WO1999053956A1

WO1999053956A1 - Remedies for obesity

Info

Publication number: WO1999053956A1
Application number: PCT/JP1999/001992
Authority: WO
Inventors: Masamichi Okada; Fumikazu Wanibuchi; Hiromi Takeuchi; Hirotsune Itahana
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1998-04-16
Filing date: 1999-04-14
Publication date: 1999-10-28
Also published as: AU3170099A

Abstract

Novel compositions for treating obesity. Means for solution: since an agonist of mGluR Group II receptor shows an inhibitory effect on hyperorexia, it is found out that this mGluR Group II receptor agonist is efficacious in treating obesity.

Description

Specification

Obesity drug

Technical field

The present invention relates to a novel pharmaceutical composition as a therapeutic agent for obesity of a compound having an action as an agonist of mGluR2 / R3 belonging to Group II which is a subgroup of the metabotropic receptor mGluRs which is one of glutamate receptors. About. Background art

In recent years, obesity has been defined as "a medical condition that requires or requires medical weight loss when there is or is predicted to be a health disorder caused by excessive accumulation of body fat". Also, diabetes, cardiovascular diseases For stroke and some cancers, obesity has been suggested to be an important risk factor for these diseases. For these reasons, obesity is gaining importance as a disease to be treated, but for patients who do not achieve the desired effects of diet and exercise therapy, aggressive pharmacotherapy is desired, resulting in a safer and more effective treatment. It is expected that new drugs will appear.

By the way, the control of appetite is performed in the hypothalamus, which is the center of the eating control mechanism, by balancing the neural activities in the nerve nuclei called the satiety center and the feeding center. Appetite regulation in the hypothalamus is regulated by neurotransmitters such as brain amines, brain amino acids, and neuropeptides (hormones and clinical studies, 45 (2): 145-152, 1997). As a regulatory mechanism of appetite involving the receptor for brain amine, it is known that adrenergic,) 8 receptor, dopamine receptor, serotonin receptor, histamine receptor and GABA receptor are involved. (Japanese clinical, 53: 33-39, 1995). Dexfenfluramine, a serotonin receptor agonist, has been shown to be effective as a therapeutic agent for obesity (Drugs, Nov. 52 (5): 696-724, 1996). Also, it has been reported that Sibutramine, an inhibitor of re-absorption of noradrenaline, also has a therapeutic effect on obesity (Int. 丄 Obes "21: Suppl. 1, S25-S29, 1997).

Glutamate, one of the above amino acids in the brain, is also known to be a major excitatory transmitter in the hypothalamus (Science. 250: 1276-1278, 1990), but is related to glutamate receptor agonists. No report has been reported on the therapeutic effect of these substances on obesity, and the following is a summary of studies relating to the dartamic acid receptor at this time. Glutamate receptors to which dalmic acid binds, like many other neurotransmitter receptors, fall into two broad categories. One is an ion channel type (iGluRs) and the other is a metabolic regulation type (mGluRs). Research on iGluRs has been relatively advanced in its physiological role.For example, for its subtypes, NMDA receptor and AMPA receptor, their antagonists have been identified in rat brain. It has been reported that when administered to specific sites or intraperitoneally, it has an effect of suppressing or enhancing food intake (丄 Neurosci., 15: 6779-6788. 1995; Am. J. Physiol., 270 : R443-449; ibid., 273: R790-796; Pharm. Bio. & Beh., 56: 145-149, 1997). However, their effects as therapeutic agents for obesity have not been confirmed.

On the other hand, mGluRs have been reported to be expressed in hypothalamic nuclei, which play an important role in feeding regulation (J. Comp. Neurol., 332: 121-135. 1992; ibid., 335: 252-266, 1993; Neuroscience, 53: 1009-1018, 1993), and the effects of mGluRs agonists on eating behavior have not been reported. It belongs to the agonist of subgroup Group II of mGluRs, and disclosed in (1S, 2S, 5R, 6S) 12-aminobisic mouth [3.1.0] disclosed in JP-A-8-188561. Xan-2,6-dicarboxylic acid (hereinafter sometimes referred to as LY354740) has been reported as a highly selective mGluR2 / R3 agonist at the recombinant human mGlu receptor (Neuropharmacology, 36: 1-1 1.1997 Although it has been reported to have an anxiolytic effect (丄 Pharmacol. Exp. Thr., 284: 651-660, 1998), no effect on eating behavior has been reported so far. Disclosure of the invention

An object of the present invention is to provide a therapeutic composition containing an organic compound as an active ingredient for the treatment of obesity, particularly for obesity which cannot be treated by means such as diet, or for an auxiliary method such as diet. To provide. The present inventors have conducted intensive studies to achieve the above object, and confirmed that an agonist of mGluR Group II receptor is effective for fasting-induced hyperphagia. The present inventors have found for the first time that a body agonist is effective as a therapeutic agent for obesity, and have completed the present invention.

That is, the present invention relates to an agonist of mGluR Group II receptor, in other words, mGluR2 / R3 receptor. The present invention relates to a pharmaceutical composition for treating obesity, comprising: an agonist of mGluR Group II receptor, which comprises an effective amount for improving obesity. Preferably, the pharmaceutical composition wherein the agonist of the mGluR Groupll receptor is (1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-1,2,6-dicarboxylic acid. The present invention further relates to a pharmaceutical composition for controlling appetite, which comprises an agonist of mGluR Group II receptor effective for controlling appetite.

The present invention also relates to a method for treating obesity, which comprises administering a therapeutically effective amount of an agonist of the mGR Group II receptor. Preferably, the agonist of the mGR Group II receptor is (1S, 2S, 5R, 6S) —2-aminobicyclo [3.1.0] hexane-1,2,6-dicarboxylic acid. The present invention relates to a method for treating obesity, and a method for regulating appetite comprising administering a therapeutically effective amount of an agonist of the mGluR Group II receptor.

Furthermore, the use of an agonist of the mGluR Group II receptor for the manufacture of a medicament for the treatment of obesity, preferably the use of (1 S, 2 S, 5 R, 6 S) —2-Aminobicyclo [3.1.0] hexane—Use of 2,6-dicarboxylic acid, as well as the use of agonists of the mGluR Group II receptor for the manufacture of appetite regulators It is. According to the present invention, there is provided a therapeutic agent for obesity comprising an effective amount of mGluR Group II receptor agonist for ameliorating obesity and a pharmaceutically acceptable auxiliary for pharmaceutical preparation. The receptor agonist is (1S, 2S, 5R, 6S) —2-aminobicyclo [3.1.0] hexan-2,6-dicarboxylic acid or a pharmaceutically acceptable salt thereof An obesity treatment is provided.

Further provided is an appetite modulator comprising an effective amount of mGluR Group II receptor agonist for regulating appetite and a pharmaceutically acceptable formulation aid. In the present invention, the agonist belonging to the mGluR Groupll receptor is a compound having an activity of activating mGluR2, and Z or R3 receptor.

Preferably, cells expressing mGluR2 and R3 are used, and cAMP production after stimulation with fuskolin in the presence of IB MX according to the method described in Neuron., 8: 169-179, 1992. Shows a dose-dependent inhibitory effect when measured with a cAMP measuring kit, and shows an activity equal to or higher than that of glutamic acid in affinity for mGluR2 and / or R3 receptor Say matter.

Examples of such an effect include, in addition to LY354740 described above, (2S, 1'S, 2'R, 3'R) —2— (2′—carboxy-3) disclosed in JP-A-3-261748. '— (Methoxymethyl) cyclopropyl) glycine (hereinafter sometimes referred to as MCG-I), disclosed in Br. J. Pharmac 0l., 107: 539-543, 1992. 2 ′S) 1-2- (carboxycyclopropyl) glycine (hereinafter sometimes referred to as L-CCG-1) disclosed in WO93 / 08158 (2S, 1′R, 2′R, 3′R) — 2— (2 ′, 3′—dicarboxycyclopropyl) glycine (hereinafter also referred to as DCG-IV), (1S, 3R) disclosed in Trends Pharmacol. Sci ”11: 508,1990 — 1 —Aminocyclopentane-1,3-dicarboxylic acid (hereinafter sometimes referred to as (1S, 3R) -ACPD), (2R, 4R) disclosed in US Pat. No. 5,473,007 — 4—Aminopyrrolidine—2, 4 Dicarboxylic acid (hereinafter sometimes also referred to as (2R, 4R) -APDC), (S) -3-carboxy-4-hydroxy disclosed in Eur. 丄 Pharmacol., Mol. Pharmacol., 267: 77-84, 1994. Examples include phenyldaricin (hereinafter sometimes referred to as (S) -3C4HPG), and the like, or salts, hydrates, solvates, and the like of these compounds.

All of the above compounds can be synthesized by the methods described in the literature, patent specification, or patent publication in which each compound is disclosed, or can be obtained from the sources described therein.

Other mGluR Group II receptor agonists can be manufactured by a conventional method. The therapeutic agent for obesity or appetite regulator according to the present invention is usually formulated and used.

Contains, as an active ingredient, one or more compounds exhibiting an activity as mGluR Group II receptor agonists used in the present invention or pharmaceutically acceptable salts, hydrates or solvates thereof. The formulation to be prepared is prepared by mixing with a carrier, excipient, and other additives that are formulation auxiliaries usually used in pharmaceutical formulation.

The carrier or excipient, which is a formulation auxiliary, may be solid or liquid, and may be, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, arabia gum, crude oil, sesame oil, cocoa butter. , Ethylene glycol and the like and other commonly used ones.

Administration is oral in tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in injections such as intravenous and intramuscular injections, suppositories, transdermals, etc. Good. The dose is determined according to the individual case, taking into account the symptoms, age, sex, etc. of the administration subject. However, in the case of oral administration, the dose is usually 1 to 1, OOO mg per adult per day. It is preferably administered in the range of 5 to 200 mg once a day or divided into several doses, or in the case of parenteral administration, 1 to 500 mg per adult per day. It can be administered subcutaneously, intravenously, or intraperitoneally in a single dose or several times daily in the range of mg, or it can be administered continuously intravenously within a range of 1 hour to 24 hours a day. Of course, as described above, the dose varies under various conditions, so that an amount smaller than the above dose range may be sufficient in some cases.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with metasilicic acid and magnesium aluminate. In accordance with a conventional method, the composition may contain an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium dalcolate calcium, and a stable agent such as lactose. And a solubilizing agent such as glutamic acid or aspartic acid. If necessary, the tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as Contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as crude oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further comprise adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be manufactured as a sterile solid composition and dissolved in sterile water or a sterile solvent for injection before use. Monkey <example

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example (manufacture of tablets)

Tablets are prepared using the following ingredients:

Ingredient dose (mg / tablet)

2-Aminobicyclo [3.1.0] Hexane-2,6-cyclo 'carwood' acid monohydrate 250

Cellulose (microcrystal) 400

Silicon dioxide (fume) 1 0

_ Stearic acid 5

a s † 665 mg The ingredients are mixed and compressed to form tablets, each weighing 665 mg. Hereinafter, the therapeutic effect of obesity according to the present invention will be shown by test results in an experimental system using mice.

(Test example)

(1S, 2S, 5R, 6S) -2-Aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid monohydrate against hyperphagia induced by fasting for 20 hours We examined the effect of suppressing the above.

(1S, 2S, 5R, 6S) -2-Aminobicyclo [3.1.0] hexane_2,6-dicarboxylic acid monohydrate can be obtained from 、 Med. Chem., 40528-537 1997 The compound was synthesized according to the production method described in (1).

Male ddY mice that had been fasted for 20 hours were divided into groups of 10 mice, and mice of the test drug administration group were given a predetermined amount of (1S, 2S, 5R, 6S) — 2— Test drugs prepared by dissolving aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid monohydrate in physiological saline, and mice in the control group to which no test drug was administered were physiologically treated. Each saline was administered by subcutaneous injection. Immediately after the end of the administration, the mice were allowed free access to food and water, and the amount of food consumed was measured from immediately after to 1 hour later. In addition, the presence or absence of the fasting-induced anorexia suppression effect by the test drug administration is determined by the control without the test drug. The comparison was made with the amount of food consumed by the mice in the group. Figure 1 shows the amount of food consumed by mice in each group including the non-fasted and saline-administered group for 1 hour immediately after the start of feeding. The symbol ## in FIG. 1 indicates that there is a significant difference compared with the control group, which is a non-fasted / saline administration group, at P <0.01 when a significant difference test is performed by a T test. The symbol ** in the figure indicates that there is a significant difference compared with the fasted / saline administration group when P <0.01 when the significant difference test is performed by the Dunnet test.

As is evident from the results shown in FIG. 1, the amount of food consumed by the mice in the fasted 'physiological saline administration group, which was the control group to which no test drug was administered, was significantly increased as compared to the mice in the non-fasted group. However, this increased consumption was 0.1 mg of (1 S, 2 S, 5 R, 6 S) -2-aminobicyclo [3.1.0] hexane-1,2,6-dicarboxylic acid monohydrate. Subcutaneous administration at doses of / kg, 1.0 mg / kg, or 10 mg / kg significantly and dose-dependently suppressed.

The agonistic activity of (1 S, 2 S, 5 R, 6 S) —2-aminobicyclo [3 · 1. 36 (1)

As shown in 1-11, 1997, the agonist activity (EC ₅₀ ) for human mGluR2 receptor based on the inhibitory effect of forskolin-stimulated CAMP formation was 5.1 ± 0.3 nM, the activity for mGluR3 receptor (EC ₅₀ ). The EC ₅₀ ) is 24.3 ± 0.5 nM, confirming that it is a potent mGluR Group II receptor agonist.

Therefore, a compound exhibiting an action as an mGluR Group II receptor agonist has an action to suppress fasting-induced hyperphagia, and is therefore useful as a therapeutic agent for obesity or a food intake regulator.

Claims

The scope of the claims

1. A pharmaceutical composition for treating obesity, comprising an effective amount of an mGluR Group II receptor agonist for ameliorating obesity and a pharmaceutically acceptable pharmaceutical auxiliary.

2. The receptor agonist of mGluR Groupll is (1S, 2S, 5R, 6S) -12-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid or its pharmaceutically The pharmaceutical composition according to claim 1, which is an acceptable salt.

3. A pharmaceutical composition for appetite regulation, comprising an appetite-controlling effective amount of an mGluR Group II receptor agonist and a pharmaceutically acceptable pharmaceutical aid.