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