Oculoselective drugs and prodrugs

Abstract

Compounds of the following formula are disclosed: Methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating patients by administration of the pharmaceutical compositions are disclosed.

1 .- 19 . (canceled) 
   
   
       20 . A compound of Formula II: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  and R 2  are each independently H, W, or a phenoxyl protecting group; 
 R 3  is hydrogen, straight chain or branched C 1 -C 10  alkyl, cycloalkyl, amino, C 1 -C 10  alkoxy, —NHC(═O)R a , or —C(═O)N(H)R a ; 
 R a  is alkyl, aryl, or heterocyclyl; 
 R 4  is H or W; 
 Z is —O— or —O(C═O)—; 
 R 5  is H, straight chain or branched C 1 -C 10  alkyl, cycloalkyl, C 1 -C 10  alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, phenyl substituted with C 1 -C 10  alkyl, C 1 -C 10  alkoxy, or halo, or cycloalkyl substituted with at least one straight or branched C 1 -C 10  alkyl; 
 W is: 
 
     
     
       
         
         
             
             
         
       
       
         each R 6  is independently H, straight chain or branched C 1 -C 10  alkyl, or straight chain or branched C 1 -C 10  alkoxyalkyl; and 
         R 7  is straight chain or branched alkyl, cycloalkyl, aryl, or aralkyl; 
         provided that: 
         when Z is —O(C═O)—, then R 5  is other than H; 
       
       or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof. 
     
   
   
       21 . A compound according to  claim 20  of formula II wherein R 4  is H. 
   
   
       22 . A compound according to  claim 20 , wherein R 1  and R 2  are each independently H or W. 
   
   
       23 . (canceled) 
   
   
       24 . A compound according to  claim 20 , of Formula II(a): 
     
       
         
         
             
             
         
       
     
   
   
       25 . A compound according to  claim 20 , wherein R 4  is W. 
   
   
       26 . (canceled) 
   
   
       27 . A compound according to  claim 26  wherein R 3  is C 1 -C 10  alkyl, R 5  is tetrahydrofuran-3-yl, and W is: 
     
       
         
         
             
             
         
       
     
   
   
       28 . (canceled) 
   
   
       29 . A compound according to  claim 25  wherein R 1  and R 2  are each aralkyl. 
   
   
       30 . A compound according to  claim 25  wherein R 4  is: 
     
       
         
         
             
             
         
       
     
   
   
       31 . A compound according to  claim 20 , wherein at least one of the R 6  substituents is other than H. 
   
   
       32 . A compound according to  claim 20 , wherein each R 6  is independently H, C 1 -C 5  alkyl or lower alkoxyalkyl. 
   
   
       33 . A compound according to  claim 20 , wherein each R 6  is independently H, methyl, or CH 2 OCH 3 . 
   
   
       34 . A compound according to  claim 20 , wherein each W is independently: 
     
       
         
         
             
             
         
       
     
   
   
       35 . (canceled) 
   
   
       36 . A compound according to  claim 20  wherein R 3  is H or C 1 -C 5  alkyl. 
   
   
       37 . A compound according to  claim 20  wherein R 3  is methyl. 
   
   
       38 . A compound according to  claim 20 , wherein R 5  is furanyl, dihydrofuranyl, or tetrahydrofuranyl. 
   
   
       39 . A compound according to  claim 38 , wherein R 5  is tetrahydrofuran-3-yl. 
   
   
       40 . A compound according to  claim 20 , wherein W is: 
     
       
         
         
             
             
         
       
     
   
   
       41 . (canceled) 
   
   
       42 . A compound according to  claim 20 , wherein R 5  is 3-alkyltetrahydrofuran-3-yl. 
   
   
       43 . (canceled) 
   
   
       44 . A compound according to  claim 43 , of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       45 . A pharmaceutically acceptable salt of a compound according to  claim 43 , of formula:
   [A].HX;   wherein A is a compound according to  claim 43  and HX is an acid selected from the group consisting of hydrochloric, sulfuric, maleic, fumaric, oxalic, succinic, citric, and tartaric acids.   
   
   
       46 .- 58 . (canceled) 
   
   
       59 . A method of treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises administering to the eye of the patient a composition comprising an opthalmologically acceptable carrier or diluent and a compound according to  claim 20 , or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or prevent the development of, or reduce the symptoms of glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy. 
   
   
       60 . The method according to  claim 59 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma. 
   
   
       61 . (canceled) 
   
   
       62 . The method according to  claim 59 , wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.