Hydroxypropylamines

• US 20030125365A1
• Filed: 10/04/2002
• Published: 07/03/2003
• Est. Priority Date: 10/04/2001
• Status: Active Grant

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Sherer, Brian, Fisher, Jed F., Jacobs, Jon S.
• Granted Patent: US 7,244,755 B2
• Time in Patent Office: Days
• 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 aryl, heteroaryl, heterocyclyl, aryl-(C₁-C₆)alkyl-, heteroaryl-(C₁-C₆)alkyl-, or heterocyclyl-(C₁-C₆)alkyl-, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

NO₂, —

NR₁₀₅R′

₁₀₅, —

CO₂R, —

N(R)COR′

, or —

N(R)SO₂R′

, —

C(═

O)—

(C₁-C₄) alkyl, —

SO₂-amino, —

SO₂-mono or dialkylamino, —

C(═

O)-amino, —

C(═

O)-mono or dialkylamino, —

SO₂—

(C₁-C₄) alkyl, or

C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or

C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, —

C₁-C₆ alkyl and mono- or dialkylamino, or

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

CAN, —

CF₃, —

C₁-C₃ alkoxy, amino, mono- or dialkylamino and —

C₁-C₃ alkyl, or

C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and

the heterocyclyl group is optionally further substituted with oxo.

3. A compound according to claim 2 wherein

R_N is —

C (═

O)—

(CRR′

)_0-6R₁₀₀;

R₁₀₀ represents aryl, heteroaryl, heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —

CH[(CH₂)_0-2—

O—

R₁₅₀]—

(CH₂)_0-2-aryl, —

CH [(CH₂)_0-2—

O—

R₁₅₀]—

(CH₂)_0-2-heterocyclyl or —

CH[(CH₂)_0-2—

O—

R₁₅₀]-(CH₂)_0-2-heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from

—

OR, —

NO₂, C₁-C₆ alkyl, halogen, —

C═

N, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

O—

P(═

O)(OR)(OR′

), —

(CH₂)_0-4—

CO—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

CONR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl), —

(CH₂)_0-4—

CO—

(CH₂)_0-4 (C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₁₀, —

(CH₂)_0-4—

CO—

R₁₂₀, —

(CH₂)_0-4—

CO—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₄₀, —

(CH₂)_0-4—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO₂—

(CH₂)_0-4—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀) —

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀) —

CO—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R₁₁₀)₂, —

(CH₂)_0-4—

O—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

COOH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl, or

R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, or

R₁₀₀ is —

(C₁-C₆ alkyl)-O—

C₁-C₆ alkyl) or —

(C₁-C₆ alkyl)-S—

(C₁-C₆ alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅ groups, or

R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups.

4. A compound according to claim 3 wherein

R_N is —

C(═

O)—

R₁₀₀; and

R₁₀₀ represents aryl, or heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from

—

OR, —

NO₂, C₁-C₆ alkyl, halogen, —

C≡

N, —

OCF₃, —

CF₃, (CH₂)_0-4—

O—

P(═

O)(OR)(OR′

), —

(CH₂)_0-4—

CO—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

CONR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl), (CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl), —

(CH₂)_0-4—

CO—

(CH₂)_0-4(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₁₀, —

(CH₂)_0-4—

CO—

R₁₂₀, —

(CH₂)_0-4—

CO—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₄₀, —

(CH₂)_0-4—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO₂—

(CH₂)_0-4—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

N(R₁₅₀) —

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀) —

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀) —

CO—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R₁₁₀)₂, —

(CH₂)_0-4—

O—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

COOH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀) —

SO₂—

R₁₀₅, —

(CH₂)_0-4-C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

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

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

7. 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-C₁₀alkenyl or C₂-C₁₀alkynyl, 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.

8. A compound according to claim 7 wherein R_C is hydrogen.

9. 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-threopentitol,

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-tetradeoxy-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-tetradeoxy-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.

10. 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 compriseing administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.

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

12. A method of treatment according to claim 10, wherein the disease is dementia.

13. The use of a compound or salt according to claim 1 for the manufacture of a medicament.

14. The use of a compound or salt according to claim 1 for the manufacture of a medicament for use in 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, or diffuse Lewy body type of Alzheimer'"'"'s disease.

17. 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 compriseing administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.

18. A method of treatment as in claim 17, wherein the patient is a human.

19. A method of treatment according to claim 17, wherein the disease is dementia.

20. The use of a compound or salt according to claim 1 for the manufacture of a medicament.

21. The use of a compound or salt according to claim 1 for the manufacture of a medicament for use in 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, or diffuse Lewy body type of Alzheimer'"'"'s disease.

22. A method according to claim 17, where the method is for treating Alzheimer'"'"'s disease.

23. A method of preparing a compound of claim 1.

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

15. A compound of the formula 5:

16. A compound of the formula 4: