Hydroxypropylamines

• US 7,244,755 B2
• Filed: 10/04/2002
• Issued: 07/17/2007
• Est. Priority Date: 10/04/2001
• Status: Expired due to Fees

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Sherer, Brian, Fisher, Jed F., Jacobs, Jon S.
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US10/264,707
• Publication Number:
  US 20030125365A1
• Time in Patent Office: 1,747 Days
• Field of Search: 564/86, 564/156, 564/158, 548/236, 514/374, 514/603, 514/620
• US Class Current: 514/374
• 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 215/28 and containing six-membered aromatic rings
• 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 311/17 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

Disclosed are compounds of formula I:

and the pharmaceutically acceptable salts thereof wherein the variables R_N, R₁, R₂, R₃, R_P and R_C are defined herein. These compounds are 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 useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

Claims

1. A compound of the formula:

2. A compound according to claim 1 wherein

R₁ is —

CH₂-phenyl where the ring portion is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, C₁–

C₄ alkoxy, hydroxy, —

NO₂, and

C₁–

C₄ alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, SH, NH₂, NH(C₁–

C₆ alkyl), N—

(C₁–

C₆ alkyl)(C₁–

C₆ alkyl), C≡

N, CF₃.

3. A compound according to claim 2 wherein

R_N is —

C(═

O)—

R₁₀₀.

4. A compound according to claim 3 wherein R₂ and R₃ are each hydrogen.

5. A compound according to claim 4 wherein Rp is hydrogen.

6. A compound according to claim 1 wherein

R_c is hydrogen, —

(CR₂₄₅R₂₅₀)_0-4-aryl, —

(CR₂₄₅R₂₅₀)_0-4-heteroaryl, —

(CR₂₄₅R₂₅₀)_0-4-heterocyclyl,

C₂–

C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R₂₀₅, R₁₁₀, R₁₂₀, R₁₃₀, —

OC═

ONR₂₃₅R₂₄₀, —

S(═

O)_0-2(C₁–

C₆ alkyl), —

SH, and —

S(═

O) ₂NR₂₃₅R₂₄₀,

—

(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, —

CO₂H, and —

CO₂—

(C₁–

C₄ alkyl), or

C₂–

C₁₀ alkenyl or C₂–

C₁₀ alkynyl, each of which is optionally substituted with 1, 2, or 3 independently selected R₂₀₅ groups, wherein

each aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀, and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or 4 independently selected R₂₁₀ groups.

7. A compound according to claim 6 wherein R_c is hydrogen.

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

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-ethylbenzyl)amino]-D-erythro-pentitol,

5-amino-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol,

5-amino-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-L-threo-pentitol,

5-(cyclohexylamino)-1,2,4,5-tetradeoxy-1(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol,

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-ethylbenzyl)amino]-L-threo-pentitol,

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(2-ethylbenzyl)amino]-D-erythro-pentitol,

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5[(4-ethylbenzyl)amino]-L-threo-pentitol,

1,2,4,5-tetracieoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-ethylbenzyl)amino]-D-erythro-pentitol,

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-[(3-[(dipropylamino)carbonyl]-5-{[(2-hydroxyethyl)amino]sulfonyl}benzoyl)amino]-5-[(3-ethylbenzyl)amino]-L-threo-pentitol,

1,2,4,5-tetracieoxy-1-(3,5-difluorophenyl)-2-{[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoyl]amino}-5-[(3-ethylbenzyl)amino]-L-threo-pentitol,

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-[(3-[(dipropylamino)carbonyl]-5-{[(2-hydroxyethyl)amino]sulfonyl}benzoyl)amino]-5-[(2-ethylbenzyl)amino]-D-erythro-pentitol, and

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-[(3-[(dipropylamino)carbonyl]-5-{[(2-hydroxyethyl)amino]sulfonyl}benzoyl)amino]-5-[(3-ethylbenzyl)amino]-D-erythro-pentitol.

9. A method for the treatment 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.

10. A method of treatment as in claim 9, wherein the patient is a human.

11. A pharmaceutical composition comprising a compound according to claim 1.