Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
View Patent ↗The disclosures herein relate generally to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, pharmaceutical compositions thereof, methods of making prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, methods of using prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, and pharmaceutical compositions thereof for treating or preventing common diseases and/or disorders such as spasticity and/or acid reflux disease. The disclosures herein also relate to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof which are suitable for oral administration and to sustained release oral dosage forms thereof.
1. A compound of Formula (V):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 3 and R 4 are each hydrogen;
R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl and cyclohexyl; and
R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl and cyclohexyl.
2. The compound of claim 1 having Formula (VI):
3. The compound of claim 1 or 2 , wherein R 2 is isopropyl.
4. The compound of claim 1 or 2 , wherein R 1 is methyl, ethyl, n-propyl or isopropyl.
5. The compound of claim 1 or 2 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl or cyclohexyl, and R 2 is hydrogen.
6. The compound of claim 1 or 2 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl or cyclohexyl, and R 2 is methyl, n-propyl, or isopropyl.
7. The compound of claim 1 , wherein R 1 is isopropyl, and R 2 is isopropyl.
8. The compound of claim 2 , wherein R 1 is isopropyl, and R 2 is isopropyl.
9. The compound of claim 8 , which is substantially one diastereomer.
10. The compound of claim 8 , wherein the stereochemistry at the carbon to which R 2 and R 3 are attached is of the S-configuration.
11. The compound of claim 8 , wherein the stereochemistry at the carbon atom to which R 2 and R 3 are attached is of the R-configuration.
12. The compound of claim 1 or 2 , wherein R 2 is hydrogen and R 1 is phenyl.
13. The compound of claim 1 or 2 , wherein R 2 is isopropyl and R 1 is methyl.
14. The compound of claim 1 or 2 , wherein R 2 is isopropyl and R 1 is n-propyl.
15. The compound of claim 1 or 2 , wherein R 2 is methyl and R 1 is n-propyl.
16. The compound of claim 1 or 2 , wherein R 2 is methyl and R 1 is isopropyl.
17. The compound of claim 1 or 2 , wherein R 2 is methyl and R 1 is phenyl.
18. The compound of claim 1 or 2 , wherein R 2 is hydrogen and R 1 is 1,1 -diethoxyethyl.
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable vehicle.
20. The composition of claim 19 comprising an oral sustained release dosage form.
21. The composition of claim 20 , wherein the dosage form is adapted to be swallowed by a patient in order to introduce the dosage form into an intestinal lumen of the patient;
the dosage form further being adapted to release the compound of claim 1 gradually into the intestinal lumen of the patient over a period of hours after said swallowing, said gradual release causing cleavage of the compound of claim 1 after said swallowing to provide a therapeutic concentration of baclofen in the plasma of the patient.
22. The composition of claim 21 , wherein baclofen is R-baclofen.
23. The composition of claim 21 , wherein the period of hours comprises at least about 6 hours.
24. The composition of claim 21 , wherein the period of hours comprises at least about 8 hours.
25. The composition of claim 21 , wherein the period of hours comprises at least about 12 hours.