Novel Alpha-Hydroxy Carboxylic Acid And Derivatives And Other Gras- Based Prodrugs Of Opioids And Uses Thereof

• US 20170196851A1
• Filed: 03/29/2017
• Published: 07/13/2017
• Est. Priority Date: 04/27/2015
• Status: Active Grant

• Current Assignee: John K. Thottathil
• Original Assignee: John K. Thottathil
• Inventors: Thottathil, John K.
• Granted Patent: US 10,449,190 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
• CPC Class Codes: C07D 489/12 the bridge containing only two carbon atoms

Abstract

The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to opioids in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

Claims

1. An opioid prodrug of any of the following formulae where the prodrug moiety X is attached covalently to the opioid molecule,

2. The opioid prodrug of claim 1 wherein the opioid is hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.

3. The opioid prodrug of claim 2 wherein the prodrug moiety X is chemically/covalently attached to hydrocodone or hydromorphone at their 6^th position oxygen atoms as a ketone enolate ester.

4. The opioid prodrug of claim 2 wherein the prodrug moiety X is chemically/covalently attached to morphine, codeine or dihydrocodeine at their 6^th position oxygen atom as an alcohol ester.

5. The opioid prodrug of claim 2 wherein the prodrug moiety X is chemically/covalently attached to buprenorphine at its 17^th position oxygen atom as an alcohol ester.

6. The opioid prodrug according to claim 1, wherein X is a prodrug moiety ligand, selected from the group consisting of alpha-hydroxy carboxylic acid and derivatives as monomers, alpha-hydroxy carboxylic acid homo-oligomers, alpha-hydroxy carboxylic acid hetero oligomers with another alpha-hydroxy carboxylic acid, alpha-hydroxy carboxylic acid hetero oligomers with amino acid, alpha-hydroxy carboxylic acid hetero oligomers with dicarboxylic acids, alpha-hydroxy carboxylic acid hetero oligomers with fatty acids, fatty acids, and other GRAS-based reagents.

7. The opioid prodrug according to claim 6 wherein homo- and hetero-‘

mers’

are linear or branched ‘

mers’

wherein the hetero-‘

mers’

are cross linked with other GRAS reagents.

8. The opioid prodrug according to claim 6 wherein the alpha-hydroxy carboxylic acid is selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, pantothenic acid, 2-hydroxy glutaric acid, 3-hydroxy glutaric acid, and other poly-hydroxy carboxylic acids derived from sugars and carbohydrates.

9. The opioid prodrug according to claim 6 wherein the amino acid is selected from the group consisting of any of the 22 naturally occurring proteinogenic amino acids, non-natural amino acids, naturally occurring (L)-isomers, non-natural (D)-isomers, varying mixtures of the (L) and (D) isomers, racemates and mixtures of diastereomers

10. The opioid prodrug according to claim 6 wherein the fatty acid is a long chain carboxylic acid, ranging in length from eight carbons (C8) to twenty carbons (C20).

11. The opioid prodrug according to claim 10 wherein the fatty is sorbic acid, stearic acid, oleic acid, palmitic acid, or linoleic acid.

12. The opioid prodrug according to claim 6 wherein the dicarboxylic acid of the hetero oligomer with alpha-hydroxy carboxylic acid is fumaric acid, maleic acid, or succinic acid.

13. The opioid prodrug according to claim 6 wherein X is a prodrug moiety consisting of any of ligands 1-16

14. The opioid prodrug according to claim 6 wherein X is a prodrug moiety represented by ligand 17

15. The opioid prodrug according to claim 14, wherein FA is sorbic acid, stearic acid, oleic acid, palmitic acid, or linoleic acid.

19. An oral pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

21. A method of treating pain comprising orally administering the composition of claim 19 to a patient.

16. An opioid prodrug compound represented by any one of formulae 1-90.

17. The opioid prodrug of claim 16 wherein the opioid is Hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.

18. A pharmaceutical composition comprising one or more of the opioid prodrugs according to claim 16 and one or more pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 16, wherein the compound is a pharmaceutically acceptable salt form.