Levodopa prodrugs, and compositions and uses thereof
View Patent ↗Prodrugs of levodopa, methods of making prodrugs of levodopa, methods of using prodrugs of levodopa, and compositions of prodrugs of levodopa are disclosed.
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 R 1 and R 2 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 R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R 3 and R 4 are independently selected from hydrogen, —C(O)OR 7 , —C(O)R 7 , and —(CR 8 R 9 )OC(O)R 10 ;
R 5 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;
R 7 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;
R 8 and R 9 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, R 8 and R 9 together with the carbon atom to which R 8 and R 9 are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R 10 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, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy;
with the provisos that
when n is 2, and R 1 , R 2 , R 3 and R 4 are hydrogen, then R 5 is not methyl or phenyl;
when n is 3, and R 1 , R 2 , R 3 and R 4 are hydrogen, then R 5 is not methyl; and
when n is an integer from 1 to 6, and R 1 , R 2 , R 3 and R 4 are hydrogen, then R 5 is not benzyl.
2. A compound according to claim 1 , wherein R 5 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
3. A compound according to claim 1 , wherein R 5 is selected from C 5-8 aryl, and substituted C 5-8 aryl substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
4. A compound according to claim 1 , wherein R 5 is selected from phenyl and pyridyl, which are optionally substituted with halo, —CN, —OH, C 1-4 alkyl, and C 1-4 alkoxy.
5. A compound according to claim 1 , wherein n is 1, and R 1 and R 2 together with the carbon atoms to which R 1 and R 2 are attached form a cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl or substituted cycloheteroalkanyl ring.
6. A compound according to claim 1 , wherein n is 1 and R 1 and R 2 together with the carbon atoms to which R 1 and R 2 are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
7. A compound according to claim 1 , wherein each R 1 and R 2 is hydrogen.
8. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from hydrogen, —C(O)OR 7 , and —C(O)R 7 .
9. A compound according to claim 8 , wherein R 7 is selected from alkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl.
10. A compound according to claim 8 , wherein R 7 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, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
11. A compound according to claim 8 , wherein R 7 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
12. A compound according to claim 8 , wherein R 7 is selected from C 5-8 aryl, C 5-8 substituted aryl, heteroaryl, substituted heteroaryl, C 6-10 arylalkyl, and substituted C 6-10 arylalkyl.
13. A compound according to claim 8 , wherein R 7 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, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
14. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from hydrogen, and —(CR 8 R 9 )OC(O)R 10 .
15. A compound according to claim 14 , wherein R 8 and R 9 are independently selected from hydrogen, C 1-16 alkyl, substituted C 1-16 alkyl, C 5-8 aryl, substituted C 5-8 aryl, C 6-10 arylalkyl, and substituted C 6-10 arylalkyl.
16. A compound according to claim 14 , wherein R 8 and R 9 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
17. A compound according to claim 14 , wherein R 10 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, C 5-8 aryl, substituted C 5-8 aryl, C 1-15 alkoxy, and substituted C 1-5 alkoxy.
18. A compound according to claim 14 , wherein R 10 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, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
19. A compound according to claim 1 , wherein R 5 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 R 5 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, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 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 R 1 and R 2 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 R 1 and R 2 independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cylohexyl, and benzyl.
36. A compound according to claim 1 , wherein each R 1 and R 2 is independently selected from hydrogen, substituted alkanyl, arylalkanyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
37. A compound according to claim 1 , wherein each R 1 and R 2 is independently selected from hydrogen and phenyl, which is optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
38. A compound according to claim 1 , wherein each R 1 and R 2 is independently selected from hydrogen and substituted C 1-4 alkyl.