OXIME DERIVATIVE SUBSTITUTED HYDROXYETHYLAMINE ASPARTYL PROTEASE INHIBITORS
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Abstract
The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
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Citations
26 Claims
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1. A compound of formula (I),
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 21)
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2. The compound according to claim 1, wherein R1 is selected from —
- CH2-aryl, wherein the aryl ring is optionally substituted with at least one group independently selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, and —
OH.
- CH2-aryl, wherein the aryl ring is optionally substituted with at least one group independently selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, and —
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3. The compound according to claim 1, wherein R1 is selected from 3-allyloxy-5-fluoro-benzyl, 3-benzyloxy-5-fluoro-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, 3-propyl-thiophen-2-yl-methyl, 3,5-difluoro-2-propylamino-benzyl, 2-ethylamino-3,5-difluoro-benzyl, 2-hydroxy-5-methyl-benzamide, 3-fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-fluoro-5-heptyloxy-benzyl, and 3-fluoro-5-hexyloxy-benzyl, 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.
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4. The compound according to claim 1, wherein R2 is selected from hydrogen, 3-Allyl-5-benzyl-2-oxo-imidazolidin-1-yl, 6-Benzyl-3,3-dimethyl-2-oxo-piperazin-1-yl, 3-Allyl-5-benzyl-2-oxo-pyrrolidin-1-yl, 5-Benzyl-3-isobutyl-2-oxo-imidazolidin-1-yl, 3-Benzyl-5-methyl-1,1-dioxo-1λ
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6-([1,2,5]thiadiazolidin-2-yl, 3-Benzyl-1,1-dioxo-1λ
6-isothiazolidin-2-yl, 2-Benzyl-5-oxo-pyrrolidin-1-yl, 5-Benzyl-3-ethyl-2-oxo-pyrrolidin-1-yl, 3-Amino-5-benzyl-2-oxo-pyrrolidin-1-yl, 3-Acetylamino-5-benzyl-2-oxo-pyrrolidin-1-yl, 5-Benzyl-3-[1,3]dioxolan-4-ylmethyl-2-oxo-pyrrolidin-1-yl, 3-Benzyl-5-oxo-morpholin-4-yl, 2-Benzyl-6-oxo-piperazin-1-yl, 8-Benzyl-6-methyl-10-oxo-6,9-diaza-spiro[4.5]dec-9-yl, 5-Benzyl-3-furan-2-ylmethylene-2-oxo-pyrrolidin-1-yl, 3-acetylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-acetylamino-3-(cyclopropylmethyl)-2-oxo-pyrrolidin-1-yl, 3-(2-amino-5-carboxypentanoylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-(2-methoxy-acetylamino)-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-ethoxycarbonylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-ethylureido-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-hydroxypropionylamino-3-(sec-butyl)-2-oxo-pyrrolidin-1-yl, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
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6-([1,2,5]thiadiazolidin-2-yl, 3-Benzyl-1,1-dioxo-1λ
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5. The compound according to claim 1, wherein RC is selected from
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6. The compound according to claim 5, wherein A5 is selected from —
- C(═
N—
OH)—
, —
C(═
N—
O—
CH3)—
, —
C(═
N—
O—
CH2CH3)—
, —
C(═
N—
O—
CH2CH2OH)—
, —
C(═
N—
O—
CH2CH2NH2)—
, —
C(═
N—
NHCH3)—
, and —
C(═
N—
CN)—
, and A1, A2, A3, and A4 are —
CH2—
.
- C(═
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7. The compound according to claim 1, wherein RC is selected from 1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-(2-amino-ethoxyimino)-cyclohexyl, 5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexyl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-yl, 1-(Acrylic acid methyl ester)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(Acrylamide)-4-(tert-Butyl-phenyl)-cyclohexane-4-yl, 1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohex-1-yl, 1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohex-1-yl, 4-methoxyimino-1-(3-thiophen-3-yl-phenyl)-cyclohexyl, 1-(3-furan-3-yl-phenyl)-4-methoxyimino-cyclohexyl, 4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]-cyclohexyl, 4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrimidin-5-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexyl, 2-Acetyl-5-(3-tert-butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl, 1-(3-tert-Butyl-phenyl)-4-methylene-cyclohexyl, and ethyl 2-(4-(3-tert-butylphenyl)cyclohexylidene)acetate.
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8. The compound according to claim 1, wherein RX is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′
- -Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phen-1-yl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, 6-tert-Butyl-pyrimidin-4-yl, 3-pyridin-4-yl-phenyl, 3-pyrimidin-5-yl-phenyl, and 3-pyrazol-1-yl-phenyl.
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9. The compound according to claim 1, wherein RX is 3-tert-Butyl-phen-1-yl.
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10. The compound according to claim 1, wherein the formula (I) compound is selected from 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.
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21. A method of inhibiting production of A-beta, comprising:
- administering to a patient a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 1.
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2. The compound according to claim 1, wherein R1 is selected from —
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11. A method of preventing or treating at least one condition that benefits from inhibition of at least one aspartyl-protease, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I), - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26)
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12. The method according to claim 11, wherein the at least one compound of formula (I) is selected from 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3, -difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.
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13. A method of preventing or treating at least one condition associated with amyloidosis, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), or pharmaceutically acceptable salts thereof, wherein R1, R2 and Rc are as defined in claim 11.
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14. The method according to claim 11, wherein the aspartyl protease is beta-secretase and the condition is Alzheimer'"'"'s disease.
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15. The method according to claim 11, wherein the aspartyl protease is beta-secretase and the condition is dementia.
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16. A method of preventing or treating at least one condition associated with amyloidosis, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one selective beta-secretase inhibitor of formula (I), further comprising a composition including beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11.
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17. A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11.
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18. A method of affecting beta-secretase-mediated cleavage of amyloid precursor protein in a patient, comprising administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11.
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19. A method of inhibiting cleavage of amyloid precursor protein at a site between Met596 and Asp597 (numbered for the APP-695 amino acid isotype), or at a corresponding site of an isotype or mutant thereof, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11.
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20. A method of inhibiting cleavage of amyloid precursor protein or mutant thereof at a site between amino acids, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11, and wherein the site between amino acids corresponds to between Met652 and Asp653 (numbered for the APP-751 isotype);
between Met671 and Asp672 (numbered for the APP-770 isotype); between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation;
orbetween Leu671 and Asp672 of the APP-770 Swedish Mutation.
- administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and Rc are as defined in claim 11, and wherein the site between amino acids corresponds to between Met652 and Asp653 (numbered for the APP-751 isotype);
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22. A method of preventing, delaying, halting, or reversing a disease characterized by A-beta deposits or plaques, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and RC are as defined in claim 11.
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23. The method in claim 22, wherein the A-beta deposits or plaques are in a human brain.
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24. A method of interacting an inhibitor with beta-secretase, comprising:
- administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and RC are as defined in claim 11, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′
, and S2′
.
- administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt thereof, wherein R1, R2 and RC are as defined in claim 11, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′
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25. A method of modifying the pharmacokinetic parameters of a pharmaceutical composition comprising at least one compound of formula (I) wherein R1, R2 and RC are as defined in claim 11, further comprising increasing at least one parameter selected from Cmax, Tmax, and half-life.
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26. A method of treating a condition in a patient, comprising:
- administering a therapeutically effective amount of at least one compound of formula (I), or at least one pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R1, R2, and RC are defined as in claim 11.
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12. The method according to claim 11, wherein the at least one compound of formula (I) is selected from 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3, -difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-methylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-methyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-ethoxyimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethoxyimino)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[4-(2-Amino-ethoxyimino)-1-(3-tert-butyl-phenyl)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-2-hydroxyimino-hexahydro-pyrimidin-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-(dimethyl-hydrazono)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-cyanoimino-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoylmethylene-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, {4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-phenylcarbamoyl-butylamino]-cyclohexylidene}-acetic acid methyl ester, 4-[1-(3-tert-Butyl-phenyl)-4-(2-hydroxy-ethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(1H-imidazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-phenoxy)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[3-(3,5-difluoro-benzenesulfonyl)-2-hydroxy-propylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-4-oxo-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-pentylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-tetrazol-1-yl-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-butylamino]-cyclohexanone oxime, 4-(3-tert-Butyl-phenyl)-4-[4-(3,5-difluoro-phenyl)-2-hydroxy-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methylamino-cyclobut-3-ene-1,2-dione, 3-[3-[1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propylamino]-4-methoxy-cyclobut-3-ene-1,2-dione, 4-(3-tert-Butyl-phenyl)-4-[2-hydroxy-4-(3-propyl-thiophen-2-yl)-3-([1,2,4]thiadiazol-5-ylamino)-butylamino]-cyclohexanone oxime, 1-(5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol and 1-(5-(3-tert-butylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamino)-4-(3,5-difluorophenyl)butan-2-ol.
Specification
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Current AssigneeElan Pharmaceuticals Incorporated (Perrigo Company PLC)
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Original AssigneeElan Pharmaceuticals Incorporated (Perrigo Company PLC)
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InventorsAquino, Jose, Maillard, Michel, Jagodzinska, Barbara, Tung, Jay, Probst, Gary, John, Varghese
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Application NumberUS12/117,094Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/381CPC Class CodesA61P 25/28 for treating neurodegenerat...A61P 43/00 Drugs for specific purposes...C07C 233/36 having the carbon atom of t...C07C 237/20 the carbon skeleton contain...C07C 251/44 with the carbon atom of at ...C07C 251/54 of hydrocarbon radicals sub...C07C 251/84 having doubly-bound carbon ...C07C 255/42 the carbon skeleton being f...C07C 255/58 containing cyano groups and...C07C 2601/04 with a four-membered ringC07C 2601/14 The ring being saturatedC07D 213/40 Acylated substituent nitrog...C07D 231/12 with only hydrogen atoms, h...C07D 231/56 Benzopyrazoles; Hydrogenate...C07D 233/64 with substituted hydrocarbo...C07D 257/04 Five-membered ringsC07D 261/20 condensed with carbocyclic ...C07D 271/10 1,3,4-Oxadiazoles; Hydrogen...C07D 285/08 1,2,4-Thiadiazoles; Hydroge...C07D 335/06 Benzothiopyrans; Hydrogenat...C07D 405/10 : linked by a carbon chain co...