IP Library › Granted Patent US 9,259,422

Granted Patent B2

US 9,259,422 · App. 14/674,578 · Granted Feb 16, 2016

Orvinol and thevinol derivatives useful in the treatment of depression

Inventors: John Lewis (Winscombe, GB); Stephen Husbands (Bath, GB)

Assignee: The University of Bath

A61K31/485 C07D489/12 C07D491/08

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,259,422
App. No.: 14/674,578
Granted: Feb 16, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides method of treating depression comprising administering to a subject compounds having formula 2: or a pharmaceutically acceptable salt or solvate thereof, wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , and X are us defined in the specification.

Claims (109)

1. A method of treating depression in a subject, the method comprising administering to said subject an effective amount of a compound of formula 2:

wherein:

R is H or alkyl;

R 1 is cyclopropylmethyl;

R 2 is H;

R 4 and R 5 are each methyl;

R 3 is aryl or heteroaryl, either of which may be substituted or unsubstituted; and

X is —CH 2 CH 2 — or —CH═CH—,

or a pharmaceutically acceptable salt or solvate thereof.

2. The method according to claim 1 , wherein X is —CH 2 CH 2 —.

3. The method according to claim 1 , wherein R 3 is substituted phenyl.

4. The method according to claim 1 , wherein R 3 is phenyl and X is —CH═CH—.

5. The method according to claim 1 , wherein R 3 is phenyl and X is —CH 2 CH 2 —.

6. The method according to claim 1 , wherein R 3 is m-tolyl and X is —CH═CH—.

7. The method according to claim 1 , wherein R 3 is 4-fluorophenyl and X is —CH═CH—.

8. The method according to claim 1 , wherein the compound of formula 2 is selected from the group consisting of:

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol; and

(1′R, 5α, 6R, 7R, 14α)-1′-(5-chloro-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol,

or a pharmaceutically acceptable salt or solvate thereof.

9. A method of treating depression in a subject, the method comprising administering to said subject an effective amount of a compound selected from the group consisting of:

(1′S, 5α, 6R, 7R, 14α)-1′-(2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4″-t-butylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-isopropylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-chlorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-chlorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3,5-dimethylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-methyl-2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(5-chloro-2-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-thienyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-pyridyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-pyridyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-propylthiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-methan-1′-ol;

(1′S, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-phenyl-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methylphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(4-fluorophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(3-methyl-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(5-chloro-2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol;

(1′R, 5α, 6R, 7R, 14α)-1′-(2-thiophenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol; and

(1′R, 5α, 6R, 7R, 14α)-1′-(4-methoxyphenyl)-1′-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7β-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1′-ol,

or a pharmaceutically acceptable salt or solvate thereof.

10. The method according to claim 9 , wherein the compound is selected from the group consisting of: