Patent EP-0138481-A2 (EP)
Inventor: FORTIN REJEAN
IPC: A61K31/54
Filed: 1984-09-28
Abstract: Phenothiazine derivatives and their analogs having the Formula 1, and salts of such compounds, are useful as inhibitors of the biosynthesis of mammalian leukotrienes. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation, and are useful as cytoprotective agents, and are made into pharmaceutical compositions. Certain of the compounds are novel. In Formula I:
     
     X is Se, S, SO, SO 2  or 0;   R' is H; C 1-6 alkyl; C 1-6 acyl; (C 1-6 acyloxy)-(C 1-6 alkyl); (C 1-6 - alkoxy)-(C 1-6 alkyl); benzoyl; substituted benzoyl having C 1-3 alkyl, halogen, CN, CF 3 , COOR 6 , CH 2 COOR 6 , (CH 2 ) n NR 8 R 9 , where n is 0, 1 or 2, C 1-3 alkoxy, and/or OH substitution, (herein called 'substituted as herein defined'); carbamoyl; CO-NHR 7 ; COOR 7 ; p-toluenesulfonyl; methanesulfonyl; an acyl group such that R'-OH is an essential amino acid; benzyl; phenethyl; (CH 2 ) P OR a  where R a  is C 1-6 alkyl or phenyl and p is an integer from 1 to 5; (CH 2 ) n COOR 6  where n is 0, 1 or 2; or (C 1-6 acyloxy)-(C 1-6 alkoxy)-carbonyl;   each of R 2 , R3, R 4  and R 5 , independently of the others, is hydrogen; C 1-6 alkyl; C 2-6 alkenyl or-(CH 2 ) q M where q is 0 or an integer from 1 to 6 and M is (a) -OR 16 ; (b) halogen; (c) -CF 3 ; (d) -SR' 6 ; (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) -CO-CH 2 OH; (m) -SOR" where R" is C 1-6 alkyl, phenyl, substituted phenyl as herein defined, (CH 2 ) m COOR 6  where m is an integer from 1 to 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 hydrogen, OH, C 1-6 alkyl, phenyl, substituted phenyl as herein defined, (CH 2 ) m COOR 6  where m is as defined above, CN, formyl, or C 1-4  perfluoroalkyl; (q) -NO z ; (r) -O-CO-R 14 ; (s) O-CO-NR 8 R 9 ; or (t) -CN;   each R 6 , independently of the others, is hydrogen, C 1-6 alkyl or phenyl;   each R 7 , independently of the others, is C 1-6 alkyl, benzyl, phenyl or (C 1-6 acyloxy)-(C 1-6 alkyl);   each R 8  and each R 9 , independently of any others, is hydrogen, C 1-4 acyl, phenyl, or substituted phenyl as herein defined; or an R 8  and an R 9  are joined through the N to which they are both attached to form a heterocycloalkyl group having from 5 to 8 ring atoms;   each R 14 , independently of the others, is hydrogen, (CH 2 ) r COOR 6  where r is 0 or an integer from 1 to 4; C 1-6 alkyl; C 1-6 alkoxy; (C 1-6 acyloxy)-(C 1-6 alkoxy); phenyl; substituted phenyl as herein defined; or C 1-6 aminoalW such that R 14 COOH is an essential amino acid;   each R 16 , independently of any others, is hydrogen, (C 1-5 alkoxy)-(C 1-5 alkyl), C 1-6 aikyl; benzyl; (C 1-6 acyloxy)-(C 1-6 alkyl); phenyl; substituted phenyl as herein defined; -(CH 2 ) m COOR 6  where m is as defined above; CN; formyl; perfluoroalkyl; or CH 2 -R 12  where R 12  is C 1-5 alkyl, dimethylamino or phenyl;   and T is hydrogen or -OR 15 , where R 15  is hydrogen, C 1-6 alkyl, (C 1-6 alkyl)-acyl, phenylacyl, substituted phenyl-acyl as herein defined; benzoyl; substituted benzoyl as herein defined; or arylsulfonyl; and compounds that are pharmaceutically acceptable salts thereof.