JP2913195B2 - 1,2-ethanediol derivatives or salts thereof and brain function improving agents containing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a compound represented by the general formula [I]: "Wherein R ¹ represents an optionally substituted phenyl group; R ²
Is a hydrogen atom or a lower alkyl group or a hydroxyl protecting group; R ³ is a hydrogen atom or a lower alkyl group;
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or The integers of 1 to 6 are shown respectively. Examples of the nitrogen-containing heterocyclic group for R ⁶ include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Nil, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl,
An imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or indazolyl group; a substituent of R ¹ is
Halogen atom, optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy,
Al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected An amino group, an optionally protected hydroxyl group, a nitro group, an oxo group and a lower alkylenedioxy group, and also a lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy substituent in R ¹ , Aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al lower alkylthio, al lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyl Mino, the substituent of the nitrogen-containing heterocyclic group in an arylsulfonylamino or heterocyclic group, and R ^6, halogen atom, optionally protected hydroxyl group, protected or unprotected carboxyl group, are protected An amino group which may be substituted, a lower alkyl group which may be substituted with an optionally protected hydroxyl group, an aryl group which may be substituted with halogen, an aroyl group which may be substituted with halogen, a lower alkoxy group May be substituted with a lower alkoxy group, a lower acyl group, an ar lower alkyl group, an ar lower alkenyl group, a heterocyclic group, a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group and an arylsulfonyl group. And may be substituted with one or more of these substituents; the amino group of the substituent in R ¹ and R ⁶ Examples of the substituent of the amino group in the present invention include a hydroxyl group which may be protected, a cycloalkyl group, a lower alkyl group which may be substituted with a hydroxyl which may be protected or a carboxyl group which may be protected, and aryl. Group, lower acyl group, ar-lower alkyl group, heterocyclic group, heterocyclic -CO- group which may be substituted with an oxo group, adamantyl group, lower alkylsulfonyl group and arylsulfonyl group. May be substituted with one or more substituents (provided that the phenyl group of R ¹ is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy or an optionally protected hydroxyl group, R ⁶ has the formula -NR ⁷ R ⁸ {R ⁷ is an ar (lower) alkyl or heterocyclic group; R ⁸ is a hydrogen atom or a lower a Kill group; or R ⁷ and R ⁸ together with the N atom the following groups [R ⁹ is an aryl or heterocyclic group; R ¹⁰ is an aryl, heterocyclic group or (. R ⁸ is showing the same meaning as mentioned above) a; R ¹¹ is
R ¹² is a carboxyl or lower alkoxycarbonyl group; and i is 0, 1, 2 or 3;
Shown respectively. ] Is excluded. ｝. The heterocyclic group as a substituent of R ¹ is pyrrolyl, pyrrolidinyl,
Piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl,
Morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl,
Thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl, indazolyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, dihydroquinoxyl Nil, quinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H
-1-thianaphthyl, 2,3-dihydrobenzofuranyl,
The benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenil, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups are respectively shown. And a brain function-improving agent comprising a 1,2-ethanediol derivative represented by the formula (I): "Wherein R ¹ represents an optionally substituted phenyl group; R ²
Is a hydrogen atom or a lower alkyl group or a hydroxyl protecting group; R ³ is a hydrogen atom or a lower alkyl group;
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or The integers of 1 to 6 are shown respectively. Examples of the nitrogen-containing heterocyclic group for R ⁶ include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Nil, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl,
An imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or indazolyl group; a substituent of R ¹ is
Halogen atom, optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy,
Al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected An amino group, an optionally protected hydroxyl group, a nitro group, an oxo group and a lower alkylenedioxy group, and also a lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy substituent in R ¹ , Aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al lower alkylthio, al lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyl Mino, the substituent of the nitrogen-containing heterocyclic group in an arylsulfonylamino or heterocyclic group, and R ^6, halogen atom, optionally protected hydroxyl group, protected or unprotected carboxyl group, are protected An amino group which may be substituted, a lower alkyl group which may be substituted with an optionally protected hydroxyl group, an aryl group which may be substituted with halogen, an aroyl group which may be substituted with halogen, a lower alkoxy group May be substituted with a lower alkoxy group, a lower acyl group, an ar lower alkyl group, an ar lower alkenyl group, a heterocyclic group, a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group and an arylsulfonyl group. And may be substituted with one or more of these substituents; the amino group of the substituent in R ¹ and R ⁶ Examples of the substituent of the amino group in the present invention include a hydroxyl group which may be protected, a cycloalkyl group, a lower alkyl group which may be substituted with a hydroxyl which may be protected or a carboxyl group which may be protected, and aryl. Group, lower acyl group, ar-lower alkyl group, heterocyclic group, heterocyclic -CO- group which may be substituted with an oxo group, adamantyl group, lower alkylsulfonyl group and arylsulfonyl group. May be substituted with at least one kind of substituent (provided that 1-phenyl-2- (2-diethylaminoethoxy) -1-ethanol, 1-phenyl-2- (2-diethylaminoethoxy) -1-propanol, -Phenyl-2- (2-dimethylaminoethoxy) -1-propanol, 2-methyl-6-hydroxy-4- Kisa-6-hexyl-phenyl-2-hexylamine, 2-methyl-6-hydroxy-4-oxa -6
-Nitrophenyl-2-hexylamine, 2-methyl-
6-hydroxy-4-oxa-6-p-chlorophenyl-2-hexylamine, 2-methyl-4-oxa-6
Phenyl-6-hydroxyhexylamine and the phenyl group of R ¹ is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy or optionally protected hydroxyl group,
⁶ is a group represented by the formula -NR ⁷ R ⁸ ｛R ⁷ is an ar lower alkyl or heterocyclic group; R ⁸ is a hydrogen atom or a lower alkyl group;
Or R ⁷ and R ⁸ together with the N atom form the following group: [R ⁹ is an aryl or heterocyclic group; R ¹⁰ is an aryl, heterocyclic group or (. R ⁸ is showing the same meaning as mentioned above) a; R ¹¹ is
R ¹² is a carboxyl or lower alkoxycarbonyl group; and i is 0, 1, 2 or 3;
Shown respectively. A phenyl group optionally substituted with a lower alkyl group for R ¹ , wherein R ⁶ is
The following groups, Excluding the case where n is 0 and R ⁶ is an amino group or an ammonio group which may be substituted. ｝. The heterocyclic group as a substituent of R ¹ is pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl,
Quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, prinyl, indazolyl, furyl, thienyl, benzothienyl, pyranyl, pyranyl ,
Oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
Dihydroquinoxalinyl, quinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3
-Dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenil, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, Isoindolyl and isoquinolyl groups are indicated, respectively. And a salt thereof.

[Prior Art] Conventionally, as a 1,2-ethanediol derivative, for example, US Pat. No. 2,928,845, Journal of Pharmaceutical Science (J. Pharm. Sci.)
50, pp. 769-771 (1961) and Pharmaco Edizion Scientifica (Farmaco. Ed. Sci), Vol.
19, pp. 1056-1065 (1964) and the like are known.

However, these compounds have been used as local anesthetics or synthetic intermediates thereof, but their use as brain function improving agents, anti-amnesic agents and anti-dementia agents is not known at all.

International Patent Application Publication No. 88/8424 describes 1,2-ethanediol derivatives used for treatment of Alzheimer's disease and other degenerative neuropathies. However, no specific description and examples of those derivatives are found in the specification.

[Problems to be Solved by the Invention] Currently, cerebral metabolic activators or cerebral circulation improving agents are used for the treatment of various dementias, particularly Alzheimer's dementia and cerebrovascular dementia.

However, no cerebral function improving agent useful for treating cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic encephalopathy, stroke, etc. has not been found yet.

An object of the present invention is to solve the above problems and provide a useful novel brain function improving agent with few side effects.

[Means for Solving the Problems] The present inventors have conducted intensive studies with the aim of solving the above problems, and as a result, the following general formula [I]: Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n have the same meanings as described above, respectively. It has been found that it exhibits excellent anti-amnesic and anti-hypoxia effects and is extremely useful as a brain function improving agent, and thus completed the present invention.

The cerebral function improving agent of the present invention is not only used as a normal cerebral function improving agent useful for treatment of sequelae of ischemic encephalopathy and stroke, but also amnesia and dementia (for example, cerebrovascular dementia, It also means an agent for treating or preventing various senile dementias and Alzheimer's disease).

 Hereinafter, the present invention will be described in detail.

In this specification, unless otherwise specified, each term has the following meaning.

A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a lower alkyl group is, for example,
A _C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; a lower alkenyl such as vinyl, propenyl, butenyl, pentenyl and the lower alkenyloxy _group, a _{C 2 to 6} alkenyl -O- group; a _{C 2 to 6} alkenyl groups such as hexenyl groups and cycloalkyl groups, for example, Shikuroperopiru, cyclobutyl, _{C 3,} such as cyclopentyl and cyclohexyl groups _A lower alkoxy group is a _C1-6 alkyl-O- group; a lower alkylthio group is a _C1-6 alkyl-S- group; an aryl group is phenyl, naphthyl, An aryloxy group is an aryl-O-
An ar-lower alkyl group is, for example, benzyl,
The ar (lower) alkoxy group, an aralkyl _{C 1 to 4} alkyl -O- group; diphenylmethyl, aralkyl _{C 1 to 4} alkyl groups, such as trityl and phenethyl groups and the ar (lower) alkylthio group, aralkyl _{C 1 to 4} alkyl A lower alkylenedioxy group, for example, a _C1-4 alkylenedioxy group such as a methylenedioxy and ethylenedioxy group; a lower acyl group, for example, a formyl, acetyl, and butyryl group the aroyl group, an aryl -CO- group; a _{C 1 to 6} acyl group such as a lower alkylsulfonyl _{group, C 1 to 6} alkyl -SO ₂ - group;
The ar (lower) alkylsulfonyl group, aralkyl C _{1 to 6} alkyl -SO ₂ group a; and arylsulfonyl group, an aryl -SO ₂ - group a; Lower alkylsulfonyloxy group,
The C _{1 to 6} alkyl -SO ₂ -O- group; and aryl sulfonyloxy group, an aryl -SO ₂ -O- group; and arylsulfonylamino group, an aryl -SO ₂ NH- group; a lower alkylsulfonyl An amino group is a C _1-6 alkyl-SO ₂ NH— group; a di-lower alkylamino group is
_An ammonio group means a tri-lower alkylammonio group such as a trimethylammonio group and a triethylammonio group;

Examples of the hydroxyl protecting group and the protecting group for the hydroxyl group, the carboxyl group and the amino group in the substituent of R ² include Protective Groups in Organic Synthesis.
c Synthesis), [Theodora W Green (T
heodra W. Green (1981), John Willie and
Sands Incorporated (John Wiley & Sons.I
nc.)], the protecting groups for ordinary hydroxyl group, carboxyl group and amino group described in [1]. Particularly, the protecting groups for hydroxyl group include, for example, lower alkyl, lower acyl, tetrahydropyranyl and substituted And ar lower alkyl groups such as benzyl which may be substituted.

The 1,2-ethanediol derivative of the general formula [I] may be used as a pharmaceutically acceptable salt, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; Formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid,
Salts with carboxylic acids such as malic acid, tartaric acid and aspartic acid; methanesulfonic acid, benzenesulfonic acid, p
-Salts with sulfonic acids such as toluenesulfonic acid and naphthalenesulfonic acid, and salts with alkali metals such as sodium and potassium.

When isomers (for example, optical isomers, geometric isomers and tautomers) are present in the 1,2-ethanediol derivative of the general formula [I] or a salt thereof, the present invention relates to all of the isomers. As well as hydrates, solvates and all crystalline forms.

Next, a method for producing the 1,2-ethanediol derivative of the general formula [I] or a salt thereof will be described.

The 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be produced by a method known per se or an appropriate combination thereof, for example, by the following production methods.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n each have the same meaning as described above, and R ^2a has the same hydroxyl protecting group as R ² ; R ^6a is a nitrogen-containing heterocyclic group which may be substituted as in R ⁶ and has a free valence at a carbon atom forming the ring; R ^6b is the same substituted as R ⁶ A nitrogen-containing heterocyclic group which may have a free valence at a nitrogen atom forming the ring or an amino group which may be substituted; R ¹³ represents the same hydroxyl-protecting group as R ² X ¹ and X ² are the same or different and each is a halogen atom; Y is a halogen atom, a leaving group such as a lower alkylsulfonyloxy group or an arylsulfonyloxy group;
Y ^a is an arylsulfonyloxy group; and m is 1
And integers from 6 to 6 are shown. In addition, general formulas [III], [IIIa], [IV], [V],
[VII], [IX], [X], [XI], [XII], [XV
Examples of the salts of the compounds of [I], [Ia], [Ib], [Ic] and [Id] include the same salts as the salts of the compounds of the general formula [I].

Next, the above-described method will be described for each manufacturing method.

Production Method 1 The compound of the general formula [II] is reacted with a compound of the general formula [III] or a salt thereof or a compound of the general formula [IIIa] or a salt thereof in the presence or absence of a base to give a compound of the general formula The compound of [Ia] or a salt thereof can be produced.

The solvent used in this reaction may be any solvent which does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; sulfoxides such as dimethyl sulfoxide; N, N-dimethyl Examples include amides such as formamide; and ethers such as tetrahydrofuran and dioxane. These solvents may be used alone or in combination of two or more. Further, a compound of the general formula [III] or a compound of the general formula [IIIa] can be used as a solvent.

In addition, examples of the base used as needed include sodium hydride, sodium metal, potassium tert-butoxide, and the like.

In this reaction, the compound of the general formula [III] or a salt thereof or the compound of the general formula [IIIa] or a salt thereof is used in an amount of 1 to 100 times, preferably 1 to 100 times the compound of the general formula [II], It is 1 to 10 times mol.

The amount of the base used as needed is 0.01 to 1.2 times the molar amount of the compound of the general formula [II].

This reaction is usually carried out at 20 to 150 ° C, preferably at 70 to 90 ° C.
Then, it may be carried out for 1 minute to 24 hours, preferably for 5 minutes to 5 hours.

Production Method 2 (1) A compound of the general formula [V] or a salt thereof is reacted with a compound of the general formula [IV] or a salt thereof in the presence or absence of a base. Can be manufactured.

This reaction may be carried out in the same manner as in Production Method 1.

The obtained compound of the general formula [V] or a salt thereof may be used for the next reaction without isolation.

(2) The compound of the general formula [V] or a salt thereof is subjected to a usual hydroxyl group protection reaction to give the compound of the general formula [V]
I] can be produced.

The obtained compound of the general formula [VI] may be used for the next reaction without isolation.

Further, by subjecting the compound of the general formula [VI] to a selective elimination reaction of a hydroxyl protecting group, the compound of the general formula [VI]
Compound [I] or a salt thereof can be produced.

The obtained compound of the general formula [VII] or a salt thereof may be used for the next reaction without isolation.

These reactions can be carried out by methods known per se, for example, Protective Groups in Organic Synthesis,
[Theodora W. Green
n) (1981), John Willie and Sons
Incorporated (John Wiley & Sons. Inc.)]
May be performed by the method described in (1) or a method analogous thereto.

The hydroxyl protecting group (R ¹³
And the combination of R ^2a ) may be appropriately selected.

(3) a compound of the general formula [VII] or a salt thereof in a solvent,
By reacting a halogenating agent or a sulfonylating agent in the presence or absence of a base, the compound represented by the general formula [VIII]
Can be produced.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile. And amides such as N, N-dimethylformamide. These solvents may be used alone or in combination of two or more.

Examples of the base used as needed include, for example, triethylamine, diisopropylethylamine,
Organic or inorganic bases such as 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), pyridine, potassium tert-butoxy, sodium carbonate, potassium carbonate and sodium hydride.

As the halogenating agent, for example, phosphorus oxychloride,
Phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and the like.

Examples of the sulfonylating agent include methanesulfonyl chloride and p-toluenesulfonyl chloride.

The amount of the halogenating agent or the sulfonylating agent and the base to be used if necessary is 1 mol or more, preferably 1 to 2 mol, per mol of the compound of the general formula [VII] or a salt thereof. .

The reaction is usually carried out at -10 to 100 ° C, preferably at 0 to 40 ° C.
C. for 10 minutes to 30 hours.

The obtained compound of the general formula [VIII] may be used in the next reaction without isolation.

(4) reacting the compound of the general formula [VIII] with the compound of the general formula [IX] or a salt thereof in the presence or absence of a base and in the presence or absence of a catalyst,
The compound of the general formula [Ib] or a salt thereof can be produced.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include the same solvents as described in the above-mentioned Production method 2 (3).

Examples of the catalyst used as needed include potassium iodide and sodium iodide.

The amount of the catalyst used as needed is determined according to the general formula [VI
0.1 to 1-fold the molar amount of the compound of the formula [II].

Examples of the base used as necessary include, for example, the same bases as described in the above-mentioned Production method 2 (3).

The amount of the compound of the general formula [IX] or a salt thereof or the base used if necessary is at least equimolar to the compound of the general formula [VIII], preferably 1 to
It is 20 times mol.

This reaction is usually performed at 10 to 150 ° C, preferably at 20 to 100 ° C.
Then, it may be carried out for 10 minutes to 20 hours.

Production Method 3 (1) A compound of the general formula [IX] or a salt thereof is reacted with a compound of the general formula [X] or a salt thereof in the presence or absence of a base. Can be manufactured.

This reaction may be carried out in the same manner as in Production Method 1.

(2) Producing a compound of the general formula [XII] or a salt thereof by reacting a compound of the general formula [XI] or a salt thereof with a sulfonylating agent in a solvent in the presence or absence of a base Can be.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include the same solvents as described in the above-mentioned Production method 2 (3).

Examples of the base used as necessary include, for example, the same bases as described in the above-mentioned Production method 2 (3).

Examples of the sulfonylating agent include p-toluenesulfonyl chloride.

The amount of the sulfonylating agent and the base used as required is 0.95 mol or more, preferably 1 to 2 mol, per mol of the compound of the general formula [XI] or a salt thereof, respectively.

The reaction is usually carried out at -10 to 100 ° C, preferably at 0 to 40 ° C.
C. for 10 minutes to 30 hours.

The obtained compound of the general formula [XII] or a salt thereof may be used for the next reaction without isolation.

(3) The compound of the general formula [XIII] can be produced by subjecting the compound of the general formula [XII] or a salt thereof to a usual hydroxyl group protection reaction.

This reaction can be carried out by methods known per se, for example, Protective Groups in Organic Synthesis, [Theodra W. Green (1)
981), John Wiley & Sons, Inc.] or a method analogous thereto.

The obtained compound of the general formula [XIII] may be used for the next reaction without isolation.

(4) reacting a compound of the general formula [XII] or a salt thereof or a compound of the general formula [XIII] with a compound of the general formula [IX] or a salt thereof in the presence or absence of a base, The compound of [Ic] or a salt thereof can be produced.

This reaction may be carried out in the same manner as in Production Method 2 (4).

Production Method 4 (1) A compound of the general formula [XVI] or a salt thereof can be produced by reacting a compound of the general formula [XIV] with a compound of the general formula [XV].

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used alone or in combination of two or more.

In this reaction, the amount of the compound of the general formula [XV] to be used is 0.8 to 100-fold the molar amount of the compound of the general formula [XIV],
Preferably, it is 0.8 to 10 moles.

This reaction may be carried out usually at -78 ° C to 100 ° C, preferably at -78 ° C to 50 ° C for 5 minutes to 24 hours.

The obtained compound of the general formula [XVI] or a salt thereof may be used for the next reaction without isolation.

The compound of the general formula [XV] used here can be synthesized by a method known per se, for example, Bulletin de la Societe Simic de France (Bull. Soc. Chim. Fr.), 1967
(5), page 153-1540.

(2) The compound of the general formula [XVI] or its salt
The compound of the general formula [Id] or a salt thereof can be produced by reacting the compound of the formula [X] or a salt thereof in the presence or absence of a base and in the presence or absence of a catalyst.

The solvent used in this reaction may be any solvent which does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; ethanol, propanol and butanol. Alcohols; nitriles such as acetonitrile; and N,
Examples thereof include amides such as N-dimethylformamide, and these solvents may be used alone or in combination of two or more.

Examples of the catalyst used as needed include potassium iodide and sodium iodide.

The amount of the catalyst used as needed is determined by the general formula [XV
It is 0.1 to 1-fold the molar amount of the compound of I] or a salt thereof.

Examples of the base used as necessary include, for example, the same bases as described in the above-mentioned Production Method 2 (3), and the compound of the general formula [IX] can also be used as the base.

The amount of the compound of the general formula [IX] or a salt thereof or the base used as needed is at least equimolar to the compound of the general formula [XVI] or a salt thereof, preferably 1 to 20 times. Is a mole.

This reaction is usually performed at 10 to 150 ° C, preferably at 20 to 100 ° C.
Then, it may be carried out for 10 minutes to 20 hours.

In addition, the reaction reagent or base used in the above reaction can be used as a solvent depending on their properties.

General formulas [II], [II
I], [IIIa], [IV], [V], [VI], [VII],
[VIII], [IX], [X], [XI], [XII], [XII
In the compounds of [I], [XIV], [XV] and [XVI], when isomers (for example, optical isomers, geometric isomers and tautomers) exist, all of these isomers are used Hydrates, solvates and all crystalline forms can be used.

Formulas [II] [III], [IIIa], [IV], [V],
[VI], [VII], [VIII], [IX], [XII], [XII
I], [XIV], [XV], [XVI], [I], [Ia], [I
b) In the compounds of [Ic] and [Id], a compound having a hydroxyl group, an amino group or a carboxyl group may be prepared by protecting these hydroxyl group, amino group or carboxyl group with an ordinary protecting group in advance. Thereafter, if necessary, these protecting groups can be eliminated by a method known per se.

The thus obtained 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography.

Further, the 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be subjected to, for example, an oxidation reaction, a reduction reaction, an addition reaction, an acylation reaction, an alkylation reaction, a sulfonylation reaction, a deacylation reaction, a substitution reaction. The 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be derived by appropriately combining known methods such as a dehydration reaction and a hydrolysis reaction.

The compound of the general formula [II], which is a raw material for producing the 1,2-ethanediol derivative of the general formula [I] or a salt thereof, can be prepared by a method known per se, for example, Journal of American Chemical. Society (JACS), 87th
Vol. 1, p. 1353 (1965), New Laboratory Chemistry, Vol. 14, Vol.
It can be manufactured on page 579 (1977, Maruzen) and the like.

When the 1,2-ethanediol derivative of the general formula [I] or a salt thereof is used as a medicament, pharmaceutically acceptable excipients, carriers and diluents may be appropriately mixed with formulation auxiliaries. , Tablets, capsules, powders,
It can be administered orally or parenterally in the form of granules, fine granules, pills, suspensions, emulsions, solutions, syrups or injections. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, body weight and symptoms of the patient. In the case of oral administration, usually 0.01 to 1 day per adult.
500 mg may be administered in one to several divided doses.

Next, the pharmacological action of the 1,2-ethanediol derivative of the general formula [I] or a salt thereof used in the present invention will be described.

The test compound numbers used in the following pharmacological tests are as follows:
The compound numbers in Production Examples were cited.

1. Anti-hypoxia activity A group of 10 ddY female mice (5 to 6 weeks old) is orally administered 100 mg / Kg of a test compound dissolved in physiological saline.
One hour after administration (or 30 minutes ^* ), the mouse is placed in a 300 ml glass container, and 4% oxygen and 96%
A gaseous mixture of nitrogen was aerated at 5 l / min, and the time from the start of aeration to the death of the mouse was measured.

 The control group was orally administered only saline.

The anti-hypoxia effect of the test compound is represented by the following formula: I asked more.

 Table 1 shows the results.

2. Anti-amnesic effect a) Electroconvulsive shock (ECS) -induced amnesia model A test compound dissolved in a physiological saline solution was intraperitoneally administered to 10 ddY male mice (5 to 6 weeks old) per group. After an hour, the mouse is stepped through two chambers of light and dark.
-Through) type passive avoidance training foil (MPA-100M, manufactured by Muromachi Kikai Co., Ltd.)
After 0.5 seconds, a current (1.6 mA, 3 seconds) was applied to the grid on the floor to attempt acquisition, and immediately afterwards, ECS (25 m
A, for 0.5 seconds). As a test trial, the mice were placed again in the light room 24 hours later, and the time (reaction latency) until the mice entered the limbs in the dark room was measured for up to 300 seconds.

The reaction latency was measured in the same manner for the mice of the control group to which only saline was administered intraperitoneally.

The anti-amnesic effect was defined as the median of the response latency and represented by the following symbols.

−: 0 to 60 seconds +: 61 to 100 seconds ++: 101 to 150 seconds ++: 151 to 300 seconds The results are shown in Table-2.

b) Cycloheximide-induced amnesia model. Cycloheximide impairs the memory retrieval process in mice, according to Yamazaki et al.
Vol. 127-136 (1983)]. Therefore, the following test was performed.

Methods: Drugs, Spirit, and Behavior, Volume 3, pages 127-136 (1983)
Year) and Nippon Pharmacology Journal, Vol. 89, pp. 243-252 (19
1987).

In addition, as a device, a black acrylic box with a floor portion of 22 cm long, 22 cm wide, 21 cm high made of stainless steel grid and a table with 7 cm long, 7 cm wide, 2 cm high provided in one corner of the grid of the floor. A step-down passive avoidance training foil was used.

For a group of 10 ddY male mice (5-6 weeks old),
Cycloheximide (120mg / Kg) dissolved in physiological saline
Is administered subcutaneously, and 15 minutes after the administration, the mouse is placed on a table in the above device. Immediately after the mouse dropped on the floor, a 2 mA current was applied to the floor grid for 2 seconds, and the acquisition trial was performed by immediately returning the mouse to the home cage. As a test trial, after 24 hours, each test compound dissolved in physiological saline was orally administered to the cycloheximide-treated mouse, and 30 minutes after the administration, the mouse was placed on the table in the above apparatus, and the mouse descended from the table Time (reaction latency) up to 300
Measured for seconds.

The response latency was measured in the same manner for mice in the control group to which only saline was orally administered.

The anti-amnesic effect was defined as the median of the response latency and represented by the following symbols.

−: 0 to 60 seconds +: 61 to 100 seconds ++: 101 to 150 seconds ++: 151 to 300 seconds The results are shown in Table-3.

3. Acetylcholinesterase inhibitory activity The method of Ellman et al. [Biochemical Pharmacol.
95, 1961].

That is, acetylthiocholine as a substrate is added to a phosphate buffer containing 5,5′-dithiobis- (2-nitrobenzoic acid) [DTNB], a test compound and mouse brain homogenate as a source of acetylcholinesterase, and the mixture is incubated. The resulting 5-thio-2-nitrobenzoic acid was measured at 412 nm.

Acetylcholinesterase inhibitory activity was expressed as the inhibition rate when the final concentration of the test compound was 10 μg / ml.

 Table 4 shows the results.

4. Acute toxicity A test compound dissolved in physiological saline was intravenously administered to three ddY male mice (5 to 6 weeks of age) per group, and the acute toxicity was examined.

As a result, test compound numbers 1, 2, 3, 6, 8, 9,
15, 16, 25, 30, 33, 34, 38, 40, 42, 44, 46, 52, 5
3, 54, 65, 67, 70, 71, 112, 119, 120, 126, 132, 14
7, 151, 159, 160, 170, 176, 178, 182, 190, 194, 20
Compounds 9, 219, 220 and 221 showed no death at 50 mg / Kg.

From the above test results, it can be easily understood that the 1,2-ethanediol derivative of the general formula [I] or a salt thereof exhibits excellent anti-hypoxia action, anti-amnestic action and acetylcholinesterase inhibitory action, and has low toxicity. It can be understood.

These results indicate that the cerebral function improving agent of the present invention is useful for treating cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic encephalopathy, stroke, and the like.

[Effects of the Invention] Therefore, it is clear that the 1,2-ethanediol derivative of the general formula [I] or a salt thereof is a compound extremely useful as a brain function improving agent.

Next, a method for producing the 1,2-ethanediol derivative of the general formula [I] or a salt thereof will be specifically described with reference to production examples.

The mixing ratios of the solvents are all volume ratios,
The carrier in the column chromatography was silica gel manufactured by Merck [Kieselgel 60, art.7734 (Kieselg
el 60, Art.7734)].

The abbreviations used below have the following meanings.

Me: methyl, Et: ethyl, i-Pr: isopropyl, tB
u: tert-butyl, Ac: acetyl, Ph: phenyl, DPM: diphenylmethyl, Bz: benzyl, Tr: trityl, IPA: isopropyl alcohol, IPE; diisopropyl ether, PTS;
p-Toluenesulfonic acid [] in the text and tables indicates a recrystallization solvent.

Production Example 1 (1) A mixture of 10.8 g of (L) -dibenzoylcystine, 1.6 g of lithium borohydride, 2.4 g of tert-butanol and 180 ml of tetrahydrofuran was refluxed for 1 hour, and then refluxed for 6 hours.
Cool to 0 ° C. To this mixture, 6.1 g of 4-benzyloxyphenacyl bromide is added, and the mixture is stirred at the same temperature for 30 minutes and further at -40 to -30 ° C for 3 hours. After completion of the reaction, the reaction mixture is introduced into a mixture of 100 ml of water and 200 ml of diethyl ether, and the organic layer is separated. The organic layer is sequentially washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene) to give (S) -1- (4
-Benzyloxyphenyl) -2-bromoethanol 2.
Get 8g.

(2) (S) -1- (4-benzyloxyphenyl)-
2.8 g of 2-bromoethanol was dissolved in a mixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran, 4 ml of an aqueous solution in which 0.8 g of potassium hydroxide was dissolved was added to this solution under ice-cooling, and the resulting mixture was allowed to stand at the same temperature for 5 minutes. And even at room temperature
Stir for 10 minutes. Then, the reaction mixture is introduced into a mixture of 50 ml of diethyl ether and 50 ml of ice water, and the organic layer is separated. The aqueous layer is extracted with 25 ml of diethyl ether. The extract is combined with the organic layer, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 1.4 g of (S) -2- (4-benzyloxyphenyl) oxirane.

Melting point: 56-61 ° C Similarly, the following compound is obtained.

(S) -2- (3-methylphenyl) oxirane (S) -2- (4-phenoxyphenyl) oxirane Production Example 2 (1) (+)-Diisopinocan phenyl chloroborane 23
g in 30 ml of tetrahydrofuran,
C., and 12 g of 4-benzyloxyphenacyl bromide are added to this solution and the resulting mixture is stirred at -20 to -15.degree. C. for 4 hours. Then, the reaction mixture is introduced into a mixture of 150 ml of diethyl ether and 100 ml of ice water, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (eluent; hexane: toluene = 1: 2) to obtain 6.8 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol.

(2) (R) -1- (4-benzyloxyphenyl)-
Dissolve 6.0 g of 2-bromoethanol in a mixed solvent of 50 ml of methanol and 25 ml of tetrahydrofuran, and add 5 g of an aqueous solution in which 1.5 g of potassium hydroxide was previously dissolved under ice-cooling.
is added and the resulting mixture is stirred at the same temperature for 5 minutes and further at room temperature for 10 minutes. Then, after introducing the reaction mixture into a mixture of 100 ml of diethyl ether and 100 ml of ice water, the organic layer is separated. The aqueous layer is extracted with 50 ml of diethyl ether. The extract is combined with the organic layer, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.7 g of (R) -2- (4-benzyloxyphenyl) oxirane.

Melting point: 58-67 ° C Similarly, the following compound is obtained.

(R) -2- (3-methylphenyl) oxirane (R) -2- (4-phenoxyphenyl) oxirane Production Example 3 2- (N, N-dimethylamino) ethanol in 31 ml of tert
-Add 3.4 g of potassium butoxide and raise the temperature to 80 ° C.
Add 2- (3-fluorophenyl) oxirane 7.
After dropwise adding 7 g over 40 minutes, the mixture obtained is stirred at the same temperature for 3 hours. Then, add 200 ml of ice water to the reaction mixture.
After introduction into a mixture of and 200 ml of ethyl acetate, the organic layer is separated off. Add 50 ml of water to the separated organic layer, and add 6N hydrochloric acid.
After adjusting to pH 1, the aqueous layer is separated. 100 ml of chloroform is added to the separated aqueous layer, and p is added with a 2N aqueous sodium hydroxide solution.
After adjusting to H11, the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 5: 1). The obtained oil is dissolved in 25 ml of acetone, and hydrogen chloride gas is introduced into the solution. The precipitated crystals are collected, washed with acetone, and dried to give 2-
[2- (N, N-dimethylamino) ethoxy] -1- (3
3.1 g of (fluorophenyl) ethanol hydrochloride (compound no. 1) are obtained.

Melting point: 164-165 ° C [EtOH] The compounds in Table 5 are obtained in the same manner.

In Table 5, R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁶ , na and nb each represent a substituent or an integer of the following formula.

Production Example 4 1-benzyl-4-hydroxypiperidine 5.00 g, ter
1.97 g of potassium t-butoxide and dimethyl sulfoxide
The temperature of 4 ml of the mixture is raised to 80 ° C., and 2.10 g of styrene oxide is added dropwise to this solution over 40 minutes, and the resulting mixture is stirred at the same temperature for 3 hours. The reaction mixture was then introduced into a mixture of 100 ml of ice water and 80 ml of ethyl acetate,
After adjusting the pH to 11.5 with N hydrochloric acid, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 10: 1). The obtained oil was dissolved in 8 ml of ethanol, and 6
1 ml of N-dry ethanol solution of hydrogen chloride and 20 ml of diethyl ether are added and the resulting mixture is stirred at room temperature for 30 minutes. The precipitated crystals are collected, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to give 2-
930 mg of the hydrochloride salt of (1-benzylpiperidin-4-yloxy) -1-phenylethanol (Compound No. 113) are obtained.

Melting point: 193-195 ° C. In the same manner, the compounds in Table 6 are obtained.

In Table 6, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer of the following formula.

Production Example 5 (1) 4-benzyl-2-hydroxymethylmorpholine
A mixture of 4.30 g, potassium tert-butoxide 930 mg and dimethylsulfoxide 4 ml is heated to 80 ° C. After 2.50 g of styrene oxide was added dropwise to this solution over 20 minutes, the resulting mixture was stirred at the same temperature for 2 hours. Then, the reaction mixture was mixed with 30 ml of diethyl ether and 30 ml of ice water.
And the organic layer is separated. 10 ml of water is added to the separated organic layer, the pH is adjusted to 2.0 with 6N hydrochloric acid, and the aqueous layer is separated. After adding 30 ml of diethyl ether to the separated aqueous layer and adjusting the pH to 11 with a 2N aqueous sodium hydroxide solution, the organic layer is separated. The separated organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 1: 1) to give oily 1-phenyl-2-[(4-benzylmorpholine -2-yl) methoxy] ethanol (Compound No. 14
4) Obtain 2.00g.

 Similarly, compounds of Table-7 are obtained.

Note that R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 7 each represent a substituent or an integer of the following formula.

(2) A mixture of 1.00 g of 1-phenyl-2-[(4-benzylmorpholin-2-yl) methoxy] ethanol, 500 mg of 5% palladium-carbon and 10 ml of methanol is hydrogenated at normal temperature and normal pressure for 4 hours. . After the reaction, the palladium-carbon is removed. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: methanol = 10: 1) to give an oily substance of 450m
get g. This oil is dissolved in 2.5 ml of isopropanol, 220 mg of fumaric acid are added to the resulting solution, and the resulting mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected, washed with 2 ml of isopropyl alcohol, and dried to give 1-
Phenyl-2-[(morpholin-2-yl) methoxy]
460 mg of 1/2 fumarate of ethanol (Compound No. 151) are obtained.

Melting point: 146.5-147 ° C [EtOH] The compounds in Table 8 are obtained in the same manner.

In Table 8, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer of the following formula.

(3) 1- (3-methoxyphenyl) -2-[(4-tritylmorpholin-2-yl) methoxy] ethanol 7 g
Was dissolved in 35 ml of acetone.
After adding 2.6 ml of a dry ethanol solution of hydrogen chloride and stirring at room temperature for 2 hours, the solvent is distilled off under reduced pressure. After adding 50 ml of water and 30 ml of ethyl acetate to the obtained residue,
Separate the aqueous layer. After washing the separated aqueous layer with ethyl acetate, 50 ml of chloroform is added, the pH is adjusted to 11 with a 1N aqueous sodium hydroxide solution, and the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: methanol = 5: 1) to obtain 1 g of an oil. This oily substance is isopropanol
After dissolving in 3 ml, 430 mg of fumaric acid was added to this solution,
The resulting mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected and dried to give 1- (3-methoxyphenyl) -2-
[(Morpholin-2-yl) methoxy] 1/1 of ethanol
800 mg of fumarate (Compound No. 155) are obtained.

Melting point: 122-123.5 ° C [EtOH] In the same manner, the compounds in Table 9 are obtained.

Note that R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 9 each represent a substituent or an integer of the following formula.

Production Example 6 (1) 5.1 g of potassium tert-butoxide was added to 105 ml of ethylene glycol-mono-tert-butyl ether, and the temperature was raised to 80 ° C. To this solution, 35.0 g of 2- (3-chlorophenyl) oxirane was added dropwise over 1 hour, and the resulting mixture was stirred at the same temperature for 2 hours. Then, the reaction mixture is introduced into a mixture of 100 ml of ice water and 100 ml of ethyl acetate, and the organic layer is separated. The separated organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was further distilled under reduced pressure. A fraction having a boiling point of 140 to 146 ° C./0.9 mmHg was collected to give a colorless oily 1- (3-chlorophenyl)-. 2- (2-tert
-Butoxyethoxy) ethanol 37.7 g are obtained.

(2) 37.0 g of 1- (3-chlorophenyl) 2- (2-tert-butoxyethoxy) ethanol was added to 70 ml of methylene chloride.
In 12.9 g of pyridine and 1 part of acetic anhydride.
6.9 g are added and the resulting mixture is stirred at room temperature for 24 hours. Then, the reaction mixture was introduced into a mixture of 150 ml of ice water and 100 ml of methylene chloride, and adjusted to pH 2 with 6N hydrochloric acid.
Separate the organic layer. The separated organic layer is sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure, oily 1-acetoxy-1- (3-chlorophenyl) -2 is obtained.
40.0 g of-(2-tert-butoxyethoxy) ethane are obtained.

(3) 1-acetoxy-1- (3-chlorophenyl)-
40.0 g of 2- (2-tert-butoxyethoxy) ethane was dissolved in 40 ml of methylene chloride, and 80 ml of trifluoroacetic acid was added to this solution under ice-cooling.
Stir for hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 100 ml of toluene is added to the obtained residue, and the solvent is further distilled off under reduced pressure. The residue obtained is dissolved in a mixture of 90 ml of ethanol and 10 ml of water, 10.7 g of sodium hydrogen carbonate are added to this solution at room temperature, and the pH is adjusted to 6 to 7 with a saturated aqueous solution of sodium hydrogen carbonate. Then, the solution is concentrated to about half the volume under reduced pressure, 100 ml of ethyl acetate is added to the obtained concentrated solution, and the organic layer is separated. The aqueous layer is extracted with a further 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to give oily 1-
Acetoxy-1- (3-chlorophenyl) -2- (2-
19.4 g of hydroxyethoxy) ethane are obtained.

(4) 1-acetoxy-1- (3-chlorophenyl)-
95.0 m of methylene chloride containing 19.0 g of 2- (2-hydroxyethoxy) ethane and 9.1 ml of methanesulfonyl chloride
16.4 ml of triethylamine was added dropwise to the mixture of 1 under ice cooling over 1 hour, and the resulting mixture was stirred at the same temperature for 10 minutes and further at room temperature for 1 hour. The reaction mixture was then introduced into a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water, and 6N
After adjusting the pH to 2.0 with hydrochloric acid, the organic layer is separated. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-methane 24.5 g of sulfonyloxyethoxy) ethane are obtained.

(5) 1-acetoxy-1- (3-chlorophenyl)-
2- (2-methanesulfonyloxyethoxy) ethane 1.
40 g was dissolved in 7 ml of N, N-dimethylformamide, and 0.69 ml of N-methylpiperazine and potassium carbonate were added to this solution.
1.03 g are added and the resulting mixture is stirred at 80 ° C. for 3 hours. Subsequently, the reaction mixture is cooled and introduced into a mixture of 30 ml of ice water and 30 ml of diethyl ether, and the organic layer is separated off. The aqueous layer is extracted with a further 20 ml of diethyl ether.
The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 7 ml of methanol and 45 mg of sodium methoxide are added to the obtained residue, and the resulting mixture is left at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure, and ethyl acetate 20 ml was added to the obtained residue.
After adding 10 ml of water and water, the organic layer is separated off. The aqueous layer is extracted with a further 20 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed with saturated saline, and then purified by column chromatography (eluent; chloroform: methanol = 10: 1). 10 ml of ethanol is added to the obtained oil.
Then, 1.2 ml of a 6N ethanol solution of dry hydrogen chloride are sequentially added, 10 ml of diethyl ether is further added to the obtained mixture, and the resulting mixture is stirred for 30 minutes. The precipitated crystals are collected, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to give 1- (3-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl).
Ethoxy] ethanol dihydrochloride (Compound No. 158) 770
get mg.

Melting point: 211-213 ° C [MeOH-EtOH] In the same manner, the compounds in Table-10 are obtained.

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 10 each represent a substituent or an integer of the following formula.

Production Example 7 1- (4-benzyloxyphenyl) -2- [2-
(N, N-dimethylamino) ethoxy] ethanol hydrochloride 2.0 g, 10% palladium-carbon 500 mg and methanol 1
0 ml of the mixture is hydrogenated at normal temperature and normal pressure for 2 hours.
After completion of the reaction, the palladium-carbon is removed, and the solvent is distilled off under reduced pressure to give 1- (4-hydroxyphenyl) -2-.
1.4 g of the hydrochloride of [2- (N, N-dimethylamino) ethoxy] ethanol (compound no. 170) are obtained.

Melting point: 169.5-170.5 ° C [EtOH] Similarly, the compounds in Table 11 are obtained.

In addition, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 11 each represent a substituent or an integer of the following formula.

Production Example 8 1- (3-methylphenyl) -2- [2- (morpholin-4-yl) ethoxy] ethanol 1 g and pyridine 0.65
ml and 0.99 ml of acetic anhydride are added and the resulting mixture is stirred at room temperature for 3 hours. Then, the solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was mixed with 20 ml of ethyl acetate and water.
After adding 10 ml and adjusting the pH to 10 with potassium carbonate, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; chloroform: ethanol = 30:
If purified in 1), oily 1-acetoxy-1- (3-
1 g of methylphenyl) -2- [2- (morpholin-4-yl) ethoxy] ethane (Compound No. 178) is obtained.

 Similarly, compounds of Table 12 are obtained.

Note that R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 12 each represent a substituent or an integer of the following formula.

Production Example 9 1-acetoxy-1- (3-hydroxyphenyl)-
50 ml of a mixture of 3.30 g of 2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride and chloroform-water (1: 1)
Was added to the resulting mixture under ice cooling, and sodium carbonate 750 m
After adding g, the organic layer is separated. After the separated organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, 20 ml of benzene is added to the obtained residue, and the obtained mixture is heated to 60 ° C. A solution of 870 mg of ethyl isocyanate in 5 ml of benzene was added dropwise to the solution over 10 minutes, and the resulting mixture was stirred at the same temperature for 40 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 10: 1) to obtain an oil. The obtained oil was dissolved in 10 ml of ethanol, hydrogen chloride gas was introduced into the solution, and the solvent was distilled off under reduced pressure to obtain 1-acetoxy-1- [3- (N-ethylcarbamoyloxy) phenyl. ] -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 18
9) Obtain 1.90g.

Melting point: 111.5-113.5 ° C. [Me ₂ CO] Similarly, oily 1-acetoxy-1- [3- (3
-Chlorophenylcarbamoyloxy) phenyl] -2
This gives hydrochloride of-[2- (N, N-dimethylamino) ethoxy) ethane (Compound No. 190).

Production Example 10 (1) 9.5 g of potassium tert-butoxide was added to 92 ml of ethylene glycol, and the temperature was raised to 80 ° C. 2-
A solution of 34.7 g of (4-benzyloxyphenyl) oxirane in 220 ml of dimethyl sulfoxide was added dropwise over 3 hours, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture is then cooled, introduced into a mixture of ice water 1 and 600 ml of ethyl acetate and adjusted to pH 7 with 6N hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with 200 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: ethanol = 10: 1) to give 1- (4-benzyloxyphenyl) -2- (2- 25 g of (hydroxyethoxy) ethanol are obtained.

Melting point: 116.5-117 ° C [MeCN] (2) 1- (4-benzyloxyphenyl) -2- (2
-Hydroxyethoxy) ethanol 22.7 g pyridine 140
Dissolve in ml and cool to -20 ° C. After adding 19 g of p-toluenesulfonyl chloride to this solution, the resulting mixture is heated to 0 ° C. and reacted at the same temperature for 15 hours. The reaction mixture was then added to 300 ml of ice water and diethyl ether 2
After introducing the mixture into 00 ml of the mixture and adjusting the pH to 2 with 6N hydrochloric acid, the organic layer is separated. The aqueous layer was further diluted with 100 ml of diethyl ether.
Extract with Combine the extract with the previously separated organic layer,
After washing with 1N hydrochloric acid, water and saturated saline solution in that order, it is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The obtained residue is subjected to column chromatography (eluent;
Purification with toluene: ethyl acetate = 3: 1) gives an oily 1
-(4-benzyloxyphenyl) -2- [2- (p-
Toluenesulfonyloxy) ethoxy] ethanol 20.5
get g.

(3) 1- (4-benzyloxyphenyl) -2- [2
-(P-Toluenesulfonyloxy) ethoxy] pyridinium-p- at room temperature in a mixture of 20 ml of ethanol and 40 ml of methylene chloride containing 8.2 g of 3,4-dihydro-2H-pyran.
After addition of 2.3 g of toluenesulfonate, the mixture is refluxed for 30 minutes. Then, after cooling the reaction mixture, it is introduced into a mixture of 100 ml of ice water and 100 ml of methylene chloride, and the organic layer is separated. The organic layer is washed with water and dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, pale yellow oily 1- (4-benzyloxyphenyl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethane is obtained. 18.6g is obtained.

(4) 1- (4-benzyloxyphenyl) -1- (2
A mixture of 2 g of -tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethane, 5.9 ml of a 40% aqueous solution of methylamine and 20 ml of ethanol is refluxed for 2 hours. The reaction mixture is then cooled,
After introduction into a mixture of 50 ml and 50 ml of diethyl ether, the organic layer is separated off. Add aqueous layer to diethyl ether
Extract twice with 20 ml each. The extract is combined with the previously separated organic layer, 10 ml of water is added, the pH is adjusted to 1.0 with 6N hydrochloric acid, and the aqueous layer is separated. After stirring the separated aqueous layer at room temperature for 30 minutes, 30 ml of chloroform is added, the pH is adjusted to 12 with a 5% aqueous sodium hydroxide solution, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
10 ml of acetone is added to the obtained residue, and hydrogen chloride gas is introduced into the mixture under ice cooling. The precipitated crystals are collected, washed with acetone, and dried to give 1- (4-benzyloxyphenyl) -2- (2-methylaminoethoxy).
620 mg of the hydrochloride salt of ethanol (Compound No. 191) are obtained.

Melting point: 173 to 173.5 ° C [EtOH] The compounds in Table 13 are obtained in the same manner.

In Table 13, R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁶ , na and nb each represent a substituent or an integer of the following formula.

Production Example 11 2-[(imidazol-4-yl) methoxy] -1-
A mixture of 500 mg phenyl-ethanol, 1.1 ml pyridine, 1.1 ml triethylamine and 1.1 ml acetic anhydride was added to 10
After stirring at 0 ° C. for 1 hour, the mixture is cooled to room temperature, and the solvent is distilled off under reduced pressure. 1.1 ml of methyl iodide and 5 ml of acetonitrile were added to the residue obtained, and the mixture was allowed to stand at room temperature for 24 hours.
Leave for a time. Then, the solvent is distilled off under reduced pressure, 4 ml of ethanol and 6.8 ml of a 5% aqueous sodium hydroxide solution are added to the obtained residue, and the mixture is stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and 30 ml of chloroform was added to the residue.
And 20 ml of water are added and the organic layer is separated off. The organic layer is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained oil is subjected to column chromatography (eluent; chloroform: ethanol = 10: 1).
The resulting white crystals were added with diisopropyl ether and collected to obtain 450 mg of 2-[(1-methylimidazol-5-yl) methoxy] -1-phenylethanol (Compound No. 214).

Melting point: 102-105 ° C. In the same manner, the following compound is obtained.

1- (4-benzyloxyphenyl) -2-[(1-
Methyl imidazol-5-yl) methoxy] ethanol (Compound No. 215) Melting point: 148.5-150.5 ° C. [IPA-AcOEt] Production Example 12 1.08 g of 2- (2-aminoethoxy) -1-phenyl-ethanol, 730 mg of nicotinic acid, A solution of 810 mg of 1-hydroxybenzotriazole and 0.83 ml of triethylamine in 5 ml of tetrahydrofuran was added under ice-cooling to N, N '.
1.23 g of dicyclohexylcarbodiimide are added and the mixture is stirred for 5 minutes at the same temperature and for 1 hour at room temperature. Then, 11 ml of ethyl acetate is added to the reaction mixture, and the insoluble matter is removed. After adding 5 ml of water to the solution and adjusting the pH to 2 with 6N hydrochloric acid, the aqueous layer is separated. The organic layer is extracted with a further 5 ml of water. The extract is combined with the previously separated aqueous layer, and after adding 20 ml of chloroform and adjusting the pH to 10 with potassium carbonate, the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; chloroform:
Purification with ethanol (15: 1) gives 400 mg of oily 2- (2-nicotinoylaminoethoxy) -1-phenyl-ethanol (Compound No. 216).

IR (neat) cm ^-1 ; ν _{C = O} 1635 Production Example 13 (1) 5 g of (S) -4-benzyl-2-acetoxymethylmorpholine was dissolved in 10 ml of ethanol, and
A solution of 1 g of sodium hydroxide dissolved in 5 ml of water is added under ice cooling. After stirring the mixture at room temperature for 10 minutes, the reaction mixture is introduced into 50 ml of ice water and extracted with 50 ml of chloroform. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 30: 1),
3.6 g of oily (S) -4-benzyl-2-hydroxymethylmorpholine are obtained.

(2) Dissolve 3.5 g of (S) -4-benzyl-2-hydroxymethylmorpholine in 5 ml of ethanol, add 5 ml of 5.9N ethanol solution of dry hydrogen chloride under ice-cooling to this solution, and stir at the same temperature for 10 minutes. I do. Then add 5%
A mixture of 500 mg of palladium-carbon and 10 ml of methanol is added and the mixture is hydrogenated at 40 ° C. for 3 hours. After completion of the reaction, palladium-carbon is removed, and the solvent is distilled off under reduced pressure to obtain a yellow oil. 20 ml of dry methylene chloride and 4.7 ml of triethylamine are added to this and the mixture is stirred at room temperature for 30 minutes. Under ice cooling, a solution of 4.7 g of trityl chloride dissolved in 10 ml of methylene chloride is added dropwise over 20 minutes. After stirring the mixture at room temperature for 3 hours, the reaction mixture is introduced into 50 ml of ice water, and the organic layer is separated. After adding 20 ml of water to the separated organic layer and adjusting the pH to 12 with a 1N aqueous sodium hydroxide solution, the organic layer is separated. After the separated organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to obtain a yellow oil. 10 ml of diisopropyl ether was added thereto, and the precipitated crystals were collected and dried to obtain 2.7 g of (S) -4-trityl-2-hydroxymethylmorpholine.

Melting point: 142.0-142.5 ° C [AcOEt-IPE] Similarly, a (2R) -isomer having the following physical properties is obtained.

Melting point: 142.0-142.5 ° C [AcOEt-IPE] (3) Production Example 5 (1) was obtained using (S) -2-phenyloxirane and (S) -4-trityl-2-hydroxymethylmorpholine instead of styrene oxide and 4-benzyl-2-hydroxymethylmorpholine. )
(1S, 2'S) -1-phenyl-2
-[(4-Tritylmorpholin-2-yl) methoxy]
This gives ethanol (Compound No. 217).

(4) Dissolve (1S, 2'S) -1-phenyl-2-[(4-tritylmorpholin-2-yl) methoxy] ethanol in 20 ml of acetone, and add 5.9N dry hydrogen chloride to this solution under ice-cooling. After adding 7 ml of an ethanol solution and stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure. The residue obtained is introduced into a mixture of 30 ml of ice water and 30 ml of ethyl acetate,
Separate the aqueous layer. After washing the separated aqueous layer with 30 ml of ethyl acetate, 50 ml of chloroform is added, the pH is adjusted to 11 with a 2N aqueous sodium hydroxide solution, and the organic layer is separated. The separated organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
1.9 g are obtained. This is dissolved in ethanol (10 ml), and oxalic acid (720 mg) is added to the resulting solution and dissolved by heating. After leaving overnight at room temperature, the precipitated crystals are collected and dried, (1
S, 2'S) -1-phenyl-2-[(morpholine-2-
Yl) methoxy] ethanol oxalate (compound number
218) Obtain 1.8g.

Melting point: 130-132 ° C [EtOH] Similarly, the following compound is obtained.

(1R, 2'S) -1-phenyl-2-[(morpholine-
2-yl) methoxy] ethanol maleate (Compound No. 219) Melting point: 136-136.5 ° C [EtOH] (1R, 2'R) -1-phenyl-2-[(morpholine-
2-yl) methoxy] ethanol maleate (Compound No. 220) Melting point: 136-136.5 ° C [EtOH] (1R, 2'R) -1-phenyl-2-[(morpholine-
2-yl) methoxy] ethanol oxalate (Compound No. 221) Melting point: 131-132.5 ° C [EtOH] Production Example 14 (1) 1.19 g of 4-benzylthiobenzaldehyde was dissolved in 20 ml of tetrahydrofuran and cooled to -10 ° C. To this solution, a 10 ml solution of tetrahydrofuran containing 2M 2-chloroethoxymethylmagnesium chloride is added dropwise over 10 minutes, and the mixture is stirred for 1 hour under ice cooling.
Then, the reaction mixture is introduced into a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 1 g of ammonium chloride, adjusted to pH 2 with 6N hydrochloric acid, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [eluent: toluene: ethyl complex salt = 20: 1] to give 1- (4-benzylthiophenyl) -2- (2- Chloroethoxy) ethanol 1.
Obtain 34g.

Melting point: 49.5-50.5 ° C [Hexane-IPE] (2) 1- (4-benzylthiophenyl) -2- (2-
Chloroethoxy) ethanol 600mg, 50% dimethylamine aqueous solution 4ml, potassium iodide 310mg and ethanol 5m
After the mixture was refluxed for 4 hours, an additional 4 ml of a 50% aqueous dimethylamine solution was added, and the mixture was refluxed for 4 hours. Then, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, 30 ml of ethyl acetate and 30 ml of water were added to the obtained residue, the mixture was adjusted to pH 10.5 with potassium carbonate, and the organic layer was separated. Take. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in 15 ml of acetone, and the solution was diluted with 0.4 N of a 5N dry ethanol solution of hydrogen chloride.
After l was added and the precipitated crystals were collected, 590 mg of the hydrochloride salt of 1- (4-benzylthiophenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol (Compound No. 222) was obtained.

Melting point: 173.5-174.5 ° C [EtOH] The compounds in Table 14 are obtained in the same manner.

In Table 14, R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁶ , na and nb each represent a substituent or an integer of the following formula.

[Examples] Next, the present invention will be specifically described with examples, but the present invention is not limited to these.

Example 1 (tablet) 1- (4-benzyloxyphenyl) -2- [2-
A tablet containing 50 mg of (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 48) is prepared by the following method using the following formulation.

Per tablet: The mixture of the above components is kneaded with an 8% aqueous solution of polyvinylpyrrolidone K-90, dried at 40 ° C., and the components are mixed.

Example 2 (Capsule) 2- [2- (N, N-dimethylamino) ethoxy] -1
A capsule containing 50 mg of the hydrochloride salt of-[4- (4-phenyloxy) phenyl] ethanol (compound No. 54) is prepared by the following method using the following formulation.

Per capsule: The mixture of the above components is kneaded with an 8% aqueous solution of polyvinylpyrrolidone K-90, dried at 40 ° C., and the components are mixed. 150 mg per capsule is filled into a No. 3 gelatin capsule to obtain a capsule.

Example 3 (Liquid) 2- [2- (N, N-dimethylamino) ethoxy] -1
A solution containing 25 mg of hydrochloride salt of-(3-trifluoromethylphenyl) ethanol (Compound No. 42) is prepared by the following method using the following formulation.

Per ampoule: Compound No. 42 Compound 25 mg Methyl parahydroxybenzoate 1 mg Total 26 mg Dissolve the specified components in physiological saline to make the total volume 1 ml. After aseptically filtering this solution, the solution is filled into an ampoule to obtain a liquid preparation.

Example 4 (Formulation for injection) 2- [2- (N, N-dimethylamino) ethoxy] -1
An injection preparation containing 25 mg of hydrochloride salt of (3-fluorophenyl) ethanol (Compound No. 1) is prepared by the following method using the following formulation.

Compound No. 1 Compound 25 mg Mannit 75 mg Total 100 mg The above components were dissolved in 1.5 ml of distilled water for injection, and the solution was subjected to aseptic filtration, filled into a 3 ml mini vial, and lyophilized to obtain a preparation for injection.

Example 5 (fine granules) 2- (1-benzylpiperidin-4-yloxy)-
1-phenylethanol hydrochloride (Compound No. 112) 50 m
A fine granule containing g is prepared by the following method using the following formulation.

A mixture of the above components was treated with polyvinylpyrrolidone K-90.
After granulating at high speed with an 8% aqueous solution of the above, the mixture is sieved through a 32 mesh sieve and dried to obtain a fine granule.

Example 6 (tablet) 2- [2- (N, N-dimethylamino) ethoxy] -1
-(3-methylphenyl) ethanol hydrochloride (Compound No. 15) and 1- (4-benzyloxyphenyl)-
2-[(1-Methylimidazol-5-yl) methoxy] ethanol (Compound No. 215) is formulated in the same manner as in Example 1 to obtain tablets each containing 50 mg of the compound.

Example 7 (capsule) 2- [2- (N, N-dimethylamino) ethoxy] -1
-(3-methylphenyl) ethanol hydrochloride (Compound No. 15) and 1- (4-benzyloxyphenyl)-
2-[(1-Methylimidazol-5-yl) methoxy] ethanol (Compound No. 215) is formulated in the same manner as in Example 2 to obtain capsules each containing 50 mg of the compound.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/435 A61K 31/435 31/445 31/445 31/47 31/47 31/535 31/535 31/54 31/54 C07C 317/22 C07C 317/22 C07D 207/08 C07D 207/08 207/14 207/14 207/27 207/27 211/14 211/14 211/22 211/22 211/40 211/40 211/70 211 / 70 215/06 215/06 217/04 217/04 231/12 231/12 233/64 103 233/64 103 257/04 257/04 N 279/12 279/12 295/08 295/08 Z 317 / 54 317/54 453/02 453/02 (56) References Chim. Ther. , Vol. 5 No. 1 (1970) p. 1-p. 9 Chem. Abstr. , Vol. 63 (1965) 557 g Chem. Abstr. , Vol. 63 (1965) 8201C (58) Fields investigated (Int. Cl. ⁶ , DB name) CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) General formula "Wherein R ¹ represents an optionally substituted phenyl group; R ²
Is a hydrogen atom or a lower alkyl group or a hydroxyl protecting group; R ³ is a hydrogen atom or a lower alkyl group;
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or The integers of 1 to 6 are shown respectively. Examples of the nitrogen-containing heterocyclic group for R ⁶ include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Nil, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl,
An imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or indazolyl group; a substituent of R ¹ is
Halogen atom, optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy,
Al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected An amino group, an optionally protected hydroxyl group, a nitro group, an oxo group and a lower alkylenedioxy group, and also a lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy substituent in R ¹ , Aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al lower alkylthio, al lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyl Mino, the substituent of the nitrogen-containing heterocyclic group in an arylsulfonylamino or heterocyclic group, and R ^6, halogen atom, optionally protected hydroxyl group, protected or unprotected carboxyl group, are protected An amino group which may be substituted, a lower alkyl group which may be substituted with an optionally protected hydroxyl group, an aryl group which may be substituted with halogen, an aroyl group which may be substituted with halogen, a lower alkoxy group May be substituted with a lower alkoxy group, a lower acyl group, an ar lower alkyl group, an ar lower alkenyl group, a heterocyclic group, a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group and an arylsulfonyl group. And may be substituted with one or more of these substituents; the amino group of the substituent in R ¹ and R ⁶ Examples of the substituent of the amino group in the present invention include a hydroxyl group which may be protected, a cycloalkyl group, a lower alkyl group which may be substituted with a hydroxyl which may be protected or a carboxyl group which may be protected, and aryl. Group, lower acyl group, ar-lower alkyl group, heterocyclic group, heterocyclic -CO- group which may be substituted with an oxo group, adamantyl group, lower alkylsulfonyl group and arylsulfonyl group. May be substituted with one or more substituents (provided that the phenyl group of R ¹ is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy or an optionally protected hydroxyl group, R ⁶ has the formula -NR ⁷ R ⁸ {R ⁷ is an ar (lower) alkyl or heterocyclic group; R ⁸ is a hydrogen atom or a lower a Kill group; or R ⁷ and R ⁸ together with the N atom the following groups [R ⁹ is an aryl or heterocyclic group; R ¹⁰ is an aryl, heterocyclic group or (. R ⁸ is showing the same meaning as mentioned above) a; R ¹¹ is
R ¹² is a carboxyl or lower alkoxycarbonyl group; and i is 0, 1, 2 or 3;
Shown respectively. ] Is excluded. ｝. The heterocyclic group as a substituent of R ¹ is pyrrolyl, pyrrolidinyl,
Piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl,
Morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl,
Thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl, indazolyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, dihydroquinoxyl Nil, quinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H
-1-thianaphthyl, 2,3-dihydrobenzofuranyl,
The benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenil, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups are respectively shown. The brain function improving agent containing the 1,2-ethanediol derivative represented by these, or its salt. 2. The general formula "Wherein R ¹ represents an optionally substituted phenyl group; R ²
Is a hydrogen atom or a lower alkyl group or a hydroxyl protecting group; R ³ is a hydrogen atom or a lower alkyl group;
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or The integers of 1 to 6 are shown respectively. Examples of the nitrogen-containing heterocyclic group for R ⁶ include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Nil, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl,
An imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or indazolyl group; a substituent of R ¹ is
Halogen atom, optionally substituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy,
Al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected An amino group, an optionally protected hydroxyl group, a nitro group, an oxo group and a lower alkylenedioxy group, and also a lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy substituent in R ¹ , Aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al lower alkylthio, al lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyl Mino, the substituent of the nitrogen-containing heterocyclic group in an arylsulfonylamino or heterocyclic group, and R ^6, halogen atom, optionally protected hydroxyl group, protected or unprotected carboxyl group, are protected An amino group which may be substituted, a lower alkyl group which may be substituted with an optionally protected hydroxyl group, an aryl group which may be substituted with halogen, an aroyl group which may be substituted with halogen, a lower alkoxy group May be substituted with a lower alkoxy group, a lower acyl group, an ar lower alkyl group, an ar lower alkenyl group, a heterocyclic group, a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group and an arylsulfonyl group. And may be substituted with one or more of these substituents; the amino group of the substituent in R ¹ and R ⁶ Examples of the substituent of the amino group in the present invention include a hydroxyl group which may be protected, a cycloalkyl group, a lower alkyl group which may be substituted with a hydroxyl which may be protected or a carboxyl group which may be protected, and aryl. Group, lower acyl group, ar-lower alkyl group, heterocyclic group, heterocyclic -CO- group which may be substituted with an oxo group, adamantyl group, lower alkylsulfonyl group and arylsulfonyl group. May be substituted with at least one kind of substituent (provided that 1-phenyl-2- (2-diethylaminoethoxy) -1-ethanol, 1-phenyl-2- (2-diethylaminoethoxy) -1-propanol, -Phenyl-2- (2-dimethylaminoethoxy) -1-propanol, 2-methyl-6-hydroxy-4- Kisa-6-hexyl-phenyl-2-hexylamine, 2-methyl-6-hydroxy-4-oxa -6
-Nitrophenyl-2-hexylamine, 2-methyl-
6-hydroxy-4-oxa-6-p-chlorophenyl-2-hexylamine, 2-methyl-4-oxa-6
Phenyl-6-hydroxyhexylamine and the phenyl group of R ¹ is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy or optionally protected hydroxyl group,
⁶ is a group represented by the formula -NR ⁷ R ⁸ ｛R ⁷ is an ar lower alkyl or heterocyclic group; R ⁸ is a hydrogen atom or a lower alkyl group;
Or R ⁷ and R ⁸ together with the N atom form the following group: [R ⁹ is an aryl or heterocyclic group; R ¹⁰ is an aryl, heterocyclic group or (. R ⁸ is showing the same meaning as mentioned above) a; R ¹¹ is
R ¹² is a carboxyl or lower alkoxycarbonyl group; and i is 0, 1, 2 or 3;
Shown respectively. A phenyl group optionally substituted with a lower alkyl group for R ¹ , wherein R ⁶ is
The following groups, Excluding the case where n is 0 and R ⁶ is an amino group or an ammonio group which may be substituted. ｝. The heterocyclic group as a substituent of R ¹ is pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl,
Quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, prinyl, indazolyl, furyl, thienyl, benzothienyl, pyranyl, pyranyl ,
Oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,
Dihydroquinoxalinyl, quinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3
-Dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenil, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, Isoindolyl and isoquinolyl groups are indicated, respectively. The 1,2-ethanediol derivative represented by these, or its salt. R ² is a hydrogen atom or a hydroxyl protecting group; n R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group; n R ⁵ is a hydrogen atom; R ⁶ is a di-lower An amino or nitrogen-containing heterocyclic group which may be different from alkylamino or a nitrogen-containing heterocyclic group or an ammonio group; wherein the nitrogen-containing heterocyclic group represented by R ⁶ is The 1,2-ethanediol derivative or a salt thereof according to claim 2, which is a quinolinyl, quinuclidinyl, thiazolyl or thiadiazolyl group.