KR930012005B1 - 1,2-ethandiol derivative and salt thereof, process for producing the same and cerebral function improving agent comprising the same - Google Patents

Abstract

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Description

1,2-ethanediol derivatives and salts thereof, preparation methods thereof, and brain function containing same-improvers

The present invention relates to 1,2-ethanediol derivatives and salts thereof, methods for their preparation and brain function-improving agents containing the same. Brain function-enhancing agents of the present invention are useful for treating cerebrovascular dementia, senile dementia, Alzheimer's dementia, sequelae and stroke of ischemic brain disease.

1,2-ethanediol derivatives are described, for example, in US Pat. No. 2,928,845; J. Pharm, Sci., Vol. 50, pp. 769-771 (1961); Farmaco. Ed. Sci., Vol. 19, pp. 1056-1065 (1964) and the like.

These compounds are useful as local anesthetics. However, its use as an agent for improving brain function, for treating amnesia or as a neurotropic agent is not known.

It is described in WO 88/8424 that 1,2-ethanediol derivatives can be used to treat Alzheimer's disease and other degenerative neurological diseases. However, the patent application does not describe specific descriptions or examples of these derivatives.

Agents such as brain metabolism enhancers, cerebrovascular dilatates and the like are currently used to treat a variety of dementia, particularly Alzheimer's type dementia and cerebrovascular dementia.

However, no brain function improving agent has yet been found to be useful for treating the onset and stroke of cerebrovascular dementia, senile dementia, Alzheimer's dementia, ischemic brain disease.

It is an object of the present invention to provide novel 1,2-ethanediol derivatives and salts thereof.

Another object of the present invention is to provide a method for preparing the novel 1,2-ethanediol derivatives and salts thereof.

Still another object of the present invention is to provide a novel brain function improving material which is useful for treating cerebrovascular dementia, senile dementia, Alzheimer's dementia, secondary and stroke of ischemic brain disease and having few side effects.

The present inventors have studied to solve the above problem. As a result, it was found that the 1,2-ethanediol derivatives of the general formula (I) or salts thereof exhibited excellent antifoam treatment activity and excellent hypoxia therapeutic activity and were very useful as brain function improving agents.

Wherein R ¹ is a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, R ² is a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group, R ³ is a hydrogen atom or a lower alkyl group, nR ⁴ and nR ⁵ are the same or different from each other, a hydrogen atom or a lower alkyl group, and R ⁶ is an amonio group or a substituted or unsubstituted amino-containing heterocyclic Or pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidyl morpholinyl, thiomorpholinyl, quinolyl, quinolinyl, Tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, furi Neil And a substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of indazolyl, n is 0 or an integer of 1 to 6, wherein the substituent for R ¹ is a halogen atom, substituted or unsubstituted amino, Lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl , Arylsulfonyl, loweralkyl-sulfonylamino, arylsulfonylamino and heterocyclic groups and protected amino groups, selected from the group consisting of protected or non-protected hydroxyl groups, nitro groups, oxo groups and lower alkylenedioxy and, the substituents of R ¹ substituted lower alkyl, aryl, aralkyl, lower alkyl, lower alkoxy, aralkyl-lower alcohol City, aryloxy, carbamoyl oxy, lower alkylthio, lower alkenyl Carbonyl, lower alkenyloxy, aralkyl-lower alkylthio, aralkyl-lower alkylsulfonyl, arylsulfonyl, lower alkyl-sulfonylamino, aryl-sulfonylamino or a heterocyclic group, and R ⁶ a nitrogen-containing heteroaryl substituted as between Click groups each represent a halogen atom, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a protected or unprotected carboxyl group, an unsubstituted lower alkyl group, a lower alkyl substituted by a protected or unprotected hydroxyl group, respectively. Groups, unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by lower alkoxy groups, lower acyl groups, ar-lower alkyl groups Ar-lower alkenyl groups, heterocyclic groups, heterocyclic-CO-groups, oxo groups, lower alkyl sulfonyl groups and aryl sulfonyl Have one or more substituent selected from the group consisting of; Substituted amino groups which are substituents of R ¹ and amino groups substituted as R ⁶ are each lower alkyl substituted by a protected or unprotected hydroxyl group, an unsubstituted lower alkyl group, a protected or unprotected carboxyl or hydroxyl group. Groups, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, unsubstituted or oxo-substituted heterocyclic-CO-groups, adamantyl groups, lower alkylsulfonyl groups And at least one substituent selected from the group consisting of arylsulfonyl groups, provided that R ¹ can be optionally substituted by halogen atoms or lower alkyl, lower alkylenedioxy, lower alkoxy, or protected or unprotected hydroxyl groups Phenyl group, R ⁸ is —NR ⁷ R ⁸ , wherein R ⁷ is an ar-lower alkyl or heterocyclic group, and R ⁵ is a hydrogen atom or Or a lower alkyl group, or R ⁷ and R ⁸ together with the N atom,

(여기서, R⁹은 아릴 또는 헤테로사이클릭 그룹이고, i는 0 또는 1 내지 3의 정수이다),

(여기서, R¹⁰은 아릴, 헤테로사이 클릭 또는

헤케로사이클릭 그룹이며,R⁸및 i는 상기 정의한 바와 같다),

(여기서, R¹¹은 아릴그룹이다),

(여기서, R¹²는 카복실 그룹 또는 저급 알콜시카보닐 그룹이다) 또는

여기서, R¹²는 상기 정의한 바와 같다)을 형성한다]인 화합물 및 R¹이 비치환되거나 저급 알킬-치환된 페닐 그룹이고, R⁶이 디-저급 알킬아미노 그룹,

,

또는

인 화합물은 제외되며; 상기 모든 헤테로사이클릭 그룹은 R⁶에서 정의한 질소-함유 헤테로사이클릭 그룹과 푸릴, 티에닐, 벤조티에닐, 피라닐, 이소벤조푸라닐, 옥사졸릴, 벤조푸라닐, 인돌릴, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤조티아졸릴, 퀴녹살릴, 디하이드로퀴녹살릴, 2,3-디하이드로벤조티에닐, 2,3-디하이드로 벤조피폴릴, 2,3-디하이드로-4H-1-티아나프틸, 2,3-디하이드로벤조푸라닐, 벤조[b]디옥사닐, 이미다조[2,3-a]피리딜, 벤조[b]피페라지닐, 크로메닐, 이소티아졸릴, 이속사졸릴, 옥사디아졸릴, 피리다지닐, 이소인돌릴 및 이소퀴놀릴로 이루어진 그룹중에서 선택된다.

(Wherein R ⁹ is an aryl or heterocyclic group and i is 0 or an integer from 1 to 3),

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, wherein R ⁸ and i are as defined above),

(Wherein R ¹¹ is an aryl group),

Wherein R ¹² is a carboxyl group or a lower alcoholcarbonyl group) or

Wherein R ¹² is as defined above) and R ¹ is an unsubstituted or lower alkyl-substituted phenyl group, R ⁶ is a di-lower alkylamino group,

,

or

Phosphorus compounds are excluded; All of the above heterocyclic groups are nitrogen-containing heterocyclic groups defined in R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl , Benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydro benzopipolyl, 2,3-dihydro-4H-1-thianaph Methyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, cromenyl, isothiazolyl, isoxazolyl , Oxadiazolyl, pyridazinyl, isoindoleyl and isoquinolyl.

Incidentally, the brain function-improvement agents referred to herein, as well as the effects exhibited by conventional brain function improvers, not only treat or prevent the effects of forgetfulness and dementia (eg cerebrovascular dementia, senile dementia and Alzheimer's dementia). Refers to brain function-improving agents.

Within this specification, the following terms have the following definitions unless stated otherwise.

The term “halogen atom” means, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; The term “lower alkyl group” means a C ₁ -C ₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like; The term “lower alkoxy group” refers to a C ₁ -C ₆ alkyl-O-group; The term “lower alkylthio group” refers to a C ₁ -C ₆ alkyl-S-group; The term “lower alkenyl group” refers to a C ₂ C ₆ alkenyl group such as vinyl, propenyl, budenyl, pentenyl, hexenyl, etc., and the term “lower alkenyloxy group” refers to a C ₂ -C ₆ alkenyl -O- group; The term “cycloalkyl group” refers to a C ₃ -C ₆ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; The term “aryloxy group” refers to an aryl-O-group; The term “aryl group” refers to a phenyl, naphthyl, indanyl and indenyl group; The term ＂ar-lower alkyl group＂ means an ar-C ₁ -C ₄ alkyl-O- group such as benzyl, diphenyl methyl, trityl, phenethyl, and the like; The term ＂ar-lower alkylthio group＂ means an aryl-C ₁ -C ₄ alkyl-S-group; The term “lower alkylenedioxy group” refers to C ₁ -C ₄ alkylenedioxy such as methylenedioxy, ethylec dioxy and the like; The term “lower acyl group” refers to a C ₁ -C ₆ acyl group such as formyl, acetyl, butyryl, etc. and the term “aroyl group” refers to an aryl-CO-group; The term “lower alkylsulfonyl group” refers to a C ₁ -C ₆ alkyl-SO ₂ group; The term “arylsulfonyl group” refers to an aryl-SO ₂ -group; The term “ar-lower alkylsulfonyl group” refers to an aryl-C ₁ -C ₆ alkyl-SO ₂ group; The term “lower alkylsulfonyloxy group” refers to a C ₁ -C ₆ alkyl-SO ₂ —O-group; The term “aryl-sulfonyloxy group” refers to an aryl-SO ₂ —O-group; The term “lower alkylsulfonylamino group” refers to a C ₁ -C ₆ alkyl-SO ₂ -NH-group; The term “arylsulfonylamino group” refers to an aryl-SO ₂ NH-group; The term “di-lower alkylamino group” refers to a di-C ₁ -C ₆ alkyl-NH-group; The term “ammonio group” refers to a tri-lower alkylammonio group such as trimethyl ammonio, triethylammonio; The term "lower alkoxycarbonyl group" means a C ₁ -C ₆ alkyl-O-CO- group and the like.

The protecting groups for hydroxyl groups, carboxyl groups and amino groups are the hydroxyl groups, carboxyl, described as protecting groups in Organic Synthesis [Theodra W. Green (1981), John Wiley & Sons, Inc.]. Common protecting groups for groups and amino groups.

In particular, protecting groups for hydroxyl groups include, for example, lower alkyl, lower acyl, tetrahydropyranyl and ar-lower alkyl groups (eg substituted or unsubstituted benzyl).

The salt of the 1,2-ethanediol derivative of formula [I] may be a pharmaceutically acceptable salt. For example, salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc .; Salts with carboxylic acids such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid and the like; Salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenulfonic acid and the like; And salts with alkali metals such as sodium, potassium and the like.

When the 1,2-ethanediol derivatives of the general formula [I] or salts thereof are isomers (eg, optical isomers, geometric isomers, tautomers), all of these isomers are included in the present invention. Hydrates, solvates and all crystalline forms of the compounds according to the invention are also included in the invention.

Hereinafter, a method for preparing the 1,2-ethanediol derivative of the general formula [I] or a salt thereof is described.

The 1, 2- ethanediol derivative of general formula [I] or its salt can be manufactured by a well-known method or its suitable combination, for example by the following manufacturing process.

[Manufacturing Process 1]

[Manufacturing Process 2]

[Manufacturing Process 3]

[Manufacturing Process 4]

In the above scheme, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are as defined above; R ^2a represents the same hydroxyl-protecting group as in the definition of R ² ; R ^6a represents the same substituted or unsubstituted nitrogen-containing heterocyclic group as in the definition of R ⁶ , provided that the heterocyclic group has free valences on the carbon atom to form the heterocyclic ring; R ^6b represents the same substituted or unsubstituted nitrogen-containing heterocyclic group as in the definition of R ⁶ , provided that the nitrogen-containing heterocyclic group has free atoms on the nitrogen atom that forms the heterocyclic ring, or A substituted or unsubstituted amino group; R ¹³ represents the same hydroxyl-protecting group as in the definition of R ² ; X ¹ and X ² may be the same or different and represent a halogen atom; Y represents a removable group such as a halogen atom, a lower alkyl-sulfonyloxy group, an arylsulfonyl oxy group and the like; Y ^a represents an arylsulfonyl oxy group; m is an integer of 1-6.

General formulas [III], [IIIa], [IV], [V], [VII], [VII], [VII], [XI], [XII], [XVI], [Ia], [Ib], As salts of the compounds of [Ic] and [Id], the same salts as those of the compounds of the general formula [I] can be mentioned.

The manufacturing process is described below.

[Manufacturing Process 1]

A compound of formula (Ia) or a salt thereof by reacting a compound of formula (II) with a compound of formula (III) or a salt thereof, or a compound of formula (IIIa) or a salt thereof in the presence or absence of a dua group To obtain.

The solvent that can be used for the reaction may be used as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons (eg benzene, toluene, xylene, etc.); Sulfoxides such as dimethyl sulfoxide and the like; Amides such as N, N-dimethylformamide and the like; And ethers such as tetrahydrofuran, dioxane and the like. These solvents may be used alone or in the form of a mixture of two or more. Moreover, the compound of general formula (III) and (IIIa) can be used as a solvent.

Examples of the base optionally used include sodium hydride, sodium metal and potassium tert-butoxide.

In the above reaction, the compound of formula (III) or a salt thereof, or the compound of formula (IIIa) or a salt thereof is in an amount of 1 to 100 mol, preferably 1 to 10 mol per mol of the compound of formula (II) Use

The base as an optional component is used in an amount of 0.01 to 1.2 moles per mole of the compound of formula (II).

The reaction can be carried out usually at 20 to 150 ℃, preferably 70 to 90 ℃ for 1 minute to 24 hours, preferably 5 minutes to 5 hours.

[Manufacturing Process 2]

(1) The compound of formula (II) is reacted with a compound of formula (IV) or a salt thereof in the presence or absence of a base to give a compound of formula (V) or a salt thereof.

The reaction can be carried out in the same manner as described in Preparation Process 1.

The obtained compound of formula (V) or a salt thereof can be used in the subsequent reaction without separation.

(2) The compound of formula (V) or a salt thereof is subjected to a conventional hydroxyl group protection reaction to give a compound of formula (VI).

The compound of formula (VI) obtained can be used in the subsequent reaction without separation.

Subsequently, the compound of formula (VI) is subjected to selective removal of the hydroxyl-protecting group to obtain a compound of formula (VII) or a salt thereof.

The obtained compound of formula (VII) or a salt thereof can be used in subsequent reaction without separation.

These reactions can be carried out according to known methods, for example, according to the methods described in, or similar to, Protective Group in Organic Synthesis (Theodra W. Green (1981), John wiley & Sons, Inc.). Can be.

Mixtures of hydroxyl-protecting groups (R ¹³ and R ^2a ) to be used in these reactions may be appropriately selected.

(3) A compound of formula (VIII) is reacted with a halogenating agent or sulfonylating agent in a solvent in the presence or absence of a base to give a compound of formula (VIII).

The solvent to be used in the reaction has an adverse effect on the reaction. Any solvent may be used as long as dksg. For example, halogenated hydrocarbons (eg methylene chloride, chloroform, etc.); Ethers such as tetrahydrofuran, dioxane, etc .; Nitriles (such as acetnitriyl) and amides (such as N, N-dimethylformamide, etc.). These solvents may also be used alone or in the form of a mixture of two or more.

Bases optionally used include, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5,4,0] undec-7-ene (DBU). ), Pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like.

As the halogenating agent, for example, phosphorus oxychloride, phosphorus oxybiromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and the like can be mentioned.

As the sulfonylating agent, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be mentioned.

The halogenating agent, sulfonylating agent and base as optional components are each used in an amount of at least 1 mole, preferably 1 to 2 moles per mole of the compound of formula (III) or salt thereof.

The reaction can usually be carried out for 10 minutes to 30 hours at -10 to 100 ℃, preferably 0 to 40 ℃.

The obtained compound of formula (VII) can be used for subsequent reaction without separation.

(4) The compound of formula (VII) is reacted with a compound of formula (IV) or a salt thereof in the presence or absence of a base and a catalyst to obtain a compound of formula (Ib) or a salt thereof.

The solvent to be used in the reaction may be used as long as it does not adversely affect the reaction. For example, there are solvents as mentioned in manufacturing process 2 (3).

As the catalyst optionally used, for example, potassium iodide, sodium iodide and the like.

Such a catalyst is used in an amount of 0.1 to 1 mole per mole of the compound of formula (VII).

Bases to be optionally used include, for example, bases as mentioned in (3) of Production Process 2.

The compound of formula (VII) or a salt thereof and a base as an optional component are each used in an amount of at least 1 mole, preferably 1 to 20 moles per mole of the compound of formula (VII).

The reaction can usually be carried out at 10 to 150 ℃, preferably 20 to 100 ℃ for 10 minutes to 20 hours.

[Manufacturing Process 3]

(1) The compound of formula (II) is reacted with a compound of formula (VII) or a salt thereof in the presence or absence of a base to give a compound of formula (XI) or a salt thereof.

(2) The compound of formula (XI) or a salt thereof is reacted with a sulfonylating agent in a solvent with or without a base to give a compound of formula (XII) or a salt thereof.

The solvent to be used in the reaction may be used as long as it does not adversely affect the reaction. For example, the same solvent as mentioned in manufacturing process 2 (3) can be mentioned.

As the base to be optionally used, for example, the same base as mentioned in the preparation process 2 (3) may be mentioned.

As the sulfonylating agent, for example p-toluenesulfonyl chloride and the like can be mentioned.

The sulfonylating agent and base as optional components are each used in an amount of at least 0.95 moles, preferably 1 to 2 moles per mole of the compound of formula [XI] or a salt thereof.

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

The compound of the general formula [XII] or a salt thereof to be obtained may be used in the subsequent reaction without being separated.

(3) The compound of formula [XII] or a salt thereof is subjected to a conventional hydroxyl group protection reaction to give a compound of formula [XIII].

The reaction can be carried out according to known methods, for example, as described in Protective Groups in Organic Synthesis (Theodra W. Green (1981), John Wiley & Sons, Inc.) or similar methods. .

The obtained compound of formula [XIII] can be used in the subsequent reaction without being separated.

(4) A compound of formula [Ic] by reacting a compound of formula [XIII] or a salt thereof, or a compound of formula [XIII] with a compound of formula [XIII] or a salt thereof in the presence or absence of a base, or Its salt is obtained.

The reaction can be carried out in the same manner as described in (4) of Production Process 2.

[Manufacturing Process 4]

(1) A compound of the general formula [XIV] is reacted with a compound of the general formula [XV] to obtain a compound of the general formula [XVI] or a salt thereof.

The solvent to be used in the reaction may be any solvent as long as it does not adversely affect the reaction. Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; And aromatic hydrocarbons) such as benzene, toluene and the like. These solvents may be used alone or in combination of two or more thereof.

In this reaction, the compound of the general formula [XV] is used in an amount of 0.8 to 100 moles, preferably 0.8 to 10 moles per mole of the compound of the general formula [XIV].

The reaction can typically be carried out at −78 ′ to 100 ° C., preferably at −78 ° to 50 ° C. for 5 minutes to 24 hours.

The obtained compound of formula [XVI] or a salt thereof can be used in the subsequent reaction without separation.

Incidentally, the compounds of the general formula [XV] to be used in the reaction are known methods, for example, Bull, Soc. Chim, Fr., 1967 (5), pp, 1533-40.

(2) The compound of formula [XVI] or a salt thereof is reacted with a compound of formula [VII] or a salt thereof in the presence or absence of a base to obtain a compound of formula [Id] or a salt thereof.

The solvent to be used in the reaction may be any solvent as long as it does not adversely affect the present reaction. For example, halogenated hydrocarbons (eg methylene chloride, chloroform, etc.); Ethers such as tetrahydrofuran, dioxane, etc .; Alcohols such as ethanol, propanol, butanol, etc .; Nitriles (such as acetonitrile); And amides such as N, N-dimethylformamide and the like can be mentioned. These solvents may be used alone or in combination of two or more thereof.

As the base to be optionally used, for example, bases such as those mentioned in (3) of Production Process 2 may be mentioned.

The compound of the formula [VII] or a salt thereof and the base as an optional component are each used in an amount of at least 1 mole, preferably 1 to 20 moles per mole of the compound of the general formula [XVI] or a salt thereof.

The reaction can usually be carried out at 10 to 150 ℃, preferably 20 to 100 ℃, for 10 minutes to 20 hours.

In the preparation process, the reactants or bases may also be used as solvents depending on the nature of the reactants or bases. In the above manufacturing process, [II], [III], [IIIa], [IV], [V], [VI], [VII], [VII], [VII], [VII], [XI], [ If the compounds of XII], [XIII], [XIV], [XV] and [XVI] have isomers (eg optical isomers, geometric isomers, tautomers), the compounds may be used in any isomeric form. In addition, compound rules may be used in hydrate form, solvate form, or in any crystalline form.

General formulas [II], [III], [IIIa], [IV], [V], [VI], [VII], [VII], [VII], [VII], [XI], [XII], If [XIII], [XIV], [XV], [XVI], [Ia], [Ib], [Ic] and [Id] have hydroxyl groups, amino groups or carboxyl groups, these groups are conventional Protection groups may be pre-protected and, after reaction, the protection groups may be removed, if desired, by known methods.

The compound thus obtained is subjected to conventional separation and purification methods such as column chromatography, crystallization, distillation, extraction and the like.

The 1,2-ethanediol derivatives of general formula [I] or salts thereof are well known (e.g. oxidation reaction, reduction reaction, addition reaction, acylation reaction, acylation reaction, alkylation reaction, sulfonylation reaction, deacylation reaction). , Substitution reaction, dehydration reaction, hydrolysis reaction, etc.) may be suitably combined and applied to other 1,2-ethanediol derivatives of the general formula [1] or salts thereof.

Compounds of the general formula [II], which are starting materials in the preparation of the compounds of the present invention, are known in the art, for example in JACS. vol. 87, p. 1353 (1965) and Shin Jikken Kagaku Koza, vol. 14, p. 579 (1977), Maruzen.

When the compound of the present invention is used as a medicament, it may be appropriately mixed with excipients such as fillers, carriers, diluents and the like, which are conventionally used for tablets, capsules, powders, granules, pills, suspensions, emulsions, solutions, It may be formulated as a syrup, injection solution, or the like. These agents can be administered orally or parenterally. The route of administration, dosage and frequency of administration may be appropriately determined according to the age, weight and symptoms of the patient. However, in the case of oral administration, generally 0.01 to 500 mg of the compound may be administered to adult patients once or several times a day. have.

The following examples describe the pharmacological activity of representative compounds of the present invention.

The number of test compounds used in the following pharmacological tests refers to the number of compounds shown in the preparation examples to be described later.

[One. Effect of Test Compounds on Hypoxia]

Test compounds (100 mg / kg) dissolved in biological saline are administered orally to ddY female mice (5-6 weeks after birth, each group consisting of 10 mice). One hour (or 30 minutes) after administration, each mouse is placed in a 300 ml glass chamber and a gas mixture consisting of 4% oxygen and 96% nitrogen is passed through the chamber at a rate of 5 l / min. From the onset time of gas passage to the lethal time of each mouse is measured.

The control mouse group was orally administered with physiological saline only.

The hypoxic therapeutic activity of the test compound is calculated as follows:

The results are shown in Table 1.

TABLE 1

[2. Effect of Experimental Compounds on Forgetfulness]

[(1) Electroconvulsion genus (ECS) -induced forgetfulness]

Test compounds dissolved in physiological saline are administered intraperitoneally to ddy male mice (5-6 weeks after birth, each group consisting of 10 mice). One hour after administration of the test compound, the acquisition test of the passive avoidance work assay is performed. Each mouse is placed in the bright compartment of the passive avoidance device (MPA-100M manufactured by Muromachi kikai) of the type through two mesenteric stages consisting of a light compartment and a dark compartment. Once the mouse enters the dark compartment, close the guillotine door in the dark compartment: 0.5 seconds later, apply an unavoidable footshock (1.6 mA, 3 seconds). The ECS (25 mA, 0.5 sec) is then applied through both eyes of the mouse. After 24 hours, in the confinement test, the mice are placed back in the bright compartments and the response latencies of the mice entering the dark compartments are measured. If the mouse avoids 300 seconds or more, 300 seconds is set as the upper limit.

Response latency for control mice intraperitoneally administered only physiological saline is also measured in the same manner.

Forgetfulness therapeutic activity is taken as an average of the response latency of 10 mice and is 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.

TABLE 2

[(2) Effect of Test Compounds on Cycloheximid-Induced Forgetfulness]

The fact that cycloheximide interferes with the memory recovery process in mice has been reported by Yamazaki et al. [Drugs, Mind and Action, vol. 3, pp. 127-136 (1983). Therefore, the following test is performed.

Tests are described in Drugs, Mind and Action, vol. 3, pp. 127-136 (1983) and Folia Pharmacological Japonica, vol. 89, pp. 243-252 (1987).

The test apparatus uses a step-down type passive avoidance training box. The device consists of a stainless steel bottom with a 22 cm x 22 cm x 21 cm height black acrylic resin with a 7 cm x 7 cm x 2 cm height platform at one corner of the bottom grid. It's a box.

Cycloheximid is dissolved in physiological saline and injected subcutaneously at a dose of 120 mg / kg in ddY male mice (5-6 weeks after birth, each group consisting of 10 mice). In the acquisition test, 15 minutes after administration, each mouse is placed on the platform of the test device. As soon as the mouse is placed on the platform, a 2 mA current is applied for 2 seconds and then immediately returned to the cage. Restraint tests are conducted 24 hours after the acquisition test. Each mouse treated with cycloheximide was orally dosed with a test compound dissolved in physiological saline, and 30 minutes after administration, the mouse was placed on the platform again and the latency of the mouse descending was measured. If the mouse avoids 300 seconds or more, set 300 seconds as the upper limit.

Control mice with oral administration of physiological saline are also measured for response latency.

Forgetfulness therapeutic activity is taken as the average value of the response latency of 10 mice and is represented by the following symbol.

-0 to 60 seconds

+: 61 to 100 seconds

++: 101 to 150 seconds

+++: 151 to 300 seconds

The results are shown in Table 3.

TABLE 3

[3. Inhibitory Activity against Acetylcholinesterase]

This test is performed according to the method of Elman et al. [Biochem, Pharmacol., Vol. 7, pp. 88-95, 1961.

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

When the final concentration of the test compound is 10 µl / ml, the inhibitory activity of the test compound against acetylcholinesterase is expressed as percent inhibition.

The results are shown in Table 4.

TABLE 4

[4. Acute toxicity]

Test compounds dissolved in physiological saline are administered intravenously to a group of 3ddY male mice (5-6 weeks old) to test the acute toxicity of the test compounds.

As a result, test compounds 1, 2, 3, 6, 8, 9, 15, 16, 25, 30, 33, 34, 38, 40, 42, 44, 46, 52, 53, 54, 65, 67, 70, 71, 112, 119, 120, 126, 132, 147, 151, 159, 160, 170, 176, 178, 182, 190, 194, 209, 219, 220, 221, 229, 235, 236, 240, 251, 256, 279, 283, 309, 312, 313, 315, 316, 319, 325, 327, 337, 360, 368, 369, 375, 377, 385, 390 and 396 do not kill at 50 mg / kg. Do not.

From the above test results, it is easily recognized that the compound of the present invention has excellent hypoxia, amnesia, and inhibitory activity against acetylcholine esterase and low toxicity.

From the above results, it is easily recognized that the brain function improving agent of the present invention is also useful for treating cerebrovascular disease, senile dementia, Alzheimer's dementia, secondary development of ischemic brain disease and stroke.

In the following, the preparation of the compounds according to the invention is described in detail by the preparation examples.

In the preparation examples, the mixing ratio of the eluent is in all cases by volume and uses silica gel (Kieselgel 60, Art.7734) manufactured by Merck Co. as a carrier for column chromatography.

The meanings of abbreviations used in the production examples are as follows.

Me: methyl, Et: ethyl, i-Pr isopropyl, t-Bu: tert-butyl, Ac: acetyl, Ph: phenyl, OPM: diphenylmethyl, Bz: benzyl, Tr: trityl, IPA: isopropyl Alcohol, IPE: diisopropyl ether, PTS: p-toluenesulfonic acid.

In the following description and tables, the material in [] refers to the solvent used for crystallization.

Preparation 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 is refluxed for 1 hour and then cooled to -60 ° C. To this was added 6.1 g of 4-benzyloxyphenacyl bromide. The mixture is stirred for 30 minutes at the same temperature and for an additional 3 hours at -40 ° to -30 ° C. The reaction mixture is added to a mixture of 100 ml of water and 200 ml of diethyl ether. The organic layer is separated, washed with water, and saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride solution are added in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene) to give 2.8 g of (S) -1- (4-benzyloxyphenyl) -2-bromoethanol.

(2) 2.8 g of (S) -1- (4-benzyloxyphenyl) -2-bromoethanol is dissolved in a mixed solvent of 20 ml of metaol and 10 ml of tetrahydrofuran. While ice-cooling, 0.8 g of potassium hydroxide dissolved in 4 ml of water was added to the solution. The mixture is stirred at the same temperature for 5 minutes and at room temperature for an additional 10 minutes. The reaction mixture is added to a mixture of 50 ml of diethyl ether and 50 ml of ice water. The organic layer is separated. The aqueous layer is extracted with 25 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent to give 1.4 g of (S) -2- (4-benzyloxyphenyl) oxirane.

Melting Point: 56 ~ 61 ℃

Using the same method, the following compounds are obtained.

(S) -2- (3-methylphenyl) oxirane

(S) -2- (4-phenoxyphenyl) oxirane

Production Example 2

(1) A solution of 23 g of (+)-diisopinecamperphenylchloroborane dissolved in 30 ml of tetrahydrofuran is cooled to -25 deg. To this was added 12 g of 4-benzyloxyphenacyl bromide. The resulting mixture is stirred at -20 ° C to -15 ° C for 4 hours. The reaction mixture is added to a mixture of 150 ml of diethyl ether and 100 ml of ice water. The organic layer is separated, washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue thus obtained was purified by column chromatography (eluent: hexane: toluene = 1: 2) to give 6.8 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol.

(2) 6.0 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol is dissolved in a mixed solvent of 50 ml of methanol and 25 ml of tetrahydrofuran. While ice-cooling, a 1.5 g solution of potassium hydroxide dissolved in 5 ml of water was added thereto. The resulting mixture is stirred for 5 minutes at the same temperature and for another 10 minutes at room temperature. The reaction mixture is added to 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 previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure to remove the solvent yielded 3.7 g of (R) -2- (4-benzyloxyphenyl) oxirane.

Melting Point: 55 ~ 67 ℃

Using the same method, the following compounds are obtained.

(R) -2- (3-methylphenyl) oxirane

(R) -2- (4-phenoxyphenyl) oxirane

Preparation Example 3

3.4 g potassium tert-butoxide is added to 31 ml 2- (N, N-dimethylamino) ethanol. The resulting compound is heated to 80 ° C. To this was added dropwise 7.7 g of 2- (3-fluorophenyl) oxirane over 40 minutes. The mixture is stirred at the same temperature for 3 hours. The reaction mixture is added to a mixture of 200 mL ice water and 200 mL ethyl acetate. The organic layer is separated. 50 ml of water is added to the organic layer. Adjust the mixture to pH 1 with 6N saline. The aqueous layer is separated and mixed with 100 ml of chloroform. The resulting mixture is adjusted to pH 11 with 2N aqueous sodium hydroxide solution. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 5/1). The oily product obtained is dissolved in 25 ml of acetone. Hydrogen chloride gas is blown into the solution. The resulting crystals were collected by filtration, washed with acetone and dried to give 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-fluorophenyl) ethanol hydrochloride (Compound No. 1) 3.1 g is obtained.

Melting Point: 164-165 캜 [EtOH]

Using the same method, the following compounds are obtained.

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

TABLE 5

Production Example 4

A mixture of 5.00 g of 1-benzyl-4-hydroxypyridine, 1.97 g of potassium tert-butoxide and 4 ml of dimethyl sulfoxide is heated to 80 ° C. To this was added dropwise 2.10 g of styrene oxide for 40 minutes. The resulting mixture is stirred at the same temperature for 3 hours. To the reaction mixture was added a mixture of 100 ml of ice water and 80 ml of ethyl acetate. Adjust the pH of the mixture to 11.5 with 6N hydrochloric acid. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1). The oily product obtained is dissolved in 8 ml of ethanol. 1 ml of 6N anhydrous hydrogen chloride ethanol solution and 20 ml of diethyl ether are added to this solution. The mixture is stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to 2- (1-benzylpiperidin-4-yloxy) -1-phenylethanol hydrochloride ( Compound No. 113) 930 mg is obtained.

Melting Point: 193-195 ℃

The same method is used to obtain the compound shown in Table 6.

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

TABLE 6

(1) A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide is heated to 80 ° C. To this was added 2.50 g of styrene oxide dropwise for 20 minutes. The resulting mixture is stirred at the same temperature for 2 hours. The reaction mixture is added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer is separated and mixed with 10 ml of water. Adjust the pH of the mixture to 2.0 with 6N hydrochloric acid. The aqueous layer is separated and mixed with 30 ml of diethyl ether. The pH of the mixture is adjusted to 11 with 2N aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue was purified by column chromatography (eluent: toluene / ethyl acetate = 1/1) to give oily 1-phenyl-2- [4-benzylmorpholin-2-yl) methoxy) ethanol (Compound No. 144). 2.00 g are obtained.

The same method is used to obtain the compound shown in Table 7.

In Table 7, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer used in the following general formula.

TABLE 7

(2) Hydrogenation of 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 for 4 hours at room temperature under atmospheric pressure Let's do it. After the reaction is completed, the palladium-carbon is removed at leisure. The solvent is removed by distillation under reduced pressure. The residue was purified by column chromatography (eluent: chloroform / ethanol = 10/1) to give 450 mg of an oily product. The oily product is dissolved in 2.5 ml of isopropanol. This solution is mixed with 220 ml of fumaric acid and the mixture is stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with 2 ml of isopropane and dried to ½ fumarate of 1-phenyl-2-[(morpholin-2-yl) methoxy) ethanol (Compound No. 151) ) 460 mg.

Melting point: 146.5 to 147 ° C. [ethanol]

Using the same method, the compounds shown in Table 8 are obtained.

In Table 8, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or integer used in the following general formula:

TABLE 8

(3) 7 g of 1- (3-methoxyphenyl) -2-[(4-trityl-morpholin-2-yl) methoxy] ethanol is dissolved in 35 ml of acetone. While ice-cooling, 2.6 ml of a 5.9 N dry hydrogen chloride-ethanol solution is added to this solution. The mixture is stirred at room temperature for 2 hours and after the reaction is complete, the solvent is distilled off under reduced pressure. To the resulting residue was added a mixture of 50 ml of water and 30 ml of ethyl acetate. The aqueous layer is separated and washed with ethyl acetate. 50 ml of chloroform are added thereto. The resulting mixture is adjusted to pH 11 with 1N aqueous sodium hydroxide solution. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol = 5/1) to give 1 g of an oily product. The oily product is dissolved in 3 ml of isopropanol. Here 430 ml of fumaric acid is added. The mixture is stirred at rt for 1 h. The resulting crystals were collected by filtration and dried to give 800 mg of 1/2 fumarate (Compound No. 155) of 1- (3-methoxyphenyl) -2-[(morpholin-2-yl) methoxy) ethanol. do :

Melting Point: 122 to 123.5 ° C. [ethanol]

Using the same method, the compounds shown in Table 9 are obtained.

In Table 9, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or integer used in the following general formula:

TABLE 9

Preparation Example 6

(1) 5.1 g of potassium tert-butoxide was added to 105 ml of ethylene glycol mono-3-butyl ether. The mixture is heated to 80 ° C. To this was added dropwise 35.0 g of 2- (3-chlorophenyl) oxirane for 1 hour. The mixture is stirred at 80 ° C. for 2 hours. The reaction mixture is added to a mixture of 100 mL ice water and 100 mL ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained was further distilled under reduced pressure to give 37.7 g of colorless oily 1- (3-chlorophenyl) -2 (2-tert-butoxyethoxy) ethanol having a boiling point of 104 to 146 ° C / 0.9mmHg. do.

(2) 37.0 g of 1- (3-chlorophenyl) -2- (2-tert-butoxyethoxy) ethanol is dissolved in 70 ml of methylene chloride. 12.9 g of pyridine and 16.6 g of acetic anhydride are added to this solution. The resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is added to a mixture of 150 ml ice water and 100 ml methylene chloride. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated and washed in this order with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to yield 40.0 g of oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-tert-butoxyethoxy) ethane.

(3) 40.00 g of 1-acetoxy-1- (3-chlorophenyl) -2- (tert-butoxyethoxy) ethane was dissolved in 40 ml of methylene chloride. 80 ml of trifluoroacetic acid is added to this solution with ice cooling. The mixture is stirred at rt for 12 h. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue is mixed with 100 ml of toluene. Distillation under reduced pressure further removes the solvent. The residue thus obtained is dissolved in a mixture of 90 ml of ethanol and 10 ml of water. To this solution is added 10.7 g of sodium bicarbonate at room temperature. The pH of the mixture is adjusted to 6-7 with saturated aqueous sodium hydrogen carbonate solution and concentrated to about 1/2 the volume under reduced pressure. 100 ml of ethyl acetate is added to the concentrate. The organic layer is separated. The aqueous layer is extracted using 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Distillation under reduced pressure removes the solvent. The residue was purified by column chromatography (eluent: toluene / ethyl acetate = 3/1) to obtain oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-hydroxyethoxy) -ethane. 19.4 g are obtained.

(4) To a mixture of 19.0 g of 1-acetoxy-1- (3-chlorophenyl) -2- (2-hydroxyethoxy) -ethane and 95.0 ml of ethylene chloride containing 9.1 ml of methanesulfonyl chloride, 16.4 ml of ethylamine is added dropwise for 1 hour with ice cooling. The resulting mixture is stirred at the same temperature for 10 minutes and further stirred at room temperature for 1 hour. The reaction mixture is added to a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water. The resulting mixture is adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 24.5 g of oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-methanesulfonyloxyethoxy) ethane.

(5) 1.40 g of 1-acetoxy-1- (3-chlorophenyl) -2- (2-methanesulfonyloxyethoxy) ethane is dissolved in 7 ml of N, N-dimethylformamide. To this solution was added 0.69 ml of N-methylpiperazine and 1.03 g of potassium carbonate. The mixture is stirred at 80 ° C. for 3 hours. The reaction mixture is cooled and added to a mixture of 30 mL ice water and 30 mL diethyl ether. The organic layer is separated. The aqueous layer is extracted using 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue thus obtained is mixed with 45 ml of methanol 7 ml sodium methoxide. The mixture is left at room temperature overnight. The solvent is removed by distillation under reduced pressure. 20 ml of ethyl acetate and 10 ml of water were added to the obtained residue.

The organic layer is separated. The aqueous layer is extracted with 20 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed with saturated aqueous sodium chloride solution and purified by column chromatography (eluent: chloroform / methanol = 10/1).

To the resulting oily product are added 10 ml of ethanol and 6N anhydrous hydrogen chloride-ethanol solution in this order. To the resulting mixture was added 10 ml of diethyl ether. The mixture is stirred for 30 minutes. The resulting crystals were collected by filtration, 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) 770 mg of ethoxy] ethanol dihydrochloride (Compound No. 158) are obtained.

Melting Point: 211 to 213 ° C [Methanol-Ethanol]

Using the same method, the compounds shown in Table 10 are obtained.

In Table 10, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n represent substituents or integers used in the following general formulas:

TABLE 10

Production Example 7

A mixture of 2.0 g of 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride, 500 mg of 10% palladium-carbon and 10 ml of methanol was added at room temperature under atmospheric pressure. Hydrogenate for 2 hours. After the reaction is complete, the palladium-carbon is removed by filtration. Filtration under reduced pressure removes the solvent, and 1.4 g of 1- (4-hydroxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 170) is obtained.

Melting Point: 169.5-170.5 ° C. [ethanol]

Using the same method, the compounds shown in Table 11 are obtained.

In Table 11, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or integer used in the following general formula:

TABLE 11

Preparation Example 8

0.65 ml of pyridine and 0.99 ml of acetic anhydride are added to 1 g of 1- (3-methylphenyl) -2- [2- (morpholin-4-yl) ethoxy] ethanol.

The mixture is stirred at room temperature for 3 hours. The reaction mixture is distilled off under reduced pressure to remove the solvent. 20 ml of ethyl acetate and 10 ml of water are added to the residue. Potassium carbonate is used to adjust the pH of the mixture to 10. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. Purify the residue by column chromatography (eluent: chloroform / ethanol = 30/1) to give oily 1-acetoxy-1- (3-methylphenyl) -2- [2- (morpholin-4-yl) ethoxy ] 1 g of ethane (Compound No. 178) is obtained.

Using the same method, the compounds shown in Table 12 are obtained.

In Table 12, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or integer used in the following general formula:

TABLE 12

Preparation Example 9

50 ml of a 1: 1 mixture of chloroform and water are added to 3.30 g of 1-acetoxy-1- (3-hydroxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride. 750 mg of sodium carbonate is added to the mixture with ice cooling. The organic layer is separated and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue is mixed with 20 ml of benzene. This mixture is heated to 60 ° C. To the resulting solution, a solution of 870 mg of ethyl isocyanate dissolved in 5 ml of benzene was added dropwise within 10 minutes. The mixture is stirred at the same temperature for 40 minutes. After the reaction is complete, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1) to give an oily product. Dissolve the oily product in 10 ml of ethanol. Blow hydrogen chloride gas into the solution. Distillation under reduced pressure to remove the solvent 1-acetoxy-1- [3- (N-ethylcarbamoyloxy) phenyl] -2- [2- (N, N-dimethylaminoethoxy] ethane hydrochloride (Compound No. 189) 1.90 g is obtained.

Melting Point: 111.5 ~ 113.5 ° C. [Me ₂ CO]

Oily 1-acetoxy-1- [3- (3-chlorophenylcarbamoyloxy) phenyl] -2- [2- (N, N-dimethylamino) ethoxy] hydrochloride using the same method (Compound No. 190) is obtained.

Preparation Example 10

(1) 9.5 g of potassium tert-butoxide is added to 92 ml of ethylene glycol. The mixture is heated to 80 ° C. To this was added dropwise 34.7 g of 2- (4-benzyloxyphenyl) oxirane dissolved in 220 ml of dimethyl sulfoxide for 3 hours. The resulting mixture is stirred at 80 ° C. for 30 minutes. The reaction mixture is cooled and added to a mixture of 1 liter of ice water and 600 ml of ethyl acetate. The resulting mixture is adjusted to pH 7 with 6N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate. This extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 10/1) to give 25 g of 1- (4-benzyloxyphenyl) -2- (2-hydroxyethoxy) ethanol.

Melting Point: 116.5 ° C to 117 ° C [MeCN]

(2) 22.7 g of 1- (4-benzyloxyphenyl) -2- (2-hydroxyethoxy) ethanol is dissolved in 140 ml of pyridine. The solution is cooled to -20 ° C. 19 g of p-toluenesulfonyl chloride is added thereto. The resulting reaction is heated to 0 ° C. and stirred at the same temperature for 15 hours. The reaction mixture is added to a mixture of 300 mL ice water and 200 mL diethyl ether. Adjust the pH of the resulting mixture to 2 with 6N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 100 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using 1N hydrochloric acid, water and saturated aqueous sodium chloride solution. Dry over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue was purified by column chromatography (eluent: toluene / ethyl acetate = 3/1) to give oily 1- (4-benzyloxyphenyl) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethanol 20.5 g are obtained.

(3) 40 ml of methylene chloride containing 8.2 g of 3,4-dihydro-2H-pyran and 1- (4-benzyloxyphenyl) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethanol To 20 g of the mixture is added 2.3 g of pyridinium p-toluenesulfonate at room temperature. The resulting mixture is refluxed for 30 minutes. The reaction mixture is cooled and a mixture of 100 mL ice water and 100 mL methylene chloride is added. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate.

The solvent was removed by distillation under reduced pressure, and a pale yellow oily 1- (4-benzyloxyphenyl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-tolueneselfonyloxy) ethoxy] 18.6 g of ethane is obtained.

(4) 1- (4-benzyloxyphenyl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) ethoxy] toluene 2g, 40% methylamine aqueous solution 5.9 ML and 20 mL of ethanol are refluxed for 2 hours.

The reaction mixture is cooled and added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer is separated. The aqueous layers are each extracted with 20 ml of diethyl ether each. The extract is combined with the previously separated organic layer. The combined organic layers are mixed with 10 ml of water. Adjust the mixture to pH 1.0 with 6N hydrochloric acid. The aqueous layer is separated and stirred for 30 minutes at room temperature. To this was added 30 ml of chloroform. The resulting mixture is adjusted to pH 12.0 with 5% aqueous sodium hydroxide solution. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The residue is mixed with 10 ml of acetone. While ice-cooled, hydrogen chloride gas is blown into this mixture. The resulting crystals are collected by filtration, washed with acetone and dried to yield 620 mg of 1- (4-benzyloxyphenyl) -2- (2-methylaminoethoxy) ethanol hydrochloride (Compound No. 191). .

Melting point: 173 to 173.5 ° C. [ethanol]

Using the same method, the compounds shown in Table 13 are obtained.

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 used in the following general formula:

TABLE 13

Production Example 11

A mixture of 500 mg of 2-[(imidazol-4-yl) methoxy] -1-phenyl-ethanol, 1.1 ml of pyridine, 1.1 ml of triethylamine and 1.1 ml of acetic anhydride is stirred at 100 ° C. for 1 hour. The reaction mixture is cooled to room temperature. Distillation under reduced pressure removes the solvent. To the residue were added 1.1 ml of methyl iodide and 5 ml of acetonitrile. The mixture is left at room temperature for 24 hours. Distillation under reduced pressure removes the solvent. 4 ml of ethanol and 6.8 ml of 5% aqueous sodium hydroxide solution are added to the obtained residue. The resulting mixture is stirred at rt for 6 h. Distillation under reduced pressure removes the solvent. 30 ml of chloroform and 20 ml of water were added to the obtained residue. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. The oily product obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1). Diisopropyl ether was added to the resulting white crystals, and the resulting mixture was filtered to yield 450 mg of 2-[(1-methylimidazol-5-yl) methoxy] -1-phenylethanol (Compound No. 214). do.

Melting Point: 102 to 105 ° C

The following compounds are prepared in the same manner.

1- (4-benzyloxyphenyl) -2-[(1-methylimidazol-5-yl) -methoxy] ethanol (Compound No. 215)

Melting Point: 148.5 ~ 150.5 ℃ [IPA-AcOEt)

Preparation Example 12

1.23 g of 2- (2-aminoethoxy) -1-phenylethanol dissolved in 5 ml of tetrahydrofuran while cooling 1.23 g of N, N'-dicyclohexylcarbodiimide, 730 mg of nicotinic acid, 1-hydroxy To a solution of 810 mg of benzotriazole and 0.83 ml of triethylamine are added. The resulting mixture is stirred at the same temperature for 5 minutes and then further stirred at room temperature for 1 hour. 11 ml of ethyl acetate is added to the reaction mixture. Insoluble material is filtered off. 5 ml of water is added to the filtrate and the pH of the mixture is adjusted to 2 with 6N hydrochloric acid. Separate the aqueous layer. The organic layer is extracted with 5 ml of water. Combine the extract with the aqueous layer previously separated. The combined aqueous layers are mixed with 2 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform / ethanol = 15/1) to give 400 mg of oily 2- (2-nicotinoylaminoethoxy) -1-phenylethanol (Compound No. 216). do.

IR (knit) cm ^-1 : υc = o 1635

Preparation Example 13

(1) 5 g of (S) -4-benzyl-2-acetoxymethylmorpholine is dissolved in 10 ml of ethanol. To this solution is added a solution of 1 g of sodium hydroxide dissolved in 5 ml with ice cooling. The mixture is stirred for 10 minutes at room temperature. The reaction mixture is added to 50 ml of ice water and extracted with 50 ml of chloroform. The organic layer is washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform / ethanol = 30/1) to obtain 3.6 g of oily (S) -4-benzyl-2-hydroxymethylmorpholine.

(2) 3.5 g of (S) -4-benzyl-2-hydroxymethylmorpholine is dissolved in 5 ml of ethanol. To this solution is added 5 ml of a 5.9 N anhydrous hydrogen chloride-ethanol solution with ice cooling. The resulting mixture is stirred at the same temperature for 10 minutes. To this was added a mixture of 500 mg of 5% palladium-carbon and 10 ml of methanol. The resulting compound is hydrogenated at 40 ° C. for 3 hours. After the reaction is completed, the palladium-carbon is filtered off. The solvent is distilled off under reduced pressure to give a yellow oily product. To this oily product are added 20 ml of anhydrous methylene chloride and 4.7 ml of triethylamine. The resulting mixture is stirred at room temperature for 30 minutes. A solution of 4.7 g of trityl chloride dissolved in 10 ml of methylene chloride was added dropwise with ice cooling for 20 minutes. The mixture is stirred at room temperature for 3 hours and added to 50 ml of ice water. The organic layer is separated and 20 ml of water is added thereto. The resulting mixture is adjusted to pH 12 with 1N aqueous sodium hydroxide solution. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give a yellow oily product. The oily product is mixed with 10 ml of diisopropyl ether. The resulting crystals were collected by filtration to obtain 2.7 g of (S) -4-trityl-2-hydroxymethylmorpholine.

Melting Point: 142.0 ~ 142.5 ℃ [AcOEt-IPE]

(2R) -form having the following properties is obtained in the same manner.

Melting Point: 142.0 ~ 142.5 ℃ [AcOEt-IPE]

(3) The same method as in (1) of Preparation Example 5 was repeated, but styrene oxide and 4-benzyl-2-hydroxymethyl morpholine were respectively added to (S) -2-phenyloxirane and (S) -4. Oily (1S, 2'S) -1-phenyl-2-[(4-tritylmorpholin-2-yl) methoxy] ethanol (Compound No. 217) by replacement with -trityl-2-hydroxymethylmorpholine To obtain.

(4) (1S, 2'S) -1-phenyl-2-[(4-tritylmorpholin-2-yl) methoxy] ethanol is dissolved in 20 ml of acetone. To the solution was added 7 ml of 5.9 N anhydrous hydrogen chloride-ethanol solution with ice cooling. The resulting mixture is stirred at room temperature for 30 minutes to carry out the reaction. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue thus obtained is added to a mixture of 30 ml of ice water and 30 ml of ethyl acetate. The aqueous layer was separated and washed with 30 ml of ethyl acetate followed by 50 ml of chloroform. The pH of the resulting mixture is adjusted to 11 using 2N aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give 1.9 g of a yellow oily product. This oily product is dissolved in 10 ml of ethanol. To this solution was added 720 mg of oxalic acid. The resulting mixture is heated to give a solution. This solution is left overnight at room temperature. The resulting crystals were collected by filtration and dried to give 1.8 g of (1S, 2'S) -1-phenyl-2 [(morpholin-2-yl) methoxy] ethanol oxalate (Compound No. 218).

Melting Point: 130-132 ° C. [EtOH]

The following compounds are obtained in the same way.

(1R, 2'S) -1-phenyl-2-[(morpholin-2-yl) -methoxy] ethanol maleate (Compound No. 219)

Melting Point: 136-136.5 ° C. [EtOH]

(1S, 2'R) -1-phenyl-2-[(morpholin-2-yl) -methoxy] ethanol maleate (Compound No. 220)

Melting Point: 136-136.5 ° C. [EtOH]

(1R, 2'R) -1-phenyl-2-[(morpholin-2-yl) -methoxy] ethanol oxalate (Compound No. 221)

Melting Point: 131-132.5 ° C. [EtOH]

Preparation Example 14

(1) 1.19 g of 4-benzylthiobenzaldehyde is dissolved in 20 ml of tetrahydrofuran. The solution is cooled to -10 ° C. To this was added dropwise 10 ml of a tetrahydrofuran solution containing 2M of 2-chloroethoxymethylmagnesium chloride in 10 minutes. The resulting mixture is cooled on ice and stirred for 1 hour. The reaction mixture is added to a mixture of 50 ml ice water, 50 ml ethyl acetate and 1 g ammonium chloride. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: toluene / ethyl acetate = 20/1] to obtain 1.34 g of 1- (4-benzylthiophenyl) -2- (2-chloroethoxy) ethanol.

Melting Point: 49.5-50.5 ° C. [hexane-IPE]

(2) A mixture of 600 mg of 1- (4-benzylthiophenyl) -2- (2-chloroethoxy) ethanol, 4 ml of 50% aqueous dimethylamine solution, 310 mg of potassium iodide and 5 ml of ethanol was refluxed for 4 hours. . An additional 4 ml of 50% aqueous dimethylamine solution is added to the reaction mixture. The resulting mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature. The solvent is distilled off under reduced pressure. 30 ml of ethyl acetate and 30 ml of water were added to the obtained residue. The pH of the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is dissolved in 15 ml of acetone. 0.4 ml of 5N anhydrous hydrogen chloride-ethanol solution was added to this solution. The resulting crystals were collected by filtration to obtain 590 mg of 1- (4-benzylthiophenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 222).

Melting Point: 173.5-174.5 ° C. [EtOH]

The compounds shown 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 substituents or integers used in the following general formulas:

TABLE 14

Preparation Example 15

A mixture of 13.2 g of potassium tert-butoxide and 47.2 mL of 2- (N, N-dimethylamino) ethanol is heated to 80 ° C. Here, 40.0 g of 2- (1-naphthyl) oxirane is added dropwise within 3.5 hours. The resulting mixture is stirred at 80-85 ° C. for 1.5 hours. The reaction mixture is cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice water. The resulting mixture is adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is distilled off to obtain a fraction having a boiling point of 152 to 163 ° C / 0.6 to 0.8 mmHg. The oily product obtained is dissolved in 200 ml of acetone. Hydrogen chloride gas is blown into the solution with ice cooling. The resulting crystals were collected by filtration, washed with acetone and dried to give 2- [2- (N, N-dimethylamino) ethoxy] -1- (1-naphthyl) ethanol hydrochloride (Compound No. 228) 22.7 g is obtained.

Melting Point: 196-197 ° C. [EtOH]

The compounds described in Table 15 are obtained in the same manner.

In Table 15, R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁶ , na and nb are each a substituent or an integer used in the following general formula.

TABLE 15

(1) A mixture of 6.0 g of 2-hydroxymethyl-2-tritylmorpholine, 1.0 g of potassium tert-butoxide and 6 ml of dimethyl sulfoxide is heated to 80 ° C. To this was added dropwise a solution of 2.8 g of 2- (2-naphthyl) oxirane dissolved in 6 ml of dimethyl sulfoxide at 80 to 85 ° C in 2 hours. The resulting mixture is stirred at the same temperature for 3 hours. The reaction mixture was cooled down and added to a mixture of 60 mL ice water and 60 mL ethyl acetate. The organic layer is separated, washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.0 g of oily 1- (2-naphthyl) -2-[(4-tritylmorpholin-2-yl) -methoxy] -ethanol (Compound No. 254).

In the same manner, an oily 1- (1-naphthyl) -2-[(4-tritylmorpholin-2-yl) methoxy] -ethanol (Compound No. 255) is obtained.

(2) 9.0 g of 1- (2-naphthyl) -2-[(4-tritylmorpholin-2-yl) methoxy] -ethanol is dissolved in 50 ml of acetone. To this was added 3.5 ml of a 5.9 N anhydrous hydrogen chloride-ethanol solution while ice-cooling. The reaction is carried out by stirring the mixture at room temperature for 2 hours. After terminating the reaction, the solvent is distilled off under reduced pressure. 50 ml of water and 30 ml of ethyl acetate were added to the obtained residue. The aqueous layer is separated and washed with 30 ml of ethyl acetate. To this was added 50 ml of ethyl acetate. The resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol = 5/1) to give 1.2 g of an oily product. The oily product is dissolved in 5 ml of isopropanol. 0.5 g of fumaric acid is added to this solution. The mixture is heated to give a solution. The solution is left overnight at room temperature. The resulting crystals were collected by filtration to obtain 0.9 g of 1- (2-naphthyl) -2-[(morpholin-2-yl) methoxy] ethanol 1/2 fumarite (Compound No. 256).

Melting Point: 141-144 캜 [EtOH]

In the same manner, amorphous 1- (1-naphthyl) -2-[(morpholin-2-yl) methoxy] ethanol hydrochloride (Compound No. 257) is obtained.

Preparation Example 17

(1) A mixture of 4.5 g of potassium tert-butoxide and 45 ml of ethylene glycol is heated to 80 ° C. To this was added 13.7 g of 2- (1-naphthyl) oxirane dropwise within 1 hour. The resulting mixture is stirred at the same temperature for 1 hour. The reaction mixture is cooled and added to a mixture of 50 ml of ethyl acetate and 50 ml of ice water. The organic layer is separated. The aqueous layers are extracted twice with 20 ml of ethyl acetate each. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent = toluene / ethyl acetate = 1/3) to give 8.3 g of 2- (2-hydroxyethoxy) -1- (1-naphthyl) -ethanol. .

Melting Point: 91-92 ° C [IPE)

In the same way, 2- (2-hydroxyethoxy) -1- (2-naphthyl) ethanol is obtained.

Melting Point: 105 ~ 106 ℃ (AcOEt)

(2) 8.3 g of 2- (2-hydroxyethoxy) -1- (1-naphthyl) -ethanol are dissolved in 50 ml of pyridine. The solution is cooled to -25 ° C. To this was added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture is left at 0-5 ° for 24 hours and at room temperature for 4 hours. The reaction mixture is added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture is adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate = 10/1), and then colorless and oily to 1- (1-natyl) -2- [2- (p-toluenesulfonyloxy). 6.3 g of oxy] ethanol are obtained.

In the same manner, colorless, oily 1- (2-naphthyl) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethanol is obtained.

(3) 6.3 g of 1- (1naphthyl) -2- (2-p-toluenesulfonyloxy) ethoxy] ethanol and 0.82 g of pyridinium p-toluenesulfonate dissolved in 63 ml of methylene chloride and 3,4 To a solution of 2.97 ml of dihydro-2H-pyran was added at room temperature. The resulting mixture is stirred at room temperature for 20 minutes and at 35-40 ° C. for 10 minutes. The reaction mixture is cooled, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene / ethyl acetate = 10/1) to give a colorless, oily 1- (1-naphthyl) -1- (tetrahydropyran-2-yloxy) -2 7.53 g of-[2- (p-toluenesulfonyloxy) ethoxy] ethane are obtained.

In the same manner, colorless oily 1- (2-naphthyl) -1- (tetrahydropyran-2-yloxy) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethane is obtained.

(4) 7.5 g of 1- (1-naphthyl) -1- (tetrahydropyran-2-yloxy) -2- [2- (p-toluenesulfonyloxy) -ethoxy] ethane, N-methyl pipe A mixture of 2.65 ml of lazine, 3.96 g of potassium carbonate and 38 ml of N, N-dimethylformamide is stirred at 90-100 ° C. for 2 hours. The reaction mixture is cooled and added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer is separated. The aqueous layers are extracted twice with 25 ml of diethyl ether each. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 10/1) to give a colorless, oily 2- [2- (4-methylpiperazin-1-yl) ethoxy] -1- (1 3.36 g of -naphthyl) -1- (tetrahydropyran-2-yloxy) ethane (Compound No. 258) are obtained.

(5) 3.3 g of 2- [2- (4-methylpiperazin-1-yl) ethoxy] -1- (1-naphthyl) -1- (tetrahydropyran-2-yloxy) ethane with acetone 30 Dissolve in ml. The solution is dissolved in 30 ml of p-toluenesulfonic acid at room temperature. To this solution is added 3.46 g of p-toluenesulfonic acid monohydrate and 7 ml of water at room temperature. The resulting mixture is stirred at the same temperature for 30 minutes and at 40 ° C. for 1 hour. The reaction mixture is added to a mixture of 60 ml of chloroform and 60 ml of ice water. The mixture is adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer is separated. The aqueous layer is extracted with 20 ml of chloroform. The extract is combined with the previously separated organic layer. The combined organic layers are washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is further dissolved in 40 ml of acetone. Hydrogen chloride gas is blown into the solution with ice cooling. The resulting solution is stirred for 30 minutes at room temperature. 40 ml of diethyl ether was added thereto. The resulting mixture is stirred at the same temperature for 30 minutes. The resulting crystals were collected by filtration, washed with acetone and dried to give 2- [2- (4-methylpiperazin-1-yl) ethoxy) -1- (1-naphthyl) ethanol dihydrochloride (Compound No. 259 ) 2.35 g is obtained.

Melting Point: 230.5-231.5 ° C. [MeOH]

Production Example 18

The same procedure as in (4) and (5) of Preparation Example 17 was repeated, except that N-methylpiperazine was replaced with N- (p-fluorobenzoyl) piperidine to yield 2- {2- [4- (p -Fluorobenzoyl) piperidin-1-yl] ethoxy} -1- (1-naphthyl) ethanol hydrochloride (Compound No. 260) is obtained.

Melting Point: 204.5-205.5 ° C. [MeOH]

Preparation Example 19

2 g of 1- (1-naphthyl) -1-tetrahydropyran-2-yloxy) -2- [2- (p-toluenesulfonyloxy) ethoxy] ethane is dissolved in 20 ml of ethanol. To this solution is added 6.60 g of 40% aqueous methylamine solution at room temperature. The mixture is refluxed for 1 hour. The reaction mixture is cooled and added to a mixture of 20 mL ice water and 50 mL diethyl ether. The organic layer is separated. The aqueous layer is extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. 15 ml of water is added to the combined organic layers and the resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer is separated. The organic layers are extracted twice with 10 ml of water each. Combine the extract with the aqueous layer previously separated. The combined aqueous layers are mixed with 25 ml of chloroform and adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer is separated. The aqueous layers are extracted twice with 10 ml of chloroform each. The extract is combined with the previously separated organic layer. The combined organic layers are dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to yield 1.27 g of an oily product. The oily product is dissolved in 10 ml of acetone. Hydrogen chloride gas is blown into this solution with ice cooling. To this was added 10 ml of diethyl ether. The resulting crystals were collected by filtration to give 0.72 g of 2- [2- (N-methylamino) ethoxy] -1- (1-naphthyl) ethanol hydrochloride (Compound No. 261).

Melting Point: 137.5 ~ 139 ℃ [IPA]

The compounds described in Table 16 are obtained in the same manner.

In Table 16, R ¹ , R ² , R ³ , R ⁴ _a , R ⁴ _b , R ⁶ , na and nb are each a substituent or an integer used in the following general formula.

TABLE 16

A mixture of 3.5 g potassium tert-butoxide, 9.4 g N-tritylethanolamine and 50 ml dimethyl sulfoxide is heated to 85 ° C. To this was added 5.3 g of 2- (1-naphthyl) oxirane. The resulting mixture is stirred at the same temperature for 5 minutes. The reaction mixture is cooled and added to a mixture of 100 ml of ethyl acetate and 150 ml of ice water. The organic layer is separated. The aqueous layer is extracted with 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order using water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. 80 ml of 50% aqueous formic acid solution and 40 ml of tetrahydrofuran were added to the obtained residue. The resulting mixture is stirred at 50-60 ° C. for 1 hour. Cool the reaction mixture. The solvent is removed by distillation under reduced pressure. To the residue thus obtained was added 60 ml of ethyl acetate and 60 ml of water. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. Separate the aqueous layer. The organic layers are extracted twice with 15 ml of water each. Combine the extract with the aqueous layer previously separated. 100 ml of chloroform is added to the combined aqueous layers, and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. 10 ml of diisopropyl ether is added to the obtained residue. The resulting crystals were collected by filtration and dried to give 1.8 g of 2- (2-aminoethoxy) -2- (1-naphthyl) ethanol (Compound No. 267).

Melting Point: 89.5-92 ° C. [CHCl ₃ -Et ₂ O]

Preparation Example 21

7 ml of water and 7 ml of dioxane are added to 0.7 g of 2- (2-aminoethoxy) -1- (1-naphthyl) -ethanol to obtain a solution. 0.32 g of potassium carbonate is added to the solution. The resulting mixture is heated to 50 ° C. To this was added 0.25 g of 2-chloropyrimidine. The resulting mixture is refluxed for 3 hours. 0.32 g of potassium carbonate and 0.35 g of 2-chloropyrimidine are added thereto. The resulting mixture is again refluxed for 2.5 hours. The reaction mixture is cooled and added to a mixture of 20 ml of ethyl acetate and 20 ml of ice water. The organic layer is separated. The aqueous layer is extracted with 10 ml of ethyl acetate. The extract is combined with the previously separated organic layer. 15 ml of water is added to the combined organic layers and the resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid. Separate the aqueous layer. The organic layer is extracted with 10 ml of water. Combine the extract with the aqueous layer previously separated. 50 ml of methylene chloride is added to the combined aqueous layers, and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 20/1) to give an oily product. To the oily product 4 ml of ethanol and 0.21 g of maleic acid are added. The resulting mixture is stirred at room temperature for 1 hour. 2 ml of diethyl ether is added to the reaction mixture. The resulting mixture is stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried to afford 0.53 g of 1- (1-naphthyl) -2- [2-[(pyrimidin-2 yl) amino] ethoxy] -ethanol maleate (Compound No. 268). do.

Melting Point: 101.5 to 103 ° C. [EtOH-AcOEt]

Preparation Example 22

0.62 g of N, N'-dicyclohexylcarbodiimide was added to 0.7 g of 2- (2-aminoethoxy) -1- (1-naphthyl) ethanol, 0.37 g of nicotinic acid, 0.41 g of 1-hydroxybenzotriazole, To a mixture of 0.42 ml of triethylamine and 4 ml of tetrahydrofuran are added with ice cooling. The resulting mixture is stirred at the same temperature for 5 minutes and further at room temperature for 1 hour. 6 ml of ethyl acetate is added to the reaction mixture. Insoluble matters are removed by filtration. 15 ml of ethyl acetate and 20 ml of water are added to the filtrate. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. Separate the aqueous layer. The organic layers are extracted twice with 10 ml of water each. Combine the extract with the aqueous layer previously separated. 30 ml of chloroform is added to the combined aqueous layers, and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluant: chloroform / ethanol = 10/1) to give an oily product. The oily product is dissolved in 7 ml of acetone. 0.43 ml of 5N anhydrous hydrogen chloride-ethanol solution was added to this solution. The resulting mixture is stirred at room temperature for 1 hour. 3 ml of diethyl ether is added to the reaction mixture. The resulting mixture is stirred at the same temperature for 1 hour. The resulting crystals are collected by filtration and dried to afford 0.67 g of 1- (1-naphthyl) -2- [2- (nicotinoylamino) ethoxy] ethanol hydrochloride (Compound No. 269).

Melting Point: 162.5-163.5 ° C. [EtOH-AcOEt]

Preparation Example 23

2- (1-naphthyl) oxirane and 1,4-diformyl-2-pipera instead of 2- (2-naphthyl) -oxirane and 2-hydroxymethyl-4-tritylmorpholine Repeating the same method as in (1) of Preparation Example 16 using genyl methanol, oily 2-[(1,4-diformylpiperazin-2-yl) methoxy] -1- (1-naphthyl) Obtained Ethanol (Compound No. 270).

The compounds shown in Table 17 are obtained in the same manner.

In Table 17, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and N each represent a substituent or an integer used in the following general formula.

TABLE 17

Preparation Example 24

250 mg of 2-[(1,4-diformylpiperazin-2-yl) methoxy] -1- (1-naphthyl) -ethanol is dissolved in 1.5 ml of methanol. To this solution, 1.5 mg of 5M anhydrous hydrogen chloride-ethanol solution was added. The mixture is allowed to stand overnight at room temperature. The resulting crystals were collected by filtration, washed with ethanol and dried to afford 180 mg of 1- (1-naphthyl (-2-[(piperazin-2-yl) methoxy] ethanol dihydro chloride (Compound No. 274)). To obtain.

Melting Point: 199 to 201 ° C (Decomposition)

Preparation Example 25

The compound obtained in the same manner as in (1) of Preparation Example 16 was reacted with hydrogen chloride gas in the same manner as in the preparation of the hydrochloride of Preparation Example 22, to obtain a compound shown in Table 18.

In Table 18, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer used in the following general formula.

TABLE 18

Production Example 26

The compound shown in Table 19 is obtained by the same method as in (1) and (2) of Preparation Example 16.

In Table 19, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer used in the following general formula.

TABLE 19

Preparation Example 27

Reacting 2- (imidazol-5-yl) methoxy-1- (1-naphthyl) ethanol with methyl iodide to give an oily 2- (1-methylimidazol-5-yl) methoxy-1- (1-naphthyl) ethanol (Compound No. 283) is obtained.

Preparation Example 28

(1) 6.0 g of 6-benzyloxy-2-naphthaldehyde is dissolved in 60 ml of tetrahydrofuran. The solution is cooled to -30 ° C. After 10 minutes, 30 ml of a tetrahydrofuran solution containing 1.6 M of 2-chloroethoxymethylmagnesium chloride are added dropwise thereto. The resulting mixture is stirred with ice cooling for 1 hour. The reaction mixture is added to a mixture of 100 mL ice water, 100 mL ethyl acetate and 3.6 g ammonium chloride. The mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated and washed in this order using water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium chloride. The solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluant: toluene / ethyl acetate = 20/1) to give a solid. 10 ml of diisopropyl ether is added to the solid. The resulting mixture is stirred at room temperature for 1 hour. The resulting crystals are collected by filtration and dried to yield 4.7 g of 1- (6-benzyloxy-2-naphthyl) -2- (2-chloroethoxy) ethanol.

Melting Point: 86 ~ 87.5 ℃ [IPE]

(2) A mixture of 4.5 g of [1- (6-benzyloxy-2-naphthyl (-2- (2-chloroethoxy) ethanol), 1 g of potassium iodide, 10 ml of 50% aqueous dimethylamine solution and 20 ml of ethanol, The reaction mixture is added with 10 ml of 50% aqueous dimethylamine solution, and the resulting mixture is further refluxed for 6 hours The reaction mixture is cooled down and concentrated to almost half the volume under reduced pressure. 100 ml and 100 ml of water are added The mixture is adjusted to pH 10.5 with potassium carbonate The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue was distilled off under reduced pressure, and 30 ml of diethyl ether was added to the obtained residue, and the resulting crystals were collected by filtration and dried to obtain 1- (6-benzyloxy-2-naphthyl) -2- [2- (N 3.9 g of N-dimethylamino) ethoxy] ethanol (Compound No. 284) The.

Melting Point: 100 to 100.5 ° C. [EtOH-H ₂ O]

1- (6-benzyloxy-2-naphthyl) -2- [2- (N, N-dimethyl-amino) ethoxy] ethanol was treated in the same manner as in Example 22 to give 1- (6-benzyloxy- 2-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 285) is obtained.

Melting Point: 220 ~ 220.5 ℃ [EtOH]

Preparation Example 29

Suspend 3.0 g of 1- (6-benzyloxy-2-naphthyl) -2- [2- (N, N-dimethylamino) -ethoxy] ethanol in 12 ml of pyridine. 1.6 ml of acetic anhydride is added to the suspension. The resulting mixture is stirred at room temperature for 24 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. To the obtained residue was added 60 ml of ethyl acetate and 60 ml of water. The mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated. The aqueous layer is extracted with 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue is dissolved in 30 ml of acetone. To the solution is added 1.5 ml of a 5N anhydrous hydrogen chloride-ethanol solution. The resulting mixture is stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried, then 1-acetoxy-1- (6-benzyloxy-2-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 286) 2.6 g are obtained.

Melting Point: 157-158 ° C. [MeCN]

Preparation Example 30

2.0 g of 1-acetoxy-1 (6-benzyloxy-2-naphthyl) -2- [2-) N, N-dimethylamino) ethoxy] ethane hydrochloride, 0.5 g of 5% palladium-carbon and ethanol 40 mL of the mixture is hydrogenated at room temperature under atmospheric pressure. After completion of the reaction, the filadium-carbon is filtered off. The solvent is distilled off under reduced pressure. Acetone is added to the obtained residue. The resulting crystals were collected by filtration and dried to give 1-acetoxy-1- (6-hydroxy-2-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 287) 0.76 g is obtained.

Melting Point: 150.5 ~ 151.5 ° C. [EtOH]

Preparation Example 31

A mixture of 360 mg of 1-acetoxy-1 (6-hydroxy-2-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride, 10 ml of water and 15 ml of chloroform The pH is adjusted to 9 using a saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated. The aqueous layer is extracted twice with 10 ml of chloroform each. The extract is combined with the previously separated organic layer. The combined organic layers are washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue is dissolved in 6 ml of benzene. 0.12 ml of ethyl isocyanate is added to the solution. The resulting mixture is stirred at 80 ° C. for 4 hours. The reaction mixture is cooled. The solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (eluent: chloroform / ethanol = 20/1) to give an oily product. The oily product was treated in the same manner as in Production Example 22 to give 1-acetoxy-1- [6- (N-ethylcarbamoyl) oxy-2-naphthyl] -2- [2- (N, N- as amorphous 150 mg of dimethylamino) ethoxy] ethane hydrochloride (Compound No. 288) are obtained.

Preparation Example 32

2- [2- (N, N-dimethylamino) ethoxy] -1 (8-nitro-1-naphthyl) ethanol is obtained in the same manner as in (1) and (2) of Preparation Example 27. This compound was reacted with oxalic acid in the same manner as in (2) of Preparation Example 16 to obtain 2- [2- (N, N-dimethylamino) ethoxy] -1 (8-nitro-1-naphthyl) ethanol oxalate (Compound No. 289) is obtained.

Melting Point: 150 ~ 158.5 ℃

Preparation Example 33

A mixture of 150 mg of 2- [2- (N, N-dimethyl-amino) ethoxy] -1- (8-nitro-1-naphthyl) ethanol oxalate, 150 mg of 5% piladium-carbon and 3 ml of methanol Is hydrogenated at room temperature under atmospheric pressure for 30 minutes. After completion of the reaction, the piladium-carbon is filtered off. The filtrate is distilled off under reduced pressure to remove the solvent. The obtained residue is added to a mixture of 30 ml of ice water and 30 ml of chloroform. The mixture is adjusted to pH 11 with 2N aqueous sodium hydroxide solution. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue is dissolved in 1 ml of ethanol. To this solution is added 0.2 ml of a 5.9 N anhydrous hydrogen chloride-ethanol solution. The resulting crystals were collected by filtration, dried and 110 mg of 1- (8-amino-1-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol dihydrochloride (Compound No. 290) was obtained. To obtain.

Melting point: 195-198 ° C. (decomposition) [AcEt-EtOH]

Preparation Example 34

Triethylamineol 1- (8-amino-1-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride is added. The resulting mixture was reacted with methanesulfonyl chloride to give an oily 2- [2- (N, N-dimethylamino) ethoxy] -1- (8-methylsulfonylamino-1-naphthyl) ethanol hydrochloride (Compound No. 291).

Preparation Example 35

After repeating the same method as (1) and (2) in Preparation Example 28, using instead of 4- (N, N-dimethylamino) -1-naphthylaldehyde-6-benzyloxy-2-naphthaldehyde , Oily 1- [4- (N, N-dimethylamino) -1-naphthyl] -2- [2- (N, N-dimethyl-amino) ethoxy] ethanol dihydrochloride (Compound No. 292) To obtain.

Preparation Example 36

13 ml of ethanol are added to 1.3 g of 1- [4- (N, N-dimethylamino) -1-naphthyl] -2- [2- (N, N-dimethylamino) ethoxy] ethanol dihydrochloride. The resulting mixture is refluxed for 1 hour. Cool the reaction mixture. The solvent is distilled off under reduced pressure. To the obtained residue was added a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture is adjusted to pH 10 with potassium carbonate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily 1-ethoxy-1- [4- (N, N-dimethylamino) -1-naphthyl] -2- [2- (N, N-dimethyl-amino) ethoxy] 1.3 g of ethane (Compound No. 293) are obtained.

Preparation Example 37

(1) 9.6 g of 5-bromo-1-hydroxyindane is dissolved in 100 ml of anhydrous methylene chloride. To this solution, 570 mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran are added at room temperature. The resulting mixture is stirred at the same temperature for 3 hours. The reaction mixture is added to ice water. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under pressure. The residue thus obtained was purified by column chromatography (eluant: toluene / ethyl acetate = 15/1) to obtain 13.1 g of oily 5-bromo-1- (tetrahydropyran-2-yloxy) indane.

(2) 8.1 g of 5-bromo-1- (tetrahydropyran-2-yloxy) -indane is dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To this solution was added dropwise 20 ml of a 1.5N n-butyllidium hexane solution at -64 占 폚 for 10 minutes. The resulting mixture is stirred at the same temperature for 5 minutes. To this was added 2.3 ml of anhydrous N, N-dimethylformamide. The reaction mixture is heated to room temperature and added to a mixture of 10 ml ice water, 100 ml diethyl ether and 2 g ammonium chloride. The organic layer is separated, washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under pressure. The residue thus obtained was purified by column chromatography (eluant: toluene / ethyl acetate = 15/1) to obtain 6.5 g of 5-formyl-1- (tetrahydropyran-2-yloxy) indane.

(3) The procedure of (1) and (2) of Preparation Example 28 was carried out using 5-formyl-1 (tetraadropyran-2-yloxy) indane in place of 6-benzyloxy-2-naphthaldehyde. Repeatedly obtain oily 2- [2- (N, N-dimethylamino) ethoxy] -1- [1- (tetrahydropyran-2-yloxy) indan-5-yl] ethanol (Compound No. 294). .

(4) 2.5 g of 2- [2- (N, N-dimethylamino) ethoxy] -1- [1- (tetrahydropyran-2-yloxy) indan-5-yl] ethanol, 8 ml of acetic anhydride, and A mixture of 0.64 mL of pyridine is stirred at room temperature for 1 hour. The reaction mixture is added to a mixture of 50 mL ice water and 50 mL diethyl ether. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform / methanol = 10/1) to give oily 1-acetoxy-2- [2- (N, N-dimethylamino) ethoxy] -1- [1- 1.9 g of (tetrahydropyran-2-yloxy) -indan-5-yl] ethane (Compound No. 29) are obtained.

(5) 1.8 g of 1-acetoxy-2- [2- (N, N-dimethylamino) ethoxy] -1- [1- (tetrahydropyran-2-yloxy) -indan-5-yl] ethane To 30 ml of a 4: 2: 1 mixed solution of acetic acid, tetrahydrofuran and water. The resulting mixture is stirred at 70 ° C. for 2 hours. The reaction mixture is cooled and added to a mixture of 100 ml of water and 100 ml of diethyl ether. The resulting mixture is adjusted to pH 8.5 with potassium tantanium. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off under distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 10/1) to give oily 1-acetoxy-1-[(1-hydroxy) indan-5-yl] -2- [2- 1.0 g of (N, N-dimethylamino) ethoxy] ethane (Compound No. 296) is obtained.

(6) 1.0 g of 1-acetoxy-1-[(1-hydroxy) indan-5-yl] -2- [2- (N, N-dimethylamino) -ethoxy] ethane was dissolved in 5 ml of pyridine. Let's do it. 0.3 ml of methanesulfonyl chloride was added to this solution at room temperature. The resulting mixture is stirred overnight at the same temperature. The reaction mixture is added to a mixture of 50 mL ice water and 50 mL diethyl ether. The resulting mixture is adjusted to pH 8.5 with potassium carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol = 10/1) to give oily 1-acetoxy-1- (1H-inden-6-yl) -2- [2- (N, N 80 mg of -dimethylamino) ethoxy] ethane (Compound No. 297) is obtained.

(7) 80 mg of 1-acetoxy-1- (1H-inden-6-yl) -2- [2- (N, N-dimethylamino) -ethoxy] ethane was dissolved in 0.5 ml of methanol. 80 mg of 28% sodium methoxide-methanol solution was added to the solution while cooling with ice. The resulting mixture is stirred for 20 minutes at room temperature. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol = 20/1) to give a yellow oily product. This oily product was dissolved in 0.1 ml of ethanol, and 0.1 ml of a 5.9 N anhydrous hydrogen chloride-ethanol solution was added to this solution at room temperature. The resulting crystals are collected by filtration to give 20 mg of 1- (1H-inden-6-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 298).

Melting Point: 168-171 [deg.] C. (Decomposition) [AcOEt-EtOH]

Note: In the names of compounds 297 and 298 obtained above, the term “inden-6yl” is used because it is not clear which carbon of indene the carbon of the ethoxy group is bound to.

Preparation Example 38

1-[(1-hydroxy) indan-5-yl] -2- [2- (N, N-dimethylamino) in the same manner as in the preparation of the salt salt of Preparation Example 37 (5) and Preparation Example 22 Ethoxy] ethanol hydrochloride (Compound No. 299) is obtained.

Melting Point: 150 ~ 152 ℃ [IPA]

Preparation Example 39

2- [2- (N, N-dimethylamino) ethoxy] -1- (1-naphthyl) ethanol hydrochloride in the presence of triethylamine was reacted with acetic acid martial arts in pyridine to give oily 1-acetoxy-2- ( 2- (N, N-dimethylamino) ethoxy] -1- (1-naphthyl) ethane (Compound No. 300) is obtained.

Preparation Example 40

The compound obtained from 2- [2- (6-methyl-naphthyl)] oxirane in the same manner as in Preparation Example 16 (1) was reacted with hydrogen chloride gas in the same manner as in the preparation of hydrochloride of Preparation Example 22 to obtain oily properties. Obtain 2- [2- (N-methyl-2,3-dihydropyridin-6N-5-yl) methoxy] -1- [2- (6-methylnaphthyl)] ethanol (Compound No. 301). .

Preparation Example 41

In the same manner as in (1) and (2) of Preparation Example 28, the compound shown in Table 20 was obtained.

In Table 20, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n are substituents or integers used in the following general formulas, respectively.

TABLE 20

Preparation Example 42

1.7 g of potassium tert-butoxide was added to 31 ml of 2- (N, N-dimethylamino) ethanol, and the resulting mixture was heated to 80 ° C. To this solution was added dropwise a 5.2 g solution of 2- (benzo [b] thiophen-5-yl) oxirane dissolved in 8 ml of dimethyl sulfoxide for 1.5 h at 80-85 ° C. The resulting mixture is stirred at the same temperature for 1 hour. The reaction mixture is cooled and added to a mixture of 60 mL ethyl acetate and 60 mL ice water. The organic layer is separated. The aqueous layer is extracted with 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer. 5 ml of ice water is added to the combined glass layers and the resulting mixture is adjusted to pH 1.5 using 6N hydrochloric acid. The organic layer was separated and 5 ml of chloroform was added thereto. The pH of the resulting mixture is adjusted to 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The resulting oily product is dissolved in 50 ml of acetone. 4.3 ml of 5N anhydrous hydrogen chloride-ethanol solution was added to the solution. The resulting mixture was stirred for 1 hour at room temperature and 20 ml of diethyl ether was added thereto. The resulting mixture is stirred for an additional hour. The resulting crystals were collected by filtration and dried to give 1- (benzo [b] -thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 312) 3.3 g are obtained.

Melting Point: 191.5 to 192.5 ° C. [EtOH-Me ₂ CO]

The compounds described in Table 21 are obtained in the same manner.

In Table 21, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n represent substituents or integers used in the following general formulas, respectively:

TABLE 21

Preparation Example 43

A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoside is heated to 80 ° C. 2.4 g of 2- (benzo [b] furan-5-yl) oxirane is added thereto. The resulting mixture is stirred at 85-90 ° C. for 15 minutes. The reaction mixture is added to a mixture of 50 mL ice water and 50 mL ethyl acetate. The resulting mixture is adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer is separated and 30 ml of ethyl acetate is added thereto. The resulting mixture is adjusted to pH 9.5 with potassium carbonate. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous burn magnesium. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 50/1) to give 1- (benzo [b] furan-5-yl) -2- (pyridin-3-ylmethoxy) -ethanol ( 0.56 g of compound number 339) is obtained.

Melting Point: 85-86 ° C. [IPE-EtOH]

The compounds described in Table 22 are obtained in the same manner.

In Table 22, R <^1> , R <^2> , R <^3> , R <^4> , R <^6> and n represent the substituent or integer used by the following general formula, respectively.

Table 22

Preparation Example 44

(1) A mixture of 5.7 g of potassium tert-butoxide and 57 ml of ethylene glycol is heated to 80 ° C. To this was added a solution of 18 g of 2- (benzo [b] thiophen-5-yl) oxirane dissolved in 30 ml of dimethyl sulfoxide for 1.5 hours. The resulting mixture is stirred at the same temperature for 30 minutes. The reaction mixture is added to a mixture of 120 mL ice water and 80 mL ethyl acetate. The organic layer is separated. The aqueous layers are extracted twice with 30 ml of ethyl acetate each. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous cyclic magnesium. The solvent is distilled off under reduced pressure. The residue was purified by column chromatography (eluent: chloroform / ethanol = 20/1) to give 9.1 g of 1- (benzo [b] thiophen-5-yl) -2- (2-hydroxy ethoxy) -ethanol. To obtain. Melting Point: 119-120.5 ° C. [EtOH-AcOEt]

(2) Dissolve 9.0 g of 1- (benzo [b] thiophen-5-yl) -2- (2-hydroxyethoxy) ethanol in 54 ml of pyridine. To the solution was added 7.2 g of p-toluenesulfonyl chloride at -25 ° C. The mixture is left at 0-5 [deg.] C. for 24 hours and then left at room temperature for 4 hours. The reaction mixture is added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The pH of the resulting mixture is adjusted to 2.0 using 6N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 30 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue was purified by column chromatography (eluent: toluene / ethyl acetate = 10/1) to give a colorless oily 1- (benzo [b] thiophen-5-yl) -2- [2- (p-toluenesul 7.7 g of vinylyl) ethoxy] ethanol is obtained.

(3) 1- (benzo [b] thiophen-5-yl) -2- [2- (p-toluenesulfonyloxy, in which 0.97 g of pyridinium p-toluenesulfonate was dissolved in 40 ml of methylene chloride at room temperature 7.6 g of) ethoxy] ethanol and 3.5 ml of 3,4-dihydro-2H-pyran are added. The mixture is stirred at the same temperature for 20 minutes and then further stirred at 40 to 45 ° C. for 30 minutes. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to thereby give a colorless oily 1- (benzo [b] -thiophen-5-yl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) Dissolve 1.5 g of ethoxy] ethane. To this solution was added 4.9 mL of 40% aqueous ethylamine solution. The reaction mixture is refluxed for 1 hour. The reaction mixture is added to a mixture of 20 mL ice water and 20 mL diethyl ether. The organic layer is separated. The aqueous layer is extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. 20 ml of water is added to the combined organic layers. The pH of the resulting mixture is adjusted to 1.5 using hydrochloric acid and stirred at room temperature for 20 minutes. Separate the aqueous layer.

The organic layer is extracted with 10 ml of water. Combine the extract with the aqueous layer previously separated. 30 ml of methylene chloride is added to the combined aqueous layers. The pH of the resulting mixture is adjusted to 11 using 10% aqueous sodium hydroxide solution. The organic layer is separated. The aqueous layer is extracted with 15 ml of methylene chloride.

The extract is combined with the previously separated organic layer and the combined organic layers are dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in 7 ml of acetone. 0.5 ml of 5N anhydrous hydrogen chloride-ethanol solution was added to the solution. The resulting mixture is stirred at room temperature for 1 hour. 7 ml of diethyl ether is added to the reaction mixture. The resulting crystals were collected by filtration to give 0.5 g of 1- (benzo [b] thiophen-5-yl) -2- (N-methylaminoethoxy) ethanol hydrochloride (Compound No. 347).

Melting Point: 201.5 to 202.5 ° C. [EtOH-Me ₂ CO]

The compounds described in Table 23 are obtained in the same way.

In Table 23, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer used in the following general formula.

TABLE 23

Production Example 45

1) 2- (benzo [b] furan-5-yl) -oxirane and 3-pyridinmethanol were respectively converted to 2- (benzo [b] thiophen-5-yl) oxirane and 1,4-diformyl- Repeating in the same manner as in Preparation Example 43, except that 2-piperazinemethanol was substituted, the arithmetic 1- (benzo [b] thiophen-5-yl) -2-[(1,4-diformylpy Rerazin-2yl-) methoxy] ethanol (Compound No. 354) is obtained.

2) 270 mg of 1- (benzo [b] thiopan-5-yl) -2-[(1,4-diformylpiperazin-2-yl) methoxy] ethanol is dissolved in 1.5 ml of methanol. 1.5 ml of 5N anhydrous hydrogen chloride-ethanol solution was added to the solution. The resulting mixture is allowed to stand overnight at room temperature. The obtained crystals were collected by filtration, washed with ethanol and dried to give 1- (benzo [b] thiophen-5-yl) -2-[(piperazin-2-yl) methoxy] ethanol dihydro chloride (compound 355) 150 mg is obtained.

Melting Point: 216 to 218 ° C (Decomposition)

Preparation Example 46

1) A mixture of 10 g of 2- (N-tritylamino) ethanol, 3.7 g of potassium tert-butoxide and 30 ml of dimethylsulfoxide is heated to 85 ° C. To this was added a solution of 5.8 g of 2- (benzo [b] thiophen-5-yl) oxirane dissolved in 10 ml of dimethyl sulfoxide. The resulting mixture is stirred at the same temperature for 5 minutes. The reaction mixture is added to a mixture of 100 ml of ethyl acetate in 150 ml of ice water. The organic layer is separated. The aqueous layer is extracted with 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. 70 ml of 50% aqueous formic acid solution and 30 ml of tetrahydrofuran were added to the obtained residue. The resulting mixture is stirred at 50-60 ° C. for 1 hour. The solvent is distilled off under pressure. 50 ml of ethyl acetate and 30 ml of water were added to the obtained residue. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated. The glass layers are extracted twice with 10 ml of water each. Combine the extract with the aqueous layer previously separated. 50 ml of methylene chloride is added to the combined aqueous layers and the resulting mixture is adjusted to pH 10.5 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 to obtain 1.2 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol (Compound No. 356).

Melting Point: 87-90.5 ° C. [EtOH-IPE]

2) 1.1 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol is dissolved in 10 ml of ethanol. 290 mg of fumaric acid is added to this solution. The resulting mixture is stirred for 30 minutes at room temperature. 7 ml of diethyl ether is added to the reaction mixture. The resulting mixture is stirred at the same temperature for 1 hour. The resulting crystals are collected by filtration and dried to give 1.2 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol 1/2 fumarate (Compound No. 357). .

Melting Point: 204.5-205.5 ° C. [MeOH-EtOH]

Preparation Example 47

The same procedure as in Production Example 46 was repeated except that 2- (N-tritylamino) -ethanol was replaced with (1-tritylimiazol-4-yl) methanol, and the melting point was 128 to 129 ° C. Obtain 1- (benzo [b] thiophen-5-yl) -2-[(imidazolyl) -methoxy] ethanol (Compound No. 358), which is [AcOEt].

In the name of the obtained compound, the term “imidazolyl” methoxy ＂is used because it is not clear which carbon-transported bond of the carbon of the methoxy group is 4- and 5-position of the imidazolyl group. do.

Preparation Example 48

0.46 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol is dissolved in a mixture of 5 ml of water and 5 ml of dioxane. To this is added 0.21 g of sodium carbonate. The resulting mixture is heated to 50 ° C. To this was added 0.22 g of 2-chloropyrimidine. The resulting mixture is completed for 3 hours. The reaction mixture is added to a mixture of 30 mL ice water and 30 mL ethyl acetate. The organic layer is separated. The aqueous layer is extracted with 10 ml of ethyl acetate. The extract is combined with the glass layer previously separated. 20 ml of water is added to the combined organic insects and the resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer is separated. The organic layer is extracted with 10 ml of water. The extract is combined with the previously separated aqueous layer. 50 ml of methylene chloride is added to the combined aqueous layers and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 20/1) to give an oily product. To the oily product are added 2 ml of ethanol and 70 mg of maleic acid. The resulting mixture is stirred at room temperature for 1 hour. 2 ml of diethyl ether is added to the reaction mixture. The resulting crystals were collected by filtration and dried to give 1- (benzo [b] -thiophen-5-yl) -2-{[2- (pyrimidin-2-yl) amino] ethoxy} -ethanol 1/2 0.28 g of maleate (Compound No. 359) is obtained.

Melting Point: 113.5 ~ 144.5 ℃ [IPA-AcOEt]

Preparation Example 49

0.45 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol, 0.23 g of nicotinic acid, 0.26 g of 1-hydroxybenzotriazole, 0.26 ml of triethylamine and tetra To a mixture of 3 ml of hydrofuran, 0.39 g of N, N'-dicyclohexyl carbodiimide was added with ice cooling. The resulting mixture was stirred at the same temperature for 5 minutes and then further stirred at room temperature for 2 hours. 20 ml of water and 20 ml of ethyl acetate are added to the reaction mixture. Insoluble matters are removed by filtration. The filtrate is adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer is separated. The organic layers are extracted twice with 5 ml of water each. Combine the extract with the aqueous layer previously separated. 30 ml of chloroform is added to the combined aqueous layers and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1). The resulting oily product is dissolved in 3 ml of ethanol. To this solution was added 0.24 mL of 5N anhydrous hydrogen chloride-ethanol solution. The resulting mixture is stirred at room temperature for 1 hour. 1.5 ml of diethyl ether is added to the reaction mixture. The resulting mixture is stirred at the same temperature for 1 hour. The resulting crystals were filtered and vertically dried to afford 0.31 g of 1- [benzo [b] thiophen-5-yl) -2- [2- (nicotinoylamino) ethoxy] ethanol hydrochloride (Compound No. 360). To obtain.

Melting Point: 152-153 ° C [EtOH-AcOEt]

Preparation Example 50

(1) 1.6 g of 4-methyl-2-formyl thiazole is dissolved in 30 ml of tetrahydrofuran. The solution is cooled to -30 ° C. To this was added dropwise 10 ml of a tetrahydrofuran solution containing 1.6 M 2-chloroethoxymethyl magnesium chloride for 10 minutes. The mixture is stirred with ice cooling for 1 hour. The reaction mixture is added 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammonium chloride to the mixture. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid and stirred at the same temperature for 5 minutes. The reaction mixture is adjusted to pH 6 using saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated and washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate = 4/1) to give 1.3 g of oily 1- (4-methyl-2-thiazolyl) -2- (2-chloroethoxy) ethanol. To obtain.

(2) A mixture of 1.2 g of 1- (4-methyl-2-thiazolyl) -2- (2-chloroethoxy) ethanol, 3 ml of 50% aqueous dimatylamine solution, 0.45 g of potassium iodide and 20 ml of ethanol Reflux over time. 3 ml of 50% aqueous dimethyl amine solution is added to the reaction mixture. The resulting mixture is refluxed for 3 hours. The solvent is distilled off under reduced pressure. The residue thus obtained was added with 30 ml of ethyl acetate and 30 ml of water. The resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer is separated and washed with 10 ml of ethyl acetate. To this was added 30 ml of ethyl acetate. The resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated and washed in this order with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed midstream under reduced pressure. The obtained residue is dissolved in 6 ml of ethanol. To this solution was added 0.6 ml of a 5N anhydrous hydrogen chloride-ethanol solution and 6 ml of diethyl ether. The mixture is stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with 2 ml of a 1: 1 mixture of diethyl ether and ethanol and dried to give 1- (4-methyl-2-thiazolyl) -2 [2- (N, N-dimethyl 390 mg of amino) ethoxy] ethanol hydrochloride (Compound No. 361) are obtained.

Melting Point: 159 ~ 160 ℃ [IPA-AcOEt]

The compounds shown in Table 24 are obtained in the same manner.

In Table 24, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n each represent a substituent or an integer of the following general formula.

TABLE 24

Production Example 51

1) A mixture of 9.2 g of 1- (2-thienyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol and 185 ml of acetic anhydride is refluxed for 10 minutes. The reaction mixture is added dropwise to a mixture of 7.8 ml of concentrated nitric acid and 27 ml of acetic anhydride at 0 ° C. for 30 minutes. The resulting mixture is stirred at the same temperature for 2 hours. The reaction mixture is added to saturated aqueous sodium hydrogen carbonate solution and the pH of the resulting mixture is adjusted to pH 7 using 40% aqueous sodium hydroxide solution. The resulting mixture was adjusted to pH 10 with 40% aqueous sodium hydroxide solution and 300 ml of chloroform was added thereto. The organic layer is separated and 300 ml of water is added thereto. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated and 300 ml of chloroform is added thereto. The resulting mixture is adjusted to pH 10 with 40% aqueous sodium hydroxide solution. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily 1- (5-nitro-2-thienyl) -1-acetoxy-2- [2- (N, N-dimethylamino) -ethoxy] ethane (Compound No. 404) 10.4 Obtain G.

2) Dissolve 320 mg of 1- (5-nitro-2-thienyl) -1-acetoxy-2- [2- (N, N-dimethylamino) -ethoxy ethane in 10 ml of methanol. To this solution is added 1.27 ml of an aqueous 1N sodium hydroxide solution. The resulting mixture is stirred at room temperature for 1 hour. 40 ml of chloroform and 40 ml of water are added to the reaction mixture. The organic layer is separated and 30 ml of water is added thereto. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated and 30 ml of meloform is added thereto. The resulting mixture is adjusted to pH 11 with 10% aqueous solution of titanium hydroxide. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. To this residue was added 3 ml of methanol and 1 ml of 5N anhydrous hydrogen chloride-ethanol solution. The solvent is distilled off under reduced pressure. 5 ml of ethanol are added to the obtained residue. The resulting crystals were collected by filtration and dried to give 170 ml of 1- (5-nitro-2-thiethyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol (Compound No. 405). do.

Melting Point: 189 ~ 191.5 ° C. (decomposition)

Preparation Example 52

1) 3.4 g of 2- [2- (N, N-dimethylamino) ethoxy] -1- (6-benzioxybenzo [b] -furan-2-yl) ethanol is dissolved in 10 ml of pyridine. 1.8 ml of acetic anhydride is added to this solution. The resulting mixture is stirred at room temperature for 17.5 hours. The solvent is distilled off under reduced pressure. 40 ml of ethyl acetate and 40 ml of water were added to the obtained residue. The resulting mixture is adjusted to pH 7 with sodium hydrogen carbonate. The organic layer is separated. The aqueous layer is extracted with 20 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layers are washed in this order with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 1/1) to give oily 1-acetoxy-1- (6-benzyloxybenzo [b] furan-2-yl) -2- [ 3.25 g of 2- (N, N-dimethylamino) -ethoxy] ethane (Compound No. 406) are obtained.

IR (knit) cm ^-1 :

2) 1-acetoxy-1- (6-benzyloxybenzo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) -ethoxy] ethane 3.2 g 5% palladium-carbon A mixture of 0.6 g, concentrated hydrochloric acid 0.67 ml and methanol 30 ml was hydrogenated under high pressure at room temperature for 1.5 hours. After the reaction is complete, the palladium-carbon is filtered off. The solvent is distilled off under reduced pressure. 20 ml of chloroform and 20 ml of water are added to the obtained residue. The resulting mixture is adjusted to pH 7 with sodium hydrogen carbonate. The organic layer is separated. The aqueous layer is extracted with 10 ml of chloroform. The extract is combined with the previously separated organic layer. The combined organic layers are washed with 5 ml of water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol = 7/1) to give oily 1-acetoxy-1- (6-hydroxybenzo [b] furan-2-yl) -2- [ 1.57 g of 2- (N, N-dimethylamino) ethoxy] ethane (Compound No. 407) are obtained.

IR (knit) cm ^-1 : υ _c = _o 1740

3) Dissolve 0.65 g of 1-acetoxy-1- (6-hydroxybenzo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethane in 3.5 ml of benzene. Let's do it. 0.33 ml of ethyl isocyanate is added to this solution. The resulting mixture is stirred at 80 ° C. for 30 minutes. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 6/1) to give an oily product. The oily product was treated with anhydrous hydrogen chloride using conventional methods to give oily 1-acetoxy-1- (6-N-ethyl carbamoyloxybenzo [b] furan-2-yl) -2- [2- (N, 0.58 g of N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 408) is obtained.

IR (knit) cm ^-1 : υ _c = _o 1730

In the following the invention is described in more detail by way of examples. However, the present invention is not limited by these examples.

Example 1 (Tablet)

Tablets each containing 50 mg of 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride (Compound No. 48) were used in the following formulation according to the following method To prepare.

Component ① is mixed with an aqueous solution containing 8% polyvinylpyrrolidone K-90. The mixed product is dried at 40 ° C. and mixed with component ②. The resulting mixture is reformed into pills having a weight of 175 mg and a diameter of 8 mm, respectively.

Example 4 (Capsule)

Capsules each containing 50 mg of 2- [2- (N, N-dimethylamino) ethoxy] -1- [4- (4-phenyloxy) phenyl] ethanol hydrochloride (Compound No. 54) were prepared in the following method. It is prepared by the following prescription.

Sugar Sugar Capsules:

Ingredient ① is mixed with an aqueous solution containing 8% of polyvinylpyrrolidone K-90. The mixed product is dried at 40 ° C. and then mixed with component ②. The resulting mixture is filled into No. 3 gelatin capsule in an amount of 150 mg per capsule to obtain a capsule.

Example 3 (Liquid)

A solution containing 25 mg of 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-trifluoromethylphenyl) ethanol hydrochloride (Compound No. 42) was used in the following formulation according to the following method To prepare.

Per ampoule:

Compound number 42 25 mg

1 mg methyl paraoxybenzoate

26 mg in total

The components are dissolved in physiological saline to make the total volume of the solution 1 ml. The solution is sterile filtered and filled with ampoules to give a solution.

Example 4 (injection amount)

Injection solution containing 25 mg of 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-fluorophenyl) ethanol hydrochloride (Compound No. 1) was prepared using the following prescription according to the following method. Manufacture.

Compound number 1 25 mg

Mannitol 75mg

100 mg in total

The components are dissolved in 1.5 ml of distilled water prepared for injection. The solution is sterile filtered, filled into 3 ml small vials and lyophilized to give an injection solution.

Example 5 (Granule)

Fine particles each containing 50 mg of 2- (1-benzylpiperidin-4-yloxy) -1-phenylethanol hydrochloride (Compound No. 112) were prepared using the following formulation according to the following method.

Compound number 112 50 mg

α-starch 200 mg

Tableted Sucrose 250mg

Lactose 470mg

Polyvinylpyrrolidone K-90 30mg

Total 1000 mg

Component ① is granulated under high speed stirring with an aqueous solution containing 8% polyvinylpyrrolidone K-90. The granules obtained are sorted through a 32-mesh screen and dried to give a particulate.

Example 6 (Tablet)

As in Example 1, 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-methylphenyl) ethanol hydrochloride (Compound No. 15), 2-[(1-methylimidazole -5-yl) methoxy] -1- (4-benzyloxyphenyl) -ethanol (Compound No. 215), 2- [2- (N, N-dimethylamino) ethoxy] -1- (1-naphthyl Ethanol Hydrochloride (Compound No. 228), 2- [2- (N, N-dimethylamino) ethoxy] -1- (2-naphthyl) -ethanol Hydrochloride (Compound No. 229), 2- [2- (N, N-dimethylamino) ethoxy] -1- (benzo [b] thiophen-5-yl) ethanol hydrochloride (Compound No. 312), no. 345), 2- (2-amino-ethoxy)- 1- (benzo [b] thiophen-5-yl) -ethanol 1/2 fumarate (Compound No. 357), 2- [2- (N, N-diethylamino) -ethoxy] -1- (benzo [b] thiophen-5-yl) ethanol hydrochloride (Compound No. 388) and 2- [2- (4-belzylpiperazin-1-yl) ethyl] -1- (benzo [b] -furan-5- 1) Ethanol dihydrochloride (Compound No. 394) The process treatment as in Example 2 to give a tablet containing each 50㎎ a mixture of the compound of the compound.

Example 7 (Capsules)

As in Example 2, 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-methyl-phenyl) ethanol hydrochloride (Compound No. 15), 2-[(1-methylami Dazol-5-yl) methoxy] -1- (4-benzyloxyphenyl) -ethanol (Compound No. 215), 2- [2- (N, N-dimethylamino) -ethoxy] -1- (1- Naphthyl) ethanol hydrochloride (Compound No. 228), 2- [2- (N, N-dimethylamino) ethoxy] -1- (2-naphthyl) -ethanol hydrochloride (Compound No. 229), 2- [ 2- (N, N-dimethylamino) ethoxy] -1- (benzo [b] thiophen-5-yl) ethanol hydrochloride (Compound No. 312), 2-[(N-methyl-1H-1,2 , 5,6-tetra hydropyridin-3-yl) methyl] -1- (benzo [b] -thiophen-5-yl) ethanol (Compound No. 345), 2- (2-aminoethoxy) -1- (Benzo [b] thiophen-5-yl) ethanol 1/2 fumarate (Compound No. 357), 2- [2- (N, N-dimethylamino) ethoxy] -1- (benzo [b] thiophene -5-yl) ethanol hydrochloride (Compound No. 388), and 2- [2- (4-benzylpi Rajin-1-yl) ethyl] -1- (benzo [b] furan-5-yl) ethanol dihydrochloride (Compound No. 394) was reacted to obtain a capsule containing 50 mg of each of the compounds. do.

Claims (39)

1,2-ethanedioxane derivative of formula (I) or a salt thereof,

Wherein R ¹ is substituted or phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, R ² is a hydrogen atom, a lower alkyl group or a hydroxyl-insured group, and R ³ is A hydrogen atom or a lower alkyl group, nR ⁴ and nR ⁵ are the same or different from each other, a hydrogen atom or a lower alkyl group, R ⁶ is an ammonia group or a substituted or unsubstituted amino-containing heterocyclic group, or pyrrolyl , Pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroqui Nolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and inda Substituted group selected from the group consisting of reels or unsubstituted nitrogen-containing heterocyclic group; n is 0 or an integer from 1 to 6; Substituents on R ¹ are halogen atom, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower al Kenyloxy, af-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, loweralkyl-sulfonylamino, arylsulfonylamino and heterocyclic groups and protected amino groups, protected or unprotected hydroxyl groups , Nitro group, oxo group and lower alkylenedioxy group; R substituted lower alkyl as a substituent of the ^first, aryl, aralkyl, lower alkyl, lower alkoxy, aralkyl-lower alkoxy, aryloxy, carbamoyl oxy, lower alkylthio, lower alkenyl, lower alkenyloxy, aralkyl-lower alkylthio , Ar-lower alkylsulfonyl, arylsulfonyl, lower alkyl sulfonylamino, arylsulfonylamino or heterocyclic groups and substituted nitrogen-containing heterocyclic groups as R ⁶ are each a halogen atom, protected or unprotected Lower alkyl groups substituted by hydroxyl groups, protected or unprotected amino groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl groups, protected or unprotected hydroxyl groups Unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, Lower alkoxy groups substituted by lower alkoxy groups, lower acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocyclic groups, heterocyclic-CO- groups, oxo groups, lower alkylsulfonyl groups, and One or more substituents selected from the group consisting of arylsulfonyl groups; The amino group substituted as a substituent of R ¹ and the amino group substituted with R ⁶ are each a lower group substituted by a protected or unprotected hydroxyl group, an unsubstituted lower alkyl group, a protected or unprotected carboxyl or hydroxyl group. Alkyl group, cycloalkyl group, aryl group, lower acyl group, ar-lower alkyl group, heterocyclic group, unsubstituted or oxo-substituted heterocyclic-CO- group, adamantyl group, lower alkylsulfonyl group And at least one substituent selected from the group consisting of arylsulfonyl groups, provided that R ¹ is optionally substituted by halogen atom or lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group Is a group, R ⁶ is -NR ⁷ R ⁸ wherein R ⁷ is an ar-lower alkyl or heterocyclic group, and R is ⁸ is a hydrogen atom or a lower alkyl group, or R ⁷ and R ⁸ together with a nitrogen atom

Wherein R ⁹ is an aryl or heterocyclic group and i is 0 or an integer from 1 to 3;

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, R ⁸ and i are as defined in position),

(Wherein R ¹¹ is an aryl group),

(Wherein R ¹² is a carboxyl group or a lower alkoxycarbonyl group) or

Wherein R ¹² is as defined above; and R ¹ is an unsubstituted or lower alkyl-substituted phenyl group, and R ⁶ is a di-lower alkyl amino

or

,

Phosphorus compounds are excluded; The aforementioned heterocyclic groups are all nitrogen-containing heterocyclic groups mentioned in the definition of R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, Benzamidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 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, chromenyl, isothiazolyl , Isoxazolyl, oxdiazolyl, pyridazinyl, isoindoleyl and isoquinolyl groups. The compound of claim 1, wherein R ¹ is a substituted or unsubstituted phenyl group; R ² is a hydrogen atom or a hydroxyl-protecting group; nR ⁴ is the same or different hydrogen atom or lower alkyl group from each other; nR ⁵ is a hydrogen atom; R ⁶ is a substituted or unsubstituted amino-containing heterocyclic group other than ammonia group or di-lower alkylamino, or pyrrolyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolyl 1,2-ethanediol derivatives or salts thereof, which are substituted or unsubstituted nitrogen-containing heterocyclic groups selected from the group consisting of quinolizinyl, teprahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups . The compound of claim 1, wherein R ¹ is a substituted or unsubstituted naphthyl group, and R ² is a hydrogen atom or a hydroxy-protecting group; nR ⁴ is the same or different hydrogen atom or lower alkyl group from each other; nR ⁵ is a hydrogen atom; R ⁶ is an ammonia group or a substituted or unsubstituted amino-containing heterocyclic group, or pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, morpholi 1,2-ethanediol, which is a substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of nil, quinolyl, quinolinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups Derivatives or salts thereof. The 1,2-ethanediol derivative according to claim ¹ or a salt thereof, wherein R ¹ is substituted or unsubstituted heterocyclic group. The compound of claim 1, wherein R ¹ is a naphthyl, indanyl or tetrahydronaphthyl group which may be optionally substituted by halogen atom or lower alkyl group; R ² is a hydrogen atom; R ³ is a hydrogen atom, nR ⁴ and nR ⁵ are hydrogen atoms; R ⁶ is a morpholinyl group, a pyridyl group, an imidazolyl group or a phenyl-C ₁ -C ₄ alkyl group-substituted piperazinyl group having free valences on the carbon atom forming the ring, or a lower alkyl or a cycle An amino group which may be optionally substituted by a Laurentyl group; 1,2-ethanediol derivatives or salts thereof wherein n is an integer from 1 to 4. The compound of claim 1, wherein R ¹ is a benzothienyl, benzofuranyl or 2,3-dihydrobenzothienyl group; R ² is a hydrogen atom; R ³ is a hydrogen atom; nR ⁴ and nR ⁵ are hydrogen atoms; R ⁶ is a pyridyl group, a piperidinyl group optionally substituted by lower alkyl group, a 1,2,5,6-tetrahydropyridyl group optionally substituted by lower alkyl group, an imidazolyl group Or a phenyl C ₁ -C ₄ alkyl group-substituted piperazinyl group or an amino group which may be optionally substituted by lower alkyl or cycloalkyl group; 1,2-ethanediol derivatives or salts thereof wherein n is an integer from 1 to 4. The 1,2-ethanediol derivative or salt thereof according to claim 1, wherein the derivative or salt is 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. . The 1,2-ethanediol derivative or salt thereof according to claim 1, wherein the derivative or salt is 1- (4benzyloxyphenyl) -2-[(1-methyl-5imidazolyl) methoxy] ethanol or a salt thereof. The 1,2-ethanediol derivative or salt thereof according to claim 1, wherein the derivative or salt is 2- (imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof. The 1,2-ethanediol derivative or salt thereof according to claim 1, wherein the derivative or salt is 2- (1-methyl-5-imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof. The 1,2-ethane of claim 1, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. Diol derivatives or salts thereof. The 1,2-ethane of claim 1, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) propoxy] ethanol or a salt thereof. Diol derivatives or salts thereof. The 1,2-ethanedioxane derivative or salt thereof according to claim 1, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- (amidazolylmethoxy) ethanol or a salt thereof. The 1,2-ethanediol derivative or salt thereof according to claim 1, wherein the derivative or salt is or salt thereof. The 1,2-ethanediol of claim 1, wherein the derivative or salt is 1- (benzo [b] furan-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. Derivatives or salts thereof. A compound of formula (II) is reacted with a compound of formula (III) or a salt thereof or a compound of formula (IV) or a salt thereof, so that 1,2-ethanediol of formula (I ') Process for preparing derivatives or salts thereof.

Wherein R ¹ is substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group; R ³ is a hydrogen atom or a lower alkyl group; nR ⁴ and nR ⁵ are the same or different hydrogen atoms or lower alkyl groups from each other; R ⁶ is an ammonia group or a substituted or unsubstituted amino-containing heterocyclic group or is pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, Pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl A substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, and purinyl midindazolyl groups; n is 0 or an integer from 1 to 6; Substituents on R ¹ are halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, arger alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyl Oxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic groups, protected amino groups, protected or unprotected hydroxy groups, nitro Group, oxo group, and lower alkylenedioxy group; R substituted lower alkyl as a substituent of the ^first, aryl, aralkyl, lower alkyl, lower alkoxy, aralkyl-lower alkoxy, aryloxy, carbamoyl oxy, lower alkylthio, lower alkenyl, lower alkenyloxy, aralkyl-lower alkylthio , Ar-lower alkylsulfonyl, aryl sulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic groups and substituted nitrogen-containing heterocyclic groups as R ⁶ are each a halogen atom, protected or unprotected Hydroxyl groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by protected or unprotected hydroxyl groups, unsubstituted or halogen-substituted Lower substituted by aryl group, unsubstituted or halogen-substituted aroyl group, unsubstituted lower alkoxy group, lower alkoxy group Group consisting of a cooxy 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 One or more substituents selected from; The amino group substituted as a substituent of R ¹ and the amino group substituted with R ⁶ are each substituted by a protected or unprotected hydroxyl group, an unsubstituted lower alkyl group, a protected or unprotected carboxyl or hydroxyl group, respectively. Lower alkyl groups, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, unsubstituted or oxo-substituted heterocyclic-CO- groups, adamantyl groups, lower alkylsulfonyl Having at least one substituent selected from the group consisting of a group and an arylsulfonyl group, provided that R ¹ can be optionally substituted by halogen atom or lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxy group Phenyl group, R ⁶ is —NR ⁹ R ⁸ , wherein 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 with} this nitrogen atom

Where R ⁹ is an aryl or heterocyclic group and i is 0 or an integer from 1 to 3,

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, R ⁸ and i are as defined above),

(Wherein R ¹¹ is an aryl group),

(Wherein R ¹² is a carboxyl group or a lower alkoxy carbonyl group) or

Wherein R ¹² is as defined above; and R ¹ is an unsubstituted or lower alkyl-substituted phenyl group, R ⁶ is a di-lower alkylamino group,

,

or

Phosphorus compounds are excluded; The aforementioned heterocyclic groups are all nitrogen-containing heterocyclic groups mentioned in the definition of R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, Benzamidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenthienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H- 1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl Isoxazolyl, oxadiazolyl, pyrazinyl, isoindolyl and isoquinolyl; mR ⁴ and mR ⁵ are the same or different hydrogen atoms or lower alkyl groups; m is an integer from 1 to 6; R ^6a represents the same substituted or unsubstituted nitrogen-containing heterocyclic group as in the definition of R ⁶ , provided that the heterocyclic group has a free valency on the carbon atom forming the heterocyclic ring. A method for preparing a 1,2-ethanediol derivative of formula (I-a) or a salt thereof, characterized by reacting a compound of formula (A) with a compound of formula (B) or a salt thereof.

Wherein R ¹ represents a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, and R ^2a represents a hydroxy-protecting group; R ³ represents a hydrogen atom or a lower alkyl group; mR ⁴ and mR ⁵ represent the same or different hydrogen atom or lower alkyl group from each other; R ^6b is a substituted or unsubstituted amino-containing heterocyclic group or has a free valence on the carbon atom that forms the heterocyclic ring, and includes pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl , Pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, terahydroisoquinolinyl, quinuclidinyl, A substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of thiazolyl, tetrazolyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups; m represents an integer of 1 to 6; Substituents on R ¹ are halogen atom, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower al Kenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arsulfonyl, lower alkylsulfonyl amino, arylsulfonylamino and heterocyclic groups, protected amino groups, protected or unprotected hydroxy groups , Nitro group, oxo group and lower alkylenedioxy group selected from the group consisting of; R substituted lower alkyl as a substituent of the ^first, aryl, aralkyl, lower alkyl, lower alkoxy, aralkyl-lower alkoxy, aryloxy, carbamoyl oxy, lower alkylthio, lower alkenyl, lower alkenyloxy, aralkyl-lower alkylthio , aralkyl-lower alkylsulfonyl, arylsulfonyl, lower alkyl-sulfonylamino, aryl-sulfonylamino or a hetero-phase cyclic group and a nitrogen-substituted as R ^{6b-containing} heterocyclic group are each a halogen atom, a protected or unprotected hydroxy Unsubstituted or halogen-substituted allyl, substituted or unsubstituted amino group, protected or unprotected carboxyl group, unsubstituted lower alkyl group, lower alkyl group substituted by protected or unprotected hydroxyl group Lower alkoxy substituted by groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups Substituents selected from the group consisting of lower alsyl group, ar-lower alkyl group, ar-lower alkenyl group, heterocyclic group, heterocyclic-CO- group, oxo group, lower alkylsulfonyl group and alisulfonyl group With one or more substituted and substituted amino groups as substituents of R ¹ and substituted amino groups as R ^6b , respectively, are protected or unprotected hydroxyl groups to unsubstituted lower alkyl groups, protected or unprotected carboxyl or hydroxyl groups. Lower alkyl groups, cycloalkyr groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, unsubstituted or oxo-substituted heterocyclic-CO- groups, adamantyl groups, substituted by At least one substituent selected from the group consisting of lower alkyl sulfonyl groups and arylsulfonyl groups, provided that R ¹ is A phenyl group which may be optionally substituted by halogen atom or lower alkyl, lower alkenedioxy, lower alkoxy or protected or unprotected hydroxyl group, R ^6b is —NR ⁷ R ⁸ where R ⁷ is ar-lower An alkyl group or a heterocyclic group, R ⁸ is a hydrogen atom or a lower alkyl group, or R ⁷ and R ⁸ together with a nitrogen atom

(Wherein R ⁹ represents an aryl or heterocyclic group and i represents 0 or an integer from 1 to 3),

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, R ⁸ and i are as defined above),

(Wherein R ¹¹ represents an aryl group),

(Wherein R ¹² represents a carboxyl group or a lower alkoxycarbonyl group) or

Wherein R ¹² is as defined above; and R ¹ represents an unsubstituted or lower-alkyl-substituted phenyl group, R ^6b represents a di-lower alkylamino group,

,

or

Compounds that represent are excluded; The heterocyclic groups are all nitrogen-containing heterocyclic groups mentioned in the definition of R ^6b and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benz Imidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1 -Thianiphthyl, 2,3-dihydrobenzothienyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, Isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups. Use of 1,2-ethanediol derivatives of general formula (I) or salts thereof for the manufacture of a medicament for the treatment of patients with secondary or stroke of cerebrovascular dementia, senile dementia, Alzheimer's dementia, ischemic brain disease

Wherein R ¹ represents a substituted or unsubstituted phenyl, nattyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic ring; R ² represents a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group; R ³ represents a hydrogen atom or a lower alkyl group; nR ⁴ and nR ⁵ represent the same or different hydrogen atoms or lower alkyl groups, and R | ⁶ is an ammonio group or a substituted or unsubstituted amino-containing heterocyclic group or is pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl , Morpholinyl, thiomorpholinyl, quinolyl, quinolininyl, tetrafluoroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, already A substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of dazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups; n represents 0 or an integer from 1 to 6; Substituents on R ¹ are halogen atom, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower al Kenyloxy, ar-lower alkyldio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, allylsulfonylamino and heterocyclyl groups, protected amino groups, protected or unprotected hydroxyl groups, Selected from the group consisting of nitro group, oxo group and lower alkylenedioxy group; R substituted lower alkyl as a substituent of the ^first, aryl, aralkyl, lower alkyl, lower alkoxy, aralkyl-lower alkoxy, aryloxy, carbamoyl oxy, lower alkylthio, lower alkenyl, lower alkenyloxy, aralkyl-lower alkylthio , Ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arsulfonylamino or heterocyclyl groups, and substituted nitrogen-containing heterocyclic groups as R ⁶ are each a halogen atom, protected or protected Unsubstituted hydroxy groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by protected or unprotected hydroxyl groups, unsubstituted or halogen- Lower aryl groups substituted by substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups Among the group consisting of a cooxy 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 allylsulfonyl group Substituted amino groups as substituents of R ¹ and substituted amino groups as R ⁶ , each having one or more substituents selected, are protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, protected or unprotected carboxyl or hydroxyl Lower alkyl group, cycloalkyl group, aryl group, lower acyl group, ar-lower alkyl group, heterocyclic group, unsubstituted or oxo-substituted heterocyclic-CO- group, adamantyl, substituted by a hydroxyl group At least one substituent selected from the group consisting of a group, a lower alkylsulfonyl group and an arylsulfonyl group, provided that R ¹ is a phenyl group which may be optionally substituted by halogen atom or lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group, and R ⁶ is —NR ⁷ R ⁸ [(where R ⁷ Is an ar-lower alkyl group or heterocyclic group, R ⁸ is a hydrogen atom or a lower alkyl group, or R ⁷ and R ⁸ together with a nitrogen atom

(Wherein R ⁹ represents an aryl or heterocyclic group and i represents 0 or an integer from 1 to 3),

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, R ⁸ and i are as defined above),

(Wherein R ¹¹ represents an aryl group),

(Wherein R ¹² represents a carboxyl group or a lower alkoxycarbonyl group) or

To form wherein R ¹² is as defined above; are excluded; All of the heterocyclic groups include R ⁶ is a nitrogen-containing heterocyclic group mentioned in the definition, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benz Amidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 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, chromenyl, isothiazolyl Isoxazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups. ^19. The compound of claim 18, wherein R ¹ represents a substituted or unsubstituted phenyl group; R ² represents a hydrogen atom or a hydroxyl-protecting group; nR ⁴ represent the same or different hydrogen atom or lower alkyl group from each other; nR ⁵ represents a hydrogen atom; R ⁶ is an ammonio group or a substituted or unsubstituted amino-containing heterocyclic group, or pyrrolyl, pyrrolidinyl, papridinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1,2 representing a substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of morpholinyl, quinolyl, quinolinyl, tetrahydroquinolinyl, quinucridinyl, thiazolyl and thiadiazolyl groups Use of ethanediol derivatives or salts thereof ^19. The compound of claim 18, wherein R ¹ represents a substituted or unsubstituted naphthyl group; R ² represents a hydrogen atom or a hydroxyl-protecting group; nR ⁴ represent the same or different hydrogen atom or lower alkyl group from each other; nR ⁵ represents a hydrogen atom; R ⁶ is an ammonio group or a substituted or unsubstituted amino-containing heterocyclic group, or pyrrolyl, pyrrolidinyl, papridinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1,2 representing a substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group consisting of morpholinyl, quinolyl, quinolinyl, tetrahydroquinolinyl, quinucridinyl, thiazolyl and thiadiazolyl groups Use of ethanediol derivatives or salts thereof. The use of 1,2-ethanediol derivatives or salts thereof according to claim 18, wherein R ¹ represents a substituted or unsubstituted heterocyclic group. ^19. The compound of claim 18, wherein R ¹ is substituted or unsubstituted phenyl, naphthyl, indanyl, tetrahydronaphthyl, furyl, thienyl, pyridyl, quinolyl, benzothienyl, 23-dihydrobenzofuranyl, Indolyl, benzofuranyl, 2,3-dihydrobenzothienyl, 1,2,3,4-tetrahydroquinolinyl or imidazolyl group, wherein R ⁶ is an ammonio group or substituted or unsubstituted An amino-containing heterocyclic group or consisting of pyrrolinyl, piperidyl, piperazinyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl, quinuclidinyl and tetrazolyl A substituted or unsubstituted nitrogen-containing heterocyclic group selected from the group; The substituent on R ¹ is a halogen atom, a lower alkyl group; Lower alkenyl groups; Phenyl groups which may be optionally substituted by halogen atoms or lower alkyl or lower alkoxy groups; Phenyl-C _1-4 alkyl group; Lower alkoxy groups which may be optionally substituted by pyridyl, furyl or thienyl groups; Phenyl-C _1-4 alkoxy groups which may be optionally substituted by halogen atoms or lower alkyl, hydroxyl or lower alkoxy groups; Phenoxy group; Tenylaminocarbonyloxy groups which may be optionally substituted by halogen atoms; Lower alkylaminocarbonyloxy groups; Lower alkylthio groups; Panylsulfonylamino group; Amino groups which may be optionally substituted by lower alkyl groups; Hydroxyl groups; Nitro group; Oxo group; Phenyl-C _1-4 alkylthio group; Phenyl-C _1-4 alkylsulfonyl group; Thienyl groups; It is selected from the group consisting of a pyridyl group and a lower alkylenedioxy group, and when R ⁶ is a substituted amino group, the substituent on R ⁶ may be a lower alkyl group which may be optionally substituted by hydroxyl group; Lower acyl groups; Phenyl-C _1-4 alkaline group; Pyrimidinyl groups; Pyridine-carbonyl group, and adamantyl group is selected from the group with one eojin, R ⁶ is a substituted nitrogen-containing heterocyclic group when the substituents on R ⁶ is a halogen atom, a hydroxyl group; Lower alkyl groups which may be optionally substituted by hydroxyl groups; Amino group; Lower acyl groups which may be optionally substituted by pyrrolidinyl groups; Phenyl-C _1-4 alkyl group; Phenyl-C _2-4 alkenyl group; Aroyl groups substituted by halogen atoms; Selected from the group consisting of a pyridyl group and an oxo group; Provided that R ¹ is a halogen atom or a phenyl group which may be optionally substituted by lower alkyl, lower alkoxy, lower alkylenedioxy or a hydroxyl group, wherein R ⁶ is —NR ⁷ R ⁸ wherein R ⁷ is phenyl-C _1-4 alkyl or pyrimidinyl group, R ⁸ represents a hydrogen atom or a lower alkyl group, or R ⁷ and R ⁸ together with a nitrogen atom (wherein R ⁹ represents a phenyl group and i is 0 or Form an integer of 1 to 3). The compound of claim 22, wherein R ¹ is a phenyl group which may be optionally substituted by halogen atoms; Phenyl-C _1-4 alkoxy group; Phenyl group; Thienyl groups; Lower alkoxy group optionally substituted by phenoxy group or thienyl group which may be optionally substituted by halogen atom or lower alkoxy group; R ² , R ³ , nR ⁴ and nR ⁵ are each hydrogen atoms; Morpholinyl groups having free valences on the carbon atom where R ⁶ forms a ring; Pyridyl group; Use of a 1,2-ethanediol derivative or salt thereof, which is an imidazolyl group which may be optionally substituted by lower alkyl group or an amino group which may be optionally substituted by lower alkyl or cycloalkyl group. The compound of claim 22, wherein R ¹ is a naphthylindanyl or tetrahydronaphthyl group which may be optionally substituted by halogen atom or by lower alkyl group; R ² , R ³ , nR ⁴ and nR ⁵ are each hydrogen atoms; Morpholinyl groups having free valences on the carbon atom where R ⁶ forms a ring; Pyridyl groups; Imidazolyl group; Phenyl-C _1-4 alkyl group-substituted piperazinyl group or amino group which may be optionally substituted by lower alkyl or cycloalkyl group; Use of 1,2-ethanediol derivatives or salts thereof where N is an integer from 1 to 4 The compound of claim 22, wherein R ¹ is a benzothienyl, benzofuranyl or 2,3-dihydrobenzothienyl group; R ² , R ³ , nR ⁴ and nR ⁵ are each hydrogen atoms; A 1,2,5,6-tetrahydropyridyl group, wherein R ⁶ may be optionally substituted by a pyridyl group, a lower alkyl group, a piperidinyl group, or a lower Langyl group; Imidazolyl group; Phenyl-C _1-4 alkyl group-substituted piperazinyl group or amino group which may be optionally substituted by lower alkyl or cycloalkyl group; The use of 1,2-ethanediol derivative or its salt whose n is an integer of 1-4. The 1,2-ethanediol derivative according to claim 18, wherein the derivative or salt is 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. Use of salts. The 1,2-ethanediol derivative according to claim 18, wherein the derivative or salt is 1- (4-benzyloxyphenyl) -2-[(1-methyl-5-imidazolyl) methoxy] ethanol or a salt thereof. Use of salts thereof. The use of 1,2-ethanediol derivatives or salts thereof according to claim 18, wherein the derivative or salt is 2- (imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof. Use of a 1,2-ethanediol derivative or salt thereof according to claim 18, wherein the derivative or salt is 2- (1-methyl-5-imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof. . The 1,2- according to claim 18, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. Use of ethanediol derivatives or salts thereof. The 1,2- according to claim 18, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [3- (N, N-dimethylamino) propoxy] ethanol or a salt thereof. Use of ethanediol derivatives or salts thereof. The use of 1,2-ethanediol derivatives or salts thereof according to claim 18, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- (imidazolylmethoxy) ethanol or salts thereof. . The use of 1,2-ethanediol derivatives or salts thereof according to claim 18, wherein the derivative or salt is or salt thereof. The 1,2-ethane of claim 18, wherein the derivative or salt is 1- (benzo [b] furan-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. Use of diol derivatives or salts thereof. Use of a 1,2-ethanediol derivative or salt thereof according to claim 18, wherein the derivative or salt is 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-methylphenyl) ethanol or a salt thereof. . Brain function improving agent comprising 1,2-ethanedioxane derivative of formula (I) or salt thereof

Wherein R ¹ is a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, and R ² is a hydrogen atom, a lower alkyl group or a hydroxy-protecting group; R ³ is a hydrogen atom or a lower alkyl group; nR ⁴ and nR ⁵ are the same or different hydrogen atoms or lower alkyl groups, and R ⁶ is an ammonio group or a substituted or unsubstituted amino-containing heterocyclic group or is pyrrolyl, pyrrolidini, piperidyl, pyre Lazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolininyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl , Quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imizazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups Ring nitrogen-containing heterocyclic group; n is 0 or an integer from 1 to 6; Substituents on R ¹ are halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower al Kenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonyl amino, arylsulfonylamino and heterocyclic groups, protected amino groups, protected or unprotected hydroxy groups, Selected from the group consisting of nitro groups, oxo groups and lower alkylenedioxy groups, substituted lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower Alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, allylsulfonyl amino or Heterocyclic Cleveland group, and R ⁶ substituted nitrogen as-containing heterocyclic Cleveland group are each a halogen atom, an unprotected or a hydroxyl group, an unprotected beam or non-protected amino group, protected or protected carboxyl group, unsubstituted Lower alkyl groups, lower alkyl substituted by protected or unprotected hydroxyl groups, unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy Lower alkoxy groups, lower acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocyclic groups, heterocyclic-CO- groups, oxo groups, lower alkylsulfonyl groups and arylsulls substituted by groups It contains a substituent selected from the group consisting of a sulfonyl group and more than one, an amino group substituted as the substituent of R ¹ R ⁶ are substituted amino groups are each protected are not protected as a hydroxyl group, an unsubstituted lower alkyl group, protected or substituted by non-carboxyl or hydroxyl group is not protected alkyl group, cycloalkyl group, aryl group, lower acyl group, A substituent selected from the group consisting of an ar-lower alkyl group, a heterocyclic group, an unsubstituted or oxo-substituted heterocyclic-CO- group, adamantyl group, lower alkyl sulfonyl group and isylsulfonyl group Wherein R ¹ is a phenyl group optionally substituted by halogen atom or lower alkyl, lower alkylenedioxy, lower alkoxy or a protected or unprotected hydroxy group, and R ⁶ is a general formula-NR ⁷ R ⁸ [wherein R ⁷ is an ar-lower alkyl group or heterocyclic group and R ⁸ is a hydrogen atom or Lower alkyl group; R ⁷ or R ⁸ together with the nitrogen atom

Wherein R ⁹ is an aryl group or heterocyclic group and I is 0 or an integer from 1 to 3

Wherein R ¹⁰ is aryl, heterocyclic or

Heterocyclic group, R ⁸ and I are as defined above),

Wherein R ¹¹ is an aryl group

In which R ¹² is a carboxyl group or a lower alkoxycarbonyl group or a general formula

Wherein R ¹² is as defined above) are excluded; The heterocyclic group is a nitrogen-containing heterocyclic group mentioned in the definition of R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimi Dazolyl, benzolsazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 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, cromenyl, isothiazolyl, isox It is selected from the group consisting of sazolyl, oxadiazolyl, pyrazinyl, isoindolyl and isoquinolyl groups. The 1,2 or 2 compound according to claim 1, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-diethylamino) ethoxy] ethanol or a salt thereof. Ethanediol derivatives or salts thereof. 19. The compound of claim 18, wherein the derivative or salt is 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dienylamino) ethoxy] ethanol or a salt thereof. Use of ethanediol derivatives or salts thereof 37. The brain function improving agent according to claim 36, which is a treatment for cerebrovascular dementia, senile dementia, Alzheimer's dementia, ischemic brain disease secondary or stroke.