Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof

• US 10,457,627 B2
• Filed: 09/22/2016
• Issued: 10/29/2019
• Est. Priority Date: 09/23/2015
• Status: Active Grant

• Current Assignee: XWPharma Ltd.
• Original Assignee: XW Laboratories, Inc.
• Inventors: Xiang, Jia-Ning, Xu, Xuesong, Zhang, Xuan
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US15/762,559
• Publication Number:
  US 20190194120A1
• Time in Patent Office: 1,132 Days
• Field of Search: 514423, 514546, 514547, 560155
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 229/08 the nitrogen atom of the amino group being further bound to hydrogen atoms
• CPC Class Codes: C07C 229/34 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 233/47 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 Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07C 2601/06 with a five-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/34 with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 317/14 : having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 69/22 : having three or more carbon atoms in the acid moiety
• CPC Class Codes: C07C 69/24 : esterified with monohydroxylic compounds
• CPC Class Codes: C07C 69/28 : esterified with dihydroxylic compounds
• CPC Class Codes: C07C 69/34 : Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
• CPC Class Codes: C07C 69/608 : Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
• CPC Class Codes: C07C 69/612 : Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
• CPC Class Codes: C07C 69/618 : having unsaturation outside the six-membered aromatic ring
• CPC Class Codes: C07C 69/738 : Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07C 69/74 : Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 69/76 : Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/78 : Benzoic acid esters
• CPC Class Codes: C07C 69/96 : Esters of carbonic or haloformic acids
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/44 : attached in position 4
• CPC Class Codes: C07D 211/46 : having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 213/79 : Acids; Esters
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 277/30 : 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 Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/12 : only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 317/64 : Oxygen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present disclosure discloses prodrugs of gamma-hydroxybutyric acid as well as compositions and uses thereof.

Claims

1. A compound having the chemical structure shown in Formula (IA):

2. The compound of claim 1, wherein at least one of R_h and R_f is hydrogen or C_1-3 alkyl.

3. The compound of claim 2, wherein both R_h and R_f are hydrogen or C_1-3 alkyl.

4. The compound of claim 1, wherein R_f is —

COR⁵, and R⁵ is C_1-3 alkoxyl or C_5-6 cycloalkyloxyl.

5. The compound of claim 1, wherein both R_h and R_f are hydrogen.

6. The compound of claim 5, wherein the molecular weight of the compound is no more than 450 Da.

7. The compound of claim 5, wherein a hydrogen comprises protium or deuterium.

8. The compound of claim 5, wherein the compound can be converted to gamma-hydroxybutyric acid and enter into the human circulatory system through a biological process after oral administration.

9. A method of treating a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutically effective amount of the compound of claim 5, wherein the subject suffers from a disease or condition selected from narcolepsy, excessive daytime sleepiness, cataplexy, fibromyalgia, chronic fatigue, and tardive dyskinesia.

10. The method of claim 9, wherein the disease or condition is narcolepsy, excessive daytime sleepiness, or cataplexy.

11. The method of claim 9, wherein the administration is conducted no more than two times per day.

12. The method of claim 9, wherein the administration is via oral administration.

13. The method of claim 9, wherein the compound is formulated in a unit dosage form.

14. The method of claim 12, wherein administering the compound orally comprises administering the compound in an emulsion, syrup, elixir, suspension, slurry, or solution.

15. A pharmaceutical composition comprising:

the compound of claim 1 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein both R_h and R_f are hydrogen.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is a solid.

18. The pharmaceutical composition of claim 16, wherein the pharmaceutically acceptable carrier comprises a solvent for dissolving or dispersing the compound.

19. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is formulated in a unit dosage form.

20. The pharmaceutical composition of claim 19, wherein the compound of Formula (IA) is present in the unit dosage form in an amount from 1 gram to 18 grams.

21. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated in a sustained release form.

22. The method of claim 10, wherein the disease or condition is narcolepsy.

23. The method of claim 10, wherein the disease or condition is excessive daytime sleepiness.

24. The method of claim 10, wherein the disease or condition is cataplexy.

25. The method of claim 14, wherein administering the compound orally comprises administering the compound in a solution.

26. The method of claim 13, wherein the compound of Formula (IA) is present in the unit dosage form in an amount from 1 gram to 18 grams.

27. The compound of claim 1, wherein the compound is selected from the group consisting of:

28. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated for oral administration.

29. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated in a liquid dosage form.

30. The compound of claim 5, wherein the compound is

31. The compound of claim 5, wherein the compound is

32. The method of claim 9, wherein the administration is via oral, nasal, intravenous, subcutaneous, or intramuscular administration.