Claims
- 1. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- 2. A method of treating Alzheimer's disease in a subject in need of such treatment comprising administering to the subject a compound disclosed in claim 1, or a pharmaceutically acceptable salt thereof.
- 3. A method of treating Alzheimer's disease by modulating the activity of beta amyloid converting enzyme, comprising administering to a subject in need of such treatment a compound disclosed in claim 1, or a pharmaceutically acceptable salt thereof.
- 4. The method according to claim 1, further comprising the administration of a P-gp inhibitor, or a pharmaceutically acceptable salt thereof.
- 5. A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down'syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:
- 6. The method according to claim 5 wherein the compound of formula (I) is selected from the group consisting of:
(i) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (ii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)amino-4-phenylbutyl]carbazate, (iii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (iv) t-butyl 3-isopropyl-3- [(3S) -2-oxo-3- (N-quinaldoyl-L-asparaginyl)amino-4-phenylbuty1]carbazate, (v) t-butyl 3-(1-methyl-3-phenylpropen-3-yl)-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (vi) t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (vii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (viii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-diazabicyclo[4.4.0]decane, (ix) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane (x) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-[N-(2-pyridyl)methoxycarbonyl)-L-valyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4:4.0]decane (xi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (xii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-glutaminyl)amino-4-phenylbutyl]-3,4odiazabicyclo[4.4.0]decane, (xiii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-threonyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (xiv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]hept-5-ene, (xv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-phenylmethoxycarbonyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane, (xvi) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-L-valyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1 ]heptane, (xvii) 2-[N-(1S)(2-methyl-1-methoxycarbonylpropyl) carbamoyl]-3-[(2R or S,3S)-2-hydroxy-3-[N-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane, (xviii) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane, (ixx) 1-[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine, (xx) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-1,2,3,4-tetrahydrophthalazine, (xxi) 1-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phyenylbutyl]-2-isopropyl hydrazine, (xxii) 1-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2-isoprolaylhydrazine, (xxiii) 1-(t-butylamino)carbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine, (xxiv) t-butyl 3-isopropyl-3-[(2R or S,38)-2-hydroxy-3-(N-picolinoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxv) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)methoxycarbonyl-anthraniloyl)amino-4-phenylbutyl]carbazate. (xxvi) t-butyl 3-benzyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (xxvii) t-butyl 3-benzyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxviii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino-4-phenylbutyl]carbazate, (xxix) t-butyl 3-cyclohexyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxx) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(1-carbamoylmethyl)acryloyl)amino-4-phenylbutyl]carbazate, (xxxi) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio-2-carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate, (xxxii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(1-benzoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxxiii) 1-t-butyloxycarbonyl-2-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahydropyridazine, (xxxiv) 1-t-butyloxycarbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]hexahydropyridazine, (xxxv) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-3-cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4,4,0]decane; or pharmaceutically acceptable salts thereof.
- 7. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a composition comprising one or more pharmaceutically acceptable carriers and a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- 8. (Canceled)
- 9. A method for inhibiting beta-secretase activity, comprising contacting an effective amount for inhibition of a compound of formula (I):
- 10. A method for inhibiting cleavage of an amyloid precursor protein (APP) isotype at a site in the APP isotype that is susceptible to cleavage, comprising contacting said APP isotype with an effective cleavage inhibitory amount of a compound of formula (I):
- 11. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound of formula (I):
- 12. The method of claim 11, wherein the cell is an animal cell.
- 13. The method of claim 12, wherein the animal cell is a mammalian cell.
- 14. The method of claim 13, wherein the mammalian cell is human.
- 15. A composition comprising beta-secretase complexed with a compound of formula (I):
- 16. A method for producing a beta-secretase complex comprising the composition of claim 15.
- 17. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibiting amount of a compound of formula (I):
- 18. The method of claim 17, wherein said animal is a human.
- 19. A method for treating or preventing a disease characterized by beta-amyloid deposits on or in the brain, comprising administering to a subject in need of such treatment or prevention an effective therapeutic amount of a compound of formula (I):
- 20. A method of treatment according to claim 5, further comprising administration of one or more therapeutic agents selected from the group consisting of an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, P-gp inhibitors, an A beta peptide, and an anti-A beta peptide.
- 21. (Canceled)
- 22. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof:
- 23. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (IB) or a pharmaceutically acceptable salt thereof:
- 24. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (IC) or a pharmaceutically acceptable salt thereof:
- 25. A method of treating or preventing Alzheimer's disease in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (ID) or a pharmaceutically acceptable salt thereof:
- 26. A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof:
- 27. A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (IB) or a pharmaceutically acceptable salt thereof:
- 28. A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (IC) or a pharmaceutically acceptable salt thereof:
- 29. A method of treating a subject who has, or in preventing a subject from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating subjects with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (ID) or a pharmaceutically acceptable salt thereof:
- 30. The method of claim 5, wherein the compound is of the formula B:
- 31. The method according to claim 30, wherein the compound is of the structure represented by formula (C) or (D):
- 32. The method according to claim 30, wherein the compound is selected from the group:
(i) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)amino-4-phenylbutyl]carbazate; (ii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]carbazate; (iii) t-butyl 3-isopropyl-3-[(3S)-2-oxo-3-(N-quinaldyl-L-asparaginyl)-amino-4-phenylbutyl]carbazate; (iv) t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]carbazate; and (v) 1-[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropyl-hydrazine; or pharmaceutically acceptable salts thereof.
- 33. The method according to claim 30, wherein said compound has the formula:
- 34. The method according to claim 30, wherein c of the formula is 0.
Parent Case Info
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/315,550, filed on Aug. 28, 2001.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US02/27408 |
8/28/2002 |
WO |
|
Provisional Applications (1)
|
Number |
Date |
Country |
|
60315550 |
Aug 2001 |
US |