초록 ▼

Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, methods of making acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, methods of using acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, and pharma

Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, methods of making acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, methods of using acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, and pharmaceutical compositions comprising acyloxyalkyl carbamate prodrugs 3-aminopropylphosphinic acid and analogs thereof for treating diseases or disorders such as mild cognitive impairment, cognitive impairment associated with Alzheimer's disease Alzheimer's disease, depression, anxiety, and epilepsy are disclosed. Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphinic acid and analogs thereof, which are suitable for oral administration and sustained release oral dosage forms are also disclosed.

대표청구항 ▼

What is claimed is: 1. A compound of Formula (I): a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is chosen from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,

What is claimed is: 1. A compound of Formula (I): a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is chosen from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R2 and R3 is chosen from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or R2 and R3 together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; R4 is chosen from C2-6 alkyl and substituted C2-6 alkyl; R5 is chosen from hydrogen, hydroxy, mercapto, fluoro, oxo, C1-4 alkyl, substituted C1-4 alkyl, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl; R6 and R7 is chosen from hydrogen, C1-6 alkyl, C1-6 alkoxy, aryl, substituted aryl, C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl; and R8 is chosen from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl. 2. The compound of claim 1, wherein R1 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. 3. The compound of claim 1, wherein R1 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl, and 3-pyridyl. 4. The compound of claim 1, wherein R1 is chosen from propyl, isopropyl, tert-butyl, cyclohexyl, and phenyl. 5. The compound of claim 1, wherein R2 is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, and cyclohexyl, and R3 is hydrogen. 6. The compound of claim 1, wherein R2 is chosen from hydrogen, methyl, and isopropyl; and R3 is hydrogen. 7. The compound of claim 1, wherein R3 is hydrogen. 8. The compound of claim 1, wherein R4 is chosen from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, n-heptyl, allyl, 2-methylallyl, but-3-enyl, propargyl, but-2-ynyl, but-3-ynyl, pent-3-ynyl, 2-methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 1-hydroxyethyl, 1-hydroxybutyl, 1-hydroxyisobutyl, benzyl, 1-hydroxybenzyl, and diethoxymethyl. 9. The compound of claim 1, wherein R4 is chosen from ethyl and n-propyl, n-butyl. 10. The compound of claim 1, wherein R5 is chosen from hydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl. 11. The compound of claim 1, wherein R5 is chosen from hydrogen and hydroxy. 12. The compound of claim 1, wherein each of R6, R7, and R8 is hydrogen. 13. The compound of claim 1, wherein each of R6 and R7 is hydrogen, and R8 is chosen from 3,5-dichlorobenzyl, 1-(3-chlorophenyl)ethyl, 1-(3,4-dichlorophenyl)ethyl, 1-(3-chloro-4-iodophenyl)ethyl, 1-(4-chloro-3-iodophenyl)ethyl, 3,4-dimethylbenzyl, 1-(2,4-dimethoxyphenyl)ethyl, 1-(2,5-dimethoxyphenyl)ethyl, 1-(2,6-dimethoxyphenyl)ethyl, 1-(3,4-dimethoxyphenyl)ethyl, 1-(3,5-dimethoxyphenyl)ethyl, 1-(3,4,5-trimethoxyphenyl)ethyl, 3-carboxybenzyl, 3-cyanobenzyl, 4-carboxybenzyl, 4-cyanobenzyl, 1-(3-carboxyphenyl)ethyl, 1-(3-cyanophenyl)ethyl, 1-(4-carboxyphenyl)ethyl, 1-(4-cyanophenyl)ethyl, 3-phenylprop-2-yl, 2-(3,4-dichlorophenyl)propyl, 3-(3,4-dichlorophenyl)prop-2-yl, and 3-phenyl-3-hydroxyprop-2-yl. 14. The compound of claim 1, wherein each of R6 and R7 is hydrogen, and R8 is chosen from 1-(3,4-dichlorophenyl)ethyl, 1-(3-carboxyphenyl)ethyl, 1-(4-carboxyphenyl)ethyl, 3,5-dichlorobenzyl, 3-carboxybenzyl, and 4-carboxybenzyl. 15. The compound of claim 1, wherein R1 is chosen from propyl, isopropyl, tert-butyl, cyclohexyl, and phenyl; R2 is chosen from hydrogen, methyl, and isopropyl; R4 is n-butyl; and each of R3, R5, R6, R7, and R8 is hydrogen. 16. The compound of claim 1, wherein the compound is chosen from: 3-{[1-Isobutanoyloxyethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{-Isobutanoyloxyisobutoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}propyl(n-butyl)phosphinic acid; 3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-hydroxypropyl(n-butyl)phosphinic acid; 3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2R)-fluoropropyl (n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl (n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2R)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Isobutanoyloxyethoxy]carbonylamino}-(25)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Cyclohexanoyloxyethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(2S)-fluoropropyl(n-butyl)phosphinic acid; 3-{[1-Isobutanoyloxyethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[1-Butanoyloxyethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[1-Pivaloyloxyethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxyethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[Isobutanoyloxymethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[Butanoyloxymethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[Pivaloyloxymethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[Cyclohexanoyloxymethoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; 3-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-2-oxopropyl(n-butyl)phosphinic acid; and a pharmaceutically acceptable salt of any of the foregoing. 17. A pharmaceutical composition comprising a therapeutically effective amount of at least one pharmaceutically acceptable vehicle and at least one compound of Formula (I): a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is chosen from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted hetero alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R2 and R3 is chosen from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R2 and R3 together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; R4 is chosen from C2-6 alkyl and substituted C2-6 alkyl; R5 is chosen from hydrogen, hydroxy, mercapto, fluoro, oxo, C1-4 alkyl, substituted C1-4 alkyl, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl; R6 and R7 is chosen from hydrogen, C1-6 alkyl, C1-6 alkoxy, aryl, substituted aryl, C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl; and R8 is chosen from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl. 18. The pharmaceutical composition of claim 17, wherein the therapeutically effective amount is effective for treating a disease chosen from mild cognitive impairment, cognitive impairment associated with Alzheimer's disease, depression, anxiety, and epilepsy. 19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a sustained release oral formulation. 20. A method of treating a disease chosen from a mild cognitive impairment, cognitive impairment associated with Alzheimer's disease, depression, anxiety, and epilepsy in a patient comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 17. 21. The method of claim 20, wherein a therapeutically effective concentration of the corresponding 3-aminopropylphosphinic acid analog is maintained in the plasma of the patient for at least about 4 hours after the pharmaceutical composition is orally administered to the patient.