Substituted Ureas and Carbamates

• US 20080306136A1
• Filed: 04/01/2008
• Published: 12/11/2008
• Est. Priority Date: 11/27/2002
• 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: Pulley, Shon R., Tucker, John A.
• Application Number:
  US12/060,544
• Publication Number:
  US 20080306136A1
• Time in Patent Office: Days
• US Class Current: 514/432
• 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 of the formula:

3. A compound according to claim 1 of the formula

4. A compound according to claim 3, 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

R₂₄₅R₂₅₀, R₂₀₀, and R₂₁₀ are as defined above.

5. A compound according to claim 4, 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.

6. A compound according to claim 5, 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)_1-4-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.

7. A compound according to claim 3, wherein

R_c is (CR₂₄₅R₂₅₀)₁-aryl, where the aryl 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;

or

CR₂₄₅R₂₅₀ represents a C₃-C₇ cycloalkyl group.

8. A compound according to claim 7, wherein

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

9. A compound according to claim 8, 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.

10. A compound according to claim 8, wherein R₂₄₅ is hydrogen and R₂₅₀ is C₁-C₃ alkyl.

11. A compound according to claim 8, wherein R₂₄₅ and R₂₅₀ are both hydrogen.

12. A compound according to claim 8, wherein the phenyl in (CR₂₄₅R₂₅₀)₁-phenyl is substituted with

(a) 1 R₂₀₀ group and 1 heteroaryl group optionally substituted with 1 R₂₀₀ group;

or

(b) 1 R₂₀₀ group and 1 phenyl group optionally substituted with 1 R₂₀₀ group;

or

(c) 1 R₂₀₀ group, and 1 heterocycloalkyl which is optionally substituted with one R₂₀₀ or ═

O.

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

14. A compound according to claim 12, wherein CR₂₄₅R₂₅₀ represents a C₅-C₇ cycloalkyl group.

15. A compound according to claim 12, wherein CR₂₄₅R₂₅₀ represents a C₃-C₆ cycloalkyl group.

22. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer'"'"'s disease, for helping prevent or delay the onset of Alzheimer'"'"'s disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer'"'"'s disease in those who would progress from MCI to AD, for treating Down'"'"'s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including 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 and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a substituted aminoalcohol of the formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein X, T, R₂₀, R₁, R₂, R₃, R_N and R_C are as defined in claim 1.

23. A method for making a compound of formula I

16-18. -18. (canceled)

19. A compound selected from the group consisting of:

phenyl((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)carbamate;

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

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;

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

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

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;

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

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

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

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;

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

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

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

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.

20. A compound of the formula:

21. A compound which has the formula: