Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors

• US 7,385,085 B2
• Filed: 07/11/2005
• Issued: 06/10/2008
• Est. Priority Date: 07/09/2004
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Maillard, Michel, Jagodzinska, Barbara, Tung, Jay, Probst, Gary, John, Varghese, Aquino, Jose
• Primary Examiner(s): Eyler; Yvonne
• Assistant Examiner(s): CUTLIFF, YATE KAI RENE
• Application Number:
  US11/177,324
• Publication Number:
  US 20060135581A1
• Time in Patent Office: 1,065 Days
• Field of Search: None
• US Class Current: 564/185
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 251/54 of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 251/84 having doubly-bound carbon atoms of hydrazone groups being part of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 255/42 the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• CPC Class Codes: C07C 255/58 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 285/08 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings

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.

Claims

1. A compound of formula (I),

2. The compound according to claim 1, wherein R₁ is optionally substituted with at least one group independently selected from halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, and —

OH.

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-hydroxybenzyl, 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, 3-fluoro-5-hexyloxy-benzyl, 4-hydroxybenzyl, 3-hydroxy-benzyl, 3,5-difluoro-2-hydroxy-benzyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.

4. The compound according to claim 1, wherein R₂ is selected from hydrogen, 3-4-dioxo-cyclobut-1-enylamino, 2-methoxy-3-4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.

5. The compound according to claim 1, wherein R_C is selected from

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—

.

7. The compound according to claim 1, wherein R_C is selected from 1-(3-tert-Butyl-phenyl)-4-hydroxyimino-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-methoxyiminocyclohexyl, 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, 1-(3-tert-Butyl-phenyl)-4-(methyl-hydrazono)-cyclohexyl, 1-(3-tert-Butyl-phenyl)-4-cyanoiminocyclohexyl, 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-ylphenyl)-4-methoxyimino-cyclohexyl, 4-methoxyimino-1-[3-(1H-pyrrol-2-yl)-phenyl]cyclohexyl, 4-methoxyimino-1-(3-pyridin-4-yl-phenyl)-cyclohexyl, 4-methoxyimino-I-(3-pyrimidin-5-yl-phenyl)-cyclohexyl, 4-methoxyimino-1-(3-pyrazol-1-yl-phenyl)-cyclohexyl, 1-(3-tert-Butylphenyl)-4-methylene-cyclohexyl, and ethyl 2-(4-(3tert-butylphenyl)cyclohexylidene)acetate.

8. The compound according to claim 1, wherein R_x is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methylcyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′

-Acetylamino-biphenyl-3-yl, 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-isobutyl-phenyl, 3-isopropyl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 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-trifluoromethyl-phenyl, and 4-Acetyl-3-tert-butyl-phenyl.

9. The compound according to claim 1, wherein R_x is 3-tert-Butyl-phen-1-yl.

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-[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-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoyl methylene-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-hydroxyethylidene)-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-[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-[1-(3-tert-Butyl-phenyl)-4-methylcarbamoyl methylene-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-hydroxyethylidene)-cyclohexylamino]-2-(3,5-difluoro-benzyl)-3-hydroxy-N-phenyl-butyramide, 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-difluorophenoxy)-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, 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, and 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.