Alpha-truxillic acid derivatives and pharmaceutical compositions thereof

Patent metadata

Field	Value
Publication number	US-11739047-B2
Application number	US-202117174030-A
Country	US
Kind code	B2
Filing date	Feb 11, 2021
Priority date	Mar 11, 2016
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

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, said compound having the structure: Formula (I)

First claim

What is claimed is:

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)OH and the other of R 1 or R 2 is —C(═O)OR 13 or —C(═O)O-alkyl-R 14 ,
wherein
R 13 is cycloalkyl, aryl or heteroaryl, and
R 14 is CF 3 , cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; and

R 3 , R 4 , R 5 , R 6 , Ry, R 8 , R 9 , R 10 , R 11 and R 12 are each independently, H—OR 15 or halogen
wherein R 15 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, or heteroaryl,

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 1-naphthyl or 2-naphthyl or —C(═O)O-alkyl-R 14 where the alkyl is a branched C 2 alkyl and the R 14 is phenyl,
or an enantiomer or racemate thereof;
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)OH and the other of R 1 or R 2 is —C(═O)OR 13 or —C(═O) O-alkyl-R 14 ,
wherein
R 13 is cycloalkyl, aryl or heteroaryl, and
R 14 is CF 3 , cycloalkyl, aryl or heteroaryl; and

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 15 or halogen
wherein R 15 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, or heteroaryl,

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 1-naphthyl or 2-naphthyl, or —C(═O)O-alkyl-R 14 where the alkyl is a branched C 2 alkyl and the R 14 is phenyl,
or is an enantiomer or racemate thereof;
or is a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein when one of R 1 or R 2 of the compound 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 tolyl, 1-naphthyl or 2-naphthyl, or —C(═O)O-alkyl-R 14 where the alkyl is a branched C 2 alkyl and the R 14 is phenyl.

4. The method of claim 1 , wherein when one of R 1 or R 2 of the compound is —C(═O)OH and the other of R 1 or R 2 is —C(═O)OR 13 where R 13 is 1-naphthyl or 2-naphthyl, then one, two, or four of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is other than —H.

5. The method of claim 1 ,
wherein
(a) one of R 1 or R 2 of the compound is —C(═O)R 13 ,
wherein R 13 is cycloalkyl, aryl or heteroaryl; and

the other of R 1 or R 2 is —C(═O)OH;
(b) one of R 1 or R 2 of the compound is —C(═O)O-alkyl-R 14 ,
wherein R 14 is CF 3 , cycloalkyl, aryl or heteroaryl; and

the other of R 1 or R 2 is —C(═O)OH;
(c) one of R 1 or R 2 of the compound is —C(═O)O—(C 1-6 alkyl)-R 14 ,
wherein R 14 is CF 3 , cycloalkyl, aryl or heteroaryl; and

the other of R 1 or R 2 is —C(═O)OH; or
(d) one of R 1 or R 2 of the compound is —C(═O)O—CH 3 —R 14 ,
wherein R 14 is CF 3 , cycloalkyl, aryl or heteroaryl; and

the other of R 1 or R 2 is —C(═O)OH.

6. The method of claim 1 , wherein the aryl of the compound is a substituted aryl.

7. The method of claim 6 , wherein the aryl of the compound is substituted with a halogen, —OH, heteroaryl, C 2 -C 6 alkynyl or —O(alkyl), amide, aryl, hydroxyaryl, F, Cl, Br, —OH, I, —NHC(O)CH 3 , triazolyl, C 2 alkylnyl, phenyl, o-hydroxyphenyl or —OCH 3 .

8. The method of claim 1 , wherein the heteroaryl of the compound is a substituted heteroaryl.

9. The method of claim 8 , wherein the heteroaryl is substituted with a halogen, —OH, heteroaryl, C 2 -C 6 alkynyl or —O(alkyl), amide, aryl or hydroxyaryl, F, Cl, Br, —OH, I, —NHC(O)CH 3 , triazolyl, C 2 alkylnyl, phenyl, o-hydroxyphenyl or —OCH 3 .

10. The method of claim 1 , wherein the cycloalkyl of the compound is a substituted cycloalkyl.

11. The method of claim 10 , wherein the cycloalkyl of the compound is substituted with a phenyl or a fused benzo group.

12. The method of claim 1 , wherein the cycloalkyl of the compound is:

13. The method of claim 1 , wherein one of R 1 or R 2 of the compound is:

and
the other of R 1 or R 2 of the compound is —C(═O)OH; or wherein one of R 1 or R 2 of compound is

and
the other of R 1 or R 2 of the compound is —C(═O)OH.

14. The method of claim 1 , wherein
(a) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of the compound are each independently, —H, halogen or —OR 15 , wherein R 15 is —H or C 1-10 alkyl;
(b) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of the compound are each independently, —H or —NO 2 ; or
(c) wherein R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 and R 12 of the compound are each —H; and R 5 and R 10 are each halogen or —OR 15 , wherein R 15 is —H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, or heteroaryl.

15. The method of claim 1 , wherein one, two, or four of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of the compound is other than —H.

16. The method of claim 1 , wherein the compound is the (S,S) enantiomer or the compound is the (R,R) enantiomer.

17. The method of claim 1 , wherein the compound has the following structure:

or is an enantiomer or racemate thereof;
or is a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound inhibits binding of an FABP ligand to the FABP.

19. The method of claim 18 , wherein the FABP ligand is an endocannabinoid ligand.

20. The method of claim 18 , wherein the FABP ligand is anandamide (AEA) or 2-arachidonoylglycerol (2-AG).

Assignees

• Univ New York State Res Found

Inventors

• Ojima Iwao
• Deutsch Dale
• Kaczocha Martin
• Hu Kongzhen
• Tong Simon
• Elmes Matthew
• Yan Su

Classifications

• C07C69/753 Primary

  of polycyclic acids · CPC title

• C07C61/04

  Saturated compounds having a carboxyl group bound to a three or four-membered ring · CPC title

• C07C69/757

  having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] in the acid moiety · CPC title

• C07C205/55

  having nitro groups or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton · CPC title

• C07C233/25

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title