KR950013764B1 - Pyroglutamide derivatives, method of preparing them and antidementia composition containing them - Google Patents

Abstract

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Description

[Name of invention]

Pyroglutamide derivatives, preparation method thereof, and agent for treating dementia containing the same

Detailed description of the invention

The present invention relates to a D- pyroglutamide derivative useful as a pharmaceutical, a method for producing the same, and an agent for treating dementia containing the same.

The D- pyroglutamide derivative which concerns on this invention can be represented by the following general formula [I].

)가 노인 의료에 있어서 큰 비중을 차지하게 되고 있으나 아직까지 그 치료법의 확립은 이루어지고 있지 않다. 뇌 대사 부활제, 뇌혈류 개선제, 정신 안정제, 콜린 작용제 등의 약물 요법이 시도되고 있으나 효과는 불일정하고 만족할 만한 의약품은 없다.As the population ages,

) Occupy a large portion of the elderly medical care, but the treatment is not yet established. Drug therapy, such as brain metabolism revitalizers, cerebral blood flow improvers, mental stabilizers, choline agonists, and the like has been tried, but there are no unsatisfactory and satisfactory drugs.

Recently, some compounds such as anilacetam and pramiracetam are being developed as a treatment for dementia. In addition, Japanese Patent Application Laid-Open No. 52-125166 or Japanese Patent Laid-Open No. 51-115472 discloses a thyrotropin releasing hormone (TRH) compound.

The present inventors have attempted to invent a substance having an excellent fragrance action from a completely new point of view in view of the above-mentioned phenomenon of delay of drug development aimed at treating dementia. It is therefore an object of the present invention to provide a new form of treatment for dementia.

The inventors have examined the fragrance effect on various compounds for many years, but fortunately, they found a group of compounds having excellent fragrance effect on mammals and extremely low toxicity. Special Place No. 61-011359, Japanese Special Place No. 61-038024)

Although the compound of this invention is represented by general formula [I], Japanese Unexamined-Japanese-Patent No. 51-8266 discloses DL-N-piperidino pyroglutamide as a manufacturing intermediate of an antiulcer agent. This compound is also disclosed in Japanese Patent Laid-Open No. 49-14462 as a raw material. Therefore, the racemate (DL-form) of the compound represented by general formula [I] is not a novel compound.

There has been no literature suggesting the pharmacological action of the present invention regarding these compounds.

The compound of the present invention is represented by the general formula [I] but has an asymmetric carbon therein.

[Ⅰ]

[Ⅰ]

In the conventional manufacturing method, even if D is used as a raw material, L is mixed in addition to D in the process of producing Compound [I]. Therefore, isolation by optical splitting or the like is necessary, which is an industrially disadvantageous method.

The present inventors have found that only D-form is obtained in high yield and high optical purity by reacting with piperidine using a compound represented by the following general formula [III], or a reactive derivative thereof. Of the compounds represented by the general formula [I], only the D-body was found to have excellent fragrance action, and thus the present invention was completed based on these compounds:

The compound represented by general formula [I] which is a compound of this invention can be manufactured, for example by the following method.

[A law]

[I] is prepared by reacting piperidine with compound [III]. This amidation reaction is, for example, a method of directly condensing [III] and pyreridine with dicyclohexylcarbodiimide (DCC), diphenyl phosphoryl azide (DDPA), or the reactive derivative of [III], For example, a method of appropriately reacting an acid anhydride, an imidazolide, or a mixed acid anhydride (anhydride with methyl carbonate, anhydride with ethyl carbonate, anhydride with isobutyl carbonate), the active ester method, and the like can be used. . When using these polycondensing agents, for example DCC, the reaction can be carried out in a suitable solvent (e.g., halogenated hydrocarbons such as methylene chloride, chloroform, ether solvents such as tetrahydrofuran, dioxane, acetonitrile, N, N -Dimethylformamide, etc.), usually at about -30 ° C to about 30 ° C. It is preferable to use a molar molar to slightly excess compound [III] and DCC per mole of piperidine.

In addition, when using the active ester method, [I] can be manufactured as follows, for example.

In the formula, R represents a residue of an alcohol or a phenol.

Active ester [IV] is manufactured by making compound [III] react with the alcohol or phenol represented by [V], and a condensing agent. The esterification reaction can be performed by, for example, [III] using a suitable solvent (e.g., halogenated hydrocarbons such as methylene chloride, chloroform, aprotonic solvents such as acetonitrile, N, N-dimethylformamide, dioxane, tetrahydro [V] (e.g., penta) in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DDPA), etc.) in an ether solvent such as furan) Chlorphenol, paranitrophenol, N-hydroxyquinoline, N-hydroxysuccinimide, N-hydroxybeanstriazole, and the like).

The amount of [V] and the condensing agent used is preferably at least mol, preferably at least 1.1 mol and at least 1.2 mol, with respect to 1 mol of [III].

The ester [IV] produced as described above can be isolated and purified once, or can be induced to [I] by reacting piperidine without isolation.

The said amidation reaction can be performed by making 1.1 mol or more and preferably 2.0 mol or more piperidine react with 1 mol of [IV] in the same solvent used for the said esterification reaction at 0-160 degreeC.

[B method]

Compound [I] can also be manufactured by making piperidine react with compound [II].

The amidation reaction can be carried out by a method known per se. For example, it can carry out normally at room temperature (20-30 degreeC) using sugar molar or more, preferably 1.0-1.3 mol of piperidine with respect to compound [II].

The solvent in this case may be any inert solvent, for example, an alcohol solvent such as methanol, ethanol, isopropanol, a halogenated hydrocarbon solvent such as fluoroform, carbon tetrachloride, and an aromatic hydrocarbon such as benzene, toluene, and xylene. A solvent, an ether solvent such as tetrahydrofuran, dioxane, or an aprotic polar solvent such as N or N-dimethylformamide can be used, and may be solvent-free.

[II] and [III] used as raw materials of the above-mentioned manufacturing methods can be easily manufactured by a well-known method. When using a racemate (DL body) as a raw material, [I] is obtained as a mixture of D body and L body, but the D body can be separated and purified by the usual optical division method.

Compound [I] obtained by each of the above methods can be isolated and purified by, for example, a method known per se, by concentration, liquid conversion, conversion, solvent extraction, crystallization, recrystallization, fractionation, chromatography, or the like.

The result of the pharmacological test which shows the usefulness of the compound of this invention is demonstrated in detail below.

[One. Improvement effect on scoporamine forgetfulness]

Assay: After acquiring passive avoidance learning (PAR), administration of scoporamine (0.5 mg / kg) and test drug at the same time intraperitoneally to the rats, and then passive passive avoidance learning response (maintenance) after 1 hour did. The positive reaction rate (number of positive animals / number of animals used) at that time is shown in Table 1.

When the test drug was orally administered in the above test, maintenance was performed 2 hours after drug administration. Anilacetam was used as a reference. The minimum effective amount which shows a significant improvement effect at the time of intraperitoneal and oral administration is shown in (1) of Table 2.

TABLE 1

Remarkable effects of the compounds of the present invention are apparent.

[2. Improvement Effect on Electric Shock Forgetfulness]

The same method used for scoporamine forgetfulness was used.

After the acquisition, the rats were given an electric shock, and after the convulsions were recovered, the test drug was intraperitoneally and orally administered. After 1 and 3 hours, the maintenance was carried out, and the positive response rate was measured. The minimum effective amount is shown in Table 2 (2).

[3. Improvement Effect on Excess Carbon Dioxide Forgetfulness]

After 30 and 60 minutes of intraperitoneal or oral administration of the test drug, the rats were left in a chamber filled with carbon dioxide for 12 seconds, and after 2 minutes, the buzzer was transferred to a plurality of compact mantle plural to stimulate the condition. Active evasion learning and escape learning were carried out, and the minimum effective amount showing the improvement effect was measured in (2) of Table 2 by measuring the positive rate (number of positive animals / use animals) of the sixth escape learning acquisition test.

The minimum effective amounts in Table 2 were all expressed as effective amounts (mg / kg) showing an improvement effect of p <0.05 significance in the x ² assay.

TABLE 2

Each test number of Table 2 shows the following.

(1) Improvement effect on Socoporamine forgetfulness

(2) Improvement effect on electric shock dryness

(3) Improvement effect on excess carbon dioxide forgetfulness

Useful effects of the compounds of the present invention are apparent.

[4. Acute toxicity]

Male rats were observed for toxic symptoms for 7 days after intravenous and oral administration of N- (5-oxo-D-prolyl) piperidine.

Intravenous administration of 1000 mg / kg did not result in death and almost no toxic symptoms were identified. In the case of oral administration, there was no death at 3000 mg / kg, and no toxic symptoms were confirmed.

The safety of the compounds of the invention is clear.

When the compound of the present invention is administered as a medicament, it is a human pharmaceutical composition containing, for example, 0.1 to 99.5%, preferably 0.5% to 90%, of the compound of the present invention as it is or in a pharmaceutically acceptable non-toxic and inert carrier. It is good to administer to the animal containing.

As the carrier, one or more solid, semisolid or liquid diluents, fillers and other prescription preparations are used. The pharmaceutical composition is preferably administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, in tissue, topically or rectally. It is, of course, administered in formulations suitable for these methods of administration, for example tablets, granules, powders, capsules, injections, suppositories and the like. For example, oral administration is particularly preferred.

The dosage for the treatment of dementia is preferably adjusted after taking into consideration the condition of the patient such as age and weight, the route of administration, the nature and extent of the disease, etc. However, in the case of an adult, the range of 1 mg / 5 g per day is generally used as an active ingredient of the present invention. It is good and preferably the range of 150 mg-3 g is common. In some cases, even lower doses are sufficient and vice versa. Moreover, it can also divide and administer in several times a day.

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to examples of the present invention.

Example 1

Synthesis of N- (5-oxo-D-prolyl) piperidine

A solution of 45.0 g of D-pyroglutamic acid, 450 ml of acetonitrile and 22.8 g of piperidine is cooled with ice water and stirred, and then 71.9 g of dicyclohexylcarbodiimide is added at 10 DEG C or lower. Furthermore, it is made to react at room temperature for 5 hours. Insolubles are filtered off from the reaction mixture, and the solvent is distilled off under reduced pressure from the filtrate.

The residue is purified by silica gel column chromatography to give 60.0 g of oily product. When this is crystallized in a mixture solvent of ethyl acetate-diethyl ether, 44.7 g of N- (5-oxo-D-prolyl) piperidine having a melting point of 94.0 to 95.0 占 폚 is obtained.

Luminous intensity [α] ²⁴ + 48.32 ° [water C = 1]

Elemental Analysis Value: C ₁₀ H ₁₆ N ₂ O ₂

Calculated (%): C; 61.20, H; 8.22, N; 14.27

Found (%): C; 61.16, H; 8.17, N; 14.30

Example 2

(1) Synthesis of D-pyroglutamic acid pentachlorophenyl ester

A suspension of 1.3 g of D-pyroglutamic acid, 3.1 g of pentachlorophenol, and 26 ml of methylene chloride is cooled with ice water and 2.5 g of dicyclohexylcarbodiimide is added with stirring. Then, the mixture was stirred for 1 hour under cooling and 5 hours at room temperature. Insolubles are removed by filtration from the reaction mixture, and the insolubles are washed with 50 ml of methylene chloride. The filtrate and the tax solution were combined, and the residue obtained by distilling the solvent off under reduced pressure was recrystallized from ethanol to obtain 2.8 g of the title compound having a melting point of 191 to 193 ° C.

Radiance [α] ²³ -16.03 ° [DMF C = 2]

Elemental Analysis Value: C ₁₁ H ₁₅ Cl ₅ NO ₃

Calculated (%): C; 35.10, H; 1.34, N; 3.72

Found (%): C; 35.18, H; 1.57, N; 3.66

(2) Synthesis of N- (5-oxo-D-prolyl) piperidine

To a suspension of 2.8 g of D-pyroglutamic acid pentachlorophenyl ester and 17 ml of methylene chloride, 1.3 g of piperidine is added and stirred at room temperature for 5 hours. Insolubles are filtered off from the reaction mixture and the solvent is distilled off under reduced pressure from the filtrate. The residue is dissolved in toluene and extracted with water. After adding saturated salt to the aqueous layer and saturating, chloroform is extracted. After drying the chloroform layer with anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The oily residue was crystallized in the mixed solvent of ethyl acetate and ether, and 1.2 g of the title compounds which have a melting point of 94.5-96 degreeC were obtained.

Radiance [α] ²⁴ + 48.85 ° [water C = 1]

Elemental Analysis Value: C ₁₀ H ₁₆ N ₂ O ₂

Calculated (%): C; 61.20, H; 8.22, N; 14.27

Found (%): C; 61.12, H; 8.08, N; 14.31

[effect]

As evident from the above results, the compound of the present invention is useful as a therapeutic agent for dementia because of its aromatic action and low toxicity to mammals including humans. As a medicament for senile dementia, it can also be used as a medicament for dementia due to delay in mental development, encephalitis sequelae, cerebral palsy, stroke, cerebral arteriosclerosis, head trauma and the like.

Claims (4)

D-pyroglutamide derivatives represented by the following general formula [I]:

A method for producing a D-pyroglutamide derivative represented by the following general formula [I], characterized by reacting piperidine with D-pyroglutamic acid or a reactive derivative thereof:

D-pyrogluta represented by the following general formula [I] characterized by reacting D-pyroglutamic acid with a substance represented by the following formula (V) and a condensing agent and reacting piperidine with the produced ester: Method for preparing the mead derivative:

Wherein R represents a residue of an alcohol or a phenol. The following dementia treatment agent whose main component is N- (5-oxo-D-prolyl) piperidine represented by the following general formula [I]: