Levodopa Prodrugs, and Compositions and Uses Thereof

Abstract

Prodrugs of levodopa, methods of making prodrugs of levodopa, methods of using prodrugs of levodopa, and compositions of prodrugs of levodopa are disclosed.

1 - 45 . (canceled) 
   
   
       46 . A method of treating Parkinson's disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein
 n is an integer from 1 to 6; 
 each R 1  and R 2  is independently selected from hydrogen, alkenyl, alkynyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or optionally, when n is 1, then R 1  and R 2  together with the carbon atom to which R 1  and R 2  are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; 
 R 3  and R 4  are independently selected from hydrogen, —C(O)OR 7 , —C(O)R 7 , and —(CR 8 R 9 )OC(O)R 10 ; 
 R 5  is selected from alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
 R 7  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
 R 8  and R 9  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl or optionally, R 8  and R 9  together with the carbon atom to which R 8  and R 9  are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
 R 10  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
 wherein each substituent group is independently selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6 alkoxy; 
 with the provisos that:
 when n is 2, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not methyl or phenyl; 
 when n is 3, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not methyl; and 
 when n is an integer from 1 to 6, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not benzyl. 
 
 
   
   
       47 . The method of  claim 46 , wherein R 5  is selected from C 5-8  aryl, and substituted C 5-8  aryl substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
   
   
       48 . The method of  claim 46 , wherein R 5  is selected from phenyl and pyridyl, which are optionally substituted with halo, —CN, —OH, C 1-4  alkyl, and C 1-4 alkoxy. 
   
   
       49 . The method of  claim 46 , wherein each R 1  and R 2  is independently selected from hydrogen and substituted C 1-4  alkyl. 
   
   
       50 . The method of  claim 46 , wherein each R 1  and R 2  is hydrogen. 
   
   
       51 . The method of  claim 46 , wherein R 3  and R 4  are independently selected from hydrogen, —C(O)OR 7 , and —C(O)R 7 . 
   
   
       52 . The method of  claim 51 , wherein R 7  is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and benzyl; where the aryl ring of the benzyl group is optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
   
   
       53 . The method of  claim 46 , wherein R 5  is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, and styryl; where the aryl ring of the benzyl or styryl group is optionally substituted with one or more substituents are selected from halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6  alkoxy. 
   
   
       54 . The method of  claim 46 , wherein the compound of Formula (I) is selected from: 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Chlorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Methylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Methoxyphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Butylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-tert-Butylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Isopropylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Ethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-diethoxycarbonyloxyphenyl)propanoate; 
     3-Phenoxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-(4-Fluorophenoxy)propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     (2R)-2-(4-Fluorophenoxy)isopropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     (2S)-2-(4-Fluorophenoxy)isopropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and
 a pharmaceutically acceptable salt of any of the foregoing. 
 
   
   
       55 . The method of  claim 46 , wherein the compound of Formula (I) is selected from: 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-(4-Fluorophenoxy)propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-Phenoxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and
 a pharmaceutically acceptable salt of any of the foregoing. 
 
   
   
       56 . The method of  claim 46 , wherein the compound of Formula (I) when administered to a patient exhibits a colonic bioavailability of levodopa that is at least 2-fold greater than the colonic bioavailability of levodopa when levodopa is administered to the patient. 
   
   
       57 . The method of  claim 46 , comprising administering a decarboxylase inhibitor, a catechol O-methyltransferase inhibitor, or a combination thereof. 
   
   
       58 . The method of  claim 46 , comprising administering the compound of Formula (I) as a pharmaceutical composition formulated for oral administration. 
   
   
       59 . The method of  claim 58 , wherein the pharmaceutical composition is a sustained release formulation. 
   
   
       60 . A method of treating disease selected from depression, attention deficit disorder, schizophrenia, manic depression, cognitive impairment disorders, restless legs syndrome, periodic limb movement disorders, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, congestive heart failure, and excessive daytime sleepiness, in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I): 
     
       
         
         
             
             
         
       
       a stereoisomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein 
       n is an integer from 1 to 6; 
       each R 1  and R 2  is independently selected from hydrogen, alkenyl, alkynyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or optionally, when n is 1, then R 1  and R 2  together with the carbon atom to which R 1  and R 2  are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; 
       R 3  and R 4  are independently selected from hydrogen, —C(O)OR 7 , C(O)R 7 , and —(CR 8 R 9 )OC(O)R 10 ; 
       R 5  is selected from alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
       R 7  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
       R 8  and R 9  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl or optionally, R 8  and R 9  together with the carbon atom to which R 8  and R 9  are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
       R 10  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 
       wherein each substituent group is independently selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy; 
       with the provisos that:
 when n is 2, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not methyl or phenyl; 
 when n is 3, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not methyl; and 
 
       when n is an integer from 1 to 6, and R 1 , R 2 , R 3  and R 4  are hydrogen, then R 5  is not benzyl. 
     
   
   
       61 . The method of  claim 60 , wherein R 5  is selected from C 5-8  aryl, and substituted C 5-8 aryl substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
   
   
       62 . The method of  claim 60  wherein R 5  is selected from phenyl and pyridyl, which are optionally substituted with halo, —CN, —OH, C 1-4 alkyl, and C 1-4  alkoxy. 
   
   
       63 . The method of  claim 60 , wherein each R 1  and R 2  is independently selected from hydrogen and substituted C 1-4  alkyl. 
   
   
       64 . The method of  claim 60 , wherein each R 1  and R 2  is hydrogen. 
   
   
       65 . The method of  claim 60 , wherein R 3  and R 4  are independently selected from hydrogen, —C(O)OR 7 , and —C(O)R 7 . 
   
   
       66 . The method of  claim 65 , wherein R 7  is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and benzyl; where the aryl ring of the benzyl group is optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
   
   
       67 . The method of  claim 60 , wherein R 5  is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, and styryl; where the aryl ring of the benzyl or styryl group is optionally substituted with one or more substituents are selected from halo, —CN, —NO 2 , —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
   
   
       68 . The method of  claim 60 , wherein the compound of Formula (I) is selected from: 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Chlorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Methylpbenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Methoxyphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Butylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-tert-Butylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Isopropylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Ethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-diethoxycarbonyloxyphenyl)propanoate; 
     3-Phenoxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-(4-Fluorophenoxy)propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     (2R)-2-(4-Fluorophenoxy)isopropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;
 (2S)-2-(4-Fluorophenoxy)isopropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and 
 a pharmaceutically acceptable salt of any of the foregoing. 
 
   
   
       69 . The method of  claim 60 , wherein the compound of Formula (I) is selected from: 
     2-(4-Fluorophenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(2,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     2-(3,4-Dimethylphenoxy)ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-(4-Fluorophenoxy)propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; 
     3-Phenoxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and
 a pharmaceutically acceptable salt of any of the foregoing. 
 
   
   
       70 . The method of  claim 60 , wherein the compound of Formula (I) when administered to a patient exhibits a colonic bioavailability of levodopa that is at least 2-fold greater than the colonic bioavailability of levodopa when levodopa is administered to the patient. 
   
   
       71 . The method of  claim 60 , comprising administering a decarboxylase inhibitor, a catechol O-methyltransferase inhibitor, or a combination thereof. 
   
   
       72 . The method of  claim 60 , comprising administering the compound of Formula (I) as a pharmaceutical composition formulated for oral administration. 
   
   
       73 . The method of  claim 72 , wherein the pharmaceutical composition is a sustained release formulation.