Abstract:
Phenothiazone derivatives and analogs thereof, pharmaceutical compositions and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This is division of U.S. Ser. No. 786,257, filed Oct. 10, 1985, now U.S. Pat. No. 4,667,032 which is a continuation-in-part of application Ser. No. 559,471, filed Dec. 12, 1983, now abandoned, which is a continuation-in-part of application Ser. No. 536,487, filed Sept. 28, 1983, now abandoned, which is a continuation-in-part of application Ser. No. 459,924, filed Jan. 22, 1983, now abandoned. 
     U.S. Pat. No. 4,667,032 (Lau et al.) is incorporated herein by reference in its entirety. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     One embodiment of the present invention is a pharmaceutical composition containing a compound of the Formula I: ##STR1## wherein 
     X is in the 1 or 3 position and is O, S or NR wherein R is H, C 1  -C 6  branched or linear alkyl, CN or phenyl; 
     Y is O, Se, S, SO, SO 2  or NR; and the broken line represents an optical double bond between the 1 and 2 or 2 and 3 position; 
     R 1 , R 2 , R 3  and R 4  are independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1-6 carbon atoms; 
     (3) alkenyl having 2-6 carbon atoms; 
     (4) --(CH 2 ) n  M wherein n is 0-6 and M is 
     (a) OR 5  ; 
     (b) halogen; 
     (c) CF 3  ; 
     (d) SR 5  wherein R 5  is H; lower alkoxy-lower alkyl; lower acyloxy-lower alkyl; C 1  -C 6  alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C 1  -C 3  alkyl, halogen, CN, CF 3 , COOR 6 , CH 2  COOR 6 , (CH 2 ) n  NR 8  R 9  wherein n is 0 to 2, C 1  -C 3  alkoxy, OH, halo-C 1  -C 6  -alkyl; --(CH 2 ) m  COOR 6 , wherein m is 0 to 6 and R 6  is H, phenyl, or C 1  -C 6  alkyl; CN; formyl; perfluoroalkyl; or CH 2  -R 12  wherein n is 0 to 4, R 12  is C 1  -C 5  alkyl, dimethylamino or phenyl; 
     (e) phenyl or substituted phenyl as defined above for R 5  ; 
     (f) COOR 6  ; 
     (g) ##STR2##  wherein R 14  is H, (CH 2 ) n  COOR 6  wherein n is 0 to 4, C 1  -C 6  alkyl, CF 3 , phenyl, or substituted phenyl as defined above for R 5  ; 
     (h) tetrazole; 
     (i) ##STR3##  wherein R 7  is C 1  -C 6  alkyl, benzyl or phenyl; (j) --NR 8  R 9  wherein R 8  and R 9  are independently selected from H, phenyl or substituted phenyl as defined above for R 5 , C 1  -C 4  alkyl, C 1  -C 4  alkylamino alkyl, or may be joined through the N to form a heterocycloalkyl or 5-8 ring atoms; 
     (k) --NHSO 2  R 10  wherein R 10  is OH, C 1  -C 6  alkyl, C 1  -C 6  -alkoxy, phenyl, or CF 3  ; 
     (l) ##STR4## (m) --SOR 11  wherein R 11  is C 1  -C 6  alkyl, phenyl or substituted phenyl as defined above for R 5 , (CH 2 ) m  COOR 6  wherein m is 1 to 6, CN, formyl or perfluoro-C 1  -C 4  alkyl; 
     (n) --CONR 8  R 9  ; 
     (o) --SO 2  NR 8  R 9  ; 
     (p) --SO 2  R 13  wherein R 13  is OH, C 1  -C 6  alkyl, H, phenyl or substituted phenyl as defined above for R 5 , (CH 2 ) m  COOR 6  wherein m is 1 to 6, CN, formyl or perfluoro-C 1  -C 4  alkyl; 
     (q) NO 2  ; 
     (r) ##STR5## (s) ##STR6## (t) ##STR7## (u) CN; (v) NR 15  R 16  wherein R 15  and R 16  are such that HNR 15  R 16  is an essential amino acid; or 
     any two of R 1 , R 2 , R 3  and R 4  are joined (e.g. as --(CH 2 ) 3-4  --) to add a fourth ring to the three ring structure, said ring having 5 or 6 carbon atoms and being saturated or unsaturated; and, T is H, halogen or CF 3 . 
     The numbers surrounding Formula I designate the substituent positions. T, R 1 , R 2 , R 3  and R 4  may be positioned anywhere in the structure. As an example of compounds with a fourth ring, compounds of Formula II may be prepared by linking two of the substituent groups; R 1 , R 2 , R 3 , R 4  : ##STR8## wherein Z may be CH, CH 2  or a bond, the broken lines represent optional double bonds and R represents the substituent groups of Formula I (R 1 , R 2 , R 3 , R 4  and/or T) not used to create the fourth ring.