JP2513197B2 - Pyroglutamide derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pyroglutamide derivative useful as a medicine and salts thereof.

More specifically, the present invention relates to a pyroglutamide derivative represented by the following general formula [I].

Here, A represents a cyclic amino group with or without a substituent. The cyclic amino group may further contain a nitrogen atom as a hetero atom in the ring in addition to the nitrogen atom. In addition, as the substituent,
You can list the following.

Alkyl, diarylalkyl, aralkyl,
Aryl, hydroxyalkyl, hydroxy,
Alkanoyl, aralkylcarbonyl, aralkyloxycarbonyl, aralkenylcarbonyl, arylcarbonyl (aroyl), heterocyclic carbonyl,
Alkoxycarbonyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl (carbamoyl), carbamoylalkyl, carbamoylalkylcarbonyl, oxo, heterocycle, aryloxyalkyl, alkanoylamino.

(Prior Art) With the aging of the population, dementia has come to occupy a large weight in the medical care for the elderly, but its medical method has not been established yet. Although drug therapy such as cerebral metabolism activating agent, cerebral blood flow improving agent, tranquilizer, cholinergic agent, etc. is being tried, the effect is uncertain and there is no satisfactory drug.

Recently, some compounds such as aniracetam and pramiracetam are being developed as Nootropics. In addition, JP-A-52-125166 and JP-A-51-1154
No. 72 publication discloses TRH (Thyrotropin releasing hormone)
Such compounds are disclosed.

(Problems to be Solved by the Invention) The inventors of the present invention created a substance having an excellent nootropic action from a completely new viewpoint in view of the above-mentioned current delay in the development of pharmaceuticals for the purpose of treating dementia. Tried. The object of the present invention was therefore to provide a new type of nootropics.

(Means for Solving the Problems) The present inventors have been synthesizing new compounds for many years and examining their nootropic effects. Fortunately, the compounds represented by the above general formula [I] have been investigated. It was found that they have excellent nootropic effects on mammals and have extremely low toxicity, and have completed the present invention.

The present invention is represented by the general formula [I], and in JP-A-51-8266, N-piperidinopyroglutamide and N-pyrrolidinopyroglutamide are used for the production of pore ulcer agents. It is disclosed as the body. In addition, these compounds
It is also disclosed as a raw material in JP-A-49-14462. Therefore, among the compounds represented by the general formula [I],
The compound in which A is an unsubstituted pyrrolidino or piperidino is not a novel compound although there is no description suggesting a pharmacological action relating to the present invention, so the present invention does not include these compounds.

Examples of the cyclic amino group represented by A in the general formula [I] include a cyclic amino group having 4 to 10 members.

Specific examples of such an amino group include azetidino, pyrrolidino, piperidino, azepino, azocino, piperazino, homopiperazino, tetrahydroisoquinoline and the like.

These cyclic amino groups can have a substituent at any position. Examples of such substituents include those mentioned above.

When the above-mentioned includes aryl, the aryl is alkyl, alkoxy, aralkyloxy, alkanoyl, alkoxycarbonyl, halogen,
It also includes a case where it is substituted with one or more same or different substituents selected from halogenoalkyl, nitro or methylenedioxy.

In addition, when the above-mentioned ~ contains an amino group, the amino group forms a ring having 4 to 8 members (in this case, a nitrogen atom, a sulfur atom as a hetero atom in addition to the nitrogen atom in this ring). Or containing an oxygen atom, or having only one nitrogen atom as a hetero atom). Examples of these cyclic amino groups include pyrrolidino, piperidino, azepino, piperazino, morpholino,
Examples thereof include thiomorpholino. These amino groups are also included when they are substituted with one or more alkyl, aralkyl, aralkyloxycarbonyl, or carbamoyl which may be the same or different.

If these substituents are described more specifically, the following can be mentioned.

That is, as the alkyl, a linear or branched lower alkyl having 1 to 4 carbon atoms is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Etc. can be mentioned.

As the diarylalkyl, the carbon number of the alkyl is 1
To 4 are preferred, and examples thereof include diphenylmethyl, diphenylethyl, diphenylpropyl, diphenylbutyl and the like.

The aralkyl preferably has 7 to 12 carbon atoms, and examples thereof include benzyl, phenethyl, phenylpropyl, naphthylmethyl, and naphthylethyl.

Examples of the aryl include phenyl, α-naphthyl, α-naphthyl, anthryl, biphenyl and the like.

The hydroxyalkyl preferably has 2 to 4 carbon atoms and can have a hydroxy group at any position. For example, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl and the like can be mentioned.

The alkanoyl preferably has 1 to 7 carbon atoms, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and heptanoyl.

Examples of the aralkyl in aralkylcarbonyl and the aralkyl in aralkyloxycarbonyl include the same ones as described above.

The aralkenylcarbonyl preferably has 8 to 10 carbon atoms, and examples thereof include cinnamoyl.

As the aryl in the arylcarbonyl, the same ones as described above can be mentioned.

The heterocycle in the heterocyclic carbonyl is preferably one having a member number of 4 to 8 containing at least one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- Thienyl, 3-
Thienyl, 2-freel, 3-freel, morpholino,
Examples thereof include thiomorpholino.

As alkoxy in alkoxycarbonyl,
A straight-chain or branched one having 1 to 5 carbon atoms is preferable, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, Examples include isopentyloxy and the like.

The alkyl in aminoalkyl, the alkyl in aminoalkylcarbonyl, the alkyl in carbamoylalkyl, and the alkyl in carbamoylalkylcarbonyl are preferably those having 1 to 3 carbon atoms.

As the heterocycle, the same ones as described in the description of heterocycle carbonyl can be mentioned.

Examples of the halogen include chlorine, bromine, fluorine, iodine and the like.

Examples of aralkyl in aralkyloxy include the same ones as described above.

Examples of halogenoalkyl include trifluoromethyl and the like.

Method for Producing Compound of the Present Invention The compound of the present invention can be produced, for example, by the method shown below.

Each manufacturing method will be described in detail below.

Method A: Compound [II] is reacted with various amines represented by AH to produce [I]. This amidation reaction
It can be carried out by a method known per se. For example, [I
I) is used in an equimolar amount or more, preferably 1.0 to 1.3 mol of amine, usually about 50 to 160 ° C., preferably about 90 to 1
It can be carried out at a temperature of 20 ° C. Particularly conveniently, it can be carried out at the boiling point of the solvent used.

As such a solvent, any solvent may be used as long as it is inert, for example, alcohol solvents such as methanol, ethanol and isopropanol, chloroform, halogenated hydrocarbon solvents such as carbon tetrachloride, benzene and toluene. , An aromatic hydrocarbon solvent such as xylene, an ether solvent such as tetrahydrofuran or dioxane, or an aprotic polar solvent such as N, N-dimethylformamide can be used, and there is no solvent. May be.

Method B: Compound [III] is reacted with various amines represented by AH to produce [I]. This amidation reaction can be performed by a method known per se. For example,
A method of directly condensing [III] and various amines with dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (DDPA), or a reactive derivative of [III],
For example, a method of appropriately reacting an acid anhydride, imidazolide or a mixed acid anhydride (an anhydride with methyl carbonic acid, an anhydride with ethyl carbonic acid, an anhydride with isobutyl carbonic acid, etc.),
The active ester method or the like can be used. Of these, when using a condensing agent, for example, DCC, the reaction is carried out in a suitable solvent (for example, methylene chloride, halogenated hydrocarbons such as chloroform, tetrahydrofuran, ether solvents such as dioxane, acetonitrile, N, N-dimethylformamide, etc.) at about -30 ° C to about 180 ° C. It is advisable to use equimolar or a slight excess of compound [III] and DCC with respect to 1 mol of amine.

Regarding the compound in which A is a cyclic amino group further having a nitrogen atom as a hetero atom in the general formula [I] and the nitrogen is substituted, the compound produced by the above production method is alkylated, acylated or It can also be produced by performing amination and the like. That is, it can be manufactured by the C to E methods.

Method C: [IV] obtained by Method A or Method B is alkylated [I]
a] can be obtained. This alkylation reaction can be carried out by a method known per se.

As the alkylating agent, those used in ordinary alkylation reactions can be used, and examples thereof include corresponding alkyl halides (chloride, bromide, iodide, etc.), sulfuric acid esters, sulfonic acid esters and the like. For example, when using an alkyl halide,
The reaction is carried out in a suitable solvent (for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatics such as benzene and toluene). Group hydrocarbons, acetonitrile, N, N-
In an aprotic polar solvent such as dimethylformamide or the like, or a mixture thereof, a base (for example,
It is preferable to carry out the reaction at room temperature to the boiling point of the reaction solvent in the presence of sodium hydrogen carbonate, potassium carbonate, pyridine, trialkylamine, etc.

In this case, it is preferable to use an equivalent amount or more of alkyl halide with respect to [IV]. And reaction promotion,
Amount of catalyst (about 0.01 to 0.1 molar equivalent) to improve yield
Sodium iodide or potassium iodide can be added.

Method D: If [IV] obtained by Method A or Method B is acylated, [I]
b] can be obtained. This acylation reaction can be carried out by a method substantially similar to Method B, or can also be produced by reacting an acid halide with [IV].

When an acid halide is used, the reaction is usually carried out in a solvent (for example, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene). Hydrogen, acetonitrile, aprotic polar solvent such as N, N-dimethylformamide, etc., water, or a mixture thereof) in a base (for example, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, Pyridine, trialkylamine, etc.)
The reaction temperature is preferably about -10 ° C to about 100 ° C.

In this case, the amount of acid halide used is preferably equivalent to or more than [IV].

Method E: [Ic] can be produced by acylating [IV] obtained by Method A or Method B and then reacting it with an amine. These reactions can be carried out in substantially the same manner as in Method D or Method E.

When a diamine such as piperazine is reacted in the above-mentioned production method, one amine is protected by a known method to react with [II] or [III], and then the protecting group is removed to give [I] obtain.

[II] and [III] used as raw materials in the above-mentioned production methods are commercially available and can be easily obtained. Similarly, amines are commercially available or can be produced by known methods.

The compound [I] obtained by each of the above methods can be isolated in the form of a free base by a method known per se. For example, it can be isolated and purified by concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography and the like.

It can also be isolated in the form of an acid addition salt. Such acid addition salts may be physiologically acceptable salts, and examples thereof include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, acetates, and maleates. Mention may be made of organic acid salts such as acid salts, fumarates, succinates, tartrates, citrates, malates and the like.

The compound of the present invention is represented by the general formula [I], and it is clear that it has an asymmetric carbon atom (* mark below).

Therefore, the compound of the present invention has D-form and L-form optically active forms, and each optical isomer and a mixture thereof are naturally included in the scope of the present invention.

These isomers can be individually produced if desired.

For example, by using an optically active substance (D-form or L-form) as the starting compound [II] or [III], the corresponding optical isomer (D-form or L-form) of [I] can be obtained. Further, when the produced [I] is a mixture of D-form and L-form, these can be separated and purified into respective isomers by a usual optical resolution method.

It was found that among the optically active [I] thus obtained, the D-form generally has more preferable physiological activity than the corresponding L-form.

The results of pharmacological tests showing the usefulness of the compound of the present invention will be described in detail below.

1. Scopolamine amnesia improvement effect Test method: After passive avoidance learning (PAR) acquisition (acquisition trial),
Scopolamine 0.5 mg / kg and a test drug were simultaneously intraperitoneally administered to rats, and 1 hour later, a passive avoidance learning reaction (holding trial) was performed again. Reaction positive rate at that time (number of positive animals /
The number of animals used) is shown in Table 1. When the test drug was orally administered in the above test, the retention trial was performed 2 hours after the drug administration.

Aniracetam and the compounds of Examples Nos. 3 and 72 were intraperitoneally and orally administered, and the minimum effective dose showing a significant improving effect is shown in Table 2 (1).

The remarkable effect of the compound of the present invention is clear.

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

After the acquisition trial, the rats were given an electric shock and after the convulsions had healed, the test substance was administered intraperitoneally and orally.
And after 3 hours, a holding trial was performed to measure the reaction positive rate,
The minimum effective dose showing a significant improvement effect is shown in (2) of Table 2.

3. Improvement effect on excess CO ₂ amnesia After intraperitoneal or oral administration of the test substance,
Minutes and 60 minutes later, the rat was placed in a chamber filled with CO ₂ gas for 12 seconds, and 3 minutes later, moved into a two-compartment shuttle box for active avoidance learning and escape learning using the buzzer as a conditional stimulus. Then, the positive rate (the number of positive animals / the number of animals used) in the learning acquisition test in the 6th trial was measured, and the minimum effective dose showing a significant improving effect is shown in (3) of Table 2. The minimum effective doses in Table 2 are expressed as effective doses (mg / kg) that show a significant improving effect at p <0.05 in the X ₂ test.

The useful effect of the compound of the present invention is clear.

4. Acute toxicity After the intravenous and oral administration of the compound of the present invention of Examples Nos. 3 and 72 to male mice, the toxic symptoms were observed for 7 days.

After intravenous administration of 1000 mg / kg, there were no deaths and no toxic symptoms were observed with any of the compounds.

In addition, in the case of oral administration, there were no deaths and no toxicity symptoms for any of the compounds at 3000 mg / kg.

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

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

As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other auxiliary agents for formulation are used.
Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intratically, locally or rectally. It goes without saying that the dosage form is suitable for these administration methods, such as tablets, granules, powders, capsules, injections and suppositories. For example, oral administration is particularly preferred.

The dose as a cognitive enhancer is preferably adjusted in consideration of the patient's condition such as age and weight, administration route, the nature and degree of disease, etc. Amounts generally range from 1 mg to 5 g, preferably from 150 mg to 3 g per day. In some cases, lower doses may be sufficient, and conversely higher doses may be required. It can also be divided into several times a day for administration.

(Example) Hereinafter, the present invention will be described in more detail with reference to Examples relating to the production of the compound of the present invention.

Example 1 (Method A) 4-Benzyl-N- (2-pyrrolidone-5-carbonyl) piperidine 4.3 g of methyl pyroglutamate and 7.9 g of 4-benzylpiperidine are dissolved in 20 ml of toluene and heated under reflux for 24 hours while stirring. The reaction solution is subjected to silica gel column chromatography to obtain 7.2 g of a product. When recrystallized from diethyl ether, the desired compound with a melting point of 160-161 ° C
6.5 g was obtained.

Elemental analysis value (as C ₁₇ H ₂₂ N ₂ O ₂ ) Calculated value (%) C: 71.30 H: 7.74 N: 9.78 Measured value (%) C: 71.50 H: 8.17 N: 9.71 Example 2 (method B) 1 -(2-Pyrrolidone-5-carbonyl) piperazine Pyroglutamic acid 112.4 g, N-carbobenzoxypiperazine 147.7 g, dicyclohexylcarbodiimide 179.7
g and acetonitrile 6.7 are stirred and heated under reflux for 6 hours. The insoluble matter is removed from the reaction mixture by filtration, and the solvent is distilled off from the filtrate under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 190 g of oily N-carbobenzoxy-N '-(2-pyrrolidone-5-carbonyl) piperazine. Dissolve 30 g of this in 450 ml of methanol, and
Perform catalytic reduction with 3.0 g of% palladium carbon while stirring at room temperature. The catalyst was removed from the reaction solution by filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 20 g of a product. When this was recrystallized from a mixed solvent of methanol-ethyl acetate, the melting point was 162-1.
17.5 g of the target compound at 63 ° C. was obtained.

Elemental analysis value (as C ₉ H ₁₅ N ₃ O ₂ ) Calculated value (%) C: 54.81 H: 7.67 N: 21.30 Measured value (%) C: 54.74 H: 7.73 N: 21.29 Example 3 (method B) 4 -Morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine 1.6 g of pyroglutamic acid, 2.1 g of 1- (morpholinocarbonylmethyl) piperazine, 2.47 g of DCC, and 130 ml of acetonitrile while stirring and heating under reflux for 48 hours. To do. The insoluble matter is removed from the reaction mixture by filtration, and the solvent is distilled off from the filtrate under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 3.0 g of the product. This was recrystallized from a mixed solvent of ethyl acetate-isopropanol-n-hexane to obtain 2.6 g of the desired compound having a melting point of 167-169 ° C.

Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₄ ) Calculated value (%) C: 55.54 H: 7.46 N: 17.27 Measured value (%) C: 55.31 H: 7.49 N: 17.14 Example 4 (method C) 4 -Morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine 1- (2-pyrrolidone-5-carbonyl) piperazine
3.7 g, 4-chloroacetylmorpholine 3.7 g, anhydrous potassium carbonate 4.4 g, and N, N-dimethylformamide 20 ml are added, and the mixture is heated with stirring at 70 to 75 ° C. for 1 hour. The insoluble material is filtered off from the reaction mixture, and the solvent is distilled off from the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to give 5.7 g of product. When this was recrystallized from a mixed solvent of ethanol-ethyl acetate-diethyl ether,
4.2 g of the target compound having a melting point of 167-169 ° C. were obtained.

Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₄ ) Calculated value (%) C: 55.54 H: 7.46 N: 17.27 Measured value (%) C: 55.36 H: 7.58 N: 17.23 Example 5 (method D) 4 -Ethoxycarbonyl-1- (2-pyrrolidone-5-
Carbonyl) piperazine 1- (2-pyrrolidone-5-carbonyl) piperazine
2.1g, anhydrous potassium carbonate 2.5g, and acetonitrile 120m
The mixed solution of 1 is cooled with ice water, and a solution of 1.1 g of ethyl chlorocarbonate in 10 ml of acetonitrile is added dropwise thereto while stirring. After the dropping, the mixture is further stirred at room temperature overnight. The solvent is distilled off from the reaction mixture under reduced pressure. Methylene chloride is added to the residue and the insoluble matter is filtered off. The solvent is distilled off from the filtrate under reduced pressure to obtain 2.3 g of an oily product. This was crystallized from ethyl acetate and recrystallized to obtain 2.1 g of the desired compound having a melting point of 147 to 148.5 ° C.

Elemental analysis value (as C ₁₂ H ₁₉ N ₃ O ₄ ) Calculated value (%) C: 53.52 H: 7.11 N: 15.60 Measured value (%) C: 53.36 H: 7.32 N: 15.60 Example 6 (method E) 4 -Morpholinoacetyl-1- (2-pyrrolidone-5-
Carbonyl) piperazine N- (2-pyrrolidone-5-carbonyl) piperazine
A mixed solution of 2.3 g, 50 ml of methylene chloride and 2.8 g of anhydrous potassium carbonate is cooled with ice water, and 1.3 g of chloroacetyl chloride is added dropwise thereto while stirring. After the dropping, the mixture is further stirred at room temperature for 1 hour. The insoluble matter was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 2.3 g of oily N- (2-pyrrolidone-5-carbonyl) -N'-chloroacetylpiperazine.
This is dissolved in 15 ml of N, N-dimethylformamide, 0.8 g of morpholine and 2.2 g of anhydrous potassium carbonate are added, and the mixture is heated at 80 ° C. for 3 hours while stirring. The insoluble matter is removed from the reaction mixture by filtration, and the solvent is distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give the product
Get 2.5g. When recrystallized from a mixed solvent of methanol and ethyl ether, 2.1 g of the target compound having a melting point of 204 to 205 ° C is obtained.
was gotten.

Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₄ ) Calculated value (%) C: 55.54 H: 7.46 N: 17.27 Measured value (%) C: 55.23 H: 7.87 N: 17.01 Described in Examples 1 to 6. Example 7 as in method
The following compounds were prepared.

Example 7 4-Phenyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 201-202 ° C Elemental analysis value (as C ₁₅ H ₁₉ N ₃ O ₂ ) Calculated value (%) C: 65.91 H: 7.01 N: 15.37 measured value (%) C: 65.93 H: 7.08 N: 15.12 Example 8 4-benzhydryl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 147-148.5 ° C Elemental analysis value (C ₂₂ H ₂₅ N ₃ as O ₂₎ calculated (%) C: 72.70 H: 6.93 N: 11.56 Found (%) C: 72.53 H: 7.06 N: 11.32 example 9 4- (3-chlorophenyl) -1- (2- Pyrrolidone-
5-Carbonyl) piperazine: Melting point 185.5-186.5 ° C Elemental analysis value (as C ₁₅ H ₁₈ ClN ₃ O ₂ ) Calculated value (%) C: 58.54 H: 5.89 N: 13.65 Measured value (%) C: 58.51 H: 5.92 N: 13.77 Example 10 4- (2-chlorophenyl) -1- (2-pyrrolidone-
5-carbonyl) piperazine: mp 165-167 ° C. Elemental analysis (C ₁₅ H ₁₈ ClN ₃ as O ₂₎ Calculated (%) C: 58.54 H: 5.89 N: 13.65 Found (%) C: 58.41 H: 6.01 N: 13.60 Example 11 4- (4-chlorophenyl) -1- (2-pyrrolidone-
5-Carbonyl) piperazine: Melting point 244.5-246.5 ° C Elemental analysis value (as C ₁₅ H ₁₈ ClN ₃ O ₂ ) Calculated value (%) C: 58.54 H: 5.89 N: 13.65 Measured value (%) C: 58.57 H: 5.92 N: 13.67 example 12 4- (4-fluorophenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp 212 to 213.5 ° C. elemental analysis (C ₁₅ H ₁₈ FN ₃ as O ₂₎ calculated ( %) C: 61.84 H: 6.23 N: 14.42 Actual value (%) C: 61.77 H: 6.34 N: 14.38 Example 13 4- (2-methylphenyl) -1- (2-pyrrolidone-
5-Carbonyl) piperazine: Melting point 212-213 ° C Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₂ ) Calculated value (%) C: 66.87 H: 7.37 N: 14.62 Measured value (%) C: 66.70 H: 7.50 N: 14.70 Example 14 L-(-)-4- (2-methylphenyl) -1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 122-1
23.5 ° C Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₂ ) Calculated value (%) C: 66.87 H: 7.37 N: 14.62 Measured value (%) C: 66.79 H: 7.60 N: 14.55 Example 15 1- ( 2-pyrrolidone-5-carbonyl) -4- (3-
Trifluoromethylphenyl) piperazine: melting point 133.5
〜134.5 ℃ Elemental analysis value (as C ₁₆ H ₁₈ F ₃ N ₃ O ₂ ) Calculated value (%) C: 56.30 H: 5.32 N: 12.31 Measured value (%) C: 56.59 H: 5.41 N: 12.41 Example 16 4- (2-methoxyphenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: Melting point 157-158 ° C Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₃ ) Calculated value (%) C: 63.35 H : 6.98 N: 13.85 Found (%) C: 63.25 H: 7.07 N: 13.87 Example 17 4- (4-methoxyphenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 190-192 ° C Element Analytical value (as C ₁₆ H ₂₁ N ₃ O ₃ ) Calculated value (%) C: 63.35 H: 6.98 N: 13.85 Measured value (%) C: 63.19 H: 7.22 N: 13.76 Example 18 4- (4-acetyl) Phenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 227.5-229.0 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ O ₃ ) Calculated value (%) C: 64.74 H: 6.71 N: 13.32 Actual measurement Value (%) C: 64.65 H: 6.84 N: 13.30 Example 19 4-Benzyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 139.5-141.5 ° C. Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₂ ) Calculated value (%) C: 66.88 H: 7.37 N: 14.62 Found (%) C: 66.60 H: 7.56 N: 14.60 Example 20 4- (2-chlorobenzyl) -1- (2-pyrrolidone-
5-Carbonyl) piperazine: Melting point 92.5-93.5 ° C Elemental analysis value (as C ₁₆ H ₂₀ ClN ₃ O ₂ ) Calculated value (%) C: 59.72 H: 6.26 N: 13.06 Measured value (%) C: 59.72 H: 6.32 N: 13.17 Example 21 4- (4-chlorobenzyl) -1- (2-pyrrolidone-
5-carbonyl) piperazine: mp 163-165 ° C. Elemental analysis (C ₁₆ H ₂₀ ClN ₃ as O ₂₎ Calculated (%) C: 59.72 H: 6.26 N: 13.06 Found (%) C: 59.44 H: 6.39 N: 12.80 Example 22 4- (4-fluorobenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 142-143 ° C Elemental analysis value (as C ₁₆ H ₂₀ FN ₃ O ₂ ) Calculated value ( %) C: 62.94 H: 6.60 N: 13.76 Actual value (%) C: 62.81 H: 6.79 N: 13.57 Example 23 4- (4-methylbenzyl) -1- (2-pyrrolidone-
5-carbonyl) piperazine: mp 144.5-145.5 ° C. Elemental analysis (C ₁₇ H ₂₃ N ₃ as O ₂₎ Calculated (%) C: 67.75 H: 7.69 N: 13.94 Found (%) C: 67.71 H: 7.88 N: 13.94 Example 24 1- (2-pyrrolidone-5-carbonyl) -4- (2-
Trifluoromethylbenzyl) piperazine hemifumarate: Melting point 133.5-135.5 ° C Elemental analysis value (as C ₁₇ H ₂₀ F ₃ N ₃ O ₂ 1 / 2C ₄ H ₄ O ₄ ) Calculated value (%) C: 55.20 H: 5.36 N 10.16 Found (%) C: 55.06 H: 5.38 N: 10.12 Example 25 4- (4-methoxybenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 145-147 ° C Elemental analysis value ( C ₁₇ as H ₂₃ N ₃ O ₃₎ calcd (%) C: 64.33 H: 7.30 N: 13.24 Found (%) C: 64.29 H: 7.68 N: 13.21 example 26 4- (3,4-methylenedi Oxybenzyl) -1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 109-1
11 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ O ₄ ) Calculated value (%) C: 61.62 H: 6.39 N: 12.68 Measured value (%) C: 61.67 H: 6.55 N: 12.63 Example 27 4-benzoyl -1- (2-pyrrolidone-5-carbonyl) piperazine: mp one hundred seventy-three to one hundred and seventy-four ° C. elemental analysis (C ₁₆ H ₁₉ N ₃ as O ₃₎ calculated (%) C: 63.77 H: 6.35 N: 13.94 Found ( %) C: 63.59 H: 6.49 N: 13.98 Example 28 L-(−)-4-benzoyl-1- (2-pyrrolidone-
5-Carbonyl) piperazine: Melting point 113.5-115.5 ° C Elemental analysis value (as C ₁₆ H ₁₉ N ₃ O ₃ ) Calculated value (%) C: 63.77 H: 6.35 N: 13.94 Measured value (%) C: 63.70 H: 6.82 N: 13.95 example 29 4- (2-methylbenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp 206-207 ° C. elemental analysis (as _{C 17 H 21 N 3 O 3} ) calcd ( %) C: 68.74 H: 6.71 N: 13.32 Found (%) C: 64.49 H: 6.94 N: 13.09 Example 30 4- (3-methylbenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp 175 to 176.5 ° C. elemental analysis (as _{C 17 H 21 N 3 O 3} ) calcd (%) C: 64.74 H: 6.71 N: 13.32 Found (%) C: 64.49 H: 6.94 N: 13.09 example 31 4- (4-Methylbenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 162-164 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ O ₃ ) Calculated value (%) C: 64.74 H : 6.71 N: 13.32 Found (%) C: 64.41 H: 6.80 N: 13.24 Example 32 4- (2,4-dimethylbenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 213-215 ° C Elemental analysis value (C ₁₈ as H ₂₃ N ₃ O ₃₎ calcd (%) C: 65.63 H: 7.04 N: 12.76 Found (%) C: 65.57 H: 7.26 N: 12.77 example 33 4- (4-methoxybenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp from 180.5 to 182.5 ° C. elemental analysis (C ₁₇ H ₂₁ N ₃ as O ₄₎ calculated (%) C: 61.61 H: 6.39 N: 12.68 Found ( %) C: 61.70 H: 6.56 N: 12.72 Example 34 1- (2-pyrrolidone-5-carbonyl) -4- (3,4,
5-trimethoxybenzoyl) piperazine: melting point 170-17
2 ℃ Elemental analysis value (as C ₁₉ H ₂₅ N ₃ O ₆ ) Calculated value (%) C: 58.30 H: 6.44 N: 10.74 Measured value (%) C: 58.27 H: 6.59 N: 10.75 Example 35 4- ( 4-Nitrobenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: Melting point 205.5-207.5 ° C Elemental analysis value (as C ₁₆ H ₁₈ N ₄ O ₅ ) Calculated value (%) C: 55.49 H: 5.24 N : 16.18 Found (%) C: 55.33 H: 5.34 N: 16.23 Example 36 4- (4-fluorobenzoyl) -1- (2-pyrrolidone-5-carbonyl) pepyrazine: melting point 195.5-197.5 ° C.
(Decomposition) Elemental analysis value (as C ₁₆ H ₁₈ FN ₃ O ₃ ) Calculated value (%) C: 60.18 H: 5.68 N: 13.16 Measured value (%) C: 60.20 H: 5.71 N: 13.20 Example 37 4- (2-chlorobenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 175-177 ° C Elemental analysis value (as C ₁₆ H ₁₈ ClN ₃ O ₃ ) Calculated value (%) C: 57.23 H: 5.40 N: 12.51 measured value (%) C: 57.21 H: 5.46 N: 12.43 Example 38 4- (4-chlorobenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 179-181 ° C Elemental analysis value (C ₁₆ H ₁₈ as ClN ₃ O ₃₎ calcd (%) C: 57.23 H: 5.40 N: 12.51 Found (%) C: 56.94 H: 5.54 N: 12.45 example 39 4- (2,4-dichloro Benzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 206-208 ° C. Elemental analysis value (as C ₁₆ H ₁₇ Cl ₂ N ₃ O ₃ ) Calculated value (%) C: 51.91 H: 4.63 N: 11.35 Measured value (%) C: 52.00 H: 4.63 N : 11.31 Example 40 4-phenyl-1- (2-pyrrolidone-5-carbonyl) piperazine: mp 150.5-152.0 ° C. Elemental analysis (C ₁₇ H ₂₁ as N ₃ O ₃₎ Calcd (%) C: 64.74 H: 6.71 N: 13.32 Found (%) C: 64.37 H: 6.89 N: 13.28 Example 41 4- (4-methoxyphenylacetyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 148.5-1
49.5 ° C. Elemental analysis (as _{C 18 H 23 N 3 O 3} ) Calcd (%) C: 62.59 H: 6.71 N: 12.17 Found (%) C: 62.55 H: 6.90 N: 12.22 Example 42 4- ( 4-chlorophenyl-acetyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp 185 through 187 ° C. elemental analysis (C ₁₇ H ₂₀ ClN ₃ as O ₃₎ calculated (%) C: 58.37 H: 5.76 N : 12.01 Found (%) C: 58.50 H: 5.84 N: 12.09 Example 43 4-Methyl-1- (2-pyrrolidone-5-carbonyl)
Piperazine: Melting point 129-131 ℃ Elemental analysis value (as C ₁₀ H ₁₇ N ₃ O ₂ ) Calculated value (%) C: 56.85 H: 8.11 N: 19.89 Measured value (%) C: 56.85 H: 7.96 N: 19.37 Conducted example 44 4-acetyl-1- (2-pyrrolidone-5-carbonyl) piperazine: mp one hundred and eighteen to one hundred and twenty-three ° C. elemental analysis _{(C 11 H 17 N 3 O} 3 · 1 / 6H 2 O as a calculated value (%) C: 54.53 H: 7.21 N: 17.34 Actual value (%) C: 54.55 H: 7.82 N: 17.37 Example 45 4-propanoyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 138-139 ° C Elemental analysis value ( C ₁₂ H ₁₉ as N ₃ O ₃₎ calcd (%) C: 56.90 H: 7.56 N: 16.59 Found (%) C: 56.76 H: 7.78 N: 16.53 example 46 4- carbobenzoxy-1- ( 2-Pyrrolidone-5-carbonyl) piperazine: Melting point 162-164 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ O ₄ ) Calculated value (%) C: 61.62 H: 6.39 N: 12.68 Measured value (%) C: 61.46 H: 6.46 N: 12.56 Example 47 4-Cinna Yl-1- (2-pyrrolidone-5-carbonyl) piperazine: mp two hundred twenty-nine to two hundred thirty-three ° C. (decomposition) Elemental analysis (as _{C 18 H 21 N 3 O 3} ) Calcd (%) C: 66.04 H: 6.47 N: 12.84 Found (%) C: 65.83 H: 6.61 N: 13.12 Example 48 4- (4-methylcinnamoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 253.5-255.5 ° C.
(Decomposition) Elemental analysis value (as C ₁₉ H ₂₃ N ₃ O ₃ ) Calculated value (%) C: 66.84 H: 6.79 N: 12.31 Measured value (%) C: 66.73 H: 6.91 N: 12.26 Example 49 4- (4-Methoxycinnamoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: Melting point 204-231 ° C Elemental analysis value (as C ₁₉ H ₂₃ N ₃ O ₄ ) Calculated value (%) C: 63.85 H: 6.49 N: 11.76 Found (%) C: 63.94 H: 6.59 N: 11.76 Example 50 4- (N, N-Dimethylcarbamoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 178.5-17
9.5 ℃ Elemental analysis value (as C ₁₂ H ₂₀ N ₄ O ₃ ) Calculated value (%) C: 53.72 H: 7.51 N: 20.88 Measured value (%) C: 53.61 H: 7.79 N: 20.71 Example 51 4-isopropyl Aminocarbonylmethyl-1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 125-1
27 ° C Elemental analysis value (as C ₁₄ H ₂₄ N ₄ O ₃ ) Calculated value (%) C: 56.74 H: 8.16 N: 18.90 Measured value (%) C: 56.54 H: 8.43 N: 18.76 Example 52 4-nicotinoyl -1- (2-pyrrolidone-5-carbonyl) piperazine: mp from 199.5 to 201.5 ° C. elemental analysis (C ₁₅ as H ₁₈ N ₄ O ₃₎ calculated (%) C: 59.59 H: 6.00 N: 18.53 Found ( %) C: 59.31 H: 6.01 N: 18.32 Example 53 1- (2-pyrrolidone-5-carbonyl) -4- (2-
Thienoyl) piperazine: Melting point 170.5-172.5 ° C Elemental analysis value (as C ₁₄ H ₁₇ N ₃ O ₃ S) Calculated value (%) C: 54.71 H: 5.57 N: 13.67 Measured value (%) C: 54.62 H: 5.56 N : 13.80 example 54 4- (2-pyridyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: mp 211-212.5 ° C. elemental analysis (C ₁₄ H ₁₈ N ₄ as O ₂₎ calculated (%) C: 61.30 H: 6.61 N: 20.42 Found (%) C: 61.25 H: 6.73 N: 20.38 Example 55 4-Methyl-N- (2-pyrrolidone-5-carbonyl)
Piperidine: Melting point 107-109 ° C Elemental analysis value (as C ₁₁ H ₁₈ N ₂ O ₂ ) Calculated value (%) C: 62.83 H: 8.63 N: 13.32 Measured value (%) C: 62.40 H: 8.90 N: 13.17 Implemented Example 56 4-Phenyl-N- (2-pyrrolidone-5-carbonyl) piperidine: Melting point 198-199 ° C Elemental analysis value (as C ₁₆ H ₂₀ N ₂ O ₂ ) Calculated value (%) C: 70.56 H: 7.40 N : 10.29 Found (%) C: 70.68 H: 7.66 N: 10.15 Example 57 4-ethoxycarbonyl-N- (2-pyrrolidone-5-
Carbonyl) piperidine: Melting point 158.0-159.5 ° C Elemental analysis value (as C ₁₃ H ₂₀ N ₂ O ₄ ) Calculated value (%) C: 58.19 H: 7.51 N: 10.44 Measured value (%) C: 58.18 H: 7.82 N: 10.44 Example 58 4-carbamoyl-N- (2-pyrrolidone-5-carbonyl) piperidine hemihydrate: melting point 172-173 ° C Elemental analysis value (as C ₁₁ H ₁₇ N ₃ O ₃ 1 / 2H ₂ O) calculation Value (%) C: 53.22 H: 7.31 N: 16.92 Actual value (%) C: 53.67 H: 7.79 N: 16.76 Example 59 4-Hydroxy-N- (2-pyrrolidone-5-carbonyl) piperidine: Melting point 147.0- 148.5 ° C Elemental analysis value (as C ₁₀ H ₁₆ N ₂ O ₃ ) Calculated value (%) C: 56.59 H: 7.60 N: 13.20 Measured value (%) C: 56.71 H: 7.94 N: 13.12 Example 60 N- ( 2-Pyrrolidone-5-carbonyl) hexamethyleneimine: Melting point 87-89 ° C Elemental analysis value (as C ₁₁ H ₁₈ N ₂ O ₂ ) Calculated value (%) C: 62.83 H: 8.63 N: 13.32 Measured value (%) C: 62.84 H: 8.92 N: 13.39 Example 61 4- (2-pyrrolidone-5-carbonyl) -2-keto-piperazine: mp 198-200 ° C. Elemental analysis (as _{C 9 H 13 N 3 O 3} ) Calcd (%) C: 51.28 H: 6.20 N: 19.89 Found (%) C: 51.21 H: 6.20 N: 19.80 Example 62 L-(−)-4- (morpholinocarbonylmethyl) -1
-(2-Pyrrolidone-5-carbonyl) piperazine maleate: Melting point 201 to 202.5 ° C Elemental analysis value (as C ₁₅ H ₁₄ N ₄ O ₄ · C ₄ H ₄ O ₄ ) Calculated value (%) C: 51.81 H : 6.41 N: 12.72 Found (%) C: 51.61 H: 6.67 N: 12.73 Example 63 4-pyrrolidinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 179-180 ° C Elemental analysis value (As C ₁₅ H ₂₄ N ₄ O ₃ ) Calculated value (%) C: 58.42 H: 7.84 N: 18.17 Measured value (%) C: 58.26 H: 8.02 N: 18.06 Example 64 4-Piperidinocarbonylmethyl- 1- (2-pyrrolidone-5-carbonyl) piperazine: mp 181 through 183 ° C. elemental analysis (as _{C 16 H 26 N 4 O 3} ) calculated (%) C: 59.61 H: 8.13 N: 17.38 Found (% ) C: 59.46 H: 8.48 N: 17.23 Example 65 4-hexyluiminocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 143-144 ° C Elemental content Value (as _{C 17 H 28 N 4 O 3} ) Calculated (%) C: 60.69 H: 8.39 N: 16.65 Found (%) C: 60.42 H: 8.45 N: 16.45 Example 66 4-diisopropylamino-carbonyl-methyl - 1- (2
-Pyrrolidone-5-carbonyl) piperazine: melting point 189
～190.5 ° C. Elemental analysis (as _{C 17 H 30 N 4 O 3} ) Calculated (%) C: 60.33 H: 8.93 N: 16.55 Found (%) C: 60.03 H: 9.24 N: 16.55 Example 67 4- morpholinoethyl -1- (2-pyrrolidone-5-carbonyl) piperazine maleate: mp 179-181 ° C. elemental analysis (as _{C 15 H 26 N 4 O 3} · 2C 4 H 4 O 4 · 1 / 2H 2 O ) Calculated value (%) C: 50.09 H: 6.40 N: 10.16 Measured value (%) C: 49.99 H: 6.74 N: 10.22 Example 68 4-pyrrolidinoethyl-1- (2-pyrrolidone-5-carbonyl) piperazine maleate: mp one hundred sixty-nine to one hundred seventy ° C. elemental analysis _{(C 15 H 26 N 4 O} 2 · 2C 4 H 4 O 4 · 1 / 2H 2 O ) calculated value (%) C: 51.58 H: 6.59 N: 10.46 Actual value (%) C: 51.60 H: 6.90 N: 10.29 Example 69 4-piperidinoethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 131-133 ° C Elemental analysis value (C ₁₆ H ₂₈ N ₄ O ₂₎ calculated value (%) C: 62.31 H: 9.15 N: 1 8.17 Found (%) C: 61.83 H: 9.16 N: 18.08 Example 70 4-Pyrrolidinoacetyl-1- (2-pyrrolidone-5-
Carbonyl) piperazine: Melting point 166.5-168.0 ° C Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₃ ) Calculated value (%) C: 57.58 H: 7.89 N: 17.91 Actual value (%) C: 57.55 H: 8.04 N: 17.99 Example 71 4-piperidinoacetyl-1- (2-pyrrolidone-5-
Carbonyl) piperazine: Melting point 195-196 ° C Elemental analysis value (as C ₁₉ H ₂₆ N ₄ O ₃ ) Calculated value (%) C: 59.61 H: 8.13 N: 17.38 Measured value (%) C: 59.16 H: 8.42 N: 17.43 Example 72 D-(+)-4-morpholinocarbonylmethyl-1-
(2-pyrrolidone-5-carbonyl) piperazine maleate: mp one hundred and ninety-nine to two hundred and one ° C. Elemental analysis (C ₁₅ H ₂₄ N ₄ as _{O 4 · C 4 H 4 O} 4) Calculated (%) C: 51.81 H: 6.41 N: 12.72 Found (%) C: 51.75 H: 6.29 N: 12.76 Example 73 D-(+)-4-ethoxycarbonyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 71-73 ° C. elemental analysis _{(C 12 H 19 N 3 O} 4 · 1 / 4H 2 O ) calculated value (%) C: 52.64 H: 7.18 N: 15.35 Found (%) C: 52.69 H: 7.26 N: 15.46 example 74 D - (+) - 4- morpholino-1- (2-pyrrolidone-5-carbonyl) piperazine: mp 139-141 ° C. elemental analysis (as _{C 15 H 24 N 3 O 4} · 1 / 4H 2 O) Calculated value (%) C: 54.78 H: 7.51 N: 17.04 Measured value (%) C: 54.88 H: 7.66 N: 17.12 Example 75 4- (2-phenoxyethyl) -1- (2-pyrrolidone-5-carbonyl ) Piperazine: melting point 131.5 〜133.0 ℃ Elemental analysis value (as C ₁₇ H ₂₃ N ₃ O ₃ ) Calculated value (%) C: 64.33 H: 7.30 N: 13.24 Measured value (%) C: 64.38 H: 7.28 N: 13.29 Example 76 4- [2- (4-methylphenoxy) ethyl] -1-
(2-Pyrrolidone-5-carbonyl) piperazine: melting point
From 146 to 147.5 ° C. Elemental analysis (as _{C 18 H 25 N 3 O 3} ) Calcd (%) C: 65.24 H: 7.60 N: 12.68 Found (%) C: 65.26 H: 7.60 N: 12.70 Example 77 4 -[2- (2-chlorophenoxy) ethyl] -1-
(2-Pyrrolidone-5-carbonyl) piperazine: melting point
133-134 ℃ Elemental analysis value (as C ₁₇ H ₂₂ ClN ₃ O ₃ ) Calculated value (%) C: 58.04 H: 6.30 N: 11.94 Measured value (%) C: 57.95 H: 6.30 N: 11.90 Example 78 D -(+)-4- (4-methylbenzyl) -1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 71-73
℃ Elemental analysis value (as C ₁₇ H ₂₃ N ₃ O ₂ · H ₂ O) Calculated value (%) C: 63.93 H: 7.89 N: 13.16 Measured value (%) C: 63.88 H: 7.92 N: 13.25 Example 79 D-(−)-5- (2-carbamoyl-L-pyrrolidinocarbonyl) -2-pyrrolidone: melting point 210 to 211.5 ° C. Elemental analysis value (as C ₁₀ H ₁₅ N ₃ O ₃ ) Calculated value (%) C: 53.32 H: 6.71 N: 18.66 Found (%) C: 53.40 H: 6.76 N: 18.74 Example 80 1- (2-Pyrrolidone-5-carbonyl) -4-thiomorpholinocarbonylmethylpeperazine: melting point 194-195 ° C. Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₃ S) Calculated value (%) C: 52.92 H: 7.11 N: 16.46 Measured value (%) C: 52.91 H: 7.10 N: 16.44 Example 81 4- (4) -Methoxycarbonylbenzyl) -1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 113.5
～115.5 ° C. Elemental analysis (C ₁₈ H ₂₃ N ₃ as O ₄₎ Calculated (%) C: 62.59 H: 6.71 N: 12.17 Found (%) C: 62.37 H: 6.85 N: 12.15 Example 82 4- (2-Hydroxyethyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 129-131 ° C Elemental analysis value (as C ₁₁ H ₁₉ N ₃ O ₃ ) Calculated value (%) C: 54.76 H: 7.94 N: 17.41 Found (%) C: 54.67 H: 8.06 N: 17.48 Example 83 4- (2-morpholinocarbonylethyl) -1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 135-1
36.5 ° C Elemental analysis value (as C ₁₆ H ₂₆ N ₄ O ₄ ) Calculated value (%) C: 56.79 H: 7.74 N: 16.56 Measured value (%) C: 56.59 H: 7.89 N: 16.42 Example 84 4- [ 3- (4-methylphenoxy) propyl] -1-
(2-Pyrrolidone-5-carbonyl) piperazine: melting point
107 to 108.5 ° C Elemental analysis value (as C ₁₉ H ₂₇ N ₃ O ₃ ) Calculated value (%) C: 66.06 H: 7.88 N: 12.16 Measured value (%) C: 65.94 H: 7.96 N: 11.92 Example 854 -[2- (4-Methoxycarbonylphenoxy) ethyl] -1- (2-pyrrolidone-5-carbonyl) piperazine: Melting point 127-129 ° C Elemental analysis value (as C ₁₉ H ₂₅ N ₃ O ₅ ) Calculated value (% ) C: 60.79 H: 6.71 N: 11.19 Actual value (%) C: 60.62 H: 6.82 N: 11.02 Example 86 4- [3- (4-methoxycarbonylphenoxy) propyl] -1- (2-pyrrolidone-5 - carbonyl) piperazine: mp from 141 to 142.5 ° C. elemental analysis (C ₂₀ H ₂₇ N ₃ as O ₅₎ calculated (%) C: 61.68 H: 7.00 N: 10.79 Found (%) C: 61.60 H: 7.13 N 10.71 Example 87 4- [2- (4-benzyloxyphenoxy) ethyl]
-1- (2-pyrrolidone-5-carbonyl) piperazine: mp 110 to 112 ° C. Elemental analysis (C ₂₄ H ₂₉ N ₃ as O ₄₎ Calculated (%) C: 68.07 H: 6.90 N: 9.92 Found ( %) C: 68.00 H: 7.00 N: 9.96 Example 88 4- (3-morpholinopropionyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 184-185 ° C. Elemental analysis value (C ₁₆ H ₂₆ N _{4 O 4 · 1 / 2H 2} O ) calculated value (%) C: 55.32 H: 7.83 N: 16.13 Found (%) C: 55.65 H: 7.94 N: 16.08 example 89 4- morpholinocarbonyl-methyl-1- (2-Pyrrolidone-5-carbonyl) homopiperazine Oily substance.

Elemental analysis value (as C ₁₆ H ₂₆ N ₄ O ₄ ) Calculated value (%) C: 56.79 H: 7.74 N: 16.56 Measured value (%) C: 56.83 H: 7.62 N: 16.57 Example 90 N- (2- Pyrrolidone-5-carbonyl) -1,2,3,4-
Tetrahydroisoquinoline, melting point 153-155 ° C.

Elemental analysis value (as C ₁₄ H ₁₆ N ₂ O ₂ ) Calculated value (%) C: 68.83 H: 6.60 N: 11.47 Measured value (%) C: 68.96 H: 6.56 N: 11.53 Example 91 4-acetamido-1 -(2-Pyrrolidone-5-carbonyl) piperidine: melting point 234.5-236 ° C.

Elemental analysis value (as C ₁₂ H ₁₉ N ₃ O ₃ ) Calculated value (%) C: 56.90 H: 7.56 N: 16.59 Measured value (%) C: 56.76 H: 7.74 N: 16.63 Example 92 4- (4- Benzyloxycarbonylpiperazinocarbonylmethyl) -1- (2-pyrrolidone-5-carbonyl)
Piperazine: melting point 171-174 ° C.

Elemental analysis (C ₂₃ H ₃₁ N ₅ as O ₅₎ Calculated (%) C: 60.38 H: 6.83 N: 15.31 Found (%) C: 60.14 H: 7.12 N: 15.09 Example 93 4- piperazino Carbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine maleate: melting point
142-144 ° C.

Elemental analysis _{(C 15 H 25 N 5 O} 3 · C 8 H 8 O 8 · 1 / 4H 2 O ) Calculated value (%) C: 49.33 H: 5.98 N: 12.51 Found (%) C: 49.28 H : 5.99 N: 12.46 Example 94 4- [4- (4-Methylbenzyl) piperazinocarbonylmethyl] -1- (2-pyrrolidone-5-carbonyl)
Piperazine: melting point 168-170.5 ° C.

Elemental analysis (as _{C 23 H 33 N 5 O 3} ) Calculated (%) C: 64.61 H: 7.78 N: 16.38 Found (%) C: 64.55 H: 7.87 N: 16.24 Example 95 4- [3- (4-Methylphenyl) propyl] -1-
(2-Pyrrolidone-5-carbonyl) piperazine: melting point
74-76 ° C.

Elemental analysis value (as C ₁₉ H ₂₇ N ₃ O ₂ ) Calculated value (%) C: 69.27 H: 8.26 N: 12.75 Measured value (%) C: 69.31 H: 8.14 N: 12.76 Example 96 N- (2- Pyrrolidone-5-carbonyl) piperidine-
4-one: melting point 153-155 ° C.

Elemental analysis (as _{C 10 H 14 N 2 O 3} ) Calculated (%) C: 57.13 H: 6.71 N: 13.32 Found (%) C: 56.94 H: 6.61 N: 13.03 Example 97 D - (+) -4-morpholinocarbonylmethyl-1-
(2-Pyrrolidone-5-carbonyl) piperazine: melting point
129-129.5 ° C.

Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₄ 1 / 2C ₂ H ₅ OH) Calculated value (%) C: 55.32 H: 7.83 N: 16.13 Measured value (%) C: 55.48 H: 7.80 N: 16.26 Example 98 4-benzyloxycarbonyl-1- (2-pyrrolidone-
5-Carbonyl) homopiperazine: melting point 111-113 ° C.

Elemental analysis (C ₁₈ H ₂₃ N ₃ as O ₄₎ Calculated (%) C: 62.59 H: 6.71 N: 12.17 Found (%) C: 62.57 H: 6.75 N: 12.20 Example 99 4-morpholinophenyl acetyl - 1- (2-pyrrolidone-5-
Carbonyl) homopiperazine fumarate: melting point 148-1
50 ° C.

Elemental analysis value (as C ₁₆ H ₂₆ N ₄ O ₄・ C ₄ H ₄ O ₄・ 1 / 2H ₂ O) Calculated value (%) C: 52.34 H: 6.70 N: 12.21 Measured value (%) C: 52.26 H : 6.68 N: 11.99 Example 100 4-morpholinocarbonyl-1- (2-pyrrolidone-5
-Carbonyl) piperazine: melting point 183-185 ° C.

Elemental analysis (C ₁₄ H ₂₂ N ₄ as O ₄₎ Calculated (%) C: 54.18 H: 7.14 N: 18.05 Found (%) C: 54.07 H: 7.25 N: 17.76 Example 101 2- [4- (2-L-carbamoylpyrrolidinocarbonylmethyl) piperazinocarbonyl] -D-pyrrolidino-
5-one: melting point 239-242 ° C.

Elemental analysis value (as C ₁₆ H ₂₅ N ₅ O ₄ 1 / 2CH ₃ OH) Calculated value (%) C: 52.94 H: 7.41 N: 19.06 Measured value (%) C: 54.33 H: 7.41 N: 19.11 Example 102 4-Piperidino-1- (2-pyrrolidone-5-carbonyl) piperidine: mp 147-150 ° C.

Elemental analysis value (as C ₁₅ H ₂₅ N ₃ O ₂ ) Calculated value (%) C: 64.49 H: 9.02 N: 15.04 Measured value (%) C: 64.33 H: 8.98 N: 14.97 Example 103 D-(+) -4-Benzyloxycarbonyl-1- (2-
Pyrrolidone-5-carbonyl) piperazine: melting point 49-52
° C.

Elemental analysis (C ₁₇ H ₂₁ N ₃ as O ₄₎ Calculated (%) C: 61.46 H: 6.46 N: 12.56 Found (%) C: 61.30 H: 6.12 N: 12.63 Example 104 N-(2- Pyrrolidone-5-carbonyl) -2,6-cis-dimethylpiperidine: melting point 177-181 ° C.

Elemental analysis value (as C ₁₂ H ₂₀ N ₂ O ₂ ) Calculated value (%) C: 64.26 H: 8.99 N: 12.49 Measured value (%) C: 64.11 H: 9.11 N: 12.47 Example 105 D-(+) -4-thiomorpholinocarbonylmethyl-1
-(2-Pyrrolidone-5-carbonyl) piperazine maleate: melting point 159-161 ° C.

Elemental analysis value (as C ₁₅ H ₂₄ N ₄ O ₃ S ・ C ₄ H ₄ O ₄ ) Calculated value (%) C: 49.99 H: 6.18 N: 12.27 Measured value (%) C: 49.84 H: 6.20 N: 12.28 Example 106 1- (4-aminobutanoyl) -4- (2-pyrrolidone-5-carbonyl) piperazine Melting point 101-102 ° C.

Elemental analysis _{(C 13 H 22 N 4 O} 3 · 1 / 2H 2 O ) Calculated value (%) C: 53.59 H: 7.96 N: 19.22 Found (%) C: 53.75 H: 7.73 N: 18.97 Example 107 1- [4- (N-benzyloxycarbonylamino) butanoyl] -4- (2-pyrrolidone-5-carbonyl) piperazine: melting point 157-159.5 ° C.

Elemental analysis value (as C ₂₁ H ₂₈ N ₄ O ₅ ) Calculated value (%) C: 60.56 H: 6.78 N: 13.45 Measured value (%) C: 60.58 H: 6.70 N: 13.42 (effect) Clarified from the above results As described above, the compound of the present invention has a nootropic effect on mammals including humans and has low toxicity, and thus is useful as a therapeutic agent for dementia. It can be used as a remedy for senile dementia and as a remedy for mental retardation, encephalitis sequelae, cerebral palsy, stroke, cerebral arteriosclerosis, dementia associated with head trauma and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/535 A61K 31/535 31/54 31/54 31/55 31/55 C07D 401/06 207 C07D 401/06 207 401/14 207 401/14 207 403/06 207 403/06 207 405/14 207 405/14 207 409/14 207 409/14 207 (56) Reference JP-A-51-8266 (JP , A) JP 52-10267 (JP, A) JP 57-18611 (JP, A) JP 59-80663 (JP, A) JP 59-104350 (JP, A) JP 60-156700 (JP, A)

Claims (2)

(57) [Claims] 1. A pyroglutamide derivative represented by the following general formula [I] and a physiologically acceptable salt thereof. Here, A represents a 6-10 membered cyclic amino group having the following characteristics (a), (b) and (c). (A) In addition to the nitrogen atom bonded to the carbonyl group, the ring further contains a nitrogen atom as a hetero atom, or has only one nitrogen atom as a hetero atom. (B) The cyclic amino group is substituted with a substituent selected from the following. Alkyl, diarylalkyl, aralkyl,
Aryl, hydroxyalkyl, hydroxy, alkanoyl, aralkylcarbonyl, aralkyloxycarbonyl, aralkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, carbamoylalkyl,
Carbamoylalkylcarbonyl, oxo, heterocycle, aryloxyalkyl, alkanoylamino. (C) A is 2,2,6,6-tetramethylpiperidino, 3-
Not hydroxypiperidino or 4-hydroxypiperidino. 2. A cognitive enhancer comprising the pyroglutamide derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.