Indolyamides As Modulators For An Ep2 Receptor

  • Published: Feb 3, 2010
  • Earliest Priority: Jul 30 2008
  • Family: 2
  • Cited Works: 35
  • Cited by: 0
  • Cites: 43
  • Additional Info: Cited Works Published

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Substituted indole compounds (I) and their isomers, diastereomers, enantiomers, salts or cyclodextrin clathrate, are new. Substituted indole compounds of formula (I) and their isomers, diastereomers, enantiomers, salts or cyclodextrin clathrate, are new. X : CH or N; Y 1>O, N, S, NH,-CH=N-, -N=CH-, -N=N- or -CH=CH- (when X is N); R 1>H or 1-6C alkyl (optionally substituted); R 2>1-4C alkoxy or 1-6C alkyl (both can be arbitrarily substituted), H, halo, CN or -S(O) q-CH 3; q : 0-2; R 3>H, 1-4C alkoxy or halo; R 4>H or F; R 5>H or halo; R 6>, R 9>H, F or Cl; R 7>H or R 10>, provided that when R 7>is H, then R 8>is R 10>, and when R 8>is H, then R 7>is R 10>; R 10>-CONH-R 11>or CO-NR 11>R 12>; R 11>, R 12>1-6C alkyl (which is substituted with one or more -S(O) p-R 13>, OH, CN, COOH, CO-NH 2, SO 2NH 2, SO 2NH-R 13>, CO-NH-SO 2-R 13>, SO 2-NH-CO-R 13>, 1-6C acyl, OR 13>, CO 2-R 13>,-NR 13>R 14>, NH-R 13>, CO-NHR 13>, CO-NR 13>R 14>, NH-COR 13>, NH-SO 2R 13>, NR 15>-COR 13>, NH-CONH 2, NH-CO-NHR 13>, NH-CO-NR 13>R 14>, NR 15>-CO-NH-R 13>or NR 15>-CO-N(1-6C alkyl)-R 13>, or 6-12C aryl, 5-12C heteroaryl or 3-6C cycloalkyl (all substituted with 1 or 2 substituents of T)), or 3-6C cycloalkyl, 6-12C aryl or 5-12C heteroaryl (all substituted with 1-3 substituents of T, NH-(3-6C cycloalkyl), CO-NH(1-6C-alkyl) or CON(1-6C-alkyl) 2); T : CONH 2, SO 2NH 2, CONHCH 3, CON(CH 3) 2, SO 2NHCH 3, CO-NH-SO 2CH 3or 1-6C acyl; either R 13>-R 15>1-6C-alkyl, 3-6C-cycloalkyl, 6-12C-aryl, 5-12C-heteroaryl, CH 2-6-12C-aryl or CH 2-5-12C-heteroaryl; or R 13>R 15>together with N-CO-N-CO-NH group : 5 or 6 membered ring, which optionally contains additional heteroatoms and substituted one, two or three times, by halo, amino, OH, CN or 1-6C-alkyl that optionally substituted; and p : 0-2. Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with a cyclooxygenase inhibitor, which are aspirin, naproxen, indomethacin, meloxicam, ibuprofen, celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide), parecoxib (N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonylpropionamide), rofecoxib (4-(4-mesylphenyl)-3-phenylfuran-2(5H)-one), valdecoxib (4-[5-methyl-3-phenyl-4-isoxazoyl)] benzenesulfonamide, NS-398 (N-methyl-2-cyclohexanoxy-4-nitrobenzenesulfonamide), lumiracoxib [2-(2'-chloro-6'-fluorophenyl)]-amino-5-methylbenzeneacetic acid, ceracoxib and etoricoxib. [Image] ACTIVITY : Antiinfertility; Gynecological; Analgesic; Contraceptive; Osteopathic; Cytostatic; Neuroprotective; Nootropic; Antiparkinsonian; Antiinflammatory; Gastrointestinal-Gen.; Antiulcer; Nephrotropic; Antiarteriosclerotic; Respiratory-Gen.; Antimicrobial. MECHANISM OF ACTION : Prostaglandin E2 (subtype EP2) receptor modulator. The prostaglandin E2 (subtype EP2) receptor antagonistic activity of (I) was tested using an in vitro method. The result showed that 1H-indol-2,6-dicarboxylic acid 6-carbamoylmethyl-amide 2-{[2-(7-fluoro-2,4-dimethyl-1H-indol-3-yl)-ethyl]-amide} exhibited an IC 50value of 0.022 mu M.


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Document History
  • Publication: Feb 3, 2010
  • Application: Jul 30, 2008
    EP EP 08161444 A
  • Priority: Jul 30, 2008
    EP EP 08161444 A

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