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 method of synthesizing a compound of Formula (I) comprising contacting a compound of Formula (XXIII) with a compound of Formula (IV):
wherein:
R 1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloaklyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cyloalkyl, substituted cycloalkyl or optionally, R 2 and R 3 together with the carbon atom to which they are bonded from a cycloalkyl or substituted cycloalkyl;
R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl; and
R 5 is selected from the group consisting of substituted aryl, heteroaryl and substituted heteroaryl; and
R 9 and R 10 are hydrogen.
2. The method of claim 1 , wherein R 2 and R 3 in the compound of Formula (XXIII) are different, such that the carbon atom to which these substitutents are attached is a stereogenic center.
3. The method of claim 1 , wherein R 1 is isopropyl, R 2 is isopropyl, R 3 is hydrogen, the stereochemistry at the carbon to which R 2 and R 3 are attached is of the S-configuration and the compound of Formula (I) is substantially one diastereomer.
4. The method of claim 1 , wherein R 1 is isopropyl, R 2 is isopropyl, R 3 is hydrogen, the stereochemistry at the carbon to which R 2 and R 3 are attached is of the R-configuration and the compound of Formula (I) is substantially one diastereomer.
5. The method of claim 1 , wherein R 1 is isopropyl, R 2 is isopropyl, R 3 is hydrogen, R 4 is hydrogen, R 5 is 4-cholorophenyl, R 9 is hydrogen and R 10 is hydrogen.
6. The method of claim 1 , wherein the method is carried out at a temperature between −20° C. and 40° C.
7. The method of claim 1 , wherein the method is performed in the presence of an inorganic base.
8. The method of claim 7 , wherein the inorganic base is selected from an alkali metal bicarbonate and alkali metal carbonate salt.
9. The method of claim 1 , wherein the method is carried out in a solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, dichloroethane, chloroform, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, pyridine, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol, water and combinations thereof.
10. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (V):
11. The method of claim 10 , wherein the compound of Formula (I) has the structure of Formula (VI):