Indole-2-alkanoic acids and their use as prostaglandin antagonists

Claim 2

A pharmaceutical composition useful as a prostaglandin antagonist in mammals comprising a prostaglandin antagonizing amount of compound of the Formula I or a compound that is a pharmaceutically acceptable salt thereof: where R 1 is H or alkyl of 1 to 6 carbons or R 1 and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7; R 2 is where each R 8 is independently H, OH, C 1 to C 4 -O-alkyl or alkyl of 1 to 4 carbons; or an R 1 and an R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7. R 9 is COOR 1 ; CH 2 OH; CHO; tetrazole; NHSO 2 R 10 wherein R 10 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; CONHSO 2 R 10 ; hydroxymethylketone; CN; or CON(R 8 ) 2 ; X is O; S; SO; SO 2 ; NR 11 wherein R 11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR 1 R 8 ; or the unit wherein the dotted line represents an optional triple bond and in which the R 1 and R 8 substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 6; R 3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R 4 ; or C 1 to C 4 alkylphenyl or C 1 to C 4 alkylphenyl in which the phenyl is substituted by R 4 ; R 4 , R 5 , R 6 and R 7 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 12 ; b) halogen; c) CF 3 ; d ) sR 12 ; e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; f) COOR 13 ; g) h) tetrazole; O i) -NH-C-R 15 wherein R 15 is C 1 to C 6 alkyl, benzyl or phenyl; j) -NR 13 R 13 ; k) -NHSO 2 R 16 wherein R 16 is C 1 to C 6 alkyl, phenyl, or CF 3 ; 1) m) -SOR 12 ; n) -CONR 13 R 13 ; o ) -SO 2 NR 13 R 13 ; P) -SO 2 R 12 ; q ) NO 2 ; r) S) t) u) CN; each R 12 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 13 , CH 2 COOR 13 , C 1 to C 3 alkoxy, or C 1 to C 4 perfluoroalkyl; each R 13 is independently H, phenyl or C 1 to C 6 alkyl; and, each R 14 independently is H, (CH 2 ) n COOR 13 wherein n 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 12 ; and a pharmaceutically acceptable carrier.

Claim 3

A composition according to Claim 1, wherein: R 1 is H or alkyl of 1 to 3 carbons or R 1 and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7, with the proviso that R 1 on the benzylic carbon attached to the indole nitrogen is H; R 2 is wherein: each R 8 is independently H, or alkyl of 1 to 4 carbons; or an R 1 and an R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7. R 9 is COOR 1 ; CH 2 OH; CHO; or tetrazole; X is O; S; SO; SO 2 ; NR 11 wherein R 11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR 1 R 8 ; or the unit wherein the dotted line represents an optional triple bond and in which the R 1 and R 8 substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 3; R 3 is alkyl of 1 to 6 carbons, but is not cycloalkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M wherein M is a) OR 12 ; b) halogen; c) CF 3 ; d) SR 12 ; e) -SOR 12 ; f) -SO 2 R 12 ; g) wherein R 14 is H, (CH 2 ) n COOR 13 wherein n 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 12 ; H, C 1 to C 6 alkyl, CF 3 , phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; h) CN; each R 12 is independently 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 13 , CH 2 CO OR 13 , wherein R 13 is H , phenyl; C 1 to C 6 alkyl or C 1 to C 4 perfluoroalkyl; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Claim 4

A compound of the Formula Ia: wherein: R 1 is H or alkyl of 1 to 6 carbons or R 1 and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7; R is wherein: each R 8 is independently H, OH, C 1 , to C 4 -O-alkyl, or alkyl of 1 to 4 carbons or R and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7; R 9 is COOR 1 ; CH 2 OH; CHO; tetrazole; NHSO 2 R 10 wherein R 10 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; CONHSO 2 R 10 ; hydroxymethylketone; CN; or CON(R ) 2 ; X is O; S; SO; SO 2 ; NR 11 wherein R 11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR 1 R 8 ; or the unit wherein the dotted line represents an optional triple bond and in which the R 1 and R 8 substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 6, with the proviso that when R 1 and R 8 are H , X is CH 2 , R 4 is 5-methoxy and R 6 is halogen, then the sums of p, q and r is 3 to 6; R 3 is H , alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R 4 ; or C 1 to C 4 alkylphenyl or C 1 to C 4 alkylphenyl in which the phenyl is substituted by R 4 ; R 4 , R 5 , R 6 and R 7 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 12 ; b) halogen; c) C F 3 ; d) SR 12 ; e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; f ) COOR 13 ; g) h) tetrazole; i) wherein R 15 is C 1 to C 6 alkyl, benzyl or phenyl; j) -NR 13 R 13 ; k) -NHSO 2 R 16 wherein R 16 is C 1 to C 6 alkyl, phenyl, or CF 3 ; 1) m) -SOR12; n) -CONR 13 R 13 ; o) -SO 2 NR 13 R 13 ; p) -SO 2 R 12 ; q ) NO 2 ; r) s) t) u) CN; each R 12 is independently 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 13 , CH 2 COOR 13 C 1 to C 3 alkoxy, or C 1 to C 4 perfluoroalkyl; each R 13 is independently H, phenyl or C 1 to C6 alkyl; each R 14 is independently H, (CH 2 ) n COOR 13 wherein n is 0 to 4, C 1 to C 6 alkyl, C F 3 , phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R 12 ; or a pharmaceutically acceptable salt thereof.

Claim 5

A compound of the Formula Ia: wherein: R 1 is H or alkyl of 1 to 6 carbons or R 1 and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7; R is wherein: each R 8 is independently H, OH, C 1 , to C 4 -O-alkyl, or alkyl of 1 to 4 carbons or R and R 8 taken together form a group (CH 2 ) v wherein v is 1 to 7; R 9 is COOR 1 ; CH 2 OH; CHO; tetrazole; NHSO 2 R 10 wherein R 10 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; CONHSO 2 R 10 ; hydroxymethylketone; CN; or CON(R ) 2 ; X is O; S; SO; SO 2 ; NR 11 wherein R 11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR 1 R 8 ; or the unit wherein the dotted line represents an optional triple bond and in which the R 1 and R 8 substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 6, with the proviso that when R 1 and R 8 are H , X is CH 2 , R 4 is 5-methoxy and R 6 is halogen, then the sums of p, q and r is 3 to 6; R 3 is H , alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R 4 ; or C 1 to C 4 alkylphenyl or C 1 to C 4 alkylphenyl in which the phenyl is substituted by R 4 ; R 4 , R 5 , R 6 and R 7 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 12 ; b) halogen; c) C F 3 ; d) SR 12 ; e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; f ) COOR 13 ; g) h) tetrazole; i) wherein R 15 is C 1 to C 6 alkyl, benzyl or phenyl; j) -NR 13 R 13 ; k) -NHSO 2 R 16 wherein R 16 is C 1 to C 6 alkyl, phenyl, or CF 3 ; 1) m) -SOR12; n) -CONR 13 R 13 ; o) -SO 2 NR 13 R 13 ; p) -SO 2 R 12 ; q ) NO 2 ; r) s) t) u) CN; each R 12 is independently 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 13 , CH 2 COOR 13 C 1 to C 3 alkoxy, or C 1 to C 4 perfluoroalkyl; each R 13 is independently H, phenyl or C 1 to C6 alkyl; each R 14 is independently H, (CH 2 ) n COOR 13 wherein n is 0 to 4, C 1 to C 6 alkyl, C F 3 , phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R 12 ; or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of Claim 3 wherein: R 1 is H or alkyl of 1 to 3 carbons, with the proviso that R 1 on the benzylic carbon attached to the indole nitrogen is H; R 2 is wherein: each R8 is independently H or alkyl of 1 to 4 carbons, with the proviso that at least one of the R 1 or R 8 substituents in R 2 is not hydrogen; R 9 is C OOH ; CH 2 OH; CHO; or tetrazole; X is CR 1 R 8 ; r and q are each independently 0 to 3 and p is 0 or 1 provided that the total of p, q and r is 2 to 3; R 3 is alkyl of 1 to 6 carbons, but not cycloalkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M wherein M is a) OR 12 ; b) halogen; c) CF 3 ; d) SR 12 ; e) -SOR 12 ; f ) -SO 2 R 12 ; g) wherein R 14 is H , C 1 to C 6 alkyl, CF 3 , phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; h) CN; each R12 is independently H; C 1 to C 6 alkyl; or benzyl; or a pharmaceutically acceptable salt thereof.

Claim 7

A compound of Claim 3 wherein: R 1 is H or alkyl of 1 to 3 carbons, with the proviso that R 1 on the benzylic carbon attached to the indole nitrogen is H; R 2 is wherein: each R 8 is independently H or alkyl of 1 to 4 carbons; R 9 is COOH; CH 2 OH; CHO; or tetrazole; X is O; S; SO; or SO 2 ; r and q are each independently 0 to 3 and p is 1 provided that the total of p, q and r is 2 to 3; R 3 is alkyl of 1 to 6 carbons, but not cycloalkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M wherein M is a) OR 12 ; b) halogen; c) CF 3 ; d) SR 12 ; e) -SOR 12 ; f ) -SO 2 R 12 ; g) wherein R 14 is H , C 1 to C 6 alkyl, CF 3 , phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R 12 ; h) CN; each R 12 is independently H; C 1 to C 6 alkyl; or benzyl; or a pharmaceutically acceptable salt thereof.

Claim 8

The compounds of Claim 3: 3-[l-(p-Chlorobenzyl)-5-chloro-3-methyl-2-indolyl]-propionic acid; 3-[l-(p-Chlorobenzyl)-3-methyl-5-fluoro-2-indolyl]-propionic acid; 3-[l-p-Chlorobenzyl-3-methyl-4,6-dichloro-2- indolyl]propionic acid; 3-[l-(p-Chlorobenzyl)-3-methyl-4-methoxy-2- indolyl]propionic acid; 3-[l-(p-chlorobenzyl)-3-methyl-6-methoxy-2- indolyl]propionic acid; 3-[l-(p-Chlorobenzyl)-3,4-dimethyl-2-indolylpro- pionic acid and 3-[l-(p-chlorobenzyl)-3,6-dimethyl-2-indolyl]propionic acid (as a mixture); 1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-(4'-carboxybutyl)indole; 3-[1-(p-Chlorobenzyl)-3,5-dimethyl-2-indolyl]-propionic acid; 1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-(3-carboxypropyl)indole; 3-[1-(p-Chlorobenzyl)-3-methyl-2-indolyl]propionic acid; 3-[1-(p-Chlorobenzyl)-5-bromo-3-methyl-2-indolyl]-propionic acid; 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(2-carboxyethyl)indole; 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(2-carboxyethyl)indole S-oxide; 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(3-carboxypropyl)indole; 4-[1-(p-Chlorobenzyl)-3-methyl-5-fluoro-2-indolyl]-butanoic acid; 3-[1-(p-Thiomethylbenzyl)-3-methyl-5-fluoro-2- indolyl]propanoic acid; 3-[1-p-Methylsulfoxylbenzyl)-3-methyl-5-fluoro-2- indolyl]-propanoic acid; 3-[1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-indolyl]-butanoic acid; 3-Methyl-4-[l-p-chlorobenzyl-5-methoxy-3-methylindol-2-yl]butanoic acid; 3-Methyl-4-[1-p-chlorobenzyl-5-fluoro-3-methylindol-2-yl]butanoic acid; 3-(l-p-Chlorobenzyl-3-methyl-5-methoxyindol-2-yl)-2,2-dimethylpropanoic acid; 3-[1-p-Chlorobenzyl-5-hydroxy-3-methylindol-2-yl]-propionic acid; 3-[1-p-Chlorobenzyl-5-acetoxy-3-methylindol-2-yl]-propionic acid; 3-[4,6-dichloro-1-(4-chlorobenzyl)-3-methyl-1H-indol-2-yl]propanoic acid; 3-[l-(4-chlorobenzyl)-4-methoxy-3-methyl-lH-indol-2-yl]propanoic acid; 2-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]methoxylacetic acid; 3-[1-(4-bromobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]2-methyl-propanoic acid; 3-[1-(4-iodobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethyl-propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethyl-propanol; 3-[1-(4-chlorobenzyl)-3-methoxy-5-hydroxyindol-2-yl]-2,2-dimethyl-propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-propanol; 3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-2,2-dimethyl propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-3-methyl-propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]butanoic acid; Methyl 4-[1-(4-chlorobenzyl)-3-methyl-5-fluoro- indol-2-yl]-butanoate; 3-[1-(4-chlorobenzyl)-3-methyl-4-propyl-5-hydroxy- indol-2-yl]-propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-prop-2-enoxy- indol-2-yl]-propanoic acid; 3-[1-(4-chlorobenzyl-3-methyl-5-methoxyindol-2-yl]-2,2-dimethyl-propanoate; 3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-2-methyl-butanoic acid; 1-(4-chlorobenzyl)-3-methyl-5-methoxy-1H-indole-2-methoxy acetic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-chloroindol-2-yl]-2,2-dimethyl-propanoic acid; methyl-3[1(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl]propanoate; 3-[1-(4-aminobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl]-2,2-dimethyl propanoic acid; 4-[1-(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl]-2,2-dimethyl butanoic acid; 4-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-1H-indol-2-yl]-2,2-dimethyl butanoic acid; 4-[1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2-yl]-3-methyl butanoic acid; 3-[1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2-yl]-2,2-dimethyl propanoic acid; 3-[1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2-yl]-3-methyl propanoic acid; 3-[l-(4-chlorobenzyl)-5-ethoxy-3-methyl-lH-indol-2-yl]-2,2-dimethyl propanoic acid; 4-[l-(4-chlorobenzyl-5-fluoro-3-methyl-lH-indol-2-yl]-2,4,3,3-tetramethyl butanoic acid; 4-[l-(4-chlorobenzyl-5-fluoro-3-methyl-lH-indol-2-yl]-4,3,3-trimethyl butanoic acid; 4-[1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl butanoic acid; 4-[1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl]-2,3,3-trimethyl butanoic acid; 4-[l-(4-chlorobenzyl-5-methoxy-3-methyl-lH-indol-2-yl]-2,2,3-trimethyl butanoic acid; 4-[1-(4-chlorobenzyl-5-ethoxy-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl butanoic acid; 4-[1-(4-chlorobenzyl-5-chloro-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl butanoic acid; 4-[1-(4-chlorobenzyl-3-methyl-5-trifluoromethyl-1H-indol-2-yl]-2,4,3,3-tetramethyl butanoic acid; 4-[1-(4-chlorobenzyl-3-methyl-5-trifluoromethylthio- lH-indol-2-yl]-2,4,3,3-tetramethyl butanoic acid; 3-[1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl propanoic acid; 3-[1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2-yl)-2,3,3-trimethyl propanoic acid; 3-[1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2-yl]-2,2,3,3-tetramethyl propanoic acid; 3-[1-(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl propanoic acid; 3-(1-(4-chlorobenzyl)-5-fluoro-3-methyl-1H-indol-2-yl]-2,2,3-trimethyl propanoic acid; 3-[l-(4-chlorobenzyl)-5-chloro-3-methyl-lH-indol-2-yl]-2,2,3-trimethyl propanoic acid; 3-(1-p-chlorobenzyl-3-methyl-5-methoxyindol-2-yl)-2,2-diethyl propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-2,2-diethyl propanoic acid; 3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-2-ethyl propanoic acid; 3-[1-(4-chlorobenzyl)-3-ethyl-5-fluoroindol-2-yl]-3-methyl propanoic acid; and 3-[1-(4-chlorobenzyl-3-methyl-5-methoxy-2-indolyl] pentanoic acid.

Claim 9

A composition as claimed in Claim 1 for use in the inhibition of leukotriene synthesis in a mammal.

Claim 10

A compound as claimed in Claim 3 for use in the inhibition of leukotriene synthesis in a mammal.

Claim 11

A composition as claimed in Claim 1 or 2 that additionally comprises a second active ingredient that is a non-steroidal anti-inflammatory drug; a peripheral analgesic agent; a cyclooxygenase inhibitor; a leukotriene antagonist; a leukotriene biosynthesis inhibitor; an H 2 -receptor antagonist; an antihistaminic agent; a prostaglandin antagonist; an ACE inhibitor, or a thromboxane synthetase inhibitor, in which the weight ratio of the compound of Formula I to the second active ingredient is in the range from 1000:1 to 1:1000.

Claim 12

A pharmaceutical composition comprising a compound as claimed in any one of Claims 3 to 6 together with a second active ingredient as defined in Claim 9.