α- and γ-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 method of inhibiting the activity of a Fatty Acid Binding Protein (FABP) comprising contacting the FABP with a compound having the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)OR 13 , —C(═O)NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)R 13 , -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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-NHR 15 , -alkyl-NHR 15 R 16 , -alkyl-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 a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound has the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)OR 13 , —C(═O)NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)R 13 , -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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-NHR 15 , -alkyl-NHR 15 R 16 , 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,
wherein 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 —CH 3 , —CH 2 CH 3 , tolyl or propyl 1-bromo-1-methylpropanoyloxybutyl ester, or —C(═O)NR 13 R 14 where one of R 13 or R 14 is phenyl and the other is —H, or both of R 13 and R 14 are —H, and
or an enantiomer or pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound has the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)OR 13 , —C(═O) NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)R 13 , -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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 , 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,
wherein 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 —CH 3 , —CH 2 CH 3 , —(CH 2 ) 4 CH 3 , —(CH 2 ) 7 CH 3 , —CH(CH 3 ) 2 , —CH 2 C(O)CH 3 , tolyl, 1-Naphthol or propyl 1-bromo-1-methylpropanoyloxybutyl ester, or —C(═O)NR 13 R 14 where one of R 13 or R 14 is phenyl and the other is —H, or both of R 13 and R 14 are —H, and
or an enantiomer or pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound has the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)CR 13 , —C(═O)NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)Rn, -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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-NHR 15 , -alkyl-NHR 15 R 16 , -alkyl-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,
wherein when one of R 1 or R 2 is —C(αO)OH, then the other of R 1 or R 2 is other than —C(═O)OR 13 where R 13 is alkyl, heteroalkyl, substituted phenyl or benzyl, —C(═O)NHR 13 R 14 where one of R 13 or R 14 is —H, phenyl or substituted phenyl and the other is —H, or —C(═O)NR 13 R 14 where R 13 and R 14 combine to form a piperidine or morpholine,
or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 ,
wherein
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 alkyl, heteroalkyl, substituted phenyl or benzyl, —C(═O)NHR 13 R 14 where one of R 13 or R 14 is —H, phenyl or substituted phenyl and the other is —H, or —C(═O)NR 13 R 14 where R 13 and R 14 combine to form a piperidine or morpholine.
6. The method of claim 1 , wherein the compound has the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)OR 13 , —C(═O) NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)R 13 , -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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-NHR 15 , -alkyl-NHR 15 R 16 , -alkyl-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 a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound has the structure:
wherein
one of R 1 or R 2 is —C(═O)R 13 , —C(═O)OR 13 , —C(═O)NR 13 R 14 , -alkyl-OC(═O)OR 13 , -alkyl-OC(═O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(═O)R 13 , -alkyl-NHC(═O)OR 13 , -alkyl-NHC(═O)NR 13 R 14 , -alkyl-NHC(═S)NR 13 R 14 , or -alkyl-NHC(═NR 13 )NR 13 R 14 ,
wherein R 13 and R 14 are each, independently, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or combine to form a cycloalkyl or heterocyclyl; and
the other of R 1 or R 2 is —C(═O)OR 13 , wherein R 13 is H;
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-NHR 15 , -alkyl-NHR 15 R 16 , -alkyl-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 a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound inhibits binding of an FABP ligand to the FABP.
13. The method of claim 1 , wherein the FABP ligand is an endocannabinoid ligand.
14. The method of claim 1 , wherein the FABP ligand is anandamide (AEA) or 2-arachidonoylglycerol (2-AG).