Substituted ureas and carbamates

• US 7,351,738 B2
• Filed: 11/26/2003
• Issued: 04/01/2008
• Est. Priority Date: 11/27/2002
• Status: Expired due to Fees

• 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: Pulley, Shon R., Tucker, John A.
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/723,220
• Publication Number:
  US 20040209925A1
• Time in Patent Office: 1,588 Days
• Field of Search: 549/404, 564/56, 514/456
• US Class Current: 514/456
• 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 271/20 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 271/52 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 311/47 Y being a hetero atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/42 attached in position 4
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/68 with nitrogen atoms directly attached in position 4
• CPC Class Codes: C07D 311/76 Benzo[c]pyrans
• CPC Class Codes: C07D 317/72 spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention provides 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 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 of the formula

3. A compound according to claim 2, wherein

R₁ is C₁-C₁₀ alkyl optionally substituted with 1 or 2 groups independently selected from halogen, —

OH, ═

O, —

CN, —

CF₃, —

OCF₃, —

C₃-C₇ cycloalkyl, —

C₁-C₄ alkoxy, amino, mono-dialkylamino, aryl, heteroaryl or heterocycloalkyl, wherein the aryl group is optionally substituted with 1 or 2 R₅₀ groups;

R₅₀ is halogen, OH, CN, —

CO—

(C₁-C₄ alkyl), —

NR₇R₈, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, and C₃-C₈ cycloalkyl;

R₇ and R₈ are selected from H;

—

C₁-C₄ alkyl optionally substituted with 1, 2, or 3 groups selected from —

OH, —

NH₂ and halogen;

—

C₃-C₆ cycloalkyl;

—

(C₁-C₄ alkyl)-O—

(C₁-C₄ alkyl);

—

C₂-C₄ alkenyl; and

—

C₂-C₄ alkynyl;

R_C is selected from —

(CR₂₄₅R₂₅₀)_0-4-aryl;

—

(CR₂₄₅R₂₅₀)_0-4-heteroaryl;

—

(CR₂₄₅R₂₅₀)_0-4-heterocycloalkyl;

where the aryl and heteroaryl groups attached to the —

(CR₂₄₅R₂₅₀)_0-4—

group are optionally substituted with 1, 2, 3 or 4 R₂₀₀ groups;

where the heterocycloalkyl group attached to the —

(CR₂₄₅R₂₅₀)_0-4 group is optionally substituted with 1, 2, 3, or 4 R₂₁₀ groups; and

R₂₄₅ R₂₅₀, R₂₀₀, and R₂₁₀ are as defined above.

4. A compound according to claim 3, wherein

R_C is —

(CR₂₄₅R₂₅₀)_0-4-heterocycloalkyl;

where the heterocycloalkyl group attached to the —

(CR₂₄₅R₂₅₀)_0-4—

group is optionally substituted with 1, 2, 3, or 4 R₂₁₀ groups, wherein R₂₄₅, R₂₅₀, and R₂₁₀ are as defined above.

5. A compound according to claim 4, wherein

R₁ is C₁-C₁₀ alkyl substituted with one aryl group, where the aryl group is optionally substituted with 1 or 2 R₅₀ groups;

R_C is —

(CR₂₄₅R₂₅₀)_1-4-aryl or —

(CR₂₄₅R₂₅₀)_0-4-heteroaryl,

R₂₄₅ and R₂₅₀ are independently selected from H, —

(CH₂)_0-4CO₂C₁-C₄ alkyl, —

(CH₂)_0-4CO₂H, —

C₁-C₄ alkyl, —

(C₁-C₄ alkyl)OH, or

R₂₄₅, R₂₅₀ and the carbon to which they are attached form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1 or 2 carbon atoms are optionally replaced by —

O—

, —

S—

, —

SO₂—

, or —

NR₂₂₀—

, where R₂₂₀ is as defined above; and

wherein the aryl and heteroaryl groups attached to the —

(CR₂₄₅R₂₅₀)_1-4—

groups are optionally substituted with 1 or 2 R₂₀₀ groups.

6. A compound according to claim 2, wherein

R_C is (CR₂₄₅R₂₅₀)₁-aryl, where the aryl (preferably phenyl or naphthyl, more preferably phenyl) is optionally substituted with 1, 2, or 3 R₂₀₀ groups;

and

R₂₄₅ is H and R₂₅₀ is H or C₁-C₆ alkyl;

or

R₂₄₅ and R₂₅₀ are independently C₁-C₃ alkyl (preferably both are methyl);

or

CR₂₄₅R₂₅₀ represents a C₃-C₇ cycloalkyl group.

7. A compound according to claim 6, wherein

the (CR₂₄₅R₂₅₀)₁-aryl is (CR₂₄₅R₂₅₀)₁-phenyl where the phenyl is optionally substituted with 1, 2, or 3 R₂₀₀ groups.

8. A compound according to claim 7, wherein the phenyl in (CR₂₄₅R₂₅₀)₁-phenyl is substituted with 1-3 independently selected R₂₀₀ groups, or 1 or 2 independently selected R₂₀₀ groups, and 1 heteroaryl group optionally substituted with 1 R₂₀₀ group or 1 phenyl group optionally substituted with 1 R₂₀₀ group.

9. A compound according to claim 7, wherein R₂₄₅ is hydrogen and R₂₅₀ is C₁-C₃ alkyl.

10. A compound according to claim 7, wherein R₂₄₅ and R₂₅₀ are both hydrogen.

11. A compound according to claim 7, wherein the phenyl in (CR₂₄₅R₂₅₀)₁-phenyl is substituted with

(a) 1 R₂₀₀ group and 1 heteroaryl group, wherein the heteroaryl is optionally substituted with 1 R₂₀₀ group;

or

(b) 1 R₂₀₀ group and 1 phenyl group, wherein the 1 phenyl group is optionally substituted with 1 R₂₀₀ group;

or

(c) 1 R₂₀₀ group, and 1 heterocycloalkyl group wherein the heterocycloalkyl group is optionally substituted with 1 R₂₀₀ group or ═

O.

12. A compound according to claim 11, wherein CR₂₄₅R₂₅₀ represents a C₃-C₇ cycloalkyl group.

13. A compound according to claim 11, wherein CR₂₄₅R₂₅₀ represents a C₅-C₇ cycloalkyl group.

14. A compound according to claim 11, wherein CR₂₄₅R₂₅₀ represents a C₃-C₆ cycloalkyl group.

15. A compound according to claim 11, wherein CR₂₄₅R₂₅₀ represents a C₆ cycloalkyl.

16. A compound according to claim 7,

wherein the phenyl in (CR₂₄₅R₂₅₀)₁-phenyl is substituted with 1 R₂₀₀ group;

or

1 R₂₀₀ group and one heteroaryl group wherein the heteroaryl group is optionally substituted with

1 R₂₀₀ group or

1 R₂₀₀ group and 1 phenyl group wherein the 1 phenyl group is optionally substituted with one R₂₀₀ group.

17. A compound according to claim 7, wherein the phenyl in (CR₂₄₅R₂₅₀)₁-phenyl is substituted with 1 R₂₀₀ group.

20. The compound according to claim 1 that is 3-(3-((2S,3R)-1-(3,5-difluorophenyl)-4-(1-(3-ethylphenyl)butylamino)-3-hydroxybutan-2-yl)ureido)-N,N-dipropylpropanamide.

21. A method of treating a patient who has Alzheimer'"'"'s Disease who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.

18. A compound selected from the group consisting of:

methyl (3S)-3-{[(2R,3S)-3-[(anilinocarbonyl)amino]-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-3-(3-bromophenyl)propanoate;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[4-(3-ethylphenyl)tetrahydro-2H-pyran-4-yl]amino}-2-hydroxypropyl)-N′

-phenylurea;

N-benzyl-N′

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

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

-phenylurea;

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

-propylurea;

N-(sec-butyl)-N′

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

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

-phenylurea;

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

-phenylurea;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-2H-chromen-4-yl}amino)-2-hydroxypropyl]-N′

-phenylurea;

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

-phenylurea;

N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-isopropyl-3,4-dihydro-1H-isochromen-4-yl)amino]propyl}-N′

-phenylurea;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-1H-isochromen-4-yl}amino)-2-hydroxypropyl]-N′

-phenylurea;

N³-[({(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino) carbonyl]-N¹,N¹-dipropyl-b-alaninamide; and

2-{[({(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]amino}-N,N-dipropylethanesulfonamide.

19. A compound which has the formula: