Internal 1, 15-lactones of fluprostenol and related prostaglandin F2a analogs and their use in the treatment of glaucoma and intraocular hypertension

Abstract

Novel derivatives of prostaglandin compounds of the F-series (PGF), specifically macrocyclic internal 1,15-lactones of fluprostenol and related PGF analogs, such as cloprostenol or latanoprost. The novel analogs can be formulated into ophthalmic solutions and topically applied for the treatment of the increased intraocular pressure caused by glaucoma and the reduction of ocular hypertension.

What is claimed is:  
     
         1 . A compound of the general formula:  
       
         
           
           
               
               
           
         
         wherein X is O, S, NH or CH 2 ;  
         R 1  and R 2  are the same and are either H, CH 3  or F;  
         R 9  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;  
         R 11  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;  
         represents any combination of a single bond, or a cis or trans double bond;  
         Z is H, Cl, Br, I, CF 3 , CH 3 , or C 1 -C 10  straight chain or branched alkyl;  
         Y is O, S, NH or CH 2 .  
       
     
     
         2 . The compound of    claim 1    wherein R 9  and R 11  are H; Y is O, S, or NH; and Z is CH 3 .  
     
     
         3 . The compound of    claim 1    wherein X is CH 2 ; R 1 , R 2  is H; Y is O; and Z is CF 3 .  
     
     
         4 . The compound of    claim 1    wherein X is CH 2 ; R 1 , R 2  is H; Y is O; and Z is Cl.  
     
     
         5 . The compound of    claim 1    wherein X is CH 2 ; R 1 , R 2  is H; Y is CH 2 ; and Z is H.  
     
     
         6 . A method of treating increased intraocular pressure in the eye of a human or animal comprising the step of: 
 administering a therapeutically effective amount of at least one compound of the general formula to the eye:                          wherein X is O, S, NH or CH 2 ;    R 1  and R 2  are the same and are either H, CH 3  or F;    R 9  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;    R 11  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;    represents any combination of a single bond, or a cis or trans double bond;    Z is H, Cl, Br, I, CF 3 , CH 3 , or C 1 -C 10  straight chain or branched alkyl;    Y is O, S, NH or CH 2 .    
     
     
         7 . The method of    claim 6    wherein the compound is selected from the group consisting of a 1,15-lactone of fluprostenol, a 1,15-lactone of cloprostenol, and a 1,15-lactone of latanoprost.  
     
     
         8 . A topical ophthalmic composition for treating increased intraocular pressure comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the general formula:  
       
         
           
           
               
               
           
         
         wherein X is O, S, NH or CH 2 ;  
         R 1  and R 2  are the same and are either H, CH 3  or F;  
         R 9  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;  
         R 11  is H, or C 1 -C 20  straight chain, saturated or unsaturated or branched acyl;  
         represents any combination of a single bond, or a cis or trans double bond;  
         Z is H, Cl, Br, I, CF 3 , CH 3 , or C 1 -C 10  straight chain or branched alkyl;  
         Y is O, S, NH or CH 2 .  
       
     
     
         9 . The topical ophthalmic composition of    claim 8    wherein the compound is selected from the group consisting of a 1,15-lactone of fluprostenol, a 1,15-lactone of cloprostenol, and a 1,15-lactone of latanoprost.  
     
     
         10 . A topical formulation for treating increased intraocular pressure comprising the following ingredients by weight percent:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Fluprostenol 1,15-lactone 
                    0.002 
                 
                     
                   Dextran 70 
                   0.1  
                 
                     
                   Hydroxypropyl Methylcellulose 
                   0.3  
                 
                     
                   Sodium Chloride 
                   0.77 
                 
                     
                   Potassium Chloride 
                   0.12 
                 
                     
                   Disodium EDTA 
                   0.05 
                 
                     
                   Benzalkonium Chloride 
                   0.01 
                 
                     
                   HCl and/or NaOH 
                   to pH = 7.0-7.6 
                 
                     
                   Purified water 
                   q.s. to 100%