Hydrazone modulators of cannabinoid receptors

Patent metadata

Field	Value
Publication number	US-9079854-B2
Application number	US-201213647134-A
Country	US
Kind code	B2
Filing date	Oct 8, 2012
Priority date	Jul 13, 2007
Publication date	Jul 14, 2015
Grant date	Jul 14, 2015

Abstract

Hydrazone compounds which modulate cannabinoid receptors are presented. Pharmaceutical compositions containing these compounds, methods of using these compounds as modulators of cannabinoid receptors and processes for synthesizing these compounds are also described herein.

First claim

We claim the following:

1. A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of obesity and addiction, the hydrazone compound comprising a compound of structural Formula I:

or a salt or prodrug thereof, wherein:
R 1 is selected from the group consisting of n-hexyl and 2-cyclohexyl ethyl.

2. The method of claim 1 , the hydrazone compound comprising the structural formula IV:

or pharmaceutically acceptable salt thereof.

3. The method of claim 1 , the hydrazone compound comprising the structural formula V:

or pharmaceutically acceptable salt thereof.

4. A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of obesity and addiction, the hydrazone compound comprising a compound of structural Formula III:

or a salt or prodrug thereof, wherein:
R 1 is selected from the group consisting of n-hexyl and 2-cyclohexyl ethyl;
R 2 is selected from the group consisting of a hydrogen atom or a methoxy;
R 3 is selected from the group consisting of NR 4 R 5 , aryl, heteroaryl, alkenyl, an alkynyl, an alkoxyl, a cycloalkyl containing from 5 to 10 carbon atoms and containing eventually —CO—, —O—, —S—, —SO—, —SO 2 —, —CHOH— or —NR 12 —, or one of the radicals defined by the following structure:

wherein R 4 and R 5 taken together form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 14 —;
R 6 is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms;
R 7 is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms;
R 6 and R 7 taken together might form a cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 13 —;
R 8 is selected from the group consisting of hydrogen and alkyl from 1 to 3 carbon atoms;
R 9 and R 10 vary independently and are selected from the group consisting of methyl or a hydrogen;
R 11 is selected from the group consisting of aryl, heteroaryl or an alkyl from 1 to 6 carbon atoms;
R 12 is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms;
R 13 is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms; and
R 14 represents an alkyl containing from 1 to 3 carbon atoms.

5. A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of obesity and addiction, the hydrazone compound comprising a compound of structural Formula II:

or a salt or prodrug thereof; wherein:
X is selected from the group consisting of C═O, C═S, or SO 2 ;
R 1 is selected from the group consisting of alkyl containing from 6 to 12 carbon atoms, a polyether, a substituted benzyl and a radical defined by the following structure:

where n is an integer ranging from 1 to 4; but if R 2 is an alkoxy at position 6, then R 1 can also be selected from the group consisting of alkyl containing from 1 to 12 carbon atoms;
R 2 and R′ 2 vary independently and are selected from the group consisting of hydrogen, aryl, alkyl, cycloalkyl, aralkyl, alkenyl, alkynyl, halogen, an alkoxyl or a hydroxyl;
R 3 is selected from the group consisting of NR 15 R 16 , aryl, a heteroaryl, alkenyl, an alkynyl, an alkoxyl, a cycloalkyl containing from 5 to 10 carbon atoms and containing eventually —CO—, —O—, —S—, —SO—, —SO 2 —, —CHOH— or —NR 12 — or one of the radicals defined by the following structure:

wherein R 4 and R 5 taken together form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms that are eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 14 —;
R 6 is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms;
R 7 is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms;
R 6 and R 7 taken together can form a cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 13 —;
R 8 is selected from the group consisting of hydrogen and alkyl from 1 to 3 carbon atoms;
R 9 and R 10 vary independently and are selected from the group consisting of methyl or a hydrogen;
R 11 is selected from the group consisting of aryl, heteroaryl, or alkyl containing from 1 to 6 carbon atoms, but if R 2 is alkoxyl, R 11 is heterocycloalkyl;
R 12 is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms;
R 13 is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms;
R 14 represents an alkyl containing from 1 to 3 carbon atoms; and
R 15 and R 16 vary independently and are selected from the group consisting of an alkyl containing 1 to 6 carbon atoms or taken together might form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms that are eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 14 —.

6. The method of claim 4 , the hydrazone compound comprising the structural formula VI:

or pharmaceutically acceptable salt thereof.

Assignees

• Cleveland Clinic Foundation

Inventors

• Attala Mohamed Naguib
• Diaz Philippe

Classifications

• C07D209/40 Primary

  Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D409/12

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