Acyloxyalkyl carbamate prodrugs, methods of synthesis and use

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 (I): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, hydrates or solvates thereof, or isomers of any of the foregoing, wherein:
 R 1  is selected from the group consisting of acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; 
 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 or trialkylsilyl; and 
 R 5  is 4-fluorophenyl. 
 
     
     
         54 . The compound of  claim 53 , wherein R 4  is hydrogen. 
     
     
         55 . The compound of  claim 53  wherein R 1  is selected from the group consisting of C 1-6  alkyl, substituted C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, substituted phenyl, C 7-9  phenylalkyl and pyridyl. 
     
     
         56 . The compound of  claim 53 , wherein R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. 
     
     
         57 . The compound of  claim 53 , wherein R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. 
     
     
         58 . 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. 
     
     
         59 . 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, and R 3  is hydrogen. 
     
     
         60 . 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. 
     
     
         61 . The compound of  claim 53 , wherein R 2  is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R 3  is methyl. 
     
     
         62 . The compound of  claim 53 , wherein R 4  is selected from the group consisting of 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 and aryldialkylsilyl. 
     
     
         63 . 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. 
     
     
         64 . The compound of  claim 53 , wherein R 4  is hydrogen, allyl, benzyl or trimethylsilyl. 
     
     
         65 . The compound of  claim 53 , wherein:
 R 1  is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl;   R 2  is chosen from hydrogen, methyl, n-propyl, and isopropyl;   R 3  is hydrogen; and   R 4  is hydrogen.   
     
     
         66 . The compound of  claim 53 , wherein R 2  is methyl. 
     
     
         67 . The compound of  claim 66 , wherein the stereochemistry at the carbon to which R 2  and R 3  are attached is of the S-configuration and the compound is substantially one diastereomer. 
     
     
         68 . The compound of  claim 66 , wherein the stereochemistry at the carbon to which R 2  and R 3  are attached is of the R-configuration and the compound is substantially one diastereomer. 
     
     
         69 . The compound of  claim 53 , wherein R 2  is isopropyl. 
     
     
         70 . The compound of  claim 69 , wherein the stereochemistry at the carbon to which R 2  and R 3  are attached is of the S-configuration and the compound is substantially one diastereomer. 
     
     
         71 . The compound of  claim 69 , wherein the stereochemistry at the carbon to which R 2  and R 3  are attached is of the R-configuration and the compound is substantially one diastereomer. 
     
     
         72 . The compound of  claim 53 , wherein:
 R 1  is isopropyl;   R 2  is isopropyl; and   the stereochemistry at the carbon to which R 2  and R 3  are attached is of the S-configuration, and the compound is substantially one diastereomer.   
     
     
         73 . The compound of  claim 53 , wherein:
 R 1  is isopropyl;   R 2  is isopropyl; and   the stereochemistry at the carbon to which R 2  and R 3  are attached is of the R-configuration, and the compound is substantially one diastereomer.   
     
     
         74 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         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 or trialkylsilyl; and 
         R 5  is 4-fluorophenyl. 
       
     
     
         75 . The compound of  claim 74 , wherein R 4  is hydrogen. 
     
     
         76 . A method of treating or preventing spasticity or a symptom of spasticity in a patient comprising administering a compound of  claim 53  to a patient in need of such treatment. 
     
     
         77 . The method of  claim 76 , wherein the symptom of spasticity is selected from the group consisting of stiffness, involuntary movements and/or pain associated with spasticity. 
     
     
         78 . A method of treating or preventing gastro-esophageal reflux disease in a patient comprising administering a compound of  claim 53  to a patient in need of such treatment. 
     
     
         79 . A method of treating or preventing drug addiction in a patient comprising administering a compound of  claim 53  to a patient in need of such treatment. 
     
     
         80 . A method of treating or preventing alcohol addiction or abuse, or nicotine addiction or abuse, in a patient comprising administering a compound of  claim 53  to a patient in need of such treatment. 
     
     
         81 . A method of treating or preventing cough or emesis in a patient comprising administering a compound of  claim 53  to a patient in need of such treatment. 
     
     
         82 . The method of any one of  claims 76 - 81 , wherein the compound is administered with a proton pump inhibitor or an H2 antagonist. 
     
     
         83 . The method of  claim 82 , wherein the proton pump inhibitor is selected from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole sodium. 
     
     
         84 . The method of  claim 82 , wherein the H2 antagonist is selected from rantidine, cimetidine and famotidine. 
     
     
         85 . A pharmaceutical composition comprising a compound of  claim 53  and a pharmaceutically acceptable vehicle. 
     
     
         86 . A pharmaceutical composition comprising a compound of  claim 53 , a proton pump inhibitor or an H2 antagonist, and a pharmaceutically acceptable vehicle. 
     
     
         87 . The composition of  claim 86 , wherein the proton pump inhibitor is selected from omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole sodium. 
     
     
         88 . The composition of  claim 86 , wherein the H2 antagonist is selected from rantidine, cimetidine and famotidine. 
     
     
         89 . The composition of one of  claims 85 - 88 , comprising an oral sustained release dosage form. 
     
     
         90 . The composition of  claim 89 , wherein the dosage form is adapted to be swallowed by a patient in order to introduce the dosage form into an intestinal lumen of the patient;
 the dosage form further being adapted to release the compound of  claim 53  gradually into the intestinal lumen of the patient over a period of hours after said swallowing, said gradual release causing a baclofen analog to be cleaved from the compound of  claim 53  after said swallowing and providing a therapeutic concentration of the baclofen analog in the plasma of the patient.   
     
     
         91 . The composition of  claim 90 , wherein the period of hours comprises at least about 6 hours. 
     
     
         92 . The composition of  claim 90 , wherein the period of hours comprises at least about 8 hours. 
     
     
         93 . The composition of  claim 90 , wherein the period of hours comprises at least about 12 hours. 
     
     
         94 . The composition of  claim 90 , wherein the dosage form releases from 0 to 30% of the compound of claim  1  in 0 to 2 hours, from 20 to 50% of the compound of claim  1  in 2 to 12 hours, from 50 to 85% of the compound of  claim 53  in 3 to 20 hours and greater than 75% of the compound of  claim 53  in 5 to 18 hours.