10,10-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure

Abstract

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I; wherein the dashed line indicates the presence or absence of a bond, the hatched wedge indicates the α (down) configuration, and the solid triangle indicates the β (up) configuration; B is a single, double, or triple covalent bond; n is 0-6; X is CH 2 , S or O; Y is any pharmaceutically acceptable salt of CO 2 H, or CO 2 R, CONR 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 ,CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, SONR 2 , or R is H, C 1-6 alkyl or C 2-6 alkenyl; R 2 and R 3 are C 1-6 linear alkyl which may be the same or different, and may be bonded to each other such that they form a ring incorporating the carbon to which they are commonly attached; R 4 is hydrogen, R, C(═O)R, or any group that is easily removed under physiological conditions such that R 4 is effectively hydrogen; R 5 is hydrogen or R; R 6 is i) hydrogen; ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by O or a halogen; or iii) aryloxy, heteroaryloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl, C 6-10 aryl or C 3-10 heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6-10 aryl, C 3-10 heteroaryl, aryloxy, heteroaryloxy, C 1-6 alkyl, OR, SR, and SO 2 R. Some of the compounds of the present invention and some of their methods of preparation are also novel an nonobvious.

1 . A method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma a therapeutically effective amount of a compound represented by the general Formula I:  
       
         
           
           
               
               
           
         
       
       wherein the dashed lines indicate the presence or absence of a bond, the hatched wedges indicate the α (down) configuration, and the solid triangles indicate the β (up) configuration; 
 B is a single, double, or triple covalent bond;  
 n is 0-6;  
 X is CH 2 , S or O;  
 Y is CONHCH 2 CH 2 OH or CON(CH 2 CH 2 OH) 2 ,  
 R 2  and R 3  are C 1-6  linear alkyl which may be the same or different, and may be bonded to each other such that they form a ring incorporating the carbon to which they are commonly attached;  
 R 4  is hydrogen, R, C(═O)R, or any group that is easily removed under physiological conditions such that R 4  is effectively hydrogen;  
 R is H, C 1-6  alkyl or C 1-6  alkenyl;  
 R 5  is hydrogen or R; and  
 R 6  is 
 i) hydrogen;  
 ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by O or a halogen; or  
 iii) aryloxy, heteroaryloxy, C 3-8  cycloalkyloxy, C 3-8  cycloalkyl, C 6-10  aryl or C 3-10  heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6-10  aryl, C 3-10  heteroaryl, aryloxy, heteroaryloxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
 
 
     
     
         2 . A method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma a therapeutically effective amount of a compound selected from the group consisting of 
 (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester (21, 22);    (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid (23, 24);    (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid methyl ester (34,35);    (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid (36,37);    (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid methyl ester (38,39);    (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid (40,41);    (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (50,51)    (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (52,53)    (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (54,55)    7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoic acid (56,57)    (Z)-7-[(1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (58,59)    (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid ethylamide (60,61)    (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid diethylamide (62,63)    (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (2-hydroxy-ethyl)-amide (64,65)    (3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy-2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone (66,67) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid amide (68,69)    (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (70,71)    7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid methyl ester (72,73)    7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid (74,75).    
     
     
         3 . A compound represented by Formula I:  
       
         
           
           
               
               
           
         
       
       wherein the dashed lines indicate the presence or absence of a bond, the hatched wedges indicate the α (down) configuration, and the solid triangles indicate the β (up) configuration; 
 B is a single, double, or triple covalent bond;  
 n is 0-6;  
 X is CH 2 , S or O;  
 Y is any pharmaceutically acceptable salt of CO 2 H, or CO 2 R, CONR 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, SONR 2 , or  
                     
 R is H, C 1-6  alkyl or C 2-6  alkenyl;  
 R 2  and R 3  are C 1-6  linear alkyl which may be the same or different, and may be bonded to each other such that they form a ring incorporating the carbon to which they are commonly attached;  
 R 4  is hydrogen, R, C(═O)R, or any group that is easily removed under physiological conditions such that R 4  is effectively hydrogen;  
 R 5  is hydrogen or R;  
 R 6  is 
 i) hydrogen;  
 ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by O or a halogen; or  
 iii) aryloxy, heteroaryloxy, C 3-8  cycloalkyloxy, C 3-8  cycloalkyl, C 6-10  aryl or C 3-10  heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6-10  aryl, C 3-10  heteroaryl, aryloxy, heteroaryloxy, C 1-6  alkyl, OR, SR, and SO 2 R; and  
 the compound of Formula I is not a compound of Formula II  
                     
 wherein A is CO 2 H, CO 2 Me, or CO 2 Et;  
 
 D is a single, double, or triple covalent bond;  
 E is a linear, branched, or cycloalkyl chain of 3 to 7 carbons, trifluoromethylbutyl, hydroxylalkyl, or CH 2 R 7  wherein R 7  is phenyl, cyclopentyl, phenoxy, chlorophenoxy, propoxy, or —CH 2 SCH 2 CH 3 ;  
 J is hydrogen, R, C(═O)R, or any group that is easily removed under physiological conditions such that R 4  is effectively hydrogen; and  
 G is H or CH 3 .  
 
     
     
         4 . The compound of  claim 3  wherein A is CO 2 R 8 , wherein R 8  is any linear, branched, or cyclic alkyl group having from 3 to 6 carbons.  
     
     
         5 . The compound of  claim 3  which is further represented by Formula III  
       
         
           
           
               
               
           
         
       
       wherein Y is CO 2 R, or any pharmaceutically acceptable salt of CO 2 H.  
     
     
         6 . The compound of  claim 5  wherein R 6  is C 6-10  aryl or C 3-10  heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
     
     
         7 . The compound of  claim 6  wherein R 6  is napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
     
     
         8 . The compound of  claim 7  wherein Y is CO 2 H or CO 2 Me.  
     
     
         9 . The compound of  claim 8  where R 6  is 3-chlorobenzothien-2-yl.  
     
     
         10 . The compound of  claim 9  where n is 2.  
     
     
         11 . The compound of  claim 10  where B is a single bond.  
     
     
         12 . The compound of  claim 3  which is further represented by Formula IV  
       
         
           
           
               
               
           
         
       
       wherein Y is CO 2 R or any pharmaceutically acceptable salt of CO 2 H; and 
 R 6  is C 6-10  aryl or C 3-10  heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
 
     
     
         13 . The compound of  claim 12  wherein Y is CO 2 H or CO 2 Me.  
     
     
         14 . The compound of  claim 13  wherein R 6  is phenyl.  
     
     
         15 . The compound of  claim 14  wherein B is a double bond.  
     
     
         16 . The compound of  claim 13  wherein R 6  is napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
     
     
         17 . The compound of  claim 16  wherein R is 3-chlorobenzothien-2-yl.  
     
     
         18 . The compound of  claim 17  wherein B is a double or triple bond.  
     
     
         19 . The compound of  claim 3  which is further represented by Formula V  
       
         
           
           
               
               
           
         
       
       wherein at least one of R 2  and R 3  is not methyl.  
     
     
         20 . The compound of  claim 19  wherein R 2  and R 3  have a total number of carbon atoms of 6 or less.  
     
     
         21 . The compound of  claim 20  wherein R 5  is hydrogen.  
     
     
         22 . The compound of  claim 3  wherein said compound is selected from the group consisting of 
 (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester (21, 22);  
 (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid (23, 24);  
 (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid methyl ester (34, 35);  
 (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid (36,37);  
 (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid methyl ester (38,39);  
 (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid (40,41);  
 (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (50,51)  
 (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (52,53)  
 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (54,55)  
 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoic acid (56,57)  
 (Z)-7-[(1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (58,59)  
 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid ethylamide (60,61)  
 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid diethylamide (62,63)  
 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (2-hydroxy-ethyl)-amide (64,65)  
 (3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy-2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone (66,67) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid amide (68,69)  
 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (70,71)  
 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid methyl ester (72,73)  
 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid (74,75).  
 
     
     
         23 . The compound of  claim 4   3  which is further represented by Formula XIII  
       
         
           
           
               
               
           
         
       
       wherein B represents a single or double bond; =p 1  and R 6  is napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
     
     
         24 . The compound of  claim 23  wherein R 6  is benzothien-2-yl.  
     
     
         25 . The compound of  claim 24  wherein Y is any pharmaceutically acceptable salt of CO 2 H, or CO 2 R, CONR 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 , or  
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 25  wherein the dashed line indicates the presence of a bond and B is a double bond.  
     
     
         27 . The compound of  claim 25  wherein the dashed line indicates the presence of a bond and B is a single bond.  
     
     
         28 . The compound of  claim 25  wherein the dashed line indicates the absence of a bond and B is a double bond.