Alpha- and gamma-truxillic acid derivatives and pharmaceutical compositions thereof
The present invention provides a compound, and method of inhibiting the activity of a Fatty Acid Binding Protein (FABP) comprising contacting the FABP with a compound, having the structure:
1. A compound having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O)NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently, H, halogen, —NO 2 , —CN, —NHR 15 , —NR 15 R 16 , —SR 15 , —SO 2 R 15 , —OR 15 , —CO 2 R 15 , CF 3 , -alkyl-NR 15 R 16 , -alykl-OR 15 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl,
or an enantiomer or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O) NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H, halogen, —NO 2 , —CN, —NHR 15 , —NR 15 R 16 , —SR 15 , —SO 2 R 15 , —OR 15 , —CO 2 R 15 , CF 3 , -alkyl-NR 15 R 16 , -alykl-OR 15 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl;
when one of R 1 or R 2 is —C(═O)OH and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each H, then the other of R 1 or R 2 is other than —C(C═O)OR 13 where R 13 is 1-naphthyl,
or an enantiomer or pharmaceutically acceptable salt thereof.
3. The compound of claim 1 ,
wherein
one of R 1 or R 2 is
and
the other of R 1 or R 2 is —C(═O)OH.
4. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
6. A compound having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O)NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H, halogen, —NO 2 , —CN, —NHR 15 , —NR 15 R 16 , —SR 15 , —SO 2 R 15 , —OR 15 , —CO 2 R 15 , CF 3 , -alkyl-NR 15 R 16 , -alykl-OR 15 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl,
or an enantiomer or pharmaceutically acceptable salt thereof.
7. The compound of claim 6 having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O)NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H, halogen, —NO 2 , —CN, —NHR 15 , —NR 15 R 16 , —SR 15 , —SO 2 R 15 , —OR 15 , —CO 2 R 15 , CF 3 , -alkyl-NR 15 R 16 , -alykl-OR 15 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl;
when one of R 1 or R 2 is —C(═O)OH and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each H, then the other of R 1 or R 2 is other than —C(═O)OR 13 where R 13 is 1-naphthyl,
or an enantiomer or pharmaceutically acceptable salt thereof.
8. The compound of claim 6 ,
wherein
one of R 1 or R 2 is
and
the other of R 1 or R 2 is —C(═O)OH.
9. The compound of claim 6 having the structure:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 6 having the structure:
or a pharmaceutically acceptable salt thereof.
11. A process for producing the compound of claim 6 comprising:
(a) contacting a compound having the structure:
with acetic anhydride in the presence of sodium acetate so as to produce a compound having the structure:
(b) reacting the product of step (a) with a nucleophile (Nuc) in the presence of an amine base so as to produce a mixture of enantiomers having the structures:
12. The process of claim 11 , wherein the nucleophile used B in step (b) is selected from the group consisting of
a chiral nucleophile; or
(S)-(−)-1-phenylethanol.
13. The process of claim 11 , wherein the products of step (b) are
14. The process of claim 11 , further comprising
(c) separating the diastereomeric products of step (b) to produce enantiopure compounds having the structure:
(d) reacting a product of step (c) with a coupling reagent in the presence of a nucleophile so as to produce enantiopure compounds having the structure:
(e) reacting the product of step (d) with hydrogen in the presence of palladium on carbon to produce an enantiopure
compound having the structure:
15. A method of inhibiting the activity of a Fatty Acid Binding Protein (FABP) comprising contacting the FABP with the compound of claim 1 .
16. A method of inhibiting the activity of a Fatty Acid Binding Protein (FABP) comprising contacting the FABP with the compound of claim 6 .
17. The method of claim 15 , wherein the compound inhibits B binding of an FABP ligand to the FABP; wherein the FABP ligand is an endocannabinoid ligand, anandamide (AEA) or 2-arachidonoylglycerol (2-AG).
18. The method of claim 16 , wherein the compound inhibits B binding of an FABP ligand to the FABP; wherein the FABP ligand is an endocannabinoid ligand, anandamide (AEA) or 2-arachidonoylglycerol (2-AG).
19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.
21. The compound of claim 1 having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O)NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H or —OR 15 ,
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl,
or an enantiomer or pharmaceutically acceptable salt thereof.
22. The compound of claim 6 having the structure:
wherein
one of R 1 or R 2 is —C(═O)OR 13 , —C(═O)NHR 13 , -alkyl-C(═O)NHR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , or -alkyl-NHR 13 ,
wherein R 13 is an unsubstituted bicyclic aryl or unsubstituted heteroaryl; and
the other of R 1 or R 2 is —C(═O)OH;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H or —OR 15 ,
wherein R 15 and R 16 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl,
or an enantiomer or pharmaceutically acceptable salt thereof.