Substituted 1-arylethyl-4-acylaminopiperidine derivatives as opioid/alpha-adrenoreceptor modulators and method of their preparation

Patent metadata

Field	Value
Publication number	US-9765027-B2
Application number	US-201514834185-A
Country	US
Kind code	B2
Filing date	Aug 24, 2015
Priority date	Aug 22, 2014
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The invention provides compounds that bind with high affinities to the μ-, δ- and κ-opioid receptors and α 2 -adrenoreceptor. In addition to providing these compounds with novel pharmacological binding properties, the invention also describes detailed novel methods for the preparation of representative compounds and a scheme for the synthesis of related compounds that bind to the opioid receptors and/or α 2 -adrenoreceptor.

First claim

The invention claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is selected from the group consisting of optionally substituted C 1-10 alkyl, and optionally substituted furanyl;
A is ethylene; and
Y is selected from the group consisting of unsubstituted aryl, optionally substituted thiophenyl, or a moiety of the formula —C(═O)—X 1 , wherein X 1 is —OR 5 or —NR 6 R 6 , wherein each of R 5 and R 6 is H or C 1-10 alkyl.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, and fur-3-yl.

3. The compound of claim 1 , wherein Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR 5 , wherein R 5 is C 1-10 alkyl.

4. The compound of claim 1 selected from the group consisting of:
N-(1-phenethylpiperidin-4-yl)propionamide;
methyl 3-(4-propionamidopiperidin-1-yl)propanoate;
N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide;
N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide;
N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide; and
8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide.

5. A method of treating a condition selected from opioid tolerance and dependence, opioid-induced constipation, alcohol abuse, opioid abuse, cocaine abuse, depression, opioid induced immune response depression, opioid-overdose-induced respiratory depression, nicotine withdrawal symptoms, obesity, psychosis, dyskinesia associated with Parkinson's disease, Raynaud's disease, hypertension, scleroderma or a combination thereof, said method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need of such a treatment.

6. The method claim 5 , wherein said clinical condition is dyskinesia associated with Parkinson's disease.

7. A compound of the formula:

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is selected from the group consisting of optionally substituted C 1-10 alkyl, and optionally substituted furanyl;
A is C 1-10 alkylene; and
Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR 5 , wherein R 5 is C 1-10 alkyl.

8. The compound of claim 7 , wherein R 1 is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, and fur-3-yl.

9. The compound of claim 8 , wherein R 1 is ethyl.

10. The compound of claim 7 , wherein A is ethylene.

11. The compound of claim 10 , wherein Y is phenyl.

Assignees

• The Arizona Board Of Regents On Behalf Of The Univ Of Arizaona
• Univ Arizona

Inventors

• Vardanyan Ruben S
• Hruby Victor J

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D211/58 Primary

  attached in position 4 · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4468

  having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl · CPC title