Alpha-chloro and alpha-bromo phosphonate analogs of lysophosphatidic acid and methods of making and using thereof
Described herein is the synthesis and pharmacology of a series of α-substituted methylene phosphonate analogs, in which the α-CH 2 moiety is replaced with CHCl or CHBr.
1. A compound having the formula I
wherein
each R 1 is, independently, hydrogen, a branched or straight chain C 1 to C 25 alkyl group, a cationic counterion, or both R 1 form a cyclic or heterocyclic group; R 3 is a branched or straight chain C 1 to C 25 alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group,
or the pharmaceutically acceptable salt or ester thereof,
wherein the stereochemistry at carbon a is substantially S, and the stereochemistry at carbon b is substantially R or substantially S.
2. The compound of claim 1 , wherein R 3 is a branched or straight chain C 1 to C 25 alkyl group, and each R 1 is hydrogen.
3. The compound of claim 2 , wherein R 3 is an oleate group or a palmitate group.
4. The compound of claim 1 , wherein the stereochemistry at carbon b is substantially R.
5. The compound of claim 1 , wherein the stereochemistry at carbon b is substantially S.
6. The compound of claim 1 , wherein the compound is 1-(S)-bromo-3-(S)-hydroxy-4-(palmitoyloxy)butyl]phosphonate.
7. The compound of claim 1 , wherein the compound is 1-(R)-bromo-3-(S)-hydroxy-4-(palmitoyloxy)butyl]phosphonate.
8. A pharmaceutical composition comprising a pharmaceutically-acceptable compound and the compound of claim 1 .
9. The compound of claim 1 , wherein the stereochemistry at carbon a is greater than 95% the S enantiomer with respect to the R enantiomer.
10. The compound of claim 9 , wherein the stereochemistry at carbon b is greater than 95% the S enantiomer with respect to the R enantiomer.
11. The compound of claim 9 , wherein the stereochemistry at carbon b is greater than 95% the R enantiomer with respect to the S enantiomer.