JPH0577652B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a brain metabolism activator containing a novel imidazolidinone derivative as an active ingredient. (Prior Art) Conventionally, certain imidazolidinone derivatives, such as 1-pyrrolidinoethyl-3-pyridyl-2-
It is known that imidazolidinone derivatives have a gastric motility-promoting effect, and 1-alkyl-3-pyridyl-2-imidazolidinone derivatives have herbicidal activity (Japanese Patent Application Laid-Open Nos. 61-33172 and 61-194082). . (Structure and Effects of the Invention) The present invention relates to a brain metabolism activator comprising a novel imidazolidinone derivative represented by the following general formula or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

[Chem. A phenyl group which may have a substituent selected from the group, Q represents a methylene group or a single bond, m represents 1 to 4, and n represents 0, 1 or 2.) The compound which is an active ingredient of the present invention ( ) or a pharmacologically acceptable acid addition salt thereof has an excellent effect of activating brain metabolism and can be used to treat various diseases caused by disorders of brain metabolism. For example, the compound () or its pharmacologically acceptable acid addition salt has the effect of prolonging survival time under KCN-induced cerebral anoxia and decompression hypoxic cerebral hypoxia, and protective effect against cerebral ischemia, as shown in the experimental examples below. , K.C.N.
It has the effect of improving induced brain energy metabolism disorder and can significantly activate brain metabolism. Therefore,
The compound () according to the present invention can be used to treat brain metabolic disorders or various symptoms based on brain metabolic disorders, such as senile dementia, decreased spontaneity, decreased basic motivation, delayed thinking,
It can be used to treat and prevent problems such as decreased attention, numbness, fatigue, emotional disorders, depression, and language disorders. In addition, the compound () or a pharmacologically acceptable salt thereof has a scopolamine-induced memory impairment ameliorating effect, an anti-maximal electroconvulsive effect, an inhibitory effect on brain acetylcholinesterase (AChE) activity, and a GABA-like or GABA-enhancing effect, It can be used as an anti-dementia drug or a treatment for memory disorders. Furthermore, the compound () or a pharmacologically acceptable salt thereof can also be used as an antidepressant because it has the effect of shortening forced swimming immobility time and increasing the amount of locomotor activity. Furthermore, the active ingredient of the present invention, Compound (2), and its salt have low toxicity and high safety as a medicine. For example, the acute toxicity ( _LD50 ; male Std/ddY mice, calculated from mortality rate 7 days after oral administration) of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone according to the present invention. is 1500mg/Kg
That's all. As an example of the imidazolidinone derivative () which is the active ingredient of the present invention, in the general formula (), R
is a pyridyl group, a lower alkyl-pyridyl group or a pyrimidinyl group, ring A is a phenyl group which may have a substituent selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a trihalogeno-lower alkyl group, and Q is a single bond Examples include compounds that are . Among these, preferred compounds are those in the general formula () in which R is a pyridyl group, methylpyridyl group, or pyrimidinyl group, and ring A is a phenyl group, chlorophenyl group, methylphenyl group, methoxyphenyl group, or trifluoromethylphenyl group. It is. Moreover, a more preferable compound has the general formula ()
, R is a 3-pyridyl group, 4-pyridyl group, 6-methyl-2-pyridyl group or 2-pyrimidinyl group, ring A is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2 -Methoxyphenyl group, 3-methoxyphenyl group, 2-methylphenyl group, 3-methylphenyl group, 2-trifluoromethylphenyl group or 3-trifluoromethylphenyl group. In addition, in the imidazolidinone derivative, the formula: -
Unless otherwise specified, substructures represented by CH=CH− are of the formula

[Formula] and

It means either the cis form (ie, (Z)-configuration) or the trans form (ie, (E)-configuration) represented by the formula, or a mixture thereof. The imidazolidinone derivative that is the active ingredient of the present invention can be used as a free base or as an acid addition salt thereof. Examples of pharmacologically acceptable acid addition salts include addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; addition salts with organic acids such as oxalic acid, methanesulfonic acid, and tartaric acid; glycine, lysine, arginine, aspartic acid,
Examples include addition salts with amino acids such as glutamic acid. A brain metabolism activator containing an imidazolidinone derivative or an acid addition salt thereof as an active ingredient can be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously). The daily dosage of imidazolidinone derivatives or acid addition salts thereof varies depending on the patient's age, weight, condition, type of disease, symptoms, etc., but usually the daily dosage is per 1 kg of body weight. About 1-100mg, preferably about 5-100mg
50mg is appropriate. Further, upon administration, it is preferable to use the imidazolidinone derivative or its acid addition salt as a pharmaceutical preparation together with a pharmaceutical excipient suitable for oral or parenteral administration. As suitable excipients, for example, starch, lactose, potassium phosphate, corn starch, gum arabic, stearic acid, and other known pharmaceutical excipients can be used as appropriate. When administered orally, it may be a solid preparation such as a tablet, granule, or capsule, or a liquid preparation such as a solution, suspension, or emulsion. On the other hand, when administered parenterally, it can be used as an injection, suppository, etc. Incidentally, the imidazolidinone derivative which is the active ingredient of the present invention has, for example, the general formula

[Chemical formula] (However, rings A, m and n have the same meanings as above, and X ¹ represents a reactive residue.) Compound () represented by the general formula

[Formula] (However, the symbols have the same meanings as above.) A compound represented by () or its salt (e.g., mineral acid salt, organic acid salt, alkali metal salt) is mixed with a deoxidizing agent (e.g., hydrogenated The product can be produced by condensation under cooling or heating in the presence or absence of an alkali metal, alkali metal alkoxide, KF-alumina, etc.) and, if desired, converting the product into an acid addition salt thereof. In the above reaction, the starting material compound () is, for example, a halogen atom, ^a lower alkylsulfonyloxy group, a substituted or unsubstituted phenylsulfonyloxy group (phenylsulfonyloxy group, p-toluene A compound having a sulfonyloxy group, etc.) can be suitably used. Experimental example 1 (Anti-maximal electric shock convulsion effect) (Experimental method) A sample was orally administered to Std/ddY male mice (1 group: 5 mice), and 60 minutes later an electrical stimulation device (manufactured by Kyoto Keikiki, 150MA) was administered. Corneal current application (DC,
(25 mA, 0.15 seconds), the presence or absence of tonic extensor convulsions was observed, and the number of cases in which convulsions were suppressed was determined. The specimen was dissolved or suspended in a 0.5% carboxymethyl cellulose (CMC) solution and administered (the same applies to the following experimental examples). (Results) The following compounds according to the present invention are all administered at
At 100 mg/Kg, the development of tonic extensor convulsions was completely suppressed.

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[Table] Yes.

Experimental Example 2 (Anti-KCN-induced brain anoxia effect) (Experimental method) The specimen was orally administered to Std/ddY male mice (group 1; 5 mice). KCN2.4mg/60 minutes after sample administration
Kg was administered into the tail vein, and the survival time of the mice was measured. Note that a 0.5% CMC solution was administered to the control group instead of the sample solution. (Results) All five animals in the 0.5% CMC solution administration group died, but in the specimens No. 1 to 9 described in Experimental Example 1 and the following 100 mg/Kg administration group of the compound according to the present invention, all animals in each group survived. It showed a significant protective effect against brain anoxia.

[Table] Experimental Example 3 (Increase in locomotor activity) (Experimental method) The specimen was orally administered to Std/ddY male mice (1 group: 10 to 12 mice). 55 minutes after administration of the sample, 0.03 to 0.1 mg/Kg of apomorphine was subcutaneously administered, and the locomotor activity was measured for 15 minutes from 5 minutes later using ANIMEX (manufactured by Farad). (Results) Compound (E)-1-cinnamyl-3 according to the present invention
-(6-methyl-2-pyridyl)-2-imidazolidinone and (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone compared to the control group (CMC solution administration group). Locomotor activity was significantly increased at doses of 10 mg/Kg and 45 mg/Kg or higher, respectively. Experimental example 4 (Forced swimming immobility time shortening effect) (Experimental method) The sample was orally administered to Std/ddY male mice (1 group: 10 mice), and 60 minutes after administration, the sample was poured into 25°C water to a depth of 16 cm.
Each mouse was allowed to swim for 6 minutes in a beaker filled with water, and the time the mouse remained motionless (the state in which the mouse stopped struggling and floated with its neck above the water surface) was measured. (Results) Compound (E)-1-cinnamyl-3- according to the present invention
(6-Methyl-2-pyridyl)-2-imidazolidinone significantly shortened the immobility time at doses of 2 mg/Kg or more compared to the control group (CMC solution administration group). Experimental Example 5 (Experimental Method) (A) Anti-decompression hypoxia-induced cerebral hypoxia The test sample was orally administered to Std/ddY male mice (1 group: 10 mice), and 60 minutes after administration, each mouse was given a volume of approximately 1 The cells were placed in a sealed glass container, and the pressure was reduced to 165 mmHg for about 5 seconds using a vacuum pump, and the survival time was measured. Survival time was defined as the time from the start of decompression until the complete cessation of body movements except for heartbeat. (B) Protective effect against cerebral ischemia The specimen was intraperitoneally administered to Std/ddY male mice (1 group: 15 to 20 mice). Decapitation was performed 30 minutes after administration, and the duration of gasping was measured. (C) Scopolamine-induced memory impairment improvement effect When a Std/ddY male mouse habitually moves to the dark room using a learning box with two light and dark rooms, the foot
I tried to acquire it by giving a shock. Immediately after the trial, the specimen was orally administered, and 24 hours later, the time taken to move from the light room to the dark room (reaction latency) was measured. In addition, 1 mg/Kg of spocolamine was subcutaneously administered to the amnesia model group 30 minutes before the acquisition trial. (D) GABA-enhancing effect A microelectrode was inserted extracellularly into a single Purkinje cell in the cerebellum of a male wistar rat, and electrophoretic and systemic administration of the sample caused spontaneous firing and GABA activation.
We investigated the effect on (E) AChE activity inhibition effect AChE activity was measured using the brain crude synaptosome fraction of male Wistar rats as the enzyme material and acetylthiocholine as the substrate, and the production rate of the reaction product thiocholine was used as an indicator. The inhibitory concentration (IC ₅₀₎ was determined. In each of the above experiments,
For the control group, 0.5% CMC was added instead of the sample solution.
solution was administered. (Results) The results when (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone according to the present invention was used as a specimen are as follows.

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[Table] Experimental example 6 (KCN-induced brain energy metabolism disorder improvement effect) (Experimental method) Std/ddY male mice (1 group: 6 mice) were given (E)-1-cinnamyl-3-(3-pyridyl) as a sample. )
-2-imidazolidinone was administered intraperitoneally. administration
Thirty minutes later, 2.4 mg/Kg of KCN was administered intravenously over 5 seconds, and 60 seconds later, the whole body was frozen and brain energy metabolism-related substances were quantified. Note that a 0.5% CMC solution was administered instead of the sample solution to the normal control group (KCN not administered) and the KCN control group. In addition, the brain energy metabolism disorder improving effect was expressed as a ratio (%) when brain energy-related substances, lactic acid/pyruvic acid ratio, and energy storage in the normal control group were set as 100. (Results) The results are as follows.

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[Table] As is clear from the above results, (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone increases creatine-P, ATP, and
It suppressed the decrease in glucose, glycogen and energy storage, and also suppressed the increase in the lactic acid/pyruvic acid ratio. Production example 1 (1) 150g of 3-aminopyridine and 1000ml of toluene
176 g of 2-chloroethyl isocyanate is added dropwise to the solution under ice cooling. After stirring at room temperature for 5 hours, the precipitated crystals were collected by filtration to obtain N-
318 g of (2-chloroethyl)-N'-(3-pyridyl)urea are obtained. MP136-138℃ (2) Sodium hydride (60% oily dispersion) was added to a mixture of 150 g of N-(2-chloroethyl)-N'-(3-pyridyl)urea, 500 ml of tetrahydrofuran, and 500 ml of dimethylformamide under ice cooling. 31.6
Add g. After stirring for 10 minutes under ice-cooling and 2 hours at room temperature, 10 ml of acetic acid was added and the solvent was distilled off. Saturated saline and chloroform are added to the residue, and insoluble matter is filtered off. After washing and drying the chloroform layer, the solvent was distilled off, and the residue was recrystallized from chloroform-hexane to obtain 1-(3-pyridyl).
108.5 g of -2-imidazolidinone is obtained. MP161～163℃ (3) 1-(3-pyridyl)-2-imidazolidinone
150g N,N-dimethylformamide 1500ml
In solution, add sodium hydride (60% oily dispersion 40
Add g. After stirring the mixture at room temperature for 10 minutes, cinnamyl chloride (trans isomer) was added under ice cooling.
Add 154g dropwise and stir for 2 hours. After adding 10 ml of acetic acid, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing and drying, chloroform was distilled off, isopropyl ether was added to the residue, the precipitated crystals were collected by filtration, and recrystallized from ethanol to obtain colorless prism crystals (E)-1-
238.1 g of cinnamyl-3-(3-pyridyl)-2-imidazolidinone are obtained. Yield: 92.7%M.
P.114.5-116℃ Hydrochloride (crystalline polymorph): MP188-190℃ (recrystallized from methanol-isopropanol) and 206-209℃ (recrystallized from methanol-isopropanol) Hydrobromide: MP180-199℃ (Recrystallized from isopropanol) Sulfate: MP195-198℃ (Recrystallized from ethanol-methanol) Methanesulfonate: MP155-156℃ (Recrystallized from isopropal) Production Examples 2-41 Production Example 1-(2) Obtained 1-(3-pyridyl)-2-
The imidazolidinone and cinnamyl compound () are treated in the same manner as in Production Example 1-(3) to obtain the compounds listed in Table 1 below. Furthermore, among the compounds listed in Table 1 below, Production Example 16
The compound has a (Z)-configuration (i.e., cis configuration),
All others have the (E)-configuration (ie, the transformer configuration).

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[Table] Production Examples 18-27 (1) The aminopyridine compound () and 2-chloroethyl isocyanate () are treated in the same manner as in Production Example 1-(1) to obtain the compounds listed in Table 2 below.

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[Table] (2) By treating the compound obtained above in the same manner as in Production Example 1-(2), the compounds listed in Table 3 below are obtained.

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[Table] (3) The imidazolidinone compound () and cinnamyl compound () obtained above were treated in the same manner as in Production Example 1-(3) to obtain the compounds listed in Table 4 below. All of the compounds listed in Table 4 below have the (E)-configuration (ie, trans-configuration).

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[Table] Production examples 28-48 Production examples 1-(1), Production examples 18-(2), 19-(2) and 24-
The imidazolidinone compound () obtained in (2) and the compound () are treated in the same manner as in Production Example 1-(3) to obtain the compounds listed in Table 5 below.

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[Table] Production Examples 49 to 52 (1) The amine compound () and 2-chloroethyl isocyanate () are treated in the same manner as in Production Example 1-(1) to obtain the compounds listed in Table 6 below.

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[Table] (2) The compounds obtained in (1) above are treated in the same manner as in Production Example 1-(2) to (3) to obtain the compounds listed in Table 7 below. All of the compounds listed in Table 7 below have the (E)-configuration (ie, trans-configuration).

[Table] Production Examples 53-60 (1) Add 4 g of benzyltriphenylphosphonium chloride to a suspension of tetrahydrofuran under cooling.
- Add 7.07 ml of 1.6M hexane solution of butyllithium. After stirring at room temperature, 1 g of 2-hydroxytetrahydrofuran is added, and the mixture is further stirred at room temperature. Then, after refluxing, insoluble matter was filtered off, and the solvent was distilled off. By purifying the residue with silica gel column chromatography, (E)-5-phenyl-4-
1.2 g of penten-1-ol are obtained as a colorless oil. MS (m/e): 162 (M ⁺ ), 144 (M-H ₂ O) In addition, the corresponding triphenyl phosphonium compound is treated in the same manner as above to obtain the compounds listed in Table 8 below.

[Table] (2) Dissolve 1.6 g of (E)-5-phenyl-4-penten-1-ol obtained in (1) above in pyridine, and add 2.0 g of para-toluenesulfonyl chloride.
After stirring under cooling, water is added, further stirred, and ether is added. After washing the mixture, the organic phase is dried and the solvent is distilled off under reduced pressure. By purifying the residue with silica gel column chromatography, (E)-5-
2.6 g of phenyl-1-p-toluenesulfonyloxy-4-pentene are obtained as an oil. Further, the products obtained in Production Examples 51-(1) to 57-(1) were treated in the same manner as above to obtain the compounds listed in Table 9 below.

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[Table] (3) The compounds obtained in (2) above were treated in the same manner as in Production Example 1-(3) to obtain the compounds shown in Table 10 below.

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[Table] Production example 69 (1) Dissolve 1.6 g of N-(3-pyridylmethyl)ethylenediamine in 30 ml of tetrahydrofuran,
Add 1.49 g of carbonyldiimidazole at 0°C. The mixture is stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. The solvent was distilled off, the residue was purified by silica gel column chromatography (solvent: chloroform-methanol = 15:1), and recrystallized from isopropanol-hexane to obtain 1-(3
-pyridylmethyl)-2-imidazolidinone
Obtain 1.43g. MP58～86℃ (2) By treating this product and cinnamyl chloride (trans isomer) in the same manner as in Production Example 1-(3), (E)-
1-cinnamyl-3-(3-pyridylmethyl)-
2-imidazolidinone is obtained. Yield 65%. (oxalate) MP105-115℃ (decomposition) (isopropanol-
(recrystallized from isopropyl ether) Production Example 70 (1) By treating N-(4-pyridylmethyl)-ethylenediamine in the same manner as in Production Example 69-(1), 1-(4-pyridylmethyl)-2-imidazo Get Lysinone. MP153-155℃ (recrystallized from isopropanol-isopropyl ether) (2) By treating this product and cinnamyl chloride (trans isomer) in the same manner as in Production Example 1-(3), (E)-
1-cinnamyl-3-(4-pyridylmethyl)-
2-imidazolidinone is obtained. Yield 69.8% Hydrochloride: MP150-52℃ (recrystallized from isopropanol-isopropyl ether) Production example 71 (1) 1.6M of n-butyllithium was added to a solution of 11.2g of phenylacetylene in tetrahydrofuran under cooling.
- Add 78.8 ml of hexane solution dropwise. Then 10~
At 20 DEG C., a solution of 26.3 g of 1-bromo-4-(2-tetrahydropyranyloxy)butane in hexamethylphosphoramide is added dropwise. After stirring at the same temperature,
Pour the reaction solution into ice water and extract with hexane. After washing the organic layer with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.
16.5 g of -phenyl-6-(2-tetrahydropyranyloxy)-1-hexyne are obtained as an oil. (2) Heat a tetrahydrofuran-diglyme solution containing 10.8 g of this product and 3.35 g of lithium aluminum hydride, and distill off the tetrahydrofuran until the internal temperature reaches 120°C. After heating under reflux at the same temperature for 1 hour, cool on ice, add ice, and extract with ethyl acetate. After washing and drying the organic layer, the solvent is distilled off and the residue is dissolved in methanol. After adding 1.1 g of para-toluenesulfonic acid and stirring for 1 hour, triethylamine was added and methanol was distilled off. By purifying the residue with silica gel column chromatography, (E)-6-phenyl-5-hexene-1-
6.47 g of all are obtained as an oil. (3) Dissolve 4.4g of this product in pyridine and add 7.1g of p-toluenesulfonyl chloride. After stirring under cooling, water is added, further stirred, and ether is added. After washing the mixture, the organic layer is dried and the solvent is distilled off under reduced pressure. By purifying the residue with silica gel column chromatography, (E)-1-phenyl-6-p-toluenesulfonyloxy-1
- 5.8 g of hexene are obtained as an oil. MS (m/e): 330 (M ⁺ ) (4) By treating this product and 1-(4-pyridyl)-2-imidazolidinone in the same manner as in Production Example 1-(3), (E) -1-(6-phenyl-5hexenyl)-3-(4-pyridyl)-2-imidazolidinone is obtained. Yield: 64.2% Mp105~107℃ (recrystallized from isopropyl ether)

Claims (1)

[Scope of Claims] 1 General formula: (However, R is a pyridyl group or a pyrimidinyl group which may have a substituent selected from a lower alkyl group and a lower alkoxy group, and Ring A is a halogen atom or a lower alkyl group. (Q represents a methylene group or a single bond, m represents 1 to 4, and n represents 0, 1 or 2.)
A brain metabolism activator comprising an imidazolidinone derivative represented by the formula or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 2. Claim 1, wherein R is a pyridyl group, a lower alkyl-pyridyl group, or a pyrimidinyl group, and Q is a single bond.
The brain metabolism activator described. 3. The brain metabolism activator according to claim 2, wherein 3R is a pyridyl group, a methylpyridyl group, or a pyrimidinyl group, and ring A is a phenyl group, a chlorophenyl group, a methylphenyl group, a methoxyphenyl group, or a trifluoromethylphenyl group. 4 R is 3-pyridyl group, 4-pyridyl group, 6-
Methyl-2-pyridyl group or 2-pyrimidinyl group, ring A is a phenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group,
2-methylphenyl group, 3-methylphenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 2-trifluoromethylphenyl group or 3-
The brain metabolism activator according to claim 3, which is a trifluoromethylphenyl group. 5 Ring A is a phenyl group, 2-chlorophenyl group,
Claim 4: 3-chlorophenyl group, 4-chlorophenyl group or 3-methylphenyl group, where n is 1
The brain metabolism activator described. 5. The brain metabolism activator according to claim 4, wherein 6R is a 3-pyridyl group or a 4-pyridyl group, ring A is a phenyl group, and n is 0. 7 R is 4-pyridyl group, ring A is phenyl group, n
The brain metabolism activator according to claim 4, wherein is 2. 8 (E)-1-cinnamyl-3-(3-pyridyl)-
A brain metabolism activator comprising 2-imidazolidinone or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 9 (E)-1-cinnamyl-3-(6-methyl-2
-Pyridyl)-2-imidazolidinone or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 10. Brain metabolic activation according to claims 1 to 9, which is a therapeutic/preventive agent for senile dementia, decreased spontaneity, decreased motivation, delayed thinking, decreased attention, numbness, easy fatigability, emotional disorder, and/or language disorder. agent. 11. The brain metabolism activator according to claims 1 to 9, which is a therapeutic/preventive agent for dementia and/or memory disorders. 12 Claims 1 to 9 which are therapeutic/preventive agents for depression.
The brain metabolism activator described.