Opioid ketal compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2016264589-A1
Application number	US-201615146619-A
Country	US
Kind code	A1
Filing date	May 4, 2016
Priority date	May 24, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

This invention relates to opioid ketal compounds of Formula (I), Formula (II), or Formula (III):

or a pharmaceutically acceptable salts thereof, wherein R 1 is H or CH 3 , R 2 is H or OH, n is 0, 1, 2 or 3, R 3 and R 4 are independently H or optionally substituted C 1 -C 4 alkyl, or when n is 0, then R 3 and R 4 and the carbon atoms to which they are attached together form six, or seven membered ring, which is optionally mono or disubstituted by C 1 -C 4 alkyl. The invention also relates to oxycodone ketal compounds of Formula (IV) or (V):

or a pharmaceutically acceptable salts thereof. The invention also relates to the use of such compounds for the treatment, prevention, or amelioration of pain.

First claim

What is claimed is:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is H or CH 3 ,
R 2 is H or OH,
n is 0, 1, 2 or 3,
R 3 and R 4 are independently H or optionally substituted C 1 -C 4 alkyl, or
when n is 0, then R 3 and R 4 and the carbon atoms to which they are attached together form a five, six, or seven membered ring, which is optionally mono or disubstituted by C 1 -C 4 alkyl, and wherein the carbon atoms labeled * and ** are independently in the R or S configuration.

2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in which the carbon atom labeled * and the carbon atom labeled ** are both in the R or the S configuration.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in which the carbon atom labeled * is in the R configuration and the carbon atom labeled ** is in the S configuration.

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in which the carbon atom labeled * is in the S configuration and carbon atom labeled ** is in the R configuration.

5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H, n is 1, and R 3 and R 4 are each CH 3 .

6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H or OH, n is 2, and R 3 and R 4 are each CH 3 .

7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, R 2 is H, n is 1, and R 3 and R 4 are each CH 3 .

8 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H, n is 0, and R 3 and R 4 together with the carbon atoms to which they are attached form a six membered carbon ring.

9 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is OH, n is 1, and R 3 and R 4 are independently —CH 2 CH 3 and CH 2 CH 2 CH 3 , and the carbon atoms labeled * and the carbon atom labeled ** are independently in the R or S configurations.

10 . A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof, or a mixture of the compounds or the pharmaceutically acceptable salts thereof according to claim 1 , and a pharmaceutically acceptable carrier.

11 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment, amelioration or prevention a therapeutically effective amount of the compound or a mixture of the compounds according to claim 1 , or a molar equivalent of a pharmaceutically acceptable salt thereof.

12 . A method of slowing the onset of activity of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of the compound or a mixture of the compounds according to claim 1 , or a pharmaceutically acceptable salt thereof.

13 . The method according to claim 11 , further comprising co-administering one or more other therapeutic agents.

14 . The method according to claim 13 , wherein said one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

15 . The method according to claim 13 , wherein said one or more other therapeutic agents are one or more opioid agonists.

16 . The method according to claim 13 , wherein said one or more other therapeutic agents are one or more opioid antagonists.

17 . A compound of Formula IV or Formula V:

or a pharmaceutically acceptable salt thereof.

18 . The compound according claim 17 , which has the Formula IV, and wherein the carbon atoms labeled * are both in the R or the S configuration.

19 . The compound according to claim 17 , which has the Formula IV, and wherein one carbon atom labeled * is in the R configuration, and the other carbon atom labeled * is in the S configuration.

20 . The compound according to claim 17 , which has the formula V, and wherein the carbon atom labeled * is in the R or the S configuration.

21 . A mixture comprising at least two isomers selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

22 . The mixture according to claim 21 , comprising the isomers IVC and IVD, or the pharmaceutically acceptable salts thereof.

23 . The mixture according to claim 21 , comprising isomers IVA, IVB, IVC, and IVD or the pharmaceutically acceptable salts thereof.

24 . The mixture according to claim 23 , wherein the isomers IVC and IVD together are present in an aggregate molar amount greater than isomers IVA and IVB together.

25 . A mixture comprising at least two isomers selected from the group consisting of

and the pharmaceutically acceptable salts thereof.

26 . The mixture according to claim 25 , comprising isomers VA, VB, VC, and VD or the pharmaceutically acceptable salts thereof.

27 . A pharmaceutical composition, comprising a mixture or the pharmaceutically acceptable salts thereof according to claim 21 , and a pharmaceutically acceptable carrier.

28 . A pharmaceutical composition, comprising a mixture or the pharmaceutically acceptable salts thereof according to claim 25 , and a pharmaceutically acceptable carrier.

29 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment, amelioration or prevention a therapeutically effective amount of the mixture according to claim 21 , or molar equivalent of the pharmaceutically acceptable salts thereof.

30 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment, amelioration or prevention a therapeutically effective amount of the mixture according to claim 25 , or molar equivalent of the pharmaceutically acceptable salts thereof.

Assignees

• Rhodes Tech

Inventors

• Kupper Robert J
• Glowaky Raymond C

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D489/09

  containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D489/02

  with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone · CPC title