Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
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 (II) with a compound of Formula (III):
in the presence of a member of the group selected from an organic base, an inorganic base, and a metal salt, wherein:
the organic base is selected from triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazobicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]undec-7-ene or a combination thereof;
X is fluoro, chloro, bromo or iodo;
R 1 is selected from the group consisting of acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloaklyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarboyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterarylalkyl and substituted heteroarylalkyl or optionally, R 2 and R 3 together with the carbon atom to which they are bonded from a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
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 4-cholorophenyl.
2. The method of claim 1 , wherein R 4 is hydrogen.
3. The method of claim 1 , wherein R 1 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, substituted phenyl, C 7-9 phenylalkyl and pyridyl.
4. The method of claim 1 , wherein R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclohexyl, 2-pyridyl, 2-pyridyl and 4-pyridyl.
5. The method of claim 1 , wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl and 3-pyridyl.
6. The method of claim 1 , wherein R 2 and R 3 are independently selected from hydrogen, C 1-4 alkyl, substituted C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxycarbonyl, phenyl, substituted phenyl, C 7-9 phenylalkyl and pyridyl.
7. The method of claim 1 , wherein R 2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, penethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, and R 3 is hydrogen.
8. The method of claim 1 , wherein R 2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, or cyclohexyl and R 3 is hydrogen.
9. The method of claim 1 , wherein R 2 is selected from methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and cyclohexyloxycarbonyl and R3 is methyl.
10. The method of claim 1 , wherein R 4 is selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, substituted phenyl, C 7-9 phenylalkyl, substituted C 7-9 phenylalkyl, trialkylsilyl and aryldialkylsilyl.
11. The method of claim 1 , wherein R4 is selected from hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and phenyldimethylsily.
12. The method of claim 1 , wherein R 4 is selected from hydrogen, allyl, benzyl and trimethylsilyl.
13. The method of claim 1 , wherein:
R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl, and 3-pyridyl;
R 2 is selected from hydrogen, methyl, n-propyl, and isopropyl;
R 3 is hydrogen; and
R 4 is hydrogen.
14. The method of claim 1 , wherein R 2 is methyl.
15. The method of claim 1 , wherein R 2 is isopropyl.
16. The method of claim 15 , wherein R 1 is isopropyl.