JP2887492B2 - 1,2-ethanediol derivatives and salts thereof - Google Patents

Description

The present invention relates to a novel 1,2-ethanediol derivative [I], its intermediate [I '] and salts thereof,
More specifically, the present invention relates to the following compounds.

General formula In the formula, R ¹ is a heterocyclic group consisting of a 5-membered ring, a 6-membered ring having at least ^one of an oxygen atom, a sulfur atom, and a nitrogen atom, or a fused or bridged ring thereof, 2-O-cyclohexylidene-3-O-methyl-6-O- (2-pyridinylmethyl) -α-D-glucofuranose and 1,2: 3,4-
Di-O-cyclohexylidene-6-O- (2-pyridinylmethyl) -D-mannitol), a halogen atom, a hydroxyl group, a nitro group, an oxo group,
A hydroxyl, carboxyl or amino group which may be substituted with a lower alkylenedioxy group, which may be substituted with a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar-lower alkyl group; A lower alkyl group which may be substituted with a halogen; an aroyl group which may be substituted with a halogen; a lower alkoxy group which may be substituted with a lower alkoxy group; a halogen atom; a lower acyl group; A lower alkyl group; an al-lower alkenyl group; an oxo group; a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, or a heterocyclic group comprising a fused or bridged ring thereof; A 5-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, 6
A heterocyclic -CO- group comprising a membered ring or a fused or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group which may be substituted with one or more groups selected from the group consisting of amino, lower alkyl, aryl, Al lower alkyl,
Lower alkoxy, al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or oxygen atom, sulfur atom, May be substituted with a 5-membered ring, a 6-membered ring having any one or more of nitrogen atoms or a heterocyclic group consisting of a condensed ring or a bridged ring thereof, and R ³ represents a hydrogen atom or a lower alkyl group. N n R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a lower alkyl group; R ⁶ is an ammonium group or a lower alkyl, a lower acyl, a 2-tetrahydropyranyl or an ar lower alkyl group; Good hydroxyl group; lower alkyl , Lower acyl, 2-tetrahydropyranyl or ar (lower) alkyl-lower alkyl group which may be substituted by optionally substituted hydroxyl or carboxyl group group; a cycloalkyl group;
An aryl group; a lower acyl group; an al-lower alkyl group: a heterocyclic group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, or a fused or bridged ring thereof; A heterocyclic -CO- group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted by an oxo group, or a fused or bridged ring thereof; An adamantyl group; a lower alkylsulfonyl group; an amino group which may be substituted with one or more groups selected from arylsulfonyl groups, or a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar-lower alkyl group. A hydroxyl, carboxyl or amino group which may be substituted; a lower alkyl group which may be substituted with a hydroxyl group; An aryl group which may be substituted with a halogen; a lower alkoxy group which may be substituted with a lower alkoxy group; a halogen atom; a lower acyl group; an al-lower alkyl group; an al-lower alkenyl group; A heterocyclic group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom or a fused or bridged ring thereof; any of an oxygen atom, a sulfur atom and a nitrogen atom 5-membered ring having at least one kind, 6
A heterocyclic -CO- group comprising a membered ring or a condensed or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group, which may be optionally substituted with one or more groups selected from an oxygen atom and / or Or a nitrogen-containing heterocyclic group having a 5- or 6-membered ring having a sulfur atom or a fused or bridged ring thereof, and n represents 0 or an integer of 1 to 6, respectively. A 1,2-ethanediol derivative represented by the formula: Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and n are the same as described above, and R ² is acyl, lower alkyl,
Shows lower alkenyl, ar-lower alkyl, tetrahydrofuryl, tetrahydrothionyl, tetrahydropyranyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, alkylsulfonyl, arylsulfonyl and silyl groups. And a salt thereof.

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

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

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

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

However, a compound that can be used as a cerebral function improving agent useful for treating cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic encephalopathy and stroke has not yet been found.

An object of the present invention is to provide a compound that can solve the above-mentioned problems and can be used as a useful brain function improving agent with few side effects.

[Means for Solving the Problems] The present inventors have conducted intensive studies for the purpose of solving the above problems, and as a result, the following general formula [I] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are
Each has the same meaning as described above. It has been found that the novel 1,2-ethanediol derivative represented by the formula (I) and its salt exhibit excellent anti-amnesic action and anti-hypoxia action and are extremely useful as a brain function improving agent, and have the general formula [I ' ] Has been found to be useful as an intermediate of the compound of [I], thereby completing the present invention.

The term “cerebral function improving agent” in the present specification is used not only as a usual brain function improving agent useful for treatment of sequelae of ischemic encephalopathy and stroke, but also for amnesia and dementia (for example, cerebrovascular disease). Senile dementia, various senile dementias, Alzheimer's disease, etc.).

 Hereinafter, the present invention will be described in detail.

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

A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a lower alkyl group is, for example,
A _C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; a lower alkenyl such as vinyl, propenyl, butenyl, pentenyl and A C _2-6 alkenyl group such as a hexenyl group; a lower alkenyloxy group refers to a C _2-6 alkenyl-O— group; a cycloalkyl group includes a C _2-6 alkenyl group such as a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group. _A lower alkoxy group is a _C1-6 alkyl-O- group; a lower alkylthio group is a _C1-6 alkyl-S- group; an aryl group is phenyl, naphthyl , Indanyl and indenyl groups; an aryloxy group is an aryl-O-
An ar-lower alkyl group is, for example, benzyl,
The ar (lower) alkoxy group, an aralkyl _{C 1 to 4} alkyl -O- group; diphenylmethyl, aralkyl _{C 1 to 4} alkyl groups, such as trityl and phenethyl groups and the ar (lower) alkylthio group, aralkyl _{C 1 to 4} alkyl A lower alkylenedioxy group, for example, a _C1-4 alkylenedioxy group such as a methylenedioxy and ethylenedioxy group; a lower acyl group, for example, a formyl, acetyl, and butyryl group the aroyl group, an aryl -CO- group; a _{C 1 to 6} acyl group such as a lower alkylsulfonyl _{group, C 1 to 6} alkyl -SO ₂ - group;
The ar (lower) alkylsulfonyl group, aralkyl _{C 1 to 6} alkyl -SO ₂ - group; and arylsulfonyl group, an aryl -SO ₂ - group a; Lower alkylsulfonyloxy _{group, C 1 to 6} alkyl -SO the ₂ -O- group; and aryl sulfonyloxy group, an aryl -SO ₂ -O- group; and arylsulfonylamino group, an aryl an -SO ₂ NH- group; and a lower alkylsulfonylamino group, _{C 1} the ₆ alkyl -SO ₂ NH- groups: the di-lower alkylamino group,
A diC _1-6 alkylamino group; an ammonio group includes, for example, a tri-lower alkylammonio group such as a trimethylammonio group and a triethylammonio group; a nitrogen-containing heterocyclic group includes, for example, pyrrolyl, pyrrolidinyl,
Piperidyl, piperacinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl,
Morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl,
It contains one or more nitrogen atoms as hetero atoms forming the ring such as thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, prenyl and indazolyl groups, and further contains one or more oxygen atoms or sulfur atoms. Good 5 or 6
A heterocyclic group of a membered ring, a condensed ring or a bridged ring; the term "heterocyclic group" means the above-mentioned nitrogen-containing heterocyclic group and, for example, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl , Benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl,
Benzothiazolyl, quinoxalyl, dihydroquinoxalinyl, 2,3-dihydrobezothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl,
Such as 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxathiazolyl, pyridazinyl, isoindolyl and inkinolyl groups A 5- or 6-membered ring containing at least one heteroatom atom selected from nitrogen, oxygen or sulfur atoms, which may contain one or more oxygen atoms or sulfur atoms as a ring-forming heteroatom atom A fused or bridged heterocyclic group; and a heterocyclic carbonyl group is a heterocyclic-
CO-group.

Examples of the group substituted by hydroxyl in R ² and the group substituted by hydroxyl, carboxyl and amino in the substituents of R ¹ and R ⁶ described above include:
Protective Groups in Organic Synthesis,
[Theodora W. Green
n) (1981), John Willie and Sons
Incorporated (John Wiley & Sons. Inc.)]
And the protecting groups for ordinary hydroxyl group, carboxyl group and amino group described in the above.In particular, in the protecting group for hydroxyl group, acyl groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
2- (trimethylsilyl) ethoxycarbonyl, 2-
(Phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphoryl) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1
-Naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, bivaloyl, benzoyl and the like;
Methyl, ethyl, propyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl; and lower alkenyl groups such as allyl.
Lower alkyl groups include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, cyphenylmethyl and trityl; lower alkoxyalkyl groups include methoxymethyl, bendoxymethyl, 2-methoxyethoxymethyl, -Trichloroethoxymethyl,
2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1
A lower alkylthio-lower alkyl group such as methylthiomethyl; an alkyl-sulfonyl group such as methanesulfonyl; an aryl-sulfonyl-sulfonyl group such as p-toluenesulfonyl; However, examples of the silyl group include trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldifersilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl, and the like. , Lower acyl and 2-tetrahydropyranyl groups and ar-lower alkyl groups are particularly preferred.

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

In the case of the 1,2-ethanediole derivative of the general formula [I] or a salt thereof, when isomers (for example, optical isomers, geometric isomers and tautomeric residues) are present, the present invention relates to all of the isomers As well as hydrates, solvates and all crystalline forms.

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

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

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n have the same meaning as described above: R ^2a represents the same group as R ² ;
^6a is a nitrogen-containing heterocyclic group of R ⁶ having a free valence at a carbon atom forming the ring; R ^6b is a nitrogen-containing heterocyclic group of R ⁶ forming the ring A group having a free valence or an optionally substituted amino group at the nitrogen atom; R ⁷ is
R ² the same groups as; X ¹ and X ² are the same or different halogen atom: Y is a halogen atom, a leaving group such as a lower alkylsulfonyloxy group or an arylsulfonyloxy group; Y ^a is And m represents an integer of 1 to 6, each representing an arylsulfonyloxy group; In addition, the general formulas [III], [IIIa], [IV], [V],
[VII], [IX], [X], [XI], [XII], [XV
Examples of the salts of the compounds of [I], [Ia], [Ib], [Ic] and [Id] include the same salts as described for the salts of the compound of the general formula [I].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

These reactions are carried out in a manner known per se, for example, Protective Groups in Organic Synthesis, [Theodra W. Green (1)
981), John Wiley & Sons, Inc.] or a method analogous thereto.

The hydroxyl protecting group (R ⁷
And the combination of R ^2a ) may be appropriately selected.

(3) By reacting a compound of the general formula [VII] or a salt thereof with a halogenating agent or a sulfonylating agent in a solvent in the presence or absence of a base, the compound of the general formula [VI]
II] can be produced.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(2) a compound of the general formula [XI] or a salt thereof in a solvent,
The compound of the general formula [XII] or a salt thereof can be produced by reacting the sulfonylating agent in the presence or absence of a base.

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

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

Examples of the sulfonylating agent include p-toluenesulfonyl chloride.

The amounts of the sulfonylating agent and the base used if necessary are 0.95 times or more, and preferably 1 to 2 times, respectively, the mol of the compound of the general formula [XI] or a salt thereof.

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

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

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

This reaction can be carried out in a manner known per se, for example, Protective Groups in Organic Synthesis, [Theodra W. Green (198)
1 year), John Wiley & Sons, Inc.] or a method analogous thereto.

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

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

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

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

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

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

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

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

The compound of the general formula [XV] used here can be synthesized by a method known per se, for example, Bulletin de la Societe Simic de France (Bull. Soc. Chim. Fr.), 1967
(5), page 1533-1540.

(2) By reacting a compound of the general formula [XVI] or a salt thereof with a compound of the general formula [IX] or a salt thereof in the presence or absence of a catalyst and in the presence or absence of a base, A compound of the general formula [Id] or a salt thereof can be produced.

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

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

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

Examples of the base used as needed include the same bases as described in the above-mentioned Production method 2 (3). Further, a compound of the general formula [IX] or a salt thereof may be used as the base. Can also.

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

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

Further, the reaction reagent or base used in each of the above-mentioned production methods can be used as a solvent depending on their properties.

The general formulas [II], [III],
[IIIa], [IV], [V], [VI], [VII], [VII
I], [IX], [X], [XI], [XII], [XIII],
In the compounds of [XIV], [XV] and [XVI], when isomers (for example, optical isomers, geometric isomers and tautomers; etc.) are present, all of these isomers may be used. Hydrates, solvates and all crystalline forms can be used.

Formulas [II], [III], [IIIa], [IV],
[V], [VI], [VII], [VIII], [IX], [XI
I], [XIII], [XIV], [XV], [XVI], [I],
Among the compounds of [Ia], [Ib], [Ic] and [Id], compounds having a hydroxyl group, an amino group or a carboxyl group are previously prepared from these hydroxyl groups,
The amino group or the carboxyl group may be protected with a usual protecting group, and after the reaction, if necessary, these protecting groups may be eliminated by a method known per se. The thus obtained 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography.

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

The compound of the general formula [II], which is a raw material for producing the compound of the present invention, can be prepared by a method known per se, for example, the Journal of American Chemical Society (JA).
CS), 87, 1353 (1965), New Laboratory Chemistry Course,
Vol. 14, p. 579 (1977, Maruzen) and the like.

When the compound of the present invention is used as a medicament, pharmaceutically acceptable excipients, carriers and diluents and other formulation auxiliaries may be appropriately mixed, and these may be used in the usual manner as tablets, capsules, powders, granules. , Pills, suspensions, emulsions, solutions, syrups or injections can be administered orally or parenterally. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, body weight and symptoms of the patient. In the case of oral administration, 0.01 to 500 mg per day is usually divided into one to several times for an adult. Should be administered.

Next, the pharmacological action of the representative compounds of the present invention will be described.

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

1. Anti-hypoxia activity A group of 10 ddY female mice (5 to 6 weeks old) is orally administered 100 mg / kg of a test compound dissolved in physiological saline.
30 minutes after administration, the mouse is placed in a 300 ml glass container,
A mixed gas consisting of 4% oxygen and 96% nitrogen was bubbled into the glass container at 5 l / min, and the time from the start of ventilation to the death of the mouse was measured.

 The control group was orally administered only saline.

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

 Table 1 shows the results.

2. Anti-amnesic effect a) Electroconvulsive shock (ECS) -induced amnesia model A test compound dissolved in physiological saline was intraperitoneally administered to 10 ddY male mice (5 to 6 weeks old) per group. One hour later, the mice were stepped through two chambers of light and dark (St.
ep-through) Passive avoidance training box (HPA-100M, manufactured by Muromachi Kikai Co., Ltd.)
After 0.5 seconds, a current (1.6 mA, 3 seconds) was applied to the grid on the floor to perform an acquisition trial. Immediately after that, ECS (2
5 mA for 0.5 seconds). As a test trial, the mice were placed again in the light room 24 hours later, and the time (reaction latency) until the mice entered the limbs in the dark room was measured for up to 300 seconds.

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

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

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

b) Cycloheximide-induced amnesia model Cycloheximide impairs the memory retrieval process in mice. Yamazaki et al. [Drug, Mental and Behavioral, Vol. 3,
127-136 (1983)]. Therefore, the following test was performed.

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

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

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

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

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

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

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

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

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

 Table 4 shows the results.

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

As a result, test compound numbers 1, 2, 4, 5, 8, 14,
Compounds of 16, 26, 49, 57, 58, 64, 66, 74, 79 and 85 did not show any death at 50 mg / kg.

From the above test results, it can be easily understood that the compound of the present invention has excellent anti-hypoxia action, anti-amnestic action and acetylcholinesterase inhibitory action, and has low toxicity.

[Effect of the Invention] Therefore, the compound of the present invention is a compound which can be used as a brain function improving agent which is extremely useful for treatment of cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic encephalopathy and stroke. It is clear that there is.

Next, the production method of the compound of the present invention will be specifically described with production examples.

The mixing ratios of the solvents are all volume ratios, and the carrier in column chromatography is silica gel [Kieselgel 60, art.
0, Art.7734)].

 The abbreviations used below have the following meanings.

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

Example 1 2- (N, N-dimethylamino) ethanol in 31 ml of tert
-Add 1.7 g of potassium butoxide and raise the temperature to 80 ° C.
To this mixture is added 2- (benzo [b] thiophene-5 in advance.
A solution prepared by dissolving 5.2 g of 1-yl) oxirane in 8 ml of dimethyl sulfoxide is added dropwise at 80 to 85 ° C. over 1.5 hours, and the resulting mixture is stirred at the same temperature for 1 hour. The reaction mixture was then cooled, 60 ml of ethyl acetate and 60
Introduce into the ml mixture and separate the organic layer. The aqueous layer is extracted with a further 30 ml of ethyl acetate. The extract was combined with the previously separated organic layer, and after adding 50 ml of ice water, the mixture was adjusted to pH 1.5 with 6N hydrochloric acid.
Adjust to, and separate the aqueous layer. After adding 50 ml of chloroform to the separated aqueous layer and adjusting the pH to 10.5 with potassium carbonate, the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was dissolved in 50 ml of acetone. To this solution was added 4.3 ml of a 5N dry hydrogen chloride-ethanol solution, followed by stirring at room temperature for 1 hour. To this mixture is added diethyl ether 20
After adding 1 ml and stirring for another 1 hour, the precipitated crystals were collected.
When dried, 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy]
3.3 g of the hydrochloride of ethanol (Compound No. 1) are obtained.

_{Mp: 191.5~192.5 ℃ [EtOH-Me 2} CO] in the same manner to obtain a compound of Table 5.

Note that R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n in Table 5
Represents a substituent or an integer of the following formula, respectively.

Example 2 A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoxide was heated to 80 ° C.
The mixture was heated to 2.4 g, and 2.4 g of 2- (benzo [b] furan-5-yl) oxirane was added to the mixture.
Stir at 85-90 ° C for 15 minutes. Then, the reaction mixture was cooled with ice water.
Introduce into a mixture of 50 ml and 50 ml of ethyl acetate and add 6N hydrochloric acid.
After adjusting to pH 1, the aqueous layer is separated. 30 ml of ethyl acetate is added to the separated aqueous layer, the pH is adjusted to 9.5 with potassium carbonate, and the organic layer is separated. The separated Ariiso layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: ethanol = 50: 1) to give 1- (benzo [b] furan-5-yl) -2. 0.56 g of-(pyridin-3-ylmethoxy) ethanol (Compound No. 28) is obtained.

Melting point: 85-86 ° C [IPE-EtOH] Similarly, the compounds in Table-6 are obtained.

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

Example 3 (1) A mixture of 5.7 g of potassium tert-butoxide and 57 ml of ethylene glycol was heated to 80 ° C.
18 g of (benzo [b] thiophen-5-yl) oxirane
Was dissolved in 30 ml of dimethyl sulfoxide dropwise over 1.5 hours, and the resulting mixture was stirred at the same temperature for 30 minutes. Then, the reaction mixture is introduced into a mixture of 120 ml of ice water and 80 ml of ethyl acetate, and the organic layer is separated. The aqueous layer is further extracted twice with 30 ml portions of ethyl acetate. The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform: ethanol = 20: 1) to give 1- (benzo [b] thiophen-5-yl) -2. 9.1 g of-(2-hydroxyethoxy) ethanol are obtained.

Melting point: 119-120.5 ° C [EtOH-AcOEt] (2) 1- (benzo [b] thiophen-5-yl)-
9.0 g of 2- (2-hydroxyethoxy) ethanol was dissolved in 54 ml of pyridine, and 7.2 g of p-toluenesulfonyl chloride was added to this solution at -25 ° C.
Incubate at ５5 ° C. for 24 hours and at room temperature for 4 hours. Then, the reaction mixture is introduced into a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether, adjusted to pH 2.0 with 6N hydrochloric acid, and the organic layer is separated. The aqueous layer is extracted with a further 30 ml of diethyl ether. The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give 1- (benzo [b] thiophen-5-colorless oil. Ill) -2
-[2- (p-toluenesulfonyloxy) ethoxy]
7.7 g of ethanol are obtained.

(3) 1- (benzo [b] thiophen-5-yl)-
7.6 g of 2- [2- (p-toluenesulfonyloxy) ethoxy] ethanol and 3,4-dihydro-2H-pyran
To a solution of methylene chloride (40 ml) in which 3.5 ml was dissolved was added 0.97 g of pyridinium-p-toluenesulfonate at room temperature.
And stir for 30 minutes. Then, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure, a colorless oily 1- (benzo [b] thiophen-5-yl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) is obtained. Ethoxy] ethane (8.7 g) is obtained.

(4) 1- (benzo [b] thiophen-5-yl)-
1- (2-tetrahydropyranyloxy) -2- [2-
(P-toluenesulfonyloxy) ethoxy] ethane 1.
5 g is dissolved in 15 ml of ethanol, 4.9 ml of a 40% aqueous solution of methylamine is added to this solution, and the resulting mixture is refluxed for 1 hour. Then, the reaction mixture is introduced into a mixture of 20 ml of ice water and 20 ml of diethyl ether, and the organic layer is separated. The aqueous layer is extracted with a further 20 ml of diethyl ether. The extract is combined with the previously separated organic layer, 20 ml of water is added, and 6N
After adjusting the pH to 1.5 with hydrochloric acid, the mixture is stirred at room temperature for 20 minutes. The aqueous layer is separated, and the organic layer is further extracted with 10 ml of water. The extract is combined with the previously separated aqueous layer, and after adding 30 ml of methylene chloride, the pH is adjusted to 11 with a 10% aqueous sodium hydroxide solution, and the organic layer is separated. The aqueous layer was further treated with 15 ml of methylene chloride
Extract with The extract is combined with the previously separated organic layer, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was dissolved in 7 ml of acetone, and 0.5 ml of a 5N dry hydrogen chloride-ethanol solution was added to this solution.
And the resulting mixture is stirred at room temperature for 1 hour. Subsequently, 7 ml of diethyl ether was added to the reaction mixture, and the precipitated crystals were collected. The hydrochloride of 1- (benzo [b] thiophen-5-yl) -2- (N-methylaminoethoxy) ethanol (Compound No. 36) 0.5 g is obtained.

_{Mp: 201.5~202.5 ℃ [EtOH-Me 2} CO] in the same manner to obtain a compound of Table 7.

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

Example 4 (1) Instead of 2- (benzo [b] furan-5-yl) oxirane, 2- (benzo [b] thiophen-5-
The reaction was carried out in the same manner as in Example 2 using 1,4-diformyl-2-piperazinemethanol in place of yl) oxirane and 3-pyridinemethanol, and if treated, the oily 1- (benzo [b] thiophene- 5-yl) -2-
[(1,4-Diformylpiperazin-2-yl) methoxy] ethanol (Compound No. 43) is obtained.

(2) 1- (benzo [b] thiophen-5-yl)-
Dissolve 270 mg of 21-[(1,4-diformylpiperazin-2-yl) methoxy] ethanol in 1.5 ml of methanol,
To this solution is added 1.5 ml of 5N dry hydrogen chloride-ethanol solution and the resulting mixture is left at room temperature overnight. The precipitated crystals are collected, washed with ethanol, and dried to give 1-
This gives 150 mg of the dihydrochloride salt of (benzo [b] thiophen-5-yl) -2-[(piperazin-2-yl) methoxy] ethanol (Compound No. 44).

Melting point: 216-218 ° C. (decomposition) Example 5 (1) 10 g of 2- (N-tritylamino) ethanol, t
A mixture of 3.7 g of potassium ert-butoxide and 30 ml of dimethyl sulfoxide was heated to 85 ° C., and a solution in which 5.8 g of 2- (benzo [b] thiophen-5-yl) oxirane was dissolved in 10 ml of dimethyl sulfoxide in advance was added to the mixture. And stirred for 5 minutes at the same temperature. Then, the reaction mixture is introduced into a mixture of 150 ml of ice water and 100 ml of ethyl acetate, and the organic layer is separated. The aqueous layer is extracted with a further 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 70 ml of a 50% aqueous formic acid solution and 30 ml of tetrahydrofuran are added to the obtained residue, and the resulting mixture is stirred at 50 to 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was treated with 50 ml of ethyl acetate.
And 30 ml of water, adjust the pH to 2 with 6N hydrochloric acid, and separate the aqueous layer. The organic layer is extracted with two additional 10 ml portions of water. The extract was combined with the previously separated aqueous layer, methylene chloride (50 ml) was added, and the mixture was adjusted to pH 10.5 with potassium carbonate.
Separate the organic layer. After washing the separated organic layer with water,
Dry over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, 1- (benzo [b] thiophen-5-yl)
-2- (2-aminoethoxy) ethanol (compound number
45) 1.2g is obtained.

Melting point: 87-90.5 ° C [EtOH-IPE] (2) 1- (benzo [b] thiophen-5-yl)-
1.1 g of 2- (2-aminoethoxy) ethanol was dissolved in 10 ml of ethanol, and 290 mg of fumaric acid was added to this solution.
The resulting mixture is stirred at room temperature for 30 minutes. Then, 7 ml of diethyl ether is added to the reaction mixture, and the resulting mixture is stirred at the same temperature for 1 hour. The precipitated crystals are collected and dried to give 1- (benzo [b] thiophen-5-yl) -2-.
1.2 g of 1 / 2-fumarate salt of (2-aminoethoxy) ethanol (Compound No. 46) are obtained.

Melting point: 204.5-205.5 ° C [MeOH-EtOH] Example 6 Instead of 2- (N-tritylamino) ethanol,
The reaction was carried out in the same manner as in Example 5 using (1-tritylimidazol-4-yl) methanol, and the melting point was obtained.
1- (benzo [b] thiophen-5-yl) -2-[(imidazolyl) methoxy] showing 128-129 ° C [AcOEt]
Ethanol (Compound No. 47) is obtained.

[In the name of this compound, the designation (imidazolyl) methoxy is so named because it is not yet clear which carbon atom at the 4- or 5-position of the imidazolyl group is bonded to the carbon atom of the methoxy group. Example 7 1- (benzo [b] thiophen-5-yl) -2-
0.42 g of (2-aminoethoxy) ethanol is dissolved in a mixture of 5 ml of water and 5 ml of dioxane, 0.21 g of sodium carbonate is added to this solution, and the temperature is raised to 50 ° C. 0.22 g of 2-chloropyrimidine is added to this mixture, and the resulting mixture is refluxed for 3 hours. The reaction mixture is then added to ice water 30
It is introduced into a mixture of 30 ml of ethyl acetate and 30 ml of ethyl acetate, and the organic layer is separated off. The aqueous layer is extracted with a further 10 ml of ethyl acetate. The extract is combined with the previously separated organic layer, and 20 ml of water is added.
After adjusting the pH to 1.5 with 6N hydrochloric acid, the aqueous layer is separated. The organic layer is extracted with a further 10 ml of water. The extract is combined with the previously separated aqueous layer, 50 ml of methylene chloride is added, the pH is adjusted to 10.5 with potassium carbonate, and the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 20: 1) to obtain an oil. 2 ml of ethanol and 70 mg of maleic acid are added to the oil obtained and the resulting mixture is stirred at room temperature for 1 hour. Then, 2 ml of diethyl ether was added to the reaction mixture, and the precipitated crystals were collected and dried to give 1- (benzo [b] thiophen-5-yl).
-2-{[2- (pyrimidin-2-yl) amino] ethoxy} 1/2 maleate of ethanol (Compound No. 4
8) Obtain 0.28g.

Melting point: 113.5-114.5 ° C [IPA-AcOEt] Example 8 1- (Benzo [b] thiophen-5-yl) -2-
0.45 g of (2-aminoethoxy) ethanol, nicotinic acid
To a mixture of 0.23 g, 1-hydroxybenzotriazole 0.26 g, triethylamine 0.26 ml and tetrahydrofuran 3 ml, under ice cooling, N, N'-dicyclohexylcarbodiimide 0.39 g was added, and the resulting mixture was stirred at the same temperature for 5 minutes.
Stir at room temperature for another 2 hours. Then add water to the reaction mixture.
20 ml and 20 ml of ethyl acetate are added and the insolubles are removed.
After adjusting the solution to pH 1.5 with 6N hydrochloric acid, the aqueous layer is separated.
The organic layer is extracted with two additional 5 ml portions of water. Extract liquid
30 ml of chloroform is added to the previously separated aqueous layer, adjusted to pH 10.5 with potassium carbonate, and then the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroporum: ethanol = 10: 1). The obtained oil is dissolved in 3 ml of ethanol, 0.24 ml of a 5N dry hydrogen chloride-ethanol solution is added to this solution, and the obtained mixture is stirred at room temperature for 1 hour. Diethyl ether in the reaction mixture
1.5 ml is added, and the mixture is further stirred at the same temperature for 1 hour. The precipitated crystals are collected and dried to obtain 0.31 g of 1- (benzo [b] thiophen-5-yl) -2- [2- (nicotinoylamino) ethoxy] ethanol hydrochloride (Compound No. 49).

Melting point: 152-153 ° C [EtOH-AcOEt] Example 9 (1) 1.6 g of 4-methyl-2-formylthiazole is dissolved in 30 ml of tetrahydrofuran and cooled to -30 ° C.
To this solution, 10 ml of a 1.6 M solution of 2-chloroethoxymethylmagnesium chloride in tetrahydrofuran is added dropwise over 10 minutes, and the resulting mixture is stirred under ice cooling for 1 hour. Then, the reaction mixture was mixed with 50 ml of ice water and 50 ml of ethyl acetate.
And 2 g of ammonium chloride and mixed with 6N hydrochloric acid.
After adjusting to pH 2, the mixture is stirred at the same temperature for 5 minutes. Then
After the reaction mixture is adjusted to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 4: 1) to give an oily 1- (4-methyl-2-thiazolyl)-. 1.3 g of 2- (2-chloroethoxy) ethanol are obtained.

(2) 1- (4-methyl-2-thiazolyl) -2-
A mixture of 1.2 g of (2-chloroethoxy) ethanol, 3 ml of a 50% aqueous dimethylamine solution, 0.45 g of potassium iodide and 20 ml of ethanol is refluxed for 3 hours. Then, 3 ml of a 50% aqueous solution of dimethylamine is added to the reaction mixture, and the resulting mixture is refluxed for another 3 hours. The solvent is distilled off under reduced pressure,
30 ml of ethyl acetate and 30 ml of water were added to the obtained residue,
After adjusting the pH to 1.5 with 6N hydrochloric acid, the aqueous layer is separated. The separated aqueous layer is washed with 10 ml of ethyl acetate, added with 30 ml of ethyl acetate, adjusted to pH 10.5 with potassium carbonate, and then the organic layer is separated. The separated organic layer is sequentially washed with 10 ml of water and 10 ml of saturated saline, and then dried over anhydrous magnesium sulfate.
The soot was distilled off under reduced pressure, and the obtained residue was ethanol 6m
and 6 ml of 5N dry hydrogen chloride-ethanol solution and 6 ml of diethyl ether are added to the solution, and the resulting mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected, washed with 2 ml of a mixture of diethyl ether-ethanol (1: 1), and dried to give 1- (4-methyl-2-thiazolyl) -2- [2- (N, N- Dimethylamino) ethoxy]
390 mg of the hydrochloride salt of ethanol (Compound No. 50) are obtained.

Melting point: 159-160 ° C [IPA-AcOEt] Similarly, the compounds in Table-8 are obtained.

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

Example 10 (1) A mixture of 9.2 g of 1- (2-thienyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol and 18 ml of acetic anhydride is refluxed for 10 minutes. The reaction mixture was then added to a mixture of concentrated nitric acid (7.8 ml) and acetic anhydride (27 ml) at 0 ° C.
After dropwise addition over a period of minutes, the resulting mixture is cooled at the same temperature for 2 minutes.
Stir for hours. The reaction mixture is then introduced into a saturated aqueous sodium hydrogen carbonate solution while adjusting the pH to 7 with a 40% aqueous sodium hydroxide solution. The resulting mixture was adjusted to pH 10 with a 40% aqueous sodium hydroxide solution, and then chloroform 300 ml
And the organic layer is separated. 300 ml of water in the separated organic layer
And the pH is adjusted to 2 with 6N hydrochloric acid, and the aqueous layer is separated.
After adding 300 ml of chloroform to the separated aqueous layer and adjusting the pH to 10 with a 40% aqueous sodium hydroxide solution, the organic layer is separated. The separated organic layer is 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. 93) 10.4 get g.

(2) 1- (5-Nitro-2-thienyl) -1-acetoxy-2- [2- (N, N-dimethylamino) ethoxy] ethane (320 mg) was dissolved in methanol (10 ml), and 1N sodium hydroxide was added to the solution. 1.27 ml of an aqueous solution are added and the resulting mixture is stirred at room temperature for 1 hour. Then, 40 ml of chloroform and 40 ml of water are added to the reaction mixture, and the organic layer is separated. 30 ml of water is added to the separated organic layer, the pH is adjusted to 2 with 6N hydrochloric acid, and then the aqueous layer is separated. 30 ml of chloroform is added to the separated aqueous layer, and the pH is adjusted to 11 with a 10% aqueous sodium hydroxide solution, and then the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 3 ml of methanol and 1 ml of 5N dry hydrogen chloride-ethanol solution are added to the obtained residue, and the solvent is distilled off under reduced pressure. 5 ml of ethanol was added to the obtained residue, and the precipitated crystals were collected and dried to give 1- (5-nitro-2-thienyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol ( 170 mg of compound No. 94) are obtained.

Melting point: 189-191.5 ° C (decomposition) Example 11 (1) 2- [2- (N, N-dimethylamino) ethoxy] -1- (6-benzyloxybenzo [b] furan-
Dissolve 3.4 g of 2-yl) ethanol in 10 ml of pyridine,
To this solution 1.8 ml of acetic anhydride are added and 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 are added to the obtained residue, and the mixture is adjusted to pH 7 with sodium hydrogen carbonate, and then the organic layer is separated.
The aqueous layer is extracted with a further 20 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; chloroform: ethanol = 1: 1).
If purified in 1), oily 1-acetoxy-1- (6-
Benzyloxybenzo [b] furan-2-yl) -2-
3.25 g of [2- (N, N-dimethylamino) ethoxy] ethane (Compound No. 95) are obtained.

IR (neat) cm ^-1 ; ν _{C =} 1740 (2) 1-acetoxy-1- (6-benzyloxybenzo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) ) Ethoxy] A mixture of 3.2 g of ethane, 0.6 g of 5% palladium-carbon, 0.67 ml of concentrated hydrochloric acid and 30 ml of methanol is hydrogenated at normal temperature and normal pressure for 1.5 hours. After the reaction,
Palladium-carbon is removed. The solvent is distilled off under reduced pressure,
After adding 20 ml of chloroform and 20 ml of water to the obtained residue and adjusting the pH to 7 with sodium hydrogen carbonate, the organic layer is separated. The aqueous layer is further extracted with 10 ml of chloroform.
The extract is combined with the previously separated organic layer, washed with 5 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform: methanol = 7: 1) to give oily 1-acetoxy-1- (6-hydroxybenzo [b] ] Furan-2-yl) -2- [2- (N,
N-dimethylamino) ethoxy] ethane (Compound No. 9
6) Obtain 1.57g.

IR (neat) cm ^-1 ; ν _{C =} 1740 (3) 1-acetoxy-1- (6-hydroxybenzo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) [Ethoxy] ethane (0.65 g) was dissolved in benzene (3.5 ml), and to this solution was added ethyl isocyanate (0.33 ml).
Stir the resulting mixture at 80 ° C. for 30 minutes. The solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 6: 1) to give an oil. This oily substance is treated with dry hydrogen chloride in a conventional manner to give oily 1-acetoxy-
1- (6-N-ethylcarbamoyloxybenzo [b]
Furan-2-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 97) 0.58 g
Get.

IR (neat) cm ^-1 ; ν _{C =} 1730 [Formulation Examples] Next, the present invention will be specifically described with formulation examples, but the present invention is not limited thereto.

Formulation Example 1 (tablet) 2- [2- (N, N-dimethylamino) ethoxy] -1
A tablet containing 50 mg of the hydrochloride salt of (-benzo [b] thiophen-5-yl) ethanol (Compound No. 1) is prepared by the following method using the following formulation.

The mixture of the above components is kneaded with an 8% aqueous solution of polyvinylpyrrolidone K-90, dried at 40 ° C., the components are mixed, and the mixture is compressed into a circular tablet having a weight of 175 mg per tablet and a diameter of 8 mm.

Formulation Example 2 (capsule) 2- [2- (N, N-dimethylamino) ethoxy] -1
-A capsule containing 50 mg of the hydrochloride salt of (benzo [b] thiophen-5-yl) ethanol (Compound No. 1),
It is prepared by the following method using the following formulation.

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

Formulation Example 3 (tablet) 2-[(N-methyl-1H-1,2,5,6-tetrahydropyridin-3-yl) methyl] -1- (benzo [b] thiophen-5-yl) ethanol (compound No. 34), 2-
1 / 2-Fumarate of (2-aminoethoxy) -1- (benzo [b] thiophen-5-yl) ethanol (Compound No. 46), 2- [2- (N, N-diethylamino) ethoxy]- 1- (benzo [b] thiophen-5-yl) ethanol hydrochloride (Compound No. 77) or 2- [2- (4
-Benzylpiperazin-1-yl) ethyl] -1- (benzo [b] furan-5-yl) ethanol dihydrochloride (Compound No. 83) was formulated in the same manner as in Formulation Example 1 and contained 50 mg of the compound. Tablets to be obtained.

Formulation Example 4 (capsule) 2-[(N-methyl-1H-1,2,5,6-tetrahydropyridin-3-yl) methyl] -1- (benzo [b] thiophen-5-yl) ethanol ( Compound No. 34), 2-
1 / 2-Fumarate of (2-aminoethoxy) -1- (benzo [b] thiophen-5-yl) ethanol (Compound No. 46), 2- [2- (N, N-diethylamino) ethoxy]- 1- (benzo [b] thiophen-5-yl) ethanol hydrochloride (Compound No. 77) or 2- [2- (4
-Benzylpiperazin-1-yl) ethyl] -1- (benzo [b] furan-5-yl) ethanol dihydrochloride (Compound No. 83) was formulated in the same manner as in Formulation Example 2 and contained 50 mg of the compound. To obtain capsules.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/415 A61K 31/415 31/44 AAM 31/44 AAM 31/445 31/445 31/47 31/47 31/495 31 / 495 31/535 31/535 C07D 209/04 C07D 209/04 209/14 209/14 209/34 209/34 213/64 213/64 213/74 213/74 215/12 215/12 233/64 105 233/64 105 235/04 235/04 241/06 241/06 307/52 307/52 307/81 307/81 333/28 333/28 333/58 333/58 401/12 213 401/12 213 409 / 12 207 409/12 207 211 211 213 213 413/12 213 413/12 213 333 333 453/02 453/02 521/00 521/00 // C07C 31/20 C07C 31/20 (72) Inventor Hirokazu Narita Toyama 6-40 Okudahonmachi, Toyama City, Japan (56) References JP-A-3-197422 (JP, A) JP-A-3-47158 (JP, A) International Publication No. 88/8424 (WO , A1) Chemical Abstracts Abstract No. 109: 129471 (1988) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D

Claims (2)

(57) [Claims] (1) General formula In the formula, R ¹ is a heterocyclic group comprising a 5-membered ring, a 6-membered ring having at least ^one of an oxygen atom, a sulfur atom, and a nitrogen atom, or a condensed or bridged ring thereof, 2-O-cyclohexylidene-3-O-methyl-6-O- (2-pyridinylmethyl) -α-D-glucofuranose and 1,
2: 3,4-di-O-cyclohexylidene-6-O- (2-
Pyridinylmethyl) -D-mannitol), which may be substituted with a halogen atom, a hydroxyl group, a nitro group, an oxo group, a lower alkylenedioxy group, a lower alkyl, a lower acyl, 2-tetrahydropyranyl or A hydroxyl, carboxyl or amino group optionally substituted with a lower alkyl group; a lower alkyl group optionally substituted with a hydroxyl group; an aryl group optionally substituted with a halogen; optionally substituted with a halogen An aroyl group; a lower alkoxy group optionally substituted with a lower alkoxy group; a halogen atom; a lower acyl group; an ar lower alkyl group; an ar lower alkenyl group; an oxo group; any one of an oxygen atom, a sulfur atom, and a nitrogen atom 5- or 6-membered ring having the above or a fused ring or bridge thereof A 5-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom;
A heterocyclic -CO- group comprising a membered ring or a fused or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group which may be substituted with one or more groups selected from the group consisting of amino, lower alkyl, aryl, Al lower alkyl,
Lower alkoxy, al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or oxygen atom, sulfur atom, May be substituted with a 5- or 6-membered ring having any one or more of nitrogen atoms or a heterocyclic group comprising a fused ring or a bridged ring thereof, and R ³ represents a hydrogen atom or a lower alkyl group. N n R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group; R ⁶ is an ammonio group or a lower alkyl, a lower acyl, 2-tetrahydropyranyl or an ar lower alkyl group; A hydroxyl group; lower alkyl Le, lower acyl, 2-tetrahydropyranyl or ar (lower) alkyl-lower alkyl group which may be substituted by optionally substituted hydroxyl or carboxyl group group; a cycloalkyl group;
An aryl group; a lower acyl group; an ar-lower alkyl group; a heterocyclic group comprising a 5-membered ring, a 6-membered ring or a condensed or bridged ring thereof having at least one of an oxygen atom, a sulfur atom and a nitrogen atom; A heterocyclic -CO- group consisting of a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with an oxo group, or a fused or bridged ring thereof; An amino group optionally substituted with one or more groups selected from the group consisting of an adamantyl group; a lower alkylsulfonyl group; and an arylsulfonyl group; or an amino group, which is substituted with a lower alkyl, a lower acyl, 2-tetrahydropyranyl or an ar-lower alkyl group. A hydroxyl, carboxyl or amino group which may be substituted; a lower alkyl group which may be substituted with a hydroxyl group; An aryl group which may be substituted with a halogen; a lower alkoxy group which may be substituted with a lower alkoxy group; a halogen atom; a lower acyl group; an al-lower alkyl group; an al-lower alkenyl group; A heterocyclic group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom or a fused or bridged ring thereof; any of an oxygen atom, a sulfur atom and a nitrogen atom 5-membered ring having at least one kind, 6
A heterocyclic -CO- group comprising a membered ring or a condensed or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group, which may be optionally substituted with one or more groups selected from an oxygen atom and / or Or a nitrogen-containing heterocyclic group having a 5- or 6-membered ring having a sulfur atom or a fused or bridged ring thereof, and n represents 0 or an integer of 1 to 6, respectively. The 1,2-ethanediol derivative represented by these, and its salt. 2. The general formula Wherein R ¹ is a heterocyclic group comprising a 5-membered ring, a 6-membered ring or a condensed or bridged ring thereof having at least ^one of an oxygen atom, a sulfur atom and a nitrogen atom; Atom, hydroxyl group, nitro group, oxo group,
A hydroxyl, carboxyl or amino group which may be substituted with a lower alkylenedioxy group, which may be substituted with a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar-lower alkyl group; A lower alkyl group which may be substituted with a halogen; an aroyl group which may be substituted with a halogen; a lower alkoxy group which may be substituted with a lower alkoxy group; a halogen atom; a lower acyl group; A lower alkyl group; an al-lower alkenyl group; an oxo group; a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, or a heterocyclic group comprising a fused or bridged ring thereof; A 5-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, 6
A heterocyclic -CO- group comprising a membered ring or a fused or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group which may be substituted with one or more groups selected from the group consisting of amino, lower alkyl, aryl, Al lower alkyl,
Lower alkoxy, al lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or oxygen atom, sulfur atom, It may be substituted by a heterocyclic group comprising a 5-membered ring or a 6-membered ring having any one or more of nitrogen atoms or a condensed or bridged ring thereof, and R ² is acyl, lower alkyl, lower alkenyl , ar (lower) alkyl, tetrahydrofuryl, tetrahydronaphthyl thionyl, tetrahydropyranyl, lower alkoxy - lower alkyl, lower alkylthio - lower alkyl, alkylsulfonyl, arylsulfonyl, and silyl groups, R ³ is a hydrogen atom Other lower alkyl radical, n pieces of R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ⁶ is an ammonio group or a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar (lower) A hydroxyl group optionally substituted with an alkyl group; a lower alkyl group optionally substituted with a hydroxyl or carboxyl group optionally substituted with a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar-lower alkyl group; Cycloalkyl group;
An aryl group; a lower acyl group; an ar-lower alkyl group; a heterocyclic group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom, or a fused or bridged ring thereof; A heterocyclic -CO- group consisting of a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with an oxo group, or a fused or bridged ring thereof; An adamantyl group; a lower alkylsulfonyl group; an amino group which may be substituted with one or more groups selected from arylsulfonyl groups, or a lower alkyl, lower acyl, 2-tetrahydropyranyl or ar-lower alkyl group. A hydroxyl, carboxyl or amino group which may be substituted; a lower alkyl group which may be substituted with a hydroxyl group; An aryl group which may be substituted with a halogen; a lower alkoxy group which may be substituted with a lower alkoxy group; a halogen atom; a lower acyl group; an al-lower alkyl group; an al-lower alkenyl group; A heterocyclic group comprising a 5- or 6-membered ring having at least one of an oxygen atom, a sulfur atom and a nitrogen atom or a fused or bridged ring thereof; any of an oxygen atom, a sulfur atom and a nitrogen atom 5-membered ring having at least one kind, 6
A heterocyclic -CO- group comprising a membered ring or a condensed or bridged ring thereof; a lower alkylsulfonyl group; an arylsulfonyl group, which may be optionally substituted with one or more groups selected from an oxygen atom and / or Or a nitrogen-containing heterocyclic group having a 5- or 6-membered ring having a sulfur atom or a fused or bridged ring thereof, and n represents 0 or an integer of 1 to 6, respectively. The 1,2-ethanediol derivative represented by these, and its salt.