Dantrolene prodrugs and methods of their use
The disclosure is directed to dantrolene prodrugs, compositions thereof, and methods of their use in the treatment of disease.
1. A compound of formula I
wherein R is
—P(O)(OH) 2 or —P(O)(OR 1 )(OR 2 );
R 1 is H, —C 1-26 alkyl, aryl, C 1-6 alkC(O)O—C 1-26 alkyl, —C 1 alkOC(O)C 1-26 alkyl, or C 1 alkOC(O)OC 1-26 alkyl; and
R 2 is —C 1-26 alkyl, aryl, C 1-6 alkC(O)O—C 1-26 alkyl, —C 1 alkOC(O)C 1-26 alkyl, or C 1 alkOC(O)OC 1-26 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R is —P(O)(OH) 2 .
3. The compound of claim 1 , wherein R is P(O)(OR 1 )(OR 2 ).
4. The compound of claim 3 , wherein R 1 is H.
5. The compound of claim 3 , wherein R 1 is —C 1-26 alkyl.
6. The compound of claim 3 , wherein R 1 is aryl.
7. The compound of claim 3 , wherein R 1 is C 1-6 alkC(O)O—C 1-26 alkyl.
8. The compound of claim 3 , wherein R 1 is —C 1 alkOC(O)C 1-26 alkyl.
9. The compound of claim 3 , wherein R 1 is C 1 alkOC(O)OC 1-26 alkyl.
10. The compound of claim 4 , wherein R 2 is —C 1-26 alkyl, aryl.
11. The compound of claim 4 , wherein R 2 is C 1-6 alkC(O)O—C 1-26 alkyl.
12. The compound of claim 4 , wherein R 2 is —C 1 alkOC(O)C 1-26 alkyl.
13. The compound of claim 4 , wherein R 2 is C 1 alkOC(O)OC 1-26 alkyl.
14. The compound of claim 1 , in the form of a pharmaceutically acceptable salt.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient.
16. A method of treating a disorder responsive to dantrolene in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof;
wherein the disorder is selected from malignant hyperthermia, chronic spasticity, exertional heat stroke, cardiac arrhythmias, tachycardia, atrial fibrillation, cardiac arrest, myocardial infarction, heart failure, myocardial injury, cardiomyopathy, central core disease, amyotrophic lateral sclerosis, rhabdomyolysis, Duchenne muscular dystrophy, ataxia, detrusor overactivity, overactive bladder, seizure, epilepsy, neuroleptic malignant syndrome, human stress disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, ischemia-reperfusion injury, neuronal reperfusion injury, hypoxia, cerebral aneurysm, subarachnoid hemorrhage, stroke, hyperthermia associated with drug abuse, hyperthermia associated with drug overdose, nerve agent exposure, nerve gas exposure, or acetylcholine accumulation.
17. The method of claim 16 , wherein the administration is intravenous administration.
18. The method of claim 16 , wherein the administration is intramuscular administration.
19. The method of claim 16 , wherein the administration is oral administration.
20. The method of claim 16 , wherein the administration is subcutaneous.
21. The method of claim 16 , wherein the administration is intranasal.
22. The method of claim 16 , wherein the administration is intraosseous.
23. A compound of formula II-A
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 23 , wherein the compound of formula II-A is