Cycloalkyl-dione derivatives and methods of their use
The present invention is directed to carboxylic acid-containing pharmaceutical compounds where the carboxylic acid moieties have been substituted with cycloalkyl-dione derivatives, as well as tautomers and pharmaceutically acceptable salt forms thereof. These bioisosteric replacements improve the compound's ability to effectively cross the blood brain barrier and result in improved pharmacokinetic, toxicological, and/or safety profiles.
1. A compound of formula I:
wherein
A is
n is 0, 1, or 2;
m is 0 or 1;
R 1 is H or C 1-6 alkyl and
R 2 is H, C 1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
X is O or N;
or a tautomer or pharmaceutically acceptable salt form thereof.
2. The compound of claim 1 , wherein A is
3. The compound of claim 2 , wherein m is 0.
4. The compound of claim 1 , X is O.
5. The compound of claim 1 , wherein n is 1.
6. The compound of claim 1 , wherein R 1 is H.
7. The compound of claim 1 , wherein R 2 is C 1-6 alkyl.
8. The compound of claim 7 , wherein R 2 is methyl.
9. The compound of claim 7 , wherein R 2 is ethyl.
10. The compound of claim 7 , wherein R 2 is propyl.
11. The compound of claim 7 , wherein R 2 is isopropyl.
12. The compound of claim 7 , wherein R 2 is —CH 2 -cyclopropyl.
13. The compound of claim 7 , wherein R 2 is cyclohexyl.
14. The compound of claim 1 , wherein R 2 is substituted or unsubstituted aryl.
15. The compound of claim 1 , wherein R 2 is H.
16. The compound of claim 2 , wherein m is 1.
17. The compound of claim 16 , wherein R 2 is cyclohexyl.
18. The compound of claim 1 , wherein A is
19. The compound of claim 18 , wherein R 1 is H.
20. The compound of claim 1 , wherein the compound is of formula IA
21. The compound of claim 20 , wherein R 1 is H.
22. The compound of claim 20 , wherein R 1 is C 1-6 alkyl.
23. The compound of claim 20 , wherein R 1 is H and R 2 is H.
24. The compound of claim 20 , wherein R 1 is H and R 2 is C 1-6 alkyl.
25. The compound of claim 24 , wherein R 2 is methyl, ethyl, propyl, isopropyl, or —CH 2 -cyclopropyl.
26. The compound of claim 1 , wherein X is N.
27. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
28. A method of treating thrombus, Alzheimer's disease, diabetic nephropathy, bronchial asthma, or allergic rhinitis in a patient comprising administering to the patient a therapeutically effective amount of a pharmaceutical formulation according to claim 27 .