3, 7or3 and 7 thia or oxa 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 hatched lines represent the α configuration, a triangle represents the β configuration, a wavy line represents the α configuration or the β configuration and a dotted line represents the presence or absence of a double bond; A and B are independently selected from the group consisting of O, S and CH 2 ; provided that at least one of A or B is S; D represents a covalent bond or CH 2 , O, S or NH; X is CO 2 R, CONR 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R SONR 2 or Y is O, OH, OCOR 2 , halogen or cyano; Z is CH 2 or a covalent bond; R is H, or R 2 ; R 1 is H, R 2 , phenyl, or COR 2 ; R 2 is C 1 -C 5 lower alkyl or alkenyl and R 3 is benzothienyl, benzofuranyl, naphthyl or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5 alkyl, halogen, CF 3 , CN, NO 2 , NR 2 , CO 2 R and OR.

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 hatched lines represent the α configuration, a triangle represents the β configuration, a wavy line represents either the α configuration or the β configuration and a dotted line represents the presence or absence of a double bond;  
         A and B are independently selected from the group consisting of O, S and CH 2 , provided that at least one of A or B is S;  
         D represents a covalent bond or CH 2 , O, S or NH;  
         X is CO 2 R, CONR 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, SONR 2  or  
         
           
             
             
                 
                 
             
           
         
          Y is O, OH, OCOR 2 , halogen or cyano;  
         Z is CH 2  or a covalent bond;  
         R is H or R 2 ;  
         R 1  is H, R 2 , phenyl, or COR 2 ;  
         R 2  is C 1 -C 5  lower alkyl or alkenyl and R 3  is benzothienyl, benzofuranyl, naphthyl, or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5  alkyl, halogen, CF 3 , CN, NO 2 , NR 2 , CO 2 R and OR.  
       
     
     
         2 . The method according to  claim 1  wherein said compound is represented by the general formula II;  
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 2  wherein said compound is represented by the general formula III;  
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1  wherein Z represents a covalent bond.  
     
     
         5 . The method of  claim 1  wherein D represents a covalent bond or is CH 2 .  
     
     
         6 . The method of  claim 1  wherein X is CO 2  R.  
     
     
         7 . The method of  claim 6  wherein R is selected from the group consisting of H, methyl, i-propyl, and n-propenyl.  
     
     
         8 . The method of  claim 1  wherein R is H, or n-propenyl.  
     
     
         9 . The method of  claim 1  wherein R 1  is H.  
     
     
         10 . The method of  claim 1  wherein D is CH 2 .  
     
     
         11 . The method of  claim 10  wherein R 3  is benzo[b]thienyl, 3-chlorobenzo[b]thienyl or naphthyl.  
     
     
         12 . The method of  claim 1  wherein said compound is selected from the group consisting of 
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzothienyl)pent-1-enyl) 5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzothienyl)pent-1-enyl) -5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzothienyl)pent-1-enyl) -5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzofuranyl)pent-1-enyl) -5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester,  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzofuranyl)pent-1-enyl) -5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid and  
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(benzofuranyl)pent-1-enyl) -5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester.  
 
     
     
         13 . The method of  claim 1  wherein D is CH 2  and Z represents a covalent bond.  
     
     
         14 . An ophthalmic solution comprising a therapeutically effective amount of a compound represented by the general Formula 1  
       
         
           
           
               
               
           
         
         wherein hatched lines represent the α configuration, a triangle represents the β configuration, a wavy line represents the α configuration or the β configuration and a dotted line represents the presence or absence of a double bond;  
         A and B are independently selected from the group consisting of O, S and CH 2 ; provided that at least one of A or B is S;  
         D represents a covalent bond or CH 2 , O, S or NH;  
         X is CO 2 R, CONR 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R SONR 2  or  
         
           
             
             
                 
                 
             
           
         
          Y is O, OH, OCOR 2 , halogen or group;  
         Z is CH 2  or a covalent bond;  
         R is H or R 2 ;  
         R 1  is H, R 2,  phenyl, or COR 2 ;  
         R 2  is C 1 -C 5  lower alkyl or alkenyl and R 3  is benzothienyl, benzofuranyl, naphthyl or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5  alkyl, halogen, CF 3 , CN, NO 2 , NR 2 , CO 2 R and OR in admixture with a non-toxic, ophthalmically acceptable liquid vehicle, packaged in a container suitable for metered application.  
       
     
     
         15 . A pharmaceutical product, comprising a container adapted to dispense the contents of said container in metered form; and an ophthalmic solution according to  claim 13  in said container.  
     
     
         16 . A novel compound selected from the group consisting of 
 {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5 oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester,    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid methyl ester    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid and    {3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}acetic acid isopropyl ester.