JPH0347158A - 1,2-ethanediol derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is naphthyl, indanyl, tetrahydronaphthyl, etc.; R<2> is H, lower alkyl or hydroxylprotecting group; R<3> is H or lower alkyl; R<4> and R<5> are H or lower alkyl; R<6> is amino-containing nitrogen heterocyclic group or ammonio; n is 0-6) and a salt thereof. EXAMPLE:2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride. USE:A cerebral function improver useful for treating sequela of ischemic encephalopathy and cerebral apoplexy and also treating and preventing amnesia and dementia. PREPARATION:A compound shown by formula II is reacted with a compound shown by formula III or a salt thereof or a compound shown by the formula HO-R<6a> (R<6a> is group having free atom valence in carbon forming nitrogen- containing heterocyclic ring among the same nitrogen-containing heterocyclic group as R<6>) or a salt thereof in a solvent such as benzene optionally in the presence of a base (e.g. sodium hydroxide) at 20-150 deg.C to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a 17i-order 1° rest and its salt, general formula [■]: 2-ethanediol derivative, specifically [in the formula, - represents an optionally substituted naphthyl, indanyl, indenyl or tetrahydronaphthyl group; R
2 is a hydrogen atom or a lower alkyl or hydroxyl group II; R3 is a hydrogen atom or a lower alkyl group; n R and R5 are the same or different and are a hydrogen atom or a lower alkyl group; R6 is a substituted an optional amine, a nitrogen-containing heterocyclic group, or an ammonio group; and n represents O or an integer of 1 to 6, respectively. A 1,2-ethanediol derivative and a salt thereof.

[wherein R1 is an optionally substituted naphthyl, indanyl, indenyl or tetrahydronaphthyl group;
R2 is a hydrogen atom or a lower alkyl or hydroxyl protecting group; R3 is a hydrogen atom or a lower alkyl group; n R and R5 are the same or different hydrogen atoms or a lower alkyl group; R6 is substituted; an optional amine or nitrogen-containing heterocyclic group, or an an-2A group; and n represents O or an integer of 1 to 6, respectively. The present invention relates to 1,2-ethanediol derivatives and their salts.

[Prior Art] Conventionally, as 1,2-ethanediol derivatives, for example, US Patent No. 2,928,845, di-17-nal.
On 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 intermediates thereof, their use as brain function improving agents, anti-amnestic agents, and anti-dementia agents is completely unknown.

Also, International Patent Application Publication No. 88/8424 describes 1,2-ethanediol derivatives used in the treatment of Alzheimer's disease and other degenerative neurological disorders. However, in that specification, there are no 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 compound useful as a brain function improving agent for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's disease, sequelae of ischemic brain injury, and stroke has not yet been found.

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

[Means for Solving the Problems] As a result of intensive research aimed at solving the above problems, the present inventors found that the following general formula []: In the formula, R1, R2, l('', R', R'', R6 and n each have the same meanings as above.'' A novel 1,2-ethanediol derivative and its salt exhibits excellent anti-amnestic and anti-hypoxia effects. They discovered that it is extremely useful as a brain function improving agent, and completed the present invention.

In addition, the term "brain function improving agent" in this specification is used not only as a normal brain function improving agent useful for the treatment of sequelae of ischemic brain injury and stroke, but also for amnesia and dementia (e.g., cerebrovascular disease). It refers to a therapeutic or preventive agent for sexual dementia, various senile dementias, Alzheimer's disease, etc.).

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, a methyl, ethyl, rhopropyl, isopropyl, n-butyl, isobutyl, tert-butyl, pendel, and hexyl group. A lower alkenyl group refers to an alkenyl group such as vinyl, propenyl, butenyl, benzonyl d3 and hexenyl; a lower alkenyloxy group refers to an alkenyl group such as vinyl, propenyl, butenyl, benzonyl d3 and hexenyl group; -6 0- group; cycloalniyl group refers to, for example, cyclopropyl, cyclobutyl, cyclopendel, and cyclohexyl groups; 3-6 alkyl group; lower alkoxy group refers to C1-6 alkyl group; 〇- group; lower alkylthio group refers to Cal: 1-8- group; aryl group refers to 1-6 phenyl, naphthyl, indanyl, and indenyl group; aryloxy group refers to aryl-O group The lower alkyl group refers to an alkyl group such as benzyl, diphenylmethyl, trityl, and phenethyl; the lower alkoxy group refers to an alkyl-1 to 4 〇- group; Al lower alkylthio group means Al C1-4
Alkyl-8- group; lower alkylenedioxy group is
For example, C alkylenedioxy groups such as methylenedioxy and ethylenedioxy groups;
C1-6 acyl groups such as acetyl and butyryl;
Aroyl group refers to aryl-C〇- group; lower alkylsulfonyl group refers to C1-6 alkyl-502- group;
The lower alkylsulfonyl group refers to the alkyl5O2- group; the arylsulfonyl group refers to the aryl5O2- group; the lower alkylsulfonyloxy group refers to the 01-6 alkyl so2-o- group. ;Arylsulfonyloxy group, hourly 5o2-0-18
;Arylsulfonylamino group is aryl-3O
2NH- group: lower alkyl sulfur 1 to 6 SO2NH- group; di-lower alkylamino group means di-C
Alkylamino group: ammonio group and 1 to 6 are tri-lower alkylammonio groups such as trimethylammonio and trimethylammonio group:
The nitrogen-containing heterocyclic group is, for example, pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, te]herahydropyridyl, tetrahydroisoquinolinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, te]hera. Hydroquinolinyl, quinuclidinyl, deazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,
Purinyl or imidazolinyl contains one or more nitrogen atoms as heteroatoms forming the ring, and generally contains one or more r! 5 which may contain an i element atom or a sulfur atom
The heterocyclic group refers to a six-membered ring, a fused ring, or a bridged ring heterocyclic group. Nil, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, penzokylyzolyl, benzothiazolyl, dihydrokyzolyl, quinoxalyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzopyrrolyl, 2,3-dihydro-
4-day-1-thia J-phydyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2.3
-a]Pyridyl, benzolb]piperazinyl, chromenyl, isothiazolyl, isoxasilyl, oxadiazolyl, ridazinyl, isoindolyl and isoquinolyl groups, etc., containing one or more oxygen or sulfur atoms as a heteroatom forming the ring. a 5- or 6-membered ring, fused ring, or bridged ring heterocyclic group containing at least one heteroatom selected from nitrogen, oxygen, or sulfur atoms; The carbonyl group means a heterocyclic -〇〇- group.

Examples of substituents for the naphthyl, indanyl, indenyl, or tetrahydronaphthyl group in R1 include:
Halogen atom, optionally substituted amino, lower alkyl, aryl, lower alkyl, lower alkoxy,
al-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower al-lower alkyl, al-lower alkylthio, al-lower alkylsulfonyl, lower alkylsulfonylamino, arylsulfonyl, arylsulfonylamino or heterocyclic group or protection Examples include protected amino groups, protected hydroxyl groups, dioxygen, oxo groups, and lower alkylenedioxy groups;
Lower alkyl, aryl, al-lower alkyl, lower alkoxy, al-lower alkoxy, aryloxy, carbamoyloxy, 1 as a substituent of Uzidronaphthyl group
As a substituent for alkyldio, lower alkenyl, lower alkenyloxy, al-lower alkylthio, al-lower alkylsulfonyl, lower alkylsulfonylamino, arylsulfonyl, arylsulfonylamine or heterocyclic group and the nitrogen-containing heterocyclic group in R6: , a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, a lower alkyl group optionally substituted with an optionally protected hydroxyl group, Aryl group optionally substituted with halogen, aroyl group optionally substituted with halogen, lower alkoxy group optionally substituted with lower alkoxy group, lower acyl group, al lower alkyl group, al lower alkenyl group, Examples include a heterocyclic group, a heterocyclic -CO- group, an oxo group, a lower alkylsulfonyl group, and an arylsulfonyl group, which may be substituted with one or more of these substituents.

In addition, the amino group in the substituent of R1 and the substituent of the amino group in R6 include an optionally protected hydroxyl group, a cycloalkyl group, an optionally protected hydroxyl group, and an optionally protected carboxyl group. Optionally substituted lower alkyl group, aryl group, lower acyl group, lower alkyl group, heterocyclic group, heterocyclic -CO- group optionally substituted with oxo group, adamantyl group, lower alkylsulfonyl and arylsulfonyl groups, which may be substituted with one or more of these substituents.

In addition, as the hydroxyl protecting group and the protecting group for the hydroxyl group, carboxyl group, and amino group in the substituents of R2 explained above, Protective Groups in Organic Synthesis (Protectec
tive Groups in OrganicSyn
Theis), Theodora W. Green (1981), John Wiley & Sons, I
nc, )], and examples thereof include the usual protecting groups for hydroxyl 11-base, carboxyl group, and amino group, and in particular, as protecting groups for hydroxyl group, for example, lower alkyl, lower acyl, and 2-tetrahydropyranyl group. and lower alkyl groups such as benzyl which may be substituted.

The salt of the 1,2-ethanediol derivative of tI] may be any pharmaceutically acceptable salt, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; formic acid , with carboxylic acids such as 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 Fukudai [I] or its salt, the present invention covers all of them. It includes isomers and also includes hydrates, solvates and all crystalline forms.

Next, a method for producing a 1,2-ethanediol derivative or a salt thereof will be described.

- The 1,2-ethanediol H form or a salt thereof in Clothing Cost [1] can be produced by methods known per se or by appropriately combining them, for example, by each production method shown below.

(Left below) [Vll rV] or its salt [Ib] or its salt EXll or its salt]) Icl or its salt [XN] or its salt rIdl or its salt 1 In the formula, R1, IR2, R3, R4, R5, R6 and n each have the same meaning as described above; R2a
is the same hydroxyl protecting group as R2; R6a is R
Among the optionally substituted nitrogen-containing heterocyclic groups similar to 6, a group having 11 Kyoko on the carbon atom forming the ring;
6b is an optionally substituted nitrogen-containing heterocyclic group similar to R6, a group having a free monovalent valence on the nitrogen atom forming the ring, or an optionally substituted amine group;
Hydroxyl retention II similar to 1<2:X and ×2
are the same or a halogen atom; Y is a leaving group such as a halogen, a lower alkylsulfonyloxy group or an arylsulfonyloxy group; Y is an arylsulfonyloxy group; and m is 1 Each represents an integer between 6 and 6. ” Also, - Clothes [I[1], [1[1al, [IV], [
Vl, [Vl], [IX], [X], [x1], [X
11. Examples of the salts of the compounds of [XM], [Ial, [Ibl, [IC] and [Idl] include the same salts as the salts of the compound of -Fukudai [I].

Next, each manufacturing method described above will be explained.

Production method 1 By reacting a compound of general formula [I] with a compound of general formula or a salt thereof, or a compound of general formula [I[1al] or a salt thereof, in the presence or absence of a base, - A compound of Fukudai [Ial or a salt thereof can be produced.

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. Further, a compound of -Fukudai [I11] or a compound of general formula [I[1aJ] can also be used as a solvent.

In addition, examples of bases that may be used as necessary include sodium hydride, thorium chloride, and tert-
Examples include buI and xicalium.

In this reaction, use of a compound or a salt thereof of the general formula [I[1] or a compound or a salt thereof of the general formula [I
00 times the molar amount, preferably 1 to 10 times the molar amount.

Further, the amount m of the base used if necessary is 0.01 to 1.2 times the mole of the compound of -Fukudai LH].

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.

By reacting the compound of general formula [IV] or a salt thereof with the compound of Fukudai [n] in the presence or absence of a base, the compound of -Fukudai [Vl or The salt can be manufactured.

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

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

(2) By subjecting the compound of -Fukudai [VI] or its salt to a usual hydroxyl group protection reaction, the compound of -Fukudai [VI] can be prepared.

The obtained compound of general formula [VI] has a single lit! It may be used as is in the reaction without adding.

Zarani, by subjecting the compound -Fukudai LVI] to a selective elimination reaction of the didroxyl protecting group, -Fukudai [VI
A compound or a salt thereof can be manufactured and sold.

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

These reactions can be performed using methods known per se, for example, 10 DekDip Groups in or Organic Synthesis.
ganicSyntllesis), [Theodora W. Green]
(1981), John Wiley &amp;
The method described in Fx 5ons, Inc.) or a method similar thereto may be used.

The combination of hydroxyl protecting groups (R7 and R2a) used in these reactions may be selected as appropriate.

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

The 1d medium used in this reaction may be any one that does not adversely affect the reaction, such as halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; and amides such as N,N-dimethylformamide.
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]launch-7-
Organic or inorganic bases such as ene (DBU), pyridine, potassium tert-butoxy, sodium carbonate, potassium carbonate and sodium hydride may be mentioned.

Examples of the halogenating agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, and thionyl 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 at least the same molar amount, preferably 1 to 2 times the molar amount, relative to the compound or salt thereof, respectively. be.

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

The compound of general formula [■] obtained by 1q may be used as it is in the next reaction without being isolated.

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

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

Further, examples of the catalyst that may be used as necessary include potassium iodide and 1 to lium iodide.

The amount of catalyst used as needed is - clothing cost [■]
The amount is 0.1 to 1 times the mole 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 or its salt or the base used if necessary is at least the same mole, preferably 1 to 2 moles, relative to the compound of -dose [■].
It is 0 times the mole.

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

By reacting the compound of general formula [XI or a salt thereof with the compound of Fukudai [II] in the presence or absence of a base, the compound of Fukudai [XI] or The 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 [XI[] or its salt 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 mentioned in (3) above can be mentioned.

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.

Examples of the sulfonylating agent include p-toluenesulfonyl chloride.

The amount of the sulfonylating agent and the base used as necessary is 0.95 times or more, preferably 1 to 2 times the mole of the compound or salt thereof, respectively.
It is twice the mole.

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

1q The compound of general formula [X1] or its salt is a single 1S11t! It may be used as is in the reaction without adding.

(3) The compound of -Fukudai [XI] can be produced by subjecting the compound of -Fukudai [X[] or a salt thereof to a usual hydroxyl group protection reaction.

This reaction can be carried out using methods known per se, such as Protective◆Groups in Organic Synthesis (P
rotective Groups in Kano Gani
cSynthesis), [Theodora W. Green (198
1 year), John Wiley & Sons, Inc.
, Inc. )] or a method similar thereto.

The resulting compound of general formula [X[Il] was isolated I! It may be used in the next reaction as it is.

(4) - By reacting the compound of the general formula [IX] or its salt with the compound of the general formula [IX] or its salt in the presence or absence of a base, - A compound of Fukudai [Icl 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 [V] with the compound of Ippukudai tXV], 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, such as ethers such as diethyl ether, tetrahydrofuran, 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 -Fukudai [XV] to be used is 0.8 to 100 times the mole, preferably 0.8 to 10 times the mole of the compound -Fukudai E store].

Further, this reaction may be carried out normally at -78°C to 100'C1, preferably -78°C to 50°C for 5 minutes to 24 hours.

The obtained general formula [X')! ] or its salt is,
Single 111t! It may be used in the next reaction as it is.

The compound of general formula [XV] used here can be prepared by a method known per se, for example, Bredein 1-U Sociede Simic de Furan L7 (BtJII).

Soc, Chim, Fr, ), 1967(5),
It can be produced by the method described on pages 1533-1540.

(2) - Reacting the compound of general formula [IX] or its salt with the compound of [X'il] or its salt in the presence or absence of a catalyst and the presence or absence of a base. By this, a compound of -Fukudai [Idl 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; for example, halogenated hydrocarbons such as methylene chloride and chloro[1-form]; ethers such as tetrahydrofuran and di-Axane; ; Alcohols such as ethanol, propatool and butanol; Nitriles such as aretonitrile; and N
, amides such as N-dimethylformamide, and the like, 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 necessary is:
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 those mentioned in (3) of the above-mentioned production method 2, and the base used is the compound of -Fukudai [IX] or its salt. You can also do that.

- The amount of the compound or salt thereof in Fukudai [IX] or the base used if necessary is at least the same mole, preferably 1 to 1 molar, relative to the compound or salt thereof in -Fukudai [XM] It is 20 times the molar amount.

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

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 [i], [I[1] in each production method described above
, [[[1al, [IV], [J], [Vl ], [V
1 [], [■], [IX], [X], [X! ], [X
In the compounds of hydrates, solvates and all crystalline forms can be used.

General formula [11], [I[l], [l[Ial, [I
V], [Vl, [VI], [VI], [■1, [IX
], [IX], [store], [store], [XV], [XM]
, [I], [Ial, [Ibl, [IC] and [
In the Idl compound, the compound having a hydroxyl group, amino group or carboxyl group must be protected with a conventional protecting group, and after the reaction, if necessary, the compound itself can be protected. These protecting groups can also be removed by known methods.

The 1,2-ethanediol derivative of general formula [I] or its salt thus obtained 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 [I] can be used, for example, in oxidation reactions, reduction reactions, addition reactions, acylation reactions, alkylation reactions, sulfonylation reactions, deacylation reactions, substitution Other 1,2-ethanediol derivatives of general formula [I] or salts thereof can be derived by appropriately combining methods known per se, such as reactions, dehydration reactions, and hydrolysis reactions.

In addition, the compound of [Ippukudai LII] which is the original illumination for producing the compound of the present invention can be prepared by a method known per se, for example,
Journal on American Chemical Society (JAC3), Volume 87, Page 1353 (1965)
), New Experimental Chemistry Course, Volume 14, Page 579 (197
7 years, round neck) etc.

When the compound of the present invention is used as a medicine, pharmaceutically acceptable excipients, carriers, diluents, and other formulation aids may be mixed as appropriate, and these can be prepared into tablets, capsules, powders, and granules by conventional methods. It can be administered orally or parenterally in the form of fine granules, pills, FJ suspensions, emulsions, solutions, syrups or injections. In addition, the administration method, dose, 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 administered to an adult with an IQ of 1[''0.01 to 500]. It may be administered in several divided doses.

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

In addition, the test compound numbers used in the following pharmacological tests are the compound numbers in Examples.

1. Anti-hyboxia effect 100 mFI/Kg 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 (or 30 minutes) after administration, mice were placed in a 300 m glass container, and a gas mixture consisting of 4% oxygen and 96% nitrogen was injected into the glass container for 51 minutes.
Aeration was performed at a rate of /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 from the following formula: Survival time of mice in the administration group Survival time of mice in the control group x 100 (%).

The results are shown in Table-1.

(Left below) 2. Anti-amnestic effect a) Electroshock (EC3) induced amnesia model 1 group 1
A test compound dissolved in physiological saline was intraperitoneally administered to 0 ddY male mice (5-6 weeks old), and 1 hour after administration, the mice were subjected to a step-through (Ste.
p-through) type passive avoidance training box (HPA-1
008, manufactured by Muromachi Kikai Co., Ltd.), and when it enters the proton, the girodine door is closed, and after 0.5 seconds, the current (to 1.6 m, 3
Acquisition trials are performed by energizing the grid on the floor for 2 seconds), followed immediately by an EC3 (to 25 m, 0.5 seconds) via both eyes.
was loaded.

As a test trial, the mouse was reintroduced 24 hours later, and the time taken for the mouse to insert its limb into the proton (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 symbols.

10~60 seconds +261~100 seconds++:
101-150 seconds +++: 151-300 seconds The results are shown in Table-2.

Table-2 (blank below) / b) Cyclobeximide
Induced Amnesia Model It has been reported by Demae 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 cm, a width of 22 cm, and a height of 21 cm, the body part of which was made of a stainless steel grid, with an IX 7 cm in one corner of the grid on the floor.
Step down with a platform 7cm wide and 2cm high (
A step-down passive avoidance training box was used.

Cycloheximide (120 m
! J/Kg> is administered subcutaneously, and 15 minutes after administration, the mouse is placed on the table in the above apparatus. Immediately after the mouse lands on the floor 2
Acquisition trials were performed by applying mA current to the floor grid for 2 seconds and immediately returning the mouse to the home page.・As a trial, 24 hours later, each test compound dissolved in physiological saline was orally administered to cycloheximide-treated mice, and 30 minutes after administration, the mice were placed on a platform in the above apparatus. The time it took for the robot to get off the platform (reaction latency) was measured for a maximum of 300 seconds.

A control in which only saline was orally administered? Response latencies were measured in the same manner for iY mice.

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

20 to 60 seconds +: 61 to ioo seconds++:
101 to 150 seconds +++: 151 to 300 seconds The results are shown in Table 3.

(Margins below) Table 3 3. Acetylcholinesterase inhibitory effect Eelman (
Ellman et al.'s method [Biochemical)? -ma'
: J Logy (Biocbem, Pllarmacol
), Vol. 7, pp. 88-95, 1961].

i.e., 5.5-dithiobis-(2-nitrobranchoic acid) [DTN8], aletylthiocholine as a substrate in a phosphate buffer containing the test compound and mouse brain homogenate as a source of acetylcholinestera. was added, incubated, and the produced 5-thio-2-nitrobenzoic acid was measured at 412.

The acetylcholinesterase inhibitory activity was expressed as the inhibition rate when the final concentration of the test compound was 10 mg///IN.

The results are shown in Table-4.

(Margins below) (Margins below) Table 4 4. Acute toxicity The test compound dissolved in physiological saline was intravenously administered to 3 LIdY male mice (5 to 6 weeks old) in group 1. , acute toxicity was investigated.

As a result, test compound number 2.8.9.13.24.2
9.52.56 and 82 compounds are 50 mH/9
No cases of death were observed.

From the above test results, it can be easily understood that the compound of the present invention exhibits excellent antihypoxia action, antiamnestic action, and aredercholinesterase inhibitory action, and has low toxicity.

Based on these results, the compound of the present invention can be used as a brain performance improving agent to treat cerebrovascular dementia, senile dementia, Alzheimer's disease, post-ischemic brain injury, and cerebral palsy. can.

[Effect of the Invention] Therefore, it is clear that the compound of the present invention is an extremely useful compound as a brain function improving agent.

[Examples] Next, the present invention will be explained by giving examples and formulation examples.

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

Furthermore, the abbreviations used below have the following meanings.

Me: methyl; E't: ethyl; 1-pr: isopropyl; Bz: benzyl; IPA: isopropyl alcohol;

Furthermore, since the substitution position on indene in Compound Nos. 70 and 71 is unknown, the estimated bonding position was used and it was written as inden-6-yl.

(Left below) Example 1 Potassium tert-butoxy 13.2S? # and 2-
(N.

A mixture of 47.2d of N-dimethylamino)ethanol'
E: 80'C15 warmer! ,2-(1-naphthyl)
40.09 g of oni-1-silane is added dropwise over a period of 3.5 hours, and the resulting mixture is further stirred at 80-85°C for 1.5 hours.

The reaction mixture was then cooled and introduced into a mixture of 100 uf of ethyl acetate and 100 nrll of ice water and 6NJ!
After adjusting the pH to 11.5 with M, the organic layer is separated.

The aqueous layer is further extracted with 50 d of ethyl acetate. The extract is combined with the previously separated organic layer, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 1 q of the residue is distilled to separate a fraction having a boiling point of 152 to 163°C, 10.6 to 0.8 mHg. The obtained oil was dissolved in 200 d of acetone, and hydrogen chloride gas was introduced into this solution while cooling with water. The precipitate was collected for i months, washed with aretone, and dried to give 2-[2-(N,N dimethylamino)-1-xy]-1-(1-naphthyl)ethanol hydrochloride (compound number' 1) 22.7SJ by 1.

Melting point: 196-197°C [EtOH] In the same manner, the compounds shown in Table 5 are obtained.

Nao, R1, R2, R3, R4a, R4b in Table-5,
R6, na and h nbLt, :tn-en,') Ki (
7) Indicates the substituent or integer of the formula.

(The following is a blank space) / / / Example 2 (1) 2- and do[1-xymethyl-4-tridelmorboline 6, OCJ, tert-bu1-xypotassium 1.0
gJ:j and dimethyl sulfoxide 6Inf! The mixture was heated to 80°C, and a solution of 6d dimethyl sulfide containing 2.89% of 2-(2-butyl)Δ21nidyrane was added at 80-85°C for 2 hours. After further stirring at the same temperature for 3 hours, the reaction mixture was cooled and added with 60ml of ice water and 60ml of ethyl acetate.
into the mixture. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure, oily 1-(2-naphthyl)-2-[(4-tritylmorpholin-2-yl)methoxy]ethanol (Compound No. 27) 9.0
(J is subtracted by 1q.

Similarly, oily 1-(1-naphthyl)-2-[(4
-tridelmorbolin-2-yl)methoxy]ethanol (compound no. 28) is obtained.

(2) 1-(2-naphthyl)-2-[(4-tritylmorpholin-2-yl)methoxy]ethanol 9.0
9 was dissolved in acetone 5 (7), and 5 was added to this solution under water cooling.
．． 9N dry hydrogen chloride-ethanol? '8 io3.57
! is added and the resulting mixture is stirred at the bottom for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, 50 parts of water and 30 parts of ethyl acetate are added to the '+Cf-diluted residue, and the aqueous layer is separated. The separated aqueous layer is washed with 30 ml of 1 tyl acetate.

Next, 50 d of ethyl acetate was added to the washed aqueous layer, the pH was adjusted to 5 with potassium carbonate, and the organic layer was 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, and the resulting residue is purified by column chromatography (eluent: chloroform:methanol = 5:1).
1.2 g of oil are obtained. The obtained oil is dissolved in 5 ml of isopropanol, and 0.59 g of fumaric acid is added to this solution and dissolved by heating. If the 1q solution is allowed to stand overnight and the precipitated product is taken off, 1-(2-naphthyl)-2-
[(morpholin-2-yl)methoxy]ethanol 1
72 ・Fumarate (compound number 29) 0.9 cJ
get.

Melting point: 141-144°C Similar to [EtOH], amorphous 1-(1-naphthyl)2-dimorpholine-2-
yl) methoxy] ethanol hydrochloride (compound number 30
).

Example 3 (1) A mixture of tert-71 to xypotassium 4.5!7 and eboulene glycol 1-ol 457 was heated to 80°C, and 13.7 g of 2-(1-naphthyl)A xylan was obtained.
was added dropwise over a period of 1 hour, and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture is then cooled and introduced into a mixture of 50 m of ethyl acetate (Bll and 50 rnl of ice water!) and the organic layer is separated. The aqueous layer is further extracted twice with 20 m of ethyl acetate (1 each time). Combined with the previously separated organic layer, washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. Under reduced pressure)
The solvent was distilled off, and the resulting residue was purified by column chromatography (eluent: toluene ethyl diacetate = 1:3) to obtain 2-(2-hydroxyl-oxy)-1-(
8.39% of ethanol (1-naphthyl) is obtained.

Melting point; 91-92°C [, I PE] Similarly, 2-(2-hydroxyethyl!-xy)-1-
Remove (2-naphthyl)ethanol.

Melting point; 105-100°C [Ac0E t ] (2)
2-(2-HydroxyE1-21-di)-1-(1
- naphthyl) ethanol 8.39 to pyridine 50 ml (l
Cool 11L of solution d to 25°C, add 6.8g of toluenesulfonyl chloride, and let the 1q liter mixture stand at 0 to 5°C for 24 hours, then leave it for 4 hours in the groove. do. Then, the reaction mixture was introduced into a mixture of 87 ml of 6N hydrochloric acid, 50 ml of ice water, and 100 ml of diethyl ether, and after adjusting the pH to 2.0 with 6N hydrochloric acid, the organic layer was separated. Add 20ml of diethyl ether to the aqueous layer.
Extract with Combine the extract with the previously separated organic layer,
After sequentially washing with 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 = 10:1) to obtain 1 as a colorless oil.
-(1-Nophthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy] 6.3 CJ is weighed for 1 q.

Similarly, a colorless oily 1-(2-naphthyl)-2-[
2-(pt~luenesulfonylAxy)ethoxy]ethanol is obtained.

(3) 1-(1-naphthyl)-2-[2-(p-
1-luenesulfonylΔxy) 1-xy]ethanol 6.3g, 3,4-dihydro-2H-pyran 2.97r
The military added 0.827 g of pyridinium toluene sulfonate to a solution of 63 g of methylene chloride in which TDL was dissolved.
was added, and the resulting mixture was heated at the same temperature for 20 minutes, and for an additional 3
Stir for 10 minutes at 5-40°C. The reaction mixture is then cooled, washed with water, and then 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 = 10:1) to obtain 1-(1-naphthyl)-1-(tetrahydrocarbon) as a colorless oil. pyran-2-yloxy)
1 q of -2-[2(p-toluenesulfonyloxy)-1-oxyJ ethane 7.539.

Similarly, a colorless oily 1-(2-naphthyl)-1-(
Tetrahydropyran-2-yloxy)-2-t2-
(p-Toluenesulfonyloxy)ethoxy]ethane is obtained.

(4) 1-(1-naphthyl)-1-(de1-lahydrobilan-2-yloxy)-2-[2-(p-!-ruenesulfonyl Axy)-1-xy]ethane 7.59,
N-Methylpiperazine 2.65mL Potassium carbonate 3.9
A mixture of 6g and N,N-dimethylformamide 38me is stirred at 90-100°C for 2 hours. Then, the reaction mixture was cooled and diluted with 100 m1iJ of diethyl ether.
3 and 100 ml of ice water.
Separate the layers. Add the aqueous layer to 25 m of diethyl needles (
! Extract twice each. 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 resulting residue was purified by column chromatography (eluent: chloroform:ethanol = 10:1) to obtain 2-[2-(4-methylpiperazine-) as a colorless oil.
1-yl)ethoxy]-1-(1-naphthyl)-1-(
1 q of 3.36 g of tetrahydropyran-2-yloxy)ethane (compound number 31) is weighed.

(5) 3.3 g of 2-[2-(4-methylpiperazine-coyl)■1-xy]-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)ethane was added to Are1-30 To this solution was added 3.4 g of p-+ luenesulfonic acid monohydrate and 7 d of water, and the resulting mixture was boiled roughly at 1 B degree for 30 minutes.
Stir at 0°C for 1 hour. The reaction mixture was then introduced into a mixture of 60 parts chloroform and 60 parts ice water, and 10%
After adjusting to pllll with an aqueous sodium hydroxide solution, the organic layer is separated. The aqueous layer was further extracted with 20 parts of chloroform. The extract is combined with the previously separated organic layer, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 40ml of acetone.
U is dissolved in U, and hydrogen chloride gas is introduced into this solution under water cooling. After stirring the solution for 30 minutes overnight, 40 ml of diethyl ether was added, and the resulting mixture was further stirred at the same temperature for 30 minutes. Next, the precipitated amount is collected in a furnace, washed with acetone, and dried to obtain 2-12 (
4-methylpiperazin-1-yl)-
2.359 of the di-JWM salt of 1-(1-naphthyl)ethanol (compound no. 32) is obtained.

Melting point; 230.5 to 231.5°C [MeOH
] Example 4 2-(2-[4-( p-fluorobenzoyl)piperidin-1-yl]ethoxy]
-1 q of hydrochloride of 1-(1-naphthyl)ethanol (compound number 33) is taken.

Melting point: 204.5-205.5°C [MeOH] Example 5 l-(1-naphthyl)-1-(tetrahydropyran-2
-yloxy)-2-[2-(p-toluenesulfonyloxy)toxy]ethane (2 g) and 20 m (l
6.60% of a 40% aqueous methylamine solution is added to this solution, and the resulting mixture is refluxed for 1 hour. The reaction mixture is then cooled and introduced into a mixture of 20 ml of ice water and 50 ml of diethyl ether, and the organic layer is separated. Add the aqueous layer to diethyl ether 207
! Extract with Combine the extract with the right 1jN layer separated earlier, add 15 m5 of water, adjust the pH to 1.5 with 6N hydrochloric acid, and separate the aqueous layer.

The organic layer is further extracted twice with 107 parts of water. The extract was combined with the previously separated aqueous layer, 25 ml of chloroform was added, and the pH was adjusted to 1 with 10% aqueous sodium hydroxide solution: A
After adjusting, separate the organic layer. The aqueous layer is further extracted twice with 10 ml portions of chloro7drum. The extract is combined with the previously separated organic layer and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 1.27 g of oil is reduced to 1.
qru. Attach this oily substance? I-n107! Hydrogen chloride gas is introduced into this solution d under water cooling. Add 10 d of diethyl ether to this and take off the precipitate to obtain 2-[2-(N-methyl)7mino)ethoxy]-1
-(1-naphthyl)ethanol hydrochloride (compound no. 3
4) Obtain 0.72g.

Melting point: 137.5-139°C [IPA] Compounds shown in Table 6 are obtained in the same manner.

In addition, R1, R2, R3, R48, R4b in Table-6,
R6, a and nb each represent a substituent or an integer of the following formula.

(Leaving space below) Example 6 A mixture of tert-bu1 to pericypotassium 3.5 CJ, N-tridelethanolamine cyto50d was heated to 85°C, and 5.39 g of 2-(1-naphthyl)2-xylan was added. , the resulting compound) is stirred at the same temperature for 5 minutes. The reaction mixture is then cooled and introduced into a mixture of t00 mN of ethyl acetate and 150 d of ice water, and the organic layer is separated. The aqueous layer is further extracted with 50 ml of ethyl acetate. Extraction) The extract was combined with the previously separated organic layer, washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, add 80% of a 50% formic acid aqueous solution to 1q of the residue.
ml and 40 ml of tetraditrofuran are added and the resulting mixture is stirred at 50-60°C for 1 hour. Then,
After the reaction mixture was flushed with cold Nl, the solvent was distilled off under reduced pressure.

60 d of ethyl acetate and 60 d of water were added to the residue, and after adjusting the pH to 112 with 6N hydrochloric acid, the aqueous layer was separated. The organic layer is extracted twice with 15 ml each of water.

Combine the extract with the previously separated aqueous layer and add chloroform 1
00ml and then pHIO,5 with potassium carbonate.
After adjusting the amount, separate the organic layer. After washing the organic layer with water, it is dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 10 ml of diisopropyl ether is added to 1 q of the residue. The precipitate was collected and dried to obtain 1.8 g of 2-(2-amineethoxy)-1-(1-naphthyl)ethanol (Compound No. 40).

Melting point: 89.5-92°C [CHCl3-Et,
O] Example 7 After adding 7 d of water and 7 ml of dioxane to 0.7 g of 2-(2-amine ethoxy)-1-(1-naphthyl)ethanol and dissolving it, and adding 0.32 g of potassium carbonate to this solution, , raise the temperature to 50°C. Then, 0.35 g of 2-chloropyrimidine was added and the resulting mixture was
After refluxing for an hour, add 0.329 i of potassium carbonate
Add r3 and 0.35':J of 2-chloropyrimidine and reflux for 5 hours. Cool the reaction mixture and add 20 mf of ethyl acetate! and after introduction into a mixture of ice water 20 mN,
Separate the organic layer. The aqueous layer was further extracted with 10 parts of ethyl acetate. Combine the extract with the organic layer separated earlier and add 1 part of water.
After adding 5d and adjusting the pH to 1.5 with 6N salt M, the aqueous layer was separated. Roughly extract the organic layer with 10 parts water. The extract was combined with the previously separated aqueous layer, 50 ml of methylene chloride was added, and then pHIO was added with potassium carbonate.
5, then separate several layers (right).The separated organic layer is washed with water and dried over anhydrous magnesium sulfate.The dissolved zH is distilled off under reduced pressure, and the resulting residue is subjected to column chromatography. Graphography (eluent; chloroborum: ethanol = 2
0:1). Add 4 ethanol to 1 q of oily substance
d and 0.21 g of maleic acid were added, and the resulting mixture was stirred for 1 hour at ¥ temperature, and then 2 m of diethyl ether was added.
I! and stirred at the same temperature for 1 hour. If the precipitated product is taken in a furnace and dried, 1-(1-naphthyl)-2(2-L (
1 q of 0.53 g of maleate salt of pyrimidin-2-yl)amino-1-ethoxy)ethanol (compound number 41) is weighed.

Melting point: 101.5-103°C [EtOH-ACO[
Pretext Overwhelming 8 In a mixture of 0.79 2-(2-aminoethoxy)-1-(1-naphthyl)ethanol, 0.379 nicotinic acid, 0.41 g of 1-hydroxybenzotriazole, 0.42 ml of triethylamine and 4 d of tetrahydrofuran, While cooling with water, 0.62!7 of N,N"-dicyclohexylcarbodiimide was added, and 1 q of the mixture was stirred at the same temperature for 5 minutes and then at the same temperature for 1 hour.

Then, after adding 6 d of ethyl acetate to the reaction mixture, insoluble materials were removed. Add 15 d of ethyl acetate and 2 d of water to the solution.
After adding 0d and adjusting the pH to 112 with 6N hydrochloric acid, the aqueous layer was separated. The organic layer is roughly extracted twice with 10 d each of water. The extract was combined with the previously separated aqueous layer, 30 mA of chloroform was added, and the mixture was saturated with potassium carbonate.
After adjusting to 5, the organic layer is separated. 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 L3: ethanol =
10:1). Add 7 m of acetone to the obtained oil.
To this solution was added 0.43 d of 5N dry aqueous chloride-ethanol solution, and the resulting mixture was stirred for 1 hour.
was added, and the resulting mixture was stirred and covered for 1 hour at the same temperature. If the precipitated crystals are collected and dried, 1-(1-naphthyl)-2
-[2-codinoylamino)ethoxy]ethanol hydrochloride (compound number @42) 0.677 is obtained.

Melting point: 162.5-163.5°CtEt-AcOE
Example 9 2-(1-naphthyl)oxirane and 1,4-diformyl-2-piperazine methanol were substituted for 2-(2-naphthyl)oxirane and 2-hydroxymethyl-4-tritylmorboline, respectively. Example 2 (1)
U, oily 2-[(1,4-diformylpiperazin-2-yl)methoxy]-1-(1-
Naphthyl) ethanol (Compound No. 43) is obtained.

Similarly, the compounds shown in Table 7 are obtained.

In addition, R1, R2, R3,1<4R6 and n in Table 7 do not each represent a substituent or an integer in the following formula.

Example 10 2-[(1,4-diformylpiperazin-2yl)methoxy]-1-(1-naphthyl)ethanol 250 mg
) in 1.5 ml of methanol, and add 5N to this solution.
Add 1.5 ml of dry hydrogen chloride-ethanol solution and add 1 q
Leave the mixture in place overnight.

The precipitated crystals are collected, washed with ethanol, and dried to form the di-Jil salt of 1-(1-naphthyl)-2-[(piperazin-2-yl)methoxy]ethanol (compound number 4).
7) Take 1q of 180 mg.

Melting point: 199-201°C (decomposition) Example 11 A compound obtained by 1q in the same manner as in Example 2 (1) was reacted with JXA hydrogen hydride gas in the same manner as in the hydrochloride manufacturing process of Example 8. Take 1q of the compound in Table 8.

In addition, R1, R2, R3, R4R6 and n in Table-8
each represents a substituent or an integer of the following formula.

(The following is a blank space) Example 12 The compounds in Table 9 were treated in the same manner as in Example 2 (1) and (2).

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

(Left below) Example 13 2-(imidazol-5-yl)methoxy-1-(1-
By reacting methyl iodide with (naphthyl)ethanol, an oily 2-(1-methylimidazol-5-yl)methoxy-
Take 1 q of 1-(1-naphthyl)ethanol (compound number 56).

Example 14 (1) 6-benzyloxy-2-naphthaldehyde6.
Dissolve 0g in 60ml of tetrahydrofuran, = 30
After cooling to °C, 30 d of a tetrahydrofuran solution containing 1.6 M 2-chloroethyl-oxymethylmagnesium dihydride was added dropwise over 10 minutes, and the resulting mixture was stirred for 1 hour under water cooling. do.

The reaction mixture was then diluted with 100 d of ice water and 10 d of ethyl acetate.
0 d and ammonium chloride, and then adjusted to p112 with 6N hydrochloric acid.
Separate one layer. 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 1q residue was subjected to column chromatography (eluent; 1 to toluene:ethyl acetate=
20:1) to obtain a solid. Add 10 parts of diisopropyl ether to the resulting solid and stir the resulting mixture for 1 EIM at room temperature. The precipitate was collected and dried to obtain 4.7 g of 1(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol.

Melting point: 86-87.5° CLIPE] (2) 1-(6-benzyloxy-2-naphthyl)
-2-(2-chloroni[l ~ 4.5 g of roxyethanol
, potassium iodide 1g, 50% dimethylamine aqueous solution 1
After refluxing a mixture of 0 ml and 20 d of ethanol for 3 hours, 10 d of a 50% aqueous dimethylamine solution was further added, and the mixture was refluxed for 6 hours. The reaction mixture is then cooled and concentrated to about half its volume under reduced pressure. Add 100% ethyl acetate to the concentrate.
d and 100 d of water, and with potassium carbonate I) 110
．． After adjusting to 5, the organic layer is separated.

The separated organic layer was sequentially washed with water A3 and saturated brine, and then dried with anhydrous sulfuric acid magnezine.The solvent was distilled off under reduced pressure, and the resulting residue was mixed with diethyl ether 30
Add m. If the precipitate is collected and dried, 1-(6-
benzyloxy-2-naphthyl)-2-[2-(N,N
-dimethylamine)ethoxy]ethanol (Compound No. 57) 3.97.

Melting point; 100-100.5°C tE to 120] Furthermore, 1-(6-benzyloxy-2
-naphthyl)-2-[2-(N,N-dimethylamino)
If 1-(6-benzyloxy-2-naphdyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol is treated in the same manner as in Example 8, hydrochloric acid The salt (compound no. 58) is obtained.

Melting point: 220-220.5°C [EtOH] Example 15 1-(6-benzyloxy-2-naphthyl)2-[2
-(N,N-dimethylamino)ethoxy]ethanol 3
．． 0 g was suspended in 12 ml of pyridine, and 1.6 d of acetic anhydride was added to this suspension. The resulting mixture was heated at room temperature for 2
After stirring for 4 hours, the solvent was distilled off under reduced pressure. 60 ml of ethyl acetate and 60 ml of water were added to the resulting residue, and the mixture was diluted with potassium carbonate to 1)+110. After adjusting the concentration, separate the organic layer. Add 307 ethyl acetate to the aqueous layer! Extract with The extract is combined with the previously separated organic layer, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in acetone 3 (7), and 5N dry hydrogen chloride was added to this solution.
Add 1.5 ml of ethanol solution and stir at the bottom for 1 hour. If the precipitated crystals are collected and dried, 1-acetoxy-
1(6-benzyloxy-2-naphthyl)-2-[2-
(N,N-dimethylamino)ethoxy]ethane hydrochloride (Compound No. 59) 2.6',j is 1q.

Melting point: 157-158°C [MeCN] Example 1G Salt of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamine)ethoxy]ethane M Salt 2 .0! ? , 0.5973 ml of 5% palladium-carbon and 40 ml of ethanol is hydrogenated at room temperature and pressure for 3 hours. After the reaction is complete, the palladium-carbon is removed and the solvent is distilled off under reduced pressure. Acetone is added to the resulting residue, and the precipitated crystals are collected monthly and dried to give 1-acetoxy-1-(6-hydroxy-2-naphthyl)-2-[2-(N,N-dimethylamino). Engineering]
・Xy1ethane hydrochloride (compound number 60) 0.76
Reduce g by 1q.

Melting point: 150. ! 1-151.5°C [EtOl-(]Example 17 Hydrochloride of 1-acetoxy-1-(6-hydronidi-2=naphthyl)-2-[2-(N,N-dimethylamino)ethoxy-1ethane A mixture of 360 mg, 10 ml of water, and 15 ml of chloroform was adjusted to pH 119 with a saturated aqueous solution of zitorium hydrogen carbonate, and then the organic layer was separated.

The aqueous layer is further extracted twice with 10 parts of chloroform.

The extract is combined with the organic layer separated earlier, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 6 ml of benzene.
was added, and 1 q of the mixture was stirred at 80°C for 4 hours.

The reaction mixture is cooled and the solvent is evaporated under reduced pressure. The 1q residue was purified by column chromatography (eluent: chloroform diethanol-20:1). If the obtained oil is treated in the same manner as in Example 8, amorphous 1-acetoxy-1-[6-(N-ethylcarbamoyl)oxy-2-naphthyl]-2-[2-(N , N-dimethylamino)ethoxy]ethane (compound number 61).

Torari custom 18 In the same manner as in Example 13 (1) and (2), 2-m
2-(N,N-dimethylamino)-oxy]-1-
Take 1q of (8-nitro-1-naphthyl)ethanol. This compound was then reacted with cichoic acid 8 in the same manner as in Example 2 (2) to give 2-[2-(N).

N-dimethylamino)ethoxy]-1-(8-21-rho-1-naphthyl)ethanol oxalate salt (Compound No. 62) is obtained.

Melting point: 150-158.5°C Example 19 2-[2-(N,N-dimethylamino)ethoxy]-1
A mixture of 150 ml of oxalate of (8-nitro-1-naphthyl)ethanol, 150 mg of 5% palladium-carbon and 3 d of methanol is hydrogenated at normal pressure for 30 minutes. Then, the palladium-carbon was removed,
The solvent is distilled off under reduced pressure. (Pour the quenched residue in ice water for 30 minutes.
m1 and chloroform 3 (7), 2N
After adjusting to 1) 811 with an aqueous sodium hydroxide solution, the Ia layer is separated. The separated organic layer is washed successively with water and saturated brine, and then dried over anhydrous 5AWIi magnesium. The solvent is distilled off under reduced pressure, the resulting residue is dissolved in 1 ml of ethanol, and 0.2 ml of 5.9N dry hydrogen chloride-ethanol solution is added to this solution. If the precipitated product is divided into i units and dried, two groups of 1-(8-amino-1-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy 1 ethanol! i salt (compound number 63) 11
Obtain 0 mg.

Melting point: 195-198°C (decomposed) [8 cOEt-Et
] Example 20 1-(8-amino-1-naphthyl)-2-[2-(N,
N-dimethylamino) engineering! Triethylamine was added to the hydrochloride of hexyl-ethanol, and the resulting mixture was reacted with methanesulfonyl chloride to form an oily 2-12-(
1 q of hydrochloride (compound amount @ 64) of N,N-dimethylamino)ethoxy]-1-(8-methylsulfonylamino-1-naphthyl)ethanol.

Example 21 A method similar to Example 14 (1) J3 and (2) using 4-(N,N-dimethylamino)-1-naphthaldehyde instead of 6-benzyloxy-2-naphthaldehyde. reacted with U, oily 1-14- (N,N-
dimethylamino)-1-naphthyl1-2-12- (N
, N-dimethylamino) 1-21] 1 q of ethanol dihydrochloride (compound amount @ 65).

Example 22 1-[4-(N,N-dimethylamino)-1-naphthyl J-2-[2-(N,N-dimethylamine)ethoxy]dibase r1i salt of ethanol 1.37 to Xtanol 13
m1 is added and the mixture is centrifuged for 1 hour. The reaction mixture is cooled and the solvent is evaporated under reduced pressure. A mixture of 20 parts of ethyl acetate and 20 ml of water is added to the obtained residue, and then the pH is adjusted to pHIO with potassium carbonate, and the Ia layer is separated. The separated organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, oily 1-ethoxy-1-L4- (N,
N-dimethylamino)-1-naphthyl]-2-t2-
(N.

N-dimethylamine)ethoxy]ethane (compound number 6
6) 1.3 (J is subtracted by 1n.

Example 23 (1) 9.69 ml of 5-bromo-1-hydroxyindan was dissolved in 100 ml of dry methylene chloride, and 570 mg of pyrinidiram toluenesulfonate and 4.5 me of 3,4-dihydro-2H-pyran were added to 1 liquid of this sweat. It is added at room temperature and the resulting mixture is stirred at the same temperature for 3 hours. The reaction mixture is then poured into ice water and the organic layer is separated. The separated organic layer was washed with 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:dilute acid salt = 15:1) to obtain oily 5-
Bromo-1-(tetrahydropyran-2-yloxy)
Indane 13.19 is obtained.

(2) Under a nitrogen atmosphere, 5-bromo-1-(Te1~
Lahydrobilan-2-yloxy)indane 8.19 is dissolved in anhydrous tetrahydrofuran ioo y, and this)
Add 20 ml of 1.5N n-butyllithium-hexane solution to solution d at -65°C over 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes and then poured with anhydrous N.

Add 2.3 d of N-dimethylformamide. Next, the reaction mixture was heated to room temperature, and then introduced into a mixture of 100 ml of ice water, 100 ml of diethyl ether (and 2 g of ammonium chloride), and the organic layer was separated. After sequentially washing with and saturated brine, dry 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 = 15:1). Then, 6.5 g of 5-pormyl-1-(tetrahydropyran-2-yloxy)indane is obtained.

(3) Instead of 6-benzyloxy-2-naphthaldehyde, 5-pormyl-1-(tetrahydropyran-2
Example 14 (1) using -yloxy)indan
and (2) to form an oily 2-[
2-(N,N-dimethylamino)ethoxy]-1-[1
-(tetrahydropyran-2-yloxy)indan-
5-yl]ethanol (compound number 67) 2.5 g
1 q.

(4) 2.5 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol,
A mixture of 8 ml of acetic anhydride and 0.64 d of pyridine is stirred at room temperature for 1 hour. After introducing the reaction mixture into a mixture of 50 ml of ice water and 50 ml of diethyl ether, the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (solute 11t:lff1:chloroform:methanol=10:1). Oily 1-acetoxy-2-[2-(N,N-dimethylamine)ethoxy]-1-[1-(tetrahydropyran-2-
1.99 of yloxy)indan-5-yl]ethane (compound no. 68) is obtained.

(5) 1-ace1~xy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(te1~rahitropyran-2-ylAxy)indan-5-yl]ethane 1
．． 89 in acetic acid-tetrahydrofuran-water (4:2:1
: volume ratio) and stirred the mixture at 70'C for 2 hours. Cool the reaction mixture and add 100 ml of water and 7! of diethyl ether.
and then diluted with potassium carbonate to pl+8.
After adjusting to 5, the organic layer is separated. After drying the separated organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is purified by column chroma 1-graphie (eluent; chloroform:ethanol = 10:1) to obtain oily 1-at1-xy-1-[(1-hydroxy)indan-5-yl]. -2-[2-(N, N
-dimethylamino)ethoxy]ethane (compound number 69
) obtain 1.09.

(6) Dissolve 1-acetoxy-1-[(1-hydroxy)indan-5-yl]-2-12-(N,N-dimethylamino)-oxy]ethane i,o in 5 ml of pyridine. To this solution was added 0.3 ml of methanesulfonyl chloride, and the resulting mixture was stirred overnight at the same temperature. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of diethyl ether and diluted with potassium carbonate.
After adjusting to 8.5, the organic layer is separated. After drying the separated organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent; chloroform:methanol = 10:1).
When purified, 80 ml of oily 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamine)ethoxy]ethane (Compound No. 70) is obtained.

(7) 8011 g of 1-acetoxy-1-(1H-inden-6-yl)-2-12-(N,N-dimethylamino)ethoxy]ethane and 0.5 m of methanol! ! 80 mg of 28% sodium methoxide-methanol solution is added to this solution d under water cooling. After stirring the 1q radish mixture for 20 minutes under vacuum, the solvent was distilled off under reduced pressure. The 1q residue was purified by column chromatography (eluent: chloroform:methanol = 20:1) to obtain a yellow oil. Next, add 0 ethanol to this
．． 0.1 ml of 5.9N dry hydrogen chloride-ethanol is added to this solution. The precipitated product i
If you have a monthly income, 1-(IH-inden-6-yl)-2-
[2-(N.

N-dimethylamino)ethoxy]ethanol hydrochloride (
Compound No. 71) 20 mg is obtained.

Melting point: 1G8-171℃ (decomposition) [ACOEt-E
t011] Example 24 1-[(1-hydroxy)indan-5
-yl]-2-[2-(N,N,-dimethylamino)ethoxy]ethanol hydrochloride (compound number 72) was added to 1q.
Ru.

Melting point: 150-152°C [IPA] Example 25 2-[2-(N,N-dimethylamino)ethoxy]-1
'-(1-Naphthyl)ethanol hydrochloride is reacted with acetic anhydride in pyridine in the presence of triethylamine to form an oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1- (1-Naphthyl)ethane (Compound No. 73) is obtained.

Example 26 The compound obtained from 2-12-(6-methylnaphthyl)]oxirane in the same manner as in Example 2(1)) was treated with chloride in the same manner as in the process for producing the hydrochloride in Example 8. Hydrogen gas is reacted to form oily 2-[2-(N-methyl-2,
3-dihydropyridine-6day-5-yl)methoxy]-
1-[2-(6-methylnaphthyl)]ethanol (compound amount @74) is obtained.

Example 27 Table 1 was prepared in the same manner as in Example 14 (1) and (2).
Take 1q of 0 compound.

In addition, R1, R2, R3, R4R6 and n in Table 10 each represent a substituent or an integer of the following formula.

(Margins below) Formulation Example 1 (Tablets) 50 mg of 2-[2-(N,N-dimethylamino)]-1-(1-naphthyl)ethanol salt M (Compound No. 1) Tablets containing the following formula are prepared in the following manner.

Per 1 tablet: -905 m3 combined with polyvinylpyrrolidone Old R5mg The mixture of the above component l, 0 tablets into a circular tablet with a diameter of 8 mm.

Formulation example 2 (capsule) 2- [2-(N,N-dimethylamino)ethoxy]-
A caprel containing 1-(2-naphthyl)ethanol hydrochloride (Compound No. 2 > 50 mFJ) is prepared in the following manner using the following formulation.

Per capsule: -905 mg in polyvinylpyrrolidone, total 150 mg The mixture of the above component (■) is mixed with polyvinylpyrrolidone with an 8% aqueous solution of ~90, and after drying at 40 ° C., the component (1) is mixed with i,
150 mg per capsule is filled into No. 3 Zeradin capsules to obtain capsules.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ “In the formula, R^1 is an optionally substituted naphthyl, indanyl, indenyl, or tetrahydronaphthyl group; R^2 is a hydrogen atom or a lower alkyl or 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 represent a hydrogen atom or a lower alkyl group; R^6 is a substituted and n is 0 or an integer of 1 to 6, respectively, and a salt thereof.