JPS63146857A - Pyroglutamide derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:D-Pyroglutamide derivative shown by the formula. EXAMPLE:N-(5-Oxo-D-prolyl)piperidine. USE:A drug having nootroptic action, useful as a remedy for dementia, suitable caused by metal growth retardation, postencephalitic symptom, cerebral palsy, cerebral arteriosclerosis, head injury, etc., showing low toxicity. PREPARATION:D-Pyroglutamic acid is reacted with a compound shown by the formula R-OH (R is alcohol or phenol residue) by the use of a condensation agent such as dicyclohexylcarbodiimide, etc., at -30-30 deg.C. Then formed ester is reacted with piperidine to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a pyroglutamide derivative useful as a pharmaceutical and a method for producing the same.

The D-pyroglutamide derivative according to the present invention has the following general formula [! ].

h (Prior art) With the aging of the population, dementia has come to occupy a large portion of geriatric medicine, but no treatment has been established yet, such as cerebral metabolism activators and cerebral blood flow improving agents. Drug treatments such as tranquilizers, cholinergic agonists, and cholinergic drugs are being attempted, but the effects are uncertain and there are no satisfactory drugs.

Recently, several compounds such as aniracetam and pramiracetam are being developed as nootropics. In addition, TRI ((Th
yrotropinreleasing hormon
e)-like compounds are disclosed.

(Problems to be Solved by the Invention) In view of the above-mentioned current state of delays in the development of pharmaceuticals aimed at treating dementia, the present inventors aimed to create a substance with excellent nootropic effects from a completely new perspective. The object of the present invention was therefore to provide a nootropic of a type hitherto unknown.

(Means for Solving the Problems) The present inventors have been studying the nootropic effects of various compounds for many years, and fortunately they have discovered that they have excellent nootropic effects on mammals. He discovered a group of compounds with extremely low toxicity and filed a patent application (patent application filed in 1983).
-011359, Japanese Patent Application No. 61-038024).

The compound of the present invention is represented by the general formula (I), and DL-N-piperidinopyroglutamide is disclosed in JP-A-51-8266 as an intermediate for producing an anti-ulcer agent. . Moreover, this compound is disclosed in Japanese Patent Publication No. 49-14462.
It is also disclosed as a raw material in the publication. Therefore, the racemic form (OL integral) of the compound represented by the general formula [I] cannot be said to be a new compound.

There has been no literature suggesting the pharmacological action of these compounds in relation to the present invention.

The compound of the present invention is represented by the general formula CI), and has an asymmetric carbon in it (marked with * below).

In conventional production methods, even if D-isomer is used as a raw material, L-isomer is mixed in with D-isomer in the process of producing CI).

Therefore, isolation by optical resolution or the like is required, which is an industrially disadvantageous method.

The present inventors have discovered that only the D form can be obtained in high yield and with high optical purity by using a compound represented by the following formula (m) or a reactive derivative thereof and reacting it with piperidine. Furthermore, it was surprisingly discovered that among the compounds represented by the general formula [I] obtained, only the D form had an excellent nootropic effect, and based on this, the present invention was completed. It is.

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

Compound (1) is produced by reacting compound (II[) with piperidine. This amidation reaction can be carried out, for example, by directly condensing (I[I) and piperidine with dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (DDPA), or by using a reactive derivative of (III), for example,
A method in which an acid anhydride, an imidazolide, a mixed acid anhydride (such as an anhydride with methyl carbonate, an anhydride with ethyl carbonate, an anhydride with Ibdel carbonate, etc.) is reacted, an active ester method, etc. can be used.

Among these, when a condensing agent such as DCC is used, the reaction is carried out using a suitable solvent (e.g. methylene chloride, halogenated hydrocarbons such as chloroform, ether solvents such as tetrahydrofuran and dioxane, acetonitrile, N, N-dimethylformamide, etc.), usually
It is carried out at about -30°C to about 30°C. Equivalent mole to a slight excess of compound CI [[ ] and O
It is better to use CC.

Compound (1) can also be produced by reacting compound (II) with piperidine.

(n) (1) This amidation reaction can be carried out by a method known per se. For example, the amount of mol or more, preferably 160 to
1.3 mol of piperidine is used, usually at room temperature (20 to 3
(0°C).

The solvent in this case may be any inert solvent, such as alcoholic solvents such as methanol, ethanol, and isopropanol, and halogenated hydrocarbons such as chloroform and carbon tetrachloride. Aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and dioxane, or aprotic polar solvents such as N,N-dimethylformamide can be used. ,
Furthermore, it may be solvent-free.

(Next page below) Dannuki (III) (IV
)゛ [I] (In the formula, R represents a residue of an alcohol or a phenol.) An active ester (
IV). This esterification reaction, for example, (I
II) in a suitable solvent (e.g. methylene chloride, halogenated hydrocarbons such as chloroform, acetonitrile,
Aprotic solvents such as N,N-dimethylformamide, ethereal solvents such as dioxane, tetrahydrofuran, etc.) in a condensing agent such as dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (
It is carried out by reacting with (V) (e.g., pentachlorophenol, paranitrophenol, N-hydroxyquinoline, N-hydroxysuccinimide, N-hydroxybenztriazole, etc.) at -0 to 160°C in the presence of (DOPA), etc.) be able to.

The amounts of (V) and the condensing agent to be used are [■] at least 1 mole per mole, preferably 1.1 mole and 1.1 mole, respectively.
It is preferable to use 2 moles or more.

The ester (rV) produced as described above can be isolated and purified, or can be led to (1) by reacting with piperidine without isolation.

This amidation reaction is carried out by adding 1.1 mol or more, preferably 2.0 mol or more of piperidine per mol of [■] 0 to 160 mol of piperidine in the same solvent as used in the esterification reaction.
The reaction can be carried out at ℃.

(U) and (U) used as raw materials for each of the above manufacturing methods
III) can be easily produced by a known method.

When using a racemic body (DL body) as a raw material, (1
) is obtained as a mixture of D-form and L-form, but D-form can be separated and purified by a conventional optical resolution method.

Compound (1) obtained by each of the above methods can be isolated by methods known per se, such as concentration, liquid conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography, etc. It can be separated and purified.

The results of pharmacological tests demonstrating the usefulness of the compounds of the present invention are detailed below.

1. Test method for the improvement effect on scopolamine amnesia: After passive avoidance learning (PAR) acquisition (acquisition trial), 0.5 mg/kg of scopolamine and the test drug were simultaneously administered intraperitoneally to the rats, and 1 hour later, the rats were given passive avoidance learning (PAR) again. A target avoidance learning response (retention trial) was conducted. 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, the retention trial was conducted 2 hours after drug administration. Aniracetam was used as a control drug. The minimum effective dose that shows a significant improvement effect when administered intraperitoneally or orally is shown in (1) of Table 2.

Table 1 *: p<0.05. **: p<o,
ot the remarkable effects of the compounds of the invention are evident.

2. Improving effect on electric shock amnesia The same method as for scopolamine amnesia was used.

After the acquisition trial, rats were given an electric shock, and after the spasticity had healed, the test drug was administered intraperitoneally and orally. After 1 and 3 hours, respectively, a retention trial was performed to measure the positive response rate, and a significant improvement effect was found. The minimum effective amount showing this is shown in (2) of Table 2.

3. After intraperitoneal administration or oral administration of the test method for improving effects on excess carbon dioxide amnesia, 30 minutes and 60 minutes later, respectively, the rats were placed in a chamber filled with carbon dioxide gas for 12 seconds; Afterwards, the animals were transferred to a two-compartment shuttle box and allowed to perform active avoidance learning and escape learning using a buzzer as a conditioned stimulus, and the positive rate (number of positive animals/number of animals used) of the 6th trial escape learning acquisition test was measured.
The minimum effective dose showing a significant improvement effect is shown in (3) of Table 2.

The minimum effective doses in Table 2 are all p<
Effective amount (mg/kg) showing significant improvement effect at 0.05
It was expressed as

Table 2 Each test number in Table 2 represents the following.

(1) Improving effect on scopolamine amnesia (2) Improving effect on electric shock amnesia (3) Improving effect on excess carbon dioxide amnesia The useful effects of the compounds of the present invention are obvious.

4. Acute toxicity After intravenous and oral administration of N-(5-oxo-D-prolyl)piperidine to male mice, toxicity symptoms were observed for 7 days.

There were no deaths after intravenous administration of 1000 mg/kg, and almost no toxic symptoms were observed.

In the case of oral administration, there were no deaths at 3000 mg/kg, and no toxic symptoms were observed.

The safety of the compounds of the present invention is clear.

When the compound of the present invention is administered as a pharmaceutical, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.1% to 99.5%, preferably from 0.5% to It is preferable to administer it to animals, including humans, as a pharmaceutical composition containing 90%. - As carriers, one or more solid, semi-solid or liquid diluents, fillers and other formulation auxiliaries are used. The pharmaceutical composition is preferably administered in dosage unit form.
The pharmaceutical composition of the present invention can be administered orally, interstitially, locally, or rectally. It goes without saying that the drug may be administered in dosage forms suitable for these administration methods, such as tablets, granules, powders, capsules, injections, suppositories, etc. For example, oral administration is particularly preferred.

The dosage as a nootropic depends on the patient's condition such as age and weight,
Although it is desirable to make adjustments taking into consideration the route of administration, the nature and severity of the disease, etc., the amount of the active ingredient of the present invention for adults is usually in the range of 1 mg to 5 g, preferably 150 mg to 5 g per day. A range of 3g is common. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required.

It can also be administered in divided doses several times a day.

(Example) The present invention will be described in more detail below with reference to Examples of the present invention.

Example I Synthesis of N-(5-oxo-D-prolyl)piperidine -pyroglutamine M 45. Og, acetonitrile 4
A solution of 50 ml and 22.8 g of piperidine is cooled with ice water, and 71.9 g of dicyclohexylcarbodiimide is added at below 10° C. while stirring. Insoluble matter was removed by filtration from the reaction mixture, which was further reacted at room temperature for 5 hours, and the solvent was distilled off from the filtrate under reduced pressure.

The residue is purified by silica gel column chromatography to obtain 60.0 g of oily product. Add this to ethyl acetate
When crystallized from a mixed solvent of diethyl ether, the melting point is 9.
4.0-95.0°C N-(5-oxo-D-prolyl)piperidine 44.7. is obtained.

Optical rotation [α) f + 48.32° [water C=1]
Elemental analysis value: Calculated value as Cl0H18N202 (%
) C: 61.20 H: 8.22 N:
14.27 Actual value (%) C: 61.16 H:
8.17 N: 14.30 Example 2 (1) Synthesis of D-pyroglutamic acid pentachlorphenyl ester - A suspension of 1.3 g of pyroglutamic acid, 3.1 g of pentachlorophenol, and 26 ml of methylene chloride was dissolved in ice water. 2.5 g of dicyclohexylcarbodiimide are added while stirring. The mixture was further stirred for 1 hour under cooling and for 5 hours at room temperature. Insoluble matter was removed from the reaction mixture by filtration, and the insoluble matter was washed with 50 ml of methylene chloride.

The filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethanol to obtain 2.8 g of the title compound having a melting point of 191-193°C.

Optical rotation [α] −16,03″ (DMF C=23
Elemental analysis value: Cu H+5C1s Calculated value as NO3 (%) C: 35.10 H: 1.34 N:
3.72 Actual value (%”) C: 35.18 H: 1
．． 57 N: 3.66 (2) N-(5-oxo-D-
Synthesis of (prolyl) piperidine - Pyroglutamic acid pentachlorphenyl ester 2
．． 8 g of methylene chloride, 1.3 g of piperidine was added to a suspension of 17 ml of methylene chloride, and the mixture was stirred at room temperature for 5 hours. Insoluble matter was removed from the reaction mixture by filtration, and the solvent was distilled off from the filtrate under reduced pressure. Dissolve the residue in toluene and extract with water. After adding salt to the aqueous layer to saturate it, it is extracted with chloroform. After drying the chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The oily residue was crystallized from a heating medium of ethyl acetate and ether to give the title compound' with a melting point of 94.5-96°C.
a 1.2 g was obtained.

Optical rotation [α degree +49.85° [water, C=1] Elemental analysis value: Calculated value (%) as CloH+5N202
C: 61.20 H: 8.22 N: 14
．． 27 Actual value (%) C: 61.12 H: 8.0
8 N 714.31 (Efficacy) As is clear from the above results, the compound of the present invention has a nootropic effect on mammals including humans, and has low toxicity, so it is useful as a therapeutic agent for dementia.

It can be used as a therapeutic agent for senile dementia, as well as dementia associated with mental retardation, sequelae of encephalitis, cerebral paralysis, stroke, cerebral arteriosclerosis, head trauma, and the like.

Claims (3)

[Claims] (1) D-pyroglutamide derivative represented by the following general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (2) D-pyroglutamic acid or its reactive derivative,
A method for producing a D-pyroglutamide derivative represented by the following general formula [I], which comprises reacting with piperidine. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (3) Reacting D-pyroglutamic acid with a substance represented by R-OH[V] (R represents a residue of alcohol or phenol) and a condensing agent, and reacting the generated ester with piperidine. characterized by
A method for producing a D-pyroglutamide derivative represented by the following general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕