. A compound of formula (V)
(V)
Figure imgf000024_0001
wherein Aa has the meaning (i), (ii) or (v) as given in claim 1 and wherein R, R, and R2 have the meanings given in claim 1.
8. A compound of formula (VII)
Figure imgf000025_0001
wherein R, R,, R2 R3 and Bb have the meanings given in claim 1.
9. A compound of formula (IX)
Figure imgf000025_0002
wherein R, R,, R2 R3 and Bb have the meanings given in claim 1.
10. A compound of formula (X)
Figure imgf000025_0003
wherein R, R,, R2 R3 and Bb have the meanings given in claim 1 and wherein R8 represents a halogen atom.
11. A compound of formula (XII)
Figure imgf000026_0001
wherein R, R,, R2, R3 and Bb have the meanings given in claim 1 and wherein R9 represents a C,.3 alkyl group.
12. A compound of formula (XVII)
Ri
R2
I Aa
I Prot
(XVII)
wherein R, R, and R2 have the meanings given in claim 1 and wherein Aa has the meaning (v) as given in claim 1 and wherein Prot represents a so-called protective group.
13. A method of treating psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders and appetite disorders, obesity, neurological disorders such as Parkinson's disease, dementia, distonia, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, ischaemia, pain and other CNS-diseases involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used.
14. A method of treating gastrointestinal disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used.
15. A method of treating cardiovascular disorders involving cannabinoid neurotransmission, characterized in that a compound as claimed in claim 1 is used.
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Cited By (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026647A1 (en) * 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
WO2003026648A1 (en) * 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. 4,5-dihydro-1h-pyrazole derivatives having potent cb1-antagonistic activity
JP2004518763A (en) * 2001-03-22 2004-06-24 ソルベイ・フアーマシユーチカルズ・ベー・ブイ 4,5-Dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
US6825209B2 (en) 2002-04-15 2004-11-30 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
WO2004111033A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 2-substitued 5, 6-diaryl-pyrazine derivatives as cb1 modulator.
WO2004111038A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
WO2004111039A1 (en) * 2003-06-19 2004-12-23 Astrazeneca Ab 2,3-substituted 5,6-diaryl-pyrazine derivatives as cb1 modulators
WO2004111034A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 3-substituted 5,6-diaryl-pyrazine-2-carboxamide and -2-sulfonamide derivatives as cb1 modulators
WO2005020988A1 (en) * 2003-09-02 2005-03-10 Solvay Pharmaceuticals Gmbh Use of 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
WO2005039566A1 (en) * 2003-10-24 2005-05-06 Solvay Pharmaceuticals Gmbh Combination treatment of obesity involving 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity and lipase inhibitors
WO2005051953A3 (en) * 2003-11-25 2005-07-28 Astrazeneca Ab Pyrrolo-pyrazine derivatives useful as cb1-modulators
WO2005074920A1 (en) * 2004-01-30 2005-08-18 Solvay Pharmaceuticals B.V. 1,3,5-trisubstituted 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
WO2005095354A1 (en) * 2004-04-03 2005-10-13 Astrazeneca Ab Therapeutic agents
WO2005108393A1 (en) 2004-05-10 2005-11-17 F. Hoffmann-La Roche Ag Pyrrole or imidazole amides for treating obesity
US6972295B2 (en) 2002-03-12 2005-12-06 Merck & Co., Inc. Substituted amides
EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
WO2006050842A1 (en) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Dibenzosuberone derivatives
US7135488B2 (en) 2003-01-02 2006-11-14 Hoffmann-La Roche Inc. Pyrrolyl-thiazole derivatives
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
WO2006060211A3 (en) * 2004-11-30 2006-12-28 Bayer Pharmaceuticals Corp Pyrazole derivatives for the treatment of sexual dysfunction
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
WO2007009690A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A Heterocyclyl-substituted pyrazoline compounds, their preparation and use as medicaments
WO2007009708A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Salts of substituted pyrazoline compounds, their preparation and use as medicaments
WO2007009697A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments
EP1749821A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments
EP1749526A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
WO2007040238A1 (en) 2005-10-04 2007-04-12 Mitsubishi Tanabe Pharma Corporation Process for production of optically active 4-hydroxy-1,2,3,4 -tetrahydroquinolines
WO2007009720A3 (en) * 2005-07-15 2007-04-12 Esteve Labor Dr Prodrugs of pyrazoline compounds, their preparation and use as medicaments
WO2007009704A3 (en) * 2005-07-15 2007-04-19 Esteve Labor Dr Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
WO2007020286A3 (en) * 2005-08-17 2007-05-10 Solvay Pharm Gmbh Method of using potassium channel inhibiting compounds
US7229999B2 (en) 2005-04-06 2007-06-12 Hoffmann-La Roche Inc. Pyridine-3-carboxamide derivatives as CB1 inverse agonists
WO2007071662A1 (en) * 2005-12-20 2007-06-28 Solvay Pharmaceuticals B.V. 4,5-dihydro- (1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators
JP2007523147A (en) * 2004-02-20 2007-08-16 アストラゼネカ アクチボラグ Pyrrole-3-carboxamide derivatives for the treatment of obesity
WO2007125048A1 (en) * 2006-04-27 2007-11-08 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising cbx cannabinoid receptor modulators and potassium channel modulators
US7294644B2 (en) 2003-01-02 2007-11-13 Hoffmann-La Roche Inc. CB 1 receptor inverse agonists
US7297707B2 (en) 2003-06-20 2007-11-20 Hoffmann-La Roche Inc. Benzothiazolyl derivatives
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
WO2008034863A2 (en) 2006-09-22 2008-03-27 Solvay Pharmaceuticals B.V. Sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US7371751B2 (en) 2003-12-08 2008-05-13 Hoffmann-La Roche Inc. Thiazole derivatives
US7384945B2 (en) 2004-10-27 2008-06-10 Hoffmann-La Roche Inc. Indole or benzimidazole derivatives as CB1 inverse agonists
US7473693B2 (en) 2003-02-06 2009-01-06 Astrazeneca Ab Stable dispersion of solid particles comprising a water-insoluble pyrazine compound
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US7524868B2 (en) 2004-02-17 2009-04-28 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US7576095B2 (en) 2005-10-06 2009-08-18 Astrazeneca Ab Therapeutic agents
US7629346B2 (en) 2006-06-19 2009-12-08 Hoffmann-La Roche Inc. Pyrazinecarboxamide derivatives as CB1 antagonists
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010012797A3 (en) * 2008-08-01 2010-04-22 Solvay Pharmaceuticals B.V. Synthesis of 3,4-diaryl-4,5-dihydro-(1h)-pyrazole-1- carboxamidine derivatives
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
US7745476B2 (en) 2004-01-30 2010-06-29 Solvay Pharmaceuticals B.V. 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
WO2010079255A1 (en) * 2009-01-12 2010-07-15 Fundación Del Hospital Nacional De Parapléjicos Para La Investigación Y La Integración (Fuhnpaiin) Use of inverse antagonists and/or agonists of cb1 receptors for preparing drugs to increase motor neurone excitability
US7763607B2 (en) 2006-04-27 2010-07-27 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising CBx cannabinoid receptor modulators and potassium channel modulators
US7781593B2 (en) 2006-09-14 2010-08-24 Hoffmann-La Roche Inc. 5-phenyl-nicotinamide derivatives
US7780989B2 (en) 2002-07-18 2010-08-24 Astrazeneca Ab Process for the preparation of crystalline nano-particle dispersions
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
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
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US7968582B2 (en) 2005-07-15 2011-06-28 Laborotorios Del Dr. Esteve, S.A. 5(S)-substituted pyrazoline compounds, their preparation and use as medicaments
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US8034949B2 (en) 2004-05-28 2011-10-11 Mitsubishi Tanabe Pharma Corporation Pyrrolidine compound and a process for preparing the same
US8058264B2 (en) 2004-10-25 2011-11-15 Abbott Products Gmbh Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of obesity and related conditions
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and 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
WO2012120050A1 (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
WO2012120058A1 (en) 2011-03-08 2012-09-13 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
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
US8410107B2 (en) 2010-10-15 2013-04-02 Hoffmann-La Roche Inc. N-pyridin-3-yl or N-pyrazin-2-yl carboxamides
US8420689B2 (en) 2005-06-02 2013-04-16 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US8669254B2 (en) 2010-12-15 2014-03-11 Hoffman-La Roche Inc. Pyridine, pyridazine, pyrimidine or pyrazine carboxamides as HDL-cholesterol raising agents
US8729101B2 (en) 2001-09-21 2014-05-20 Solvay Pharmaceuticals, B.V. 1H-imidazole derivative having CB1, agonistic, CB1 partial agonistic or CB1 antagnistic activity
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2015172059A1 (en) * 2014-05-09 2015-11-12 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Pyrazole derivatives and their use as cannabinoid receptor mediators
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3109237A1 (en) 2015-06-22 2016-12-28 AnaMar AB Novel 5-ht2 antagonists
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US20180022706A1 (en) * 2012-11-13 2018-01-25 The United States Of America As Represented By The Secretary Department Of Health And Human Services Cannabinoid receptor mediating compounds
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
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

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054730A1 (en) * 2001-03-27 2005-03-10 The Regents Of The University Of California Compounds, compositions and treatment of oleoylethanolamide-like modulators of PPARalpha
BR0313041A (en) * 2002-07-29 2005-06-21 Hoffmann La Roche Compounds; pharmaceutical compositions; method for the treatment and / or prophylaxis of diseases that are associated with cb1 receptor modulation; and use of compounds
US7765162B2 (en) * 2002-10-07 2010-07-27 Mastercard International Incorporated Method and system for conducting off-line and on-line pre-authorized payment transactions
AU2003267728A1 (en) * 2002-10-18 2004-05-04 Pfizer Products Inc. Cannabinoid receptor ligands and uses thereof
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
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
US7141669B2 (en) * 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US20040214856A1 (en) * 2003-04-23 2004-10-28 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
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
WO2004099157A1 (en) * 2003-05-07 2004-11-18 Pfizer Products Inc. Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US20040259887A1 (en) * 2003-06-18 2004-12-23 Pfizer Inc Cannabinoid receptor ligands and uses thereof
CA2537535A1 (en) * 2003-09-02 2005-03-10 Solvay Pharmaceuticals Gmbh Novel medical use of selective cb1-receptor antagonists
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
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
ITMI20041032A1 (en) * 2004-05-24 2004-08-24 Neuroscienze S C A R L PHARMACEUTICAL COMPOSITES
ITMI20041033A1 (en) * 2004-05-24 2004-08-24 Neuroscienze S C A R L PHARMACEUTICAL COMPOUNDS
WO2006039334A1 (en) * 2004-09-29 2006-04-13 Schering Corporation Combinations of substituted azetidonones and cb1 antagonists
WO2006060192A2 (en) * 2004-11-30 2006-06-08 Bayer Pharmaceuticals Corporation Pyrazole derivatives
WO2006060201A2 (en) * 2004-11-30 2006-06-08 Bayer Pharmaceuticals Corporation Pyrazole derivatives for the treatment of psychiatric disorders
WO2006060186A2 (en) * 2004-11-30 2006-06-08 Bayer Pharmaceuticals Corporation Pyrazole derivatives for the treatment of dementia and related disorders
WO2006129193A2 (en) * 2005-05-27 2006-12-07 Pfizer Products Inc. Combination of a cannabinoid-1- receptor-antagonist and a microsomal triglyceride transfer protein inhibitor for treating obesity or mainataining weight loss
US20070254863A1 (en) * 2006-04-27 2007-11-01 Jochen Antel Use of CBx cannabinoid receptor modulators as potassium channel modulators
JP5561720B2 (en) * 2006-05-05 2014-07-30 ジェンリン ディスカバリー Cannabinoid receptor antagonist / inverse agonist useful for treating cardiovascular 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
CN103145620A (en) * 2006-12-18 2013-06-12 7Tm制药联合股份有限公司 Cb1 receptor modulators
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
EP2151234A1 (en) * 2008-07-28 2010-02-10 Laboratorios Del. Dr. Esteve, S.A. Pharmaceutical formulation comprising a CB1-receptor compound in a solid solution and/or solid dispersion
US8217038B2 (en) 2009-10-07 2012-07-10 Jenrin Discovery, Inc. Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes
JP5946192B2 (en) 2010-11-18 2016-07-05 ジェンリン ディスカバリーＪｅｎｒｉｎ Ｄｉｓｃｏｖｅｒｙ Cannabinoid receptor antagonists / inverse agonists useful for the treatment of metabolic diseases including obesity and diabetes
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
EA027174B1 (en) 2012-08-01 2017-06-30 Льюис Энд Кларк Фармасьютикалз, Инк. N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as aagonists
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591764A (en) * 1988-09-27 1997-01-07 E. I. Du Pont De Nemours And Company N-acylated pyrazolines
RU2149479C1 (en) * 1999-03-23 2000-05-20 Научно-исследовательский институт электронных приборов Method for sealing vacuum enclosure of x-ray optical converter

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present

Cited By (144)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004518763A (en) * 2001-03-22 2004-06-24 ソルベイ・フアーマシユーチカルズ・ベー・ブイ 4,5-Dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
US8729101B2 (en) 2001-09-21 2014-05-20 Solvay Pharmaceuticals, B.V. 1H-imidazole derivative having CB1, agonistic, CB1 partial agonistic or CB1 antagnistic activity
KR100950430B1 (en) * 2001-09-21 2010-04-02 솔베이 파마슈티칼스 비. 브이 4,5-dihydro-1H-pyrazole derivatives with potent CB1-antagonism
US6974810B2 (en) 2001-09-21 2005-12-13 Solvay Pharmaceuticals B.V. 4,5-Dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity
KR100903760B1 (en) * 2001-09-21 2009-06-19 솔베이 파마슈티칼스 비. 브이 Novel 4,5-dihydro-1H-pyrazole Derivatives with CB1-antagonism
US7608718B2 (en) 2001-09-21 2009-10-27 Solvay Pharmaceuticals B.V. 4,5-dihydro-1H-pyrazole derivatives having potent CB1-antagonistic activity
US7528162B2 (en) 2001-09-21 2009-05-05 Solvay Pharmaceuticals, B.V. 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
WO2003026648A1 (en) * 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. 4,5-dihydro-1h-pyrazole derivatives having potent cb1-antagonistic activity
WO2003026647A1 (en) * 2001-09-21 2003-04-03 Solvay Pharmaceuticals B.V. Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US7550489B2 (en) 2002-03-12 2009-06-23 Merck & Co., Inc. Substituted pyridyoxy amides
US7816534B2 (en) 2002-03-12 2010-10-19 Merck Sharp & Dohme Corp. Substituted amides
US6972295B2 (en) 2002-03-12 2005-12-06 Merck & Co., Inc. Substituted amides
US6825209B2 (en) 2002-04-15 2004-11-30 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
US7780989B2 (en) 2002-07-18 2010-08-24 Astrazeneca Ab Process for the preparation of crystalline nano-particle dispersions
US7579369B2 (en) 2003-01-02 2009-08-25 Hoffmann-La Roche Inc. CB 1 receptor inverse agonists
US7294644B2 (en) 2003-01-02 2007-11-13 Hoffmann-La Roche Inc. CB 1 receptor inverse agonists
US7135488B2 (en) 2003-01-02 2006-11-14 Hoffmann-La Roche Inc. Pyrrolyl-thiazole derivatives
US7473693B2 (en) 2003-02-06 2009-01-06 Astrazeneca Ab Stable dispersion of solid particles comprising a water-insoluble pyrazine compound
WO2004111034A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 3-substituted 5,6-diaryl-pyrazine-2-carboxamide and -2-sulfonamide derivatives as cb1 modulators
WO2004111038A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
WO2004111033A1 (en) * 2003-06-18 2004-12-23 Astrazeneca Ab 2-substitued 5, 6-diaryl-pyrazine derivatives as cb1 modulator.
WO2004111039A1 (en) * 2003-06-19 2004-12-23 Astrazeneca Ab 2,3-substituted 5,6-diaryl-pyrazine derivatives as cb1 modulators
US7297707B2 (en) 2003-06-20 2007-11-20 Hoffmann-La Roche Inc. Benzothiazolyl derivatives
WO2005020988A1 (en) * 2003-09-02 2005-03-10 Solvay Pharmaceuticals Gmbh Use of 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
JP2007504200A (en) * 2003-09-02 2007-03-01 ゾルファイ　ファーマスーティカルズ　ゲゼルシャフト　ミット　ベシュレンクテル　ハフツング Use of 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
WO2005039566A1 (en) * 2003-10-24 2005-05-06 Solvay Pharmaceuticals Gmbh Combination treatment of obesity involving 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity and lipase inhibitors
WO2005051953A3 (en) * 2003-11-25 2005-07-28 Astrazeneca Ab Pyrrolo-pyrazine derivatives useful as cb1-modulators
US7371751B2 (en) 2003-12-08 2008-05-13 Hoffmann-La Roche Inc. Thiazole derivatives
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
US7745476B2 (en) 2004-01-30 2010-06-29 Solvay Pharmaceuticals B.V. 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
AU2005210163B2 (en) * 2004-01-30 2010-05-13 Solvay Pharmaceuticals B.V. 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
RU2360904C2 (en) * 2004-01-30 2009-07-10 Солвей Фармасьютикалс Б.В. 1,3,5-trisubstituted derivatives of 4,5-dihydro-1h-pyrazole, possessing cb1-antagonistic activity
WO2005074920A1 (en) * 2004-01-30 2005-08-18 Solvay Pharmaceuticals B.V. 1,3,5-trisubstituted 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
JP2007519686A (en) * 2004-01-30 2007-07-19 ソルベイ・フアーマシユーチカルズ・ベー・ブイ 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1 antagonistic activity
US7524868B2 (en) 2004-02-17 2009-04-28 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
JP2007523147A (en) * 2004-02-20 2007-08-16 アストラゼネカ アクチボラグ Pyrrole-3-carboxamide derivatives for the treatment of obesity
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
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
US7799804B2 (en) 2004-04-03 2010-09-21 Astrazeneca Ab Therapeutic agents
WO2005095354A1 (en) * 2004-04-03 2005-10-13 Astrazeneca Ab Therapeutic agents
US7563910B2 (en) 2004-05-10 2009-07-21 Hoffmann-La Roche Inc. Heterocyclic cannabinoid receptor antagonists
WO2005108393A1 (en) 2004-05-10 2005-11-17 F. Hoffmann-La Roche Ag Pyrrole or imidazole amides for treating obesity
US8034949B2 (en) 2004-05-28 2011-10-11 Mitsubishi Tanabe Pharma Corporation Pyrrolidine compound and a process for preparing the same
EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
US8058264B2 (en) 2004-10-25 2011-11-15 Abbott Products Gmbh Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of obesity and related conditions
US7384945B2 (en) 2004-10-27 2008-06-10 Hoffmann-La Roche Inc. Indole or benzimidazole derivatives as CB1 inverse agonists
US7786128B2 (en) 2004-10-27 2010-08-31 Hoffmann-La Roche Inc. Indole or benzimidazole derivatives as CB1 inverse agonists
WO2006050842A1 (en) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Dibenzosuberone derivatives
US7220743B2 (en) 2004-11-09 2007-05-22 Hoffmann-La Roche Inc. Heterocyclic CB1 receptor antagonists
WO2006060211A3 (en) * 2004-11-30 2006-12-28 Bayer Pharmaceuticals Corp Pyrazole derivatives for the treatment of sexual dysfunction
US7229999B2 (en) 2005-04-06 2007-06-12 Hoffmann-La Roche Inc. Pyridine-3-carboxamide derivatives as CB1 inverse agonists
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
US8420689B2 (en) 2005-06-02 2013-04-16 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2007009708A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Salts of substituted pyrazoline compounds, their preparation and use as medicaments
ES2326725B1 (en) * 2005-07-15 2010-05-11 Laboratorios Del Dr. Esteve, S.A. USE OF SUBSTITUTED PIRAZOLINE COMPOUNDS FOR THE TREATMENT OF FOOD DISORDERS, INCLUDING OBESITY OR METABOLIC SYNDROME IN PATIENTS WITH DEVELOPED DIABETES.
JP2009501181A (en) * 2005-07-15 2009-01-15 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 4-Substituted pyrazoline compounds, their preparation and their use as pharmaceuticals
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
US7994200B2 (en) 2005-07-15 2011-08-09 Laboratorios Del Dr. Esteve, S.A. Cycloalkane-substituted pyrazoline derivatives, their preparation and use as medicaments
US7968582B2 (en) 2005-07-15 2011-06-28 Laborotorios Del Dr. Esteve, S.A. 5(S)-substituted pyrazoline compounds, their preparation and use as medicaments
US8106085B2 (en) 2005-07-15 2012-01-31 Laboratorios Del Dr. Esteve, S.A. Indoline-substituted pyrazoline derivatives, their preparation and use as medicaments
WO2007009690A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A Heterocyclyl-substituted pyrazoline compounds, their preparation and use as medicaments
WO2007009722A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Octahydropentalene-substituted pyrazoline derivatives, their preparation and use as medicaments
ES2326460A1 (en) * 2005-07-15 2009-10-09 Laboratorios Del Dr. Esteve, S.A. QUATERNARY AMMONIUM SALTS OF SUBSTITUTED PIRAZOLINE COMPOUNDS, THEIR PREPARATION AND USE AS MEDICINES.
ES2326725A1 (en) * 2005-07-15 2009-10-16 Laboratorios Del Dr. Esteve, S.A. USE OF SUBSTITUTED PIRAZOLINE COMPOUNDS FOR THE TREATMENT OF FOOD DISORDERS, INCLUDING OBESITY OR METABOLIC SYNDROME IN PATIENTS WITH DEVELOPED DIABETES.
WO2007009704A3 (en) * 2005-07-15 2007-04-19 Esteve Labor Dr Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
WO2007009697A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments
ES2330992A1 (en) * 2005-07-15 2009-12-17 Laboratorios Del Dr. Esteve, S.A. Heterocyclyl-substituted pyrazoline compounds, their preparation and use as medicaments
US7829581B2 (en) 2005-07-15 2010-11-09 Laboratorios Del Dr. Esteve, S.A. Prodrugs of pyrazoline compounds, their preparation and use as medicaments
WO2007009689A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr.Esteve, S.A. 4,5-dihydr0-1h-pyrazole derivatives, their preparation and use as medicaments
WO2007009720A3 (en) * 2005-07-15 2007-04-12 Esteve Labor Dr Prodrugs of pyrazoline compounds, their preparation and use as medicaments
ES2326460B1 (en) * 2005-07-15 2010-04-19 Laboratorios Del Dr. Esteve, S.A. QUATERNARY AMMONIUM SALTS OF SUBSTITUTED PIRAZOLINE COMPOUNDS, THEIR PREPARATION AND USE AS MEDICINES.
EP1749821A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments
EP1749526A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
EP1749820A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Salts of substituted pyrazoline compounds, their preparation and use as medicaments
ES2330992B1 (en) * 2005-07-15 2010-07-06 Laboratorios Del Dr. Esteve, S.A. HETEROCICLILS REPLACED PIRAZOLINE COMPOUNDS, ITS PREPARATION AND USE AS MEDICATIONS.
WO2007009724A3 (en) * 2005-07-15 2007-04-05 Esteve Labor Dr Cycloalkane-substituted pyrazoline derivatives, their preparation and use as medicaments
WO2007009723A3 (en) * 2005-07-15 2007-04-05 Esteve Labor Dr Azepane- or azocane-substituted pyrazoline derivatives, their preparation and use as medicaments
WO2007009721A3 (en) * 2005-07-15 2007-03-29 Esteve Labor Dr Indoline-substituted pyrazoline derivatives, their preparation and use as medicaments
WO2007020286A3 (en) * 2005-08-17 2007-05-10 Solvay Pharm Gmbh Method of using potassium channel inhibiting compounds
WO2007040238A1 (en) 2005-10-04 2007-04-12 Mitsubishi Tanabe Pharma Corporation Process for production of optically active 4-hydroxy-1,2,3,4 -tetrahydroquinolines
US7875626B2 (en) 2005-10-06 2011-01-25 Astrazeneca Ab Therapeutic agents
US7576095B2 (en) 2005-10-06 2009-08-18 Astrazeneca Ab Therapeutic agents
WO2007071662A1 (en) * 2005-12-20 2007-06-28 Solvay Pharmaceuticals B.V. 4,5-dihydro- (1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators
US7763607B2 (en) 2006-04-27 2010-07-27 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising CBx cannabinoid receptor modulators and potassium channel modulators
WO2007125048A1 (en) * 2006-04-27 2007-11-08 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising cbx cannabinoid receptor modulators and potassium channel modulators
US7629346B2 (en) 2006-06-19 2009-12-08 Hoffmann-La Roche Inc. Pyrazinecarboxamide derivatives as CB1 antagonists
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
US7781593B2 (en) 2006-09-14 2010-08-24 Hoffmann-La Roche Inc. 5-phenyl-nicotinamide derivatives
WO2008034863A2 (en) 2006-09-22 2008-03-27 Solvay Pharmaceuticals B.V. Sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists
JP2010504302A (en) * 2006-09-22 2010-02-12 ソルベイ・フアーマシユーチカルズ・ベー・ブイ Sulfonylpyrazoline carboxamidine derivatives as 5-HT6 antagonists
US8722887B2 (en) * 2006-09-22 2014-05-13 Abbvie Bahamas, Ltd. Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-HT6 antagonists
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2010012797A3 (en) * 2008-08-01 2010-04-22 Solvay Pharmaceuticals B.V. Synthesis of 3,4-diaryl-4,5-dihydro-(1h)-pyrazole-1- carboxamidine derivatives
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2010079255A1 (en) * 2009-01-12 2010-07-15 Fundación Del Hospital Nacional De Parapléjicos Para La Investigación Y La Integración (Fuhnpaiin) Use of inverse antagonists and/or agonists of cb1 receptors for preparing drugs to increase motor neurone excitability
US9238027B2 (en) 2009-01-12 2016-01-19 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability
US9592237B2 (en) 2009-01-12 2017-03-14 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US8410107B2 (en) 2010-10-15 2013-04-02 Hoffmann-La Roche Inc. N-pyridin-3-yl or N-pyrazin-2-yl carboxamides
US8669254B2 (en) 2010-12-15 2014-03-11 Hoffman-La Roche Inc. Pyridine, pyridazine, pyrimidine or pyrazine carboxamides as HDL-cholesterol raising agents
EP3243385A1 (en) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012120058A1 (en) 2011-03-08 2012-09-13 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
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120050A1 (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
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and 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
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US11939297B2 (en) 2012-11-13 2024-03-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor mediating compounds
US11485709B2 (en) 2012-11-13 2022-11-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor mediating compounds
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
US10787419B2 (en) 2012-11-13 2020-09-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor mediating iminopyrazole compounds
US20180022706A1 (en) * 2012-11-13 2018-01-25 The United States Of America As Represented By The Secretary Department Of Health And Human Services Cannabinoid receptor mediating compounds
US10683270B2 (en) 2012-11-13 2020-06-16 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
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. 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
EP4424697A2 (en) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051725A1 (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
WO2015172059A1 (en) * 2014-05-09 2015-11-12 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Pyrazole derivatives and their use as cannabinoid receptor mediators
AU2019227889B2 (en) * 2014-05-09 2021-03-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Pyrazole derivatives and their use as cannabinoid receptor mediators
EP3109237A1 (en) 2015-06-22 2016-12-28 AnaMar AB Novel 5-ht2 antagonists
US10544103B2 (en) 2015-06-22 2020-01-28 Anamar Ab 5-HT2 antagonists
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds

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