Methods for treating neurogenic orthostatic hypotension

Patent metadata

Field	Value
Publication number	US-10238642-B2
Application number	US-201715685119-A
Country	US
Kind code	B2
Filing date	Aug 24, 2017
Priority date	Aug 30, 2016
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

The invention relates to methods for treating neurogenic orthostatic hypotension and symptoms thereof using 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine or a pharmaceutically-acceptable salt thereof.

First claim

What is claimed is:

1. A method for treating neurogenic orthostatic hypotension and the symptoms thereof in a human patient, the method comprising administering to the patient a compound of formula I:

or a pharmaceutically-acceptable salt thereof; wherein the patient has multiple system atrophy, pure autonomic failure, or Parkinson's disease.

2. The method of claim 1 , wherein administration of the compound to the patient results in one or more of: (a) an increase in the patient's seated systolic blood pressure; (b) an increase in the patient's standing time; and (c) a decrease in dizziness or lightheadedness experienced by the patient.

3. The method of claim 2 , wherein administration of the compound to the patient increases the patient's seated systolic blood pressure.

4. The method of claim 2 , wherein administration of the compound to the patient increases the patient's standing time.

5. The method of claim 2 , wherein administration of the compound to the patient decreases dizziness or lightheadedness experienced by the patient.

6. The method of claim 1 or 2 , wherein the compound is 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine hydrochloride.

7. The method of claim 1 or 2 , wherein the compound is a crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 4.44±0.20, 10.22±0.20, 17.16±0.20 and 21.78±0.20.

8. The method of claim 7 , wherein the crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine is further characterized by having one or more additional diffraction peaks at 20 values selected from 8.11±0.20, 13.18±0.20, 16.06±0.20, 18.38±0.20, 23.76±0.20, 26.32±0.20, 27.24±0.20, 29.60±0.20 and 31.94±0.20.

9. The method of claim 1 or 2 , wherein the compound is a crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine characterized by a differential scanning calorimetry trace having a melting point of about 197±2° C.

10. The method of claim 1 or 2 , wherein the patient has multiple system atrophy.

11. The method of claim 1 or 2 , wherein the compound is administered in an amount ranging from about 0.5 mg/day to about 20 mg/day.

12. The method of claim 1 or 2 , wherein the compound is administered in an amount ranging from about 1 mg/day to about 10 mg/day.

13. A method for treating neurogenic orthostatic hypotension and the symptoms thereof in a human patient, the method comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula I:

or a pharmaceutically-acceptable salt thereof; wherein the patient has multiple system atrophy, pure autonomic failure, or Parkinson's disease.

14. The method of claim 13 , wherein administration of the pharmaceutical composition results in one or more of: (a) an increase in the patient's seated systolic blood pressure; (b) an increase in the patient's standing time; and (c) a decrease in dizziness or lightheadedness experienced by the patient.

15. The method of claim 14 , wherein administration of the composition to the patient increases the patient's seated systolic blood pressure.

16. The method of claim 14 , wherein administration of the composition to the patient increases the patient's standing time.

17. The method of claim 14 , wherein administration of the composition to the patient decreases dizziness or lightheadedness experienced by the patient.

18. The method of claim 13 or 14 , wherein the compound is 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine hydrochloride.

19. The method of claim 13 or 14 , wherein the compound is a crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 4.44±0.20, 10.22±0.20, 17.16±0.20 and 21.78±0.20.

20. The method of claim 19 , wherein the crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine is further characterized by having one or more additional diffraction peaks at 2θ values selected from 8.11±0.20, 13.18±0.20, 16.06±0.20, 18.38±0.20, 23.76±0.20, 26.32±0.20, 27.24±0.20, 29.60±0.20 and 31.94±0.20.

21. The method of claim 13 or 14 , wherein the compound is a crystalline hydrochloride salt of 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine characterized by a differential scanning calorimetry trace having a melting point of about 197±2° C.

22. The method of claim 13 or 14 , wherein the patient has multiple system atrophy.

23. The method of claim 13 or 14 , wherein the composition is administered in an amount sufficient to provide about 0.5 mg/day to about 20 mg/day of the compound.

24. The method of claim 13 or 14 , wherein the composition is administered in an amount sufficient to provide about 1 mg/day to about 10 mg/day of the compound.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hegde Sharathchandra S

Classifications

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D211/22

  by oxygen atoms · CPC title

• A61K31/165 Primary

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title