# US 10,118,927 B2 · Substituted piperidin-4-amino-type compounds and uses thereof

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- Number: US 10,118,927 B2
- Document ID: US10118927B2
- Status: Granted
- Kind: B2
- Application number: 14/655,882
- Filed: 2013-12-23
- Published: 2016-09-22
- Granted: 2018-11-06
- Earliest claimed: 2012-12-27
- Assignees: Purdue Pharma L.P.
- Applicants: Shionogi & Co., Ltd.; Kevin Brown; Dawit Tadesse; Naoki Tsuno; Nobuyuki Tanaka; Xiaoming Zhou
- Inventors: Kevin Brown; Dawit Tadesse; Nobuyuki Tanaka; Naoki Tsuno; Xiaoming Zhou
- Web page: https://patentgrep.com/patent/US10118927B2

## CPC

- C07D 471/08: Bridged systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 235/74: of a saturated carbon skeleton
- C07D 211/58: attached in position 4
- C07C 2602/46: the bicyclo ring system containing nine carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The disclosure relates to Substituted Piperidin-4-amino-Type Compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof wherein R1, R2, R3, Q1, Q2, E1, E2, 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.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Q1 is phenyl;
Q2 is (C3-C10)cycloalkyl, (3- to 9-membered)non-aromatic heterocycle, or a direct bond;
E1 is S(═O)2 or a direct bond;
E2 is C(═O), S(═O)2, CH2, or a direct bond;
W is N(R*) or a direct bond;
D is H, NO2, or N(R*)2;
R* is, independently for each occurrence, H or (C1-C6)alkyl unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —O(C1-C6)alkyl, and ═O;
each R2 and R3 is, independently for each occurrence, —H, -halo, —NO2, —X, —C(═Y)YX, —N(T1)(T2), —YH, or —YX;
X is, independently for each occurrence, —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, or -(5- or 6-membered)heterocycle, each of which is unsubstituted or substituted with 1 or 2 independently selected R8 groups;
each Y is O;
each R5 is independently OR9 or ═O;
each R8 is independently —OR9, ═O, or —C(═O)OR9;
each R9 is independently —H or —(C1-C6)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 T1 and T2 is independently —H or —(C1-C10)alkyl which is unsubstituted or substituted with 1, 2, or 3 independently selected R5 groups;
A and B together form a bridge such that the bridged-piperidine is:
and
—Z—R1 is:
wherein each Rz is independently —H, —(C1-C4)alkyl, —OH, or —CN.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the R1 group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein E1 is S(═O)2 or a direct bond.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein E2 is C(═O) or a direct bond.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH or a direct bond, and Q2 is (C3-C6)cycloalkyl, non-aromatic (3- to 6-membered)heterocycle, or a direct bond.

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein Q2-(R3)b is selected from

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:
E1 is a direct bond or SO2;
Q1 is phenyl;
a is selected from 0 and 1;
R2 is selected from
x is selected from 0 and 1;
E2 is C(═O);
n is selected from 0 and 1;
D is selected from H and —N(CH3)2;
W is selected from —NH and a direct bond;
Q2 is selected from pyrrolidinyl, cyclopropyl, cyclohexyl and a direct bond;
b is selected from 0 and 1; and
R3 is selected from

### Claim 9

A compound which is:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 10

A compound which is:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein —Z—R1 is:
Wherein Rz is —H, —CH3, or —CH2CH3.

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 1)

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.

### Claim 19 (depends on 9)

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

### Claim 20 (depends on 9)

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.

### Claim 21 (depends on 20)

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.

### Claim 22 (depends on 9)

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.