Substituted piperidin-4-amino-type compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10118927-B2
Application number	US-201314655882-A
Country	US
Kind code	B2
Filing date	Dec 23, 2013
Priority date	Dec 27, 2012
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The disclosure relates to Substituted Piperidin-4-amino-Type Compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof wherein R 1 , R 2 , R 3 , Q 1 , Q 2 , E 1 , E 2 , A, B, D, W, Z, a, b, n, and x are as defined herein, compositions comprising an effective amount of a Substituted Piperidin-4-amino-Type Compound, and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted Piperidin-4-amino-Type Compound.

First claim

What is claimed:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
Q 1 is phenyl;
Q 2 is (C 3 -C 10 )cycloalkyl, (3- to 9-membered)non-aromatic heterocycle, or a direct bond;
E 1 is S(═O) 2 or a direct bond;
E 2 is C(═O), S(═O) 2 , CH 2 , or a direct bond;
W is N(R*) or a direct bond;
D is H, NO 2 , or N(R*) 2 ;
R* is, independently for each occurrence, H or (C 1 -C 6 )alkyl unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —O(C 1 -C 6 )alkyl, and ═O;
each R 2 and R 3 is, independently for each occurrence, —H, -halo, —NO 2 , —X, —C(═Y)YX, —N(T 1 )(T 2 ), —YH, or —YX;
X is, independently for each occurrence, —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, or -(5- or 6-membered)heterocycle, each of which is unsubstituted or substituted with 1 or 2 independently selected R 8 groups;
each Y is O;
each R 5 is independently OR 9 or ═O;
each R 8 is independently —OR 9 , ═O, or —C(═O)OR 9 ;
each R 9 is independently —H or —(C 1 -C 6 )alkyl;
a is an integer selected from 0 and 1;
b is an integer selected from 0 and 1;
n is an integer selected from 0 and 1;
x is an integer selected from 0 and 1;
each T 1 and T 2 is independently —H or —(C 1 -C 10 )alkyl which is unsubstituted or substituted with 1, 2, or 3 independently selected R 5 groups;
A and B together form a bridge such that the bridged-piperidine is:

 and
—Z—R 1 is:

wherein each R z is independently —H, —(C 1 -C 4 )alkyl, —OH, or —CN.

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the R 1 group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein E 1 is S(═O) 2 or a direct bond.

4. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein E 2 is C(═O) or a direct bond.

5. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein D is selected from

6. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH or a direct bond, and Q 2 is (C 3 -C 6 )cycloalkyl, non-aromatic (3- to 6-membered)heterocycle, or a direct bond.

7. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein Q 2 -(R 3 ) b is selected from

8. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:
E 1 is a direct bond or SO 2 ;
Q 1 is phenyl;
a is selected from 0 and 1;
R 2 is selected from

x is selected from 0 and 1;
E 2 is C(═O);
n is selected from 0 and 1;
D is selected from H and —N(CH 3 ) 2 ;
W is selected from —NH and a direct bond;
Q 2 is selected from pyrrolidinyl, cyclopropyl, cyclohexyl and a direct bond;
b is selected from 0 and 1; and
R 3 is selected from

9. A compound which is:

or a pharmaceutically acceptable salt or solvate thereof.

10. A compound which is:

or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

12. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 12 , wherein the compound or the pharmaceutically acceptable salt or solvate thereof acts as an agonist or an antagonist at the ORL-1 receptor.

14. A method for treating pain in an animal, comprising administering to an animal in need thereof the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein A and B together form a bridge such that the bridged-piperidine is

16. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein —Z—R 1 is:

Wherein R z is —H, —CH 3 , or —CH 2 CH 3 .

17. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt, a sodium salt, a potassium salt, or a para-toluenesulfonic acid salt.

18. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound or pharmaceutically acceptable salt or solvate thereof is radiolabeled.

19. A pharmaceutical composition comprising the compound of claim 9 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

20. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with the compound of claim 9 or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 20 , wherein the compound or the pharmaceutically acceptable salt or solvate thereof acts as an agonist or an antagonist at the ORL-1 receptor.

22. A method for treating pain in an animal, comprising administering to an animal in need thereof the compound of claim 9 or a pharmaceutically acceptable salt or solvate thereof.

Assignees

• Shionogi & Co
• Brown Kevin
• Tadesse Dawit
• Tsuno Naoki
• Tanaka Nobuyuki
• Zhou Xiaoming
• Purdue Pharma Lp

Inventors

• Brown Kevin
• Tadesse Dawit
• Tanaka Nobuyuki
• Tsuno Naoki
• Zhou Xiaoming

Classifications

• C07C2602/46

  the bicyclo ring system containing nine carbon atoms · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D211/58

  attached in position 4 · CPC title

• C07C235/74

  of a saturated carbon skeleton · CPC title