Treating or preventing restless legs syndrome using prodrugs of GABA analogs

• US 20050192353A1
• Filed: 09/17/2004
• Published: 09/01/2005
• Est. Priority Date: 09/17/2003
• Status: Active Grant

• Current Assignee: Arbor Pharmaceuticals LLC
• Original Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Barrett, Ronald W., Canafax, Daniel M.
• Granted Patent: US 8,114,909 B2
• Time in Patent Office: Days
• US Class Current: 514/561
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed herein are methods of using prodrugs of gamma aminobutyric acid (GABA) analogs and pharmaceutical compositions thereof to treat or prevent restless legs syndrome in humans, and pharmaceutical compositions of prodrugs of GABA analogs useful in treating or preventing restless legs syndrome.

Claims

1. A method of treating or preventing restless legs syndrome in a patient comprising administering to the patient in need of such treatment or prevention a therapeutically effective amount of a prodrug of a GABA analog, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The method of claim 1 or 2, wherein the GABA analog is gabapentin or pregabalin.

4. The method of claim 3, wherein the prodrug of the GABA analog is administered in an amount of between about 10 mg to about 5000 mg per day.

5. The method of claim 1 or 2, wherein the restless legs syndrome is idiopathic.

6. The method of claim 1 or 2, wherein the restless legs syndrome is secondary to a medical condition.

7. The method of claim 6, wherein the medical condition is iron deficiency.

8. The method of claim 6, wherein the medical condition requires dialysis.

9. The method of claim 1 or 2, wherein the patient suffers symptoms of restless legs syndrome while awake and inactive.

10. The method of claim 1 or 2, wherein the patient suffers symptoms of restless legs syndrome while asleep.

11. The method of claim 1 or 2, wherein the prodrug is administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intranasally instillationally, intracavitarally, intravesical instillationally, intraocularly, intraarterially, intralesionally or by application to mucous membranes.

12. The method of claim 1 or 2, wherein the prodrug is administered orally.

13. The method of claim 1 or 2, comprising administering the prodrug in a sustained release oral dosage form.

14. The method of claim 13, wherein the dosage form provides a therapeutic concentration of the GABA analog in the plasma of the patient for a period of at least about 6 hours.

15. The method of claim 13, wherein the dosage form comprises an osmotic dosage form, a prodrug-releasing polymer, a prodrug-releasing lipid, a prodrug-releasing wax, tiny timed-release pills or prodrug releasing beads.

16. The method of claim 1 or claim 2, wherein the prodrug of a GABA analog has the structure of Formula (I):

17. The method of claim 16, wherein the prodrug of a GABA analog has the structure of Formulae (II) or (III):

18. The method of claim 17, wherein n is 0.

19. The method of claim 17, wherein n is 1, R¹⁶ is hydrogen and R² is selected from the group consisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, 3-indolylmethyl, —

CH₂OH, —

CH(OH)CH₃, —

CH₂CO₂H, —

CH₂CH₂CO₂H, —

CH₂CONH₂, —

CH₂CH₂CONH₂, —

CH₂CH₂SCH₃, —

CH₂SH, —

CH₂(CH₂)₃NH₂ and —

CH₂CH₂CH₂NHC(NH)NH₂.

20. The method of claim 18, wherein R²⁵ is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl and sec-butyl, R¹³ is methyl and R¹⁴ is hydrogen.

21. The method of claim 20, wherein R²⁵ is isopropyl, R¹³ is methyl and R¹⁴ is hydrogen.

22. The method of claim 1 or 2, wherein the prodrug of the GABA analog is 1-{[(α

-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid.

2. A method of improving sleep in a patient with restless legs syndrome comprising administering to the patient a therapeutically effective amount of a prodrug of a GABA analog, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

23. A method of treating or preventing restless legs syndrome in a patient comprising administering to the patient in need of such treatment or prevention a pharmaceutical composition comprising a therapeutically effective amount of a prodrug of a GABA analog, or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable vehicle.

24. The method of claim 23, wherein the prodrug of the GABA analog is 1-{[(α

-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid.

25. A pharmaceutical composition for treating a patient suffering from restless legs syndrome comprising a therapeutically effective amount of a prodrug of a GABA analog or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable vehicle.

26. The pharmaceutical composition of claim 25, wherein the prodrug of the GABA analog is 1-{[(α

-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid.

27. A pharmaceutical composition suitable for preventing restless legs syndrome in a patient at risk of restless legs syndrome comprising a therapeutically effective amount of a prodrug of a GABA analog or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable vehicle.

28. The pharmaceutical composition of claim 27, wherein the prodrug of the GABA analog is 1-{[(α

-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid.