Acyloxyalkyl carbamate prodrugs, methods

Abstract

The disclosures herein relate generally to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, pharmaceutical compositions thereof, methods of making prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, methods of using prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, and pharmaceutical compositions thereof for treating or preventing common diseases and/or disorders such as spasticity and/or acid reflux disease. The disclosures herein also relate to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof which are suitable for oral administration and to sustained release oral dosage forms thereof.

1 - 52 . (canceled) 
   
   
       53 . A compound of Formula (II): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein:
 X is fluoro, chloro, bromo or iodo; 
 R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R 2  and R 3  together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; 
 R 4  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl and trialkylsilyl; and 
 R 5  is selected from the group consisting of substituted aryl, heteroaryl and substituted heteroaryl. 
 
   
   
       54 . The compound of  claim 53 , wherein X is chloro. 
   
   
       55 . The compound of  claim 53 , wherein R 5  is selected from the group consisting of 4-chlorophenyl; R-(4-chlorophenyl), 2-chlorophenyl), 4-fluorophenyl, thien-2-yl, 5-chlorothien-2-yl, 5-bromothien-2-yl and 5-methylthien-2-yl. 
   
   
       56 . The compound of  claim 53 , having Formula (VII): 
     
       
         
         
             
             
         
       
     
   
   
       57 . The compound of  claim 53 , having Formula (VIII): 
     
       
         
         
             
             
         
       
     
   
   
       58 . The compound of  claim 53 , wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. 
   
   
       59 . The compound of  claim 53 , wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, C 1-4  alkyl, substituted C 1-4  alkyl, C 1-4  alkoxycarbonyl, C 3-6  cycloalkyl, C 3-6  cycloalkoxycarbonyl, phenyl, substituted phenyl, C 7-9  phenylalkyl and pyridyl. 
   
   
       60 . The compound of  claim 53 , wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. 
   
   
       61 . The compound of  claim 53 , wherein:
 R 2  is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl or cyclohexyl; and   R 3  is hydrogen.   
   
   
       62 . The compound of  claim 53 , wherein:
 R 2  is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl; and   R 3  is methyl.   
   
   
       63 . The compound of  claim 53 , wherein R 2  and R 3  together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. 
   
   
       64 . The compound of  claim 53 , wherein R 2  and R 3  together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. 
   
   
       65 . The compound of  claim 53 , wherein R 4  is hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl, substituted C 7-9  phenylalkyl, trialkylsilyl or aryldialkylsilyl. 
   
   
       66 . The compound of  claim 53 , wherein R 4  is hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or phenyldimethylsilyl. 
   
   
       67 . The compound of  claim 53 , wherein R 4  is hydrogen, allyl, benzyl or trimethylsilyl. 
   
   
       68 . The compound of  claim 53 , wherein:
 R 2  and R 3  are independently selected from the group consisting of hydrogen, C 1-4  alkyl, substituted C 1-4  alkyl, C 1-4  alkoxycarbonyl, C 3-6  cycloalkyl, C 3-6  cycloalkoxycarbonyl, phenyl, substituted phenyl, C 7-9  phenylalkyl and pyridyl; and   R 4  is hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl, substituted C 7-9  phenylalkyl, trialkylsilyl or aryldialkylsilyl.   
   
   
       69 . The compound of  claim 53 , wherein:
 R 2  is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl or 4-pyridyl;   R 3  is hydrogen; and   R 4  is hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl, substituted C 7-9  phenylalkyl, trialkylsilyl or aryldialkylsilyl.   
   
   
       70 . The compound of  claim 53 , wherein:
 R 2  is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl or phenyl;   R 3  is hydrogen; and   R 4  is hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl, substituted C 7-9  phenylalkyl, trialkylsilyl or aryldialkylsilyl.   
   
   
       71 . The compound of  claim 53 , wherein:
 R 2  is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, or cyclohexyloxycarbonyl;   R 3  is methyl; and   R 4  is hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl, substituted C 7-9  phenylalkyl, trialkylsilyl or aryldialkylsilyl.   
   
   
       72 . The compound of  claim 53 , wherein:
 R 2  and R 3  are independently selected from the group consisting of hydrogen, C 1-4  alkyl, substituted C 1-4  alkyl, C 1-4  alkoxycarbonyl, C 3-6  cycloalkyl, C 3-6  cycloalkoxycarbonyl, phenyl, substituted phenyl, C 7-9  phenylalkyl and pyridyl; and   
     R 4  is hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or phenyldimethylsilyl.