초록 ▼

Acyloxyalkyl carbamate prodrugs of trans-4-(aminomethyl)-cyclohexanecarboxylic acid, pharmaceutical compositions thereof, methods of making prodrugs of trans-4-(aminomethyl)-cyclohexane-carboxylic acid, and methods of using prodrugs of trans-4-(aminomethyl)-cyclohexanecarboxylic acid and pharmaceuti

Acyloxyalkyl carbamate prodrugs of trans-4-(aminomethyl)-cyclohexanecarboxylic acid, pharmaceutical compositions thereof, methods of making prodrugs of trans-4-(aminomethyl)-cyclohexane-carboxylic acid, and methods of using prodrugs of trans-4-(aminomethyl)-cyclohexanecarboxylic acid and pharmaceutical compositions thereof to treat or prevent various diseases or disorders are disclosed. Acyloxyalkyl carbamate prodrugs of trans-4-(aminomethyl)-cyclohexanecarboxylic acid and pharmaceutical compositions thereof suitable for oral and topical administration and for administration using sustained release dosage forms are also disclosed.

대표청구항 ▼

What is claimed is: 1. A compound of Formula (I): a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is selected 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, or a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is selected 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 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, 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; and R4 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, substituted aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, trialkylsilyl, and substituted trialkylsilyl. 2. The compound of claim 1, wherein R1 is selected from C1-6 alkyl, substituted C1-6 alkyl, C6-10 aryl, substituted C6-10 aryl, C3-7 cycloalkyl, substituted C3-7 cycloalkyl, C7-16 arylalkyl, and C7-16 substituted arylalkyl. 3. The compound of claim 1, wherein R1 is selected from C1-4 alkyl, substituted C1-4 alkyl, phenyl, substituted phenyl, cyclohexyl, and substituted cyclohexyl. 4. The compound of claim 1, wherein at least one of R1, R2, R3, and R4 is substituted with at least one substituent group selected from at least one of C1-3 alkyl,--OH,--NH2,--SH, C1-3 alkoxy, C1-3 acyl, C1-3 thioalkyl, C1-3 alkoxycarbonyl, C1-3 alkylamino, and C1-3 dialkylamino. 5. The compound of claim 1, wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, and cyclohexyl. 6. The compound of claim 1, wherein R4 is selected from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C3-7 cycloalkyl, substituted C3-7 cycloalkyl, C6-10 aryl, substituted C6-10 aryl, C7-16 arylalkyl, substituted C7-16 arylalkyl, C3-12 trialkylsilyl, and C7-14 aryldialkylsilyl. 7. The compound of claim 1, wherein R4 is selected from hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and phenyldimethylsilyl. 8. The compound of claim 1, wherein R4 is selected from hydrogen, allyl, benzyl, and trimethylsilyl. 9. The compound of claim 1, wherein R4 is hydrogen. 10. The compound of claim 1, wherein R2 and R3 are independently selected from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C6-10 aryl, substituted C6-10 aryl, C3-7 cycloalkyl, and substituted C3-7 cycloalkyl. 11. The compound of claim 1, wherein R2 and R3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl. 12. The compound of claim 1, wherein R2 is hydrogen, and R3 is selected from methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl. 13. The compound of claim 1, wherein R1 is selected from C1-6 alkyl, substituted C1-6 alkyl, C6-10 aryl, substituted C6-10 aryl, C3-7 cycloalkyl, substituted C3-7 cycloalkyl, C7-16 arylalkyl, and C7-16 substituted arylalkyl, and R2 and R3 are independently selected from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C6-10 aryl, substituted C6-10 aryl, C3-7 cycloalkyl, and substituted C3-7 cycloalkyl. 14. The compound of claim 1, wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, o-tolyl, and cyclohexyl, R2 is hydrogen, and R3 is selected from methyl, ethyl, n-propyl, isopropyl, phenyl, and cyclohexyl. 15. The compound of claim 14, wherein R4 is hydrogen. 16. The compound of claim 1, wherein the compound is selected from: trans-4-{[(2-methylpropanoyloxy)methoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[(2,2-dimethylpropanoyloxy)methoxycarbonyl]-aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[(3-methylbutanoyloxy)methoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[(benzoyloxy)methoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylpropanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylpropanoyloxy)propoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylpropanoyloxy)-2-methylpropoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(benzoyloxy)-2-methylpropoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(cyclohexylcarbonyloxy)-2-methylpropoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(pentanoyloxy)-2-methylpropoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(propanoyloxy)-2-methylpropoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(butanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(pentanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(3-methylbutanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(cyclohexylcarbonyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(benzoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylbenzoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(butanoyloxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylpropanoyloxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(3-methylbutanoyloxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2,2-dimethylpropanoyloxy)butoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(benzoyloxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(propanoyloxy)propoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(butanoyloxy)propoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2,2-dimethylpropanoyloxy)propoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(benzoyloxy)propoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(butanoyloxy)-2-methylpropoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(butanoyloxy)-1-cyclohexylmethoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2-methylpropanoyloxy)-1-cyclohexylmethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(acetoxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(propanoyloxy)butoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(acetoxy)-2-methylpropoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(3-methylbutanoyloxy)-2-methylpropoxycarbonyl] aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(2,2-dimethylpropanoyloxy)-2-methylpropoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; trans-4-{[1-(acetoxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; and trans-4-{[1-(propanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid; pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of any of the foregoing. 17. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) according to claim 1 and a pharmaceutically acceptable vehicle. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an oral formulation. 19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a topical formulation. 20. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a sustained release formulation. 21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is a sustained release oral formulation. 22. The pharmaceutical composition of claim 17, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of a pathology selected from excessive bleeding, a skin disease, a skin disorder, and tumor metastasis. 23. The pharmaceutical composition of claim 22, further comprising at least one cytotoxic agent. 24. A compound of Formula (I): a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any of the foregoing, wherein: R1 is selected from C1-4 alkyl, phenyl, o-tolyl, and cyclohexyl; R2 is hydrogen; R3 is selected from C1-3 alkyl, phenyl, and cyclohexyl; and R4 is selected from hydrogen, C1-4 alkyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and phenyldimethylsilyl. 25. The compound of claim 24, wherein: R1 is selected from isopropyl, isobutyl, and phenyl; R3 is selected from methyl and isopropyl; and R4 is hydrogen. 26. A compound of Formula (I): a stereoisomer thereof, a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable solvate of any of the foregoing, wherein R1is isopropyl; one of R2 and R3 is hydrogen and the other of R2 and R3 is methyl; and R4 is hydrogen. 27. The compound of claim 26, wherein the compound is selected from: (+)-trans-4-({[(1S)-1-(2-methylpropanoyloxy)ethoxy] carbonylamino}methyl)-cyclohexanecarboxylic acid; and (-)-trans-4-({[(1R)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid. 28. The compound of claim 26, wherein the compound is selected from: sodium trans-4-{[1-(2-methylpropanoyloxy)ethoxycarbonyl]-aminomethyl}-cyclohexanecarboxylate; sodium trans-4-({[(1S)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylate; and sodium trans-4-({[(1R)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylate. 29. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) according to claim 24, and a pharmaceutically acceptable vehicle. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is an oral formulation. 31. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a topical formulation. 32. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a sustained release formulation. 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is a sustained release oral formulation. 34. The pharmaceutical composition of claim 29, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of a pathology selected from excessive bleeding, a skin disease, a skin disorder, and tumor metastasis. 35. The pharmaceutical composition of claim 29, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive bleeding. 36. The pharmaceutical composition of claim 35, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive menstrual bleeding. 37. The pharmaceutical composition of claim 34, further comprising at least one cytotoxic agent. 38. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) according to claim 26, and a pharmaceutically acceptable vehicle. 39. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition is an oral formulation. 40. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition is a topical formulation. 41. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition is a sustained release formulation. 42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition is a sustained release oral formulation. 43. The pharmaceutical composition of claim 38, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of a pathology selected from excessive bleeding, a skin disease, a skin disorder, and tumor metastasis. 44. The pharmaceutical composition of claim 38, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive bleeding. 45. The pharmaceutical composition of claim 44, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive menstrual bleeding. 46. The pharmaceutical composition of claim 43, further comprising at least one cytotoxic agent. 47. The pharmaceutical composition of claim 17, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive bleeding. 48. The pharmaceutical composition of claim 47, wherein the at least one compound of Formula (I) is present in an amount effective for the treatment in a patient of excessive menstrual bleeding.