Prodrugs of levodopa, methods of making prodrugs of levodopa, methods of using prodrugs of levodopa, and compositions of prodrugs of levodopa are disclosed.
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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 P1 is an amino protecting group, and P2 and P3 are each hydroxy protecting groups;with an alcoho
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 P1 is an amino protecting group, and P2 and P3 are each hydroxy protecting groups;with an alcohol of Formula (5): andremoving P1, P2, and P3 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 R1 and R2 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 R5 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 P1 is tert-butoxycarbonyl. 3. The method of claim 1 wherein P2 and P3 are benzyl. 4. The method of claim 1, wherein: each R1 and R2 is independently selected from hydrogen, —OH, C1-4 alkyl, and substituted C1-4 alkyl wherein the substituent group is —OH; andR5 is selected from hydrogen, C1-4 alkyl, phenyl, substituted phenyl wherein each substituent group is independently selected from C1-6 alkoxy, C1-6 alkyl, halogen, and —OH; C3-8 cycloalkyl, C5-8 heteroaryl, and substituted C5-8 heteroaryl wherein each substituent group is independently selected from C1-6 alkyl and C1-6 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 R1 is independently selected from hydrogen, a straight chain C1-3 alkyl, and a branched C1-3 alkyl; andR5 is selected from phenyl and substituted phenyl wherein one or more of the substituent groups is selected from halo, —OH, C1-6 alkyl, and C1-6 alkoxy. 6. The method of claim 1, wherein the compound of Formula (I) has the structure: orwherein R11 is selected from hydrogen, halo, —OH, C1-6 alkyl, and C1-6 alkoxy, or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the compound of Formula (I) has the structure: wherein R11 is selected from hydrogen, halo, —OH, C1-6 alkyl, and C1-6 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-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; andpharmaceutically acceptable salts of any of the foregoing. 9. The method claim 1, wherein the compound of Formula (I) is selected from: (2R)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2R)-2-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2R)-2-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;3-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;3-(4-Methoxyphenylcarbonyloxy)propyl(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-phenylcarbonyloxypropyl(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-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2S)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2R)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2S)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;2-Phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride; andpharmaceutically acceptable salts of any of the foregoing. 10. The method of claim 1, wherein the compound of Formula (I) is selected from: (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;(2S)-2-phenylcarbonyloxypropyl(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; anda pharmaceutically acceptable salt of any of the foregoing. 11. The method of claim 1, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 12. The method of claim 6, wherein R11 is selected from hydrogen, fluoro, hydroxyl, and methoxy. 13. The method of claim 7, wherein R11 is selected from hydrogen, fluoro, hydroxyl, and methoxy. 14. The method of claim 1, wherein the compound of Formula (I) is (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate or a pharmaceutically acceptable salt thereof.
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이 특허에 인용된 특허 (39)
Metcalf Brian W. (Strasbourg FRX) Jung Michel (Illkirch Graffenstaden FRX), a
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