Alpha- and gamma-truxillic acid derivatives and pharmaceutical compositions thereof

Patent metadata

Field	Value
Publication number	US-9604904-B2
Application number	US-201314413621-A
Country	US
Kind code	B2
Filing date	Jul 19, 2013
Priority date	Jul 20, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

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, having the structure:

First claim

What is claimed is:

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 pal

Assignees

• Ojima Iwao
• Deutsch Dale
• Kaczocha Martin
• Berger William T
• Rizzo Robert
• Balius Trent E
• Univ New York State Res Found

Inventors

• Ojima Iwao
• Deutsch Dale
• Kaczocha Martin
• Berger William T
• Rizzo Robert
• Balius Trent E

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C235/38

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C235/40

  having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C07C69/76

  Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring · CPC title