Cardioprotective phosphonates and malonates
View Patent ↗The present invention provides for pyridoxine phosphonate analogues such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates, and (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) and to pyridoxine malonate analogues, such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates), pharmaceutical compositions, and methods for treatment of cardiovascular and related diseases, and diabetes mellitus and related diseases.
1. A compound of the formula III
in which
R 1 is hydrogen or alkyl;
R 2 is CHO, —CH 2 OH, —CH 3 or CO 2 R 8 in which R 8 is hydrogen, alkyl, or aryl; or
R 2 is —CH 2—0 -alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy or alkylcarbonyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R 6 are hydrogen; or
R 5 and R 6 are halo; and
R 7 is hydrogen, alkyl, aryl, aralkyl, or CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1 , wherein R 1 is hydrogen.
3. A compound according to claim 1 , wherein R 2 is —CH 2 O or —CH 2— O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 .
4. A compound according to claim 1 , wherein R 4 is —OH or CH 3 C(O)O—.
5. A compound according to claim 1 , wherein R 3 and R 4 taken together form ═O.
6. A compound according to claim 1 , wherein R 5 and R 6 are F.
7. A compound according to claim 1 , wherein R 7 is alkyl.
8. A compound according to claim 7 , wherein R 7 is ethyl.
9. A compound according to claim 1 selected from
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 .
11. A pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is in a form suitable for enteral or parenteral administration.