Abstract:
Tetrahydrocarbazole 1-alkanoic acids are disclosed. The compounds act as prostaglandin and thromboxane antagonists and are useful in treating asthma, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion and dysmenorrhea and as cytoprotective agents.

Description:
RELATED CASES 
     This is a division of Ser. No. 076,424, Jul. 21, 1987, U.S. Pat. No. 4,808,608, which is a continuation-in-part of Ser. No. 001,739, Jan. 9, 1987, abandoned, which is a continuation-in-part of Ser. No. 821,726, Jan. 23, 1986, abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur. 
     These compounds antagonize the actions of contractile prostaglandins, such as PGF 2 α, PGG 2 , PGH 2 , PGD 2  and TXA 2 . The use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain prostaglandins, such as PGF 2 α, PGD 2 , PGG 2 , and PGH 2 , are potent bronchospastic agents. Indeed human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF 2 α. 
     DESCRIPTION OF THE INVENTION 
     The present invention relates to novel comPounds of Formula I: ##STR1## wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) --(CH 2 ) n  M 
     wherein n is 0 to 3 and M is 
     a) OR 13  ; 
     b) halogen; 
     c) CF 3  ; 
     d) SR 13  ; 
     e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of 
     f) COOR 14  ; 
     g) ##STR2## h) tetrazole; i) ##STR3##  wherein R 16  is C 1  to C 6  alkyl, benzyl or phenyl; j) --NR 14  R 14  ; 
     k) --NHSO 2  R 17  wherein R 17  is C 1  to C 6  alkyl, 4-methylphenyl, phenyl, or CF 3  ; 
     l) ##STR4## m) --SOR 13  ; n) --CONR 14  R 14  ; 
     o) --SO 2  NR 14  R 14  ; 
     p) --SO 2  R 13  ; 
     q) NO 2  ; 
     r) ##STR5## s) ##STR6## t) ##STR7## v) N 3  ; u) CN; 
     R 7  is H or alkyl of 1 to 6 carbons; 
     R 8  is H or alkyl of 1 to 6 carbon atoms; 
     each R 9  is independently H, OH, C 1  to C 4  -0-alkyl or alkyl of 1 to 4 carbons; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; NHSO 2  R 11  wherein R 11  is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or to 1 to 6 carbons; CONHSO 2  R 11  ; hydroxymethylketone; CN; or CON(R 9 ) ; 
     r is 1 to 6; 
     each R 13  independently is H; C 1  to C 6  alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C 1  to C 3  alkyl, halogen, CN, CF 3 , COOR 14 , CH 2  COOR 14 , C 1  to C 3  alkoxy, or C 1  to C 4  perfluoroalkyl; 
     each R 14  is independently H, phenyl, benzyl or C 1  to C 6  alkyl; and, 
     each R 15  independently is H, (CH 2 ) m  COOR 14  wherein m is 0 to 4, C 1  to C 6  alkyl, CF 3 , phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R 13  ; 
     or a pharmaceutically acceptable salt thereof. 
    
    
     Preferred compounds of the present invention comprise the compounds of formula I wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) --(CH 2 ) n  M 
     wherein n is 0 or 1 and M is as defined previously for Formula I; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; CONHSO s  R 11  wherein R 11  is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; hydroxymethylketone; CN; or CON(R 9 ) ; 
     r is 1 to 6; and the remaining substituents are as defined previously for Formula I. 
     More preferred compounds of the present invention comprise the compounds of Formula I. wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) M wherein M is as defined initially for Formula I; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; hydroxymethylketone; 
     r is 1 or 2; and the remaining substituents are as defined initially for Formula I. 
     Most preferred compounds of the present invention comprise the compounds of Formula I. wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) M wherein M is 
     a) OR 13  ; 
     b) halogen; 
     c) CF 3  ; 
     d) SR 13  ; 
     e) COOR 14  ; 
     f) ##STR8## g) tetrazole; h) --SOR 13  ; 
     i) --CONR 14  R 14  ; 
     j) --SO 2  NR 14  R 14  ; 
     k) --SO 2  R 13  ; 
     l) ##STR9## m) CN; n) N 3  ; 
     each R 9  is independently H, or alkyl of 1 to 4 carbons; 
     R 10  is COOH; or tetrazole; 
     r is 1 and the remaining substituents are as defined initially for Formula I. 
     In the above most preferred embodiment, those compounds are particularly preferred wherein at least one of R 1  to R 4  is not hydrogen; one of R 5  or R 6  is not hydrogen; R 7  is hydrogen; R 9  is hydrogen, and the remaining substituents are as defined in the most preferred embodiment.