Methods of treating amyloidosis using cyclopropyl derivative aspartyl protease inhibitors

• US 7,906,556 B2
• Filed: 10/12/2006
• Issued: 03/15/2011
• Est. Priority Date: 10/12/2005
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Neitz, R. Jeffrey, Truong, Anh, Tisdale, Eric, Jagodzinska, Barbara, Tung, Jay
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): NOLAN, JASON MICHAEL
• Application Number:
  US11/546,453
• Publication Number:
  US 20070149569A1
• Time in Patent Office: 1,615 Days
• Field of Search: 564/223, 546/226, 548/375.1, 548/255, 514/406, 514/620, 514/330, 514/423
• US Class Current: 514/620
• 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: 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 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/18 the ring system containing six carbon atoms
• CPC Class Codes: C07C 323/26 the carbon skeleton being saturated and containing rings
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• 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 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain
• CPC Class Codes: C07D 295/182 Radicals derived from carboxylic acids

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 selected from (IIa), (IIb), (IIc), (IId), and (IIe), wherein R₅₀, R_50a, and R_50b are independently selected from halogen, alkyl, 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-hydroxy-benzyl,3-propyl -thiophen-2-yl-methyl, 3,5-difluoro-2-propylamino-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, 2-ethylamino-3,5-difluoro-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, 2-Hydroxy-5-methyl-benzamide, 3,5-Difluoro-4-hydroxy-benzyl, 3,5-Difluoro-benzyl, 3-Fluoro-4-hydroxy-benzyl, 3-Fluoro-5-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl, 3-Fluoro-5-heptyloxy-benzyl, 3-Fluoro-5-hexyloxy -benzyl, 3-Fluoro-5-hydroxy-benzyl, and 3-Fluoro-benzyl.

4. The compound according to claim 1, wherein R₂ is selected from C(O)—

CH₃ and —

C(O)—

CH₂F.

5. The compound according to claim 1, wherein R_C is selected from -alkyl optionally substituted with at least one R₂₀₁ group, and wherein at least one carbon within R_C is optionally replaced with —

O—

, —

S—

, or —

NH.

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

7. The compound according to claim 1, wherein the formula (I) compound is selected from:

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(3,3-dimethylbutyl)cyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(hydroxymethyl)cyclopropanecarboxamide,

N-((1H-pyrazol-1-yl)methyl)-1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)cyclopropanecarboxamide,

N-(4-(1-((2-(1H-pyrazol-1-yl)ethoxy)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-(neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(2-methyl-1-(2- (neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((neopentylthio)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-(1H-pyrazol-1-yl)butyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)propyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, -p1 N-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)-2-hydroxycyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-aminocyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-isopentylbicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-(3,3-dimethylbutoxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutylthio)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-isopentylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-((2-(1H-pyrazol-1-yl)ethoxy)methyl)bicyclo[3.1 O]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4,4-dimethylpentyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-tert-butylbenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(6-((3,3-dimethylbutylthio)methyl)bicyclo[3.1.0]hexan-6-ylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(6-((3,3-dimethylbutoxy)methyl)bicyclo[3.1.0]hexan-6-ylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((5-tert-butylisoxazol-3-yl)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(5,5-dimethylhexyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide

N-(1-(3,5-difluorophenyl)-4-(1-(5,5-dimethylhex-2-enyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(6-(4-methylpentyl)bicyclo[3.1.0]hexan-6-ylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-((1-neopentyl-1H-1,2,3-triazol-4-yl)methyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(6-(4-methylpentyl)bicyclo[3.1.0]hexan-6-ylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-ethynylcyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(naphthalen-2-ylmethyl)cyclopropylamino)butan-2-yl)acetamide,

N₁-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-3-hydroxybutan-2-yl)—

N³, N³-diethyl-5-methylisophthalamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-methyl-2-propylcyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(pyrrolidine-1-carbonyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(piperidine-1-carbonyl)cyclopropylamino)butan-2-yl)acetamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-N-neopentylcyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-N-phenylcyclopropanecarboxamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(4-methylpentyl)cyclopropylamino)butan-2-yl)acetamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-methyl-N-phenylcyclopropanecarboxamide,

N-(4-(1-(2,6-difluorobenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

N-(1-(3,5-difluorophenyl)-4-(1-(2-fluorobenzyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

or at least one pharmaceutically acceptable salt thereof.

12. A method of treating at least one condition associated with amyloidosis chosen from Alzheimer'"'"'s disease, dementia and stroke, 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) according to claim 1, or pharmaceutically acceptable salt thereof.

13. A method of inhibiting beta-secretase activity in a host, the method comprising administering to the host an effective amount of at least one compound of formula (I) according to claim 1, or at least one pharmaceutically acceptable salt thereof.

14. A method of inhibiting 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) according to claim 1, or at least one pharmaceutically acceptable salt thereof.

15. 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) according to claim 1, or at least one pharmaceutically acceptable salt thereof.

16. 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) according to claim 1, or at least one pharmaceutically acceptable salt thereof, and wherein said 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;

or

between Leu671 and Asp672 of the APP-770 Swedish Mutation.

17. 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) according to claim 1, or at least one pharmaceutically acceptable salt thereof.

18. A method of inhibiting beta-secretase, comprising:

administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I) according to claim 1, or at least one pharmaceutically acceptable salt thereof, and wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′

, and S2′

.

8. A method of treating at least one condition that benefits from inhibition of at least one aspartyl-protease chosen from Alzheimer'"'"'s disease, dementia and stroke, comprising:

administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I),

9. The method according to claim 8, wherein the at least one compound of formula (I) is selected from

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(3,3-dimethylbutyl)cyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N—

(hydroxymethyl)cyclopropanecarboxamide,

N-((1H-pyrazol-1-yl)methyl)-1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)cyclopropanecarboxamide,

N-(4-(1-((2-(1H-pyrazol-1-yl)ethoxy)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-(neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(2-methyl-1-(2-(neopentyloxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((neopentylthio)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-(1H-pyrazol-1-yl)butyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(3-(1H-pyrazol-1-yl)propyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)-2-hydroxycyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-aminocyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutoxy)methyl)-2-(1H-pyrazol-1-yl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-isopentylbicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(2-(3,3-dimethylbutoxy)ethyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((3,3-dimethylbutylthio)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-isopentylcyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(4-(6-((2-(1H-pyrazol-1-yl)ethoxy)methyl)bicyclo[3.1.0]hexan-6-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(4,4-dimethylpentyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-(4-tert-butylbenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(6-((3,3-dimethylbutylthio)methyl)bicyclo[3.1.0]hexan-6-ylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(6-((3,3-dimethylbutoxy)methyl)bicyclo[3.1.0]hexan-6-ylamino)-3-hydroxybutan-2-yl)acetamide,

N-(4-(1-((5-tert-butylisoxazol-3-yl)methyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(5,5-dimethylhexyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-(5,5-dimethylhex-2-enyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(6-(4-methylpentyl)bicyclo[3.1.0]hexan-6-ylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-((1-neopentyl-1H-1,2,3-triazol-4-yl)methyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(6-(4-methylpentyl)bicyclo[3.1.0]hexan-6-ylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-4-(1-ethynylcyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(naphthalen-2-ylmethyl)cyclopropylamino)butan-2-yl)acetamide,

N¹-(1-(3,5-difluorophenyl)-4-(1-((3,3-dimethylbutoxy)methyl)cyclopropylamino)-3-hydroxybutan-2-yl)—

N³, N³-diethyl-5-methylisophthalamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-methyl-2-propylcyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(pyrrolidine-1-carbonyl)cyclopropylamino)butan-2-yl)acetamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(piperidine-1-carbonyl)cyclopropylamino)butan-2-yl)acetamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-neopentylcyclopropanecarboxamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-phenylcyclopropanecarboxamide,

N-(1-(3,5-difluorophenyl)-3-hydroxy-4-(1-(4-methylpentyl)cyclopropylamino)butan-2-yl)acetamide,

1-(3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutylamino)—

N-methyl-N-phenylcyclopropanecarboxamide,

N-(4-(1-(2,6-difluorobenzyl)cyclopropylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)acetamide, and

N-(1-(3,5-difluorophenyl)-4-(1-(2-fluorobenzyl)cyclopropylamino)-3-hydroxybutan-2-yl)acetamide,

or at least one pharmaceutically acceptable salt thereof.

10. The method according to claim 8, wherein the aspartyl protease is beta-secretase and the condition is Alzheimer'"'"'s disease.

11. The method according to claim 8, wherein the aspartyl protease is beta-secretase and the condition is dementia.