Patent EP-1481976-A1 (EP)
Inventor: TANI KOUSUKE
IPC: A61P1/00
Filed: 2003-03-04
Abstract: 8-Azaprostaglandin derivatives (I) and their salts and cyclodextrin clathrates are new. 8-Azaprostaglandin derivatives of formula (I) and their salts and cyclodextrin clathrates are new. [Image] T : O or S; X : CH 2, O or S; A : A 1or A 2; A 12-8C n-alkylene, 2-8C n-alkenylene or 2-8C n-alkynylene all optionally substituted by 1 or 2 1-4C alkyl; A 2G 1G 2G 3; G 11-4C n-alkylene, 2-4C n-alkenylene or 2-4C n-alkynylene all optionally substituted by 1 or 2 1-4C alkyl; G 2Y, Q 1, YQ 1, Q 1Y or 1-5C alkylene; Y : S, SO, SO 2, O or NR 1; R 1H, 1-10C alkyl or 2-10C acyl; G 3bond or G 1; D : D 1or D 2; D 1COOH, COOR 2, tetrazol-5-yl or CONR 3SO 2R 4; R 3H or 1-10C alkyl; R 41-10C alkyl or phenyl; R 21-10C alkyl, phenyl, 1-10C alkyl-phenyl or Ph 1; Ph 1biphenyl; D 2CH 2OH, CH 2O-1-10C alkyl, OH, O-1-10C alkyl, CHO, CONR 6R 7, CONR 6SO 21-10C alkyl-phenyl, CO(NHBCO) mOH, O(COBNH) mH, COOR 9, OCOR 10COOZ 1Z 2Z 3, 5-oxo-1,2,4-oxadiazol-3-yl, 5-oxo-1,2,4-thiadiazol-3-yl, 5-thioxo-1,2,4-oxadiazol-3-yl or 3-hydroxy-1,2,4-oxadiazol-5-yl; B : amino acid residue; R 6, R 7H or 1-10C alkyl; R 91-10C alkyl-Ph 1or Ph 1both optionally substituted by 1-3 1-10C alkyl, O-1-10C alkyl or halo; R 10phenyl or 1-10C alkyl; m : 1 or 2; Z 11-15C alkylene, 1-15C alkenylene or 1-15C alkynylene; Z 2CO, OCO, COO, CONR z1, NR zCO, O, S, SO 2, SO 2NR z, NR zSO 2, NR z, NR zCONR z, NR zCOO, OCONR zor OCOO; Z 3H, 1-15C alkyl, 2-15C alkenyl, 2-15C alkynyl, Q zor 1-10C alkyl (substituted by O-1-10C alkyl, S-1-10C alkyl, NR z1-10C alkyl or Q z); Q zoptionally partially or totally saturated 3-15C mono-tricyclic aryl optionally containing 1-4 O, S or N and optionally substituted by 1-3J; R z, R z1H or 1-15C alkyl; or NR z1Z 35-7 membered monocyclic saturated heterocyclyl containing at least 1 O, S or N and optionally substituted by 1-3 J; J : 1-15C alkyl, 2-15C alkenyl, 2-15C alkynyl or 1-10C alkyl (substituted by O-1-10C alkyl, S-1-10C alkyl or NR z1-10C alkyl); E : CH=CHCH(OH)CH 2R 11, CH 2CH 2CH(OH)CH 2R 11, U 1U 2U 3or Q 4; R 111-10C alkyl, S-1-10C alkyl, 1-10C alkyl-Cyc, Alk q2or 1-10C alkyl-W 1W 2Q 2; W 1O, S, SO, SO 2, NR 12, CO, NR 12SO 2, NHCO or CONH; R 12H, 1-10C alkyl or 2-10C acyl; W 2bond or 1-8C alkyl (optionally substituted by 1-4C alkyl, halo or OH); U 1Q 3or 1-4C alkylene, 2-4C alkenylene or 2-4C alkynylene all optionally substituted by Q 3; U 2bond, CH 2, CHOH, O, S, SO, SO 2, NR 12, CO, NR 12SO 2, CONH 2, NH 2CO; R 12H, 1-10C alkyl or 2-10C acyl; U 31-8C alkyl-Q 4, Q 4or 1-8C alkyl, 2-8C alkenyl or 2-8C alkynyl all optionally substituted by 1-3 1-10C alkyl, halo, OH, alkoxy or NR 13R 14; R 13, R 14H or 1-10C alkyl; Q 1-Q 4Q (optionally substituted by 1-5 R); R : Alk 2, O-1-10C alkyl, S-1-10C alkyl, halo, OH, NO 2, NR 13R 141-10C alkyl-O-1-10C alkyl, Alk 2, Alk 2OAlk 2, 1-10C alkyl-NR 13R 14, Q 5, OQ 5, Alk 2Q 5, O-1-10C alkyl (optionally substituted by 1-4 halo), 1-10C alkylOQ 5, COOR 17, CHO, 1-10C hydroxyalkyl or 2-10C acyl; R 17H or 1-10C alkyl; Alk 21-10C alkyl, 2-10C alkenyl or 2-10C alkynyl; Q 5Q (optionally substituted by Alk 2, O-1-10C alkyl, 1-10C alkyl-O-1-10C alkyl, halo, OH, Alk 4or Alk 4O-1-10C alkyl; Alk 41-10C alkyl optionally substituted by 1-3 halo; Q : optionally partially or totally saturated 3-15C mono-tricyclic aryl optionally containing 1-4N, 1 or 2O and/or 1 or 2 S; Provided: (1) When E is U 1-U 2-U 3group, and U 1is C2 alkylene group or C2 alkenylene group, U 2is not a -CHOH-group; (2) When U 3is C18 alkyl group substituted with an at least 1 hydroxyl group, U 1-U 2is not C2 alkylene group or C2 alkenylene group; (3) When A is A 1, and D is D 1, E is not CH=CHCH(OH)CH 2R 11or CH 2CH 2CH(OH)CH 2R 11; (4) When T is an oxygen atom, X is one 1 CH 2, D is D 1, D 1is a COOH group, A is A 1, A 1is a linear C2-8 alkylene group, E is U 1-U 2-U 3, U 1is 1-4C alkylene group, and U 3is 1-8C alkyl group, U 2is not a single bond, a -CH 2- group, a NR 12-group, or a carbonyl group; (5) When T is an oxygen atom, X is -CH 2group, D is D 1, D 1is a COOH group, A is A 2, G 1is 1-4C alkylene group, G 2is -O- group or a -NR 1-group, G 3is a single bond, or 1-4C alkylene group, E is U 1-U 2-U 3, U 1is 1-4C alkylene group, and U 3is 1-8C alkyl group, U 2is not a single bond, - CH 2group, a NR 12-group, or a carbonyl group; (6) When T is an oxygen atom, X is - CH 2group, D is D 1, E is U 1-U 2-U 3, U 1is C2 alkylene group or C2 alkenylene group, and U 2is a -CO-group, A is not A 1; and (7) 4-[(2-{(2R)-2-[(E-[1],3S)-3-hydroxy-oct-1-enyl]-5-oxo-pyrrolidine-1-yl}ethyl)thio]-butanoic acid and 4-(2-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidine-1-yl]-1-ethyl}-1 benzoic acid) are excluded. ACTIVITY : Immunomodulator; Antiallergic; Neuroprotective; Gynecological; Analgesic; Endocrine-Gen.; Ophthalmological; Vasotropic; CNS-Gen.; Antiarthritic; Respiratory-Gen.; Antiinflammatory; Hepatotropic; Nephrotropic; Cardiovascular-Gen.; Immunosuppressive; Antibacterial; Dermatological; Vulnerary; Cytostatic; Antiulcer; Gastrointestinal-Gen.; Osteopathic. MECHANISM OF ACTION : Prostaglandin-Agonist-EP2; Prostaglandin-Antagonist-EP2; Prostaglandin-Agonist-EP4; Prostaglandin-Antagonist-EP4. In binding assays 2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid had a K ivalue for murine EP2 receptors of 14 nM.