Nitroxyl (HNO) releasing compounds and uses thereof in treating diseases
Disclosed is a compound of the formula (I) or a pharmaceutically acceptable salt thereof: (I) in which R 1 , R 2 , R 3 , and R 4 are defined herein and pharmaceutical compositions thereof. Further provided is a method of treating various disorders, such as a disorder selected from the group consisting of a cardiovascular disorder, cancer, chronic pain, alcohol dependence, and inflammation in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt of formula (I).
1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
R 2 and R 3 are the same or different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 4 is —C(═O)R 5 , wherein R 5 is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
or R 4 is a non-steroidal anti-inflammatory drug (NSAID) moiety retaining its NSAID activity,
wherein the compound of the formula (I) or pharmaceutically acceptable salt thereof releases HNO at physiological pH.
2. The compound or salt of claim 1 , wherein R 1 is optionally substituted C 1-12 alkyl, optionally substituted C 3-12 alkenyl, or optionally substituted C 3-8 cycloalkyl.
3. The compound or salt of claim 1 , wherein R 2 and R 3 are the same or different and each is hydrogen, C 1-12 alkyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted.
4. The compound or salt of claim 1 , wherein R 2 and R 3 are hydrogen.
5. The compound or salt of claim 1 , wherein R 1 is optionally substituted C 1-12 alkyl.
6. The compound or salt of claim 1 , wherein R 1 is optionally substituted C 1-4 alkyl.
7. The compound or salt of claim 1 , wherein R 1 is isopropyl.
8. The compound or salt of claim 1 , wherein R 4 is —C(═O)R 5 , wherein R 5 is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino.
9. The compound or salt of claim 8 , wherein R 5 is an optionally substituted C 1-12 alkyl.
10. The compound or salt of claim 9 , wherein the compound of formula (I) is
11. The compound or salt of claim 1 , wherein R 4 is an NSAID moiety retaining its NSAID activity.
12. The compound or salt of claim 1 , wherein said NSAID moiety is a moiety of an NSAID selected from the group consisting of aspirin, propionic acid derivatives, acetic acid derivatives, sulphonanilides, licofelone, enolic acid derivatives, fenamic acid derivatives, and selective COX-2 inhibitors.
13. The compound or salt of claim 1 , wherein the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, diclofenac, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxicab, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, nimesulide, licofenac, and niflumic acid.
14. The compound or salt of claim 1 , wherein the compound is selected from the group consisting of:
15. A compound selected from the group consisting of:
wherein:
L is a linking group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, carbonyl, thiocarbonyl, iminocarbonyl, carboxyl, and carbamoyl;
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 2 and R 3 are the same or different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocycyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
or a pharmaceutically acceptable salt of the compound, wherein the compound or pharmaceutically acceptable salt releases HNO at physiological pH.
16. A compound selected from the group consisting of:
wherein:
L is a linking group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, carbonyl, thiocarbonyl, iminocarbonyl, carboxyl, and carbamoyl;
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 2 and R 3 are the same of different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
or a pharmaceutically acceptable salt of the compound, wherein the compound or pharmaceutically acceptable salt releases HNO at physiological pH.
17. The compound or salt of claim 1 , wherein the NSAID is selected from the group consisting of aspirin, ibuprofen, and diclofenac.
18. The compound or salt of claim 17 , wherein the compound is selected from the group consisting of:
19. The compound or salt of claim 17 , wherein the NSAID is aspirin.
20. The compound or salt of claim 19 , wherein the compound or salt is:
21. A pharmaceutical composition comprising (a) the compound of claim 1 or a salt thereof and (b) a pharmaceutically acceptable carrier.
22. A method of treating a disorder in an animal comprising administering an effective amount of a compound or salt of claim 1 , wherein the disorder is chronic or acute heart failure, breast cancer, lung cancer, or inflammation.
23. The method of claim 22 , wherein the disorder is lung cancer.
24. The method of claim 22 , wherein the disorder is breast cancer.
25. The method of claim 22 , wherein the compound or a salt thereof is administered under conditions where HNO is released in a greater quantity than NO.
26. The method of claim 25 , wherein the compound or salt thereof releases substantially all HNO.
27. The method of claim 22 , wherein the compound or salt is in a delayed release pharmaceutical composition.
28. The method of claim 22 , wherein an esterase inhibiting compound is co-administered with the compound or salt thereof.
29. The method of claim 22 , wherein the animal is a human.
30. The method of claim 22 , wherein the disorder is chronic or acute heart failure and the compound of formula (I) is
31. The method of claim 22 , wherein the disorder is breast cancer or lung cancer and the compound or salt is
32. The method of claim 31 , wherein the disorder is breast cancer.
33. The method of claim 31 , wherein the disorder is lung cancer.
34. The method of claim 22 , wherein the disorder is inflammation and the compound or salt is