Opioid ketal compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2016244459-A1
Application number	US-201414893224-A
Country	US
Kind code	A1
Filing date	May 23, 2014
Priority date	May 24, 2013
Publication date	Aug 25, 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

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, wherein R 1 is CH 3 , R 2 is H, n is 1, and R 3 and R 4 are each CH 3 .

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

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

5 . The compound of claim 1 , in which the carbon atom labeled * is in the R configuration and the carbon atom labeled ** is in the S configuration.

6 . The compound of claim 1 , in which the carbon atom labeled * is in the S configuration and carbon atom labeled ** is in the R configuration.

7 . A mixture, comprising at least two stereoisomers of the compound or salt according to claim 2 , wherein the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.

8 . (canceled)

9 . 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 .

10 . (canceled)

11 . (canceled)

12 . A mixture, comprising at least two stereoisomers of the compound or salt according to claim 9 , wherein R 2 is H and the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.

13 - 17 . (canceled)

18 . 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 .

19 - 22 . (canceled)

23 . A mixture, comprising two or more stereoisomers of the compound or salt according to claim 18 , wherein the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.

24 . (canceled)

25 . 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.

26 . 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.

27 . A compound of Formula II or Formula III:

or a pharmaceutically acceptable salt thereof.

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

29 . (canceled)

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 compound or a mixture of compounds according to claim 1 , or a molar equivalent of a pharmaceutically acceptable salt thereof.

31 . (canceled)

32 . (canceled)

33 . 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 a compound or a mixture of compounds according to claim 1 , or a pharmaceutically acceptable salt thereof.

34 . A method of achieving opioid therapy in a mammal in need thereof, comprising orally administering to the mammal a therapeutically effective amount of the compound or a mixture of compounds according to claim 1 .

35 . A method of preparing a compound of Formula I according to claim 1 , comprising reacting an opioid with a diol under conditions necessary to obtain a compound of Formula I.

36 - 42 . (canceled)

43 . A compound of Formula IV or Formula V:

or a pharmaceutically acceptable salt thereof.

44 . The compound according to claim 43 which has the Formula IV.

45 . The compound according claim 44 , wherein the carbon atoms labeled * are both in the R configuration.

46 . The compound according to claim 44 , wherein the carbon atoms labeled * are both in the S configuration.

47 . The compound according to claim 44 , wherein one carbon atom labeled * is in the R configuration, and the oilier carbon atom labeled * is in the S configuration.

48 . The compound according to claim 43 , which has the formula V.

49 . The compound of claim 48 , wherein the carbon atom labeled * is in the R configuration.

50 . The compound of claim 48 , wherein the carbon atom labeled * is in the S configuration.

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

and the pharmaceutically acceptable salts thereof.

52 . The mixture according to claim 51 , comprising the isomers IVC and IVD, or the pharmaceutically acceptable salts thereof.

53 . The mixture according to claim 51 , wherein the isomer IVC is present in a molar amount greater than isomer IVD.

54 . The mixture according to claim 51 , wherein the isomer DM is present in a molar amount greater than isomer IVC.

55 . The mixture according to claim 51 , comprising isomers IVA, IVB, IVC, and IVD or the pharmaceutically acceptable salts thereof.

56 . The mixture according to claim 51 , wherein the isomers IVC and IVD together are present in an aggregate molar amount greater than isomers IVA and IVB together.

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

and the pharmaceutically acceptable salts thereof.

58 . A mixture according to claim 57 , comprising isomers VA, VB, VC, and VD or the pharmaceutically acceptable salts thereof.

Assignees

• Kupper Robert J
• Glowaky Raymond C
• 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

• A61P25/04

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

• C07D491/20

  Spiro-condensed systems · 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

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title