Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof, pharmaceutical compositions comprising acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof, methods of making prodrugs
Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof, pharmaceutical compositions comprising acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof, methods of making prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof, methods of using prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof and pharmaceutical compositions thereof for treating or preventing diseases or disorders such as spasticity or gastroesophageal reflux disease are disclosed. Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, and analogs thereof and sustained release oral dosage forms thereof, which are suitable for oral administration, are also disclosed.
대표청구항▼
What is claimed is: 1. A compound of Formula (I): stereoisomers thereof, pharmaceutically acceptable salts of thereof, a pharmaceutically acceptable solvate of thereof, and combinations thereof wherein: R1 is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
What is claimed is: 1. A compound of Formula (I): stereoisomers thereof, pharmaceutically acceptable salts of thereof, a pharmaceutically acceptable solvate of thereof, and combinations thereof wherein: R1 is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl; R2 and R3 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, and substituted cycloalkyl, or, R2 and R3 together with the carbon atom to which they are bonded form a cycloalkyl or substituted cycloalkyl ring; R4 is selected from hydrogen, methyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R5 is selected 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 are independently selected from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl, and substituted C7-9 phenylalkyl; and R8 is selected 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 R4 is selected from hydrogen and methyl. 3. The compound of claim 1, wherein R5 is selected from hydrogen, hydroxy, fluoro, oxo, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, cyclohexyl, and benzyl. 4. The compound of claim 1, wherein each of R6, R7, and R8 is hydrogen. 5. The compound of claim 1, wherein R4 is methyl, R5 is selected from hydrogen, hydroxy, fluoro, oxo, and 4-chlorophenyl, and each of R6, R7, and R8 is hydrogen. 6. The compound of claim 1 wherein R1 is selected from C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, phenyl, substituted phenyl, and C7-9 phenylalkyl. 7. The compound of claim 1, wherein R1 is selected 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, and cyclohexyl. 8. The compound of claim 1, wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, and cyclohexyl. 9. The compound of claim 1, wherein R2 and R3 are independently selected from hydrogen, C1-4 alkyl, substituted C1-4 alkyl, C1-4 alkoxycarbonyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6 cycloalkoxycarbonyl, phenyl, substituted phenyl, and C7-9 phenylalkyl. 10. The compound of claim 1, wherein R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, and phenethyl, and R3 hydrogen. 11. The compound of claim 1, wherein R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, and R3 is hydrogen. 12. The compound of claim 1, wherein R2 is selected from methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and cyclohexyloxycarbonyl, and R3 methyl. 13. The compound of claim 5, wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, and cyclohexyl, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl, and R3 is hydrogen. 14. The compound of claim 5, wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, and cyclohexyl, R2 is selected from hydrogen, methyl, n-propyl, and isopropyl, and R3 is hydrogen. 15. The compound of claim 5, wherein R1 is isopropyl, R2 is isopropyl, and R3 is hydrogen. 16. The compound of claim 1, wherein the compound is selected from: 3-{[1-isobutanoyloxyethoxy]carbonylamino}propyl methylphosphinic acid; 3-{[1-cyclohexanoyloxyethoxy]carbonylamino}propyl methylphosphinic acid; 3-{[isobutanoyloxymethoxy]carbonylamino}propyl methylphosphinic acid; 3-{[1-isobutanoyloxyethoxy]carbonylamino}-(2S )-hydroxypropyl methylphosphinic acid; 3-{[1-isobutanoyloxyisobutoxy]carbonylamino}propyl methylphosphinic acid; 3-{[benzoyloxymethoxy]carbonylamino}propyl methylphosphinic acid; 3-{[1-isobutanoyloxyisobutoxy]carbonylamino}-(2S )-hydroxypropyl methylphosphinic acid; pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof. 17. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable vehicle. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a sustained release oral dosage formulation. 19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is orally administered to a patient. 20. The pharmaceutical composition of claim 17, which following oral administration to a patient provides a compound of Formula (II) in the systemic circulation of a patient: wherein: R4 is selected from hydrogen, methyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R5 is selected 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 are independently selected from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, aryl, substituted aryl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, heteroaryl, substituted heteroaryl, C7-9 phenylalkyl and substituted C7-9 phenylalkyl; and R8 is selected 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. 21. The pharmaceutical composition of claim 17, which following administration to a patient provides a compound in the systemic circulation of the patient selected from: 3-aminopropylphosphonous acid; (3-amino-2-(4-chlorophenyl)propyl)phosphonous acid; (3-amino-2-hydroxypropyl)phosphonous acid; (2S )-(3-amino-2-hydroxypropyl)phosphonous acid; (2R)-(3-amino-2-hydroxypropyl)phosphonous acid; (3-amino-2-fluoropropyl)phosphonous acid; (2S )-(3-amino-2-fluoropropyl)phosphonous acid; (2R)-(3-amino-2-fluoropropyl)phosphonous acid; (3-amino-2-oxopropyl)phosphonous acid; (3-amino-(2S )-(4-chlorophenyl)propyl)phosphonous acid; (3-amino-(2R)-(4-chlorophenyl)propyl)phosphonous acid; 3-aminopropylmethylphosphinic acid; (3-amino-2-(4-chlorophenyl)propyl)methylphosphinic acid; (3-amino-2-hydroxypropyl)methylphosphinic acid; (2S )-(3-amino-2-hydroxypropyl)methylphosphinic acid; (2R)-(3-amino-2-hydroxypropyl)methylphosphinic acid; (3-amino-2-fluoropropyl)methylphosphinic acid; (2S )-(3-amino-2-fluoropropyl)methylphosphinic acid; (2R)-(3-amino-2-fluoropropyl)methylphosphinic acid; (3-amino-2-oxopropyl)methylphosphinic acid; (3-amino-(2S )-(4-chlorophenyl)propyl)methylphosphinic acid; and (3-amino-(2R)-(4-chlorophenyl)propyl)methylphosphinic acid.
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