EP0136893A2 — Benzo[a]phenothiazines and hydro-derivatives and pharmaceutical compositions containing them

USPTO Abstract

Pharmaceutical compositions contain a compound for the Formula or a pharmaceutically acceptable salt thereof. Certain compounds of Formula I are novel. Compounds of Formula I are useful in treating allergic conditions, asthma, cardrovascular disorders, inflammation and pain and are useful as cytoprotective agents. In Formula 1. X is O, S, SO or SO 2 ; R, is H; C,- 6 alkyl; C, - 6 acyl; C 1-6 aminoacyl; (C 1-6 acyloxy)-(C 1-6 alkyl); (C 1-6 alkoxy)-(C l - 6 alkyl); benzoyl; substituted benzoyl in which the substitution in the phenyl ring (herein called "substituted as herein defined") is halogen, C 1-3 alkyl, C 1-3 alkoxy, CN, CF 3 , COOR 6 , OH, CH 2 COOR 6 or (CH 2 ) n NR 8 R 9 where n is 0, 1 or 2; carbamoyl; CONHR 7 ; COOR 7 ; p-toluenesulfonyl; methane sulfonyl; or an acyl group such that R,-OH is an essential amino acid; each of R 2 , R 3 , R 4 and R 5 , independently of the others, is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; -(CHR 6 ) p COOR 6 , p being 0 or an integer from 1 to 4; or -(CH 2 ) m M where m is 0 or an integer from 1 to 6 and M is (a) OR, s ; (b) halogen; (c) CF 3 ; (d) SR 15 ; (e) phenyl or substituted phenyl as herein defined; (f) COOR 6 ; (g) CO-R 14 ; (h) tetrazolyl; (i) -NH-CO-R 7 ; (j) -NR 8 R 9 ; (k) -NHSO 2 R 10 where R 10 is OH, C 1-6 alkyl, C 1-6 alkoxy, or phenyl; (I) -COCH 2 0H; (m) -SOR 11 where R 11 is C 1-6 alkyl; phenyl; substituted phenyl as herein defined; (CH 2 ) m COOR 6 ;CN; formyl or C 1-4 perfluoroalkyl; (n) -CONR 8 R 9 ; (o) -SO 2 NR 8 R 9 ; (p) -SO 2 R 13 where R 13 is a hydrogen atom or a radical of the type defined for R 11 ; (q) NO 2 ; (r) O-CO-R 14 ; (s) O-CO-NR 8 R 9 ; (t) -CN; or (u) -OPO(OR 6 ) 2 : each R 6 , independently of any other, is H, phenyl or C 1-6 alkyl; each R 7 , independently of any other, is C 1-6 alkyl, benzyl, phenyl or (C 1-6 acyloxyl-(C 1-6 alkyl); each R 8 and each R 9 , independently of any other, is phenyl, substituted phenyl as herein defined, or C 1-4 alkyl, or NR 8 R 9 represents a heterocycloalkyl radical of 5 to 8 ring atoms; each R 14 , independently of any other, is H. (CH 2 ) p COOR 6 , C, 6 alkyl, C 1-6 alkoxy, (C 1-6 acyloxy)-(C 1-6 alkoxy), phenyl, substituted phenyl as herein defined, or C, -6 aminoalkyl, or R 14 is such that R 14 CO 2 H is an essential amino acid; R 15 is H, (C 1-6 alkoxy)-(C 1-6 alkyl), (C, 6 acyloxyl-(C 1-6 alkyl), C 1-6 alkyl, benzyl, -(CH 2 ) m COOR 6 , CN, formyl, C 1-4 perfluoroalkyl, CH 2 -R 12 where R 12 is C 1-5 alkyldimethylamino or phenyl, phenyl, or substituted phenyl as herein defined; the broken lines in ring A represent optional double bonds; R 2 , R 3 , R 4 and R 5 may be positioned anywhere in the structure.