Peripheral opioid receptor antagonists and uses thereof

• US 8,420,663 B2
• Filed: 08/09/2012
• Issued: 04/16/2013
• Est. Priority Date: 09/30/2008
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Bazhina, Nataliya, Donato, George Joseph III, Fabian, Steven R., Lokhnauth, John, Megati, Sreenivasulu, Melucci, Charles K., Ofslager, Christian, Patel, Niketa, Radebaugh, Galen, Shah, Syed M., Szeliga, Jan, Zhang, Huyi, Zhu, Tianmin
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US13/570,836
• Publication Number:
  US 20120316191A1
• Time in Patent Office: 250 Days
• Field of Search: 514/282, 514/289
• US Class Current: 514/282
• CPC Class Codes: A61J 1/05 for collecting, storing or administering blood, plasma or medical fluids multiple bags systems for separating or storing blood components A61M1/0209; Infusion or perfusion containers
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61M 5/178 Syringes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 489/08 Oxygen atom
• CPC Class Codes: Y10T 436/145555 Hetero-N

Abstract

The present invention provides a compound of formula I:

wherein X⁻, R¹, and R² are as defined herein, and compositions thereof.

Claims

1. A method of treating a gastrointestinal disorder in a subject, comprising administering to the subject a compound of formula III

2. The method of claim 1, wherein the gastrointestinal disorder is constipation.

3. The method of claim 2, wherein the constipation is opioid-induced.

4. The method of claim 1, wherein the compound of formula III is provided in a solution.

5. The method of claim 1, wherein the compound of formula III is of formula III-1

6. The method of claim 5, wherein the compound of formula III is provided in solution.

7. The method of claim 5, wherein the gastrointestinal disorder is constipation.

8. The method of claim 7, wherein the constipation is opioid-induced.

9. The method of claim 1, wherein the subject is receiving opioids chronically.

10. The method of claim 9, wherein the subject is a cancer patient.

11. The method of claim 1, wherein the packaged composition is selected from the group consisting of a syringe, a vial, a sachet and an ampoule.

12. The method of claim 1, wherein the packaged composition is a syringe.

13. The method of claim 1, wherein the compound of formula III is in the form of a tablet, a capsule, a powder, a solution, a suspension, an emulsion, a granule, and a suppository.

14. The method of claim 1, wherein the solution comprises less than about 190 ppm total of the compound of formula II and a compound of formula IV:

15. The method of claim 6, wherein the compound of formula III is administered by injection or infusion.

16. The method of claim 15, wherein the compound of formula III is administered by subcutaneous injection.

17. The method of claim 1, wherein the subject is receiving an opioid at a morphine equivalent dose of between about 30 and about 100 oral mg/day of methadone.

18. The method of claim 1, wherein the tungsten is present in an amount of less than 50 parts per billion.

19. The method of claim 1, wherein the tungsten is present in an amount of less than 12 parts per billion.

20. The method of claim 6, wherein the solution further comprises edetate calcium disodium and glycine hydrochloride.

21. The method of claim 6, wherein the solution comprises about 8 mg of the compound of formula III in about 0.4 mL water.

22. The method of claim 21, wherein the compound of formula III is of formula III-1

23. The method of claim 6, wherein the solution comprises about 12 mg of the compound of formula III in about 0.6 mL water.

24. The method of claim 23, wherein the compound of formula III is of formula III-1

25. The method of claim 1, wherein the compound of formula III is stable under ambient storage conditions.

26. The method of claim 25, wherein the compound of formula III is stable for at least 24 months.

27. A method of treating opioid induced constipation in a subject, comprising administering to the subject a compound of formula III-1

28. A method of treating constipation in a subject, comprising administering to the subject a unit dosage of a compound of formula III-1

29. A method of treating constipation in a subject, comprising administering to the subject a unit dosage of a compound of formula III