JPH03197422A - 1,2-ethanediol derivatives or salts thereof and brain function improving agents containing them - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a general formula [I] [wherein R1 is an optionally substituted phenyl group;
R2 is a hydrogen atom or a lower alkyl group or a hydro-tosyl protected group; R3 is a hydrogen atom or a lower alkyl group; R4 and R5 are the same or different and are a hydrogen atom or a lower alkyl group; R6 is an optionally substituted amine, a nitrogen-containing heterocyclic group, or an ammonio group; and n represents O or an integer of 1 to 6, respectively. In addition, as the nitrogen-containing heterocyclic group for R6,
pyrrolyl, pyrrolidinyl, piperidyl, piperazyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, diomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl,
Te1 - lahydroisoquinolyl, chimeclidinyl, deazolyl, tetrahydro, deadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or imidazolinyl; as a substituent for R1, a halogen atom, an optionally substituted amine, lower alkyl, aryl, lower alkyl,
lower alkoxy, al-lower alkoxy, aryloxy, carbamoyloxy-alkylthio, lower alkenyl, lower alkenyloxy, al-lower alkylthio, al-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected R
Lower alkyl, aryl, al-lower alkyl, lower alkoxy, al-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio in the substituent 1;
Substituents for the lower alkenyl, lower alkenyloxy, al-lower alkylthio, al-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group and the nitrogen-containing heterocyclic group in R6 include a halogen atom, A hydroxyl group that may be protected, a carboxyl group that may be protected, an amino group that may be protected, a lower alkyl group that may be substituted with a hydroxyl group that may be protected, a halogen Aryl group that may be substituted, aroyl group that may be substituted with halogen, lower alkoxy group that may be substituted with lower alkoxy group, lower acyl group, lower alkyl group, lower alkenyl group, heterocycle Formula groups, heterocyclic -〇〇- groups, oxo groups, lower alkylsulfonyl groups, and arylsulfonyl groups may be mentioned, and may be substituted with one or more of these substituents. The substituent for the group and the amino group in R6 is an optionally protected hydroxyl group, a cycloalkyl group, an optionally protected hydroxyl group, or an optionally protected lower alkyl group substituted with an optionally protected carboxyl group. group, aryl group, lower acyl group, lower alkyl group,
Examples include a polycyclic group, a heterocyclic -C〇- group optionally substituted with an oxo group, an adamantyl group, a lower alkylsulfonyl group, and an arylsulfonyl group, and those substituted with one or more of these substituents However, when the phenyl group of R1 is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy, or an optionally protected hydroxyl group, R is
Formula -NR7R8 (R7 is a lower alkyl or heterocyclic group; R8 is a hydrogen atom or a lower alkyl group; or R7 and R8 together with the N atom represent the following group, lyl group; R12 represents a carboxyl or lower alkoxycarbonyl group; and i is 0,1.

2 or 3, respectively. ] except when )
. 〉;Heterocyclic groups as substituents for R1 include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, 0 tetrahydropyridyl, pyrimidinyl, morpholinyl,
Thiomorporinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisodinyl, quinuclidinyl, deazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl, imidazolyl, furyl, thienyl, benzothienyl, pyranyl,
isobenzofuranyl, oxacylyl, benzofuranyl,
Indolyl, benzimidazolyl, hendioxazolyl, benzodeazolyl, dihydroquinocyrinyl, kinoki]noryl, 2,3-dihydrobenzopyrrolyl, 2,3-
Dihydrobenzopyrrolyl, 2,3-dididro 4 days-1
-thianaphthyl, 2,3-dihydrobenzofuranyl, benz[bldiok1)-l, imidazo[2,3-alpyridyl, benzoib]piperazinyl, chromenyl, isodeazolyl, isoindolyl, oxylydiazolyl, pyridazinyl, isoindolyl and Each represents an isoquinolyl group. The present invention relates to a brain function improving agent containing a 1,2-ethanediol derivative represented by ``1'' or a salt thereof.

[Prior Art] Conventionally, as 1,2-ethanediol derivatives, for example, US Pat. No. 2,928,845 @, Journal
of Pharmaceutical Sciences (J, Ph.
arm, SCi, ), Volume 50, Nos. 769-771
(1961) and Pharmaco, Ed, Sc.
i), Volume 19, pp. 1056-1065 (1964
Some of the known examples include those listed in 2010).

However, although these compounds are used as local anesthetics or synthetic intermediates thereof, their use as brain function improving agents, anti-amnestic agents, and anti-dementia agents is completely unknown.

Furthermore, International Patent Application Publication No. 8B/8424 describes 1,2-ethanediol derivatives used for the treatment of Alzheimer's disease and other degenerative neurological disorders. However, the specification does not include any specific descriptions or examples of those derivatives.

Problems to be Solved by the Invention] Currently, cerebral metabolism activators or cerebral circulation improving agents are used to treat various types of dementia, particularly Alzheimer's type dementia and cerebrovascular dementia.

However, a brain function improving agent useful for treating cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic brain injury, stroke, etc., has not yet been found.

The purpose of the present invention is to solve the above problems, have fewer side effects, and
The object of the present invention is to provide a new and useful brain function improving agent.

1 Means for Solving the Problem 1 The inventors of the present invention have conducted extensive research with the aim of solving the above problems, and have found that the following general formula [wherein R1, R2
, R3, R4, R5, R6 and n each have the same meaning as above. The present invention has been completed based on the discovery that a 1,2-ethanediol derivative represented by the formula "1,2-ethanediol derivative or a salt thereof exhibits excellent anti-amnestic and anti-hypoxia effects and is extremely useful as a brain function improving agent."

The brain function improving agent according to the present invention is not only used as a normal brain function improving agent useful for treating sequelae of ischemic brain injury and stroke, but also for amnesia and dementia (for example, cerebrovascular dementia). , various senile dementias, and Alzheimer's disease).

The present invention will be explained in detail below.

In this specification, unless otherwise specified, each article is
It has the following meaning.

A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a lower alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 3 4 pentyl and C alkyl groups such as hexyl group; lower alkenyl groups include C alkenyl groups such as vinyl, propenyl, butenyl, pentenyl and hexenyl groups; lower alkenyloxy groups include C alkenyl-2-6 〇- group; cycloalkyl group means, for example, cyclopropyl, cyclobutyl, Schif[1 pendel and cyclohexyl group; The group refers to a C1-6 alkyl-S4 group; the lower alkylthio group refers to a C1-6 alkyl group; the neararyl group refers to phenyl, naphthyl, indanyl, and indenyl groups; the aryloxy group refers to an aryl- 〇- group; Al lower alkyl group is
For example, alkyl groups such as benzyl, diphenylmethyl, trityl and phenethyl groups;
A quaternary alkoxy group refers to an alkyl-1-4 〇- group; an alkylthio group refers to an alkyl-8-1 group; a lower alkylenedi-1-4 oxy group refers to, for example, methylenedioxy or A lower acyl group is, for example, a C acyl group such as small lumyl, acetyl, and butyryl; an aroyl group is an aryl 1-6- co-i; lower alkylsulfonyl group is C1-
6 alkyl-502- group: Al-lower alkylsulfonyl group means Al-C alkyl-1-6 302 group; arylsulfonyl group means aryl-8
02- group; lower alkylsulfonyloxy group is C
1 to 6 alkyl-5O2-O- group; narylsulfonyloxy group refers to aryl-8O2-〇- group; arylsulfonylamino group refers to aryl-8O2NH- group; lower alkylsulfonylamino group refers to C Alkyl-1-6 S02NH- group is di-lower alkylamino group
Alkylamino group; ammonio group and 1 to 6 mean, for example, a tri-lower alkylammonio group such as trimethylammonio and triethylammonio group.

In addition, as the hydroxyl protecting group for R2 and the protecting group for the hydroxyl group, carboxyl group, and amino group in substituent 6, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis)
e Groups in Organic 5ynth
esis), [ShΔdora W Green (Th
eodra W.

Green) (1981), John Wiley &
ley & 5ons, Inc.)], and in particular, the protecting groups for hydroxyl groups include, for example, lower alkyl, lower acyl, tetrahydropyranyl and Examples include optionally substituted al-lower alkyl groups such as benzyl.

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

When isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the 1,2-ethanediol derivative of general formula [I] or a salt thereof, the present invention covers all isomers. It also includes hydrates, solvates and all crystalline forms.

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

The 1,2-ethanediol derivative of general formula [I] or a salt thereof can be produced by methods known per se or by appropriately combining them, for example, by each production method shown below.

(The following is a margin) 7 8 [In the formula, R1, R2, R3, R4, R5, R6 and n
have the same meanings as described above, and R2a is
R6a is a hydroxyl-protecting group similar to R2; R6a is a group having a valence of ■ [a group having a valence;
is a group having a free valence on the nitrogen atom forming the ring among the same optionally substituted nitrogen-containing heterocyclic groups as R6 or an optionally substituted amino group;
Bitroxyl protecting group as in 2;
The same or different halogen atoms; Y is a halogen atom, a leaving group such as a lower alkylsulfonyloxy group or an arylsulfonyloxy group; Ya is an arylsulfonyloxy group; and m is an integer of 1 to 6. , respectively. ” Also, - clothing cost [1], [111al, rlV], [V]
, [VI[] , [[X] , [X] , [
XIko, [XT], [X'1! ] , [Ial,
Examples of the salts of the compounds [It)], [Icl and [Idl] include the same salts as the salts of the compounds [T].

Next, each of the above-mentioned manufacturing methods will be explained.

Production method 1 By reacting a compound of general formula [n] with a compound of general formula [In] or a salt thereof, or a compound of general formula [■ old compound or a salt thereof, in the presence or absence of a base, - A compound of CI al or a salt thereof can be prepared.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, such as 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, and these solvents may be used alone or in combination of two or more. Furthermore, a compound of -Fukudai [I11] or a compound of general formula [I[[al] can also be used as a solvent.

In addition, examples of bases that may be used as necessary include hydride silium, metal sulfur, silium, and ter
Examples include potassium t-butoxy.

In this reaction, the amount of the compound of -Fukudai [I11] or its salt or the compound of general formula [I[1al] or its salt is 1 to 1 to
It is 100 times the molar amount, preferably 1 to 10 times the molar amount.

Further, the amount of the base used if necessary is 0.01 to 1.2 times the mole of the compound of -pure [n].

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

Production method 2 (1) - By reacting the compound of general formula [IV] or a salt thereof with the compound of Fukudai [II] in the presence or absence of a base, - the compound of Fukudai [V] or The salt can be manufactured.

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

The obtained compound of general formula [V] or its salt may be used as it is in the subsequent reaction without isolation.

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

The obtained compound of general formula [v1] may be used as it is in the subsequent reaction without being isolated.

Furthermore, by subjecting the compound of -Fukudai[VI] to a selective elimination reaction of the hydroxyl protecting group (=J), -Fukudai[VI]
A compound of VI[] or a salt thereof can be produced.

The obtained compound of general formula [VI] or a salt thereof may be used as it is in the subsequent reaction without being isolated.

These reactions can be carried out using methods known per se, such as Protective Groups in Or Φ Synthesis.
ganicSynthesis), [Theodora W. Green]
(1981), John Rye 4 Lee & Sons Incorporated (Jot
)n Wiley Fx 5ons, Inc. )
] or a method similar thereto.

The combination of hydroxyl protecting groups 3 (R and R2a) used in these reactions may be selected as appropriate.

(3) - By reacting the compound of Fukudai [VI] or its salt with a halogenating agent or a sulfonylating agent in a solvent in the presence or absence of a base, - Fukudai [■
] can be produced.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction, such as halogenated hydrocarbons such as methylene chloride and chloroborm; ethers such as tetrahydrofuran and diochirin; and amides such as N,N-dimethylformamide, and these solvents may be used alone or in combination of two or more.

In addition, examples of bases used as necessary include triethylamine, diisopropylethylamine,
,8-diazabicyclo-[5,4°O]undec-7-
organic or inorganic bases such as pyridine, potassium tert-butoxy, sodium carbonate, potassium carbonate and sodium hydride.

Examples of the halogenating agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, and dionyl chloride.

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

The amount of the halogenating agent or sulfonylating agent and the base used as necessary is equal to or more, preferably 1 to 2 times the mole, relative to the compound or salt thereof, respectively. It is.

This reaction typically ranges from -10 to ioo°C1, preferably 0
What is necessary is just to carry out at -40 degreeC for 10 minutes - 30 hours.

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

(4) - Reacting the compound of Fukudai [■] with the compound of general formula [IX] or a salt thereof in the presence or absence of a base and in the presence or absence of a catalyst. A compound of Ninisu, -Fukudai [Ibl or a salt thereof can be produced.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction.
The same solvents as those mentioned in (3) can be mentioned.

Furthermore, examples of catalysts that may be used as necessary include potassium iodide and sodium iodide.

The amount of catalyst used as needed is - clothing cost [■]
The amount is 0.1 to 1 times the amount of the compound.

Furthermore, examples of the base that may be used as necessary include the same bases as those described in (3) of Production Method 2 above.

The amount of the compound of general formula [IX] or its salt, or the base used if necessary, is at least the same mole, preferably 1 to 20 times the mole of the compound of formula [■], respectively. It is.

This reaction is usually carried out at 10-150°C, preferably at 20°C.
What is necessary is just to carry out at -100 degreeC for 10 minutes - 20 hours.

Production method 3 (1) -By reacting the compound of general formula [Xl or a salt thereof with the compound of -Fukudai [n] in the presence or absence of a base, the compound of -Fukudai [XI] or its salt is reacted with the compound of -Fukudai [n] or its salt. Salt can be manufactured.

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

(2) - By reacting the compound of Fukudai [XI] or its salt with a sulfonylating agent in a solvent in the presence or absence of a base, - the compound of Fukudai [X[] or its salt Can be manufactured.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction.
The same solvents as those mentioned in (3) can be mentioned.

Further, examples of the base that may be used as necessary include the base 8 as described in (3) of Production Method 2 of (e) above.

Examples of the sulfonylating agent include I)-1 to luenesulfonyl chloride.

The amount of the sulfonylating agent and the optional base to be used is 0.95 mol or more, preferably 1 to 2 times the mol of the compound or salt thereof, respectively.

This reaction is usually carried out at -10 to 100°C, preferably at 0.
What is necessary is just to carry out at -40 degreeC for 10 minutes - 30 hours.

The obtained compound of general formula [X[] or a salt thereof may be used as it is in the subsequent reaction without isolation.

(3) - Compound or monosalt of Fukudai [Xl[],
By subjecting it to a normal hydroxyl group protection reaction, -
It is possible to produce the compound of Fukudai [XI].

This reaction can be carried out using methods known per se, such as Protective Groups in Organic Synthesis (P
rotective Groups in Orga
nicSynthes is), [Theodora W. Green]
(1981), John Wiley & Sons
John Wiley Fx 5ons, Inc.
, )] or a method similar thereto.

The obtained compound of general formula [XI] may be used as it is in the subsequent reaction without being isolated.

(4) - By reacting the compound of the general formula [IX] or its salt with the compound of the general formula [IX] or the compound of the general formula [XI] in the presence or absence of a base. , -Fukudai [IC] compound or its salt can be produced.

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

Production method 4 (1) By reacting the compound of -Fukudai [■] with the compound of general formula [XV], the compound of -Fukudai [Kari] or its salt can be produced.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction; examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; 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 -Fukudai [XV] used is 0.8 to 100 times the mole, preferably 0.8 to 10 times the mole of the compound -Fukudai [store].

Moreover, this reaction may be normally carried out at -78°C to 100'C, preferably -78°C to 50°C, for 5 minutes to 24 hours.

The obtained compound of general formula [XM] or its salt may be used as it is in the next reaction without isolation.

The compound of the general formula [XV] used here can be prepared by a method known per se, for example, by a method known per se.
, Fr, ), 1967(5), No. 1533-15
It can be manufactured by the method described on page 40.

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

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

Furthermore, examples of catalysts that may be used as necessary include potassium iodide and sodium iodide.

The amount of catalyst used as needed is determined by the general formula [Kari]
The amount is 0.1 to 1 times the amount of the compound or its salt.

In addition, examples of the base that may be used as necessary include the same bases as mentioned in (3) of the above-mentioned production method 2, and the compound of -Fukudai [IX] can also be used as Jgll. .

2 The amount of the compound of general formula [IX] or its salt, or the base used if necessary, is at least equimolar, preferably 1 to 1 molar, relative to the compound of formula [XM] or its salt, respectively. It is 20 times the molar amount.

This reaction is usually carried out at 10-150°C, preferably at 20°C.
What is necessary is just to carry out at -100 degreeC for 10 minutes - 20 hours.

Furthermore, depending on the properties of the reaction reagent or base used in the above reaction, they can also be used as a solvent.

General formula [n], [II[] in each production method described above
, [nla], [IV], [V], [Vll, [Vll
], [■], [IX], EX], [XI], [X1
], [X111], [■], [XV] and [Kari] compounds, if isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, all these isomers Also, hydrates, solvates and all crystalline forms can be used.

General formula [I[], [In], [nla], [IV], [
V], [VI], [W], [■], [IX], [Kari], [X[[], [XIV], [X
V], [XVko, [II, [IaL [Ib
In the compounds of I, [Ic] and [Idl, compounds having a hydroxyl group, amine group or carboxyl group are protected in advance with a conventional protecting group, and after the reaction, If necessary, these protecting groups can be removed by methods known per se.

The 1,2-ethanediol derivative of general formula [II or its salt obtained in this manner can be isolated and purified by conventional methods such as extraction, crystallization, distillation, and column chromatography.

In addition, the 1,2-ethanediol derivative or its salt of -Fukudai[II can be reacted with, for example, oxidation reaction, reduction reaction, addition reaction, acylation reaction, alkylation reaction, sulfonylation reaction, deacylation reaction, substitution reaction. Other 1,2-ethanediol derivatives of general formula [II or salts thereof can be derived by appropriately combining methods known per se, such as dehydration reaction and hydrolysis reaction.

3 4 The compound of Ippukudai CI], which is a raw material for producing the 1,2-ethanediol derivative or its salt of -Fukudai II], can be prepared by a method known per se, for example, °, di(7-nal・Of American Chemical Society (JAC3)
), vol. 87, p. 1353 (1965), New Experimental Chemistry Course, vol. 14, p. 579 (1977, round neck)
It can be manufactured by etc.

When the 1,2-ethanediol derivative J of general formula [I] or its salt is used as a medicine, pharmaceutically acceptable excipients, carriers, diluents, and other formulation aids may be mixed as appropriate. These can be administered orally or parenterally in the form of tablets, capsules, powders, granules, fine granules, milled tablets, suspensions, emulsions, liquids, syrups or injections by conventional methods. be able to. In addition, the administration method, dosage, and frequency of administration can be appropriately selected depending on the age, weight, and symptoms of the patient, but in the case of oral administration, it is usually 100% for adults.
．． 01-500771F may be administered in one to several divided doses.

5 Next, the pharmacological action of the 1°2-ethanediol derivative of the general formula [E] or its salt used in the present invention will be described.

In addition, the test compound numbers used in the following pharmacological test chambers are the compound numbers in the production examples.

1. Anti-hyboxia effect 100 m3/KFI of the test compound dissolved in physiological saline is orally administered to 10 ddY female mice (5 to 6 weeks old) per group. One hour after administration (or 30 minutes later9), mice were placed in a 300 d glass container, and the glass container was injected with a gas mixture consisting of 4% oxygen and 96% nitrogen for 5 minutes.
Aeration was performed at a rate of e/min, and the time from the start of aeration until the mouse died was measured.

In the control group, only physiological saline was orally administered.

The antihypoxia effect of the test compound was determined using the following formula:

The results are shown in Table-1.

6 Table-1 Table-1 (Continued) 1 (Continued); Instead of putting it in a glass container 1 hour after administration,
After 0 minutes, it was placed in a glass container.

9-2. Anti-amnestic effect a) Electrical intercept shock (EC8) induced amnesia model 1 group 1
A test compound dissolved in physiological saline was intraperitoneally administered to 0 ddY male rats (5-6 weeks old), and 1 hour after the administration, the mice were placed in a step-through system (STE) consisting of two light and dark rooms.
p-through) type passive avoidance training box (HP^-1
008, manufactured by Zenmachi Kikai Co., Ltd.), and when it enters darkness, close the guillotine door, and after 0.5 seconds, apply a current (1.6 mA,
Acquisition trials were performed by energizing the floor grid for 3 s), followed immediately by EC8 (25 mA, 0.3 s) via both eyes.
5 seconds).

As a test trial, the mice were placed in the light room again 24 hours later, and the time it took for the mice to put their limbs in the dark (response latency) was measured for a maximum of 300 seconds.

Response latencies were measured in the same manner for the control group of mice to which only physiological saline was intraperitoneally administered.

Furthermore, the anti-amnestic effect was expressed as the median response latency and expressed by the following symbol.

20~60 seconds 10:61~100 seconds++:
101 to 150 seconds 10++: 15
Table 2 shows the results for 1 to 300 seconds.

b) Cycloheximide
Induced Amnesia Model It has been reported by Yamazaki et al. [Drugs, Psychiatry, and Behavior, Vol. 3, pp. 127-136 (1983)] that cycloheximide impairs the memory retrieval process in mice. Therefore, the following test was conducted.

Methods: Drugs, Minds, and Behavior, Volume 3, Nos. 127-136
(1983) and Japanese Pharmacological Journal, Vol. 89, pp. 243-252 (1987).

The device was a black acrylic box with a length of 22 Ctn, a width of 22 cm, and a height of 21 cm, the body part of which was made of a stainless steel grid, and placed 87 cm in one corner of the grid on the floor.

A step-down passive avoidance training box was used, which was equipped with a stand measuring 2 cm in width and 2 cm in height.

Cycloheximide (120 m
g/Kg) is administered subcutaneously, and 15 minutes after administration, the mouse is placed on a platform within the above apparatus. Immediately after the mouse landed on floor 1 2 , a 2 mA current was applied to the floor grid for 2 seconds, and the mouse was immediately returned to its home cage to conduct an acquisition trial. As a test trial, 24 hours later, each test compound dissolved in physiological saline was administered orally to the mice, and 30 minutes after administration, the mice were placed on the table in the above apparatus. The time taken for the mouse to get off the platform (response latency) was measured for a maximum of 300 seconds.

The response latencies of the control group of mice to which only physiological saline was orally administered were measured in the same manner.

Furthermore, the anti-amnestic effect was expressed as the median response latency and expressed by the following symbols.

70-60 seconds +261-100 seconds 10:
101 ~150 seconds Food++: 15
Table 3 does not show the results for 1 to 300 seconds.

(The following is the margin) Table 3 4 Table 3 (Continued) (The following is the margin) 3. Acetylcholinesterase inhibitory effect Eelman (
Ellman et al.'s method [Biochemical) 7-? T
]ology (Biochem, Pharmacol,)
Vol. 7, pp. 88-95, 1961].

That is, acetylthiaj-]phosphorus as a substrate was added to a 1% Phosphorus M solution containing 5,5'-dithiobis-(2-nitrobenzoic acid) [DTNB], a test compound, and mouse fan modinate as a source of acetyllolinesterase. Add and incubate to produce 5-thio-2
-Nidobenzoic acid was measured with Al2nm.

The acetylcholinesterase inhibitory activity was expressed as the inhibition rate when the final concentration of the test compound was 10jJ3/m (!).

The results are shown in Table 4.

(Margins below) / / / 5 6 Table 4 Table 4 (Continued) (Margins below) 7 4. Acute toxicity Dissolved in physiological saline in 1 group of 3 ddY male medium mice (up to 6 weeks old). The test compound was administered intravenously to examine acute toxicity.

As a result, test compound number", 2.3.6.8.9.1
5.16.25.30.33.34.38.40.42
．． 44.46.52.53.54.65.67.70.
71.112.119.120.126.132.14
7.151.159.160.170.176.178
．． For compounds 182.190.194.209.219.220 and 221, no fatal cases were observed at 501 rfl/Ky.

From the above test results, the 1,2-ethanediol derivatives or their salts manufactured by Futoshiro [Ko] exhibit excellent antihypoxia action, antiamnestic action, and acetylcholinestera U inhibitory action, and have low toxicity. can be easily understood.

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

9 B [Effect of the Invention] Therefore, it is clear that the 1,2-ethanediol derivative of -Fukudai [I] or its salt is an extremely useful compound as a brain function improving agent.

Next, the method for producing the 1,2-ethanediol derivative or its salt of -Fukudai [I] will be specifically explained by giving a production example.

The mixing ratios of solvents are all volume ratios, and the carrier in column chromatography is silica gel [Kiesel Gel 60. Art ~, 7734 (
K+eselqel 60. Art, 7734)] was used.

Furthermore, the abbreviations used below have the following meanings.

Me: methyl, Et: ethyl, 1-Pr: isoprobyl, t-Bu: tert-butyl, AC niacetyl, Ph: phenyl, DPM nidiphenylmethyl, Bz
: Benzyl, Tr nitrityl, IPA: Isopropyl alcohol, IPE; Diisopropyl ether, PTS:
f) -Toluenesulfonic acid Also, [] in the text and table
is the recrystallization solvent 0 − .

(Left below) / / 1 Production example 1 (1) (+)-Dibenzoylcystine 10.89
A mixture of 1.6 g of sodium borohydride, 2.49 g of tert-butanol and 180 parts of tetrahydrofuran was refluxed for 1 hour and then cooled to -60'C. Add 6.4-benzyloxyphenacyl bromide to this mixture.
Add 1g and incubate at the same temperature for 30 minutes, then -40~30°
Stir at C for 3 hours. After the reaction is complete, the reaction mixture is diluted with 10% water.
The mixture was introduced into a mixture of 0 mff and 200 parts diethyl ether, and the organic layer was separated. This organic layer is washed successively with water, saturated sulfur hydrogen carbonate to thulium solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (eluent: toluene) to obtain (S)-1-(4
-benzyloxyphenyl)-2-bromoethanol 2
．． Get 89.

(2) (S)-1-(4-benzyloxyphenyl)-2-bromoethanol 2.89 methanol 20
m1! and tetrahydrofuran 10rnf! Dissolved in a mixed solvent of 2! yi! Then, an aqueous solution 4me in which 0.8 g of potassium hydroxide was dissolved was added to this solution under water cooling, and the jqed mixture was stirred at the same temperature for 5 minutes and then at the lowest temperature for 10 minutes. Then, the reaction mixture was diluted with 50ml of diethyl ether. !
and ice water 507d, and then the organic layer is separated. The aqueous layer is 25ml of diethyl ether! Extract with The extract is combined with the organic layer, washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 1.43 of (S)-2-(4-benzyloxyphenyl)oxirane is obtained.

Melting point: 56-61°C Optical rotation: [α]: -15.2° (C=2.Cl
ICl5) The following compound is obtained in the same manner.

o(S)-2-(3-methylphenyl)oni-1 dirane optical rotation; [α] Knee + 15.7° (C=2.CHC
l3) 0 (S)-2-(4-phenoxyphenyl)oxyfuran optical rotation; [α] knee 12.5° (C=4. ClI
Cl3') Production Example 2 (1) A solution of 23 g of (10)-diisopinocamphenylchloroborane dissolved in 10 parts of tetrahydrofuran was cooled to -25°C, and 4-benzyloxyphenacylpropylene was added to the solution. Mido 129 is added and the resulting mixture is stirred at -20 to -15°C for 4 hours. The reaction mixture was then diluted with 150 mj of diethyl ether and 100 mj of ice water.
After introducing me into the mixture, the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent; hexane:toluene-1:2) to obtain (R
6.8 g of -1-(4-benzyloxyphenyl)-2-bromoethanol are obtained.

(2) (R)-1-(4-benzyloxyphenyl)-2-bromoethanol 6, Og to methanol 50
m! and 25 parts of tetrahydrofuran, and to this solution was added 5 ml of an aqueous solution in which 1.5 g of hydroxide was dissolved in advance under water cooling. Stir for 10 minutes. Then, the reaction mixture was introduced into a mixture of 100 parts diethyl ether and 1 part ice water, and the organic layer was separated. The aqueous layer is extracted with 50 ml of diethyl ether.

The extract is combined with the organic layer, washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate.

By distilling off the solvent under reduced pressure, 3.7 g of (R)-2-(4-benzyloxyphenyl)oxirane is obtained.

Melting point: 58-67°C Optical rotation: [α]. --14,4° (C=2. ClC
l5) In the same manner, the following compounds are obtained.

o(R)-2-(3-methylphenyl)oxirane optical rotation; [α]27=-18.6° (C=2. Cl
Cl5)0(R)-2-(4-phenoxyphenyl)oxirane optical rotation; [α]: =i1.3° (C=2.CH
Cl3) Installation example 3 2-(N,N-dimethylamino)ethanol 31me
Add 3.4 g of tert-butoxypotassium and heat to 80°C.
Raise the temperature to After 7.7 g of 2-(3-fluorophenyl)oxirane was added dropwise to this solution over 40 minutes, the resulting mixture was stirred at the same temperature for 3 hours. Then,
The reaction mixture was diluted with 200 d of ice water and 200 ml of ethyl acetate.
into the mixture, the organic layer is separated. 50m of water in the separated organic layer! ! After adjusting to 1) Hl with 6N hydrochloric acid, the aqueous layer is separated. Add 100 parts of chloroform to the separated aqueous layer, adjust p to 1 with a 2N aqueous sodium hydroxide solution, and then separate the organic layer. The separated organic layer is washed with water and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent; chloroform:ethanol = 5
: Purify by 1). The obtained oil was dissolved in 25 d of acetone, and hydrogen chloride gas was introduced into this solution. If the precipitated crystals are collected, washed with acetone, and dried, 2-
[2-(N,N-dimethylamino)ethoxy]-1-(
3-fluorophenyl)5 3.1 g of ethanol hydrochloride (Compound No. 1) are obtained.

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

Nao, R1, R2, R3, R4a, R4b in Table-5,
R6, na and nb each represent a substituent or an integer of the following formula.

(Margin below) 6 8 1 62 0 5 63 6 4 9 67 0 8 3 74 2 7 75 8 1 82 0 5 83 6 4 Production example 4 1-benzyl-4-hydroxypiperidine 5.009,
A mixture of 1.97'7 and dimethyl sulfoxide 4d was heated to 80°C, and styrene oxide 2.109 was added dropwise to this solution over a period of 40 minutes. Stir at the same temperature for 3 hours. Then, the reaction mixture was introduced into a mixture of 100 parts of ice water and 80 parts of ethyl acetate, and diluted with 6N hydrochloric acid at p+1.
After adjusting to 11.5, the organic layer is separated. The separated organic layer was washed successively with water and saturated brine, and then dried for 1 μm over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The obtained residue is purified by column chroma 1 to graphie (eluent: chloroborum:ethanol-10:1).

The obtained oil was dissolved in 8 parts of ethanol, and to this solution was added 1 part of 6N dry hydrogen chloride ethanol solution and 20 parts of diethyl ether, and the resulting mixture was dissolved at room temperature for 30 minutes.
Stir for a minute. The precipitated product is collected, washed with a mixture of ethanol and diethyl ether, and dried to give 2-(1-benzylpiperidin-4-yl7oxy)-1-phenylethanol hydrochloride (compound Number 113) Get 930my.

Melting point: 193-195°C Similarly, the compounds shown in Table 6 are obtained.

In addition, R1, R2, R3, R4, R6 and n in Table 6 each represent a substituent or an integer of the following formula.

(Left below blank) 8 9 0 1 92 Production Example 5 (1) 4-Benzyl-2-hydroxymethylmorpholine 4.309. Potassium tert-butoxy 930 m
g and dimethyl sulfoxide 4d at 80°C.
Raise the temperature to Add 2.50 styrene oxide to this solution.
After adding dropwise over a period of 20 minutes, the resulting mixture was stirred at the same temperature for 2 hours. Then, the reaction mixture was diluted with 30ml of diethyl ether. ! and 30 ml of ice water, and the organic layer was separated. After adding 10 parts of water to the separated organic layer and adjusting the PL to +2.0 with 6N hydrochloric acid, the aqueous layer was separated. Add 30 m of diethyl ether (!) to the separated aqueous layer, adjust to pllll with 2N aqueous sodium hydroxide solution, and then separate the right TA layer. Wash the separated organic layer with saturated brine, then sulfuric anhydride. Dry over magnesium. The solvent is distilled off under reduced pressure, and the resulting residue is subjected to column chromatography (solution-1 solution H1-luene: ethyl acetate = 1:
1), oily 1-phenyl-2-[(4-
2.009 of benzylmorpholin-2-yl)methoxy]ethanol (compound no. 144) is obtained.

Similarly, the compounds shown in Table 7 are obtained.

In addition, R1, R2, R3, R4, R6 and n in Table 7 each represent a substituent or an integer of the following formula.

(Margin below) 7 8 99 (2) 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxycoethanol 1.00 g, 5% palladium-carbon 500 my and methanol 10 ur
1 of the mixture is hydrogenated at room temperature and pressure for 4 hours. After the reaction is completed, the palladium-carbon is removed and covered.

The solvent was distilled off under reduced pressure, and the residue was filtered into a column.]
]71 Purification with Hegelafy (eluent: chloroform:methanol-10:1) yields 450 m7 of an oil. Dissolve this oil in 2.5d of isopropanol,
220 mg of fumaric acid is added to the resulting solution and the resulting mixture is stirred at room temperature for 1 hour. Number of deposits is i, and isopropyl alcohol is 2m! ! After washing with
1) Get 460 trty.

Melting point: 1/16.5-147°C [F↑OH] Compounds in Table 8 are obtained in the same manner.

In addition, R1, R2, R3, R4,1"<64 in Table-8
3 and n each represent a substituent or an integer of the following formula.

00 02 (3) 1-(3-methoxyphenyl)-2-[(4
-1-lythylmorpholin-2-yl)methoxy] 7 g of ethanol was dissolved in 35 d of acetone.
Under water cooling, 5.9N dry hydrogen chloride ethanol solution 2.67
After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. After adding 50 mj of water and 3 (7) of ethyl acetate to the obtained residue, the aqueous layer is separated. After washing the separated aqueous layer with ethyl acetate, 50 mj of chloroform (
! F)Hll with a 1N aqueous solution of sodium hydroxide
and separate the organic layer. The separated organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (eluent: chloroborum:methanol = 5:1).
1 g of oil is obtained. Add 3 m of this oily substance to isopropanol.
430 mg of fumaric acid are added to this solution and the resulting mixture is stirred for 1 hour at room temperature. If the precipitated crystals are collected in a furnace and dried, 1-(3-methoxyphenyl)-
172 fumarate salt of 2-[(morpholin-2-yl)methoxy]ethanol (Compound No. 155) 800
Get mg.

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

In addition, R1, R2, R3, R4, R6 and n in Table 9 each represent a substituent or an integer of the following formula.

(The following is a blank space) 03 04 Production Example 6 (1) Potassium tert-butoxy added to 105 d of ethylene glycol mono-tert-butyl ether 5.
Add 1 g and raise the temperature to 80°C. In this solution, add 2-
After 35.0 g of (3-chlorophenyl)'A xylan was added dropwise over 1 hour, the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture is then introduced into a mixture of 100 parts of ice water and 100 parts of ethyl acetate, and the organic layer is separated. The separated organic layer is washed with saturated brine and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, the resulting residue is further distilled under reduced pressure, and a fraction with a boiling point of 140 to 146°C, 10.9 mmHQ is collected to obtain 1-(3-chlorophenyl)- as a colorless oil. 37.7 g of 2-(2-tert-butoxyethoxy)ethanol are obtained.

(2) 1-(3-chlorophenyl)-2-(2-
tert-butoxyethoxy) ethanol (37.09 g) was dissolved in 70 d of methylene chloride, and 1 d of pyridine was added to this solution.
2.9 g and 16.6 g of acetic anhydride are added and the resulting mixture is stirred at room temperature for 24 hours. Next, the 05-10-day reaction mixture was introduced into a mixture of 150 mff of ice water and 100 mf of methylene chloride, and after adjusting the pH to 2 with 6N hydrochloric acid, the organic layer was separated. The separated organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure, oily 1-acetoxy-1-(3-chlorophenyl)-2-
(2-tert-but-1-oxy)ethane 40.
Get J.J.

(3) 1-acetoxy-1-(3-chlorofer) -
2-(2-tert-buty-oxyethoxy)] Ninisin 40. After dissolving J in 40 ml of methylene chloride (!) and adding 1 to 80 ml of fluoroacetic acid to this solution under water cooling, the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Toluene was added to the residue obtained by distillation.
00 me was added and the solvent was roughly distilled off under reduced pressure. 90m of ethanol for the removed residue! 2 and water 10d
Add hydrogen carbonate to this solution at room temperature.
After adding 10.7 g of lithium, the mixture was adjusted to 0.116 to 7 with a saturated hydrogen carbonate solution of 11 to 10.7 g. Then, this solution was reduced to about half its volume under reduced pressure, and 100 parts of ethyl acetate was added to the concentrated solution, and the organic layer was separated. The aqueous layer is further extracted with 50 mf2 of ethyl acetate. The extract is combined with the previously separated organic layer, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent; toluene:ethyl acetate = 3:1).
) to obtain 19.49 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane.

(4) 1-acetoxy-1-(3-chlorophenyl)-
To a mixture of 95.0 d of methylene chloride containing 19.09 d of 2-(2-hydroxyethoxy)ethane and 9.1 d of methanesulfonyl chloride was added 1 d of triethylamine under water cooling.
The mixture was added dropwise over a period of 1 hour, and the resulting mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. Then,
The reaction mixture was diluted with 50% methylene chloride and 50% ice water.
(Introduced into the mixture of step 7 and adjusted to ρ112.0 with 6N hydrochloric acid, then the organic layer was separated.

The separated organic layer is washed with water, dried with anhydrous sulfuric acid magnezi 07 ram, and the solvent is distilled off under reduced pressure to obtain an oily 1-acetoxy-1-(3-chlorophenyl)-2-
(2-methanesulfonyloxyethoxy)ethane24.
Obtain 5g.

(5) 1-are1-xy-1-(3-chlorophenyl)
-2-(2-methanesulfonyl chloride] xy) 1.409 mL of ethane was dissolved in 7 parts of N,N-dimethylformamide, and 0.69 m of N-methylpiperazine was added to this solution.
and 1.03 g of potassium carbonate are added, and the 1 q. mixture is stirred at 80'C for 3 hours. The reaction mixture is then cooled and introduced into a mixture of 30 m of ice water and 30 mQ of diethyl ether, and the organic layer is separated. The aqueous layer is further extracted with 20 mQ of diethyl ether. The extract was combined with the previously separated organic layer, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 7 m of methanol and 45 mg of sodium methoxide are added to the resulting residue, and the resulting mixture is left at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure, and 20% of ethyl acetate was added to the resulting residue.
After adding 8 parts and 10 parts of water, separate the organic layer. The aqueous layer is further extracted with 20 d of ethyl acetate. The extract is combined with the previously separated organic layer, washed with saturated saline, and then purified by column chromatography (eluent: chloroform:methanol-10:1). Add ethanol iomf to the resulting oily substance! and 6N dry hydrogen chloride ethanol solution 1
．． 27! were added sequentially, and 1 (7) of diethyl ether was further added to the resulting mixture, and the resulting mixture was stirred for 30 minutes. The precipitated crystals were separated and washed with a mixture of 2 d of ethanol and 2 m of diethyl ether!! After drying, 1-(3-chlorophenyl)-2-[2-(/
770 mg of dihydrochloride of 1-methylpiperazin-1-yl)ethoxy]ethanol (Compound No. 158) are obtained.

Melting point: 211-213°C [MeOH-Etol-1]
Similarly, the compounds shown in Table 10 are obtained.

In addition, R1, R2, R3, R4, +<'' and n in Table 10 each represent a substituent or an integer of the following formula.

(Left below) 1θq 10 111 113 12 Production Example 7 1-4-benzyloxyphenyl)-2-[2-(N
, N-dimethylamine)■1-xy]ethanol hydrochloride2. JJ, a mixture of 500 mg of 10% palladium-carbon and methanol 1 (7) is hydrogenated at this temperature and normal pressure for 2 hours. After the reaction is complete, the palladium-carbon is removed and the solvent is distilled off under reduced pressure. For example, 1-(4-hydroxyphenyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride (compound number 170) 1.4
Get 9.

Melting point: 169.5-170.5°C [EtOH] Compounds in Table 11 are obtained in the same manner.

In addition, R1, R2, R3, R4, R6 and n in Table 11 each represent a substituent or an integer of the following formula.

(Leaving space below) 14 115 Production Example 8 To 1 g of l-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethanol was added 0.657 mj of pyridine and 0.99 mj acetic anhydride to obtain the The mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off from the reaction mixture under reduced pressure, and 2 ethyl acetate was added to the resulting residue.
Add 0 l and 10 d of water, and adjust the pH to 10 with potassium carbonate.
After adjusting the amount, separate the organic layer. The separated organic layer is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent d is distilled off (under reduced pressure), and the resulting residue is purified by column chroma 1 to graphie (eluent: chloroform:ethanol-30:'l) to obtain oily 1-acetoxy-
1-(3-methylphenyl)-2-12-(morpholin-4-yl)ethoxy]ethane (compound number 178) H
Get J.

Similarly, the compounds shown in Table 12 are obtained.

In addition, R1, R2, R3, IR4, [6
and "] respectively indicate a redeemable group or an integer in the following formula.

16 18 Production Example 9 1-ace1-xy-1-(3-hydroxyphenyl)-
Hydrochloride of 2-[2-(N,N-dimethylamino)-oxy]ethane3. ．． 309 and chloroform water (1:1)
After adding 50 mg of a mixture of the above and 5 amg of sodium carbonate to the resulting mixture under water cooling, the organic layer was separated.

After drying the separated organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with benzene 2
Add 0.0 ml of water and heat the jqed mixture to 60°C. A solution of 5 ml of benzene in which 870 m91 of ethyl isocyanate was dissolved was added dropwise to this solution over a period of 10 minutes, and the resulting mixture was stirred at the same temperature for 40 minutes.

After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (eluent: chloroform:ethanol-10:1) to obtain an oil.

The obtained oil is dissolved in 10 mj of ethanol, hydrogen chloride gas is introduced into this solution, and the solvent is distilled off under reduced pressure to obtain 1-acetoxy-1-[3-(N-ethylcarbamoyloxy 2- 1.90 g of hydrochloride of [2-(N,N-dimethylamino)ethoxy]ethane (Compound No. 189) is obtained.

Melting point: 111.5 to 113.5°C [, Me2G
o] Similarly, oily 1-acetoxy-1-[3-(
3-chlorophenylcarbamoyloxy)phenyl]
-2- [2-(N,N-dimethylamino)toxy]ethane hydrochloride (compound number 190) is obtained.

Production Example 10 (1) 9.5 g of tert-butoxypotassium is added to 92 mA of ethylene glycol, and the temperature is raised to 80°C. Dimethyl sulfoxide 2 was prepared by dissolving 34.7 g of 2-(4-benzyloxyphenyl)oxirane in this solution.
After adding the 20% solution dropwise over 3 hours, the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture is then cooled, introduced into a mixture of 11 ice water and 600 mff of ethyl acetate, and adjusted to p]17 with 6N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 200 m of ethyl acetate (!).The extract was combined with the previously separated a-layer and washed sequentially with water and saturated saline, followed by anhydrous sulfuric acid. Dry with magnesium. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (eluent: chloroborum:ethanol-10:1) to obtain 1-(4-benzyloxyphenyl)- 2
-(2-hydroxyethoxy)ethanol 259 is obtained.

Melting point: 116.5-117°C [MeCN] (2)
22.79 of 1-(4-benzyloxyphenyl)-2(2-hydroxyethoxy)ethanol to 1 part of pyridine
Dissolve at 40 d and cool to -20°C.

After adding 19 g of p-toluenesulfonyl chloride to this solution, the resulting mixture was heated to O'C and reacted at the same temperature for 15 hours. Then, the reaction mixture was soaked in ice water for 30 minutes.
0ml! and 200 mff of diethyl ether, and after adjusting the pH to 2 with 6N hydrochloric acid, the organic layer was separated. Add 100 ml of diethyl ether to the aqueous layer.
Extract with Combine the extract with the organic layer separated earlier,
After sequentially washing with 1N hydrochloric acid, water and saturated saline, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (eluent: toluene:ethyl acetate-3:1) to obtain oily 1(4-benzyloxyphenyl)-2. 20.59 of -[2-(p-toluenesulfonyloxy)ethoxy]ethanol is obtained.

(3) 1-(4-benzyloxyphenyl)-2-
[2-(1)-Toluenesulfonyloxy)etogish]
To a mixture of 40 parts methylene chloride containing 20 g ethanol and 8.2 g 3,4-dihydro-211-pyran was added 2.37 g of pyridinium-p-toluenesulfonate at room temperature.
30 minutes). Then, after cooling the reaction mixture, 100 g of ice water and 100 g of methylene chloride were added.
mI! and separate the organic layer. After washing the organic layer with water, it is dried over anhydrous magnesium sulfate.

By distilling off the solvent under reduced pressure, a pale yellow oily 1-(4-benzyloxyphenyl)-1-(2-tetrahydropyranyloxy)-2-[2-(p. ~ Ruenesulfonyl A)
18.6 g of xy]ethane are obtained.

(4) 1-(4-benzyloxyphenyl)-12
4-(2-tetrahydropyranyloxy)-2-['2-
(p-Toluenesulfonyloxy)ethoxy]ethane 2 g, 40% methylamine aqueous solution 5.9 mf! and 20 d of ethanol at a rapid flow rate for 2 hours. Then,
After the reaction mixture has been cooled and introduced into a mixture of 5 (7) ice water and 50 ml of diethyl ether, the organic layer is separated off.

The aqueous layer is further extracted twice with 20 ml portions of diethyl ether. Combine the extract with the previously separated organic layer and add 10 ml of water.
After adding 7, the pH was adjusted to 1.0 with 6N hydrochloric acid, and the aqueous layer was separated. After stirring the separated aqueous layer at room temperature for 30 minutes,
Add 30ml of chloroform (!), adjust the pH to 12 with 5% sulfur hydroxide to thulium solution, and separate the organic layer. After sequentially washing the separated organic layer with water and saturated brine, wash with anhydrous magnesium sulfate. Dry. The solvent is distilled off under reduced pressure, 10 d of acetone is added to the jqed residue, and hydrogen chloride gas is introduced into this mixture while cooling with water. The precipitated crystals are taken out and washed with acetone, and then If dried, 1-(4-
Benzyloxyphenyl)-2-(2-medylaminoethoxy)ethanol hydrochloride (compound number @191) 62
Obtain 0 mg.

Melting point: 173-173.5°C [EtOH] Compounds shown in Table 13 are obtained in the same manner.

Nao, R1, R2, R3, R4a, R4b in Table 13
, R6, na and the song each represent a substituent or an integer of the following formula.

(The following are blank spaces) 25 26 29 130 31 132 Production Example 11 2-[(imidazol-4-yl)methoxy 1-1-phenyl-ethanol 500ml, pyridine 1.1ml, triethylamine 1.1mj2d5, and anhydrous vinegar M1
．． After stirring the 1 mf2 mixture at 100° C. for 1 hour, it is cooled to room temperature and the solvent is distilled off under reduced pressure.

To the resulting residue were added 1.1 mffct"i of methyl iodide and 5d of are-1-nitrile, and the mixture was stirred at room temperature for 2
Leave it for 4 hours. Then, the solvent was distilled off under reduced pressure, and 4 ml of ethanol and 6.8 mff of a 5% aqueous sodium hydroxide solution were added to the resulting residue, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and 30 ml of chloroform was added to the residue. and 20 ml of water were added, and the organic layer was separated. This organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained oil was purified by column chromatography (eluent: chloroborum:ethanol - 10:1), and diisopropyl ether was added to the obtained white crystals to give 2-[(1-methylimidazole). -5-yl)methoxy]-1-33 phenylethanol (compound number 214) 450
Get mg.

Melting point: 102-105°C Similarly, the following compound is obtained.

ol-(4-Benzyloxyphenyl)-2[(1-methylimidazol-5-yl)methyl-oxy]ethanol (Compound No. 215) Melting point: 148.5-150.5°C [IP△-AcOE
t] Production Example 12 5 m of tetrahydrofuran in which 1.08 g of 2-(2-amineethoxy)-1-phenyl-ethanol, 730 mg of di]tinic acid, 810 my of 1-hydroxybenzotriazole, and 0.83 d of triethiamine were dissolved! ! 1.23 g of N,N--dicyclohexylcarbodiimide is added to the solution under water cooling, and the mixture is stirred at the same temperature for 5 minutes and roughly at room temperature for 1 hour.

Then, 11 parts of ethyl acetate was added to the reaction mixture to remove insoluble matter. Add 5 parts of water to the 7-door solution, and add 6N hydrochloric acid to p11.
After adjusting to 2, separate the aqueous layer. Add 5 more water to the organic layer.
Extract with ml. Combine the extract with the previously separated 34 aqueous layer and 20 m of chloroform! ! After adjusting the pH to 0 with potassium carbonate, the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chroma 1 to
Graphie (eluent; chloroform:ethanol = 15
:1), 400 mg of oily 2-(2-nicotinoylaminoethoxy)-1-phenyl-ethanol (Compound No. 216) is obtained.

IR) cm-1: 1635C=0 Production Example 13 (1) Dissolve 5 g of (S)-4-benzyl-2-acetoxymebrumorpholine in ethanol 10+1,
A solution prepared by dissolving 1 g of sodium hydroxide in 5 ml of water is added to this solution while cooling on ice. After stirring the mixture at room temperature for 10 minutes, the reaction mixture is introduced into 50 g of ice water and extracted with 50 g of chloroform. The organic layer is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography 35 (eluent: chloroform:ethanol = 30:1) to obtain oily (S)-4-benzyl-2-hydroxymethyl. 3.6 g of morpholine are obtained.

(2) Dissolve 3.5 g of (S)-4-benzyl-2-hydroxymethylmorpholine in 5 d of ethanol,
To this solution is added 5 d of a 5.9N dry hydrogen chloride ethanol solution under water cooling, and the mixture is stirred at the same temperature for 10 minutes. Then,
A mixture of 500 my of 5% palladium on carbon and 10 d of methanol is added to this solution, and the mixture is subjected to hydrogenation at 40° C. for 3 hours. After the reaction is completed, the palladium-carbon is removed and the solvent is distilled off under reduced pressure to obtain a yellow oil. To this are added 20 parts dry methylene chloride and 4.7 parts triethylamine, and the mixture is stirred at room temperature for 30 minutes. A solution prepared by dissolving 4.7 g of trityl chloride in 10 ml of methylene chloride was added dropwise to this solution over a period of 20 minutes while cooling with water. After stirring the mixture at room temperature for 3 hours, the reaction mixture was washed with ice water at 50 mf! and separate the organic layer.

After adding 20 d of water to the separated organic layer and adjusting the pH to 12 with a 1N aqueous sodium hydroxide solution, the organic layer is separated. After drying the separated organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to obtain a yellow oil. 10 ml of diisopropyl ether is added to this, and the precipitated crystals are collected and dried to obtain 2.7 g of (S)-4-trityl-2-hydroxymethylmorpholine.

Melting point: 142.0-142.5°G [Ac0Et-
IPE] Optical rotation; [α], -10.9° (C = 1
, ClCl5) Similarly, (2
R) Get one piece.

Melting point: 142.0-142.5°C [ACOEt-IP
E] Optical rotation; [α]. -110.9° (C=1.C
HCl3>(3) Instead of styrene oxide and 4-benzyl-2-hydroxymethylmorpholine, (
Oily (1S, 2-3
)-1-phenyl-2-[(4-tritylmorpholine-
2-yl)methoxy]ethanol (Compound No. 217)
get.

(4) (1S, 2-8)-1-phenyl-2-[
(4-Tritylmorpholin-2-yl)methoxy]ethanol was dissolved in 20ml of acetone, and to this solution was added 7 parts of a 5.9N dry hydrogen chloride ethanol solution under water cooling.
Then, after stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. The resulting residue was introduced into a mixture of 30 mQ of ice water and 30 mQ of ethyl acetate, and the aqueous layer was separated. After washing the separated aqueous layer with 30 d of ethyl acetate, 5 d of chloroform was added.
Add 0 mA, adjust the pH to 1 with 2N aqueous sodium hydroxide solution, and separate the organic layer. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.9 g of a yellow oil.

Dissolve this in 10 d of ethanol, add 720 mg of oxalic acid to 1 q of the solution, and dissolve by heating. After standing overnight at room temperature, the precipitated crystals are collected and dried to obtain (IS,
2”5)-1-phenyl-2-[(morpholin-2-yl)methoxy]ethanol oxalate (compound no.
18) Obtain 1.8 g.

Melting point: 130-132°C [EtOH] 37 38 Optical rotation: [α]. -119.9° (C=1, C
1130H) The following compound is obtained in the same manner.

o (1R,2-8) -1-Phenyl-2-[(morpholin-2-yl)methoxy 1 ethanol maleate (Compound No. 219) Melting point: 136-136.5°C [Etol-11 optical rotation ; [α] Knee-21,7° (C-1, C11301
1)0 (18,2-R) -1-phenyl-2-[(
Morpholin-2-yl) methoxy 1 ethanol maleate (Compound No. 220) Melting point; 136-136.5°C [EtOl-1] Optical rotation; [α]: -+22.2° (C=1, CH
30+1)o (1R,2-R)-1-phenyl-2-
[(morpholin-2-yl)methoxy-1 ethanol oxalate (compound number 221) Melting point; 131-132.5°C [EtOH] Optical rotation; [α
]: -20.11° (C=1, C113
011>Production Example 14 (1) 19 g of 4-benzylthiobenzaldehyde earth is dissolved in 20 m of tetrahydrofuran and cooled to -10°C. A solution of 10 parts of tetrahydrofuran containing 282-chloroethoxymethylmagnesium chloride was added dropwise over 10 minutes to this solution, and the mixture was stirred for 1 hour under water cooling. Then, the reaction mixture was poured into 50rr of ice water.
If! , ethyl acetate 50ml and ammonium chloride 1
g and adjusted to pl+2 with 6N hydrochloric acid, and then the organic layer was separated. The separated organic layer is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [eluent; toluene:ethyl acetate].
20:1], 1-(4-benzylthiophenyl)-2-(2-chloroethoxy)ethanol 1.34
Get 7.

Melting point: 4.9.5-50.5°C [hexane-IPE] (
2) 1-(4-benzylthiophenyl)-2-(2
-chloroethoxy) ethanol 600 mg, 50% dimethylamine aqueous solution 4#112, potassium iodide 310
After refluxing a mixture of m3 and 5 ml of ethanol for 4 hours, an additional 4 ml of a 50% dimethylamine aqueous solution was added, and the mixture was refluxed for 4 hours. Then, after cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, and 30 ml of ethyl acetate and 30 mQ of water were added to the resulting residue, and after adjusting the pH to 5 with potassium carbonate, the organic layer was separated. take.

The separated organic layer is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in 15 mC of acetone, and 0.0% of a 5N dry hydrogen chloride ethanol solution was added to this solution.
4m! ! and the number of precipitated crystals is 1-(4-benzylthiophenyl)2-12-(N,N-dimedylamino)ethoxy]ethanol hydrochloride (compound number 2).
22) Obtain 590 mg.

Melting point: 173.5-174.5°C [FtOH] Compounds shown in Table 14 are obtained in the same manner.

Nao! -R', R2, R3, R"', R4 in -14
b, R6, na and nb each represent a substituent or an integer of the following formula.

41 42 [Examples] Next, the present invention will be specifically illustrated with examples, but the present invention is not limited thereto.

Example 1 (tablet) 1-(4-benzyloxyphenyl)-2-[2-(N
, N-dimethylamino)ethoxy] ethanol hydrochloride (Compound No. 48) Tablets containing 50ml are prepared in the following manner using the following formulation.

Per 1 tablet: -905 mg in polyvinylpyrrolidone 43 Total 175my The mixture of the above component (■) is mixed with polyvinylpyrrolidone with an 8% aqueous solution of 44 -90, and after drying at 40'C, the component (■) is mixed and 1 Compress into circular tablets with a tablet weight of 175 mg and a diameter of 8 shoes.

Example 2 (capsule) 2-[2-(N,N-dimethylamino)ethoxy]-
Capsules containing 50 ml of Compound No. 54) in the hydrochloride salt of 1-[4-(4-phenyloxy)phenyl]ethanol are prepared in the following manner using the following formulation.

Per capsule: 5mg of -90 in polyvinylpyrrolidone Total 1somg The mixture of the above component (■) is kneaded with an 8% aqueous solution of -90 in polyvinylpyrrolidone, and after drying at 40°C, the component (■) is mixed,
150 #I9 per capsule is filled into No. 3 geladine capsules to obtain capsules.

Example 3 (liquid) 2- [2-(N,N-dimethylamino)ethoxy]-
A solution containing 1-(3-trifluoromethylphenyl)ethanol hydrochloride (Compound No. 42) 254 is prepared in the following manner using the following formulation.

Per 1 ampoule: Compound No. 42 25mg Methyl paraoxybenzoate 1mg total
Dissolve 28 mg of the above ingredients in physiological saline to make a total volume of 1 d. After sterile filtration of this solution, it is filled into ampoules to obtain a liquid preparation.

Example 4 (injection formulation) 2- [2-(N,N-dimethylamino)ethoxy]-
An injectable formulation containing 1-(3-fluorophenyl)ethanol hydrochloride (Compound No. 1) 25#Iff is prepared in the following manner using the following formulation.

Compound No. 1 Compound 25mg Mannitol 75mg Total
100mg of the above ingredients Distilled water for the above side 1.
After dissolving in 5 mI2 and sterile filtering this solution, 3
Fill into ml mini-vials and lyophilize to obtain an injectable preparation.

Example 5 (fine granules) 2-(1-benzylpiperidin-4-yloxy)-1
-Phenylethanol hydrochloride (compound number 112) 5
A fine granule containing 0my is prepared using the following recipe and the following method.

Total 1000mff above■
Mixture of ingredients to polyvinylpyrrolidone - 8% of 90
After granulating the aqueous solution with high-speed stirring, the mixture is sieved through a 32-mesh 47-thickness sieve and dried to obtain fine granules.

Example 6 (tablet) 2- [2-(N,N-dimethylamino)ethoxy]-
Hydrochloride of 1-(3-methylphenyl)ethanol (Compound No. 15) and 1-(4-hensyloxyphenyl)-2-[(1-methylimidazol-5-yl)methoxy1ethanol (Compound No. 215) were formulated in the same manner as in Example 1 to obtain tablets each containing 5 omg of the compound.

Example 7 (capsule) 2- [2-<N,N-dimethylamino)ethoxy]-
Hydrochloride of 1-(3-methylphenyl)ethanol (Compound No. 15) and 1-(4-benzyloxyphenyl)-2-[(1-methylimidazol-5-yl)methoxy1ethanol (Compound No. 215) and 48 capsules each containing 50 mg of compound, each formulated as in Example 2.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ “In the formula, R^1 is a phenyl group that may be substituted; 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; n R^4 and R^5 are the same or different and are a hydrogen atom or a lower alkyl group; R^6 is,
an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n represents 0 or an integer of 1 to 6, respectively. The nitrogen-containing heterocyclic group for R^6 includes pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, and tetrahydroisoquinyl. nolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl,
Pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl or intazolyl group; Substituents for R^1 include halogen atom, optionally substituted amino, lower alkyl, aryl, al-lower alkyl, lower alkoxy, al-lower Alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al-lower alkylthio, al-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected amino group , optionally protected hydroxyl group, nitro group, oxo group, and lower alkylenedioxy group, and lower alkyl, aryl, al-lower alkyl, lower alkoxy, al-lower alkoxy, Aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, al-lower alkylthio, al-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group and nitrogen-containing heterocycle in R^6 Substituents for the formula group include halogen atoms, optionally protected hydroxyl groups, optionally protected carboxyl groups, optionally protected amino groups, and optionally protected hydroxyl groups. a lower alkyl group which may be substituted with a halogen, an aryl 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 lower acyl group, a lower alkyl group which may be substituted with a lower alkoxy group; group, lower alkenyl group, heterocyclic group,
Examples include a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group, and an arylsulfonyl group, and these 1
It may be substituted with more than one type of substituent; the amino group of the substituent in R^1 and the substituent of the amino group in R^6 include a hydroxyl group which may be protected,
Cycloalkyl group, lower alkyl group optionally substituted with optionally protected hydroxyl or optionally protected carboxyl group, aryl group, lower acyl group, lower alkyl group, heterocyclic group, oxo group Examples include a heterocyclic -CO- group, an adamantyl group, a lower alkylsulfonyl group, and an arylsulfonyl group which may be substituted with <However, R^1 may be substituted with one or more of these substituents. When the phenyl group of is substituted with a halogen atom, lower alkyl, lower alkylenedioxy, lower alkoxy or optionally protected hydroxyl group, R^6 has the formula -NR^7R^8(R^
7 is lower alkyl or heterocyclic group; R^8
represents a hydrogen atom or a lower alkyl group; or R^7
and R^8 together with the N atom, the following groups, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [R^9 is an aryl or heterocyclic group; R^1^0
is an aryl, a heterocyclic group, or ▲a mathematical formula, a chemical formula, a table, etc.▼a heterocyclic group (R^8 indicates the same meaning as above): R^1^1 is an aryl group ;R^
1^2 represents carboxyl or lower alkoxycarbonyl group; and i represents 0, 1, 2 or 3, respectively. ] except when )_u>;Heterocyclic groups as substituents of R^1 include pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl,
Pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl, intazolyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, dihydroquinoxalinyl,
Quinoxalyl, 2,3-dihydrobenzothienyl, 2,
3-dihydrobenzopyrrolyl, 2,3-dihydro-4H
-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]
Pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl,
Represents pyridazinyl, isoindolyl and isoquinolyl groups, respectively. '' A brain function improving agent containing a 1,2-ethanediol derivative or a salt thereof.