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
Q is —X—CO—;
X is selected from —O—, and —NH—;
n is an integer from 2 to 4;
each R 1 and R 2 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;
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 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—, R 5 is further selected from alkoxy, substituted alkoxy, cycloalkoxy, and substituted cycloalkoxy;
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;
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 R 1 and R 2 is independently selected from hydrogen and phenyl, wherein the phenyl 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.
3. A compound according to claim 1 , wherein each R 1 and R 2 is independently selected from hydrogen, —OH, C 1-4 alkyl, and substituted C 1-4 alkyl.
4. A compound according to claim 1 , wherein each R 1 and R 2 is independently selected from hydrogen, —OH, C 1-3 alkyl, and substituted C 1-3 alkyl.
5. A compound according to claim 1 , wherein each R 1 and R 2 is hydrogen.
6. A compound according to claim 1 , wherein R 5 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 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, wherein the aryl ring of the benzyl or styryl 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.
8. A compound according to claim 1 , wherein R 5 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
9. 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.
10. A compound according to claim 1 , wherein R 5 is selected from phenyl and pyridyl which are optionally substituted with halo, —OH, C 1-3 alkyl, and C 1-3 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 R 3 and are independently selected from hydrogen, —C(O)OR 7 , and —C(O)R 7 .
14. A compound according to claim 13 , wherein R 7 is selected from alkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl.
15. A compound according to claim 13 , 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.
16. A compound according to claim 13 , wherein R 7 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
17. A compound according to claim 13 , 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.
18. A compound according to claim 13 , 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.
19. 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 .
20. A compound according to claim 19 , 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 1-15 alkoxy.
21. A compound according to claim 19 , 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.
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;
R 1 is selected from hydrogen, a straight chain C 1-3 alkyl, and a branched C 1-3 alkyl; and
R 5 is selected from phenyl, and substituted phenyl wherein one or more of the substituents is selected from halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
23. A compound according to claim 22 , wherein the compound has the structure:
wherein R 11 is selected from hydrogen, halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 alkoxy.
24. A compound according to claim 22 , wherein the compound has the structure:
wherein R 11 is selected from hydrogen, halo, —CN, —NO 2 , —OH, C 1-6 alkyl, and C 1-6 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 R 1 and R 2 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 R 1 and R 2 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 R 1 and R 2 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 R 1 and R 2 is independently selected from hydrogen, —OH, C 1-6 alkyl, and substituted C 1-6 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 R 11 is selected from monosubstituted fluoro, chloro, bromo, methyl, and methoxy.