JPH04202185A - Piperazine derivative and pharmaceutical preparation containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula [R1 to R4 are H, halogen, alkyl, alkoxy, aryl(oxy), cyano, carboxyl, tetrazoyl(alkyl), etc.; R5 is H, alkyl(oxycarbonyl) or acyl]. EXAMPLE:4-[(2-Carboxyphenyl)methyl]piperazine-2-carvone dihydrochloride. USE:An antagonist for NMDA (N-methyl-D-aspartic acid) receptor. Effective for psychiatric and locomotive insufficiency diseases caused as a sequela of Huntington's chorea, epilepsy, geriatric dementia and anoxia. PREPARATION:The objective compound can be produced by condensing piperazine-2-carboxylic acid ethyl ester with a substituted benzyl bromide in an anhydrous solvent (e.g. methylene chloride) in the presence of a base (e.g. trimethylamine).

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to novel piperazine derivatives.

Furthermore, the present invention provides NM containing the piperazine derivative.
This invention relates to DA receptor antagonists.

[Prior Art and Problems to be Solved by the Invention] In the brain and spinal cord of vertebrate animals, excitatory amino acids such as glutamic acid and 7-aspartic acid play an important role as neurotransmitters. Its receptor is at least NMDA (
It is said that there are three types: N-methyl-D-aspartic acid) type, quisqualic acid type, and kainate type. It has been shown to be effective in treating mental and motor deficiencies seen after senile dementia or anoxia (Jones et al., Neuroscience).
Letter (Neurosci, Lett, ), 45
．． 157-61 (1984), Matsukgale (E.

G., McGeer et al., Nature
), 263.517-19 (1976), Simon, R. et al., Science.
, 226.850-2 (1984)).

As a piperazine derivative with NMDA antagonistic activity, 3-
((1-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CP P) is known. However, due to its low rate of brain transfer, it has no significant effect when administered peripherally. I can't wait.

One of the recent methods to increase the rate of brain transfer is to increase the lipid solubility of compounds, and for this purpose, compounds that incorporate an aryl moiety into CPP (±
)-4-[(2-phosphonophenyl)methyl]-2-piperazinecarboxylic acid or (±)-4-[(3-phosphophenyl)methyl]-2-piperazinecarboxylic acid has been reported, The antagonistic effect on NMDA receptors is significantly reduced compared to CPP (Hais (3, J.
Hays et al., Journal of Medicinal Chemistry (J, Med, Chem, ), 33.291
6-2924 (1990)).

An object of the present invention is to provide a piperazine derivative having a highly fat-soluble aryl moiety in its molecule and having an antagonistic effect on N and MDΔ receptors, which solves the above-mentioned problems.

[Means for Solving the Problems] As a result of intensive studies on novel piperazine derivatives and NMDA receptor antagonism, the present inventors found that a novel piperazine derivative represented by the following formula (I) according to the present invention has NMD
The present invention was completed based on the discovery that it has an antagonistic effect on A receptors.

That is, what solves the above problems is a novel piperazine derivative represented by the following formula (I).

1<2 [In the formula, R,, R2, R3, and R4 are each a hydrogen atom,
Represents a halogen, an alkyl group, an alkoxy group, an aryl group, an aryloxy group, a cyano group, a carboxyl group, a tetrazoyl group, a phosphono group, a carboxyalkyl group, a tetrazoylalkyl group, or a phosphonoalkyl group, and R5 is a hydrogen atom or an alkyl group. , represents an alkyloxycarbonyl group or an acyl group. ] The present invention will now be described in detail.

The piperazine derivative of the present invention can be synthesized by a condensation reaction of piperazine-2-carboxylic acid ethyl ester and substituted benzyl bromide in an anhydrous solvent such as methylene chloride using a base such as trimethylamine. Compounds not described in each synthesis example can also be synthesized using the same method.

When the piperazine derivative of formula (I) is used as an NMDA receptor antagonist and a pharmaceutical preparation for treating a disease that responds to NMDA receptor antagonism, the dosage varies depending on the symptoms, but in general, the daily dose for adults is 0. The dose is 1 to 200 mg, preferably 1 to 100 mg, and should be administered in 1 to 3 divided doses depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible. The compound used in the present invention can be used as one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner to form a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection solution. It can be applied in various formulations such as. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like.

Next, the present invention will be specifically explained by showing synthesis examples and examples, but the present invention is not limited thereto.

[Example 1] Synthesis of 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1)
1. 755 g of 4-bis(phenylmethyl)piperazine-2-carboxylic acid ethyl ester was added to 100 ml of ethanol.
Palladium on carbon was added under an argon stream, the mixture was replaced with hydrogen, and the mixture was heated and stirred for 14 hours. After filtration, the filtrate was concentrated to obtain piperazine-2-carboxylic acid ethyl ester3.
50 g was obtained.

2) o4ruylic acid methyl ester4. 61 g of N-bromosuccinimide was dissolved in 30 ml of carbon tetrachloride, and 5.
46 g of perbenzoic acid and 025 g of perbenzoic acid were added thereto, and the mixture was heated under reflux for 1 hour. After filtration, the solvent was distilled off under reduced pressure to obtain 6.21 g of 2-bromomethylbenzoic acid methyl ester.

3) Piperazine-2-carboxylic acid ethyl ester 2.0
0g was dissolved in 20ml of methylene chloride, and 10ml of a methylene chloride solution of 1.28g of triethylamine was added.
Stir for minutes at room temperature. A solution of 2.90 g of 2-bromomethylbenzoic acid methyl ester in 10 ml of methylene chloride was
℃ under an argon stream for 15 minutes, and then at room temperature for 14 minutes.
Stir for hours. After adding water and extracting with methylene chloride,
After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The residue was subjected to Shikakel column chromatography, and the eluate fraction of chloroform:methanol=50:1 was concentrated to obtain 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester.
42g was obtained.

Spectroscopic data of the compound supports the structure of formula (n) below.

' H-N M R (CD C13) δ (ppm) 1,
17 (311,t, J=7.0Hz), 2.13(
IH, s), 2.03-3.03 (6H, m) 3, 3
0-3.53 (Ill m), 3.68 (IH, s)
, 3,82 (3H,s).

4, 12 (211,q, J=7.0Hz), 7.0
6-7, 80 (4H, m) [Example 2 Synthesis of 4-[(2-carboxylphenyl)methyl]piperazine=2-carboxylic acid dihydrochloride 4-[(2-methoxycarbonylphenyl)methylcopiperazine] -2-carboxylic acid ethyl ester 1.05 g
was dissolved in 30 ml of methanol, 3.45 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 21 hours.

After further heating and stirring at 50° C. for 18 hours, the solvent was distilled off under reduced pressure. The pH was adjusted to 3 by adding 1N hydrochloric acid, and the resulting residue was extracted with ethanol, and the solvent was distilled off under reduced pressure to obtain 4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride. 1.15 g of salt was obtained.

Spectroscopic data of the compound supports the structure of formula (m) below.

'H-NMR (D20) δ (ppm) 3, 28.4
．． 33 (711, m), 4.60 (2H, s), 7
．． 47-7, 75 (411, m) [Example 3] 4-[(2-Ethoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester ■) To 300 g of toluic acid was added 10 ml of thionyl chloride, and the mixture was heated at 60°C. The mixture was heated and stirred for 20 minutes. 17 ml of ethanol was added dropwise at room temperature, and the mixture was heated and stirred at 80° C. for 2 hours, then water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by vacuum distillation to obtain 2.34 g of o-toluic acid ethyl ester.
(bp, 70°C (0.2 mml 1 g)) was obtained.

2) Dissolve 100 g of o-toluic acid ethyl ester in 10 ml of carbon tetrachloride, and dissolve 1.0 g of N-bromosuccinimide.
9 g, and perbenzoic acid 74. Add Qmg, 1.5
The mixture was heated to reflux for an hour. After filtration, the solvent was distilled off under reduced pressure to obtain 1.53 g/l of 2-bromomethylbenzoic acid ethyl ester.

3) Piperazine-2-carboxylic acid ethyl ester 1.2
4 g was dissolved in 6 ml of methylene chloride, 4 ml of a methylene chloride solution of 792 mg of triethylamine was added, and 10 ml of a methylene chloride solution of 190 g of 2-bromomethylbenzoic acid ethyl ester was added dropwise at 0° C. under an argon stream.

The mixture was added dropwise at 0° C. for 3 hours, and then stirred at room temperature for 14 hours. After adding water and extracting with methylene chloride, anhydrous sulfuric acid l-I
After drying with Jum and filtering, the solvent was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (
=t L , the chloroform:methanol-501 elution fraction was concentrated to obtain 1.37 g of 4-[(2-ethoxocarponylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester. Spectroscopic data of the compound supports the structure of formula (IV) below.

'H-NMR (CDC13) δ (ppm) 1.19
(311,t, J=7.011z), 1.37(3
11,t, J=7.01lz).

2, 07-3.10 (711, m), 3.35-3.
62 (1,1+, m), 3.70-3.98 (21
+.

m),, 4.12(211,q, J=7.0)Iz
), 4.30 (211,q, J=1.01lz).

7, 09-7.75 (4H, m) [Example 4-4-[(2-methoxycarboxylphenyl)methyl]
-Synthesis of 1-methylpiperazine-2-carboxylic acid ethyl ester 500 mg of 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester was dissolved in 20 ml of toluene, and under an argon atmosphere, 1211 ng of potassium carbonate, and 260 mg of methyl iodide were added.

After heating and stirring at 0° C. for 20 hours, water was added and extracted with toluene-ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the chloroform eluate fraction was concentrated to give 4-[(2-methoxycarboxylphenyl)
204 mg of methyl]-1-methylpiperazine-2-carboxylic acid ethyl ester was obtained.

Spectroscopic data of the compound supports the structure of formula (V) below.

IH-NMR (CDC13) δ (ppm) 1, 22 (3
11,t, J=7.01lz), 2.07-3.1
7 (1011, m).

3, 63-3.90 (21+, m), 3.88 (3
tl,,s), 4.16(2H,q, J=7.0H
z), 7.07-7, 87 (4H, m) [Example 5] Synthesis Example 2 of 4-[(2-carboxyphenyl)methyl]-1-methylpiperazine-2-carboxylic acid dihydrochloride and Using a similar method, 204 mg of 4-[(2-methoxycarbonylphenyl)methyl]-1-methylpiperazine-2-carboxylic acid ethyl ester, 0.64 ml of 2N aqueous sodium hydroxide solution, and 10 ml of methanol were added.
1 as a solvent, 223 mg of 4-[(2-carboxyphenyl)methyl]-1-methylpiperazine-2-carboxylic acid dihydrochloride was obtained.

Spectroscopic data of the compound supports the structure of formula (VI) below.

IH-NMR (D20) δ (ppm) 2,92 (3H, s), 3.30-4.04 (6H,
m), 4.17-4.47 (IH, m).

4, 49 (211, s), 7.17-8.00 (4H
, m) [Example 6] Synthesis of 4-[(2-ethoxycarbonylphenyl)methyl-1-todecylpiperacine-2-carboxylic acid ethyl ester 4-[(2-ethoxycarbonylphenyl)methyl]-
Piperazine-2-carboxylic acid ethyl ester 100mg
was dissolved in 3 ml of toluene, 24 mg of potassium carbonate was added, and 2 ml of a toluene solution of 548 mg of lauryl bromide was added dropwise under an argon stream. After heating under reflux for 5 days, water was added and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography, and the hexane:ethyl acetate=10+1 eluate fraction was concentrated to give 4-[(2-
ethoxycarbonylphenyl)methylco-1-dodenolpiperazine-2-carboxylic acid ethyl ester 130m
I got g.

Spectroscopic data of the compound supports the structure of the following formula (■).

IH-NMR (D20) δ (ppm) 0, 58-1
．． 64 (291, m), 2.27-3.03 (9) 1
．． m).

3, 62-3.92 (2H, m), 4.12 (2H,
'q, J=7.01lz).

4, 31 (2+1.q, J=7.01lz), 7
．． 17-7, 80 (411, m) [Example 7 Synthesis of 4-[(2-carboxyphenyl)methyl]-1-dodenrubiperazine-2-carboxylic acid dihydrochloride Procedure similar to Example 2 4-[(2-ethoxycarbonylphenyl)methyl]-1-dodecylpiperazine-2-
Using 130 mg of carboxylic acid ethyl ester, 0.27 ml of 2N aqueous sodium hydroxide solution, and 7 ml of a 6:1 solution of methanol and water as a solvent, 4-[(2-carboxyphenyl)methyl]-1-dodecylpiperazine-2 was prepared.
-Carboxylic acid dihydrochloride 125 mg was obtained.

=15- The spectroscopic data of the compound supports the structure of the following formula (■).

' H-N M R (D 20 ) δ (ppm) 0, 6
6-1.56 (2511, m)', 2.9'O-5,
26 (911, m).

? , '23-8.33 (4) 1. m), 10.75
(211, br s) [Example 8] 1-tert-Butoxycarbonyl-4-[(2-methoxycarbonylphenyl)methyl]-piperazine-2-
Synthesis of carboxylic acid ethyl ester 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1.50 g
10 ml of a methylene chloride solution containing 595 mg of triethylamine was added to 20 ml of a methylene chloride solution at 0°C under an argon stream, and the mixture was stirred for 10 minutes. secondary acid ter
Add 118 g of t-butyl and 20 ml of methylene chloride,
The mixture was stirred at room temperature for 1 hour. After adding water and extracting with methylene chloride, the organic layer was dried over anhydrous thorium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1-tert-butoxycarbonyl-4-
[1.69 g of (2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester was obtained.

Spectroscopic data of the compound supports the structure of formula (IX) below.

'H-NMR (CDC13) δ (ppm) 1, 16 (3
H,t, J=7.0Hz), 1.56(911,s
), 2.05-3.78 (611, m), 3.85
(311,s), 4.14(211,q, J=7.
0Hz).

4, 33-4.73 (1) 1. m>, 7.23-7
．． 83 (411, m) [Example 9 Synthesis of 1-tert-butoxycarbonyl-4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid
-Methoxycarbonylphenyl)methylcopiperazine-
1.69 g of 2-carboxylic acid ethyl ester was dissolved in 30 ml of methanol, 4.17 ml of 2N aqueous sodium hydroxide solution and 5 ml of water were added, and the mixture was stirred at room temperature for 16 hours. After further heating under reflux for 24 hours, the solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with methylene chloride. Dry over anhydrous sodium sulfate, filter and concentrate to obtain 1-tert-butoxycarbonyl-4-[(2
984 g of -carboxyphenyl)methylcopiperazine-2-carboxylic acid were obtained.

Spectroscopic data of the compound supports the structure of formula (X) below.

'H-NMR (CDC13) δ (ppm) 1, 45 (9
H, s), 2.30-4.00 (6H, m), 4.
13 (2H, br s).

4, 60-5.00 (LH, m), 7.10-8.2
0 (4H, m).

10,25(211,br s) [Example 10] 1-tert-butoxycarbonyl-4-([2-(5
-Methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-
Synthesis of dioxolen-4-yl) methyl ester 285 mg of 1-tert-butoxycarbonyl-4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid was dissolved in 5 ml of N,N-dimethylformamide, and 119 mg of potassium carbonate was dissolved. , and 4-bromomethyl-5-methyl-2-oxo-1,3-dioxolene 33
5 ml of a 2 mg N,N-dimethylformamide solution was added, and the mixture was stirred at room temperature for 16 hours at 0° C. under an argon stream. After adding water and extracting with ethyl acetate, the mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane:vinegar=
Ethyl 19-acid = 11 elution fractions were concentrated to give 1-tert-butoxycarbonyl-4-([2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylco). methyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-4
-yl) methyl ester (940 mg) was obtained.

Spectroscopic data of the compound supports the structure of formula (X[) below.

' H-N M R (CD C13) δ (ppm) 1,
44 (911, br s), 1.86-4.97 (f
ill, m), 2.13 (3H, s).

2, 23 (3H, s), 4.99 (21+, s),
7.06-7, 79 (4H, m).

[Example 11] 4-f[2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-
Synthesis of oxo-1,3-dioxolen-4-yl)methyl ester 1-tert-butoxycarbonyl-4-[
[2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)
Piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester 9
Add 4 ml of trifluoroacetic acid to 4.0 mg and incubate at room temperature for 30 minutes.
After stirring for 0 minutes, it was concentrated.

After adding water to the residue, the pH was adjusted to 9 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with methylene chloride. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4-[[2-(
5-Methyl-2-oxo-1,3-dioxolene-4-
yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester 62.5m
I got g.

Spectroscopic data of the compound supports the structure of the following formula (X[[).

'H-NMR (CDC7!3) δ (ppm) 1,87-
5.00 (12) 1. m), 2.13 (311,s
), 2.23 (3H, s).

5, 03 (211, s), 6.90-7.83 (41
1,m) [Example 12] 1-tert-butoxycarbonyl-4-[[2-(1
-Synthesis of methylpiperidine-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 1-
tert-butoxycarbonyl-4-[(2-carbonylphenyl)methylcopiperazine-2-carboxylic acid 10
0mg.

3-hydroxy-1-methylpiperidine 66, 4 mg,
119 mg of dicyclohexylcarbodiimide and 6 to 7 mg of dimethylaminopyridine were added to 18 ml of chloroform.
and stirred at room temperature for 45 hours. After adding water and extracting with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform
Methanol: 28% ammonia solution = 100: 15
: 1 elution fraction was concentrated and 1-tert-butoxycarbonyl-41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-
52.1 mg of 2-carboxylic acid was obtained.

Spectroscopic data of the compound supports the structure of formula (XI) below.

'H-NMR (CDC7!3) δ (ppm) 1, 4
1 (9H1s), 2.38 (3H,s), 1.13
-4.15 (16H, m).

4, 25-4.55 (1) 1. m), 4.85-5
．． 32 (IH, m).

7,05-7.92(IH,m) [Example 13] Synthesis of 41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 1-tert-butoxy Carbonyl-41[2-(1-
Methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 52.1mg
3 ml of trifluoric acid was added to the solution, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, water was added, and the solution was adjusted to pl+7 with an aqueous sodium hydrogen carbonate solution and concentrated again. The residue was extracted with ethanol, filtered, and the solvent was distilled off under reduced pressure to obtain 41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-
40.7 mg of carbonic acid was obtained.

Spectroscopic data of the compound supports the structure of formula (XIV) below.

IH-NMR (D20) δ (ppm) 1, 88-4.70 (1611, m), 3.02 (3
11, s), 5.27-5.80 (211, m).

7, 30-8.17 (4 tl, m) [Example 14] Synthesis of 4-[(4-chloro-2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1) 2-bromo-5 -1.03 g of chlorotoluene was dissolved in 5 ml of ether, and n-butyllithium (1,6M hexane solution) was added dropwise over 10 minutes at 0° C. under an argon stream, followed by stirring at room temperature for 2 hours. After adding excess dry ice and stirring, 2N hydrochloric acid was added to make it acidic.

After making the mixture alkaline with an aqueous sodium hydroxide solution, the aqueous layer was washed with ether, acidified again with hydrochloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 473 mg of 4-chloro-2-methyl-benzoic acid.

2) 10 ml of methanol saturated with hydrochloric acid gas was added to 4-chloro-2-methyl-benzoic acid, and the mixture was heated under reflux for 21 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with methylene chloride was concentrated to obtain 6 mg of 4-chloro-2-methylbenzoic acid methyl ester.

3) 4-chloro-
446 mg of 2-methylbenzoic acid methyl ester was converted into N-
430 mg of bromosuccinimide and 30 mg of perbenzoic acid
．． Using Qmg and using 10ml of carbon tetrachloride as a solvent,
626 mg of 2-bromomethyl-4-chlorobenzoic acid methyl ester was obtained.

4) Piperazine-
4-[(4-chloro-2
-Methquincarbonylphenyl)methylcopiperazine-
412 mg of 2-carboxylic acid ethyl ester was obtained.

Spectroscopic data of the compound supports the structure of formula (Xv) below.

'H-NMR (CDCL!3) δ (ppm) 1, 22 (
3H, t, J=7.0llz), 2.12(Ill,
brs).

2, 25-3.15 (611, m), 3.38-3.
62 (ltl, m).

3, 72-3.83 (2H, m), 4.17 (2H,
q, J=7.0tlz).

7, 12-7.75 (311, m) [Example 15 Synthesis of 4-[(2-calhoquino-4-chlorophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Example 2
Using the same method as above, 265 mg of 4-[(4-chloro-2-methquincarbonylphenyl)methylcopiperazine-2-carphonic acid ethyl ester, 0.78 ml of 2N aqueous sodium hydroxide solution, 5 ml of methanol,
Using 1 ml of water as a solvent, 289 mg of 4-[(2-carboxy-4-chlorophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride was obtained.

Spectroscopic data of the compound supports the structure of formula (nq) below.

'H-NMR (D20) δ (ppm) 3, 35-4.28 (6111m), 4.38-4.
8'0 (311, m).

7, 45-8.15 (311, m) [Example 16] Synthesis of 4-[1-(2-methoxycarbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester 1
) 1-bromo-
Using 5.43 g of 2-ethylbenzene, 25.3 ml of n-butyllithium (1,6M hexane solution), and excess dry ice, 20 ml of ether was used as a solvent.
209 g of 2-ethylbenzoic acid was obtained.

2) By the same method as in Example 14-2), 1.66 g of 2-ethylbenzoic acid methyl ester was obtained using 2.00 g of 2-ethylbenzoic acid and 30 ml of methanol saturated with hydrochloric acid gas.

3) Example] 2-ethylbenzoic acid methyl ester 1. ．． 66 g of N-bromosuccinimide], 80 g of perbenzoic acid, and 122 mg of perbenzoic acid were used to obtain 2.88 g of 2-(1-bromoethyl)benzoic acid methyl ester using 20 ml of carbon tetrachloride as a solvent.

4) Piperazine-
4-[1-(2-methoxy 180 g of carbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester was obtained.

The spectroscopic data of the compound supports the structure of the following formula (X■).

'H-NMR (CDC13) δ (ppm) 1, 03-1
．． 37 (311, m), 1.27 (311, t, J
=6.811z).

2, 00-3.17 (611, m), 2.12 (]I
t, s), 3.30-3.67 (IIl, m).

3, 87 (3H, s), 3.90-4.48 (3H,
m, ), 7.03-7.82 (411, m) [Example 17 Synthesis of 4-[1,-(2-carboxyphenyl)ethylcopiperazine-2-carphonic acid dihydrochloride Example 2 and Using the same method, 500 mg of 4-[1-(2-methoxycarbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester and 1.56 ml of 2N sodium hydroxide aqueous solution were used, and 5 ml of methanol was used.
4-[1-(2-carboxyphenyl)ethylcopiperazine-2-carboxylic acid dihydrochloride 539
mg was obtained.

The spectroscopic data of the compound supports the structure of the following formula (X■).

' H-N M R (D 20 ) δ (ppm) 1, 6
6 (311, d, J=7.0Hz), 3.13-4
．． Cl0(611,m).

4, 13-4.57 (ltl, m), 4.93-5
．． 77 (IIl, m).

7, 23-7.97 (4H, m) [Example 18 Synthesis of 4-[1-(2-methoxycarbonylphenyl)butylcopiperazine-2-carboxylic acid ethyl ester 1
) By the same method as in Example 14-2), 477 mg of 2-n-butylbenzoic acid methyl ester was obtained using 827 mg of 2-n-butylbenzoic acid and 100 ml of methanol saturated with hydrochloric acid gas.

2) Using the same method as in Example 1-2), 477 mg of 2-n-butylbenzoic acid methyl ester, 442 mg of N-bromosuccinimide, and 30.0 mg of perbenzoic acid were added. ．． 1
2-(
l-promorobenzoic acid methyl ester 67
2 mg was obtained.

3) Piperazine-
392 mg of 2-carboxylic acid ethyl ester, 251 mg of h-ethylamine, and 2-(1-bromo-n-
4-[1-(2-methoxycarbonylphenyl)butylcopiperazine-2-
385 mg of carboxylic acid ethyl ester was obtained.

Spectroscopic data of the compound supports the structure of formula (XIX) below.

'H-NMR (CDCl2) δ (ppm) 0, 70-1
．． 45 (IOH, m), 2.13-3.20 (711
, m).

=34-3, 28-3.60 (LH, m), 3.83 (38,
s), 3.83-4.35 (6H, m).

7.03-7.70 (4H, m) [Example 19] Synthesis of 4-O-(2-carboxyphenyl)butylcopiperazine-2-carboxylic acid dihydrochloride By the same method as in Example 2, 4 -[1-(2-Methoxycarbonylphenyl)butylcopiperazine-2-carboxylic acid ethyl ester 385 mg and 2N aqueous sodium hydroxide solution 0.55 ml were used in methanol.
5 ml of 4-[1-(2-carboxyphenyl)butylcopiperazine-2-carboxylic acid dihydrochloride 4 as a solvent.
20 mg was obtained.

Spectroscopic data of the compound supports the structure of formula (XX) below.

'14-NMR(D20)δ(ppm)0,
83-1.20 (511, m), 1.90-2.50
(21+, m).

3, 30-4.10 (6H, m), 4.35-5.2
0(2H, m), .

7, 45-8.17 (4H, m) [Example 20] 4-[1-(2-methoxycarbonylphenyl)-4-
Synthesis of methylpentylcopiperazine-2-carboxylic acid ethyl ester 1) 2-(4-
2-(4-
Methyl-n-pentyl)benzoic acid methyl ester 240
mg was obtained.

2) By the same method as in Example 1-2), 190 m of 2-(4-methyl-n-pentyl)benzoic acid methyl ester
g.

Using 154 mg of N-bromosuccinimide and 10.0 mg of perbenzoic acid, and using 5 ml of carbon tetrachloride as a solvent, 258 mg of 2-(1-bromo-4-methyl-n-pentyl)benzoic acid methyl ester was obtained. .

3) Piperazine-
136 mg of 2-carboxylic acid ethyl ester, 87.0 g of triethylamine, and 2-(1-bromo-4-
Methyl-n-pentyl)benzoic acid methyl ester 258
4-mg using 10 ml of methylene chloride as a solvent.
[129 mg of 1-(2-methoxycarbonylphenyl)-4-methylpentylcopiperazine-2-carboxylic acid ethyl ester was obtained.

The spectroscopic data of the compound is based on the structure of the following formula (xn).
NMR (CDC13) δ (ppm) '0, 8
5 (6H, d, J=5.8Hz), 1.00-3.
10 (1511, m).

3, 35-3.60 (LH, m), 3.88 (3H,
s).

3, 88-4.45 (30, m), 7.06-7, 8
0(4H,m) [Example 21] 4-[1-(2-carboxyphenyl)-4-methylpentyl.

Synthesis of 4-[1-(2-methoxycarbonylphenyl)-4-methylpentylcopiperazine-
Using 129 mg of 2-carboxylic acid ethyl ester and 0.341 ml of 2N aqueous sodium hydroxide solution and 5 ml of methanol as a solvent, 4-[1-(2-carboxyphenyl)-4-methylpentyl]piperazine-2-
13 buttons 1 of carboxylic acid dihydrochloride were obtained.

The spectroscopic data of the compound has the structure IH-
NMR (D20) δ (ppm) 0, 85 (6H, d, J=5.8Hz), 0.88
-2.50 (5H, m).

3.30-4.10 (611, m), 4.35-5.
20 (2H, m).

7, 40-8.10 (411, m) [Example 22] 4-[(2-cyanophenyl)methylcopiperazine-2
- Synthesis of carboxylic acid dihydrochloride 1) Using the same method as in Example 1-2), 0.48 g of 0-tolunitrile, 0.72 g of N-bromosuccinimide
Using 20 mg of benzoyl peroxide, 0.76 g of 2-(bromomethyl)benzonitrile was obtained.

2) Piperazine-
Using 429 mg of 2-carboxylic acid ethyl ester, 523 mg of 2-(bromomethyl)benzonitrile, and 300 mg of triethylamine, 4-[(2-cyanophenyl)
Methylcopiperadiate di2-carboxylic acid ethyl ester 4
14 mg was obtained.

3) By the same method as in Example 2, 4-(2-cyanophenyl)piperazine-2-carboxylic acid ethyl ester 1
34mg, 2N sodium hydroxide aqueous solution 0.25m
1 was used to obtain 148 mg of 4-[(2-cyanophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride.

Spectroscopic data of the compound supports the structure of formula (XXI) below.

' H-N M R (D 20 ) δ (ppm) 2, 8
5-3.75 (611, m), 3.85-4.05 (
II (, m).

4, 15 (2H, s), 7.40-7.85 (411
, m) [Example 23] 1-tert-butoxycarbonyl-4-[[2-(1
(2) Synthesis of ethylnisuel H-tetrazol-5-yl)phenylcomethyl)piperazine-2-carboxylate 1
) By the same method as in Example 8, 1-(te
348 mg of ethyl 2-carboxylic acid rt-butoxycarbonyl)-4-[(2-cyanophenyl)methylcopiperadiate was obtained.

2) 1-(tert-butoxycarbonyl)-4-[
A mixed solution of 348 mg of (2-cyanophenyl)methylcopiperadiate 2-2-carboxylic acid ethyl ester and 625 mg of tributyltin azide was stirred at 80° C. for 24 hours.

After adding 6N hydrochloric acid and extracting with ether, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and the methylene chloride/methanol-100.1 eluate fraction was concentrated to give 1-t4O
- ert-butoxycarbonyl-4-f[2-(1(2)
234 mg of ethylnisyl H-tetrazol-5-yl)phenylcomethyl)piperazine-2-carboxylate was obtained.

The spectroscopic data of the compound is 'H-
NMR (CDC7!3) δ (ppm) 1, 16 (3H,
t, J=7.0llz), 1.50 (9H, s).

2, 20-4.45 (811, m), 4.85 (il
l, br s).

7, 25-7.70 (3H, m), 8.10-8.4
0(LH, m).

14,0(LH,br s) [Example 24] 4-([2-(1(2)H-tetrazol-5-yl)
Synthesis of phenylcomethyl)piperazine-2-carboxylic acid 1-tert-butoxy-4-+[2-(1(2)H-
10 ml of 6N hydrochloric acid was added to 234 mg of tetrazol-5-yl)phenylcomethyl)piperazine-2-carphonic acid ethyl ester, and the mixture was heated under reflux for 20 hours. Under reduced pressure
The solvent was distilled off to obtain 181 mg of 4-4[2-(1(2)H-tetrazol-fanyl)phenylcomethyl)piperazine-2-carboxylic acid.

The spectroscopic data of the compound is ' H of the following formula (XXV)
-NMR(D20)δ(ppm)3,50-4
．． 20 (611, m), 4.40-4.75 (3H,
m).

7, 65-8.17 (411, m) [Example 25] Synthesis of 4-[(3-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Piperazine-2-carboxylic acid dihydrochloride 250 mg, 3
- After stirring a mixed solution of 282 mg of methyl (bromomethyl)benzoate and 3.95 ml of 2N aqueous sodium hydroxide solution at 70°C for 24 hours, 1N hydrochloric acid was added, and the formed crystals were collected by filtration and washed with a small amount of water. , and dried under reduced pressure to obtain 222 mg of 4-[(3-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride.

Spectroscopic data of the compound supports the structure of formula (XXV) below.

'H-NMR (D20) δ (ppm) 3, 30-3.95 (6H, m), 4.30-4.7
0 (311, m).

7, 30-8.05 (411, m) [Example 26 Synthesis of 4-[(4-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Piperazine-2-carboxylic acid dihydrochloride 252 mg, 4
4-[(4-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride was prepared in the same manner as in Example 25 using 264 mg of -(bromomethyl)benzoic acid and 3.05 ml of 2N sodium hydroxide aqueous solution. 83 mg was obtained.

Spectroscopic data of the compound supports the structure of formula (XXV) below.

-44 = IH-NMR (D20) δ (ppm) 3, 30-3
．． 94 (611, m), 4.30-4.70 (3H,
m).

7, 10(211,d, J=8.0)1z); 7.
60 (211, d, J=8.0llz) [Example 27
NMDA (N-methyl-D-aspartic acid)-induced spasm suppression effect A solution of NMDA (N-methyl-D-aspartic acid) dissolved in physiological saline and each piperazine derivative according to the present invention are added to physiological saline. The dissolved solutions were mixed 1-1, and 10 μm of the solution was directly administered into the ventricles of mice using a microsyringe. At this time, the amount of NMDA was adjusted to 0.32 μg and each piperazine derivative was adjusted to 3.2 μg to 100 μg.

The time of convulsion induction when each piperazine derivative was administered simultaneously was measured to determine the strength of NMDA antagonism. The results are shown in Table 1.

[Comparative Example] 0.32++g of NMDA was administered alone into the ventricles of mice. The results are shown in Table 1.

As shown in Table 1, the compounds (m), (X■
), (Xll), (XX), and (XXV) exhibited excellent NMDA receptor antagonism.

Although not listed in Table 1, other compounds related to the present invention also exhibited similar excellent NMDA receptor antagonism.

[Acute Toxicity] Even when the piperazine derivative according to the present invention was administered intraperitoneally to male ICR mice at 1000 mg/kg, no toxicity, including a decrease in body weight, was observed.

[Effects of the Invention] As described above, the present invention provides a novel piperazine derivative represented by the above formula (1), and since the piperazine derivative has an excellent NMDA antagonistic effect, pharmaceuticals containing this as an active ingredient can be obtained. The formulation is effective as an NMDA receptor antagonist.

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1, R_2, R_3, and R_4 are hydrogen atoms, halogens, alkyl groups, alkoxy groups, aryl groups, and aryloxy groups, respectively. group, cyano group, carboxyl group,
Tetrazole group, phosphono group, carboxyalkyl group,
It represents a tetrazole alkyl group or a phosphonoalkyl group, and R_5 represents a hydrogen atom, an alkyl group, an alkyloxycarbonyl group, or an acyl group. ] A piperazine derivative represented by the following, and an ester form of the compound. (2) NM containing the piperazine derivative according to claim 1
DA (N-methyl-D-aspartate) receptor antagonist.