Phosphodiesterase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9422242-B2
Application number	US-201414224702-A
Country	US
Kind code	B2
Filing date	Mar 25, 2014
Priority date	Dec 23, 2008
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

First claim

What is claimed is:

1. A method for treating a subject afflicted with Alzheimer's disease, Lewy body dementia, inclusion body myositis, or cerebral amyloid angiopathy, the method comprising:
administering to the subject an effective amount of a composition comprising a PDE5 inhibitor compound of Formula (V):

wherein:
A is O or N;
X is —(CH 2 ) n , C(O), S(O), or S(O) 2 ;
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 5 is hydrogen or —OR 6 ;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; and n is 1, 2, or 3,
or a pharmaceutically acceptable salt or tautomer thereof.

2. The method of claim 1 , wherein the effective amount is at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, or at least about 10 mg/kg body weight.

3. The method of claim 1 , wherein A is N.

4. The method of claim 1 , wherein R 5 is hydrogen.

5. The method of claim 1 , wherein R 5 is —OCH 3 .

6. The method of claim 1 , wherein the compound is of formula (V-1):

wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.

7. The method of claim 5 , wherein R 6 is CH 3 .

8. The method of claim 1 , wherein the compound is of formula (V-1a):

wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.

9. The method of claim 1 , wherein R 2 is CH 2 —OH.

10. The method of claim 1 , wherein R 3 is H.

11. The method of claim 1 , wherein R 3 is a halogen.

12. The method of claim 1 , wherein R 3 is chlorine.

13. The method of claim 1 , wherein R 4 is —CN.

14. The method of claim 1 , wherein R 4 is a halogen.

15. The method of claim 1 , wherein R 4 is fluorine.

16. The method of claim 1 , wherein the compound is of formula (V-1a1):

wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.

17. The method of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl or —NR 7 R 8 .

18. The method of claim 1 , wherein R 1 is —NR 7 R 8 .

19. The method of claim 1 , wherein R 1 is —NR 7 R 8 , and wherein R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl,or —NR 9 R 10 ; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with O, NR 9 or N—C(O)R 9 .

20. The method of claim 1 , wherein R 1 is —SR 7 .

21. The method of claim 1 , wherein R 1 is —S—(C 1 -C 6 )-alkyl.

22. The method of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl.

23. The method of claim 1 , wherein R 1 is cyclopropyl.

24. The method of claim 1 , wherein R 1 is dimethylamino.

25. The method of claim 1 , wherein the compound is

26. The method of claim 1 , wherein the compound is

27. A method for the treatment of at least one condition selected from the group consisting of erectile dysfunction, pulmonary hypertension, cardiovascular disorder, and gastrointestinal disorder in a subject in need of such treatment, the method comprising:
administe

Assignees

• Univ Columbia

Inventors

• Feng Yan
• Arancio Ottavio
• Deng Shixian
• Landry Donald W

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  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 title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D215/48 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61K31/4706 Primary

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title