Amino diols useful in the treatment of alzheimer's disease
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Abstract
The present invention relates to the treatment of Alzheimer'"'"'s disease and other similar diseases, and more specifically to the use of compounds that inhibit beta-secretase, an enzyme that cleaves amyloid precursor protein to produce A beta peptide, a major component of the amyloid plaques found in the brains of Alzheimer'"'"'s sufferers, in such methods.
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Citations
30 Claims
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11-12. -12. (canceled)
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14. 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, frontotemporal dementias with parkinsonism (FTDP), 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 at least one compound selected from the group consisting of formulas (I)-(X), and the pharmaceutically acceptable salts thereof:
Formula (I) - View Dependent Claims (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 15, 29)
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1. A method according to claim 14 where the disease is Alzheimer'"'"'s Disease.
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2. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (II).
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3. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (III).
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4. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (IV).
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5. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (V).
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6. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (VI).
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7. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (VII).
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8. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (VIII).
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9. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (IX).
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10. The method according to claim 1 comprising administering a compound, or pharmaceutically acceptable salt thereof, of formula (X).
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13. The method according to claim 1, further comprising the administration of a P-gp inhibitor, or a pharmaceutically acceptable salt thereof.
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15. The method according to claim 14, wherein the compound is selected from the group consisting of:
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O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-2-(R)-2-phenylethyl)-propionyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclo-hexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[2-(N-piperdino)ethyl}-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-N-[2-(N-piperdino)ethyl]-N-methylaminocarbonyl}-2-(R)-2-phenylethyl)-propionyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histindine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-(N-methyl-N-Boc-aminoethyl)-N-methylaminocarbonyl)-3-L-phenyllactyl-L-(im-tosyl)-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N-Boc-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxyhexynyl]amino]carbonyl]-3-butynyl]-N-4-[2-(dimethylamino)ethyl]-N-4-methyl-2S*-(phenylmethyl)butanediamide;
[1R*-[[[1R*-[[[1S,1*-(cyclohexylmethyl)-2S*,3R*-dihydroxyhexynyl]amino]carbonyl]-3-butynyl]amino]carbonyl]-2-phenylethyl)[2-(dimethylamino)ethyl]methylcarbamate;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N-4-[2-(2-(dimethylamino)ethyl]-N-4-[2-(dimethylamino)ethyl]-N4-methyl-2S*-(phenylmethyl)butanediamide;
[1R*-[[[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]amino]carbonyl]-2-phenylethyl)[2-(dimethylamino)ethyl]methylcarbamate;
[1R*-[[[1-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]amino]carbonyl]-2-phenylethyl)[2-(dimethylamino)ethyl]methylcarbamate;
[1R*-[[[1-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]amino]carbonyl]-2-phenylethyl][2-(dimethylamino)ethyl]methylcarbamate;
{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[4-(N-methyl-N-boc-amino)butyl-N-methyl-aminocarbonyl}-2-(R)-phenethylpropionyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-benzyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-benzyllactyl-□
-(R)-methyl-β
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-piperidino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-piperidino)ethyl]-N-methylaminocarbonyl}-2-(R)-(2-phenylethyl)-propionyl-□
(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[2-(N,N-dimethylamino)ethyl-N-methylamino-carbonyl}-2-R-benzyl-propionyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-isopropyl-aminocarbonyl}-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[4-(N-methylamino)butyl]-N-methyl-aminocarbonyl}-2-R-phenethyl-propionyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-N-methyl-N-boc-amino)ethyl)butyl]-N-methyl-aminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-methyl-N-boc-amino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3{N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl}-2-R-phenethylpropionyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane trifluoroacetate salt;
Boc-(im-Tosyl)-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(im-Tosyl)-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methyheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-(N-methyl-N-Boc-aminoethyl)-N-methylaminocarbonyl)-3-L-phenyllactic acid;
O-(N-(dimethylaminoethyl)-N-methyl-aminocarbonyl)-3-L-phenyllactic acid;
O-{N-2-(N,N-dimethylamino)ethyl}-N-methylaminocarbonyl)-2-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino-carbonyl-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N-methyl-N-Boc-amino)ethyl]-N-methyl-aminocarbonyl-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[N-[2-(N-methyl-N-Boc-amino)ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-24N,N-dimethylamino)ethyl]-N-isopropyl-aminocarbonyl-3-L-phenyl lactic acid;
3-{N-2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl□
-2-R-benzylpropionic acid hydrochloride salt;
3-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-2-R-benzylpropionyl-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)-1-(R,S)-methylethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[2-(N-methyl-N-2-(4-imidazole)ethylamino)ethyl]-N-methylaminocarbonyl}-2-R-benzylpropionyl-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N1-[2-[[1S,1R*-(cyclohexylmethyl-2S*,3R*-dihydroxy-5-hexynyl]amino]-2-oxo-1R*-(4-thiazolylmethyl)ethyl]-N-4-[2-(dimethylamino)ethyl]-N-4-methyl-2S*-(phenylmethyl)butanediamide;
[[[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino-2-oxo-1R*-(4-thiazolylmethyl)ethyl]amino]-2-oxo-1R*-(phenylmethyl)ethyl][2-(dimethylamino)ethyl]methylcarbamate;
N1-[1R*-[[[1S,1R*)-4-cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N-4-[2-(dimethyl-amino)ethyl]-N-4-methyl-2S*-(phenylmethyl)butanediamide;
[1R*-[[[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]amino]carbonyl]-2-phenylethyl)[2-dimethylamino)ethyl]methylcarbamate;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzenebutanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-2-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzofuran-2-carboxamide;
N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-2-acetamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino-]-2S*-methyl-3-oxopropyl]-N-methyl-benzenebutanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]cyclohexane-butanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-methyl-cyclohexanebutanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-methoxybenzenepropanamide;
N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-2-quinaldylamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-nalidixylamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-nalidixylamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-(R,S)-□
-methyl-hydrocinnamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]N-methyl-1H-indole-2-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-5-fluoro-1H-indole-3-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-5-fluoro-1H-indole-2-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-acetamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-propanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-7-methoxy-benzofuran-2-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methyhexyl]amino]-2S*-methyl-3-oxopropyl]4-oxo-4H-1-benzopyran-3-carboxamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]4-oxo-4H-1-benzopyran-2-carboxamide; and
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-7-chloro-benzofuran-2-carboxamide;
(3S,4S)-N-[(tert-Butyloxy)carbonyl]4-amino-3-acetoxy-5-phenylpentene;
(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(2S,3R)-Boc-L-Leucinamide of 2-amino-1-cyclohexyl-3,4-dihydroxybutane;
D,L-Monomethyl-2-(1-naphthylmethyl)succinate;
D,L-Methyl-3-(N-morpholinocarbonyl)-2-(1-naphthylmethyl) propionate;
D,L-3-(N-Morpholinocarbonyl)-2-(1-naphthylmethyl)propionic acid; and
3-(N-morpholinocarbonyl)-2-(R,S)-(1-naphthylmethyl)propionyl-L-leucinamide of (2S,3R)-2-amino-1-cyclohexyl-3,4-dihydroxybutane;
N-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-□
R*-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropanamide;
N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-□
-[[[2-(dimethylamino)ethyl]sulfonyl]methyl] benzenepropanamide;
N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cycloproylmethyl)-2-oxoethyl]-□
-[[[2-(dimethylamino)ethyl]thio]methyl]benzenepropanamide;
N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R (cyclopropylmethyl)-2-oxoethyl]-□
-[[[2-(diethylamino)ethyl]sulfonyl]methyl]benzenepropanamide;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-methyl-2S*-(phenylmethyl)-N4-[2-(1-piperidinyl)ethyl]butanediamide;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-[2-(1,3-dihydro-2H-isoindol-2-yl)ethyl]-N4-methyl-2S*-(phenylmethyl)butanediamide;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-methyl-2S*-(phenylmethyl)-N4-[2-(N-3-azabicyclo[3.2.2]nonanyl)ethyl]butanediamide;
(2S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)propionyl-L-propargylglycyl amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-methyl-N4-[2-(4-morpholinyl)ethyl]-2S*-(phenylmethyl)butanediamide;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-[2-(1H-imidazol-1-yl)ethyl]-N4-methyl-2S*-(phenylmethyl)butanediamide;
N1-[1R*-[[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-N4-methyl-2S*-(phenylmethyl)-N4-[2-(2-pyridinyl) ethyl]butanediamide;
O-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-ethoxyethyl)aminocarbonyl]-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-ethoxyethyl)aminocarbonyl]-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-homophenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-[N-methyl-N-(2-methyloxyethyl)aminocarbonyl]-3-L-homophenyllactyl-O-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-2-(R)-(2-phenylethyl)-propionyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(3S,4S)-N-[(tert-Butyloxy)carbonyl]4-amino-3-acetoxy-5-phenylpentene;
(2R, 3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
Boc-(im-Tosyl)-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(im-Tosyl)-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-methyl-2-methoxyethylaminocarbonyl)-3-L-phenyllactyl-L-histidine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-methyl-2-methoxyethylaminocarbonyl)-3-L-phenyllactyl-L-leucine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-methyl-2-methoxyethylaminocarbonyl)-3-L-phenyl lactic acid;
N-Boc-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
□
-(R)-Methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-methyl-2-methoxyethylaminocarbonyl)-3-L-phenyllactyl-□
-(R)-methyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3(N-methyl-2-methoxyethylaminocarbonyl)-2R-phenethyl propionic acid; and
3-[N-methyl-N-(2-ethoxyethyl)aminocarbonyl]-2-(R)-2-phenylethyl-□
-propionyl-□
-(R)-ethyl-□
-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(3S,4S)-N-[(tert-Butyloxy)carbonyl]4-amino-3-acetoxy-5-phenylpentene (2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal (2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane (2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane N-Boc-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (isomer A)N-Boc-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (isomer B)□
-Methyl□
□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (from isomer A)D,L-Monomethyl-2-(1-naphthylmethyl)-succinate D,L-Methyl-3-(N-morpholinocarbonyl)-2-(1-naphthylmethyl)-propionate D,L-3-(N-Morpholinocarbonyl)-2-(1-naphthylmethylpropionic acid 3-(N-morpholinocarbonyl)-(2R,S)2-(1-naphthylmethyl)-propionyl-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (from isomer A)□
-Methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (from isomer B)3-(N-morpholinocarbonyl)-2R,S)2-(1-naphthylmethyl)-propionyl-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (from isomer B)Methyl-D,L-3-aminoisobutyrate Boc-L-phenylalaninyl-D,L-□
-methyl-□
-alanine free acid(2S,3R)-N-Boc-2-amino-1-cyclohexyl-3,4-dihydroxybutane Boc-L-phenylalaninyl-D,L-□
-methyl-□
-alaninamide of (2S,3R)-2-amino-1-cylohexyl-3,4-dihydroxybutaneBoc-L-phenylalaninyl-D,L-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptaneMethyl-L-3-phenyl lactate O-(N-morpholinocarbonyl)-3-L-phenyl lactic acid O-(N-morpholinocarbonyl)-3-L-phenyllactyl-D,L-□
-methyl-□
-alanine free acidO-(N-morpholinocarbonyl)-3-L-phenyllactyl-D,L-□
-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptaneO-(N-morpholinocarbonyl)-3-L-phenyllactyl-□
-(R)-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane; and
O-(N-morpholinocarbonyl)-3-L-phenyllactyl-□
-(S)-methyl-□
-alaninamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(3S,4S)-N-[(tert-Butyloxy)carbonyl]4-amino-3-acetoxy-5-phenylpentene;
(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
L-Leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
ON-morpholinocarbonyl)-3-L-phenyllactyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-(N-morpholinocarbonyl)-3-L-phenyllactyl-L-leucine (2S,3R,4S)-N-Boc-2-amino-1-cyclohexyl-3,4-dihydroxypentane;
O-(N-morpholinocarbonyl)-3-L-phenyllactyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxypentane;
(2S,3R)-N-Boc-2-amino-1-cyclohexyl-3,4-dihydroxybutane;
O-(N-morpholinocarbonyl)-3-L-phenyllactyl-L-leucinamide of (2S,3R)-2-amino-1-cyclohexyl-3,4-dihydroxybutane;
Methyl L-3-phenyllactate;
O-(N-morpholinocarbonyl)-3-L-phenyllactic acid;
(2S,3R)-Boc-L-Leucinamide of 2-amino-1-cyclohexyl-3,4-dihydroxybutane;
D,L-Monomethyl-2-(1-naphthylmethyl)succinate;
D,L-Methyl 3-(N-morpholinocarbonyl)-2-(1-naphthylmethyl)propionate;
D,L-3-(N-Morpholinocarbonyl)-2-(1-naphthylmethyl)propionic acid; and
3-(N-morpholinocarbonyl)-2-(R,S)-(1-naphthylmethyl)propionyl-L-leucinamide of (2S,3R)-2-amino-1-cyclohexyl-3,4-dihydroxybutane;
O-{N-[2-[(N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl]-3-L-phenyllactyl-L-histidineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-□
-(R)-methyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-{N-[2-(N,N-dimethylamino}ethyl]-N-methylamino)-ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-methyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-iN-[2-N,N-dimethylamino)ethyl]-N-methylamino)-ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-□
-(R)-ethyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
3-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino)ethyl]-N-methylaminocarbonyl}-2-(R)-(2-phenylethyl-propionyl-□
-(R)-ethyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(3S,4S)-N-[(tert-Butyloxy)carbonyl]4-amino-3-acetoxy-5-phenylpentene;
(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane;
(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
L-Leucineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
Boc-(im-Tosyl)-L-histidineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
(im-Tosyl)-L-histidineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N-Boc-□
-(R)-methyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
□
-(R)-Methyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
O-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl]-3-L-phenyllactic acid; and
3{N-[2-{N-[2-(1-imidazole)ethyl]-N-methylamino}ethyl]-N-methylaminocarbonyl}-2-(R)-(2-phenylethyl)propionyl-□
-(R)-ethyl-□
-alanineamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-□
-1-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide;
N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-2-3-oxopropyl]-□
-[[(1,1-dimethylethyl)thio]methyl]benzenepropanamide;
N-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-2R*-methyl-3-[[1-oxo-3-(phenylsulfonyl)propyl]amino]propanamide;
N-[[1R*-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-□
-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide;
N-[[1R*-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]carbonyl]-3-butynyl]-□
R*-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide;
N-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-2R*-[[1-oxo-3-[phenylsulfonyl]propyl]amino]-4-pentynamide;
N-[2-[[l S,1R*-(cyclohexymethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]-1R-(cyclopropylmethyl)-2-oxoethyl]-□
R*-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide;
N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-□
R*-[[(2-methylpropyl)sulfonyl]methyl]benzenepropanamide;
N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-□
R*-[phenylsulfonyl)methyl]benzenepropanamide;
N-[[1R*-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]carbonyl]-3-butynyl]-□
R*-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide;
N-[[1R*-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]carbonyl]-3-butynyl]-□
R*-[[(2-methylpropyl)sulfonyl]methyl]benzenepropanamide;
N-[[1R*-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-hexynyl]amino]carbonyl]-3-butynyl]-α
R*-[(phenylsulfonyl)methyl]benzenepropanamide;
or a pharmaceutically acceptable salts thereof.
-
-
29. A method of treatment according to claim 14, 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.
-
1. A method according to claim 14 where the disease is Alzheimer'"'"'s Disease.
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16-17. -17. (canceled)
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18. A method for inhibiting beta-secretase activity, comprising contacting an effective amount for inhibition of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X):
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19. (canceled)
-
20. 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X):
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21-28. -28. (canceled)
-
30. (canceled)
Specification
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Current AssigneeGunnar J. Hanson, Heinrich J. Schostarez
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Original AssigneeGunnar J. Hanson, Heinrich J. Schostarez
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InventorsHanson, Gunnar J., Schostarez, Heinrich J.
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Application NumberUS10/496,091Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/616CPC Class CodesA61K 31/00 Medicinal preparations cont...A61K 31/13 Amines A61K31/04 takes prec...A61P 25/28 for treating neurodegenerat...A61P 43/00 Drugs for specific purposes...