Morphinan compounds

Patent metadata

Field	Value
Publication number	US-9868976-B2
Application number	US-201615068404-A
Country	US
Kind code	B2
Filing date	Mar 11, 2016
Priority date	May 1, 2007
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1 receptor agonist that also has NMDA antagonist activity.

First claim

I claim:

1. A method of evaluating the metabolic stability of a deuterated morphinan compound, comprising:
a. contacting a first amount of the deuterated morphinan compound with a metabolizing enzyme source for a period of time sufficient to allow the formation of a mixture comprising one or more metabolic products of the deuterated morphinan compound and a remaining amount of the deuterated morphinan compound;
b. at the period of time, determining the remaining amount of the deuterated morphinan compound and the amount of at least one of the one or more metabolic products in the mixture; and
c. comparing the remaining amount of the deuterated morphinan compound determined in step b. with the first amount of the deuterated morphinan compound and/or comparing the first amount of the deuterated morphinan compound with the amount of the at least one of the one or more metabolic products determined in step b. to determine the metabolic stability of the deuterated morphinan compound, wherein the metabolic stability is expressed as the % of the amount of the deuterated morphinan compound determined in step b. relative to the first amount and/or as the % of the at least one of the one or more metabolic products determined in step b. relative to the first amount of the deuterated morphinan compound, wherein the deuterated morphinan compound is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CH 3 , CH 2 D, CHD 2 , CD 3 , CHF 2 , and CF 3 ; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;

provided that at least one of R 1 or R 2 is CH 2 D, CHD 2 , or CD 3 .

2. The method of claim 1 , wherein the metabolizing enzyme source comprises liver microsomes.

3. The method of claim 2 , wherein the liver microsomes are pooled human liver microsomes or pooled chimpanzee liver microsomes.

4. The method of claim 1 , wherein the determining is performed by high performance liquid chromatography-mass spectrometry (HPLC-MS), mass spectrometry/mass spectrometry (MS/MS), multiple reaction monitoring (MRM), or combinations thereof.

5. The method of claim 1 , wherein the method is performed in vitro.

6. The method of claim 1 , wherein the period of time is at least 2, 5, 7, 12, 20, or 30 minutes.

7. The method of claim 1 , wherein the period of time is about 2, 5, 7, 12, 20, or 30 minutes.

8. The method of claim 1 , wherein the deuterated morphinan compound has greater metabolic stability as compared to non-deuterated dextromethorphan assessed using the same method.

9. The method of claim 1 , further comprising:
d. comparing the metabolic stability of the deuterated morphinan compound to the metabolic stability of a non-deuterated analog of the morphinan compound assessed using the same method.

10. A method of evaluating the metabolic stability of a deuterated morphinan compound in a subject, comprising:
a. administering a first amount of the deuterated morphinan compound to a subject;
b. obtaining a serum, blood, tissue, urine, or feces sample from the subject at a period of time following the administration of the compound to the subject, wherein the period of time is sufficient to allow the formation of one or more metabolic products of the deuterated morphinan compound in the sample;
c. at the period of time, determining the remaining amount of the deuterated morphinan compound and the amount of at least one of the one or more metabolic products in the sample; and
d. comparing the remaining amount of the deuterated morphinan compound determined in step b. in the sample with the first amount of the deuterated morphinan compound and/or comparing the first amount of the deuterated morphinan compound with the amount of the at least one of the one or more metabolic products determined in step b. in the sample to determine the metabolic stability of the deuterated morphinan compound, wherein the metabolic stability is expressed as the % of the remaining amount of the deuterated morphinan compound determined in step b. relative to the first amount and/or as the % of the at least one of the one or more metabolic products determined in step b. relative to the first amount of the deuterated morphinan compound, wherein the deuterated morphinan compound is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CH 3 , CH 2 D, CHD 2 , CD 3 , CHF 2 , and CF 3 ; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;

provided that at least one of R 1 or R 2 is CH 2 D, CHD 2 , or CD 3 .

11. The method of claim 10 , wherein the determining is performed by high performance liquid chromatography-mass spectrometry (HPLC-MS), mass spectrometry/mass spectrometry (MS/MS), multiple reaction monitoring (MRM), or combinations thereof.

12. The method of claim 10 , wherein the period of time is at least 0.5, 1, 1.5, 2, 4, 8 or 12 hours.

13. The method of claim 10 , wherein the period of time is about 0.5, 1, 1.5, 2, 4, 8 or 12 hours.

14. The method of claim 10 , wherein the subject is a human.

15. The method of claim 10 , wherein the deuterated morphinan compound has greater metabolic stability as compared to non-deuterated dextromethorphan assessed using the same method.

16. The method of claim 10 , further comprising:
e. comparing the metabolic stability of the deuterated morphinan compound to the metabolic stability of a non-deuterated analog of the morphinan compound assessed using the same method.

Assignees

• Concert Pharmaceuticals Inc

Inventors

• Tung Roger D

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P11/14

  Antitussive agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/195 Primary

  having an amino group · CPC title

• A61K31/49

  Cinchonan derivatives, e.g. quinine · CPC title