Benzenedicarboxylic acid derivatives
View Patent ↗New benzenedicarboxylic acid derivative compounds; pharmaceutical compositions, diagnostic methods, and diagnostic kits that include those compounds; and methods of using those compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-β activity, inhibiting angiogenesis, and treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, and glaucoma.
1. A compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —NR—(CR 3 R 4 ) m -heteroaryl or
wherein X is oriented meta or para to C-1;
m is 1-3;
R 3 , R 4 , and R 5 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C 1 -C 6 alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or alkoxy is independently unsubstituted or substituted with one or more substituent(s); and
Y is —COOH oriented meta or para relative to C-1.
2. The compound of claim 1 , wherein:
X is oriented meta relative to C-1; and
Y is oriented ortho relative to X and para relative to C-1.
3. The compound of claim 2 , wherein the compound is 2-[(2- furanylmethyl)-amino]-1,4-benzenedicarboxylic acid (10) or a pharmaceutically acceptable equivalent.
4. The compound of claim 1 , wherein:
X is oriented ortho relative to C-1; and
Y is oriented para relative to X and meta relative to C-1.
5. The compound of claim 4 , wherein the compound is:
4-[(2-furanylmethyl)amino]-1,3-benzenedicarboxylic acid (21) or a pharmaceutically acceptable equivalent.
6. The compound of claim 1 , wherein:
X is oriented meta relative to C-1; and
Y is oriented meta relative to X and meta relative to C-1.
7. The compound of claim 6 , wherein the compound is:
5-[4,5-dihydro-5-(4-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl]-1,3-benzenedicarboxylic acid (23);
5-(4,5dihydro-3methyl-5-phenyl-1H-pyrazol-1-yl)-1,3-benzenedicarboxylic acid (24); or
a pharmaceutically acceptable equivalent.
8. A pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I
or a pharmaceutically acceptable equivalent, wherein:
X is —NH—(CR 3 R 4 ) m -heteroaryl or
wherein X is oriented meta or para to C-1;
m is 1-3;
R 3 , R 4 , and R 5 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino or C 1 -C 6 alkoxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or alkoxy is independently unsubstituted or substituted with one or more substituent(s); and
Y is —COOH oriented meta or para relative to C-1; and
(ii) a pharmaceutically acceptable carrier.
9. The composition of claim 8 , wherein:
X is oriented meta relative to C-1; and
Y is oriented ortho relative to X and para relative to C-1.
10. The composition of claim 9 , wherein the compound of formula I is selected from the group consisting of:
2-[(4-carboxyphenyl)sulfonyl]-1,4-benzene-dicarboxylic acid (1);
2-[(2,5-dicarboxyphenyl)sulfonyl]-1,4-benzene-dicarboxylic acid (2);
1,2,4-benzenetricarboxylic acid (3);
2-[(2-carboxyphenyl)thio]-1,4-benzenedicarboxylic acid (4);
2-nitro-1,4-benzenedicarboxylic acid (5);
2-bromo-1,4-benzenedicarboxylic acid (6);
2-amino-1,4-benzenedicarboxylic acid (7);
2-sulfoterephthalic acid, monosodium salt (8);
2-carboxymethyl-1,4-benzenedicarboxylic acid (9);
2-[(2-furanylmethyl)-amino]-1,4-benzenedicarboxylic acid (10);
2-[(carboxymethyl)amino]- 1,4-benzenedicarboxylic acid (11); and
pharmaceutically acceptable equivalents.
11. The composition of claim 8 , wherein:
X is oriented ortho relative to C-1; and
Y is oriented para relative to X and meta relative to C-1.
12. The composition of claim 11 , wherein the compound of formula I is 4-[(2-furanylmethyl)amino]-1,3-benzenedicarboxylic acid (21) or a pharmaceutically acceptable equivalent.
13. The composition of claim 8 , wherein:
X is oriented meta relative to C-1; and
Y is oriented meta relative to X and meta relative to C-1.
14. The composition of claim 13 , wherein the compound of formula I is selected from the group consisting of:
5-[4,5-dihydro-5-(4-hydroxyphenyl)-3-phenyl-1H-pyrazol-1-yl]-1,3-benzenedicarboxylic acid (23);
5-(4,5-dihydro-3-methyl-5-phenyl-1H-pyrazol-1-yl)-1,3-benzenedicarboxylic acid (24); and
pharmaceutically acceptable equivalents.