Phenacyl 2-hydroxy-3-diaminoalkanes

• US 20050054690A1
• Filed: 04/21/2004
• Published: 03/10/2005
• Est. Priority Date: 04/21/2003
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Tucker, John, John, Varghese, Aquino, Jose, Tenbrink, Ruth, Hom, Roy, Pulley, Shon
• Application Number:
  US10/828,582
• Publication Number:
  US 20050054690A1
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 233/40 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07D 209/20 substituted additionally by nitrogen atoms, e.g. tryptophane
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/42 attached in position 4
• CPC Class Codes: C07D 311/68 with nitrogen atoms directly attached in position 4
• CPC Class Codes: C07D 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to compounds of formula (I): useful in treating Alzheimer'"'"'s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are also useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

Claims

1. A compound of formula (I):

2. A compound according to claim 1, wherein:

Z is —

(CH₂)_1-3-aryl or —

(CH₂)_1-3-heteroaryl, wherein each ring is independently optionally substituted with 1 or 2 groups independendently selected from halogen, —

OH, —

OCF₃, —

O-phenyl, —

CN, —

N₁₀₀R₁₀₁, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, (CH₂)_0-3(C₃-C₇ cycloalkyl), aryl, heteroaryl, or heterocyclyl wherein, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are optionally substituted with 1 or 2 substitutents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, —

OH, —

CN, or —

N₁₀₀R₁₀₁;

3. A compound according to claim 1, wherein X is —

(C═

O)—

.

4. A compound according to claim 1, wherein:

R₁ is —

C₁-C₆ alkyl-aryl, —

C₁-C₆ alkyl-heteroaryl, or —

C₁-C₆ alkyl-heterocyclyl, wherein each aryl group at each occurrence is optionally substituted with 1, 2 or 3 R₅₀ groups;

wherein R₅₀ is independently selected from halogen, OH, SH, CN, —

CO—

(C₁-C₄ alkyl), —

NR₇R₈, —

S(O)_0-2—

(C₁-C₄ alkyl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkyl;

wherein the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from the group consisting of C₁-C₄ alkyl, halogen, OH, —

NR₅R₆, CN, C₁-C₄ haloalkoxy, NR₇R₈, and C₁-C₄ alkoxy;

wherein R₅ and R₆ at each occurrence are independently H or C₁-C₆ alkyl;

or

wherein R₅ and R₆ and the nitrogen to which they are attached, at each occurrence form a 5 or 6 membered heterocycloalkyl ring; and

wherein R₇ and R₈ are independently selected from the group consisting of H;

—

C₁-C₄ alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —

OH, —

NH₂, and halogen;

—

C₃-C₆ cycloalkyl;

—

(C₁-C₄ alkyl)—

O—

(C₁-C₄ alkyl);

—

C₂-C₄ alkenyl; and

—

C₂-C₄ alkynyl;

wherein each heteroaryl at each occurrence is optionally substituted with 1 or 2 R₅₀ groups;

wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1 or 2 groups that are independently R₅₀ or ═

O.

5. A compound according to claim 1, wherein R₂ and R₃ are hydrogen.

6. A compound according to claim 1, wherein R₁₅ is hydrogen.

7. A compound according to claim 1, wherein

R_C is selected from the group consisting of:

—

(CH₂)_0-3—

(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —

R₂₀₅, and —

CO₂—

(C₁-C₄ alkyl); and

a monocyclic or bicyclic ring of 5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl, heteroaryl, or heterocycloalkyl groups wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring is optionally replaced with

—

NH, —

N(CO)_0-1R₂₁₅, —

N(CO)_0-1R₂₂₀, —

O, or —

S(═

O)_0-2, and wherein the monocyclic or bicyclic ring can be optionally substituted with 1, 2 or 3 groups that are independently —

R₂₀₅ —

R₂₄₅, R₂₅₀ or ═

O.

8. A compound according to claim 1 wherein R_C is

9. A compound according to claim 8 wherein one of x₁, x₂, or x₃ is SO₂.

10. A compound according to claim 8 wherein one of x₁, x₂, or x₃ is NH.

11. A compound according to claim 8 wherein x₁, x₂, and x₃ are each CH₂.

12. A compound according to claim 1 selected from the group consisting of:

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-(1H-imidazol-4-yl)acetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-3-phenylpropanamide;

2-(2-amino-1,3-thiazol-4-yl)-N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H -isothiochromen-4-yl]amino}-2-hydroxypropyl)acetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-pyridin-4-ylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-pyridin-3-ylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-pyridin-2-ylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-thien-2-ylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-(1H-indol-3-yl)acetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-hydroxy-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-2-(3-methylisoxazol-5-yl)acetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-3-thien-2-ylpropanamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-4-thien-2-ylbutanamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-4-(3,4-dimethoxyphenyl)butanamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-4-(4-methoxyphenyl)butanamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[(4S)-6-tert-butoxy-3,4-dihydro-2H-chromen-4-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[(4S)-6-tert-butoxy-1,2,3,4-tetrahydroquinolin-4-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-7-neopentyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[(1S)-7-tert-butoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-neopentyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[(4R)-6-tert-butoxy-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-neopentylphenyl)cyclohexyl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[1-(3-tert-butoxyphenyl)cyclohexyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-neopentylphenyl)cyclopropyl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[1-(3-tert-butoxyphenyl)cyclopropyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-neopentyl-1,1′

-biphenyl-2-yl)methyl]amino}propyl)-2-phenylacetamide;

N-[(1S, 2R)-3-{[(4-tert-butoxy-1,1′

-biphenyl-2-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-{(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-neopentyl-9H-fluoren-9-yl)amino]propyl}-2-phenylacetamide;

N-[(1S, 2R)-3-[(2-tert-butoxy-9H-fluoren-9-yl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-phenylacetamide;

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-(3,5-dimethoxyphenyl)acetamide;

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-(1H -imidazol-4-yl)acetamide;

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-phenylacetamide;

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-(pyridin-2-yl)acetamide;

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-(pyridin-3-yl)acetamide; and

N-((2S, 3R)-1-(3,5-difluorophenyl)-4-((R)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-hydroxybutan-2-yl)-2-(1H-indol-3-yl)acetamide.

13. A method for making a compound of formula (I)

14. A method for the treatment or prevention of Alzheimer'"'"'s disease, mild cognitive impairment Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, 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, diffuse Lewy body type of Alzheimer'"'"'s disease comprising administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.

15. A method of treatment as in claim 14, wherein the patient is a human.

16. A method of treatment according to claim 14, wherein the disease is dementia.

17. A pharmaceutical composition comprising a compound according to claim 1 in combination with a physiologically acceptable carrier or excipient.