Augmenting moieties for anti-inflammatory compounds

Patent metadata

Field	Value
Publication number	US-10752582-B2
Application number	US-201816022019-A
Country	US
Kind code	B2
Filing date	Jun 28, 2018
Priority date	Nov 3, 2008
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

Augmented or synergized anti-inflammatory constructs are disclosed including anti-inflammatory amino acids covalently conjugated with other anti-inflammatory molecules such as nonsteroidal anti-inflammatory drugs, vanilloids and ketone bodies. Further conjugation with a choline bioisostere or an additional anti-inflammatory moiety further augments the anti-inflammatory activity.

First claim

What is claimed is:

1. An anti-inflammatory drug-amino acid conjugate, comprising:
(a) at least one anti-inflammatory compound conjugated with
(b) an augmenting moiety comprising an anti-inflammatory amino acid-choline bioisostere ester, wherein the amino acid is selected from the group consisting of L-(S)-valine, L-(S)-nor-valine, L-(S)-leucine, L-(S)-iso-leucine, L-(R)-cysteine, L-(S)-proline and L-(S)-phenylalanine;

wherein said amino acid-choline bioisostere ester is an amino acid ester of HOCH 2 CH 2 C(CH 3 ) 3 ;
wherein conjugation of said conjugate is via the nitrogen atom of the amino acid of said augmenting moiety; and
wherein the anti-inflammatory activity of the conjugate is greater than the sum of its parts.

2. The conjugate of claim 1 , wherein said amino acid is selected from the group consisting of L-(S)-valine, L-(S)-proline and L-(S)-phenylalanine.

3. The conjugate of claim 1 , wherein said anti-inflammatory compound is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs).

4. The conjugate of claim 3 , wherein said NSAID is selected from the group consisting of diclofenac, ibuprofen, naproxen, and indomethacin.

5. An anti-inflammatory drug-amino acid conjugate having the structure of Formula (I)
AI—NH—CHR—C(═O)O-Q 1   Formula (I)

wherein AI represents an anti-inflammatory drug moiety selected from the group consisting of NSAID-CO—moieties; wherein R is selected from the group consisting of isopropyl, benzyl, and 2-pyrrolidinyl; and wherein Q 1 is —CH 2 CH 2 C(CH 3 ) 3 .

6. The amino acid conjugate of claim 5 , wherein for the NSAID-CO-moiety, the NSAID is selected from the group consisting of diclofenac, ibuprofen, naproxen and indomethacin.

7. An anti-inflammatory drug-amino acid conjugate selected from the group consisting of:

8. An anti-inflammatory drug-amino acid conjugate of claim 7 selected from the group consisting of:

9. The anti-inflammatory drug-amino acid conjugate of claim 7 , wherein said conjugate is

10. The anti-inflammatory drug-amino acid conjugate of claim 7 , wherein said conjugate is

11. The anti-inflammatory drug-amino acid conjugate of claim 7 , wherein said conjugate is

12. The anti-inflammatory drug-amino acid conjugate of claim 1 , wherein said augmenting moiety is a valine ester.

13. The anti-inflammatory drug-amino acid conjugate of claim 1 , wherein said augmenting moiety is an ester of L-(S)-phenylalanine.

14. The anti-inflammatory drug-amino acid conjugate of claim 1 , wherein said augmenting moiety is an ester of L-(S)-proline.

15. The anti-inflammatory drug-amino acid conjugate of claim 1 , wherein the amino acid of said amino acid-choline bioisostere ester is selected from the group consisting of L-(S)-valine, L-(S)-proline and L-(S)-phenylalanine, and wherein said anti-inflammatory compound is selected from the group consisting of the non-steroidal anti-inflammatory drugs diclofenac, ibuprofen, naproxen, and indomethacin.

Assignees

• Univ Rutgers
• Univ Lehigh

Inventors

• Laskin Jeffrey D
• Heck Diane E
• Lacey Carl J
• Heindel Ned D
• Young Sherri C

Classifications

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• C07D207/16 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D209/18

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title