JP2679872B2 - Brain dysfunction improving agent containing N-substituted piperazine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel N-substituted piperazine derivative which has an action of improving cerebral dysfunction in mammals and thus has a medical effect of improving various symptoms due to cerebral dysfunction. The present invention relates to an agent for improving brain dysfunction, which is contained as an active ingredient.

2. Description of the Related Art Generally, mammals, especially human brain tissues, have higher oxygen demand than resistant organ tissues, and therefore the brain is extremely sensitive to oxygen deficiency caused by ischemia of the brain. Is said. Therefore, a compound having an action of protecting the brain from anoxia (blood oxygen deficiency) that occurs in the brain due to cerebral ischemia and the like and a state of insufficient oxygen in the brain is useful as a cerebral dysfunction improving agent.

Senile dementia is said to be caused by a disorder of brain function caused by cerebrovascular disorder or energy metabolism disorder in the brain.
Conventionally, various drugs have been developed as anti-dementia drugs. However, the present situation is that the mechanism of senile dementia, the memory disorder caused by cerebrovascular disorder, and the mechanism of occurrence of the memory disorder have not yet been clarified. The method of finding effective pharmaceutical compounds for these diseases is not yet well established. Memory impairment in normal animals (Amnesia
As a method of inducing amnesia), there is a method of administering a drug or an anticholinergic drug that inhibits the synthesis of nucleic acid or protein, or a method of adding a brain anoxia or an ischemic load. Attempts have been made to develop a drug for improving or preventing memory impairment by using an experimentally induced model animal of Amnesia. Also, by placing under low pressure or normal pressure under oxygen deficient conditions, that is, using a model animal having brain anoxia caused by the loading of oxygen-deficient conditions, it has the effect of reducing the adverse effects of brain anoxia and thus Attempts have also been made to develop compounds that are effective in improving cerebral circulation metabolism or energy metabolism in the brain (for example, "Nippon Pharmacology").
85 , pages 323 to 328 (1985); 86 , pages 445 to 456 (1986); JP-A-54-117468 and corresponding US Pat. No. 4,369,
139).

On the other hand, an excessive increase in the concentration of calcium ions in brain nerve cells is caused by various intracellular lipases (phospholipase A).
₂ )) and proteolytic enzymes are activated to decompose the lipids that compose the cell membrane, the protein lining the cell membrane, and the like, which are known to cause impairment of nerve cell function. Therefore,
A compound having an effect of suppressing the uptake of calcium ions into the inner membrane of the brain nerve cell can be expected as a useful brain cell protective agent.

Further, in a sample of cerebral blood vessels extracted from the brain of a mammal, a compound having an action of significantly suppressing the contraction of blood vessels can also be expected as a cerebral dysfunction improving agent [Stefanovich, et al. "Durg Develop. Res." 6 , 327, (1985) and Grome, et al., "Durg Develop. Res." 5 , 111, (1985)].

Furthermore, after administration of the test compound, when the ischemic state is induced in the entire brain by stopping the flow of blood in the carotid artery of the mammal, brain cells vulnerable to the ischemic state in the brain Compounds that have the effect of reducing the necrosis rate of brain cells, that is, the effect of protecting brain cells during ischemia, can also be expected as agents for improving brain dysfunction [Izumiyama, K. et al. "Acta Neurol. Scand." 78 : 2
14-200, (1988), (Effects of dihydroer-gotoxine
mesylate on delayed neuronal death in the gerbil
hippocampus.)]].

In recent years, with the increase of old-age artificial art, there is a strong demand for an effective drug for preventing or treating brain dysfunction in elderly people. The present inventors have conducted various studies in order to meet these demands. An object of the present invention is to provide a novel compound having a cerebral circulation-improving effect and / or a brain cell-protecting effect, which has an improving effect on dysfunction of the brain of mammals, particularly humans.

DISCLOSURE OF THE INVENTION The present inventors have earnestly studied for the above object. As a result, most of the compounds represented by the following general formula (I) succeeded in creating a novel N-substituted piperazine compound. In addition, these novel compounds show an excellent protective action against mammalian brain anoxia, an inhibitory action on calcium uptake into brain inner membrane of nerve cells and / or a protective action on brain cells, and also in the isolated cerebral blood vessel specimen, vascular contraction It was found that it showed a significant inhibitory action against. Therefore, the N-substituted piperazine derivatives represented by the following general formula (I) have, as their medical effects, improvement of cerebral circulation by expansion of cerebral blood vessels and reduction of vascular resistance, and prevention and treatment of vasospasm and cerebral ischemia. It has been found that the drug is expected to exert hardening such as prevention and treatment of necrosis of cells in the cervical region, and further prevention of hardening of cerebral arteries. The present invention has been completed based on these findings.

That is, the present inventors have made general formula (I) [In the formula, m is an integer of 2 or 3, R ^a and R ^b may be the same or different from each other, and each is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. And
Z and Y are not the same as each other, and Z is (In the formula, n is an integer of 2 to 4, and R ¹ is a benzyl group, a halogen-substituted benzyl group, a phenyl group, or a carbon number of 1 to 1.
A linear or branched alkyl group having 6 or 1 to 6 carbon atoms
A substituted phenoxyalkyl group represented by the formula 6 below, wherein R ² and R ³ may be the same or different and each is a hydrogen atom or a halogen atom; (In the formula, p is an integer of 0 to 3, two R ^{7 s} may be the same or different from each other, and each is a hydrogen atom or a halogen atom), a ω, ω-diphenylalkyl group or formula (In the formula, n is an integer of 2 to 4, two R ^{8 s} may be the same as or different from each other, and each is a hydrogen atom, a halogen atom, a hydroxy group, or a linear or branched C 1-6 group. A branched alkyl group or an alkoxy group having 1 to 6 carbon atoms) represented by the formula ω-naphthyloxyalkyl group or the following formula (Wherein t is an integer of 1 to 4 and R ¹ , R ² and R ³ each have the same meaning as described above).
It is ω- phenylalkyl group; and Y is a hydrogen atom or a (C ₁ ~C ₈₎ alkyl or hydroxy (C ₁ ~C ₆₎ alkyl or (C ₁ ~C ₆₎ alkoxycarbonyl (C ₁ -C ₆ )
Alkyl group or 2-oxopyrrolidino-1-acetyl group of 2-oxopyrrolidino-1-carbonylmethyl group of (In the formula, R ⁴ , R ⁵ and R ⁶ may be the same or different from each other, and each is a hydrogen atom or a (C ₁ -C ₆ ) alkoxy group, provided that R ⁴ , R ⁵ and R ⁶ are all at the same time. A substituted benzyl group (which may not be hydrogen) or (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ have the same meanings as described above) or a ω-hydroxy-ω-phenylalkyl group represented by the following formula: (Wherein p is an integer of 0 to 3 and R ⁷ is a hydrogen atom or a halogen atom), a ω, ω-diphenylalkyl group or the following formula (Wherein r is an integer of 0 to 2 and R ⁴ , R ⁵ and R ⁶ have the same meanings as described above), a substituted benzoyl group or a substituted benzoylalkyl group or the following formula (In the formula, r is an integer of 0 to 2, R ^c , R ^d and R ^e are each a hydrogen atom or a (C ₁ -C ₆ ) alkoxy group or a halogen atom, and R ^f is a hydrogen atom or (C ₁ -C ₆ ) alkyl group, provided that when R ^f is an alkyl group, r is zero, but when r is an integer of 1 to 2, R ^c , R ^d and
Ω-hydroxy-ω represented by any two or three of R ^e are not simultaneously C _{1 to} C ₆ ) alkoxy groups)
-Substituted phenylalkyl group or the following formula (In the formula, q is an integer of 1 to 2, and R ^g , R ^h , and R ^j are each a hydrogen atom, a hydroxy group, a (C ₁ -C ₆ ) alkyl group, or a (C ₁ -C ₆ ) alkoxy. Group, provided that when q is 1, at least one of R ^g , R ^h and R ^j is a hydroxy group or an alkyl group). (In the formula, q is an integer of 1 to 2, R ⁴ , R ⁵ and R ⁶ each have the same meaning as described above, and R ^k is a (C ₁ -C ₆ ) alkyl group). ω-hydroxy-ω-alkyl-ω-
A phenylalkyl group, provided that m is an integer of 2 and Z is A ω, ω-diphenylalkyl group represented by the formula (wherein R ⁷ is a hydrogen atom), and p is 0, Y
Is (Wherein q is an integer of 1 and R ⁴ , R ⁵ and R ⁶ have the same meanings as described above) or a ω-hydroxy-ω-phenylalkyl group or the following formula (In the formula, r is an integer of 2, and R ^c , R ^d , R ^e and R ^f have the same meanings as described above), and is not a ω-hydroxy-ω-substituted phenylalkyl group, When m is an integer of 2, Z is the aforementioned ω, ω-diphenylalkyl group (R ⁷ is a hydrogen atom), and p is 2, Y is the following formula: (Wherein R ⁴ , R ⁵ and R ⁶ have the same meaning as defined above) and cannot be a substituted benzyl group]
This time, we succeeded in synthesizing a substituted piperazine derivative or a pharmaceutically acceptable oxidized salt thereof.

Examples of the above-mentioned pharmacologically acceptable oxidative addition salts include, for example, pharmacologically acceptable inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and formic acid, acetic acid, propionic acid, Addition of pharmacologically acceptable organic acids such as succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, benzoic acid, salicylic acid, and methanesulfonic acid, as well as amino acids such as aspartic acid and glutamic acid. There is salt.

The compound of the general formula (I) exhibits an action of protecting the brain from a decrease in brain function in the state of oxygen deficiency,
In addition, it shows the action of suppressing the contraction of cerebral blood vessels, and shows the action of suppressing the uptake of calcium ions into cerebral nerve cells,
Furthermore, it is particularly sensitive to cerebral anoxia, and has an action of protecting brain cells in the hippocampal region of the brain from necrosis.From these facts, the compound is clinically indicated to have cerebral infarction, cerebral arteriosclerosis, and multiinfarct dementia. , And the like, and is also useful for improving or treating mental disorders such as spontaneous depression, affective disorder, problem behavior, and impairment of intellectual function.

Preferred embodiments of the compound of the general formula (I) include 19 groups of compounds represented by the respective formulas (I-1) to (I-19) shown below.

(1) Next equation [In the formula, n is a number of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are hydrogen atoms, and Y ¹ is a hydrogen atom, 2
-Oxopyrrolidino-1-acetyl group or 2-oxopyrrolidino-1-carbonylmethyl group].

(2) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are hydrogen atoms, and Y ² is the following formula: (Wherein R ⁴ , R ⁵ and R ⁶ may be the same or different from each other and are a hydrogen atom or a methoxy group)].

(3) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are hydrogen atoms, and Y ³ is the following formula: (In the formula, R ⁴ , R ⁵ and R ⁶ may be the same or different and each is a hydrogen atom or a methoxy group).
-Substituted piperazine derivatives.

(4) The following formula [In the formula, p is an integer of 0 to 3, R ⁷ is a hydrogen atom or a halogen atom, and Y ⁴ is a hydrogen atom, a 2-oxopyrrolidino-1-acetyl group, or a 2-oxopyrrolidino-1-carbonylmethyl group.] An N-substituted piperazine derivative represented by:

(5) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group or a halogen-substituted benzyl group, and R ² and R ³ are each a hydrogen atom or a halogen atom, or R ¹ Is a phenyl group, and R ² and R ³ are each a hydrogen atom].

(6) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are hydrogen atoms, and Y ⁵ is a (C _{1 to} C ₈ ) alkyl group, hydroxy (C ₁ -C ₆₎ alkyl or (C ₁ ~
C ₆ ) is an alkoxycarbonyl (C ₁ -C ₆ ) alkyl group], which is an N-substituted piperazine derivative.

(7) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, a halogen-substituted benzyl group or a phenyl group, and R ² and
R ³ is a hydrogen atom or a halogen atom, and Y ⁶ is (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group.)].

(8) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is an alkyl group, an alkoxy group or a benzyl group, R ² and R ³ are each a hydrogen atom, and Y ⁷ is a hydrogen atom or the following formula: (Wherein q is an integer of 1 to 2 and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group), provided that R ¹
Is a benzyl group, Y ⁷ is not a hydrogen atom].

(9) The following formula [Wherein, m is an integer of 2 or 3, n is an integer of 2 to 4, two R ^{8 s} are each a hydrogen atom or a halogen atom, and Y ⁷ is a hydrogen atom or the following formula: (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group.)].

(10) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group or a halogen-substituted benzyl group, R ² and R ³ are each a hydrogen atom, and Y ⁸ is the following formula: (In the formula, p is an integer of 0 to 3 and R ⁷ is a hydrogen atom or a halogen atom)].

(11) The following formula [In the formula, m is an integer of 3, p is an integer of 0 to 3, R ⁷ is a hydrogen atom or a halogen atom, and Y ⁹ is a hydrogen atom, or (In the formula, R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group)].

(12) The following formula [In the formula, m is an integer of 3, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are hydrogen atoms, and Y ⁷ is a hydrogen atom or the following formula: (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group.)], The N-substituted piperazine derivative.

(13) Formula [In the formula, t is an integer of 1 to 4, R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom or a methoxy group, and Y ¹ is a hydrogen atom, 2-oxopyrrolidino-1. -Acetyl group or 2-oxopyrrolidino-1-carbonylmethyl group].

(14) The following formula [In the formula, p is an integer of 0 to 3, q is an integer of 1 to 2, R ⁴ , R ⁵ and R ⁶ may be the same or different and are a hydrogen atom or a methoxy group, R ⁷ Represents a hydrogen atom or a halogen atom, provided that q is an integer of 2 when p is 0 and Y ⁷ is a hydrogen atom.] Is an N-substituted piperazine derivative.

(15) The following formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are each a hydrogen atom, and Y ¹⁰ is the following formula: (In the formula, r is an integer of 0 to 2, R ⁴ , R ⁵ and R ⁶ are hydrogen atoms or a (C ₁ -C ₆ ) alkoxy group), or Y ¹⁰ is a group represented by the following formula: (In the formula, r is an integer of 0 to 2, R ^c , R ^d and R ^e are each a hydrogen atom or a (C ₁ -C ₆ ) alkoxy group, particularly a methoxy group or a halogen atom, and R ^f is Hydrogen atom or (C ₁ ~
C ₆ ) alkyl group, provided that when R ^f is an alkyl group, r
Is zero) or Y ¹⁰ is (In the formula, q is an integer of 1 to 2, and R ^g , R ^h, and R ^j are each a hydrogen atom, a hydroxy group, a (C ₁ -C ₆ ) alkyl group, or a (C ₁ -C ₆ ) alkoxy group. , Particularly a methoxy group).], An N-substituted piperazine derivative.

(16) The following formula [In the formula, n is an integer of 2 to 4, R ^a and R ^b are each a (C ₁ -C ₆ ) alkyl group, and R ¹ is a benzyl group,
R ² and R ³ are each a hydrogen atom, and Y ⁷ is a hydrogen atom or the following formula (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group.)].

(17) Formula [In the formula, n is an integer of 2 to 4, R ¹ is a benzyl group, R ² and R ³ are each a hydrogen atom, and Y ¹¹ is the following formula: (Wherein, q is an integer of 1 to 2, R ^4, R ⁵ and R ⁶ is a hydrogen atom or a (C ₁ -C ₆₎ alkoxy groups, in particular methoxy, R ^k is (C ₁ -C ₆ ) An N-substituted piperazine derivative represented by the formula (1), which is an alkyl group).

(18) Formula [In the formula, p is an integer of 0 to 3, R ⁷ is a hydrogen atom or a halogen atom, and Y ¹² is the following formula: (In the formula, r is an integer of 0 to 2, and R ⁴ , R ⁵ and R ⁶ are hydrogen atoms or (C ₁ -C ₆ ) alkoxy groups, especially methoxy groups), provided that p is Is 0 or an integer of 2 when 0 is 0], the N-substituted piperazine derivative.

(19) The following formula [In wherein, n is 2 to 4 integer and Y ^a is a hydrogen atom or a (C ₁ ~C ₄₎ alkyl group or the formula (In the formula, q is an integer of 1 to 2, R'is a hydrogen atom or a (C ₁ -C ₄ ) alkoxy group, and R ″ and R are each a (C ₁ -C ₄ ) alkoxy group. ) -Ω- [3,4-di (C
₁ -C ₄₎ alkoxy - or 2,3,4-tri (C ₁ -C ₄₎ alkoxy - phenyl] -ω- hydroxy - 1-N indicated by an alkyl group] - [(2-benzyl-phenoxy)
Alkyl] -4-N-substituted or unsubstituted piperazine.

Examples of specific compounds of the N-substituted piperazine derivatives of formula (I-1) above include the compounds listed below.

1- [2- (2-benzylphenoxy) ethyl] piperazine (compound of Example 1 described below), 1- [2- (2-
Benzylphenoxy) ethyl] -4-[(2-oxopyrrolidin-1-yl) carbonylmethyl] piperazine (compound of Example 17 below), 1- [2- (2-benzylphenoxy) ethyl] -4- [ (2-oxopyrrolidin-1-yl) acetyl] piperazine (see Example 24 below)
Compound), 1- [3- (2-benzylphenoxy) propyl] piperazine (compound of Example 12 described below), 1-
[3- (2-benzylphenoxy) propyl] -4-
[(2-oxopyrrolidin-1-yl) carbonylmethyl] piperazine (25 compound of the Examples described below) and 1
-[3- (2-Benzylphenoxy) propyl] -4-
[(2-oxopyrrolidin-1-yl) acetyl] piperazine (compound of Example 16 described below).

Examples of specific compounds of the N-substituted piperazine derivatives of formula (I-2) above include the compounds listed below.

(I) 1- [2- (2-benzylphenoxy) ethyl]
-4- (2-methoxybenzyl) piperazine, 1- [2
-(2-Benzylphenoxy) ethyl] -4- (3-methoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (4-methoxybenzyl) piperazine, 1- [2- ( 2-benzylphenoxy) ethyl] -4- (2,3-dimethoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (3,4-dimethoxybenzyl) piperazine,
1- [2- (2-benzylphenoxy) ethyl] -4-
(2,4-dimethoxybenzyl) piperazine, 1- [2-
(2-Benzylphenoxy) ethyl] -4- (2,5-dimethoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (2,6-dimethoxybenzyl) piperazine, 1- [ 2- (2-benzylphenoxy) ethyl] -4- (3,5-dimethoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (2,3,4-trimethoxybenzyl) Piperazine (compound of Example 49 described below), 1- [2- (2-benzylphenoxy) ethyl] -4- (3,4,5-trimethoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ) Ethyl] -4- (2,3,5-trimethoxybenzyl) piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (2,4,5-trimethoxybenzyl)
Piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- (2,4,6-trimethoxybenzyl) piperazine and 1- [2- (2-benzylphenoxy) ethyl] -4- (2 , 3,6-Trimethoxybenzyl) piperazine.

(Ii) 1- [3- (2-benzylphenoxy) propyl] -4- (2-methoxybenzyl) piperazine, 1-
[3- (2-benzylphenoxy) propyl] -4-
(3-methoxybenzyl) piperazine, 1- [3- (2
-Benzylphenoxy) propyl] -4- (4-methoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,3-dimethoxybenzyl) piperazine, 1- [3- (2 -Benzylphenoxy) propyl] -4- (3,4-dimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,4-dimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl]
-4- (2,5-dimethoxybenzyl) piperazine, 1-
[3- (2-benzylphenoxy) propyl] -4-
(2,6-dimethoxybenzyl) piperazine, 1- [3-
(2-Benzylphenoxy) propyl] -4- (3,5-
Dimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,3,4-trimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (3,4,5-Trimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,3,5-trimethoxybenzyl) piperazine, 1- [3- (2- Benzylphenoxy) propyl] -4- (2,4,5-trimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,4,6-trimethoxybenzyl) piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- (2,3,6-trimethoxybenzyl) piperazine.

Examples of specific compounds of the N-substituted piperazine derivatives of formula (I-3) above include the compounds listed below.

(I) 1- [2- (2-benzylphenoxy) ethyl]
-4- [2-hydroxy-2- (2-methoxybenzyl) ethyl] piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- [2-hydroxy-2- (3
-Methoxyphenyl) ethyl] piperazine, 1- [2-
(2-Benzylphenoxy) ethyl] -4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazine, 1- [2- (2-benzylphenoxy) ethyl]
-4- [2-hydroxy-2- (2,3-dimethoxyphenyl) ethyl] piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- [2-hydroxy-2-
(3,4-Dimethoxyphenyl) ethyl] piperazine (compound of Example 19 described below), 1- [2- (2-benzylphenoxy) ethyl] -4- [2-hydroxy-2- (2,
4- (dimethoxyphenyl) ethyl] piperazine, 1-
[2- (2-benzylphenoxy) ethyl] -4- [2
-Hydroxy-2- (2,5-dimethoxyphenyl) ethyl] piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- [2-hydroxy-2- (2,6-dimethoxyphenyl) ethyl] Piperazine, 1- [2-
(2-Benzylphenoxy) ethyl] -4- [2-hydroxy-2- (3,5-dimethoxyphenyl) ethyl] piperazine (compound of Example 52 described below), 1- [2- (2
-Benzylphenoxy) ethyl] -4- [2-hydroxy-2- (2,3,4-trimethoxyphenyl) ethyl] piperazine (compound of Example 54 described below), 1- [2- (2
-Benzylphenyl) ethyl] -4- [2-hydroxy-2- (3,4,5-trimethoxyphenyl) ethyl] piperazine (compound of Example 56 described below), 1- [2- (2-
Benzylphenoxy) ethyl] -4- [2-hydroxy-2- (2,3,5-trimethoxyphenyl) ethyl] piperazine, 1- [2- (2-benzylphenoxy) ethyl] -4- [2-hydroxy -2- (2,4,5-Trimethoxyphenyl) ethyl] piperazine, 1- [2- (2-
Benzylphenoxy) ethyl] -4- [2-hydroxy-2- (2,4,6-trimethoxyphenyl) ethyl] piperazine and 1- [2- (2-benzylphenoxy) ethyl] -4- [2- Hydroxy-2- (2,3,6-trimethoxyphenyl) ethyl] piperazine.

(Ii) 1- [3- (2-benzylphenoxy) propyl] -4- [2-hydroxy-2- (2-methoxyphenyl) ethyl] piperazine, 1- [3- (2-benzylphenoxy) propyl]- 4- [2-hydroxy-2-
(3-Methoxyphenyl) ethyl] piperazine, 1-
[3- (2-benzylphenoxy) propyl] -4-
[2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,3-)
Dimethoxyphenyl) ethyl] piperazine, 1- [3-
(2-Benzylphenoxy) propyl] -4- [2-hydroxy-2- (3,4-dimethoxyphenyl) ethyl]
Piperazine (compound of Example 31 described below), 1- [3-
(2-Benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,4- (dimethoxyphenyl) ethyl] piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- [2- Hydroxy-2- (2,5-
Dimethoxyphenyl) ethyl] piperazine, 1- [3-
(2-Benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,6-dimethoxyphenyl) ethyl]
Piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- [2-hydroxy-2- (3,5-dimethoxyphenyl) ethyl] piperazine, 1- [3- (2-
Benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,3,4-trimethoxyphenyl) ethyl] piperazine, 1- [3- (2-benzylphenyl) propyl] -4- [2-hydroxy -2- (3,4,5-Trimethoxyphenyl) ethyl] piperazine, 1- [3- (2-
Benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,4,5-trimethoxyphenyl) ethyl] piperazine, 1- [3- (2-benzylphenoxy) propyl] -4- [2-hydroxy -2- (2,3,5-trimethoxyphenyl) ethyl] piperazine, 1- [3- (2
-Benzylphenoxy) propyl] -4- [2-hydroxy-2- (2,4,6-trimethoxyphenyl) ethyl]
Piperazine and 1- [3- (2-benzylphenoxy)
Propyl] -4- [2-hydroxy-2- (2,3,6-trimethoxyphenyl) ethyl] piperazine.

Examples of specific compounds of the N-substituted piperazine derivatives of formula (I-4) above include the compounds listed below.

(I) 1-diphenylmethyl-4-[(2-oxopyrrolidin-1-yl) carbonylmethyl] piperazine, 1
-Diphenylmethyl-4-[(2-oxopyrrolidine-
1-yl) acetyl] piperazine, 1- (4,4-diphenyl) butyl-4-[(2-oxopyrrolidin-1-yl] carbonylmethyl] piperazine, and 1- (4,4-
Diphenyl) butyl-4-[(2-oxopyrrolidine-
1-yl) acetyl] piperazine.

(Ii) 1- [bis (4-chlorophenyl) methyl] piperazine (compound of Example 13 described later), 1- [bis (4-
Fluorphenyl) butyl] piperazine (Examples described below
14 compound), 1- [bis (4-fluorophenyl) methyl] -4-[(2-oxopyrrolidin-1-yl) carbonylmethyl] piperazine (compound of Example 21 described below), 1- [bis (4-Fluorophenyl) methyl]-
4-[(2-oxopyrrolidin-1-yl) acetyl]
Piperazine (compound of Example 22 described below), 1- [4,4-
[Bis (4-fluorophenyl) butyl] -4-[(2
-Oxopyrrolidin-1-yl) carbonylmethyl] piperazine (compound of Example 23 described below) and 1- [4,4-
[Bis (4-fluorophenyl) butyl] -4-[(2
-Oxopyrrolidin-1-yl) acetyl] piperazine (compound of Example 18 below).

In addition, examples of specific compounds of the N-substituted piperazine derivative of the above formula (I-5) include the compounds of Examples 2 to 5 described below.

Specific examples of the compound of the above formula (1-6) include the compounds of Examples 44, 45 and 46 described below.

Specific examples of the compound of the above formula (I-7) include the compounds of Examples 31, 34, 35, 36, 37, 42, 52, 54, 55, 56, 57 and the like described below.

Specific examples of the compound of the above formula (I-8) include the compounds of Examples 6, 7, 38, 39, 40, 41, 42 described later.

Specific examples of the compound of the above formula (I-9) include the compounds of Examples 8, 9, 32, 33, 43, 69 described later.

Specific examples of the compound of the formula (I-10) include those described in Example 47 below.
And there are 48 compounds.

Specific examples of the compound of the formula (I-11) include those described in Example 14 below.
And 68 compounds.

Specific examples of the compound of the formula (I-12) are described in Example 10 below.
And 67 compounds.

Specific examples of the compound of formula (I-13) include those described in Example 26 below.
And 27 compounds.

Specific examples of the compound of the formula (I-14) are described in Example 2 below.
There are 8, 29 and 30 compounds.

Specific examples of the compound of the formula (I-15) include those described in Example 5 below.
There are 0, 51, 58, 59, 60 compounds.

Specific examples of the compound of the formula (I-16) include those described in Example 65 below.
And 66 compounds.

Specific examples of the compound of the formula (I-17) are described in Example 6 below.
There are 2, 63 and 64 compounds.

Specific examples of the compound of the formula (I-18) include those described in Example 61 below.
There is a compound of

Further, specific examples of the compound of the formula (I-19) include the compounds of Examples 1, 19, 44 and 54 described later, which are particularly important compounds in the present invention. Incidentally, Examples 1, 19, 44
And each of the compounds of 54 are also redundant to the compounds of formula (I-1), the compounds of formula (I-3), the compounds of formula (I-6) and the compounds of formula (I-7) above. Included in.

Among the N-substituted piperazine derivatives of the general formula (I), the novel piperazine derivatives of the general formula (I-9) or the general formula (I-19) have distorted brain dysfunction improving activity and low toxicity. The present inventors have also found that it is particularly suitable for use as an active ingredient from the viewpoint that

Therefore, in the present invention, the following formula (I-9): [Wherein, m is an integer of 2 or 3, n is an integer of 2 to 4, two R ^{8 s} are each a hydrogen atom or a halogen atom, and Y ⁷ is a hydrogen atom or the following formula: (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group)] or a N-substituted piperazine derivative represented by the following formula ( I-19): [In the formula, n is a number of 2 to 4 and Y ^a is a hydrogen atom or a (C ₁ -C ₄ ) alkyl group or the following formula: (In the formula, q is an integer of 1 to 2, R'is a hydrogen atom or a (C ₁ -C ₄ ) alkoxy group, and R ″ and R are each a (C ₁ -C ₄ ) alkoxy group. ) -Ω- [3,4-di (C
₁ -C ₄₎ alkoxy - or 2,3,4-tri (C ₁ -C ₄₎ alkoxy - phenyl] -ω- hydroxy - 1-N indicated by an alkyl group] - [(2-benzyl-phenoxy)
Provided is an agent for improving brain dysfunction, which comprises an alkyl] -4-N-substituted or unsubstituted piperazine or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

The chemical structure of the N-substituted piperazine derivative of the general formula (I) uses piperazine or homopiperazine as a raw material, and depends on the kind or structure of the substituent Z and the kind or structure of the substituent Y to be introduced into this compound. And introducing the group Z and the group Y into the starting compound by a suitable method. Examples of suitable synthetic methods include the following eight methods: Method A to Method H. Further, the compound of the general formula (I) can be produced by appropriately combining two or more of these Method A to Method H.

Method A: This method A is It is suitable for producing a compound of the present invention of the type represented by the formula (wherein m, Z, R ^a and R ^b have the same meanings as described above). That is, this A method is (In the formula, m is an integer of 2 or 3, R ^a and R ^b have the same meanings as described above, and B is an amino protecting group which is easily removed by hydrogenolysis, for example, a benzyl group or a benzyloxycarbonyl group. 1-N-protected piperazine or homopiperazine of the following formula A-CHO (III) [wherein A is the following formula Or the following formula Or the following formula Or the following formula And n and p have the same meanings as described above,
R ¹ , R ² , R ³ , R ⁷ and R ⁸ have the same meanings as defined above], and then a reducing agent such as sodium borohydride (NaBH ₄ ) or cyano hydride Sodium borohydride (NaCNBH ₃ ) or formic acid is reacted to give the following formula A condensation product of the formula: wherein A, B, R ^a , R ^b and m are as defined above, and then the compound of formula (IV) is removed for elimination of the amino protecting group B. It comprises subjecting it to a hydrogenolysis reaction in a conventional manner to produce the compound of formula (I a) above.

In this method A, the condensation reaction between the 1-N-protected piperazine or the homopiperazine of the formula (II) and the aldehyde compound of the formula (III) is carried out by an organic solvent inert to the starting compound and the reaction agent, preferably methanol or ethanol. , Dioxane, in the presence or absence of an acid such as hydrochloric acid or acetic acid in the temperature range of -20 ° C to 100 ° C. The reaction is complete in 1 to 24 hours (see steps 3 and 4 of Example 1 below).

Then, the compound of formula (IV) is subjected to hydrogenolysis for deprotection, and after completion of the reaction, the product is purified by crystallization, precipitation, silica gel chromatography, etc.
A compound of the type represented by formula (I a) can be obtained. Furthermore,
If necessary, this can be converted into an addition salt with an acid to obtain the acid addition salt.

Method B: This method is another method suitable for preparing the compound of the type represented by the above formula (Ia). That is, the B method is (Wherein, m is an integer of 2 or 3) piperazine or the following formula in homopiperazine A-CH ₂ -X (VI) (wherein represented by, A is as defined above, X is desorption A halide compound or other functional compound of formula (I) is condensed in the presence of a base to give a compound of the formula Of a compound of the formula (I a) above (see step 3 of Example 12 below).

The leaving group X in the above formula (V) can be a halogen atom such as chlorine, bromine, iodine and the like. Further, the group X can be an alkylsulfonyloxy group or an arylsulfonyloxy group, for example, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group and the like. As the base that acts as an acid binder, inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine, diisopropylethylamine and N, N-dimethylaniline can be used. The above condensation reaction can be carried out in an inert solvent, preferably dichloromethane, DMF, dioxane, benzene, DMSO or the like in the temperature range of -20 ° C to 100 ° C. The reaction is completed in 1 to 24 hours. After completion of the reaction, the reaction product is purified by crystallization, precipitation, silica gel calm chromatography, etc., and converted to an addition salt with an acid, if necessary, to give a compound of formula (VII), that is, a compound of formula (I a) Alternatively, an acid addition salt thereof can be obtained.

Method C: This method C is (In the formula, m, ^Ra and ^Rb have the same meanings as described above, and D is Y in the general formula (I) except that it is not a hydrogen atom.
1-N-substituted piperazine or homopiperazine represented by the formula (VI), that is, the formula A-CH ₂ —X (VI) (wherein A and X are the same as above). Of the meaning) and other functional compounds are condensed in the presence of a base to give a compound of the formula (Wherein m, ^Ra , ^Rb , Z and D have the same meanings as defined above) (see Example 16 below). The method C can be carried out in the same manner as the method B.

D method: This D method is (Wherein, m, ^Ra , ^Rb and Z have the same meanings as described above) and a 4-N-substituted piperazine or homopiperazine derivative or an inorganic or organic salt thereof is represented by the following formula X-E (IX) (In the formula, X is the same leaving group as described above, and E has the same meaning as Y in the general formula (I) except that it is not a hydrogen atom), or another functional compound. Is condensed in the presence or absence of a base to give the following formula (Wherein m, Z, R ^a , R ^b and E have the same meanings as defined above) (see Example 19 below).

The leaving group X in the reactant compound of formula (IX) above can be a halogen atom, such as chlorine, bromine, iodine and the like. Further, the leaving group X can be an alkylsulfonyloxy group or an arylsulfonyloxy group, for example, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group and the like. The above condensation reaction can be performed in the presence of a base. As the base, inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine, diisopropylethylamine and N, N-dimethylaniline can be used. The above condensation reaction may be performed without a solvent or in a solvent,
It can be preferably carried out also in dichloromethane, dichloroethane, DMF, dioxane or the like. This reaction is -30 ℃
Complete within 30 minutes to 24 hours in the temperature range of ~ 100 ° C.

E method: This E method is (Wherein, m, ^Ra , ^Rb and Z have the same meanings as described above) and a 4-N-substituted piperazine or homopiperazine derivative or an inorganic or organic salt thereof is represented by the following formula (In the formula, r ′ is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ have the same meanings as described above), and the acetophenone derivative is condensed with formaldehyde or a chemically equivalent compound thereof. And this gives (Wherein m, r ′, R ^a , R ^b , R ⁴ , R ⁵ , R ⁶ and Z have the same meanings as defined above). (See middle part of Example 20). The above condensation reaction can be carried out without catalyst or in the presence of acid or base. As the acid, organic acids such as formic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid can be used.

Paraformaldehyde, trioxane, formaldehyde acetal, formaldehyde amino acetal and the like can be used as the chemically equivalent compound of formamaldehyde.

The above reaction is carried out in a suitable solvent, preferably methanol,
It can also be carried out in ethanol, terrahydrofuran, dioxane or a mixed solvent thereof with water or in water. 20
The reaction is completed within 30 minutes to 24 hours in the temperature range of ~ 1100 ° C.

F method: This F method is (In the formula, q is an integer of 1 to 2, and m, R ^a , R ^b , R ⁴ ,
R ⁵ , R ⁶ and Z have the same meanings as described above) to reduce the carbonyl group (C = 0) of the compound represented by the following formula (In the formula, q is an integer of 1 to 2, and m, R ^a , R ^b , R ⁴ ,
R ⁵ , R ⁶ and Z have the same meanings as defined above) (see the latter part of Example 20 below).

The reducing agents used in this F method are NaBH ₄ , LiAlH ₄ , L
It can be a reducing agent such as iBH ₄ , NaCNBH ₃ . Alternatively, a catalytic reduction method can be used. A suitable solvent,
The desired product can be obtained by carrying out the reduction reaction preferably in ether, tetrahydrofuran, dioxane or the like in the temperature range of −78 to 20 ° C. for 1 to 24 hours.

G method: This G method is (In the formula, q is an integer of 1 to 2, and m, R ^a , R ^b , R ⁴ ,
R ⁵ , R ⁶ and Z have the same meanings as described above) and a compound represented by the following formula R ^k MgBr (XI) [wherein R ^k is an alkyl group having 1 to 6 carbon atoms]. Magnesium bromide (Grignard reagent) was reacted according to the usual method of Grignard reaction to give the following formula (In the formula, q is an integer of 1 to 2, and m, R ^a , R ^b , R ⁴ ,
R ⁵ , R ⁶ and Z have the same meanings as described above, and R ^k is (C ₁ to
C ₄ ), which is an alkyl group) (see Example 60 below).

H method: This H method is (In the formula, m, ^Ra , ^Rb , and Z have the same meanings as described above.)
The compound of 2-oxopyrrolidino-1-acetic acid or an active ester thereof by condensation to give the following formula (In the formula, m, ^Ra , ^Rb , and Z have the same meanings as described above.)
And forming a compound of the type represented by (see Example 18 below).

As the active ester of 2-oxopyrrolidino-1-acetic acid, an ester with N-hydroxysuccinimide, N-hydroxybenztriazole or the like in the presence of N, N-dicyclohexylcarbodiimide can be used. Also, an ester with an alkyloxycarbonyloxy group such as an ethoxycarbonyloxy group or an isobutyloxycarbonyloxy group can be used.

The above condensation reaction can be carried out without solvent or in an anhydrous organic solvent, preferably in dichloromethane, dichloroethane, DMF, dioxane or the like. Reaction is -30 ℃ to 100 ℃
Complete within 30 minutes to 24 hours in the temperature range.

After completion of the reaction, the reaction product can be purified by crystallization, precipitation, silica gel column chromatography and the like, and can be converted into an addition salt with an acid, if necessary.

The compound of the general formula (I) suppresses the uptake of calcium ions into the inner membrane of cerebral nerve cells, suppresses the contraction of cerebral blood vessels, and the brain of a mouse induced by loading hypoxic conditions under reduced pressure. Although it has an effect of protecting mice from anoxia and an effect of protecting hippocampal cells from damage of brain cells of the gerbil hippocampus under ischemia, a test demonstrating these effects is shown below. In addition, a test for evaluating the acute toxicity of this compound is also described.

[1] Test of effect of suppressing calcium ion uptake into brain neuron membrane fraction (rat membrane P ₂ fraction).

Brain cell P ₂ fractions were prepared using Wistar rat brain (cerebellar was removed). Brain cell P caused by KC1 depolarization stimulation
_The inhibitory effect of the compound of the present invention on the incorporation of ⁴⁵ Ca into ₂ fractions was examined.

The brain cell P ₂ fraction used was prepared as follows. The rat brain was quickly removed, the cerebellum was removed, and the remaining brain tissue was homogenized (0.32M sucrose, 5 mM HEPES, pH 7.
Brain tissue was homogenized by adding 10 times the amount of 4). The homogenate obtained by homogenization was centrifuged at 1,000 xg for 10 minutes, and the obtained supernatant was further centrifuged at 17,000 xg for 10 minutes. The obtained precipitate was suspended again in the same homogenate solution as above and then centrifuged at 17,000 xg for 10 minutes. The resulting precipitate was incubated in the absence of Ca (132 mM NaC
l, 5 mM KCl, 1.2 mM NaH ₂ PO ₄ , 1.3 mM MgCl ₂ , 10 mM gluco
se, and 20 mM Tris-HCl, pH.7.4) and suspended for 17,000
After centrifugation at xg for 10 minutes, the obtained precipitate was suspended in an incubation solution containing 1.2 mM CaCl ₂ and centrifuged at 17,000 xg for 10 minutes. The obtained precipitate was suspended in an incubation solution containing 1.2 mM CaCl ₂ , and the obtained suspension was used as a brain cell P ₂ fraction in the experiment. All the above operations were performed at 4 ° C., and the following Ca uptake experiment was performed within 4 hours after the final precipitate was obtained.

Blaustein's method (“J. Physio
l. ” 247 , 617-655 (1975)), using the KCl depolarization stimulation method. That is, the test compound of the present invention was added to the brain cell P ₂ fraction, and the P ₂ fraction was subjected to preincubation at 32 ° C. for 15 minutes, to which a depolarizing solution (137 mM KCl, 1.2 mM NaH) containing ⁴⁵ Ca was added. ₂ PO ₄ , 1.3 mM MgCl ₂ , 1.2 mM C
ACl ₂ , 10 mM glucose and 20 mM Tris-HCl, pH.7.4) were added in an equal amount to allow incorporation of ⁴⁵ Ca into the P ₂ fraction by KCl depolarization at 32 ° C. for 3 minutes. Stop the reaction with an equal volume of ice-cold stop solution (120 mM NaCl, 5 mM KCl, 30 mM EGTA / Tris, pH 7.
4) was added and stirred. Then, the reaction mixture was immediately suction-filtered on Whatman glass filter (GF / C), and the residue on the filter was washed with 5 mM ice-cold washing solution (132 mM choline).
_{-Cl, 5mM KCl, 1.2mM NaH 2} PO 4, 1.3mM MgCl 2, 1.2mM C
It was washed twice with aCl ₂ , 10 mM glucose, 20 mM Tris-HCl, pH 7.4). After the filter was dried, the residue on the filter was measured for radioactivity with a liquid scintillation counter. The test compound was added to the brain cell P ₂ fraction at the same time as the start of preincubation. The protein concentration is lowry with bovine serum albumin as standard.
The measurement was carried out according to the method of J. Biol. Chem., 193 , 265-275 (1951).

The inhibition rate (%) of ⁴⁵ Ca uptake into the rat brain cell P ₂ fraction when the test compound was added at a concentration of 10 ⁻⁵ M or 10 ⁻⁴ M was determined and shown in Tables 1a and 1b. The tested compounds are identified with reference to the below-mentioned Example No. (the same applies hereinafter). Flunarizine was similarly tested as a comparative compound.

[2] A test for the effect of suppressing the contraction of cerebral blood vessels (rabbit basilar artery).

A white male rabbit weighing 2.5 to 3.5 kg was killed by exsanguination, and immediately the basilar artery and the thoracic aorta were separately removed and used as a spiral specimen. Those samples, the mixed gas (95%, O ₂ -5
% CO ₂ ) aerated Krebs solution (NaCl, 1
18 mM; KCl, 4.7 mM; MgCl ₂ , 1.2 mM; CaCl ₂ , 2.54 mM; KH ₂ P
It was suspended in an organ tank (5 ml) filled with O ₄ , 1.19 mM; NaHCO ₃ , 25 mM; glucose, 11 mM). Cerebral hypoarteries were equilibrated in Krebs solution under rest tension of 0.2 g and thoracic aorta for 1.5 hours, respectively. Then, KCl was cumulatively added to the Graves' fluid in the organ bath and the contractile response of the arterial preparation was recorded isometrically. The test compound was added and placed in the Krebs solution 10 minutes before the above KCl addition. The inhibitory effect of the test compound on the arterial contraction by KCl was evaluated by comparing the contraction of the artery before the addition of the test compound with the contraction of the artery by KCl after the addition of the test compound. Regarding the action curve showing the relationship between KCl concentration and arterial contraction rate, the negative logarithmic value of the molar concentration of the test compound that can suppress the maximum reaction of arterial contraction by 50% was calculated as pD ′ ₂ value, and those values were calculated. Is shown in Table 2.

[3] A test of the effect of prolonging the survival time of a mouse having cerebral anoxia caused by loading under hypoxic conditions under reduced pressure.

The test compound (in the form of an aqueous solution dissolved in purified water containing 1% Tween 80 so that the administration liquid amount was 0.1 ml / 10 g) was intraperitoneally administered to one group of 6 ddY mice. 30 minutes after administration, put each animal in a transparent airtight container and use a vacuum pump to
The pressure was reduced to 0 mmHg. The time (sec) from the start of decompression to the death of the mouse due to respiratory arrest was measured, and the measured time was defined as the survival time (sec).

The ratio of the survival time of the compound-administered group to the survival time when the mouse control group administered with purified water containing 1% Tween 80 but not containing the test compound was tested in the same manner was calculated.
The values multiplied by 100 are shown in Table 3.

[4] An evaluation test of the action of protecting cells of the hippocampal region of the gerbil brain from damage caused by tiger blood conditions.

A solution of the test compound dissolved in purified water containing 1% Tween 80 was intraperitoneally administered (ip) to gerbils, and after 30 minutes, the rats were fixed in the dorsal position without anesthesia to surgically expose the carotid artery. Blood flow in both carotid arteries was clipped for 5 minutes and the brain was placed under ischemic conditions. After removing the clip and allowing blood flow to resume, the wound was rapidly closed with an adhesive resin and the mouse was placed in a cage.

The control ischemia test group and the sham operation group were intraperitoneally administered with 0.5 ml / 100 g of purified water containing no test compound and containing only 1% Tween80. Further, the ischemic group was subjected to a surgical operation as in the test substance administration group. In the sham operation group, only the surgical operation for exposing the carotid artery was performed, and the wound was closed with an adhesive resin after being left for 5 minutes without stopping the blood flow. On the 4th day after administration of the test compound, the rat was fixed in the dorsal position again without anesthesia, and the physiological saline of the sonde from the left ventricle was adjusted to about 30%.
ml was injected. Then, about 30 ml of 10% formalin buffer was injected and killed.

Then, the whole brain was removed and immersed in 10% formalin buffer. The formalin-fixed brain was embedded in paraffin, cut into tissue sections with a thickness of about 5 μm, and brain cells were stained by the Nissl staining method. Count the number of neural pyramidal cells within a certain area (250 μm ² ) of the hippocampal CA1 site in this tissue section,
The results are shown in Table 4. Normal mouse group not subjected to the above treatment at all, and also for the mouse brain of the control ischemic group and the mouse of the sham operation group, fixed as in the above, the hippocampal CA1 site of the mouse brain of each group. The number of neuropyramidal cells within a certain area (250 μm ² ) was counted and listed in Table 4.

Brain cells in the hippocampus of the gerbil brain are susceptible to necrosis when they are placed under ischemic conditions and lack of oxygen supply. When the effect is significant, the number of neuronal pyramidal cells measured as described above (that is, the number of viable cells) is the same as the number of cells measured in the mouse brain of the control ischemic group to which the test compound was not administered. It is recognized that it is higher than that.

KB2796 used as a comparative compound in Table 4 above
The substance is Which is a compound described in JP-A-60-222472.

[5] Acute toxicity test.

Acute toxicity was tested by oral administration using mice (ddY strain, body weight 25 g, 1 group 5 mice). In this test, the LD _SO value of the compound of Example 4 and the compound of Example 8 described later was 500 mg / kg.
It was recognized that it was above.

From this, the above general formula (I-9) or (I-
The compound of 19) is recognized to have little acute toxicity to mammals.

As is clear from the above evaluation test results, the general formula (I
Since the compound of (-9) or (I-19) has low toxicity and further has a cerebral circulation-improving action and a brain cell-protecting action, it is useful as a cerebral dysfunction-ameliorating agent and is clinically used. , Cerebral infarction, cerebral arteriosclerosis, head injury and multiple sclerosis, etc. and psychiatric disorder symptoms based on these diseases, such as spontaneous depression, affective disorder, problematic behavior, intellectual dysfunction, etc. are effective. Is expected as a medical agent.

The agent for improving brain dysfunction according to the present invention can be in the form of a composition comprising a pharmaceutically acceptable liquid or solid carrier mixed with the active ingredient compound used.

The compound of the general formula (I-9) or (I-19) used in the present invention is orally or parenterally (intramuscular, subcutaneous, intravenous, etc.).
Will be given to you. The dosage form of the composition for oral administration includes tablets, capsules, powders, granules, syrups, etc., and the dosage form of the composition for parenteral administration includes injections, suppositories, etc. is there.

For preparing these compositions, a conventional carrier, that is, an excipient, a disintegrating agent, a binder, a lubricant, a coloring agent, a diluent and the like may be added.

Carriers, ie, excipients, such as lactose, glucose, corn starch, sorbit, crystalline cellulose, etc., disintegrators, such as Denbun, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc., binders Examples include dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl, cellulose,
Polyvinylpyrrolidone and the like are used as the lubricant, for example, talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like.

In preparing an injection, a buffer, a pH adjuster, a stabilizer and the like can be added to the active ingredient compound as necessary.

The dose of the compound of the general formula (I-9) or (I-19) used in the present invention varies depending on the age, body weight, difference in disease, and degree of symptoms of the patient, and is not particularly limited. It is about 100 to 1500 mg.

Next, reference examples illustrating the production of raw material compounds necessary for the production of the compound of the general formula (I), and Examples showing the production of the compound of the general formula (I) and a formulation containing compound No. 44 as an active ingredient A preparation example is shown.

Reference Example 1 (1) Production of 1- (2-benzylphenoxy) -2,2-diethoxyethane 2-benzylphenol in 50 ml of dimethylformamide
7.37 (40.0 mmol) and 2-bromo-1,1-diethoxyethane (10.2 g, 52.0 mmol) were dissolved, potassium carbonate (11.4 g) was added to the solution, and the mixture was heated to 100 ° C. for 72 hours. The solution was allowed to cool to room temperature, diluted with 200 ml of water, and the precipitated oily substance was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [elution solvent: hexane-
Purification with ethyl acetate (15: 1)] gave 11.8 g (98%) of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ; 1.21 (t, 6H), 4.59 (dq, 2H), 4.63 (d
q, 2H), 3.98 (s, 2H), 4.00 (d, 2H), 4.78 (t, 1H), 6.75
~ 6.95 (m, 2H), 6.95 ~ 7.35 (m, 7H).

(2) Preparation of 2-benzylphenoxyacetaldehyde 12.0 g (40.0 mmol) of 1- (2-benzylphenoxy) -2,2-diethoxyethane obtained in the step (1) above was dissolved in 60 ml of tetrahydrofuran, and 15 ml of 30% perchloric acid was added to the solution under water cooling. The mixture was stirred at room temperature for 48 hours after removing the ice bath. The obtained reaction solution was washed with water, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting solvent: hexane-ether (1: 1)] to obtain 8.32 g (92%) of the title compound as a colorless oily substance.

MMR (CDCl ₃ ) δ; 4.07 (s, 2H), 4.51 (s, 2H), 6.72 (d, 1
H), 6.79 (t, 1H), 7.05 to 7.35 (m, 7H), 9.75 (s, 1H).

Example 1 Synthesis of 1- [2- (2-benzylphenoxy) ethyl] piperazine (by method A) (1) Production of 1-benzyl-4- [2- (2-benzylphenoxy) ethyl] piperazine 2.26 g (10.0 mmol) of 2-benzylphenoxyacetaldehyde obtained in Reference Example 1 (2) was added to 30 m of methanol.
It was dissolved in 1 and the solution was cooled to -10 ° C. To the cooled solution was added 0.1N hydrochloric acid to adjust the pH of the solution to 6.0, 2.11 g (12.0 mmol) of 1-benzylpiperazine was added dropwise thereto, and the mixture was stirred at the same temperature for 10 minutes. To the resulting reaction solutions was added sodium cyanoborohydride (756 mg, 12.0 mmol) little by little. The reaction temperature was gradually raised to room temperature and the reaction mixture was stirred overnight. After distilling off methanol, 20 ml of 1N sodium hydride was added, and the precipitated oily substance was extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give 3.01 g (78%).
The title compound was obtained as a colorless oily substance.

NMR (CDCl ₃ ) δ; 2.46 (br, 4H), 2.55 (br, 4H), 2.78
(T, 2H), 3.50 (s, 2H), 3.96 (s, 2H), 4.07 (t, 2H), 6.
84 (d, 1H), 6.88 (t, 1H), 7.06 to 7.45 (m, 7H).

(2) 1- [2- (2-benzylphenoxy) ethyl]
Production of piperazine 1-benzyl-4- [2 obtained in the above step (1)
-(2-Benzylphenoxy) ethyl] piperazine 1.78
g (4.60 mmol) was dissolved in 50 ml of acetic acid and 10
% Pd-C (200 mg) was added, and hydrogenolysis was performed under normal pressure for 18 hours (elimination of 1-benzyl group). After completion of the reaction, the catalyst was filtered off from the reaction solution, and the filtrate was washed with methanol. The filtration and the washing solution were combined and concentrated under reduced pressure. 20 ml of water was added to the residue, and the mixture was made alkaline with 1N sodium hydroxide under ice cooling, and the precipitated oily substance was extracted with chloroform. The extract was dried and concentrated, and then purified by silica gel column chromatography [eluting solvent: chloroform-methanol (5: 1)] to obtain 966 mg (71%) of the title compound as an oily substance.

NMR (CDCl ₃ ) δ; 2.08 (brs, 1H), 2.50 (brs, 4H), 2.76
(T, 2H), 2.87 (m, 4H), 3.97 (s, 2H), 4.08 (t, 2H), 6.
8-6.92 (m, 2H), 7.03 (m, 7H).

EI-Mass analysis (M ⁺ ): 296 According to the method of Example 1, the compounds of the following Examples 2 to 11 were synthesized.

Example 2 1- [2- (2-benzyl-4-fluorphenoxy)
Ethyl] piperazine NMR (CDCl ₃ ) δ; 2.51 (br, 4H), 2.78 (t, 2H), 2.88 (m,
4H), 3.92 (s, 2H), 4.07 (t, 2H), 6.70 (m, 1H), 6.78
(M, 2H), 6.95 to 7.51 (m, 5H).

Example 3 1- {2- [2- (4-Fluorobenzyl) phenoxy] ethyl} piperazine NMR (CDCl ₃ ) δ; 1.70 (br, 1H), 2.43 (br, 4H), 2.56 (b
r, 4H), 2.79 (t, 2H), 3.96 (s, 2H), 4.08 (t, 2H), 6.77
(D, 1H), 6.89 (dd, 1H), 6.97 (dd, 2H), 7.09 (d, 1H),
7.12 (dd, 1H), 7.18 (dd, 2H).

Example 4 1- {2- [2- (4-Fluorobenzyl) 4-fluorophenoxy] ethyl} piperazine NMR (CDCl ₃ ) δ; 1.65 (br, 1H), 2.42 (br, 4H), 2.56 (b
r, 4H), 2.80 (t, 2H), 3.90 (s, 2H), 4.05 (t, 2H), 6.77
(Dd, 1H), 6.78 (dd, 1H), 6.84 (ddd, 1H), 6.96 (ddd, 1
H), 6.96 (dd, 2H), 7.16 (dd, 2H).

Example 5 1- [2- (2-phenylphenoxy) ethyl] piperazine NMR (CDCl ₃ ) δ; 1.82 (br, 1H,), 2.41 (br, 4H), 2.53
(Br, 4H), 2.83 (t, 2H), 4.10 (t, 2H), 6.95 (d, 1H),
7.04 (ddd, 1H), 7.25 to 7.45 (m, 5H), 7.55 (dd, 2H).

Example 6 1- [2- (2-Methoxyphenoxy) ethyl] piperazine NMR (CDCl ₃ ) δ; 1.73 (br, 1H), 2.69 (br, 4H), 2.84 (b
r, 4H), 2.89 (t, 2H), 3.86 (s, 3H), 4.12 (t, 2H), 6.82
~ 6.96 (m, 4H).

EXAMPLE 7 1- [2- (2-methylphenoxy) ethyl] piperazine _{NMR (CDCl 3) δ; 1.80} (br, 1H), 1.82 (s, 3H), 2.56 (b
r, 4H), 2.84 (t, 2H), 2.93 (t, 4H), 4.16 (t, 2H), 6.82
(Dd, 1H), 6.88 (dd, 1H), 7.20 to 7.45 (m, 2H).

Example 8 1- [2- (1-naphthoxy) ethyl] piperazine NMR (CDCl ₃ ) δ; 1.62 (br, 1H), 2.56 (br, 4H), 2.76
(T, 2H), 2.85 (t, 4H), 4.10 (t, 2H), 6.84 (d, 1H), 7.
37 (dd, 1H), 7.43 (d, 1H), 7.45-7.52 (m, 2H), 7.79
(M, 1H), 8.24 (m, 1H).

EXAMPLE 9 1- [2- (2-naphthoxy) ethyl] piperazine _{NMR (CDCl 3) δ; 2.3~2.9} (br, 8H), 2.91 (t, 2H), 4.20
(T, 2H), 7.14 (d, 1H), 7.16 (dd, 1H), 7.34 (ddd, 1
H), 7.44 (ddd, 1H), 7.68 to 7.78 (m, 3H).

EXAMPLE 10 1- [2- (2-Benzyl-phenoxy) ethyl] homopiperazine _{NMR (CDCl 3) δ; 1.99} (quin, 2H), 2.79 (t, 2H), 2.94
(T, 2H), 3.13 (t, 2H), 3.25 (t, 2H), 3.96 (s, 2H), 4.
03 (t, 2H), 6.84 (d, 1H), 6.92 (t, 1H), 7.10 ~ 7.40
(M, 7H).

EXAMPLE 11 1- [2- (4-benzyl phenoxy) ethyl] piperazine _{NMR (CDCl 3) δ; 2.85} (t, 2H), 2.90 (br, 4H), 3.23 (b
r, 4H), 3.92 (s, 2H), 4.06 (t, 2H), 6.80 (d, 2H), 7.09
(D, 2H), 7.13 to 7.22 (m, 3H), 7.24 to 7.32 (m, 2H).

Reference Example 2 (1) Production of 3- (2-benzylphenoxy) -1-propanol 2-benzylphenol 2.73 g (15.0 mmol) and 3
2.78 g (20.0 mmol) of bromopropanol was dissolved in 30 ml of dimethylformamide, and potassium carbonate was added to the solution.
4.14 g (30.0 mmol) was added and heated at 100 ° C. for 4 days.
After cooling, the reaction solution was diluted with 100 ml of water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate-hexane (1: 4)] to give the title compound as a colorless oily substance, 2.43 g (67%).

NMR (CDCl ₃ ) δ; 1.98 (quin, 2H), 3.71 (t, 2H), 3.98
(S, 2H), 4.07 (t, 2H), 6.8 to 6.95 (m, 2H), 7.0 to 7.3
(M, 7H).

(2) Preparation of 1-bromo-3- (2-benzylphenoxy) propane 1.30 g (5.37 mmol) of 3- (2-benzylphenoxy) -1-propanol obtained in the step (1) above and triphenylphosphine 1.83 g (6.93 mmol) was dissolved in 40 ml of acetonitrile, and 2.68 g (8.06 mmol) of carbon tetrabromide was gradually added to the solution under ice cooling. After stirring for 1 hour under ice cooling and 2 hours at room temperature, the solvent was distilled off from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate-hexane (1:10)] to obtain 1.31 g (80%) of the title compound as a colorless oily substance.

NMR (CDCl ₃ ) δ; 2.23 (quin, 2H), 3.41 (t, 2H), 3.96
(S, 2H), 4.06 (t, 2H), 6.8 to 6.95 (m, 2H), 7.00 to 7.40
(M, 7H).

Example 12 Synthesis of 1- [3- (2benzylphenoxy) propyl] piperazine (by method B) To 200 ml of dimethylformamide, 4.31 g of piperazine (50.0
Mmol), 2.07 g (15.0 mmol) of potassium carbonate and 3.81 g (12.5 mmol) of 1-bromo-3- (2-benzylphenoxy) -propane obtained in Reference Example 2 (2) were added to the solution at room temperature. It was stirred for 16 hours. 500m of reaction liquid
It was diluted with 1 and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform-methanol (1:
3)] to give 3.43 g (89%) of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ; 1.87 (br, 2H), 2.43 (m, 2H), 2.67 (b
r, 4H), 3.17 (br, 4H), 3.96 (s, 2H), 3.98 (t, 2H), 6.8
3 (d, 1H), 6.90 (t, 1H), 7.05 to 7.40 (m, 7H).

The compounds of Examples 13 to 16 below were synthesized according to the method of Example 12.

Example 13 1- [Bis (4-fluorophenyl) methyl] piperazine NMR (CDCl ₃ ) δ; 2.2 to 2.70 (br, 8H), 4.21 (s, 1H), 6.9
4 (dd, 2H), 7.32 (dd, 2H).

Example 14 1- [bis (4-fluorophenyl) methyl] homopiperazine NMR (CDCl ₃ ) δ; 2.70 (m, 2H), 1.97 (br, 1H), 2.61 (m,
4H), 2.83 (m, 2H), 2.98 (t, 2H), 4.61 (s, 1H), 6.86
(Dd, 4H), 7.35 (m, 4H).

EXAMPLE 15 1- [4,4-bis (4-fluorophenyl) butyl] piperazine _{NMR (CDCl 3) δ; 1.41} (m, 2H), 1.99 (m, 2H), 2.34 (m, 2
H), 2.2 to 2.6 (m, 8H), 3.84 (s, 1H), 6.93 (dd, 4H), 7.
17 (dd, 4H).

Example 16 1- [3- (2-benzylphenoxy) propyl] -4
Synthesis of-[(2-oxopyrrolidin-1-yl) acetyl] piperazine (by Method B) 1-[(2-oxopyrrolidin-1-yl) acetyl] piperazine acetate (described in JP-A-62-185068) 407 mg (1.50 mmol) and 1-bromo-3- (2-
Benzylphenoxy) propane 305 mg (1.00 mmol)
Was dissolved in 4 ml of dimethylformamide, 276 mg (2.00 mmol) of potassium carbonate was added to the solution, and the mixture was stirred at room temperature for 14 hours. The reaction solution is diluted with 20 ml of water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography [eluting solvent: chloroform-methanol (50: 1)] to obtain 374 mg (86%) of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ; 1.91 (m, 2H), 2.07 (quin, 2H), 2.2-
2.5 (m, 8H), 3.44 (br, 2H), 3.51 (t, 2H), 3.58 (br, 2
H), 3.96 (s, 2H), 3.98 (t, 2H), 4.10 (s, 2H), 6.84
(D, 1H), 6.89 (t, 2H), 7.0-7.4 (m, 7H).

Example 17 1- [2- (2-benzylphenoxy) ethyl] -4-
Synthesis of [(2-oxopyrrolidin-1-yl) carbonylmethyl] piperazine (by Method B) 1-chloroacetyl-2-oxopyrrolidine 646mg
(4.00 mmol) and 1- [2- (2-benzylphenoxy) ethyl] piperazine 1.18 g (4.00 mmol) were dissolved in 15 ml of dimethylformamide, and 828 mg (6.00 mmol) of potassium carbonate was added to the solution and stirred at room temperature for 5 hours. did. The reaction solution is diluted with 50 ml of water and extracted with ethyl acetate.
The extract was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [elution solvent: chloroform-
Purification with methanol (50: 1)] gave 1.36 g (81%) of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ; 2.07 (quin, 2H), 2.35 to 2.75 (m, 10
H), 2.79 (t, 2H), 3.76 (s, 2H), 3.82 (t, 2H), 3.97
(S, 2H), 4.09 (t, 2H), 6.85 (d, 1H), 6.88 (t, 1H), 7.
05 to 7.40 (m, 7H).

Example 18 1- [4,4-bis (4-fluorophenyl) butyl]-
4-[(2-oxopyrrolidin-1-yl) acetyl]
Synthesis of piperazine (by method H) (2-oxopyrrolidin-1-yl acetic acid 143 mg (1.00
Mmol), dicyclohexylcarbodiimide 208 mg
(1.01 mmol) and 1-hydroxybenzotriazole
141 mg (1.04 mmol) was dissolved in 3 ml of dimethylformamide and the solution was stirred at room temperature for 0.5 hours. To the reaction solution 1- [4,4-bis (4-fluorophenyl) butyl]
332 mg (1.00 mmol) of piperazine was added and stirred for 18 hours. The obtained reaction solution was diluted with 20 ml of water and extracted with ethyl acetate. The extract was washed with water, dried and then concentrated under reduced pressure. The residue was purified by silica gel chromatography [elution solvent: chloroform-methanol (100: 1)] to give 426 mg (96%).
The title compound was obtained as a colorless oily substance.

NMR (CDCl ₃ ) δ; 2.00 (m, 2H), 2.07 (quin, 2H), 2.35
(Br, 4H), 2.44 (t, 2H), 3.43 (br, 2H), 3.51 (t, 2H),
3.56 (br, 2H), 3.86 (t, 1H), 4.09 (s, 2H), 6.97 (m, 4
H), 7.16 (m, 4H).

Example 19 1- [2- (2-benzylphenoxy) ethyl] -4-
Synthesis of [2- (3,4-dimethoxyphenyl) -2-hydroxyethyl] piperazine (by combination of Method B and Method F) 1- [2- (2-Benzylphenoxy) ethyl] piperazine (148 mg, 0.50 mmol) and 3,4-dimethoxyphenacyl bromide (130 mg, 0.50 mmol) were added to methylene chloride 2
It was dissolved in ml, potassium carbonate 138 mg (1.00 mmol) was added to the solution, and the mixture was stirred at room temperature for 6 hours. After the solid was filtered off from the reaction solution, the filtered off was concentrated under reduced pressure. The resulting residue is 1- [2- (2-benzylphenoxy) ethyl] -4-.
It mainly consists of [(3,4-dimethoxyphenyl) carbonylmethyl] piperazine. This residue was immediately dissolved in 10 ml of methanol, and 38 mg (1.00 mmol) of sodium borohydride was added to the solution under ice cooling. The solution was stirred for 4 hours under ice cooling to carry out a reduction reaction. Methanol was distilled off from the reaction solution under reduced pressure, 20 ml of water was added to the residue, and the precipitated oily substance was extracted with ethyl acetate. After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography [eluting solvent: chloroform-methanol (100: 1)].
The title compound was obtained as 05 mg (86%) of colorless oil.

NMR (CDCl ₃ ) δ; 1.60 (br, 1H), 2.49 (t, 2H), 2.3 to 2.8
5 (m, 12H), 2.80 (t, 2H), 3.88 (s, 3H), 3.91 (s, 3H),
4.04 (t, 2H), 4.67 (m, 1H), 6.75 to 7.40 (m, 9H).

EI-Mass analysis (M ⁺ ): 476 Example 20 1- [2- (2-benzylphenoxy) ethyl] -4-
Synthesis of [3- (3,4-dimethoxyphenyl) -3-hydroxypropyl] piperazine (by Method E) 1- [2- (2-benzylphenoxy) ethyl] piperazine hydrochloride 736 mg (2.00 mmol) and 3,4 -Dimethoxyacetophenone 432 mg (2.40 mmol) in ethanol 10 m
It was dissolved in l, 0.2 ml of formalin was added and the mixture was refluxed for 18 hours. After cooling, the mixture was made alkaline with IN-sodium hydroxide, and the precipitated oily substance was extracted with ethyl acetate. The extract was washed with water, dried and then concentrated under reduced pressure. The residue was dissolved in 10 ml of ethanol, and 114 mg (3.00 mmol) of sodium borohydride was added under ice cooling.
After stirring for 8 hours to carry out a reduction reaction, the solvent was distilled off from the reaction solution, 20 ml of water was added to the residue and the mixture was extracted with ethyl acetate.
After washing with water and drying, the solvent was distilled off, and the residue was subjected to column chromatography (elution solvent: chloroform-methanol (200:
1)] to give 559 mg (57%) of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ; 1.86 (m, 2H), 2.4-2.86 (m, 10H), 2.7
9 (t, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 3.97 (s, 2H),
4.09 (t, 2H), 4.88 (dd, 1H), 7.81 ~ 7.92 (m, 4H), 7.96
(D, 1H), 7.08 to 7.29 (m, 7H).

Further, as to the method for producing the compound of the general formula (I) of the present invention, method A to method H as described above are used and the method of Examples 1, 12, 16, 17, 18, 19, and 20 is used. According to the same manner, each compound of Examples 21 to 69 below (almost all are oily substances, but some compounds are crystalline) was also synthesized. Each of the compounds produced in these examples has a group Z and a group Y shown in the general formula (I) for the identification of these compounds.
Table 5 to Table 9 below together with NMR data with specific reference to

Example 61 1- [bis (4-fluorophenyl) methyl] -4-
Synthesis of [2- [3,4-dimethoxyphenyl) carbonyl] ethyl] piperazine 1- [Bis (4-fluorophenyl) methyl] piperazine obtained in Example 13 was reacted with (3,4-dimethoxyphenyl) carbonylethyl bromide in the same manner as in Example 19, whereby The title compound was obtained as a colorless oil.

NMR (CDCl ₃ ) δ; 2.3 to 2.7 (br, 8H), 2.78 (t, 2H), 2.79
(T, 2H), 3.87 (s, 3H), 3.91 (s, 3H), 4.69 (s, 1H), 6.
65 to 6.90 (m, 3H), 6.97 (m, 4H), 7.36 (m, 4H).

Example 62 1- [2- (2-benzylphenoxy) ethyl] -4-
Synthesis of [3-hydroxy-3- (2,3,4-trimethoxyphenyl) butyl] piperazine (by method G) 1- [2- (2-benzylphenoxy) ethyl] -4
-[2- (2,3,4-trimethoxyphenylcarbonyl)
Ethyl] piperazine (1.037 g) was dissolved in toluene (5 ml), and methylmagnesium bromide (0.94M, THF solution 21.3 ml) was added dropwise under ice cooling. The Grignard reaction was carried out by stirring for 1 hour under ice cooling and overnight at room temperature. Water (5 ml) was added under ice cooling, and the reaction solution was filtered using Celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform containing 1% methanol) to give the title compound (1.064 g, 74.0%) as an oil.

NMR (CDCl ₃ ) δ; 1.52 (s, 3H), 1.9 to 2.7 (m, 12H), 2.76
(T, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 3.
97 (s, 2H), 4.06 (t, 2H), 6.66 (d, 1H), 6.83 (d, 1H),
6.89 (dt, 1H), 7.09 to 7.27 (m, 7H), 7.40 (d, 1H).

The compounds of the following Examples 63 and 64 were synthesized in the same manner as in the method of Example 62.

Example 63 1- [2- (2-benzylphenoxy) ethyl] -4-
[2-hydroxy-2- (2,3,4-trimethoxyphenyl) butyl] piperazine NMR (CDCl ₃ ) δ; 0.70 (t, 3H), 1.62 (dq, 1H), 2.03 (d
q, 1H), 2.15 to 2.5 (br, 8H), 2.54 (d, 1H), 2.70 (t, 2
H), 3.07 (d, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 3.91
(S, 3H), 3.93 (s, 2H), 4.02 (t, 2H), 7,62 (d, 1H), 7.
81 (d, 1H), 7.87 (dt, 1H), 7.06 to 7.33 (m, 8H).

Example 64 1- [2- (2-benzylphenoxy) ethyl] -4-
[3-hydroxy-3- (2,3,4-trimethoxyphenyl) pentyl] piperazine _{NMR (CDCl 3) δ; 0.72} (t, 3H), 1.35~1.85 (br, 2H), 1.
76 (dq, 2H), 1.95-2.07 (m, 2H), 2.07-2.37 (br, 4
H), 2,37 to 2.7 (br, 4H), 2.76 (t, 2H), 3.82 (s, 3H),
3.86 (s, 6H), 3.97 (s, 2H), 4.08 (t, 2H), 6.66 (d, 1
H), 6.83 (d, 1H), 6.89 (dt, 1H), 7.08 ~ 7.28 (m, 7H),
7.37 (d, 1H).

Formulation Example 1 1 part by weight of the compound of Example 44, 2.7 parts by weight of lactose, 0.8 parts by weight of corn starch, and 0.05 parts by weight of polyvinylpyrrolidone were mixed, ethanol was added to the mixture, and the mixture was granulated by a conventional method, further dried and conditioned. Grained. 0.5% in the obtained granules
(Weight) mixture with addition of magnesium stearate,
Compression molding was carried out by a conventional method to give tablets of 100 mg each.

Industrial Applicability As described above, the compound of the active ingredient used in the present invention is
Its acute toxicity is low, and as is clear from the above test examples, it has the activity of suppressing the uptake of calcium ions into the nerve cells of the mammalian brain, so it protects brain cells under ischemic conditions. It has an action of suppressing cell necrosis in the cerebral ischemic area. In addition, since it has an activity of suppressing the contraction of cerebral blood vessels, it shows an action of improving cerebral circulation disorder.

Furthermore, the compound of the active ingredient used in the present invention is, as is clear from the above-mentioned test examples, prolonging the survival time of mammals in the brain anoxia state induced by loading oxygen-deficient conditions under low pressure. Therefore, it has the action of protecting the life of the animal from the brain anoxya, and from this, it promotes the supply of oxygen to the brain, reduces the useless oxygen and ATP consumption of the brain, and the energy metabolism of the brain, It is thought that circulation is improved. Therefore, according to the present invention, the brain containing an N-substituted piperazine derivative, which is expected to be useful as a medical agent for ameliorating brain function disorders, when administered to a patient with brain function disorders A dysfunction-improving agent can be provided.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yuko Ishii 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Research Institute Co., Ltd. In-house Pharmaceutical Research Institute (72) Inventor Kiyoaki Katano 760 Meiji Confectionery, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd. Inside the Pharmaceutical Research Institute (72) Inventor Takashi Tsuruoka 760 Meiji Seika Co., Ltd., Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd. Research Institute (56) Reference JP-A-50-101370 (JP, A) JP-A-63-179850 JP, A) JP 64-3120 (JP, A) JP 50-121285 (JP, A) JP 59-101475 (JP, A) JP 63-51328 (JP, A) JP JP-A-59-134785 (JP, A) JP-A-62-167762 (JP, A) JP-A-1-104041 (JP, A) JP-A-2-138273 (JP, A) JP-A-2-243658 (JP , A) JP-A-2-233670 (JP, A)

Claims (1)

(57) [Claims] 1. The following formula (1-9): [Wherein, m is an integer of 2 or 3, n is an integer of 2 to 4, two R ^{8 s} are each a hydrogen atom or a halogen atom, and Y ⁷ is a hydrogen atom or the following formula: (In the formula, q is an integer of 1 to 2, and R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a methoxy group)] or a N-substituted piperazine derivative represented by the following formula ( I-19): [In wherein, n is 2 to 4 integer and Y ^a is a hydrogen atom or a (C ₁ ~C ₄₎ alkyl group or the formula (In the formula, q is an integer of 1 to 2, R'is a hydrogen atom or a (C ₁ -C ₄ ) alkoxy group, and R ″ and R are each a (C ₁ -C ₄ ) alkoxy group. ) -Ω- [3,4-di (C
₁ -C ₄₎ alkoxy - or 2,3,4-tri (C ₁ -C ₄₎ alkoxy - phenyl] -ω- hydroxy - 1-N indicated by an alkyl group] - [(2-benzyl-phenoxy)
Alkyl] -4-N-substituted or unsubstituted piperazine or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, a cerebral dysfunction improving agent.