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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What is 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 Q is--X--CO--; X is selected from--O--, and--NH--; n is an integer from 2 to 4; each R1 an
What is 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 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, 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; R3 and R4 are independently selected from hydrogen,--C(O)OR7,--C(O)R7, and--(CR8R9)OC(O)R10; 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, and substituted heteroarylalkyl; and when Q is--X--CO--, R5 is further selected from alkoxy, substituted alkoxy, cycloalkoxy, and substituted cycloalkoxy; 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; with the proviso that the compound of Formula (I) is not derived from 1,3-dihexadecanoylpropane-1,2,3-triol. 2. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen and phenyl, wherein the phenyl group is optionally substituted with one or more substituents selected from halo,--CN,--NO2,--OH, C1-6 alkyl, and C1-6 alkoxy. 3. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen,--OH, C1-4 alkyl, and substituted C1-4 alkyl. 4. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen,--OH, C1-3 alkyl, and substituted C1-3 alkyl. 5. A compound according to claim 1, wherein each R1 and R2 is hydrogen. 6. A compound according to claim 1, wherein R5 is selected from alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, arylalkanyl, substituted arylalkanyl, arylalkanyl, substituted arylalkenyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 7. 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, wherein the aryl ring of the benzyl or styryl group is optionally substituted with one or more substituents selected from halo,--CN,--NO2,--OH, C1-6 alkyl, and C1-6 alkoxy. 8. A compound according to claim 1, wherein R5 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 9. 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. 10. A compound according to claim 1, wherein R5 is selected from phenyl and pyridyl which are optionally substituted with halo,--OH, C1-3 alkyl, and C1-3 alkoxy. 11. A compound according to claim 1, wherein X is--O--. 12. A compound according to claim 1, wherein X is--NH--. 13. A compound according to claim 1, wherein R3 and are independently selected from hydrogen,--C(O)OR7, and--C(O)R7. 14. A compound according to claim 13, wherein R7 is selected from alkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 15. A compound according to claim 13, 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. 16. A compound according to claim 13, wherein R7 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 17. A compound according to claim 13, wherein R7 is selected from C5-8 aryl, C5-8 substituted aryl, heteroaryl, substituted heteroaryl, C6-10 arylalkyl, and substituted C6-10 arylalkyl. 18. A compound according to claim 13, 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. 19. A compound according to claim 1, wherein R3 and R4 are independently selected from hydrogen and--(CR8R9)OC(O)R10. 20. A compound according to claim 19, 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. 21. A compound according to claim 19, 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. 22. A compound according to claim 1, wherein the compound has the structure of Formula (II): 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 2 to 4; R1 is selected from hydrogen, a straight chain C1-3 alkyl, and a branched C1-3 alkyl; and R5 is selected from phenyl, and substituted phenyl wherein one or more of the substituents is selected from halo,--CN,--NO2,--OH, C1-6 alkyl, and C1-6 alkoxy. 23. A compound according to claim 22, wherein the compound has the structure: wherein R11 is selected from hydrogen, halo,--CN,--NO2,--OH, C1-6 alkyl, and C1-6 alkoxy. 24. A compound according to claim 22, wherein the compound has the structure: wherein R11 is selected from hydrogen, halo,--CN,--NO2,--OH, C1-6 alkyl, and C1-6 alkoxy. 25. A compound according to claim 1, wherein the compound 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; 2-Acetyloxyethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; (2R)-2-Phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; (2S)-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; 2-Hydroxy-3-phenylcarbonyloxypropyl (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; and 2(S)-(2-Methyl-5-pyridylcarbonyloxy)propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and pharmaceutically acceptable salts thereof. 26. A compound according to claim 1, wherein the compound 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; 2-Hydroxy-3-phenylcarbonyloxypropyl (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; and pharmaceutically acceptable salts thereof. 27. The compound of claim 25 or 26, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 28. 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. 29. A pharmaceutical composition according to claim 28, further comprising at least one decarboxylase inhibitor. 30. A pharmaceutical composition according to claim 29, wherein the at least one decarboxylase inhibitor is selected from carbidopa, a carbidopa prodrug, benserazide, and a benserazide prodrug. 31. A pharmaceutical composition according to claim 28, further comprising at least one catechol O-methyltransferase inhibitor. 32. A pharmaceutical composition according to claim 31, wherein the at least one catechol O-methyltransferase inhibitor is selected from entacapone, an entacapone prodrug, tolcapone, and a tolcapone prodrug. 33. A pharmaceutical composition according to claim 28, wherein the pharmaceutical composition is formulated for oral administration. 34. A pharmaceutical composition according to claim 28, wherein the pharmaceutical composition is a sustained release formulation. 35. A pharmaceutical composition according to claim 28, wherein the at least one compound is present in an amount effective for the treatment in a patient of Parkinson's disease. 36. A pharmaceutical composition according to claim 28, wherein the at least one compound 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, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive disorders, congestive heart failure, and excessive daytime sleepiness. 37. 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 acheived when levodopa is administered in the colon of the patient. 38. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, halo, heteroalkanyl, substituted heteroalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 39. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cylohexyl, and benzyl. 40. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 41. A compound according to claim 1, wherein each R1 and R2 is independently selected from hydrogen,--OH, C1-6 alkyl, and substituted C1-6 alkyl. 42. A compound of claim 22, wherein the compound 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; a pharmaceutically acceptable salt of any of the foregoing, and a combination of any of the foregoing. 43. A compound of claim 22, wherein the compound is selected from: (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; a pharmaceutically acceptable salt of any of the foregoing, and a combination of any of the foregoing. 44. The compound of any one of claims 42 and 43, wherein the pharmaceutically acceptable salt is selected from the hydrochloride salt. 45. The compound of any one of claims 23 and 24, wherein R11 is selected from monosubstituted fluoro, chloro, bromo, methyl, and methoxy.
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