KR950007591B1 - Pyroglutamide derivatives - Google Patents

Abstract

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Description

Pyroglutamide derivatives

The present invention relates to pyroglutamide derivatives and salts thereof useful as pharmaceuticals.

More specifically, the present invention relates to a pyroglutamide derivative represented by the following general formula (I):

[Formula 1]

즉, ① 알킬, ② 디아릴알킬, ③ 아르알킬, ④ 아릴, ⑤ 히드록시알킬, ⑥ 히드록시, ⑦ 알카노일, ⑧ 아르알킬카르보닐, ⑨ 아르알킬옥시카르보닐 , ⑩ 아르알케닐카르보닐, ⑪ 아릴카르보닐(아로일), ⑫ 복소환카르보닐, ⑬ 알콕시카르보닐, ⑭ 아미노알킬, ⑮ 아미노알킬카르보닐,

아미노카르보닐(카르바모일),

카르바모일알킬,

카르바모일알킬카르보닐,

옥소,

복소환,

아릴옥시알킬 및

알카노일아미노를 들 수 있다.Wherein A represents a substituted or unsubstituted cyclic amino group. The cyclic amino group may further contain a nitrogen atom as a hetero atom in addition to the nitrogen atom in the ring. Examples of the substituent for the cyclic amino group include the following ① to

That is, ① alkyl, ② diarylalkyl, ③ aralkyl, ④ aryl, ⑤ hydroxyalkyl, ⑥ hydroxy, ⑦ alkanoyl, ⑧ aralkylcarbonyl, ⑨ aralkyloxycarbonyl, ⑩ aralkenylcarbonyl, ⑪ arylcarbonyl (aroyl), ⑫ heterocyclic carbonyl, ⑬ alkoxycarbonyl, ⑭ aminoalkyl, 아미노 aminoalkylcarbonyl,

Aminocarbonyl (carbamoyl),

Carbamoylalkyl,

Carbamoylalkylcarbonyl,

Oxo,

Heterocycle,

Aryloxyalkyl and

Alkanoylamino can be mentioned.

With the aging of the population, dementia has become a large part of the elderly's diseases, but the treatment is not yet established. Drug therapy, such as cerebral metabolism revitalizers, cerebral blood flow improvers, mental stabilizers, choline agonists have been tried, but there are no drugs with unsatisfactory effects.

Recently, several chemical compounds, such as anilamtam or flamiracetam, are being developed as Nootropic. Further, Japanese Patent Laid-Open No. 52-125116 or Japanese Patent Laid-Open No. 51-115472 discloses a compound called TRH (tyrotropin releasing hormone, Thyrotropin releasing hormone).

The present inventors have attempted to produce a substance having excellent fragrance action from a completely new point of view, in view of the delayed development of the above-mentioned dementia medicine. Accordingly, an object of the present invention is to provide a fragrance medicine of a type that has not existed until now.

The inventors have found that, over a long period of time, while synthesizing a novel compound and examining the aromatic action of the compound, the compound represented by the general formula (I) has an excellent aromatic action for mammals and extremely low toxicity. Thus, the present invention has been completed.

Although this invention is represented by general formula (I), Japanese Unexamined-Japanese-Patent No. 51-8266 shows that N-piperidino pyroglutamide and N-pyrrolidino pyro glutamide are intermediates for manufacturing an antiulcer agent. It is disclosed as. The compound is also disclosed in Japanese Patent Laid-Open No. 49-144 62 as a raw material. Therefore, among the compounds represented by the general formula (I), there is no description suggesting the pharmacological action according to the present invention with respect to a pyrrolidino or a piperidinoin compound in which A is not substituted. These compounds are not included in the invention.

As a Hona phase amino group represented by A in General formula (I), a 4-10 membered cyclic amino group is mentioned, for example.

Specific examples of such amino groups include azetidino, pyrrolidino, piperidino, azepine, azocino, piperazino, homopiperazino, and tetrahydroisoquinolino.

의 치환기를 들 수 있다.The cyclic amino group may have a substituent at any position. As such a substituent, the above-mentioned (1) thru | or

The substituent of is mentioned.

Wherein if the substituent of the cyclic amino group is aryl, the aryl is one or more identical or different substituents selected from alkyl, alkoxy, aralkyloxy, alkanoyl, alkoxycarbonyl, halogen, halogenoalkyl, nitro or methylenedioxy It may be substituted by.

When the substituent of the cyclic amino group is an amino group, when the amino group forms a 4 to 8 membered ring (in this case, the ring contains a nitrogen atom, a sulfur atom or an oxygen atom as a heteroatom other than a nitrogen atom or , Or only one nitrogen atom is a hetero atom). Examples of such cyclic amino groups include pyrrolidino, piperidino, azino, piperazino, morpholino, thiomorpholino, and the like. The amino group may be substituted by one or more alkyl, aralkyl, aralkyloxycarbonyl or carbamoyl, identical or different.

If the said substituent is described concretely again, the following are mentioned.

That is, alkyl is preferably linear or branched lower alkyl having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary- Butyl etc. are mentioned.

The diarylalkyl is preferably one having 1 to 4 carbon atoms, and examples thereof include diphenylmethyl, diphenylethyl, diphenylpropyl and diphenylbutyl.

Aralkyl is preferably 7 to 12 carbon atoms, and examples thereof include benzyl, phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl and the like.

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

The hydroxyalkyl preferably has 2 to 4 carbon atoms, and may have a hydroxy group at any position. Examples thereof include 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl and the like.

As alkanoyl, those having 1 to 7 carbon atoms are preferable, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and the like. Can be mentioned.

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

As the arcalkenylcarbonyl, one having 8 to 10 carbon atoms is preferable, and cinnamoyl is an example.

As aryl in arylcarbonyl, the same thing as the above-mentioned is mentioned.

As the heterocycle in the heterocyclic carbonyl, a 4- to 8-membered heterocycle containing at least one nitrogen atom, oxygen atom or sulfur atom as a hetero atom is preferable, and examples thereof include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, morpholino, thiomorpholino, etc. are mentioned.

Alkoxy in alkoxycarbonyl is preferably a linear or branched one having 1 to 5 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 2 Tert-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy and the like.

As alkyl in aminoalkyl, aminoalkylcarbonyl, carbamoylalkyl and carbamoylalkyl carbonyl, alkyl having 1 to 3 carbons is preferable.

As a heterocyclic ring, the thing similar to the heterocycle defined about heterocyclic carbonyl can be mentioned.

Examples of the halogen include chlorine, bromine, fluorine and iodine. As aralkyl in aralkyloxy, the same thing as mentioned above is mentioned. Examples of the halogenoalkyl include trifluoromethyl. The compound of this invention can be manufactured, for example by the method of mentioning later;

A method:

Scheme 1

Method B:

Scheme 2

C law:

Scheme 3

(R represents a substituent of A, X represents a halogen.)

D method:

Scheme 4

E law:

Scheme 5

은 환상 또는 쇄상의 아민을 나타내고, n는 1-3이며, X는 할로겐을 나타낸다.)(

Represents cyclic or chained amines, n is 1-3 and X represents halogen.)

Each manufacturing method is explained in full detail below.

A method:

Compound (II) is reacted with various amines represented by A-H to prepare (I). This amidation reaction is usually about 50 to 160 ° C, preferably using a molar equivalent or more, preferably 1.0 to 1.3 moles of amine relative to (II), which can be carried out by a known method. It may be carried out at a temperature of about 90 to 120 ℃. In particular, it can carry out at the boiling point of the solvent used conveniently.

Any solvent used may be inert, such as alcohol solvents (e.g. methanol, ethanol and isopropanol), halogenated hydrocarbon solvents (e.g. chloroform and carbon tetrachloride), aromatic hydrocarbon solvents (e.g. benzene, toluene and Xylene), ether solvents such as tetrahydrofuran and dioxane, or aprotic polar solvents such as N, N-dimethylformamide, and the reaction can be carried out without using a solvent. It may be.

Method B:

Compound (III) is reacted with various amines represented by A-H to prepare (I). This amidation reaction can be performed by a well-known method. For example, a method of directly condensing (III) and various amines with dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (DDPA) or the like, or a reactive derivative of (III) such as an acid anhydride, A method of appropriately reacting a dozeolide or mixed acid anhydride (e.g., anhydride with methyl carbonate, anhydride with ethyl carbonate, anhydride with isobutyl carbonate), or the like, or an active ester method can be used.

In the above method, when a condensing agent such as DDC is used, the reaction is 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) at about -30 ° C to about 180 ° C. It is preferred to use equimolar to slightly excess compound (III) and DCC per mole of amine.

In general formula (I), A is a cyclic amino group which has a nitrogen atom as a hetero atom, and when the nitrogen is substituted, the compound can be manufactured by alkylating, acylating, or amination of the compound manufactured by the said manufacturing method. have. That is, it can manufacture by C-E method.

C law:

(Ia) can be obtained by alkylation of (IV) obtained by Method A or Method B. This alkylation reaction can be performed by a well-known method.

The alkylating agent may be one used in a common alkoxylation reaction, and examples thereof include a corresponding alkyl halide (eg, chloride, bromide, iodide, etc.) sulfate ester, sulfonic acid ester and the like. For example, when using an alkyl halide, the reaction may be carried out in a suitable solvent (e.g., alcohols such as methanol, ethanol, etc .; ethers such as tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, etc .; aromatics such as benzene, toluene, etc.). Hydrocarbons; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, or the like; or mixtures thereof) in the presence of a base (e.g., sodium bicarbonate, potassium carbonate, pyridine, trialkylamine, etc.) at room temperature It is good to carry out from the boiling point of the reaction solvent.

In this case, it is preferable to use an equivalent or more alkyl halide for (IV). In addition, a catalytic amount (about 0.01 to 0.1 molar equivalent) of sodium iodide or potassium iodide may be added to promote the reaction and improve the yield.

D method:

(Ib) can be obtained by acylating (IV) obtained by the A method or the B method. This acylation reaction can be carried out by substantially the same method as the B method, and can also be carried out by reacting an acid halide with (IV).

When acid halides are used, the reaction is usually carried out in solvents (e.g. ethers such as tetrahydrofuran, dioxane, etc .; halogenated hydrocarbons such as methylene chloride, chloroform, etc .; aromatic hydrocarbons such as benzene, toluene, etc .; acetonitrile, N, N Aprotic polar solvents such as dimethylformamide; water; or mixtures thereof) in the presence of a base (e.g., sodium bicarbonate, thallium carbonate, sodium hydroxide, potassium hydroxide, pyridine, trialkylamine, etc.) It is recommended to carry out at about -10 ℃ to about 100 ℃.

In this case, the amount of acid halide used should be equivalent to or greater than that of [IV].

E law:

(Ic) can be prepared by acylating (IV) obtained in Method A or B and then reacting the amine. This reaction can be performed substantially in the same manner as the D method or the E method.

In the above production method, when reacting a diamine such as piperazine, one of the amines is protected by a known method to react with (II) or (III), and then the protecting group is removed to obtain (I).

(II) and (III) used as a raw material of each said manufacturing method are commercially available and can be obtained easily. Similarly, amines are commercially available or can be manufactured by a well-known method.

Compound (I) obtained by each of the above methods can be isolated in the form of a free base by a known method. For example, it can be isolated and purified by concentration, liquid conversion, conversion, solvent extraction, crystallization, recrystallization, fractionation, chromatography, and the like.

It can also be isolated in the form of acid addition salts. Such acid addition salts may be physiologically acceptable, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; Organic acid salts such as acetate, maleate, fumarate, succinate, tartarate, citrate, malate and the like.

Although the compound of this invention is represented by the following general formula (I), it is clear that it has a member carbon in it (* table below).

[Formula 2]

Accordingly, the compounds of the present invention exist as optically active agents of Form D and Form L, but each optical isomer and mixtures thereof are included within the scope of the present invention.

The isomers can be prepared separately as needed.

For example, by using an optically active substance (type D or L) as the raw material compound (II) or (III), the corresponding optical isomer (Type D or L) of (I) can be obtained. In the case where the prepared (I) is a mixture of D-type and L-type, these can be separated and purified into their respective isomers by a conventional optical splitting method.

Of the optically active (I) calculated as described above, Form D is generally preferred to Form L, but it has been found to have physiological activity.

Hereinafter, the results of the pharmacological test to prove the usefulness of the compound of the present invention will be described in detail.

1. Improvement effect on scopolamine amnesia

Test Method: After passive evacuation (PAR) acquisition, rats received 0.5 mg / kg of scopolamine and the test drug at the same time intraperitoneally, and after 1 hour, passive evasion learning response (maintenance) was again performed. . The reaction positive rate (number of positive animals / number of animals used) is shown in Table 1 below. When the test drug was orally administered in the above test, maintenance was performed 2 hours after drug administration.

The minimum effective amount showing significant improvement when aniracetam, the compounds of Examples 3 and 72 were intraperitoneally and orally administered is shown in Table 2 (1).

TABLE 1

*: p <0.05, * *: p <0.01

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

2. Improvement effect on electric shock forgetfulness

I used the same method as scopolamine forgetfulness.

After the acquisition, the rats were given a shock shock, and after the spasms passed, the test drug was intraperitoneally and orally administered. After 1 and 2 hours, the maintenance was performed, and the positive response rate was measured. The minimum effective amount indicating is given in Table 2 (2) below.

3. Improvement effect on excess CO ₂ forgetfulness

After intraperitoneal administration or oral administration of the test drug, the rats were left in a chamber filled with CO ₂ gas for 12 seconds after 30 and 60 minutes, respectively, and after 3 minutes, the rats were transferred to a two-part shuttle box and buzzer. Active avoidance learning and evacuation learning using the conditional stimulus and measuring the positive rate (number of positive animals / number of animals used) of the learning acquisition test on the sixth trial was performed. Presented in (3). The minimum effective amounts in Table 2 below were all expressed as an effective amount (mg / kg) showing a significant improvement effect with P <0.05 in the x ₂ assay.

TABLE 2

(1) Improvement effect on scopolamine forgetfulness

(2) Improvement effect on lightning shock forgetfulness

(3) improvement effect on excess CO ₂ forgetfulness

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

4. Acute Toxicity

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

In the intravenous administration of 1000 mg / kg, no compound died and no toxic symptoms were recognized.

In the case of oral administration, there was no death and no toxic symptoms were observed in any compound at the dose of 3,000 mg / kg.

The stability of the compounds of the invention is clear.

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

As the carrier, one or more solid, semisolid or liquid diluents, fillers and other prescription adjuvants are used. The pharmaceutical composition is preferably administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intramuscularly, topically or rectally. In addition, the pharmaceutical composition of the present invention is administered in a dosage form suitable for their administration method, for example, tablets, granules, powders, capsules, injections, suppositories, and the like. For example, case administration is particularly preferred.

It is preferable to adjust the dose as an aromatic drug after taking into consideration the condition of the patient such as age and weight, the route of administration, the nature of the disease process, and the like. A range, preferably in the range of 150 mg to 3 g, is common. In some cases, less than that may be sufficient and conversely, more capacity may be required. Moreover, it can divide and administer in several times a day.

EXAMPLE

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

Example 1 (A method)

4-benzyl-N- (2-pyrrolidone-5-carbonyl) piperidine

After dissolving 4.3 g of methyl pyroglutamate and 7.9 g of 4-benzylpiperidine in 20 ml of toluene, it heated and refluxed for 24 hours, stirring. The reaction solution was treated by silica gel column chromatography to give 7.2 g of product. This was recrystallized from diethyl ether to obtain 6.5 g of the target compound having a melting point of 160 to 161 占 폚.

Elemental Analysis Value (C ₁₇ H ₂₂ N ₂ O ₂ )

Calculated (%): C; 71.30, H; 7.74, N; 9.78.

Found (%): C; 71.50, H; 8.17, N; 9.71.

Example 2 (B method)

1- (2-pyrrolidone-5-carbonyl) piperazine

112.4 g of pyroglutamic acid, 147.7 g of N-carbobenzoxypiperazines, 179.7 g of dicyclohexyl carbodiimide, and 6.7 L of acetonitrile were heated and refluxed for 6 hours while stirring. Insolubles were filtered off from the reaction mixture, and the solvent was distilled off from the filtrate under reduced pressure. The residue was treated by silica gel column chromatography to give 190 g of oily N-carbobenzoxy-N- (2-pyrrolidone-5-carbonyl) piperazine. 30 g of this was dissolved in 450 ml of methanol, followed by catalytic reduction while stirring at room temperature using 3.0 g of 5% palladium carbon. The catalyst was filtered off from the reaction solution, and the solvent was distilled off from the filtrate under reduced pressure to obtain 20 g of a product. This was recrystallized from a mixed solvent of methanol-ethyl acetate to give 17.5 g of the target compound having a melting point of 162 to 163 占 폚.

Elemental Analysis Value (C ₉ H ₁₅ N ₃ O ₂ )

Calculated (%): C; 54.81, H; 7.67, N; 21.30.

Found (%): C; 54.74, H; 7.73, N; 21.29.

Example 3 (B method)

4-morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine

A mixed solution of 1.6 g of pyroglutamic acid, 2.1 g of 1- (morpholinocarbonylmethyl) piperazine, 2.47 g of DCC, and 130 ml of acetonitrile was heated to reflux for 48 hours with stirring. Insolubles were filtered off from the reaction mixture, and the solvent was distilled off from the filtrate under reduced pressure. The residue was treated by silica gel column chromatography to give 3.0 g of product. This was recrystallized from a mixed solvent of ethyl acetate-isopropanol-n-hexane to give 2.6 g of the target compound having a melting point of 167 to 169 ° C.

Elemental Analysis Value (C ₁₅ H ₂₄ N ₄ O ₄ )

Calculated (%): C; 54.54, H; 7.46, N; 17.27.

Found (%): C; 55.31, H; 7.49, N; 17.14.

Example 4 (C method)

4-morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine

3.7 g of 1- (2-pyrrolidone-5-carbonyl) piperazine, 3.7 g of 4-chloroacetylmorpholine, 4.4 g of anhydrous potassium carbonate and 20 ml of N, N-dimethylformamide were added, followed by stirring while 70 It heated at -75 degreeC for 1 hour. Insolubles were filtered off from the reaction mixture and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 5.7 g of product. This was recrystallized from a mixed solvent of ethanol-ethyl acetate-diethyl ether to obtain 4.2 g of the target compound having a melting point of 167 to 169 ° C.

Elemental Analysis Value (C ₁₅ H ₂₄ N ₄ O ₄ )

Calculated (%): C; 54.54, H; 7.46, N; 17.27.

Found (%): C; 55.36, H; 7.58, N; 17.23.

Example 5 Method D

4-ethoxycarbonyl-1- (2-pyrrolidone-5-carbonyl) piperazine

A mixture of 2.1 g of 1- (2-pyrrolidone-5-carbonyl) piperazine, 2.5 g of anhydrous potassium carbonate, and 120 ml of acetonitrile was cooled with ice water, and 1.1 g of ethyl chlorocarbonate was dissolved in 10 ml of acetonitrile while stirring. The solution was added dropwise thereto. Then, it stirred again at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure. Methylene chloride was added to the residue, and the insolubles were filtered off. The solvent was distilled off from the filtrate under reduced pressure to obtain 2.3 g of an oily product. This was crystallized and recrystallized from ethyl acetate to obtain 2.1 g of the target compound having a melting point of 147 to 148.5 占 폚.

Elemental Analysis Value (C ₁₂ H ₁₃ N ₃ O ₄ )

Calculated (%): C; 53.52, H; 7.11, N; 15.60.

Found (%): C; 53.36, H; 7.32, N; 15.60.

Example 6 (E method)

4-morpholinoacetyl-1- (2-pyrrolidone-5-carbonyl) piperazine

After cooling a mixed solution of 2.3 g of N- (2-pyrrolidone-5-carbonyl) piperazine, 50 ml of methylene chloride and 2.8 g of anhydrous potassium carbonate with ice water, 1.3 g of chloroacetyl chloride was added dropwise while stirring. Then, it stirred at room temperature again for 1 hour. The insolubles were filtered off, and the solvent was distilled off from the filtrate to obtain 2.3 g of oily N- (2-pyrrolidone-5-carbonyl) -N'-chloroacetylpiperazine.

This was dissolved in 15 ml of N, N-dimethylformamide, 0.8 g of morpholine and 2.2 g of anhydrous potassium carbonate were added, followed by heating at 80 ° C. for 3 hours with stirring. Insolubles were filtered off from the reaction mixture, and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 2.5 g of product. This was recrystallized from a mixed solvent of methanol and ethyl ether to give 2.1 g of the target compound having a melting point of 204 to 205 캜.

Elemental Analysis Value (C ₁₅ H ₂₄ N ₄ O ₄ )

Calculated (%): C; 54.54, H; 7.46, N; 17.27.

Found (%): C; 55.23, H; 7.87, N; 17.01.

In the same manner as in the method described in Example 1-6, the following compounds of Example 7 were prepared.

Example 7

4-phenyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 201-202 ° C

Elemental Analysis Value (C ₁₅ H ₂₉ N ₃ O ₄ )

Calculated (%): C; 65.91, H; 7.01, N; 15.37.

Found (%): 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 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 (C ₁₅ H ₂₈ ClN ₃ O ₂ )

Calculated (%): C; 58.54, H; 5.89, N; 13.65.

Found (%): C; 58.51, H; 5.92, N; 13.77.

Example 10

4- (2-chlorophenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 165-167 ° C

Elemental Analysis Value (C ₁₅ H ₂₈ ClN ₃ 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 deg.

Elemental Analysis Value (C ₁₅ H ₂₈ ClN ₃ O ₂ )

Calculated (%): C; 58.54, H; 5.89, N; 13.65.

Found (%): C; 58.57, H; 5.92, N; 13.67.

Example 12

4- (4-fluorophenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 212-213.5 ° C

Elemental Analysis Value (C ₁₅ H ₁₀ FN ₃ O ₂ )

Calculated (%): C; 61.84, H; 6.23, N; 14.42.

Found (%): 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 (C ₁₆ H ₂₁ N ₃ O ₂ )

Calculated (%): C; 66.87, H; 7.37, N; 14.62.

Found (%): C; 66.70, H; 7.50, N; 14.70.

Example 14

L-(-)-4- (2-methylphenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 122-123.5 ° C

Elemental Analysis Value (C ₁₆ H ₂₁ N ₃ O ₂ )

Calculated (%): C; 66.87, H; 7.37, N; 14.62.

Found (%): 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 ° C

Elemental Analysis Value (C ₁₆ H ₁₈ F ₃ N ₃ O ₂ )

Calculated (%): C; 56.30, H; 5.32, N; 12.31.

Found (%): 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 (C ₁₅ H ₂₅ N ₃ O ₂ )

Calculated (%): 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

Elemental Analysis Value (C ₁₆ H ₂₁ N ₃ O ₃ )

Calculated (%): C; 63.35, H; 6.98, N; 13.85.

Found (%): C; 63.19, H; 7.22, N; 13.76.

Example 18

4- (4-acetylphenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 227.5-229.0 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ FN ₃ O ₃ )

Calculated (%): C; 64.74, H; 6.71, N; 13.32.

Found (%): 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 (C ₁₆ H ₂₁ FN ₃ O ₂ )

Calculated (%): C; 66.88, H; 7.37, N; 14.62.

Found (%): C; 66.60, H; 7.56, N; 14.60.

Example 20

4- (4-chlorophenyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 92.5-93.5 ° C

Elemental Analysis Value (C ₁₆ H ₂₀ ClN ₃ O ₂ )

Calculated (%): C; 59.72, H; 6.26, N; 13.06.

Found (%): C; 59.72, H; 6.32, N; 13.17.

Example 21

4- (2-chlorobenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 163-165 ° C

Elemental Analysis Value (C ₁₉ H ₂₀ ClN ₃ 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- (2-fluorobenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 142-143 ° C

Elemental Analysis Value (C ₁₆ H ₂₀ FN ₃ O ₂ )

Calculated (%): C; 62.94, H; 6.60, N; 13.76.

Found (%): C; 62.81, H; 6.79, N; 13.57.

Example 23

4- (4-methylbenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 144.5-145.5 ° C

Elemental Analysis Value (C ₁₇ H ₂₃ N ₃ 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 _{(C 17 H 20 F 3 O} 2 · 1 / 2C 4 H 4 O 4)

Calculated (%): 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 H ₂₃ N ₃ O ₃ )

Calculated (%): C; 64.33, H; 7.30, N; 13.24.

Found (%): C; 64.29, H; 7.68, N; 13.21.

Example 26

4- (3,4-methylenedioxybenzyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 109-111 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₁ O ₃ )

Calculated (%): C; 61.62, H; 6.39, N; 12.68.

Found (%): C; 61.67, H; 6.55, N; 12.63.

Example 27

4-benzoyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 173-174 ° C

Elemental Analysis Value (C ₁₆ H ₂₃ N ₃ 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 (C ₁₆ H ₂₃ N ₃ O ₃ )

Calculated (%): C; 63.77, H; 6.35, N; 13.94.

Found (%): C; 63.70, H; 6.82, N; 13.95.

Example 29

4- (2-methylbenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 206-207 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₃ O ₃ )

Calculated (%): C; 64.74, 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: melting point 175-176.5 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₃ O ₃ )

Calculated (%): 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 (C ₁₇ H ₂₁ N ₃ O ₃ )

Calculated (%): 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 H ₂₃ N ₃ O ₃ )

Calculated (%): 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: melting point 180.5-182.5 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₃ 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 170-172 ° C

Elemental Analysis Value (C ₁₃ H ₂₅ N ₃ O ₆ )

Calculated (%): C; 58.30, H; 6.44, N; 10.74.

Found (%): 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 (C ₁₆ H ₁₈ N ₄ O ₅ )

Calculated (%): 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) piperazine: melting point 195.5-197.5 ° C

Elemental Analysis Value (C ₁₆ H ₁₈ N ₃ O ₃ )

Calculated (%): C; 60.18, H; 5.68, N; 13.16.

Found (%): 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 (C ₁₆ H ₁₈ ClN ₃ O ₃ )

Calculated (%): C; 57.23, H; 5.40, N; 12.51.

Found (%): C; 57.21, H; 5.46, N; 12.43.

Example 38

4- (4-fluorobenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 179-181 ° C

Elemental Analysis Value (C ₁₆ H ₁₈ Cl ₃ O ₃ )

Calculated (%): C; 57.23, H; 5.40, N; 12.51.

Found (%): C; 56.94, H; 5.54, N; 12.45.

Example 39

4- (2,4-dichlorobenzoyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 2.6-208 ° C

Elemental Analysis Value (C ₁₆ H ₁₇ Cl ₂ N ₂ O ₃ )

Calculated (%): C; 51.91, H; 4.63, N; 11.35.

Found (%): C; 52.00, H; 4.63, N; 11.31.

Example 40

4-phenylacetyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 150.5-152.0 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₃ O ₃ )

Calculated (%): 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 148.5-149.5 ° C

Elemental Analysis Value (C ₁₈ H ₁₃ N ₃ O ₄ )

Calculated (%): C; 62.59, H; 6.71, N; 12.17.

Found (%): C; 62.55, H; 6.90, N; 12.22.

Example 42

4- (4-chlorophenylacetyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 185-187 ° C

Elemental Analysis Value (C ₁₇ H ₄₀ ClN ₃ 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 ° C

Elemental Analysis Value (C ₁₀ H ₁₇ N ₃ O ₂ )

Calculated (%): C; 56.85, H; 8.11, N; 19.89.

Found (%): C; 56.85, H; 7.96, N; 19.37.

Example 44

4-acetyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 118-123 ° C

Elemental analysis _{(C 11 H 17 N 3 O} 3 · 1 / 6H 2 O)

Calculated (%): C; 54.53, H; 7.21, N; 17.34.

Found (%): 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 N ₃ O ₃ )

Calculated (%): C; 56.90, H; 7.56, N; 16.59.

Found (%): C; 56.76, H; 7.78, N; 16.53.

Example 46

4-Carbobenzoxoxy-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 162-164 ° C

Elemental Analysis Value (C ₁₇ H ₂₁ N ₃ O ₄ )

Calculated (%): C; 61.62, H; 6.39, N; 12.68.

Found (%): C; 61.46, H; 6.46, N; 12.56.

Example 47

4-cinnamoyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 229-233 ° C (decomposition)

Elemental Analysis Value (C ₁₈ H ₂₁ N ₃ O ₃ )

Calculated (%): 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 (C ₁₃ H ₂₃ N ₃ O ₃ )

Calculated (%): C; 66.84, H; 6.79, N; 12.31.

Found (%): 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 (C ₁₃ H ₂₃ N ₃ O ₄ )

Calculated (%): 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 178.5-179.5 ° C

Elemental Analysis Value (C ₁₂ H ₄₀ N ₄ O ₃ )

Calculated (%): C; 53.72, H; 7.51, N; 20.88.

Found (%): C; 53.61, H; 7.79, N; 20.71.

Example 51

4-isopropylaminocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 125-127 ° C

Elemental Analysis Value (C ₁₄ H ₂₄ N ₄ O ₃ )

Calculated (%): C; 56.74, H; 8.16, N; 18.90.

Found (%): C; 56.54, H; 8.43, N; 18.76.

Example 52

4-nicotinoyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 199.5-201.5 ° C

Elemental Analysis Value (C ₁₅ H ₁₈ N ₄ O ₂ )

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 (C ₁₄ H ₁₇ N ₃ O ₃ S)

Calculated (%): C; 54.71, H; 5.57, N; 13.67.

Found (%): C; 54.62, H; 5.56, N; 13.80.

Example 54

4- (2-pyridyl) -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 211-212.5 ° C

Elemental Analysis Value (C ₁₄ H ₂₈ N ₄ 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) piperazine: melting point 107-109 ° C

Elemental Analysis Value (C ₁₁ H ₁₈ N ₂ O ₂ )

Calculated (%): C; 62.83, H; 8.63, N; 13.32.

Found (%): C; 62.40, H; 8.90, N; 13.17.

Example 56

4-phenyl-N- (2-pyrrolidone-5-carbonyl) piperazine: melting point 198-199 ° C

Elemental Analysis Value (C ₁₆ H ₄₀ N ₂ O ₂ )

Calculated (%): C; 70.56, H; 7.40, N; 10.29.

Found (%): C; 70.68, H; 7.66, N; 10.15.

Example 57

4-ethoxycarbonyl-N-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 158-159.5 ° C

Elemental Analysis Value (C ₁₃ H ₂₄ N ₂ O ₄ )

Calculated (%): C; 58.19, H; 7.51, N; 10.44.

Found (%): C; 58.18, H; 7.82, N; 10.44.

Example 58

4-Carbamoyl-N- (2-pyrrolidone-5-carbonyl) piperazine 1/2 hydrate: Melting point 172-173 ° C

Elemental analysis _{(C 11 H 17 N 3 O} 3 · 1/2 H 2 O)

Calculated (%): C; 53.22, H; 7.31, N; 16.92.

Found (%): C; 53.67, H; 7.79, N; 16.76.

Example 59

4-hydroxy-N- (2-pyrrolidone-5-carbonyl) piperazine: melting point 147.0-148.5 ° C

Elemental Analysis Value (C ₁₀ H ₂₀ N ₂ O ₃ )

Calculated (%): C; 56.59, H; 7.60, N; 13.20.

Found (%): 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 (C ₁₁ H ₂₈ N ₂ O ₂ )

Calculated (%): C; 62.83, H; 8.63, N; 13.32.

Found (%): C; 62.84, H; 8.92, N; 13.39.

Example 61

4- (2-pyrrolidone-5-carbonyl) -2-ketopiperazine: melting point 198-200 ° C

Elemental Analysis Value (C ₈ H ₁₃ N ₃ O ₃ )

Calculated (%): C; 51.28, H; 6.20, N; 19.89.

Found (%): C; 51.21, H; 6.20, N; 19.80.

Example 62

L- (1) -4- (morpholinocarbonylmethyl) -1- (2-pyrrolidone-5-carbonyl) piperazine maleate: Melting point 201-202.5 ° C

Elemental analysis _{(C 15 H 14 N 4 O} 4 · C 4 H 4 O 4)

Calculated (%): 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 (C ₁₅ H ₂₄ N ₄ O ₃ )

Calculated (%): C; 58.42, H; 7.84, N; 18.17.

Found (%): C; 58.26, H; 8.02, N; 18.06.

Example 64

4-piperidinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 181-183 ° C

Elemental Analysis Value (C ₁₆ H ₂₆ F ₄ O ₃ )

Calculated (%): C; 59.61, H; 8.13, N; 17.38.

Found (%): C; 59.46, H; 8.49, N; 17.23.

Example 65

4-hexyl iminocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 143-144 ° C

Elemental Analysis Value (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-diisopropylaminocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 189-190.5 ° C

Elemental Analysis Value (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-Monopolynoethyl-1- (2-pyrrolidone-5-carbonyl) piperazine maleate: Melting point 179-181 ° C

Elemental analysis _{(C 15 H 20 N 4 O} 3 · 2C 4 H 4 O 4 · 1/2 H 2 O)

Calculated (%): C; 50.09, H; 6.40, N; 10.16.

Found (%): C; 49.99, H; 6.74, N; 10.22.

Example 68

4-pyrrolidinoethyl-1- (2-pyrrolidone-5-carbonyl) piperazine maleate: melting point 169-170 ° C

Elemental Analysis Value (C ₁₅ H ₂₀ N ₄ O ₂ · 2C ₄ H ₄ O ₄ · 1/2 H ₂ O)

Calculated (%): C; 51.58, H; 6.59, N; 10.42.

Found (%): C; 51.60, H; 6.90, N; 10.29.

Example 69

4-piperidinoethyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 169-170 ° C

Elemental Analysis Value (C ₁₆ H ₂₈ N ₄ O ₂ )

Calculated (%): C; 62.31, H; 9.15, N; 18.17.

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 (C ₁₅ H ₂₄ N ₄ O ₃ )

Calculated (%): C; 57.58, H; 7.89, N; 17.91.

Found (%): 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 (C ₁₉ H ₂₆ N ₄ O ₃ )

Calculated (%): C; 59.61, H; 8.13, N; 17.38.

Found (%): C; 59.16, H; 8.42, N; 17.43.

Example 72

D-(+)-4-morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) piperazine maleate: melting point 199-201 ° C

Elemental analysis _{(C 15 H 24 N 4 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 · 1/4 H 2 O)

Calculated (%): C; 52.64, H; 7.18, N; 15.35.

Found (%): C; 52.69, H; 7.26, N; 15.46.

Example 74

D-(+)-4-morpholinoacetyl-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 139-141 ° C

Elemental Analysis Value (C ₁₃ H ₂₃ N ₃ O ₄ )

Calculated (%): C; 54.78, H; 7.51, N; 17.04.

Found (%): 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 ° C

Elemental Analysis Value (C ₁₇ H ₂₃ N ₃ O ₃ )

Calculated (%): C; 64.33, H; 7.30, N; 13.24.

Found (%): C; 64.38, H; 7.28, N; 13.29.

Example 76

4- [2- (4-methylphenoxy) ethyl] -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 146-147.5 ° C

Elemental Analysis Value (C ₁₂ H ₂₅ N ₃ O ₃ )

Calculated (%): 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 ° C

Elemental Analysis Value (C ₁₇ H ₂₂ ClN ₃ O ₃ )

Calculated (%): C; 58.04, H; 6.30, N; 11.94.

Found (%): 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 ° C

Elemental analysis _{(C 17 H 23 N 3 O} 2 · H 2 O)

Calculated (%): C; 63.93, H; 7.89, N; 13.16.

Found (%): C; 63.88, H; 7.92, N; 13.25.

Example 79

D- (1) -5- (2-carbamoyl-L-pyrrolidinocarbonyl) -2-pyrrolidone: melting point 210-211.5 ° C.

Elemental Analysis Value (C ₁₀ H ₁₅ N ₃ O ₃ )

Calculated (%): 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-thiomorpholinocarbonylmethylpiperazine: melting point 194-195 ° C

Elemental Analysis Value (C ₁₅ H ₂₄ N ₄ O ₃ S)

Calculated (%): C; 52.92, H; 7.11, N; 16.46.

Found (%): 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 Value (C ₁₈ H ₂₃ N ₃ O ₄ )

Calculated (%): C; 62.59, H; 6.71, N; 12.179.

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 (C ₁₁ H ₂₉ ClN ₃ O ₃ )

Calculated (%): 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 135-136.5 ° C

Elemental Analysis Value (C ₁₆ H ₂₆ N ₄ O ₄ )

Calculated (%): C; 56.79, H; 7.74, N; 16.56.

Found (%): C; 56.59, H; 7.89, N; 16.42.

Example 84

4- [3- (4-methylphenoxy) propyl] -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 107-108.5 ° C

Elemental Analysis Value (C ₁₉ H ₂₇ N ₃ O ₃ )

Calculated (%): C; 66.06, H; 7.88, N; 12.16.

Found (%): C; 65.94, H; 7.96, N; 11.92.

Example 85

4- [2- (4-methoxycarbonylphenoxy) ethyl] -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 127-129 ° C

Elemental Analysis Value (C ₁₉ H ₂₅ N ₃ O ₅ )

Calculated (%): C; 60.79, H; 6.71, N; 11.19.

Found (%): C; 6.62, H; 6.82, N; 11.02.

Example 86

4- [3- (4-methoxycarbonylphenoxy) propyl] -1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 141-142.5 ° C

Elemental Analysis Value (C ₂₀ H ₂₇ N ₃ 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: melting point 110-112 ° C

Elemental Analysis Value (C ₁₄ H ₂₉ N ₃ 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 _{(C 16 H 26 N 4 O} 4 · 1/2 H 2 O)

Calculated (%): C; 55.32, H; 7.83, N; 16.13.

Found (%): C; 55.65, H; 7.94, N; 16.08.

Example 89

4-morpholinocarbonylmethyl-1- (2-pyrrolidone-5-carbonyl) homopiperazine: oily substance.

Elemental Analysis Value (C ₁₆ H ₂₆ N ₄ O ₄ )

Calculated (%): C; 56.79, H; 7.74, N; 16.56.

Found (%): 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 (C ₁₄ H ₁₆ N ₂ O ₂ )

Calculated (%): C; 68.83, H; 6.60, N; 11.47.

Found (%): C; 68.96, H; 6.56, N; 11.53.

Example 91

4-acetamide-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 234.5-236 ° C

Elemental Analysis Value (C ₁₂ H ₁₃ N ₃ O ₃ )

Calculated (%): C; 56.90, H; 7.56, N; 16.59.

Found (%): 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 Value (C ₂₃ H ₃₁ N ₅ 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-piperazinocarbonylmethyl-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 · 1/4 H 2 O)

Calculated (%): 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 ° C

Elemental Analysis Value (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 (C ₁₉ H ₂₇ N ₃ O ₂ )

Calculated (%): C; 69.27, H; 8.26, N; 12.75.

Found (%): C; 69.31, H; 8.14, N; 12.76.

Example 96

N- (2-pyrrolidone-5-carbonyl) piperazin-4-one: melting point 153-155 ° C

Elemental Analysis Value (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 (C ₁₅ H ₂₄ N0O ₅ 1/2 C ₂ H ₅ OH)

Calculated (%): C; 55.32, H; 7.83, N; 16.13.

Found (%): 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 Value (C ₁₈ H ₂₃ N ₃ 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-morpholinoacetyl-1- (2-pyrrolidone-5-carbonyl) homopiperazine fumarate: melting point 148-150 ° C

Elemental analysis _{(C 16 H 26 N 4 O} 4 · C 4 H 4 O 4 · 1/2 H 2 O)

Calculated (%): C; 52.34, H; 6.70, N; 12.21.

Found (%): 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 Value (C ₁₄ H ₂₂ N0O ₅ )

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-pyrrolidin-5-one: melting point 239-242 ° C

Elemental analysis _{(C 16 H 25 N 5 O} 4 · 1/2 CH 3 OH)

Calculated (%): C; 53.94, H; 7.41, N; 19.06.

Found (%): C; 54.33, H; 7.41, N; 19.11.

Example 102

4-piperidino-1- (2-pyrrolidone-5-carbonyl) piperazine: melting point 147-150 ° C

Elemental Analysis Value (C ₁₅ H ₂₅ N ₃ O ₂ )

Calculated (%): C; 64.49, H; 9.02, N; 15.04.

Found (%): 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 Value (C ₁₇ H ₂₁ N ₃ 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-cisdimethylpiperazine: melting point 177-181 ° C

Elemental Analysis Value (C ₁₂ H ₂₀ N ₂ O ₂ )

Calculated (%): C; 64.26, H; 8.99, N; 12.49.

Found (%): 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 (C ₁₅ H ₂₄ N ₄ O ₃ S · C ₄ H ₄ O ₄ )

Calculated (%): C; 49.99, H; 6.18, N; 12.27.

Found (%): 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 (%): 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 (C ₂₁ H ₂₈ N ₄ O ₅ )

Calculated (%): C; 60.56, H; 6.78, N; 13.45.

Found (%): C; 60.58, H; 7.70, N; 13.42.

As is evident from the above results, the compound of the present invention is useful as a therapeutic agent for dementia because it has a fragile effect on mammals including humans and is also low toxicity. It can be used as a therapeutic drug for senile dementia or as a therapeutic drug for dementia associated with mental retardation, encephalopathy, cerebral palsy, stroke, cerebral arteriosclerosis, head trauma and the like.

Claims (1)

Pyroglutamide derivatives represented by the following general formula (I) and their physiologically acceptable salts:

Wherein A represents a cyclic amino group and represents a substituted or unsubstituted piperidino, azino, azocino, piperazino, homopiperazino or tetrahydroisoquinolino, and these cyclic amino groups are alkyl, diarylalkyl , Aralkyl, aryl, hydroxyalkyl, hydroxy, alkanoyl, aralkylcarbonyl, aralkyloxycarbonyl, aralkenylcarbonyl, arylcarbonyl (aroyl), heterocyclic carbonyl, alkoxycarbonyl, Substituted by a substituent selected from the group consisting of aminoalkyl, aminoalkylcarbonyl, aminocarbonyl (carbamoyl), carbamoylalkyl, carbamoylalkylcarbonyl, oxo, heterocycle, aryloxyalkyl and alkanoylamino But A is not 2,2,6,6-tetramethylpiperidino, 3-hydroxypiperidino or 4-hydroxypiperidino, or unsubstituted piperidino.