IP Library › Granted Patent US 8,163,958

Granted Patent B2

US 8,163,958 · App. 13/095,101 · Granted Apr 24, 2012

Levodopa prodrugs, and compositions and uses thereof

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Quick Facts

Patent No.: US 8,163,958
App. No.: 13/095,101
Granted: Apr 24, 2012
Kind: B2

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Abstract

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

Claims (88)

1. A method of synthesizing a compound of Formula (I):

a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of Formula (4a)

wherein P 1 is an amino protecting group, and P 2 and P 3 are each hydroxy protecting groups;

with an alcohol of Formula (5):

and

removing P 1 , P 2 , and P 3 to provide the compound of Formula (I); wherein:

Q is —X—CO—;

X is selected from —O— and —NH—;

n is an integer from 2 to 4;

each R 1 and R 2 is independently selected from hydrogen, —OH, alkyl, 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; and

R 5 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, substituted heteroarylalkylalkoxy, substituted alkoxy, cycloalkoxy, and substituted cycloalkoxy;

with the proviso that the compound of Formula (I) is not

2. The method of claim 1 wherein P 1 is tert-butoxycarbonyl.

3. The method of claim 1 wherein P 2 and P 3 are benzyl.

4. The method of claim 1 , wherein:

each R 1 and R 2 is independently selected from hydrogen, —OH, C 1-4 alkyl, and substituted C 1-4 alkyl wherein the substituent group is —OH; and

R 5 is selected from hydrogen, C 1-4 alkyl, phenyl, substituted phenyl wherein each substituent group is independently selected from C 1-6 alkoxy, C 1-6 alkyl, halogen, and —OH; C 3-8 cycloalkyl, C 5-8 heteroaryl, and substituted C 5-8 heteroaryl wherein each substituent group is independently selected from C 1-6 alkyl and C 1-6 alkoxy.

5. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (II):

a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

n is an integer from 2 to 4;

each R 1 is independently selected from hydrogen, a straight chain C 1-3 alkyl, and a branched C 1-3 alkyl; and

R 5 is selected from phenyl and substituted phenyl wherein one or more of the substituent groups is selected from halo, —OH, C 1-6 alkyl, and C 1-6 alkoxy.

6. The method of claim 1 , wherein the compound of Formula (I) has the structure:

wherein R 11 is selected from hydrogen, halo, —OH, C 1-6 alkyl, and C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound of Formula (I) has the structure:

wherein R 11 is selected from hydrogen, halo, —OH, C 1-6 alkyl, and C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound of Formula (I) is selected from:

2-Phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2-(4-Fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

3-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

3-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate:

(2R)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(2R)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(2S)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1S)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1S,2S)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1R,2R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(1S,2S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

3-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

3-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

3-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(2R)-2-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

(2R)-2-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2-[(2-Hydroxyphenyl)carbonylamino]ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(R)-(3-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(S)-(3-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(R)-(4-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(S)-(4-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(R)-(2-Ethoxy-3-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(S)-(2-Ethoxy-3-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(R)-(2-Methyl-5-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;

2(S)-(2-Methyl-5-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and

pharmaceutically acceptable salts of any of the foregoing.

9. The method claim 1 , wherein the compound of Formula (I) is selected from: