Modulation of cell death
A method of modulating cell death includes administering pyridoxal-5′phosphate, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, or pharmaceutical compositions thereof.
1 . A method of modulating cell death comprising administering a therapeutically effective amount of at least one of pyridoxal-5′-phosphate, pyridoxic acid, pyridoxal, pyridoxine, or pyridoxamine.
2 . A method of modulating cell death comprising administering a therapeutically effective amount of at least one compound of the formula
wherein
R 1 is alkyl or alkenyl, in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy;
aryl, aryloxy, arylthio, or aralkyl,in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy,halo, nitro, or alkanoyloxy; or
a pharmaceutically acceptable salt thereof.
3 . The method of claim 2 , wherein said R 1 is phenyl or naphthyl in which phenyl or naphthyl is unsubstituted or substituted by one or more groups of C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, halo, nitro, or C 1-4 alkanoyloxy.
4 . The method of claim 2 , wherein said R 1 is (2-acetoxy-2-methyl)propanyl, dimethylamino, or 1-ethanoyloxy-1-methylethyl.
5 . The method of claim 2 , wherein said R 1 is tert-butyl.
6 . The method of claim 2 , wherein said R 1 is methoxy or ethoxy.
7 . The method of claim 2 , wherein said R 1 is toluyl, naphthyl, phenyl, acetylphenyl, or 1-ethanoyloxyphenyl.
8 . The method of claim 2 , wherein said R 1 is acetylsalicyl, dimethylamino, or 2,2-dimethylethyl.
9 . The method of claim 2 , wherein said compound is 2-methyl-3-toluoyloxy-4-formyl-5-hydroxymethylpyridine.
10 . The method of claim 2 , wherein said compound is 2-methyl-3-β-naphthoyloxy-4-formyl-5-hydroxymethylpyridine.
11 . A method of modulating cell death comprising administering a therapeutically effective amount of at least one compound of the formula
wherein
R 1 is alkyl or alkenyl, in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl alkoxycarbonyl, or dialkylcarbamoyloxy,
alkoxy,
dialkylamino;
alkanoyloxy,
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy;
aryl, aryloxy, arylthio, or aralkyl,in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy,halo, nitro, or alkanoyloxy, and
R 2 is a secondary amino group; or
a pharmaceutically acceptable salt thereof.
12 . The method of claim 11 , wherein said R 1 is phenyl or naphthyl in which phenyl or naphthyl is unsubstituted or substituted by one or more groups of C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, halo, nitro, or C 1-4 alkanoyloxy.
13 . The method of claim 11 , wherein said R 1 is (2-acetoxy-2-methyl)propanyl, dimethylamino, or 1-ethanoyloxy-1-methylethyl.
14 . The method of claim 11 , wherein said wherein R 1 is tert-butyl.
15 . The method of claim 11 , wherein said wherein R 1 is methoxy or ethoxy.
16 . The method of claim 11 , wherein said R 1 is toluyl, naphthyl, phenyl, or 1-ethanoyloxyphenyl.
17 . The method of claim 11 , wherein said R 1 is dimethylamino, acetylsalicyl, or 2,2-dimethylethyl.
18 . The method of claim 11 , wherein said R 2 is a group of the formula
wherein R 3 and R 4 are each independently alkyl or when taken together form a ring with the nitrogen atom and which ring may optionally be interrupted by a nitrogen or oxygen atom.
19 . The method of claim 11 , wherein said R 2 is piperidino.
20 . The method of claim 11 , wherein said R 2 is morpholino or piperazino.
21 . The method of claim 11 , wherein said compound is 1-morpholino-1,3-dihydro-7-(p-toluoyloxy)-6-methylfuro(3,4-c)pyridine.
22 . The method of claim 11 , wherein said compound is 1-morpholino-1,3-dihydro-7-(β-naphthoyloxy)-6-methylfuro(3,4-c)pyridine.
23 . The method of claim 11 , wherein said compound is 1-morpholino-1,3-dihydro-7-pivaloyloxy-6-methylfuro(3,4-c)pyridine.
24 . The method of claim 11 , wherein said compound is 1-morpholino-1,3-dihydro-7-(dimethylcarbamoyloxy-6-methylfuro(3,4-c)pyridine.
25 . The method of claim 11 , wherein said compound is 1-morpholino-1,3-dihydro-7-acetylsalicyloxy-6-methylfuro(3,4-c)pyridine.
26 . A method of modulating cell death comprising administering a therapeutically effective amount of at least one compound of the formula
wherein
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 6 in which R 6 is hydrogen, alkyl, or aryl;
or
R 2 is —CH 2 —O-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, alkanoyloxy, alkylamino or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable salt thereof.
27 . The method of claim 26 , wherein said R 1 is hydrogen.
28 . The method of claim 26 , wherein said R 2 is —CH 2 OH, or —CH 2 —O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 .
29 . The method of claim 26 , wherein said R 3 is hydrogen and R 4 is F, MeO—, or CH 3 C(O)O—.
30 . The method of claim 26 , wherein said R 3 and R 4 are F.
31 . The method of claim 26 , wherein said R 5 is alkyl or aralkyl.
32 . The method of claim 26 , wherein said R 5 is t-butyl or benzyl.
33 . A method of claim 26 , wherein said compound is
34 . A method modulating cell death comprising administering a therapeutically effective amount of at least one compound of the formula
wherein
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 or CO 2 R 5 in which R 5 is hydrogen, alkyl, or aryl; or
R 2 is —CH 2 O-alkyl- (in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 );
R 3 is hydrogen, alkyl, aryl, or aralkyl;
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 6 in which R 6 is hydrogen, alkyl, aryl, or aralkyl; and
n is 1 to 6;
or a pharmaceutically acceptable salt thereof
35 . The method of claim 34 , wherein said R 1 is hydrogen.
36 . The method of claim 34 , wherein said R 2 is —CH 2 OH, or —CH 2 —O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 .
37 . The method of claim 34 , wherein said R 3 is hydrogen.
38 . The method of claim 34 , wherein said R 4 is alkyl or H.
39 . The method of claim 34 , wherein said R 4 is ethyl.
40 . The method of claim 34 , wherein said compound is
41 . A method modulating cell death comprising administering a therapeutically effective amount of at least one compound of the formula
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— O-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 alkanoyloxy; 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 salt thereof.
42 . The method of claim 41 , wherein R 1 is hydrogen.
43 . The method of claim 41 , 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 .
44 . The method of claim 41 , wherein said R 4 is —OH or CH 3 C(O)O—.
45 . The method of claim 41 , wherein said R 3 and R 4 taken together form ═O.
46 . The method of claim 41 , wherein said R 5 and R 6 are F.
47 . The method of claim 41 , wherein said R 7 is alkyl.
48 . The method of claim 41 , wherein said R 7 is ethyl.
49 . The method of claim 41 , wherein said compound is