IP Library › Granted Patent US 7,459,567

Granted Patent B2

US 7,459,567 · App. 11/352,646 · Granted Dec 2, 2008

Substituted thienyl and furyl acylguanidines and methods of their use as beta-secretase modulators

Assignee: Wyeth

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Quick Facts

Patent No.: US 7,459,567
App. No.: 11/352,646
Granted: Dec 2, 2008
Kind: B2

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Abstract

The present invention provides a substituted thienyl or furyl acylguanidine compound of formula I The present invention also provides methods for the inhibition of β-secretase (BACE) and for the treatment of β-amyloid deposits and neurofibrillary tangles.

Claims (68)

1. A compound of formula I

wherein:

X is S;

R 1 is hydrogen or an optionally substituted alkyl group;

R 2 and R 3 are each independently optionally substituted phenyl; and

R 4 is hydrogen or an optionally substituted alkyl group; or

a tautomer thereof, a stereoisomer thereof or a pharmaceutically-acceptable salt thereof.

2. The compound according to claim 1 wherein R 1 is hydrogen.

3. The compound according to claim 1 wherein R 2 and R 3 are each independently phenyl optionally substituted with one halogen, alkoxy, haloalkoxy, aryloxy or CONHR 7 , wherein R 7 is hydrogen or an alkyl, alkoxy, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl, alkyl ester or heteroaryl group.

4. The compound according to claim 1 wherein R 1 is hydrogen or an alkyl group optionally substituted with one hydroxy.

5. The compound according to claim 4 wherein R 2 and R 3 are each independently phenyl optionally substituted with one halogen, alkoxy, haloalkoxy, aryloxy or CONHR 7 , wherein R 7 is hydrogen or an alkyl, alkoxy, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl, alkyl ester or heteroaryl group.

6. The compound according to claim 5 wherein R 4 is hydrogen.

7. The compound according to claim 1 selected from the group consisting of:

N″-{[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]acetyl}guanidine;

N″-[(2,4-diphenylthien-3-yl)acetyl]guanidine;

N″-{[2-(4-phenoxyphenyl)-4-phenylthien-3-yl]acetyl}guanidine;

N″-{[4-(2-chlorophenyl)-2-(4-phenoxyphenyl)thien-3-yl]acetyl}guanidine;

N″-{[2-(2-chlorophenyl)-4-(4-propoxyphenyl)thien-3-yl]acetyl}guanidine;

N″-({2-(4-propoxyphenyl)-4-[2-(trifluoromethoxy)phenyl]thien-3-yl}acetyl)guanidine;

N-{[4-phenyl-2-(4-propoxyphenyl)thien-3-yl]acetyl}guanidine;

N″-{[2-phenyl-4-(4-propoxyphenyl)thien-3-yl]acetyl}guanidine;

N″-{[2-[4-(4-acetylphenoxy)phenyl]-4-(2-chlorophenyl)thien-3-yl]acetyl}guanidine;

N″-({4-(2-chlorophenyl)-2-[4-(4-propionylphenoxy)phenyl]thien-3-yl}acetyl)guanidine;

2-(4-(2-chlorophenyl)-2-{4-[2-(1H-pyrazol-4-yl)ethoxy]phenyl}thien-3-yl)-N-(diaminomethylene)acetamide;

2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide;

4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(1-ethylpropyl)benzamide;

4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(2,2,2-trifluoroethyl)benzamide;

4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-propylbenzamide;

4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(cyclopropylmethyl)benzamide;

N-butyl-4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]benzamide;

2-[4-(2-chlorophenyl)-2-(3-methyl-4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide; and

2-[4-(2-chlorophenyl)-2-(2-methyl-4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide; or

a tautomer thereof;

a stereoisomer thereof; or

a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I

wherein:

X is S;

R 1 is hydrogen or an optionally substituted alkyl group;

R 2 and R 3 are each independently optionally substituted phenyl; and

R 4 is hydrogen or an optionally substituted alkyl group; or

a tautomer thereof, a stereoisomer thereof or a pharmaceutically-acceptable salt thereof.

9. The composition according to claim 8 wherein R 1 is hydrogen or an alkyl group optionally substituted with one hydroxy.

10. The composition according to claim 9 wherein R 2 and R 3 are each independently phenyl optionally substituted with one halogen, alkoxy, haloalkoxy, aryloxy or CONHR 7 , wherein R 7 is hydrogen or an alkyl, alkoxy, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl, alkyl ester or heteroaryl group.

11. The composition according to claim 10 wherein R 4 is hydrogen.

12. The composition according to claim 8 having a compound selected from the group consisting of: