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 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 R1 and R2 is independently selected from hydrogen,

The invention claimed is: 1. A 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 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. A compound according to claim 1, wherein R5 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 3. A compound according to 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. 4. A compound according to 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. 5. A compound according to claim 1, wherein n is 1, and R1 and R2 together with the carbon atoms to which R1 and R2 are attached form a cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl or substituted cycloheteroalkanyl ring. 6. A compound according to 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. A compound according to claim 1, wherein each R1 and R2 is hydrogen. 8. A compound according to claim 1, wherein R3 and R4 are independently selected from hydrogen,--C(O)OR7, and--C(O)R7. 9. A compound according to claim 8, wherein R7 is selected from alkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 10. A compound according to claim 8, 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. A compound according to claim 8, wherein R7 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 12. A compound according to claim 8, wherein R7 is selected from C5-8 aryl, C5-8 substituted aryl, heteroaryl, substituted heteroaryl, C6-10 arylalkyl, and substituted C6-10 arylalkyl. 13. A compound according to claim 8, 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. 14. A compound according to claim 1, wherein R3 and R4 are independently selected from hydrogen, and--(CR8R9)OC(O)R10. 15. A compound according to claim 14, 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. 16. A compound according to claim 14, wherein R8 and R9 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. 17. A compound according to claim 14, 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 C1-5 alkoxy. 18. A compound according to claim 14, 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. 19. A compound according to claim 1, wherein R5 is selected from alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, arylalkanyl, substituted arylalkanyl, arylalkenyl, substituted arylalkenyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 20. A compound according to 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. 21. A compound according to claim 1 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 thereof. 22. A compound according to claim 1 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 thereof. 23. The compound of claim 21 or 22, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 24. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound of Formula (I) according to claim 1. 25. A pharmaceutical composition according to claim 24, further comprising at least one decarboxylase inhibitor. 26. A pharmaceutical composition according to claim 25, wherein the at least one decarboxylase inhibitor is selected from carbidopa, a carbidopa prodrug, benserazide, and a benserazide prodrug. 27. A pharmaceutical composition according to claim 24, further comprising at least one catechol O-methyltransferase inhibitor. 28. A pharmaceutical composition according to claim 27, wherein the at least one catechol O-methyltransferase inhibitor is selected from entacapone, and tolcapone. 29. A pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is formulated for oral administration. 30. A pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is a sustained release formulation. 31. A pharmaceutical composition according to claim 24, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of Parkinson's disease. 32. A pharmaceutical composition according to claim 24, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of a disease selected from depression, attention deficit disorder; schizophrenia, manic depression, cognitive impairment disorders, restless legs syndrome, periodic limb movement disorders, Huntington's disease, Tourette's syndrome, congestive heart failure. 33. A compound according to claim 1, which 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. 34. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen, substituted alkanyl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, halo, heteroalkanyl, substituted heteroalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 35. A compound according to claim 1, wherein each R1 and R2 independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cylohexyl, and benzyl. 36. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen, substituted alkanyl, arylalkanyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 37. A compound according to 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. 38. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen and substituted C1-4 alkyl.