IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
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출원번호 |
UP-0001618
(2007-12-11)
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등록번호 |
US-7671089
(2010-04-21)
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발명자
/ 주소 |
- Xiang, Jia-Ning
- Gallop, Mark A.
- Zhou, Cindy X.
- Nguyen, Mark
- Dai, Xuedong
- Li, Jianhua
- Cundy, Kenneth C.
- Jumbe, Nelson L.
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출원인 / 주소 |
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대리인 / 주소 |
Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
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인용정보 |
피인용 횟수 :
9 인용 특허 :
31 |
초록
Prodrugs of levodopa, methods of making prodrugs of levodopa, methods of using prodrugs of levodopa, and compositions of prodrugs of levodopa are disclosed.
대표청구항
▼
The invention claimed is: 1. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound of Formula (I) wherein the at least one compound of Formula (I) is present in an amount effective for the treatmen
The invention claimed is: 1. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound of Formula (I) wherein the at least one compound of Formula (I) is present in an amount effective for the treatment of a disease chosen from hypertension, tardive dyskinesia, and excessive daytime sleepiness: 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 R1 and R2 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 R1 and R2 together with the carbon atom to which R1 and R2 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R3 and R4 are independently selected from hydrogen, —C(O)OR7,—C(O)R7, and —(CR8R9)OC(O)R10; R5 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; R7 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; R8 and R9 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, R8 and R9 together with the carbon atom to which R8 and R9 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and R10 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, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy; with the provisos that when n is 2, and R1, R2, R3 and R4 are hydrogen, then R5 is not methyl or phenyl; when n is 3, and R1, R2, R3 and R4 are hydrogen, then R5 is not methyl; and when n is an integer from 1 to 6, and R1, R2, R3 and R4 are hydrogen, then R5 is not benzyl. 2. The pharmaceutical composition of claim 1, wherein R5 is selected from C5-8 aryl, and substituted C5-8 aryl substituted with one or more substituents selected from halo, —CN, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 3. The pharmaceutical composition of claim 1, wherein R5 is selected from phenyl and pyridyl, which are optionally substituted with halo, —CN, —OH, C1-4 alkyl, and C1-4 alkoxy. 4. The pharmaceutical composition of claim 1, wherein each R1 and R2 independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cylohexyl, and benzyl. 5. The pharmaceutical composition of claim 1, wherein each R1 and R2 is independently selected from hydrogen and phenyl, which is optionally substituted with one or more substituents selected from halo, —CN, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 6. The pharmaceutical composition of claim 1, wherein n is 1 and R1 and R2 together with the carbon atoms to which R1 and R2 are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. 7. The pharmaceutical composition of claim 1, wherein each R1 and R2 is independently selected from hydrogen and substituted C1-4 alkyl. 8. The pharmaceutical composition of claim 1, wherein each R1 and R2 is hydrogen. 9. The pharmaceutical composition of claim 1, wherein R3 and R4 are independently selected from hydrogen, —C(O)OR7, and —C(O)R7. 10. The pharmaceutical composition of claim 9, wherein R7 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, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 11. The pharmaceutical composition of claim 9, wherein R7 is selected from phenyl, pyridyl, furyl, and thienyl, the aromatic rings of which are optionally substituted with one or more substituents selected from halo, —CN, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 12. The pharmaceutical composition of claim 1, wherein R3 and R4 are independently selected from hydrogen, and —(CR8R9)OC(O)R10. 13. The pharmaceutical composition of claim 12, wherein R8 and R9 are independently selected from hydrogen, C1-16 alkyl, substituted C1-16 alkyl, C5-8 aryl, substituted C5-8 aryl, C6-10 arylalkyl, and substituted C6-10 arylalkyl. 14. The pharmaceutical composition of claim 12, wherein R8 and R9 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. 15. The pharmaceutical composition of claim 12, wherein R10 is selected from hydrogen, C1-10 alkyl, substituted C1-10 alkyl, C5-8 aryl, substituted C5-8 aryl, C1-15 alkoxy, and substituted C1-15 alkoxy. 16. The pharmaceutical composition of claim 12, wherein R10 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, where the aryl ring of the benzyl group is optionally substituted with one or more substituents selected from halo, —CN, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 17. The pharmaceutical composition of claim 1, wherein R5 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, —NO2, —OH, C1-6 alkyl, and C1-6 alkoxy. 18. The pharmaceutical composition of claim 1, 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 pharmaceutically acceptable salts of any of the foregoing. 19. The pharmaceutical composition of claim 1, 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 pharmaceutically acceptable salts of any of the foregoing. 20. The pharmaceutical composition of any one of claims 18 and 19, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 21. The pharmaceutical composition of claim 1, wherein the compound of Formula (I) when administered in the colon of a patient is taken up at a rate to achieve a bioavailability of levodopa at least 2-fold greater than the bioavailability of levodopa achieved when levodopa is administered in the colon of the patient. 22. The pharmaceutical composition of claim 1, further comprising at least one decarboxylase inhibitor. 23. The pharmaceutical composition of claim 1, further comprising at least one catechol 0-methyltransferase inhibitor. 24. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for oral administration. 25. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a sustained release formulation.
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