Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-19
2002-02-05
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S231500, C514S329000, C514S406000
Reexamination Certificate
active
06344474
ABSTRACT:
The present invention relates to a novel use of antagonists of the central cannabinoid receptors or so-called CB
1
receptors.
More particularly, the invention relates to the use of CB
1
receptor antagonists for the preparation of drugs useful in the treatment of appetency disorders. The purpose of drugs useful in the treatment of appetency disorders is to regulate consumption desires, particularly desires to consume sugars, carbohydrates, alcohol or drugs and more generally to consume appetizing ingredients.
In the present description and in the claims, appetency disorders are understood as meaning:
disorders associated with a substance and especially abuse of a substance and/or dependency on a substance,
disorders of food behaviors, especially those liable to cause excess weight, irrespective of its origin, for example: bulimia, appetency for sugars, non-insulin-dependent diabetes.
Substances are understood as meaning appetizing ingredients such as sugars, carbohydrates, alcohols or drugs.
The present invention therefore further relates to the use of a CB
1
receptor antagonist for the preparation of drugs useful in the treatment of bulimia and obesity, including obesity associated with type II diabetes (non-insulin-dependent diabetes), or more generally any disease resulting in the patient becoming overweight, and in the treatment of drug abuse or drug dependency.
Delta-9-tetrahydrocannabinol, or &Dgr;
9
-THC, is the main active constituent extracted from Cannabis sativa (Tuner, 1985; in Marijuana, 84, Ed. Harvey, DY, IRL Press, Oxford).
The effects of cannabinoids are due to an interaction with high affinity specific receptors coupled to G proteins. Two types of receptors are currently described: the CB
1
receptors, which are present predominantly in the central nervous system (Devane et al., Molecular Pharmacology, 1988, 34, 605-613), and the CB
2
receptors, which are present in the immune system (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al., 1992, Molecular Pharmacology, 42, 736-742; Munro et al., Nature, 1993, 365, 61-65). Characterization of these receptors has been made possible by the development of synthetic ligands such as CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051) and WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) and, more recently, by the discovery of the selective CB
1
receptor antagonist SR 141716 A (M. Rinaldi-Carmona et al., FEBS Lett., 1994, 350, 240-244).
Families of compounds having an affinity for the cannabinoid receptors have been described in several patents or patent applications, especially European patent application EP-576 357, which describes pyrazole derivatives, and patent application WO 96/02248, which describes especially benzofuran derivatives.
More particularly, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, also called SR 141716, of the formula
its pharmaceutically acceptable salts and their solvates are described in European patent application EP-656 354 as CB
1
central receptor antagonists.
SR 141716 A is the hydrochloride of SR 141716.
It is known that delta-9-tetrahydrocannabinol, whose international non-proprietary name is Dronabinol, is used in the treatment of anorexia, especially in patients suffering from AIDS (J. Pain Symptom Manage., 1995, 10 (2), 89-97) or cancer (J. Palliat. Care, 1994, 10 (1), 14-18).
It is further described that SR 141716 and its salts, which are central cannabinoid receptor antagonists, can be used in the treatment of appetite disorders, especially as anorexigenic agents, and in the treatment of disorders associated with the use of psychotropic substances.
Conventional anorexigenic agents cause an appetite reduction which is generally independent of the foods to be consumed.
Surprisingly, it has now been found that CB
1
receptor antagonists have a specific property by acting electively on consumption behavior disorders pertaining to appetizing substances.
Thus the administration of a CB
1
receptor antagonist makes it possible to regulate the desire to consume non-essential food items such as excess sugars, excess carbohydrates, alcohol or drugs.
In fact, after having conducted tests in animals, a novel behavior of the animal has been noted: animal tests have revealed a novel behavior: the animal no longer shows spontaneous appetency for the ingredient, for example sugar or alcohol, which usually brings pleasure to it. This lack of appetency also manifests itself when the animal has been pretreated with a neuropeptide known to increase the appetite, for example neuropeptide Y (NPY).
According to one of its aspects, the present invention relates to the use of a CB
1
receptor antagonist for the preparation of drugs useful in the treatment of appetency disorders.
The CB
1
receptor antagonists appropriate for the purposes of the invention are particularly the compounds of the formula
in which:
R
1
is hydrogen, a fluorine, a hydroxyl, a (C
1
-C
5
)alkoxy, a (C
1
-C
5
)alkylthio, a hydroxy(C
1
-C
5
)alkoxy, a group —NR
10
R
11
, a cyano, a (C
1
-C
5
)alkylsulfonyl or a (C
1
-C
5
)alkylsulfinyl;
R
2
and R
3
are a (C
1
-C
4
)alkyl or, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated 5- to 10-membered heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by a (C
1
-C
3
)alkyl or by a (C
1
-C
3
)alkoxy;
R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are each independently hydrogen, a halogen or a trifluoromethyl, and if R
1
is a fluorine, R
4
, R
5
, R
6
, R
7
, R
8
and/or R
9
can also be a fluoromethyl, with the proviso that at least one of the substituents R
4
or R
7
is other than hydrogen; and
R
10
and R
11,
are each independently hydrogen or a (C
1
-C
5
)alkyl, or R
10
and R
11
, together with the nitrogen atom to which they are bonded, form a heterocyclic radical selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl and piperazin-1-yl, which is unsubstituted or substituted by a (C
1
-C
4
)alkyl,
and their salts and their solvates.
More particularly, the present invention relates to the use of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its pharmaceutically acceptable salts and their solvates for the preparation of drugs useful in the treatment of appetency disorders.
According to the present invention, the CB
1
receptor antagonists can also be used in association with another active principle for the preparation of drugs useful in the treatment of appetency disorders, especially in the treatment of disorders of food behaviors; it is possible to use a pharmaceutical composition comprising a CB
1
receptor antagonist in association with a compound for regulating metabolic disorders, especially a &bgr;
3
-adrenergic receptor agonist, hereafter called a &bgr;
3
-agonist.
Thus the present invention further relates to pharmaceutical compositions containing a CB
1
receptor antagonist and a regulator of metabolic disorders, for example a hypolipemic, hypolydemic or lipolytic. More particularly, the present invention relates to pharmaceutical compositions containing a CB
1
receptor antagonist and a &bgr;
3
-agonist.
&bgr;
3
-agonists which can be used according to the present invention are the compounds of the formula
in which:
X is hydrogen, a halogen, a trifluoromethyl or a (C
1
-C
4
)alkyl;
R is hydrogen or a methyl which is unsubstituted or substituted by a carboxyl or an alkoxycarbonyl in which the alkoxy is (C
1
-C
6
),
and their pharmaceutically acceptable salts, indicated in EP 0 211 721 and EP 0 303 546 as intestinal spasmolytics.
Among the compounds of formula (III), the following compounds:
2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;
2-[(7-hydroxy-1,2,3,4tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)-ethanol;
2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol;
2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;
(1
Maruani Jeanne
Soubrie Philippe
Alexander Michael D.
Criares Theodore J.
Kim Jennifer
Sanofi-Synthelabo
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