JPH06305967A - Improving and therapeutic agent for cholinergic nervous insufficiency - Google Patents

Abstract

PURPOSE:To obtain the improving and therapeutic agent, containing a specific azole derivative as an active ingredient and having excellent effects on cholinergic nervous insufficiency and high safety and effective in improving and treating Alzheimer disease, etc. CONSTITUTION:The objective improving and therapeutic agent contains an azole derivative of the formula (R<1> is lower alkyl, thienyl or phenyl which may be substituted with lower alkyl or lower alkoxy; R<2> is H, lower alkyl or phenyl; X is O atom or S; Y is O atom or NH) or its acid addition salt as an active ingredient.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for improving and / or treating cholinergic nerve insufficiency, which contains a specific azole derivative as an active ingredient.

[0002]

2. Description of the Related Art Recently, Alzheimer's disease and senile dementia of the Alzheimer's type have become major problems. It is known that these diseases are deeply associated with degeneration and loss of cholinergic nerves [White House , P .; J.
Et al., Science, Volume 215, Page 1237 (19
1982) etc.]. The involvement of cholinergic nerves in memory is
It is also shown that administration of an acetylcholine antagonist to humans causes memory impairment. Therefore, a cholinergic nervous system activator can be a therapeutic agent for various dementia including Alzheimer's disease. Examples of the cholinergic nervous system activator include an acetylcholinesterase inhibitor and a muscarinic agonist that directly stimulates a muscarinic acetylcholine receptor. The muscarinic acetylcholine receptor is composed of two subtypes of M1 type and M2 type. The M1 type is mainly distributed in the central nervous system and the M2 type is mainly distributed in peripheral tissues. Since M2 type receptor activators are highly likely to lead to side effects, compounds with high M1 type selectivity can be useful cholinergic nervous system activators. By the way, a compound which is an active ingredient of the agent for improving and / or treating cholinergic nerve failure according to the present invention is disclosed in JP-A-2-
In Japanese Patent No. 229190, a therapeutic effect on gastrointestinal tract dysfunction based on a 5-HT antagonistic effect, an analgesic effect and the like are known.

[0003]

However, the action of the compounds described in the above publication on cholinergic neuropathy is not known. An object of the present invention is to provide a new drug having an excellent effect on cholinergic nerve failure and a high safety.

[0004]

In order to solve the above problems, the present inventors extensively searched for compounds that strongly bind to the muscarinic acetylcholine receptor M1 type, and as a result, a certain azole derivative against the M1 type receptor. The inventors have found that they have strong affinity and good selectivity, and completed the present invention.

That is, the present invention uses the formula

[0006]

(In the formula, R ¹ is a lower alkyl group, a thienyl group or a "lower alkyl group or a lower alkoxy group".
Represents a phenyl group which may be substituted with, R ² represents a hydrogen atom, a lower alkyl group or a phenyl group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or NH.
Indicates a group. ) Is an azole derivative or an acid addition salt thereof represented by the formula (1) as an active ingredient for improving and / or treating cholinergic nerve failure.

Preferred compounds in the present invention are 2-methyl-4-phenyl-5-thiazolecarboxylic acid tropyl ester (hereinafter referred to as compound 1) and 2,4-
Dimethyl-5-oxazolecarboxylic acid tropyl ester (hereinafter referred to as compound 2), 2- (2-thienyl) -4-oxazolecarboxylic acid tropyl ester (hereinafter referred to as compound 3), 2-phenyl-5- Methyl-4-thiazolecarboxylic acid tropyl ester (hereinafter referred to as compound 4), N-tropyl-2-phenyl-4-thiazolecarboxamide (hereinafter referred to as compound 5), 2- (3-methylphenyl)- 4-thiazolecarboxylic acid tropyl ester (hereinafter, referred to as compound 6), N-tropyl-2- (3-methylphenyl) -4-thiazolecarboxamide hydrochloride (hereinafter,
This is referred to as Compound 7. ), N-tropyl-2- (4-methoxyphenyl) -4-thiazolecarboxamide hydrochloride (hereinafter referred to as compound 8), and particularly preferred compounds are compound 3 and compound 5.

The dose of the compound of the formula (I), which is an active ingredient of the agent for improving and / or treating cholinergic nerve deficiency of the present invention, is appropriately selected depending on the administration method, the age of the patient and the symptoms of the patient. When treating an adult, usually 1 to 200 per day
Administer mg in 1 to 3 divided doses. As an administration method,
Oral or parenteral administration may be mentioned. The dosage forms for oral administration include tablets, granules, powders, capsules,
Examples include syrups, suspending agents, etc.
For parenteral administration, the dosage forms include injections, eye drops,
Suppository etc. can be mentioned. Formulations of various dosage forms include conventional excipients (eg crystalline cellulose, starch, lactose etc.), binders (eg hydroxypropyl cellulose, polyvinylpyrrolidone etc.), lubricants (eg magnesium stearate, talc etc.) ), A disintegrating agent (for example, carboxymethyl cellulose calcium, etc.) and the like, and can be produced by an ordinary production method (for example, the method described in the 12th revised Japanese Pharmacopoeia).

[0010]

INDUSTRIAL APPLICABILITY According to the present invention, diseases associated with cholinergic nerve deficiency, such as Alzheimer's disease, Alzheimer-type senile dementia, Huntington's chorea, late movement disorder,
It has become possible to provide drugs that are excellent for the improvement and treatment of mania and the like. Also, dementia due to cerebrovascular disorders such as cerebral ischemia, cerebral infarction, and cerebral hemorrhage (cerebrovascular dementia), mental disorders, memory disorders with age, dementia with Parkinson's disease, etc. Since there are many cases where symptoms occur, improvement / treatment of these diseases can be expected.

[0011]

EXAMPLES Next, the effects of the present invention will be described with reference to test examples. Test Example 1 The binding to the muscarinic acetylcholine receptor was
The method of Freedman et al. [Eur.J.Pharmaco
L., 156, 133 (1988)] with some modifications. That is, a rat cerebral cortex synaptosome membrane fraction (rich in M1 type receptors) was used [ ³
In the [H] -pirenzepine-receptor binding experiment system, the IC ₅₀ value of the sample was determined from the binding inhibition curve when a sample concentration of 10 ^-9 to 10 ^-3 M was added, and the Ki value was calculated as an index of M1 binding property. . Furthermore, rat heart membrane fraction (M
In the same manner as in [ ³ H] -N-methylscopolamine-receptor binding experimental system using (type 2 receptor-rich), M2
The M1 selectivity was evaluated by determining the Ki value indicating the binding property and calculating the M2 / M1 ratio of the Ki value. The results are shown in Table 1.

[0012]

[Table 1]

Test Example 2 Mice (ICR male, 4 weeks old, 10 mice per group) were intraperitoneally administered with oxotremorine (0.5 mg / kg) to observe tremor 10 minutes after administration. I just did
The tremor score was 1.0. In addition, score 1; sometimes a weak tremor appears. Score 2: A strong tremor sometimes appears. Score 3: A continuous strong tremor appears. That is the stage. Furthermore, when each of Compound 1 and Compounds 3 to 8 was orally administered (25,50 mg / kg) 20 minutes before the administration of oxotremorine, the tremor score increased as shown in Table 2.

[0014]

[Table 2]

The administration of the compound of formula (I) was found to enhance the tremor effect of oxotremorine.
The compounds of formula (I) have been shown to have central agonist activity.

Test Example 3 [Amnesia Improvement Test by Electric Shock Seizure] The test was conducted by Tobe Akihiro et al. [Japan.J.Pharmacol., No. 39].
Vol., Pp. 153-161 (1985)]. Passive avoidance of mice (ICR male, 4 weeks old, 10 mice per group) consisting of a light box and a dark box to which an electric shock (0.2 mA, 2 seconds) can be applied via the floor grid. It was put in the device and an acquisition trial was performed.
A holding trial was performed after 24 hours, and the latency from entering the light box to entering the dark box was measured up to 180 seconds. The maximum electric shock seizure (ECS) load was measured using an electric shock device, and immediately after the acquisition trial, current (1000 V, 20 m) was passed through both ears of the mouse.
It was performed by energizing A) for 0.2 seconds. It was confirmed that ECS was loaded by the appearance of tonic extension cramps. 5 compounds of the formula (I) were orally administered by suspending them in gum arabic immediately after ECS loading (0.3 to 3 mg / kg)
did. The results are shown in Table 3.

[0017]

[Table 3]

[0018]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyo Araki 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A formula (In the formula, R ¹ represents a lower alkyl group, a thienyl group or a phenyl group which may be substituted with a “lower alkyl group or a lower alkoxy group”, R ² represents a hydrogen atom, a lower alkyl group or a phenyl group, (X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom or an NH group.)
An agent for improving and / or treating cholinergic nerve failure, which comprises an azole derivative represented by the following formula or an acid addition salt thereof as an active ingredient.