DD299960A5 - Process for the preparation of 1,2-ethanediol derivatives and their salts, and agents for improving the cerebral function with a content thereof - Google Patents

Abstract

The invention relates to 1,2-ethanediol derivatives and their salts, processes for their preparation and agents for improving the cerebral function with a content thereof. The cerebral function enhancing agents of the present invention are useful in the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, ischemic encephalopathy sequelae, and cerebral apoplexy.

Description

Characteristic of the known techtilschen solutions

1,2-Ethanediol derivatives are known, for example, those disclosed in US Pat. Nos. 2,928,845; J. Pharm. Sci., Vol. 50, p. 769-7 / 1

(1971); Farmaco. fcd. Sci., Vol. 19, pages 1C5 & 10G5 (1964); etc. are described.

These compounds are pre-sonicated as a local anesthetic. However, it is not known anything about their concern

as a means to improve the corebral function, a! J anti-amnesiomittol or r.ls nootropin agent

WO-No. 88/8424 describes that 1,2-ethanedioluria may have been used to treat the Alzheimer's disease and aidoru

to reduce degenerative neurological disorders. In Mor Login, jedoth koine will special description or example

these derivatives indicated.

Drugs, such as agents to increase corebral metabolism, corebrovasodilato-ene and the like, are now becoming Linda; unp

various dementia conditions, in particular dementia of the Alzheimer type and corobrovoskuliiro demontia,

used.

So far, however, no means has been found to prevent the corooral function, which is used to treat

cerebrovascular dementia, senile dementia, Alzheimer's dementia, morbid conditions of ischemic encephalopathy

and cerebral apoplexy is useful.

Object of the invention

It is therefore an object of the invention to provide novel 1,2-ethanediol derivatives and their salts. Another object is to provide a process for the preparation of novel 1,2-ethanediol derivatives and their salts. A further object of the invention is to provide a novel agent for improving cerobral function which is useful for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, morbid disease states of ischemic encephalopathy and cerebral apoplexy and yet shows only slight noise effects.

Explanation of the essence of the invention

The inventors have made extensive investigations for the purpose of solving the above-mentioned problems. As a result, it has been found that a 1,2-ethanediol derivative represented by the following general formula (I) or a salt thereof has excellent anti-amnetic activity and is excellent in anti-hypoxic activity and extremely useful as an agent for improving cerebral function:

R ³ R ⁴

R '- ^ HCH-O-nj ^ R "(D

OR ² R ⁶

R ^{1 represents} a substituted or unsubstituted phono / 1-, naphthyl-, indanyl-, indenyl-, tetrahydronaphthyl- or heterocyclic Group stands; R ^{2 represents} a hydrogen atom, a lower alkyl group or a hydroxyl protective group; R ^{] represents} a hydrogen atom or a lower alkyl group;

nR ⁴ and nR ^J group are the same or different and represent hydrogen atoms or lower alkyl groups;

R ^{6 is} an ammonio group or a substituted or unsubstituted amino or nitrogen-containing heterocyclic group

where the nitrogen-containing heterocyclic group is selected from the group consisting of pyrrolyl,

Pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, Thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, Tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups;

and η is 0 or an integer from 1 to 6; wherein the substituent on R ^{1 is} selected from the group consisting of

Halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, aryl,

lower alkoxy, aryloxy, carbamoyloxy, Nioderalkylthio, Niederalkonyl, Niederalkenyloxy-, Ar-nioderalkylthio, Arnicderalkylsulfonyl-, Arylsulfonyl-, Nioderalkylsulfonylamino-, Arylsulfonylamino- and heterocyclic groups, and protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and

lower alkylenedioxy; wherein the substituted lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy,

Aryloxy, carbamoyloxy, lower alkylthio, Nioderalkenyl, Niederalkonyloxy, Ar-niodoralkylthio, Ar-niedoralkylsulfonyl-, arylsulfonyl, Niodoralkylsulfonylamino-, Arylsulfonylamino- or heterocyclic groups as dor Substiiuent of R 'and the substituted, nitrogen-containing, heterocyclic group R ^e each carry at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxyl groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl group, NORDURalkylgruppon substituted by a protected or unprotected hydroxyl, unsubstituierton or halo substituted aryl groups , unsubstituted or halo-substituted aroyl group, unsubstituted niddoralkoxy group, lower alkoxy group substituted by a lower alkoxy group, lower acyl group, arylchloroalkyl group, ariodo-neralcyl group, heterocyclic group en groups, heterocyclic CO groups, oxo group, lower alkylsulfonyl group and arylsulfonyl groups; and wherein the substituted amino group as the substituent of R 'and substituted substituent amino group as R ° have at least one L. substituent selected from the group consisting of goschützton odci unprotected hydroxyl groups, unsubstituted lower alkyl group, lower alkyl groups substituted by a protected or unprotected one Carboxyl or hydroxyl group, cycloalkyl groups, aryl groups, Niedoracrylgruppon, Ar-lower alkyl groups, heterocyclic groups, unsubstituted or oxo-substituted hetero-cyclic-CO groups, adamantyl groups, Niodoralkylsulfonylgruppen and arylsulfonyl groups, with the proviso that compounds are excluded in which R 'is a phenyl group which may optionally be substituted by the halogen atom or the lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group, and R ^{6 represents} -NR'R ⁸ , where R 'is an ariodoralkyl or heterocyclic group and R ⁸ e in hydrogen atom or a lower alkyl group, or R ⁷ and R ⁸ , when taken together with the N atom, form the following structures:

-NN- (CHo '' R 'where R ^{9 represents} an aryl or heterocyclic group and i is O or an integer y / c

f \ -IQ

is from 1 to 3, -NN-yCHp COR, wherein R ^{10 is} an aryl, heterocyclic or -N-heterocyclic group \ / _/ R ⁸

and R ⁸ and i are as defined above, "" N \ - * 0H, where R ^{n is} an aryl group,

R12 ^ - ⁷ V ¹

/ -

-N V

in which R ^{12 represents} a carboxyl group or a lower alkoxycarbonyl group, or -N), wherein R ¹²

as defined above; and that the compounds are excluded in which R ^{1 is} an unsubstituted or lower alkyl-substituted phenyl group and R ^{6 is} oino-di-lower alkylamino group,

, - N y or NO stands; wherein all of the above heterocyclic groups are selected

-N

N /

are selected from the group consisting of the nitrogen-containing heterocyclic groups as mentioned in connection with the definition of R *, and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl , Benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobonzofuranyl, Benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] iiporazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyradazinyl, isoindolyl and isoquinolyl groups. Incidentally, the term "cerebral function enhancer" as used herein refers to such an agent which does not have the effects alone as shown by conventional cerobral function improving agents, for example, ischemic encephalopathy and cerobraler sequelae Apoplexy, but also therapeutic or prophylactic effects for amnosia and dementia (e.g., cerebrovascular dementia, senile dementia, and Alzhaimnr dementia) In the present application, the following terms have the following meanings unless otherwise indicated: The term "halogen atoms" means, for example a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the term "lower alkyl group" means C 1 _e alkyl groups such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutryl, tert-butyl, pentyl, hexyl or the like; the term "lower alkenxy group" means C 1 alkyl-O-groups; the term "lower alkylthio group" means C 1-4 alkyl S groups; the term "lower alkenyl group" means C ₂ e alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl and the like; the term "Niodoralkonyloxy group" means C 1-4 alkenyl-O groups; the term "cycloalkyl group" means C 1-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl and the like; the term "aryl group" means phenyl, naphthyl, indanyl and indenyl; the term "aryloxy group" means aryl-O- groups; the term "Ar-lower alkyl group" means Ar-C 1-4 alkyl groups such as benzyl, diphonylmethyl, trityl, phenethyl and the like; the term "aralkoalkoxy group" means Ar-Ci_4-alkyl-0-groups; the term "aryl-alkylthio group" means aryl-C 1-4 -alkyl-S groups; the term "lower alkylenedioxy group" means C 1-4 -alkylenedioxy groups such as methylenedioxy, ethylenedioxy and the like; the term "lower acyl group" means C _{1 to 6} acyl groups such as formyl, acetyl, butyryl and the like; the term "aroyl group" means aryl-CO groups; the term "lower alkylsulfonyl group" means C, _e -alkyl-S0 ₂ -groupone; the term "arylsulfonyl-group" means aryl-SOj groups; the term "ar-lower alkylsulfonyl group" means aryl-C 1-4 -alkyl-SO y groups; the term "lower alkylsulfonyloxy group" means C ₁ . _6- alkyl-SO ₂ -O- groups; the term "arylsulfonyloxy group" means aryl-SO ₂ -O- groups; the term "lower alkylsulfonylamino group" means C 1-4 alkyl-SOj-NH groups; the term "arylsulfonylamino group" means aryl-SO ₂ -NH- groups; the term "di-lower alkylamino group" means di-C ,. _e alkyl NH groups; and the term "ammonio group" means tri-lower alkylamonio groups such as trimethylammonio, triethylammonio; the term "lower alkoxycarbonyl group" means Ci-e-alkyl-O-CO groups and the like.

The protecting groups for the hydroxyl group, carboxyl group and amino group include those conventional protecting groups for the hydroxyl group, carboxyl group and amino group as described in "Protective Groups in Organic Synthesis" by Theodra W. Green, 1981, John Wiley & Sons, Inc. As a protective group for the hydroxyl group, there may be specifically used, for example, N-alkyl alkyl, lower acyl and ar-lower alkyl groups such as substituted or unsubstituted benzyl or tetrahydropyranyl.

The salt of the 1,2-ethanediol derivative of the general formula (I) may be any beliobic, pharmaceutically acceptable salt. Included are, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; Salts with carboxylic acids such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid and the like; Salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like; and salts with alkali metals such as sodium, potassium and the like. If the 1,2-ethanediol derivative of the general formula (I) or its salt has isomers (e.g., optical impurities, geometric isomers, tautomers), then all of these isomers of the present invention. Further, the hydrates, solvates and all crystal forms of the compounds of the present invention are also included in the present invention. The following will describe a process for producing a 1,2-ethanediol derivative of the general formula (I) or a salt thereof. The 1,2-ethanediol derivative of general formula (I) or its salt can be prepared by methods known per se or by a suitable combination of processes known per se, e.g. B. according to the following production methods.

Production method 1 _Λ

~~ v

HO- (C)

-R

R-CHCHR

• tu]

[III] or a salt or

HO-R ^6a

[purple] od.an salt

R R

ι I 6

R-CHCH-O- (C) R

I 15 ⁿ

OH R

[Ialoder his salt

Production process 2

1 l \ 3 R-CHCHR

[II]

R HO- (C

13

(IV) or a salt

f ? ⁴

R ^{1 is} -CHCH-O- (C-) OR ¹³

¹ 2a I5 ^m

^0R R [VI]

R ³ R ⁴ ill IT

R-CHCH-O- (C-) OR °

I l ₅ ^m OH R

[V] or a salt

R ³ R ⁴ R ³ R ⁴

ι I halogenating agent ι ι ι

R-CHCH-O- (C-) OH > R-CHCH- (HOh-Y

I 2a '5 ^{m or} I 2a ^! 5

OR R sulfonylating ^{agent 0R R}

[viijoder be. [viii] salt

HR ^6b [IX]

or a salt

R ³ R ⁴

R ³ ^ -CHCH-O- (C-) R ^6b

^{2a b}

[Ib] or his salt

Production process 3

R ³ -CHCHR ³ [II]

R ι

HO- (C-) OH

"5 ^m

[X] or its salt R ³ R ⁴

ι ι l

R-CHCH-O- (O) -OH

I oh

R "

[XI] or its salt

sulfonylating

R ³ R ⁴

R-CHCH-O- (C-) Y

I l ₅ ^m

OH R

[XII] bd.seiii salt HR ^6b [ix] or its salt

R R

I ι _a

R-CHCH-O- (C-) Y

iR ^2a i ⁵ "

HR ^6b (IX)

or his salt

[XIII]

Production process 4

R R

R ¹ -CHCH-O- (C-) _Tir- R ^6b

2 '5

OR R ^D

[icpder his salt

χ ¹ R ³ R ⁴ -I '2 MgCH-O- (Of ^ -X V > b R ³ R ¹ -CH-CH- ( R ⁴ I 2 ^R3 -CHO [XV] OH [XIV] [XVI] or 6b R HR ^6b [IX] od.an .R ³ R ⁴ 1 I ' * R-CHCh-O- (C) R ι ι _ ¹ its salt salt OH

lib] or his salt

In the above reaction schemes, R ', R ³ , R ⁴ , R ⁶ , R ^e and η have the same meanings as previously defined; R ² 'represents the same hydroxyl protecting group as in the definition of R ² ; R ⁰ 'represents the same substituted or unsubstituted nitrogen-containing heterocyclic group as in the definition of R ^e , provided that the heterocyclic group has a free valency on a heterocyclic ring-forming carbon atom; R ^{eb represents} the same substituted or unsubstituted nitrogen-containing heterocyclic group as in the definition of R ⁸ , with the proviso that the nitrogen-containing heterocyclic group has a free valency on a heterocyclic ring-forming nitrogen atom or a substituted or having unsubstituted amino group; R ^{13 represents} the same hydroxyl protecting group as in the definition of R ² ; X ¹ and X ² , which may be the same or different, represent halogen atoms; Y represents an atomizable group such as a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group or the like; Y * represents an arylsulfonyloxy group; and m is an integer from 1 to 6.

As salts of the compounds of the formulas (III), (IIIa), (IV), (V), (VII), (IX), (X), (XI), (XII), (XVI), (Ia) (Ib), (Ic) and (Id), the salts may be mentioned as the salts of the compound of general formula (I). In the following, each of the above manufacturing methods will be explained.

Production method 1

A compound of the general formula (II) is reacted with a compound of the general formula (III) or its salt or a compound of the general formula (III a) or its salt in the presence or absence of a base to give a

Compound of general formula (Ia) or to obtain their salt.

The solvent to be used in this reaction may be any solvent as long as it does not adversely affect the reaction. Mention may be made, for example, of aromatic hydrocarbons such as benzene, toluene, xylene and the like; Sulfoxides such as dimethylsulfoxide and the like; Amides such as N, N-dimethylformamide and the like; and ethers such as tetrahydrofuran, dioxane and the like. These solvents may be used alone or in a mixture of two or more. It is also

possible to use the compound of the general formula (III) or (IIIa) as a solvent.

Examples of suitable bases to be used are sodium hydride, metallic sodium and potassium tert.

butoxide is mentioned.

In the reaction, the compound of the general formula (III) or its salt or the compound of the general formula (IIIa) or its salt is used in an amount of 1 to 100 moles and preferably 1 to 10 moles / mole of the compound of the general formula (II)

used.

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

used.

This reaction can be usually carried out at 20 to 15O ⁰ C, preferably 70 to 90 ° C, for 1 minute to 24 hours, preferably

5 minutes to 5 hours.

Production process 2

(1) A compound of the general formula (II) is reacted with a compound of the general formula (IV) or its salt in the presence or absence of a base to obtain a compound of the general formula (V) or its salt. This reaction can be carried out in the same manner as in Preparation Method 1.

The obtained compound of the general formula (V) or its salt can be used in the subsequent reaction without isolation.

(2) The compound of the general formula (V) or its salt is subjected to a conventional reaction to protect the hydroxyl group to obtain a compound of the general formula (VI). The resulting compound of the general formula (VI) can be used in the subsequent reaction without isolation.

Then, the compound of the general formula (VI) becomes a reaction for selectively removing the hydroxyl-protecting group

to obtain a compound of the general formula (VII) or its salt.

The resulting compound of the general formula (VII) or its salt can be used in the subsequent reaction without isolation

be used.

These reactions can be carried out according to methods known per se, for. Example by the method described in Protective Groups in Organic Synthesis (Theodra W. Green (1981), John Wiley & Sons, Inc.) or a similar method.

The combination of the hydroxyl-protecting groups (R ¹³ and R ² ') used in these reactions may suitably

to be selected.

(3) The compound of the general formula (VIII or its salt is reacted with a halogenating agent or a sulfonylating agent in a solvent in the presence or absence of a base to obtain a compound of the general formula (VIII) The solvent to be used in this reaction may be any solvent so long as it does not adversely affect the reaction, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxane and the like, nitriles such as acetonitrile and the like, and amides such as Ν, Ν-dimethylformamide and the like. These solvents may be used alone or in a mixture of two or more.

As the base to be optionally used, there may be exemplified organic and inorganic bases such as triethylamine, diisopropylethylamine, d-diazabicycloIoAl-undec-T-ene (DBU), pyridine, potassium tert-butoxide, sodium carbonate,

Mention potassium carbonate, sodium hydride and the like.

As halogenating agents, e.g. Phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride,

Thionyl chloride and the like. Called.

As sulfonylating agents, e.g. Methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.

The halogenating agent, the sulfonylating agent and the optionally used base are each used in an amount of at least 1 mole, and preferably 1 to 2 moles / mole of the compound of the general formula (VII) or its salt.

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

become.

The obtained compound of the general formula (VIII) can be used as it is in the subsequent reaction without isolation.

(4) The compound of the general formula (VIII) is reacted with a compound of the general formula (IX) or its salt in the presence or absence of a catalyst in the presence or absence of a base to give a

Compound of general formula (I b) or its salt zuhalton.

The solvent to be used in this reaction may be any solvent as long as it does not adversely affect the reaction. Mention may be made, for example, of the same solvents as used in (3) of preparation process 2

were mentioned.

As the catalyst optionally used, for example, potassium iodide, sodium iodide and the like may be mentioned. The catalyst is used in an amount of 0.1 to 1 mol / mol of the compound of the general formula (VIII).

As the base to be used, for example, one may cite the same bases as used in (3) of

Production method 2 were mentioned.

Each of the compound of the general formula (IX) or its salt and the base as an optional component is used in an amount of at least 1 mole, and preferably 1 to 20 moles / mole of the compound of the general formula (VIII).

This reaction can be usually carried out at 10 to 15O ⁰ C, preferably 20 to 100 ⁰ C, for 10 minutes to 20 hours causes

become.

Production process 3

(1) A compound of the general formula (II) is reacted with a compound of the general formula (X) or its salt in the presence or absence of a base to obtain a compound of the general formula (XI) or its salt.

The reaction can be carried out by the same method as described in Preparation Method 1.

(2) The compound of the general formula (XI) or its salt is reacted with a sulfonylating agent in a solvent in the presence or absence of a base to obtain a compound of the general formula (XII) or its salt.

The solvent to be used in this reaction may be any solvent as long as it does not adversely affect the reaction. Mention can be made z. For example, the same solvents as in (3) of Preparation Method 2

described.

As optionally used base can be z. B. mention the same bases as in (3) of preparation process (2).

As sulfonylating agent can be z. B. p-toluenesulfonyl chloride or the like. Mention.

The sulfonylating agent and the base as an optional component may each be in an amount of at least 0.95 moles and

preferably 1 to 2 mol / mol of compound of the general formula (XI) or its salt are used.

This reaction can gewähnlich at -10 to 100 ⁰ C, preferably 0 to 40 ° C, for 10 minutes to 30 hours causes

become.

The obtained compound of the general formula (XII) or its SaI; may in the subsequent reaction without isolation

be used.

(3) The compound of general formula (XII) or its salt is subjected to conventional reaction for ^c ihutz the hydroxyl group to obtain a compound of general formula (XIII).

The reaction can be carried out according to known methods, for. Example by the method described in Protective Groups in Organic Synthesis (Theodra W. Green [1981], John Wiley & Sons, Inc.) or a similar method.

The obtained compound of the general formula (XIII) can be subjected to the following reaction without isolation

become.

(4) The compound of the general formula (XII) or the other salt or the formula (XIII) is reacted with a compound of the general formula (IX) or its salt in the presence or absence of a base to obtain a compound of the general formula (Ic) or to get their salt.

This reaction can be carried out by the same method as in (4) of Preparation Method 2.

Manufacturing processes 4

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

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. Mentioned are, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; and aromatic hydrocarbons, such as benzene, toluene and deigl. These solvents may be used alone or in admixture of two

or more can be used.

In this reaction, the compound of the general formula (XV) is added in an amount of 0.8 to 100 mol, preferably 0.8

to 10 mol / mol of compound of general formula (XIV) used.

This reaction may be usually carried out at -78 to 100 "C, preferably -78 to 5O ⁰ C, for 5 minutes to 24 hours causes

become.

The resulting compound of the general formula (XVI) or its salt can in the subsequent reaction without isolation

be used.

The compound of the general formula (XV) used in this reaction can also be prepared by methods known per se, such as. B. according to the in Bull. Soc. Chim. Fr., 1967 (5), pages 1533-1540.

(2) The compound of the general formula (XVI) or its salt is reacted with a compound of the general formula (IX) or its salt in the presence or absence of a base to obtain a compound of the general formula (Id) or its salt.

The solvent to be used in this reaction may be any solvent as long as it does not adversely affect the reaction. Mention may be made, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; Ethers such as tetrahydrofuran, dioxane and the like; Alcohols such as ethanol, propanol, butanol and the like; Nitriles such as acetonitrile and the like; and amides such as Ν, Ν-dimethylformamide and the like. These solvents may be used alone or in admixture

be used from two or more.

As an optionally used base, for example, the same bases as in (3) of Preparation Process 2

mention.

The compound of the general formula (IX) or derone salt and the base as an optional component are each added in an amount of at least 1 mole, preferably 1 to 20 moles / mole of the compound of the general formula (XVI) or its salt

used.

This reaction may be usually from 10 to 150 ⁰ C, preferably 20 to 1G0 ° C, for 10 to 20 hours causes Minuteri

become.

In the above preparation methods, the reactants or base may also be used as a solvent, depending on the

Nature of the reactants or base.

In the above preparation processes, when the compounds of the general formulas (1I) ₁ (III) ₁ (IIIa), (IV) ₁ (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) have isomers (e.g., optical isomers, geometric isomers, tautomers) that use compounds in any isomeric form , Furthermore, the compounds in one

Hydrate form, a solvate form or any crystal form can be used.

If the compounds of the general formulas (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), (IX), (XII), (XIII) , (XIV), (XV), (XVI), (I), (Ia), (Ib), (Ic) and (Id) have a hydroxyl group, an amino group or a carboxyl group, it is possible to use these groups in advance protect a conventional protecting group and optionally remove the protecting group after the reaction,

namely according to known methods.

The compound thus obtained may be subjected to conventional isolation and purification procedures, such as

Column chromatography, crystallization, distillation, extraction and the like

The 1,2-ethanediol derivative of the general formula (I) or its salt can be converted to another 1,2-ethanediol derivative of the general formula (I) or its salt by subjecting the former compound to a proper combination of known reactions such as oxidation reaction, reduction reaction, addition reaction, acylation reaction, alkylation reaction, sulfonylation reaction, deacylation reaction, substitution reaction,

Dehydration reaction, hydrolysis reaction and the like.

The compound of the general formula (II) which is the starting material for the preparation of the compound of the present invention can be prepared by methods known per se, e.g. according to the JACS, Vol. 87, p. 1353 (1965) and in

Shin Jikken Kagaku Koza, Vol. 14, p. 579 (1977), Maruzen.

The compound of the present invention, when used as a drug, may be suitably mixed with diluents such as fillers, carriers, diluents and the like, and may be divided into tablets, capsules, powders, fine granules, pills, suspensions, emulsions, liquids, syrups , Injections, etc., according to conventional methods. These drugs can be administered orally or parenterally. The dose route, dose and number of administrations may be appropriately varied depending on the age, weight and symptoms of the patient. In general, however, in the case of oral administration, 0.01 to 500 mg of the compound of the present invention may be administered to an adult patient daily in one or more portions.

The following describes the pharmacological effects of representative compounds of the invention.

The numbers of the oily compounds used in the following pharmacological tests refer to

Number of the compounds given in the following Preparation Examples.

1. Effect of the test compound in hypoxia

A test compound dissolved in physiological saline (100 mg / kg) is administered orally to female ddY mice (5 to 6 weeks old, each group consisting of 10 mice). One hour (or 30 minutes) after administration, each mouse is placed in a 300 ml glass chamber and a gas mixture consisting of 4% oxygen and 96% nitrogen is passed through the chamber at a rate of 5 l / min determines the time that elapses from the beginning of the gas injection to the death of the respective mouse.

Only physiological saline is orally administered to a group of control mice.

The anti-hypoxic activity of the test compound is calculated according to the following formula:

Mean survival of mice of the administration group .... M ¹ sized survival time of control mice

The results are summarized in Table 1. Table 1

Connect. Anti-hypoxia Connect. Anti-hypoxia Vorbind. Anti-hypoxia No. activity No. Activity No. activity 1 155 132 133 · 271 150 * 2 119 134 201 · 272 185 * 3 245 · 137 163 * 279 198 9 113 139 162 » 282 160 · 14 184 ' 151 182 283 183 15 194 * 152 180 289 157 · 16 116 153 185 302 182 · 19 168 ' 167 165 303 168 23 241 · 180 176 ' 309 198 · 27 201 · 181 132 312 221 · 33 224 · 187 153 * 313 IN THE· 34 221 188 144 * 320 212 * 36 139 195 176 * 325 217 * 37 148 197 164 * 327 160 * 42 194 203 177 * 330 242 · 46 150 * 204 176 * 332 230 · 47 165 ' 207 136 * 334 246 · 48 160 208 242 » 336 224 » 49 151 209 148 * 337 309 · 54 137 211 177 * 338 144 » 55 207 213 149 339 131 · 56 182 215 197 340 163 · 53 133 218 157 * 342 157 » 61 184 · 219 222 · 343 160 » 62 127 220 183 · 344 268 » 67 247 * 221 183 · 345 185 » 71 147 222 152 » 347 162 » 83 177 * 223 149 * 348 251 » 84 175 * 224 155 349 209 * 86 130 * 225 157 * 350 147 » 87 179 228 144 353 132 · 89 156 · 229 123 357 189 · 92 169 230 177 358 211 · 95 164 231 246 365 155 · 96 176 · 232 150 368 135 · 97 138 » 236 177 369 143 · 98 164 * 237 149 375 156 * 100 171 * 238 123 377 221 * 102 KO * 239 150 383 293 * 104 160 » 243 159 385 161 * 119 175 * 246 128 386 169 * ' 120 162 » 247 124 387 228 * 121 149 » 250 145 * 388 213 * 122 142 · 251 186 * 390 248 · 123 140 * 252 190 * 394 241 * 125 172 * 256 154 396 316 * 126 172 · 259 155 · 398 171 » 129 158 · 260 124 405 137 * 131 167 * 261 126

Comment:

The mice are placed in the chamber 30 minutes after administration instead of 1 hour after the administration.

2. Effect of test compound on amnesia

(1) Electroconvulsive shock (ECS) induced amnesia

A male ddy mouse (5-6 weeks old, 10 mice each per group) is intraperitoneally administered with a test compound dissolved in physiological saline. The A quisitionsversuch in the passive avoidance task is performed 1 h after administration. Each mouse is placed in the light chamber of a two compartment penetration type passive avoidance device consisting of a light chamber and a dark chamber (MPA-100M manufactured by Muromachi Kikai). When the mouse enters the dark chamber, the trap door of the dark chamber is closed; after 0.5 sec an unavoidable foot shock (1.6 mA, 3 see) is administered. Immediately thereafter, EC3 (25 mA, 0.5 sec) is administered through both eyes of the mouse. After 24 h, the mouse is again placed in the light compartment during the retention attempt and the response latency for the mouse is measured to enter the dark chamber. If the mouse is longer than 300see the entrance:

avoids, a peak of 300see is assigned.

In a control mouse group, only physiological saline is administered intraperitoneally, and the response latency becomes

determined in the same way.

The anti-amnesia effect is taken as the middle word of the response latency times of the 10 mice and expressed by folgrnido symbols:

- = 0 to 60 see + = 61 to 100 see + + = 101 to 150sec + + + = 151 to 300 see The results are shown in Table 2.

Table 2

Connect. dose Anti-amnesia No. (Mg / kg) activity 2 3 + 3 3 + + + 8th 3 + 15 3 + + + 19 3 + 23 10 + 29 3 + 44 10 + + 48 3 + + 52 3 + 53 3 + + + 58 10 + + 61 3 + + 67 3 + + 70 3 + + 76 3 + + /8th 3 + + 115 3 + + 159 3 + 160 3 + + 170 3 + + 176 3 + + 189 3 + + + 228 10 + 229 3 + 235 10 + + 237 3 + + 239 10 + 2 <! 3 3 + + 252 3 + + + 261 3 + 266 3 + + 315 3 + + 316 3 + 319 10 + +

(2) Effect of test compound in cycloheximide-induced amnesia

From Yamazaki et al. has been reported (Drugs, Mind and Action, Volume 3, pages 127-136 [1983]) that cycloheximide in the

Recreation process of remembrance of mice intervenes. The following test was carried out.

A test is performed according to the method described in Drugs, Mind and Action, Volume 3, pages 127-136 (1983) and Folia Pharmacologica Japonica, volume 89, pages 243-252 (1987). The test \ orrichtimg is a step-down passive avoidance training box. It is a black box made of acrylic resin with 22cm χ 22cm χ 21 cm (height), the bottom area consists of a stainless steel grid and at one corner of the floor grid a platform of

7cm χ 7cm x 2cm (height).

Cycloheximide is dissolved in physiological saline and injected subcutaneously with 120 mg / kg male ddY mouse (5-6 weeks old, each group consisting of 10 mice). In an acquisition trial, 15 minutes after administration, each mouse is placed on the platform of the above test device. As soon as the mouse steps off the platform, a 2 mA current is administered to 2see, immediately after which the mouse is returned to its home cage. A retention test is performed 24 hours after the acquisition. Each mouse treated with cycloheximide is orally administered with a test compound dissolved in physiological saline. 30 minutes after the administration, the mouse is again placed on the platform and the mouse response latency to descend is measured. If the mouse is descending longer than 300sec

avoids, a peak of 300see is assigned.

A control mouse group, which has been given only physiological saline orally, is also used to measure

Subjected to response latency in the same way.

The anti-amnesia activity is determined as an average of the response latencies of the 10 mice and by the following

Symbols expressed: - = 0 to 60sec + = 61 to 100 see + + = 101 to 150sec 151 to 300sec.

The results are shown in Table 3. Table 3

Connect. dose - Anti-amnesia Connect. dose Anti-amnesia No, (Mg / kg) activity No. (Mg / kg) activity 1 3 + + 235 3 + l · + 7 10 ₊ 238 3 + 9 10 ₊ 240 3 -r 14 3 • t + + 241 3 + + 15 3 + + + 242 3 + + 16 10 244 3 + + 25 3 245 10 + + 28 10 ₊ 246 3 + + 42 3 + 248 3 + + 48 3 + + 251 3 + + + 49 3 + + 252 30 + + + 54 3 + + 257 3 + 56 3 260 3 60 3 + + + 261 3 + + + 65 3 _{+ +} 262 3 + 82 3 + + 263 10 + 83 3 266 30 -1- 84 10 + + 280 10 + 100 3 + + 312 10 + 110 10 + + 317 3 + + 112 3 + + + 320 3 + + 113 3 + + 324 10 + + 115 3 + + + 325 10 + + 147 3 + + + 333 3 ₊ 151 3 + + + 334 3 ₊ 153 3 + + 338 3 165 10 + 339 10 ₊ 178 3 + + + 340 3 ₊ 181 10 + + 341 3 ₊ 194 3 + 343 10 _{+ +} 196 3 + + + 346 3 ₊ 219 3 + 350 3 + + 220 10 + + 351 3 ₊ 221 10 + 352 3 + + 228 3 + + 353 3 ₊ 229 10 + + 358 10 + + 230 3 + 360 10 ₊ 232 10 + + 365 3 ₊ 233 3 + 367 3 + + + 234 3 + 368 3 ₊ comparison -

3. Inhibitory effect on acetylcholinesterase

A test is performed according to the method of Ellman et al. (Biochem Pharmacol., Vol 7, pp. 88-95, 1961). That is, acetylthiocholine (as a substrate) is added to a phosphate buffer solution containing 5,5'-dithio-bis (2-nitratedozoic acid) (DTNB), a test compound, and a mouse cerebral homogenate (as an acetylcholinesterase source). The resulting mixture is incubated and the amount of the resulting 5-thio-2-nitrobenzoic acid measured photometrically at 412 nm.

The inhibitory effect on acetylcholinesterase of the test compound is expressed in terms of percent inhibition at which the

Final concentration of the test compound is 10pg / ml. The results are shown in Table 4.

inhibition Connect. inhibition Connect. -21- 299 960 inhibition Table 4 (%) No. (%) No. {%) Connect. 13 73 89 237 44 No. 22 78 90 239 22 6 26 83 93 241 31 30 45 86 50 246 30 34 36 8th" 44 247 26 37 26 90 52 260 43 38 38 97 38 302 38 40 51 103 36 319 30 47 83 113 45 322 20 48 22 165 24 329 45 54 45 182 38 336 21 55 71 190 76 341 61 58 89 222 83 342 67 60 78 223 74 350 42 61 62 224 36 352 26 62 90 225 43 372 30 65 91 228 30 377 23 67 87 230 25 386 47 70 92 233 59 405 59 71 72

4. Acute toxicity

A test compound dissolved in a physiological saline solution is intravenously administered to a group of three ddY mice (male, 5-6 weeks old) for testing the acute toxicity of the test compound.

As a result, the test compounds Nos. 1,2,3,6,8,9,15,16,25,30,33,34,38,40,42,44,46,52,53,54 are found , 65,67, 70,71,112,119,120,126,132,147,151,159,160,170,176,178,182,190,194, 209,219,220,221,229,235,236,240,251,256,279,309,312,313,315,316,319,325,327,337,360,368,369,375,377,385,390, and 396, no death occurs at 50 mg / kg. From the above test results, it is apparent that the compounds of the present invention are excellent in anti-hypoxic activity, anti-amnesia activity, and acetylcholinesterase inhibitory activity and show low toxicity. It is also clear from the above results that the cerebral function improving agent of the present invention is useful for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, morbid conditions of ischemic encephalopathy and corebralor apoplexy.

exemplary

In the following, processes for the preparation of the compounds according to the invention are described by means of preparation examples. In the Preparation Examples, the indicated mixing ratios of the eluents are in all cases by volume, and as the support material in the column chromatography, a silica gel {Kieselgel 60, Art. 7734) manufactured by Merck Co. is used.

The abbreviations used in the preparation examples have the following meaning:

Me = methyl; Et = ethyl; i-Pr = isopropyl; t-Bu = tert-butyl; Ac = acetyl; Ph = phenyl; DPM = diphenylmethyl; Bz = benzyl; Tr = trityl; IPA = isopropyl alcohol; IPE = diisopropyl ether; PTS = p-toluenesulfonic acid.

In the following statements and tables, the substances indicated in square brackets refer to the solvents used in the Umkristallisaton.

Production Example 1

(1) A mixture of 10.8 g (L) -Benzoylcystin, 1.6 g of lithium borohydride, 2.4 g of tert-butanol and 180 ml of tetrahydrofuran is refluxed for 1 h and then cooled to ⁰ C -6O. 6.1 g of 4-benzyloxyphenacyl bromide are added thereto. The mixture is stirred at the same temperature and further for 3 hours at -40 to -30 ⁰ C for 30 min. The reaction mixture is added to a mixture of 100 ml of water and 200 ml of diethyl ether. The organic layer is separated, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: toluene); 2.8 g of (S) -1- (4-benzyloxyphenyl) -2-bromoethanol are obtained.

(2) 2.8 g of (S) -1- (4-benzyloxyphenyl) -2-bromoethanol are dissolved in a mixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran. The solution is added under ice-cooling with a solution of 0.8 g of potassium hydroxide dissolved in 4 ml of water. The mixture is stirred for 5 minutes at the same temperature and for a further 10 minutes at room temperature. The reaction mixture is added to a mixture of 50 ml of diethyl ether and 50 ml of ice-water. The organic layer is separated. The aqueous layer is extracted with 25 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; This gives 1.4 g of (S) -2- (4-benzyloxyphenyl) oxirane.

Mp. 56-61 ⁰ C.

Optical rotation: (a) g ⁶ = + 5.2 ° (c = 2, CHCl ₃ ).

The following compounds have been obtained in the same way

(S) -2- (3-methylphenyl) oxirane; | α) έ ⁶ = + 15.7 ° (c = 2, CHCl,) (S) -2- (4-phenoxyphenyl) oxirane; | a | £ ^B = + 12.5 ° (c = 4, CHCl ₃ ).

Herstollungsbelsplel 2

(1) A solution of 23g (+ l-Diisopinocamphenylchlorboran dissolved in 30ml of tetrahydrofuran, gokühlt to -25 ⁰ C. To this is added 12 g 4-benzyloxyphenacyl bromide. The resulting mixture is gorührt 4h at -20 to -15 ⁰ C. The Reaction mixture is added to a mixture of 150 ml of diethyl ether and 100 ml of ice-water, and the organic layer is separated ^by H, washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: hexane / toluene = 1/2) to obtain 6.8 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol.

(2) 6.0 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol are dissolved in a mixed solvent of 50 ml of methanol and 25 ml of tetrahydrofuran. Doz'j is added under ice-cooling, a solution of 1.5 g of potassium hydroxide, dissolved in 5 ml of water. The resulting mixture is stirred for 5 minutes at the same temperature and for a further 10 minutes at room temperature. The reaction mixture is added to a mixture of 100 ml of diethyl ether and 100 ml of ice-water. The organic layer wii d separated. The aqueous layer is extracted with 50 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 3.7 g of (R) -2- (4-benzyloxyphenyl) oxirane are obtained. Mp. 58bis67 ^c C

[a] g ^e = -14.4 ° (c = 2, CHCl ₃ ).

The following compounds are obtained in the same way

(R) -2- (3-methylphenyl) oxirane; | o | £ ⁷ = -18.6 ° (c = 2, CHCl ₃ ) (R) -2- (4-phenoxyphenyl) oxirane; | a] g ⁶ = -11.3 ° (c = 2, CHCl ₃ ).

Herstellungsbelsplel3

3.4 g of potassium tert-butoxide are added to 31 ml of 2- (N, N-dimethylamino) ethanol and the resulting mixture is heated to 00 ^° C.

7.7 g of 2- (3-fluorophenyl) -oxirane are added dropwise thereto in the course of 40 minutes, and the mixture is stirred for 3 hours at the same temperature. The reaction mixture is added to a mixture of 200 ml of ice-water and ethyl acetate in 2001. The organic layer is separated. The organic layer is mixed with 50 ml of water. The mixture is adjusted with 6N hydrochloric acid and pH 1. The aqueous layer is separated and mixed with 100 ml of chloroform. The resulting mixture is treated with 2N

aqueous sodium hydroxide solution adjusted to pH 11 '. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure.

The residue thus obtained is purified by column chromatography (eluent: chloroform / ethanol = 5/1). The resulting oily product is dissolved in 25 ml of acetone. Hydrogen chloride gas is blown into the solution. The resulting crystals are collected by filtration, washed with acetone and dried; 3.1 g of 2- [2- (N, N-dimethylamino) -ethoxy) -1- (3-fluorophenyl) -ethanol hydrochloride (Compound No. 1) are obtained; Mp. 164-165 ⁰ C (EtOH).

In the same way, the compounds listed in Table 5 are obtained.

In Table 5, R ', R ² , R ³ , R ⁴ *, R ^4b , R ⁶ , na and nb each show a substituent or an integer as used in the following formula.

.Q

Cu υ

(O

u- u-

ο ι

in

H H

Ο)

XJ cd

CS

PJ-U

X UO

O O e 184-185 [EtOH] in IO in U ri es χ ^ ω of "S 4J rl" -JW (R-form) ns co I (ΛC.O • p- + J • r- NJ • σ ι- Ό (0 et (Λ HCl : X) β rh S (0 β rh : (U (U I S X) « K : ro « X r ro « (S Γ rh ό Connect. No. CS

• μ u ο

H (D

I O) " hO • - J in r * ι I • ι-t in ( I I ι-ι in O r \ S • O [ - O f- υ f-i \ / H jj υ : I O - IN VO O - IN <N X I :O W W ro YY iH JJ I JJ I 0) O X I \ / t ^ W Z W I W : ω m X I rH '' in I 1 » - W X • S - ^ j ¹ U X ro X \ ξ : VO S r < I ° : VO = rh / \ / ) J O) S rf Q

in • bO • I ^s • = Z in ι • Η = S H Z ' I O O to Z η 4J it I Z in W 4J O • <n "- W Z Z HCl Z Z U U CU CU I I • Η · Η \ / S-Λ O I O : I ^s W S X K Z K r-H rH ό co

Table 5 (cont.)

12 O me H H H H me 2 1 HCl oily / ^s me 13 Il / \ Il • I Il It Il 3 3 amorphous VJ ti me 198-199 14 \ -, ·· '·   1 Il 1 1 / \ __ [EtOH] • ι 165-166 15 Il It Il Il •1 Il η [IPA]

JJ

0)

φ H H φ .α cd

η o

in ι- «

<-i CU

O M

(N · -

in

VO CTV r- \

in

cn

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οο

CM 1-1 in O I JJ i-i W in (N

CD H H <D

141-143 [EtOH-Et ₂ O] 135.5-137.5 [EtOH-Et ₂ O] oily • r HCl ζ ι S • rh = H U CM CM II • Η · Η γ I CS rh : CS Q 0 l S CD Q) Γ : ζ X : : ζ X • - S X - CS CS : ζ = ο γΗ CS m CS

S I - in • in CO r-1 Z bO * I O S co (U • Η C ⁵ in μ H X CO W ri > - ' :O rh t ~ \ <-> Q) / I I • in Ü VD CS X CVJ r CS I • rh Q) Q) Q) Q) \; S S \ / * 25 I I S X S X : X S X CS

- cn I O Γ-. r-i X · -> CS K I O O I O W) ο Φ it CO XJ • Η cn S -U ο W H M ._, ω CS »- ' :O I • i-l υ • - - rl • Φ Φ S S \ / • ¹ z φ I X K S <r S = ™ K φ S X K Z A. CTv CS co kj KJ CS O co CO

Ρ U O

in ωH H Φ

.α α)

O I r-ι O CS -P ω in t- ι O CS 4J W in 1-1 I ΙΛ σ> [MeOH (^ • [EtOH : t r-i in -a ¹ ri ri I rh oo r »o 188.5 ·· I · 184-1 rH UI CS φ r- a ri <-> * 156.5 [EtOH- ri U Z X {r- '· {r- • '· φ Φ a a " Φ ri \ / Z O I • ) ) X r-i X U Z X ro Z X ro Z r-i _Δ ri ' TU rH U CS co CO

OQ • Ρ U O pH

φ H H φ

m ri i-i • I in CTI I K to CsI CS rh r-H O • co co CO I I Γ ** 4y co r ~ i r-ι .-IKi-i I K I O O in K> -i S CS) O • O O CO 4Y co ω χ) r-4 U-J [xj CO 4J CSl r-1 C ""> W 4- * rH> -i W • S U O) (D. K S S / a · ' r-l I S S C · ' O I · • K Z K : Z K r V ( ¹ ^ jf σ " vo U rH co co U CO

I Φ \ / i-i in ι-ι : in I !-1 ^ J ¹ r- ¹ η in O K σ> K O rH X • O X CN σ> O VO O (N I O CTI -U X -P r-i 4J 4J VO -U (N W X W I W I W W M ¹ W (N 1 I X in 1 I in I-I i-l ι-> I i-l U ( > CO X Ά ro r CO (N r \ (N a \ : VO - r (N i-l O φ ' "* ⁵ rh i I O S Y / I U η r-i S : : t s S S Λ ή A O ^^ ^ - < φ S m CN

CQ • Ρ U O P

rh I 1 W ¹ O in ( I ι-ι r-i O M ¹ X H ο ω rH co X O t ** t -ι N r-4 O ω S r-i O CS r-i X CQ I XJ ^s 2 I 4-J 4JW I O O W I 1 : in in W I 1 cn XJ τ- O rh I rh I-u cn U r- W ^ »I 1 r- - rh X rh U : K * r r-i ¹ - Q) Q) S S \ / : ζ ⁵ I S - K : ) K C Ύ - X j o If) X (D Q) S S O VO O) S  ψ

Φ H H Φ

in r-y HCl S I in U 1-1 • in O) I \ ι-ι ) fao Z J VO th / K co V X Z cn S X K / •H Z co O co CS O Z cn O O O O :O KJ r-I OJ X I- ( X 4J r-t (O) (1) O Xi N I I I ω X I W I CS S in W cq Z I VO co O cn K O co co cn O ^ Z t N I · Z '· CQ 'S ¹ Z Z rh Z Z in T φ I - S O \ N PQ S CO Z * Il 1 Z cn γ ( J I Ά

t O Cn

in rH X r-1 in in f-1 : ro ^, : ι-Η m ! O O U3 CS CJ I O O Xi CS I t.) : I in o τ W JJ in Q) σ \ * <s rH "-i W J £ CS I 1 σ »α) U-I CS -4 · p : f ». * r-l ^: : U = K r iH ^: • Z Q) ω r r \ / O O I • Λ O) PU ^s in I _x .A in in X ( X I ό CU ί ο ι \ ^ "*

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to: o

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Table 5 (cont.)

³ Me (S-fprm) H H H H Me - ^N \ ^x Me 1 1 I HCl 163-164.5 [EtOH-Me ₂ CO] * k 109 ^pho ^ O (S-form) Il •1 Il Il It Il It It 187.5-188.5 [MeCN] no * ^h ·· Il Il Il © ^ Me -N-Me ^ Me η If 1/2 1,5-naphthalene-disulfonic acid 168-170 (Zers.) 111 i-Pr Il Il Il Il Me ^x Me ti Il - oily

Table 5 (cont.)

112

OH

me

BzO

me

171-173 [EtOH-Et ₂ O]

Remarks:

Optical rotation = -43.3 ° (27 ° C, c = 3, EtOH)

»« = -43.3 ° (24 ° C, c = 3, EtOH)

Obtained by treatment of Compound No. 81 with p-toluenesulfonic acid A trityl group was used as an amino-protecting group Optical rotation = -38.9 ° (28 ° C, c = 1.5, MeOH)

"= -45.8 ° (25 ° C, c = 1.5, MeOH)

385

¹¹ "

(, (25 ° C, (5 ° C

5, 5, c = 1.5, MeOH)

" = -38.5 ° (25 ° C, c = 1.5, EtCil) Obtained by reacting 1 mole of a dimethylamine form with 0.5 mole of dime thy 1-

5npahthalindisulfonat

1.5 npahthalindisulfonat

: optical rotation = +37.3 ₀ . η "+40.2 η" = + 28.4 °

c = 1.5, MeOHj c = 1.5, MeOH c = 1.5, EtOHj

Production Example 4

A mixture of 5.00 g 1-benzyl-4-hydroxypiporidin, 1.97 g of potassium tert-butoxide and 4 mL Dimuthylsulfoxid is heated to 80 ⁰ C. 2.10 g of styrene oxide are added dropwise during 40 minutes, and the resulting mixture is stirred for 3 hours at the same temperature. The reaction mixture is poured into a mixture of 100 ml b'ls water and 80 ml ethyl acetate. The pH of the mixture is adjusted to 11.5 with 6N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (eluent; chloroform / ethanol = 10/1). The resulting oily product is dissolved in 8 ml of ethanol and the solution is treated with 1 ml of a 6 N dry hydrogen chloride-ethanol solution and 20 ml of diethyl ether. The mixture is stirred for 30 min at room temperature ¹ . The resulting crystals are collected by filtration, washed in a rv ^v hung from 2 ml of ethanol and 2 ml of diethyl ether and dried; 930 mg of 2- (1-benzylpiporidin-4-yl-oxy) are obtained

1-phenylethnnol hydrochloride (Compound No. 113); Mp 193-195 ⁰ C.

The compounds listed in Table 6 were obtained in the same way.

In Table 6, R ¹ , R ² , R ¹ , R *, R ^e and η each show a substituent or an integer, as in the following formol

used:

R is -CH-CH-O-f-CH -) - R ¹

¹ 2 OR ^

Table 6

Connection no. R ¹ me Il R ² R ³ R ⁴ R ⁶ η Addition salt ζ Mp CC) 114 H ti - - / N-Dz 0 HCl 100-101.5 [ΙΡΛ] 115 O- Il Il M . < Il 202-204 ^N Bz 116 11 It Il "Φ 11 - 119-120

in ι

in o

r-H U r-i

η ω ο

in S · <->

ri ^ W

• H H: o

Ohh O

r-i

CO

r-i

O CS

in - I in in ι-ι • 4J • • O M σ " OO U co O f-i in ro CS I i-l υ ω r-H ω JJ I <CU I I S rH W in > - · M in t U-I oo O> - < • t-l U • ro ι w w X iH co rij CU oil Z in rh rh I I S r α) Γ I-l : : : <O> ^{1 year} (O) X - • * Z X (S : O Oil N l-l m CS r \ ro r-H CS CS r-l

Table 6 (cont.)

125 me qr H H H "CO) 1 HCl oily 126 · Cl ·· Il ·· / I • I ·· If 127 Il Il • 1 Br Tof • 1 · ti 128 Il M It  I - ti

in

HI

-p W

in

I

ri VO

HI

4JW

W (U CN M 1 I in O

in he «

oo

(D H H Φ

(N

σ "

ro

ro -κ (N

Cn »- *

147.5-149 [IPA AcOEt] Fl 104.5-106.5 [IPA AcOEt] 220-221 [EtOH AcOEt] HCl • : = rh ⁵ Z {ZX X "Λ S X " * = : X - : = 6 U Λ UI ώ : ro ro ro ri ro ro ό ro VO ro ro in ro

in

in ηi-H

-U

W CM υ

ιη

in

in

m in

o: o

co co

co co

"Η

Table 6 (cont.)

141 ^Me O H H H - (P) 1 - 84.5-85.5 [EtOH IPE] 142 ··  · M Il M 65.5-66.5 [EtOH-IPE] 143 It • 1 <l H " 68-69 [EtOH-I ^ E ¹

(25: C, c = 1, MeOH) (° O)

Comments: ο

+1: optical rotation = +23.3 "(5 :,,

»= -22.5 (25 ° C, c = 1, MeOH)

The reaction is effected using a trityl group as the amino-protecting group

4s The reaction is carried out using a formyl group as an amino-protecting group

causes

Production Example 5

(1) A mixture of 4.30 g of 4o: -n-2-hydro- kymothylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethy- lene sulfoxide is heated at 80 ° C and heated to 50 ° C over 20 min with 2.50 g of styrene oxide , The resulting mixture is stirred for 2 hours at the same temperature. The crude mixture is added to a mixture of 30 ml of diethyl ether and 30 ml of ice-water. The organisriio layer is abgotronnt and mixed with 10ml of water. The mixture is adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer is separated and mixed with 30 ml of diethyl ether. The mixture is adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography (eluent: toluene / ethyl acetate = 1/1); this gives 2.00 g of oily 1-Phonyl-2- | (4-benzylmorpholin-2-yl) -methoxyl ·

ethanol (compound no. 144).

In the same way, the compounds listed in Table 7 are obtained.

In Table 7, R ¹ , R ² , R ³ , R ⁴ , R ^e and η each represent a substituent or an integer, as in the following formula

used:

pj

S-9

O I

Φ H H Φ

Di- U I

K Pi

υ- ο

ο o

Mp.

ΙΛ

C. O

• ι-N

• σ ι-

• Ο Ό

 a; ιλ

UJ

pi

P!

pl

PJ

<N PJ

PJ

-W-

·

bO «3

in H

νο

-ι · H

fcO: o

u fr

ο in H

(2) A mixture of 1.00 g of 1-phenyl-2 - [(4-benzyl-morpheiin-2-yl) methoxy] ethanol, 500 mg of 5% palladium on carbon and 10 ml of methanol is allowed to stand at room temperature for 4 hours hydrogenated under atmospheric pressure. After completion of the reaction PaUadiumau'-coal is filtered off and the solvent removed by desolation under reduced pressure. The residue is purified by column chromatography (eluent: chloroform / methanol = 10/1). 450 mg of an oily product are obtained, which is dissolved in 2.5 ml of isopropanol. The solution is mixed with 220 mg fumaric acid and the mixture is stirred for 1 h at room temperature. The resulting crystals are collected by filtration, washed with 2 ml of isopropanol and dried; 460 mg of 1/2-fumarate of 1-phenyl-2 - [(morpholin-2-yl) -fiethoxy] -ethanol (Compound No. 151) are obtained; Mp. 146.5 to 147 ⁰ C [EtOH]. In the same way, the compounds listed in Table 8 are obtained.

In Table 8 R ^1, R ^2, R ^3, R *, R ⁵ and η respectively show ^": NEN substituents or an integer, as used in the following formula:

R3 R4

I i

- CH - CH - O - t CH -) ^ - R6

0R2

Table 8

Connect. No. R me R2 R3 R4 R6 η Addi ti ent salt Mp ( ⁰ C) 152 Cl H H H -Q. 1 1 /? - fumaric acid 155-156 [EtCH] 153 ^ph0H Q- Il Il Il Il Il HCl Amorphous 154 Il Il Il Il Il 1/2 fumaric acid 142-142.5 [EtOH-Me2C0]

(3) Dissolve 7g of 1- (3-methoxyphenyl) -2 - [(4-yitylmorpholin-2-yl) methoxy] ethanol in 35 ml of acetone and, under ice-cooling, add 2.6 ml of 5.9 to the solution N dry hydrogen chloride-ethanol solution. The mixture is stirred for 2 h at room temperature. After completion of the reaction, the solvent is removed by distillation under reduced pressure. To the residue thus obtained are added 50 ml of water and 30 ml of ethyl acetate. The aqueous layer is separated and washed with ethyl acetate. To this is added 50 ml of chloroform and the pH of the resulting mixture is adjusted to 11 with 1 N aqueous sodium hydroxide solution. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue thus obtained is purified by column chromatography (eluent: chloroform / methanol = 5/1); 1 g of oily product is obtained, which is dissolved in 3 ml of isopropanol. To this is added 430 mg of fumaric acid and the mixture is stirred for 1 h at room temperature. The resulting crystals are collected by filtration and dried; 800 mg of 1/2-fumarate of 1- (3-methoxyphenyl) -2 - [(morpholin-2-yl) methoxy] ethanol (Compound No. 155) are obtained. Mp 122-123.5 ° C [EtOH]

 In the same way, the compounds listed in Table 9 are obtained.

In Table 9, R ¹ , R ² , R ³ , R ⁴ , R "and η each show a substituent or an integer as used in the following formula:

R3

Rl-CH-CH-O

R4

0R2

Table 9

Connect. No. R ¹ R2 R3 R4 R6 η Additive selz Mp. (° C) 156 H H Ξ V.NH 1 1/2 Fumar . sä'zre 147-148.5 [EtOH] 157 Il Il Il ti Il Il 126-127 [IPA]

Production Example 6

(1) 5.1 g to 105ml potassium tort.-butoxide was ethylene glycol mono-tert-butylethor added and the mixture heated to 8O ⁰ C. To this is added dropwise during 1 h 35.0g 2- (3-chlorophenyl) -oxirane and the mixture is stirred for 2 h at dor gloichen temperature. The reaction mixture is added to a mixture of 100 ml of ice-water and 100 ml of ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is subjected to further distillation under reduced pressure; This gives 37.7 g of colorless, oligo 1- (3-chlorophenyl) -2- (2-tert-butoxyethoxy) ethanol, bp 140 to 146 ° C / 0.9i, imHg.

(2) Dissolve 37.0 g of 1- (3-chlorophenyl) -2- (2-tert-butoxyethoxy) ethane I in 70 mL of methylene chloride. To the solution are added 12.9 g of pyridine and 16.6 g of acetic anhydride. The resulting mixture is praised for 24 hours at room temperature. The reaction mixture is added to a mixture of 150 μl ice-water and 100 ml ice-water and 100 ml Mothylenchlcrid. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated, washed with saturated aqueous sodium hydrogencarbonate solution and water in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 40.0 g of oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-: tert-butoxysthoxy) ethane are present.

(3) Dissolve 40.0 g of 1-acetoxy-1- (3-chlorophenyl) -2- (2-tert-butoxyethoxy) dithan in 40 ml of methylene chloride and, while cooling with ice, add 80 ml of trifluoroacetic acid to the solution. Co mixture is stirred for 2 h at room temperature. After completion of the reaction, the solvent is removed under reduced pressure by distillation. The residue is mixed with 100 ml of toluene and the solvent is further removed by distillation under reduced pressure. The residue thus obtained is dissolved in a mixture of 90 ml of ethanol and 10 ml of water. To the solution is added at room temperature 10.7 g of sodium V / bicarbonate. The mixture is saturated. Aqueous sodium bicarbonate solution adjusted to pH 6 to 7 and then concentrated under reduced pressure to about the h.oilt of its volume. The concentrate is mixed with 100 ml of ethyl acetate. The organic layer is separated and the aqueous layer extracted with 50 ml of ethyl acetate. The t'xtrakt is combined with the ruvor separated, organic layer. The combined organic layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous Magnosiu.nsulfat. The solvent is removed by distillation under reduced pressure and the residue is purified by column chromatography (eluent: toluene / ethyl acetate = 3/1); This gives 19.4 g of oily 1-acetoxy-1 - (3-chlorophenyl) -2- (2-hydroxy8thoxy) ethane.

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

(5) 1.40 g of 1-acetoxy-1- (3-chlorophenyl) -2- (2-methanesulfonyloxyethoxy) -ethane are dissolved in 7 ml of N, N-dimethylformamide. The solution is treated with 0.69 ml of N-methylpiperazine and 1.03 g of potassium carbonate and the mixture is stirred at 80 ° C. for 3 hours. The reaction mixture is cooled and added to a mixture of 30 ml of ice-water and 30 ml of diethyl ether. The organic layer is separated and the aqueous layer extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue thus obtained is mixed with 7 ml of methanol and 45 mg of sodium methoxide, and the mixture is allowed to stand overnight at room temperature. The solvent is removed by distillation under reduced pressure. The residue thus obtained is mixed with 7 ml of methanol and 45 mg of sodium methoxide, and the mixture is allowed to stand overnight at room temperature. The solvent is removed by distillation under reduced pressure. The residue thus obtained is mixed with 20 ml of ethyl acetate and 10 ml of water and the organic layer is separated off. The aqueous layer is extracted with 20 ml of ethyl acetate. The extract is pre-purified with the previously separated organic layer. The combined organic layer is washed with saturated aqueous sodium chloride solution and then purified by column chromatography (eluent: chloroform / methanol = 10/1). The resulting oily product is added with 10 ml of ethanol and 1.2 ml of a 6 N dry hydrogen chloride-ethanol solution in this order. To the resulting mixture is added 10 ml of diethyl ether and the mixture is stirred for 30 min. The resulting crystals are collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether and dried; 770 mg of 10 -O-chlorophenyiO-tf-M-methylpiperazine-i-yD-ethoxylethanol dihydrochloride (Compound No. 158) are obtained; Mp. 211 to 213 ⁰ C (MeOH-EtOH).

In the same way, the compounds listed in Table 10 are obtained.

In Table 10, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and η each show a substituent or an integer, as in the following formula

used:

"-

ο

i-l

pi

Oi O

O • ι bO in = bO ^ 1 O ₌ O a σ s bO (U W O £ IO VO O η ? £ ο • H C : ο ro · - · H 4 y :O = I P << ω η = !O t ό O I PM in η L / ³ ^ S o = o = ro --J M ro ¹ ^ t ι-ι V H VO VO • IM ro H VO rh H or- H -σ <ν <Γ ι /). C ι - H I U W VO Pi = = S = = O ι-ι ^w VO / H O τ- Φ H η Pi Φ pi , α αϊ 1. "(. W EH ω • 2 "φ> σν in

Table 10 (cont.)

164

O-

Bz

HCl

164.5 166.5

165

169-171 [EtOH]

166

N N-Me

2HCl

169-171

[CH ₂ Cl ₂ -

EtOH]

167

N N-DPM

104.5 105.5 [EtOH]

168

me

^: oily _

tfa

169

• Me Me Me

1/2 1,5-naphthalene.

• disulphonic acid

.- 208-210 [MeOH-Et ₂ O]

Bemerkimg:

+ a: 1 mole of a dimethylamino form w ^ Lrd reacted with 0.5 mole of dimetliyl-1,5-naphthalenedisulfonate to image the target product

Production Example 7

A mixture of 2.0 g of 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) -ethoxy] -ethanol :: ydrochloride, 500 mg 10%

Palladium-on-carbon and 10 ml of methanol are hydrogenated for 2 h at room temperature under atmospheric pressure. After completion of the

Reaction is removed palladium on carbon by filtration. The solvent is diminished by destination

Pressure removed; This gives 1.4 g of 1- (4-hydroxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] -ethanol hydrochloride (Compound

No.170); Mp. 169.5 to 170.5 ⁰ C [EtOH].

In the same way, the compounds listed in Table 11 are obtained.

In Table 11, R ¹ , R ² , R ³ , R ⁴ , R ^e and η each show a substituent or a whole number as in the following formula

used:

R3

Rl -

CH-CH-O-f CH -) -

OR2 table 11

Connection, no.

R2

R3

Addi ts salts

HQ

b-

HCl

150-152 [EtOH]

ac

Amorphous

HO. HO

Oily

n:

HCl

145-147

H O W

"Ν

bO • Η H: o

ιη

H H

U "

in

νο

Production Example 8

Add C, 65 ml of pyridine and 0.99 ml of acetic anhydride to 1 g of 1- (3-methylpheny!) -2- [2- (morpholin-4-yl) -ethoxy] -tranol and stir the mixture for 3 h at room temperature. The reaction mixture is subjected to distillation under reduced pressure to remove the solvent. The residue is mixed with 20 ml of ethyl acetate and 10 ml of water. The pH of the mixture is adjusted to 10 with potassium carbonate. The organic layer is separated, with water and saturated, aqueous

The sodium chloride solution was washed in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform / ethanol = 30/1); one obtains ι g of oily 1-acetoxy-1-i3-methylphenyl) -2- [2- (morpholine

4-yl) - "; hoxy] ethane (Compound No. 178).

In the same way, the compounds listed in Table 12 are cured.

In Table 12, R ¹ , R ² , R ³ , R ⁴ , R ^e and each represent a substituent or an integer, as in the following formula

used:

R3

R1 - CH - CH - O

R4 C

OR 2

Table 12

/ Connection, no.

Ri

R2

R3

Addi ti oris sal ζ

fp

me

ac

oily

n;

• Me Me

n:

182 * e

PhSO ₂ NH

n:

FCI

174.5 -176.5 [EtOH]

Table 12 (cont.)

183 BzO D- AC H H ^ -Me N ^ * ^ Me 2 HCl 169.5 - 170.5 [EtOH] 184 Il Il ·· Il Il Il 131.5 - 132.5 [Me ₂ CO] 185 AcO Il It Il Il Il Il oily 186 Il Il Il Il Il - oily 187 ^ph "O" Il Il Il ti ti Il 144.5 - 146.5 [EtOH-Et ₂ O] 188 O- ac H H T X HCl Oily

Remarks:

+ d: The indicated compound is by reaction of the compound no. 174 with

Acetic anhydride obtained

e: The indicated compound is obtained by reacting Compound No. 177 with benzenesulfonyl chloride in pyridine

"Oh, I

IS) (0 (O

(O OS

Hereditary Bells 9

Add 50 ml of a 1: 1 mixture of chloroform and water to 3.30 g of 1-acyloxy-1- (3-hydroxyphonyl) -2- (2- (N, N-dimethylamino) -ethoxy] -ethane hydrochloride and spiked the mixture under ice-cooling with 750mg of sodium carbonate. the organic layer is separated and dried with anhydrous magnesium sulfate. the solvent is removed by distillation under reduced pressure, and the residue treated with 20 ml of mixed benzene the mixture is heated to 6O ⁰ C and the resulting solution. Over a period of 10 minutes, a solution of 870 mg of ethylisocyanate dissolved in 5 ml of benzene is added dropwise, the mixture is stirred for 40 minutes at the same temperature, and after the reaction has ended, the solvent is removed by distillation under reduced pressure and the residue obtained is passed through Column chromatography (eluent: chloroform / ethanol = 10/1) to give an oily product which is dissolved in 10 ml of ethanol, hydrogen chloride gas is added to the solution g. inoblasone and the solvent removed by distillation under reduced pressure; This gives 1.90 g of i-acetoxy-i-IS-IN-ethylcarbamoyloxyl-phenylJ ^ -tf-IN.N-dimethylamino) -ethoxyl-ethane hydrochloride (Compound No. 189); Mp. 111.5 to 113.5 ⁰ C [Me ₂ CO]. Oily 1-acetoxy-1-IS-O-chlorophenylcarbamoyloxyl-phenyll-1-N-dimethylaminolethoxy-ethoxy-hydrochloride (Compound No. 190) is obtained in the same manner.

Manufacturing Bills 10

(1) 9.5 g of potassium tert-butoxide are added to 92 ml of ethylene glycol and the mixture is heated to 8O ⁰ C. A solution of 34.7g 2- (4-benzyloxyphenyl) oxirane is added dropwise within 3 h, dissolved in 220 ml Dimethyl sulfoxide, and the resulting mixture is stirred for 30 minutes at the same temperature. The reaction mixture is cooled to room temperature and added to a mixture of ice-water and 600 ml of ethyl acetate. The resulting mixture is adjusted to pH 7 with 6 N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate. The extract is combined with the previously separated organic layer. Dio combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and dc ^r residue thus obtained (eluent: chloroform / ethanol = 10/1) by column chromatography; This gives 25 g of 1- (4-benzyloxyphenyl) -2- (2-hydroxyethoxyl-ethanol; mp. 116.5 to 117 ⁰ C (MeCNl.

(2) One 22,7g 1- (4-benzyloxyphenyl) solves -2- (2-hydroxyethoxy) ethanol in 140 ml of pyridine and the solution is cooled to -20 ⁰ C. The solution is treated with 19 g p-toluenesulfonyl chloride, the resulting Mixture heated to ^{0 0} C and stirred for 15h at the same temperature. The reaction mixture is added to a mixture of 300 ml of ice-water and 200 ml of diethyl ether, and the pH of the resulting mixture is adjusted to 2 with 6N hydrochloric acid. The organic layer is separated and the aqueous layer extracted with 100 ml of diethyl ether. The extract is combined with the previously separated organic layer. The combined organic layer is washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution in the following order and dried over water-free magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by column chromatography (eluent: toluene / ethyl acetate = 3/1); 20.5 g of oily 1- (4-benzyloxyphenyl) -2- [2- (p-toluenesulfonyl) -oxyethoxyl-ethanol are obtained.

(3) To a mixture of 20 g of 1- (4-benzyloxyphenyl) -2- [2- (p-toluenesulfonyloxy) -ethoxy] -ethanol and 40 mL of methylene chloride containing 8.2 g of 3,4-dihydro-2H-pyran at room temperature, 2.3 g of pyridinium p-toluenesulfonate. The resulting mixture is refluxed for 30 minutes. The reaction mixture is cooled to room temperature and added to a mixture of 100 ml of ice-water and 100 ml of methylene chloride. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 18.6 g of light yellow, oily 1- (4-benzyloxyphenyl) -1- (2-tetrahydropyranyloxy) -2- | 2- (p-toluenesulfonyloxy) -ethoxy] -ethane are obtained.

(4) A mixture of 2 g of 1- (4-benzyloxyphenyl) -1- (2-tetrahydropyranyloxy) -2- | 2- (p-toluenesulfonyloxy) -ethoxy] -ethane, 5.9 mL of a 40% aqueous methylamine solution and 20 ml of ethanol is refluxed for 2 h. The reaction mixture is cooled and added to a mixture of 50 ml of ice-water and 50 ml of diethyl ether. The organic layer is separated and the aqueous layer extracted twice with 20 ml of diethyl ether. The extracts are combined with the previously separated organic layer. The combined organic layer is mixed with 10 ml of water and the mixture is adjusted to pH 1.0 with 6N hydrochloric acid. The aqueous layer is separated and stirred for 30 minutes at room temperature. To this is added 30 ml of chloroform and the pH of the resulting mixture is adjusted to 12 with a 5% aqueous sodium hydroxide solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is mixed with 10 ml of acetone. With ice cooling, hydrogen chloride gas is injected into the mixture. The resulting crystals are collected by filtration, washed with acetone and dried; 620 mg of 1- (4-benzyloxyphenyl) -2- (2-methylaminoethoxy) -ethanol hydrochloride are obtained (Compound No. 19;); Mp. 173 to 173.5 ⁰ C IEtOH].

In the same way, the compounds listed in Table 13 are obtained.

In Table 13, R ¹ , R ² , R ³ , R ⁴ ", R ^4b , R ^6, and na and nb each show a substituent or an integer, as in the following

Formula used:

X)

ti

R)

ι-

ο ι

PJ

- o

OO έ ιη H U W ιη - -i-Pr • H ι _ ιη ο Λ ιη • ω • 180-18 [EtOH AcOEt; • (p O cn 58-158 [IPA] ° ω " 78-180 eCN-Et H C H H HS PO O • r- H ό • r- N ' H ο = X) γ- χ; = H "Xl IC (U j * -} = C ΙΛ Q) S Xl C (N CVJ <β β σ \ ₌ - η 0) Φ - U) Pi cn SJ S H \ /! 3 V O) H • α ¹ P! , ι υ «j · 0) PJ = EH " S P! H PJ Γ ζ ; & ⁵ O O  d X) ί- O) cn H

in

I <

in PM

• H

ro

I in

Ieoh

H (N

:O

• ° Ι «η s,

CO

in ι

in in

H O W (N

• ih i

"N

• P U O

VO

cn

cn

co cn

rh

¹ W 36-38 ρ oily H ,_, y T ι oily φ S 1Ig _ Φ I φ / UD Γ I ¹ S -μ φ / γ .63-16 [EtOH-MeCN] 8th : ο Z Z S O Z I U \> = ι ι ο • Il CN = ο H ι s HCl , I S-Z = = Γ4 H Z Z / S ν Φ H H S = CJ Φ I S-Z H I = O H a r = W \ / Z CN H = r-7 W Φ Φ 4J ν = α , Ω σΐ S W Y = EH \ / Z I ωζ Λ = Il j = = ₌ = Il 1 ο N CQ H ~ ο ro CN O ιη CN ο - CN CN O CN O

Table 13 (cont.) Il Il Il Il H   1 Il Il HCl 148.5 - 149.5 [IPA AcOEt] 208 Il Il Il Il Il Il Il It 173.5 - 175.5 [EtOH-Me ₂ CO] 209 O- Il Il Il Il -N-t-Bu H Il Il PTS 198-200 [EtOH AcOEt] 210 Il H H H H / Me ^x Me 1 1 ECI 161-162.5 [IPA AcOEt] 211 /O- me Il Il Il Il ti It Il oily 212 * 1 me Il Il Il Il Il Il - Il 213 * 1 " ^Bz0 "O"

Comment:

+1: The methoxylation is carried out using diazomethane-boron trifluoride

instead of 3,4-dihydro-2H-pyran, to obtain the desired product.

Manufacturing Bills 11

A mixture of 500 mg of 2 - [(imidazol-4-yl) methoxy) -1-phenylethanol, 1.1 ml of pyridine, 1.1 ml of triethylamine and 1.1 ml of acetic anhydride is stirred for 1 h at 10O ⁰ C and the cooled Reaction mixture from room temperature. The solvent is removed by distillation under reduced pressure and the residue treated with 1.1 ml of methyl iodide and 5 ml of acetonitrile. The mixture is allowed to stand at room temperature for 24 h. The solvent is removed by distillation under reduced pressure. To the residue thus obtained are added 4 ml of ethanol and 6.8 ml of 5% aqueous sodium hydroxide solution. The resulting mixture is stirred for 6 h at room temperature and the solvent is removed by distillation under reduced pressure. The obtained: Hackstand is mixed with 30ml of chloroform and 20ml of water. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the resulting oily product is purified by column chromatography (elution center: chloroform / ethanol = 10/1). Diisopropyl ether is added to the resulting white crystals and the resulting genic acid filtered; 450 mg of 2 - [(1-methylimidazol-5-yl) methoxy] -1-phenylethanol (Compound No. 214) are obtained; Mp. 102 to 105 ⁰ C.

The following compound is obtained in the same way: 1- (4-benzyloxyphenyl) -2 - [(1-methylimidazol-5-yl) methoxyethanol (Compound No. 215); Mp 148.5 to 150.5 ° C (IPA-AcOEtI.

Manufacturebelsplel 12

1.23 g of N, N'-dicyclohexylcarbodiimide are added, with ice cooling, to a solution of 1.08 g of 2- (2-aminoethoxy) -1-phenylethanol, 730 mg of nicotinic acid, 810 mg of 1-hydroxybenzotriazole and 0.83 ml of triethylamine dissolved in 5 ml of tetrahydrofuran. The resulting mixture is stirred for 5 minutes at the same temperature and for a further hour at room temperature. The reaction mixture is treated with 11 ml of ethyl acetate, and insoluble matters are filtered off. To the filtrate add 5 ml of water and adjust the pH of the mixture to 2 with 6N hydrochloric acid. The aqueous layer is separated and the organic layer extracted with 5 ml of water. The extract is combined with the previously separated aqueous layer. The combined aqueous layer is mixed with 20 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 15/1); 400 mg of oily 2- (2-nicotinoylaminoethoxy) -1-phenylethanol are obtained (compound no. IR (pure) cm " ¹ : v _c . _O 1635.

Manufacturing Balls 13

(1) Dissolve 5 g of (S) -4-benzyl-2-acetoxymethylmorpholine in 10 ml of ethanol and, under ice-cooling, add the solution to a solution of 1 g of sodium hydroxide dissolved in 5 ml of water. The mixture is stirred for 10 minutes at room temperature. D ^: e reaction mixture is added to 50 ml of ice-water and extracted with 50 ml of chloroform. The organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 30/1); 3.6 g of oily (S) -4-benzyl-2-hydroxymethylmorpholine are obtained.

(2) 3,5 g of (S) -4-benzyl-2-hydroxymethylmorpholine are dissolved in 5 ml of ethanol. 5 ml of a 5.9 N hydrogen chloride-ethanol solution are added to the solution while cooling with ice, and the resulting mixture is stirred for 10 minutes at the same temperature. To this is added a mixture of 500 mg 5% palladium-on-carbon and 10 ml of methanol. The resulting mixture is subjected to hydrogenation at 40 ° C for 3 hours. After completion of the reaction, palladium-on-carbon is filtered off and the solvent is removed by distillation under reduced pressure to obtain a yellow, oily product. 20 ml of dry methylene chloride and 4.7 ml of triethylamine are added to the oily product. The resulting mixture is stirred at room temperature for 30 minutes and then treated dropwise with a solution of 4.7 g of trityl chloride dissolved in 10 ml of methylene chloride for 20 minutes under ice cooling. The mixture is stirred for 3 h at room temperature and treated with 50 ml of ice-water. The organic layer is separated and 20 ml of water are added. The resulting mixture is adjusted to pH 12 with 1N aqueous sodium hydroxide solution. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; This gives a yellow, oily product which is mixed with 10 ml of diisopropyl ether. The resulting crystals are collected by filtration; 2.7 g of (S) -4-trityl-2-hydroxymethylmorpholine are obtained; Mp. 142.0 to 142.5 ⁰ C [AcOEt-IPE).

Optical rotation: [a] g ⁷ = -10.9 ° (c = 1, CHCl ₃ ).

In the same way, the (2R) -form having the following properties is obtained; Mp. 142.0 to 142.5 ⁰ C (AcOEt-IPE].

[a] g ⁷ = + 10.9 ° (c = 1, CHCl ₃ ).

(3) The same procedure as in (1) of Production Example 5 is repeated except that styrene oxide and 4-benzyl-2-hydroxymethylmorpholine are replaced by (S) -2-phenyloxirane and (S) -4-trityl, respectively 2-hydroxy-methylmorpholine be replaced. Oily (1S, 2'S) -1-phenyl-2 - [(4-tritylmorpholin-2-yl) methoxy] ethanol (Compound No. 217) is obtained.

(4) Dissolve (1S, 2'S) -1-phenyl-2 - [(4-tritylmorpholin-2-yl) -methoxy] -ethanol in 20 ml acetone and add, with ice-cooling, 7 ml of 5.9 N, except for the solution dry hydrogen chloride-ethanol solution. The resulting mixture is stirred at room temperature for 30 minutes to effect a reaction. After the reaction has ended, the solvent is removed by distillation under reduced pressure and the residue obtained is added to a mixture of 30 ml of ice-water and 30 ml. Ethyl acetate. The aqueous layer is separated and washed with 30 ml of ethyl acetate, after which 50 ml of chloroform are added. The resulting mixture is adjusted to pH 11 with 2 N aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure to give 1.9 g of a yellow, oily product, which is dissolved in 10 ml of ethanol. 720 mg of oxalic acid are added to the solution and the resulting mixture is heated to form a solution. The solution is allowed to stand overnight at room temperature. The resulting crystals are collected by filtration and dried; one he ^{k il} "1.8g (1 S, 2'S) -1-phenyl-2 - [(morpholin-2-yl) -methoxyl-ethanol oxalate (Compound ^No.218)!; Mp. 130 to 132 ⁰ C (EtOHl. K. ₁ "+ 19.9 ° (c = 1, CHCI _3).

In the same way, the following compounds are obtained:

(1R, 2'S) -1-phenyl-2 - [(morpholin-2-yl) -methoxy] -ethanol maleate (Compound No. 219); Mp. 136bis 136.5 ⁰ C (EtOH]; [aS ⁶ = -21.7 ° (C = LCHCI ₃₎

(IS ^ 'Rl-i-phenyl ^ ^ -Kmorpholin -YD-mothoxylVthanolmaloat (Compound Nr.22O); mp 136 to 136.5 ⁰ ClEtOH.); [a] J ⁶ = + 22.2 ° (C = I ₁ CHjOH)

(1R, 2'R) -1-phenyl-2-I (morpholin-2-yl) -methoxy-ethano! Oxalate (Compound No. 211); Mp 131 to 132.5 ⁰ C IEtOHl. (a) J ^b = -20.4 ° (C = I ₁ CH ₃ OH).

Production Example 14

(1) Dissolve 1.19 g of 4-benzylthiobenzaldehyde in 2OmI tetrahydrofuran and the solution is cooled to -1O ⁰ C Oa added dropwise within 10min 10ml of a tetrahydrofuran solution containing 2 M 2-Chlorethoxymethylmagnesiumchlorid. The resulting mixture is stirred for 1 hour under ice cooling. The reaction mixture is added to a mixture of 50 ml of ice-water, 50 ml of ethyl acetate and 1 g of ammonium chloride. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 20/1); 1.34 g of 1- (4-benzylthiophenyl) -2- (2-chloroethoxy) ethanol are obtained; Mp 49.5 to 50.5 ° C (hexane-IPE |

(2) A mixture of 600 mg of 1- (4-benzylthiophenyl) -2- (2-chloroethoxy) ethanol, 4 ml of a 50% aqueous dimethylamine solution, 310 mg of potassium iodide and 5 ml of ethanol is refluxed for 4 hours. The reaction mixture is further treated with 4 ml of a 50% aqueous dimethylamino solution and the resulting mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and the solvent is removed by distillation under reduced pressure. The residue obtained is mixed with 30 ml of ethyl acetate and 30 ml of water. The resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate, the solvent is removed by distillation under reduced pressure, the residue is dissolved in 15 ml of acetone and the solution is dissolved with 0.4 ml of 5N The resulting crystals are collected by filtration to give 590 mg of 1- (4-benzylthiophenyl) -2-I2- (N, N-dimethylamino) -ethoxy] -ethanol hydrochloride (Compound No. 222) ). mp 173.5 to 174.5 ⁰ C [EtOHl.

In the same way, the compounds listed in Table 14 are obtained. In Table 14, R ¹ , R ² , R ³ , R ⁴ \ R * ^b , R ⁶ , na, and nb each show a substituent or an integer, as in the following Formula used:

R3

I is R1-CH-CH-O

0R2

4b

C CI

4a

Table 14

-r6

Connection «Nr- rl O O R2 R3 4a 4b R6 n / A nb Addi ons-S al ζ Mp. (V. 223 H H H H --Me N ^^ "Me 1 1 HCl 194-195 [EtOH] 224 Il Il Il Il Il Il Il Il 207-208 [EtOH AcOEt] 225 » Il Il Il Il Il Il Il Maleic acid 168-170 (Zers.) 226 Il Il Il Il Il Il Il HCl 159.5 - 160.5 [EtOH AcOEt] 227 Il Il Il Il Il Il Il Il 141-142 [EtOH AcOEt]

N) CO (D.

Production Example 15

A mixture of 13.2 g of potassium tert-butoxide and 47.2 ml of 2- (N, N-Dimethylamlno) ethanol at 80 ⁰ C and added dropwise thereto while 3,5h40,0g2- (1-naphthyl) oxirane. The resulting mixture is stirred for 1.6 h at 80 to 85 ⁰ C. The reaction plate is cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice-water. The resulting mixture is mixed with 6! L hydrochloric acid adjusted to pH 11.5. The organic layer is separated and the aqueous layer extracted with 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is subjected to distillation to obtain a fraction of bp 152-163 ° C / 0.6-0.8 mm Hg. The recovered, oily product is dissolved in 200 ml of acetone. Hydrogen chloride gas is blown into the solution while cooling with ice. The resulting crystals are collected by filtration, washed with acetone and dried; 22.7 g of 2- [2- (N, N-dimethylamino) -ethoxy] -1- (1-naphthyl) -ethanol hydrochloride (Compound No. 228) are obtained; Fp.196bis 197 ⁰ C (EtOH]. In the same manner, the compounds listed in Table 16 are obtained.

In Table 15, R ¹ , R ² , R ³ , R ⁴ ', R ^4b , R ^e , na and nb each show a substituent or an integer as used in the following formula:

PS S3

-U

rl

W U.

O I

W U

u-

ν PS O

υ ο V g ο ι he "I m ι ro ij HUW Ι- »O" HUW I νΟ COO · "" HUW I ^ O a. ⁰ ^ ω crt (U YY CO (YYY  <* αϊ yy pm HIZZ  Ί * S W r-S W co S W 1.1 Η ¹ - · C O ,, ι  r υ • r- N W - ₌ - • σ ι- TD (O et ΙΛ C H m β H ^s (U (U : ₌ S S VO Qi \ / : ζ I H H Φ & PS W α ^{5 =} pi W W N W = = S = PS © «Υ / ^ ΖΓ \ ί. ¥ ® Ω t * (N ο H CN Cl CN CO Cl CO φ (N CN CN

to ho S CS rtj I Pt in in = • = in o  κ • Η ro H ro CS • j • (S ' O H USL s - r- W tu : ο CS I * j ρ ι ω ΙΛ ν- I S KCl in * W _ Hurry H CS H CS & (N ι S H = (U O) s ε ε \ / R - (P) 5 I 3 : ζ O W ζ = W - ₌ W VO S ro CS S W \ / (Q) CU / ε '  κ (Q) * ro ro (N ro (N ro CS

j • (Q 00 o / CO = hO S • - S I ⁼ t in (N / \ in'-· r H O H -l- » / ^ ¹ N \ H aj :O i fa vw \ ^ - * '/ I (U rH ω Q) a a ITV τ- \ / in"-· Ο) O I \ H S H in -U I H ^H S co ro _ r S Ο H CN H : Z O H rt ω ⁼ N Q) PQ a \ / Q EH ¹ H H O * CN M "CN * H M · CN Ω- \ IJ V ~ W m \ / Ld cn cn CN \ / * O ^ P CN

in H r H I s r Q) (N I • of 2 H in oo r O VO hg S 7 rf? CJ in - · UI · rtj = S Γ0 O \ ίη U (N VO (N in ft ω H • dft = O> rH. , • H +> -P H in η = H *-' in ft = in front\ ₌ in W-. IfIH " • H H in \ / H ^s VOv-J H I π VO φ Φ H W \ / r \ = W \ / \ V J / = w I \ * ~ ^ / ^s = r = = Z Z \ C j / ~ ₌ \ ^^^ / = (C) S S I (~ \ V / co - t ro \ - / O (N cn ΙΓΛ τ- lie I (~ \ (N φ > - ' I &

in l - *

• Hf g oo η γ.

H U

H H Φ .α cd

co

CN

00

co

H i in

I j

WHERE OO

4J H

(1) O)

CU

cn

CN

in

ow

where where

! Φ ¹ approx

cu

ο in

CN

in

in

CN

in a \ '->

I GO

CN

in

CN

cn

in ι-

I ft r * η in · - ·

a)

η in CN

Φ Λ

• Η Ο

-d

Manufacturing Bills 16

(1) A mixture of 6.0 g of 2-hydroxymethyl-4-tritylmorpholin, 1.0 g of potassium tert-butoxide and 6 ml of dimethyl sulfoxide is heated to 8O ⁰ C and added dropwise for 2 h at BO to 85 ⁰ C, a solution of 2.8 g of 2- (2-naphthyl) -oxirane gilled in 6 ml of dimethyl sulfoxide. The resulting mixture is stirred for 3 hours at the same temperatures. The reaction mixture is cooled and added to a mixture of 60 ml of ice-water and 60 ml of ethyl acetate. The organic layer was separated wild, washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent wire, removed by distillation under reduced pressure; One obtains 9.0 g of oily 1 "(2-naphthyl) 2 - [(4-tritylmorpholin-2-yl) methoxy] ethanol (Compound No. 254).

Similarly, oily 1- (1-naphthyl) -2 - ((4-tritylmorpholin-2-yl) methoxy) ethanol (Compound No. 255) is obtained.

(2) 9.0 g of 1 • (2-naphthyl) -2 - [(4-tritylmorpholin-2-yl) methoxy) -ethanel are dissolved in 50 ml of acetone and, while cooling with ice, the solution is mixed with 3.5 ml of a 5, 9 N hydrochloric acid-ethanol solution. The mixture is run for 2 hours at room temperature for the reaction. After completion of the reaction, the solvent is removed by distillation under reduced pressure and the residue obtained with 50 ml of water and 30 ml of ethyl acetate. The aqueous layer is separated and washed with 30 ml of ethyl acetate. To this is added 50 ml of ethyl acetate and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / methanol - 5/1); one gains 1.2g oily product. The oily product is dissolved in 5 ml of isopropanol and the solution is treated with 0.5 g of fumaric acid. The mixture is heated to form a solution and the solution is allowed to stand at room temperature overnight. The resulting crystals are collected by filtration; 0.9 g of 1- (2-naphthyl) -2 - [(morpholin-2-yl) methoxy] ethanol-1/2-fumarate (Compound No. 256) is obtained; Mp. 141 to 144 ⁰ C [EtOH].

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

Manufacturing label 17

(1) A mixture of 4.5 of potassium tert-butoxide and 45ml of ethylene glycol is heated to 80 ^c C and within 1 h treated dropwise with 13.7 g of 2- (1-naphthyl) -oxlran staggered '. The resulting mixture is stirred for 1 h at the same temperature. The reaction mixture is cooled and added to a mixture of 50 ml of ethyl acetate and 50 ml of ice-water. The organic layer is separated and the aqueous layer extracted twice with 20 ml of ethyl acetate each time. The extracts are combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 1/3); This gives 8.3 g of 2- (2-hydroxyethoxy) -1- (1-naphthyl-ethanol; mp. 91 to 92 ° C [IPE]).

In the same way, 2- (2-hydroxyethoxy) -1- (2-naphthyl) ethanol; Mp 105-106 ° C [AcOEt].

(2) Dissolve 8.3 g of 2- (2-hydroxyethoxy) -1- (1-naphthyl) ethanol in 50 ml of pyridine and the solution is cooled to -25 ⁰ C. To this is added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture is allowed to stand for 24 h at 0 to K ⁰ C and further for 4 h at room temperature. The reaction mixture is added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice-water and 100 ml of diethyl ether, and the pH of the resulting mixture is adjusted to 2.0 with 6 N hydrochloric acid. The organic layer is separated and the aqueous layer extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. The preconcentrated organic layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the obtained residue is purified by column chromatography (eluent: toluene / ethyl acetate = 10/1); 6.3 g of colorless, oily 1- (1-naphthyl) -2- [2- (p-toluenesulfonyloxy) -ethoxyl-ethanol are obtained. '

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

(3) 0.82 g of pyridinium p-toluenesulfonate are added to a solution of 6.3 g of 1- (1-naphthyl) -2- [2- (p-toluenesulfonyloxy) ethoxylethanol and 2.97 ml of 3,4-dihydroxyethanol]. 2H-pyran, dissolved in 63 ml of methylene chloride, at room temperature. The resulting mixture is stirred at the same temperature and additional 10 minutes at 35 to 4O ⁰ C 20min. The reaction mixture is cooled, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate 10/1) to give 7.53 g of colorless, oily 1- (1-naphthyl) -1- (tetrahydropyran-2 -yl-oxy) -2- [2- (p-toluenesulfonyloxy) -ethoxy-ethane.

Similarly, colorless, oily 1- (2-naphthyl) -1- (tetrahydropyran-2-yl-oxy) -2- [2- (p-toluenesulfonyl-oxy) -ethoxy] -ethane is obtained.

(4) A mixture of 7.5 g of 1- (1-naphthyl) -1- (ietrahydropyran-2-yl-oxy) -2- [1- (p-toluenesulfonyloxy) -ethoxy] -ethane, 2.65 ml of N- Methylpiperazine, 3.96 g of potassium carbonate and 38 ml of Ν, Ν-dimethylformamide is stirred at 90 to 100 ⁰ C for ² h. The reaction mixture is cooled to room temperature and treated with a mixture of 100 ml of diethyl ether and 100 ml of ice-water. The organic layer is separated and the aqueous layer extracted twice with 25 ml of diethyl ether.

The extracts are combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1); 3.36 g of colorless, oily 2- [2- (4-methylpiperazin-1-yl) ethoxy] -1- (1-naphthyl) -1- (tetrahydropyran-2-yl-oxy) -ethane (Compound No. .258).

(5) In 30 ml of acetone is dissolved 3.3 g of 2- [2- (4-methylpiparazin-1-yl) -ethoxyl-1- (1-naphthyl) -1- (tetrahydropyran-2-yl-oxy) -ethane. At room temperature, 3.46 g of p-toluenesulfonic acid monohydrate and 7 ml of water are added to the solution. The resulting mixture is stirred for 30 minutes at the same temperature and for a further hour at 40 ° C. The reaction mixture is added to a mixture of 60 ml of chloroform and 60 ml of ice-water. The mixture is adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer extracted with 20 ml of chloroform. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 40 ml of acetone. Hydrogen chloride gas is blown into the solution while cooling with ice. The resulting solution is stirred for 30 min at room temperature and then treated with 40 ml of diethyl ether. The resulting mixture is stirred for 30 minutes at the same temperature. The resulting crystals are collected by filtration, washed with acetone and dried; 2.35 g of 2- (2- (4-methyl-1-naphthyl) -ethoxy] -1- (1-naphthyl) -ethanol dihydrochloride (Compound No. 259) are obtained, mp 230.5 to 231.5 ⁰ C [MeOH].

Manufacturing Bullet 18

The same procedures as in (4) and (5) of Production Example 17 are repeated, but substituting N- (p-fluorobenzoyl) -piperidine for N-methylpiperazine; 2- [2- (4- (p-fluorobenzoyl) -piperidin-1-yl) -ethoxy] -1- (1-naphthyl) -ethanol hydrochloride (Compound No. 260) is obtained; Mp 204.5 to 205.5 ⁰ C [MeOH. |.

Manufacturing Bullet 19

Dissolve 2 g of 1- (1-naphthyl) -1- (tetrahydropyran-2-yl-oxy) -2-I2- (p-toluenesulfonyloxy) -ethoxy) -ethan in 20 ml of ethanol and the solution is added at room temperature with 6 , 60g of a 40% aqueous methylamine solution. The mixture is refluxed for 1 h. The reaction mixture is cooled and added to a mixture of 20 ml of ice-water and 50 ml of diethyl ether. The organic layer is separated and the aqueous layer extracted with 20 ml of diethyl ether. The extract is combined with the previously separated organic layer. To the combined organic layer is added 15 ml of water and the pH of the resulting mixture is adjusted to 1.5 with 6 N hydrochloric acid. The aqueous layer is separated and the organic layer is extracted twice with 10 ml of water each time. The extracts are combined with the previously separated organic layer. The combined aqueous layer is mixed with 25 ml of chloroform and adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer extracted twice with 10 ml of chloroform. The extracts are combined with the previously separated organic layer. The combined organic layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; This gives 1.27 g of oily product, which is dissolved in 10 ml of acetone. Under ice-cooling, hydrogen chloride gas is blown into the solution. Add 10 ml of diethyl ether and collect the resulting crystals by filtration; 0.72 g of 2- | 2- (N-methylamino) -ethoxy) -1- (1-naphthyl) -ethanol hydrochloride (Compound No. 261) is recovered; Mp 137.5bin 139 ⁰ CiIPA]. The compounds listed in Table 16 were obtained in the same manner.

In Table 16, R ¹ , R ² , R ³ , R ⁴ ", R ^4b , R ^e , na and nb each show a substituent or an integer as used in the following formula:

-CH-CH-OH-CH -, L2 ua

n / A

R {-CH

4b

nb

Table 16

Connect. No. • R ¹ R ² R ³ R ^4a R ^4b R ⁶ n / A nb Addition salt Z Mp ( ⁰ C) 262 H H H H i-Pr 1 1 HCl 180-181 [EtOH] 263 Il Il ti Il Il ^X H Il ·· - 159.5-162 264 Il Il Il Il Il / t-Bu -N ^ H   1 Il 1/2-year-old acid 184-185 [IPA-AcOEt] 265 Il 11 Il Il / Me -N ^ H Il Il HCl 170-171 [EtOH] 266 Il   I Il Il Il i-Pr ^ H Il Il Il 180.5-181.5 [IPA-EtOH]

Production Example 20

Heating a mixture of 3.5 g of potassium tert-butoxide, 9.4 g of N-Tritylethanolamin and 50ml of dimethylsulfoxide at 85 ⁰ C, gives 5.3 g of 2- (1-naphthyl) oxirane added and the resulting mixture stirred for 5 min at the same temperature. The reaction mixture is cooled and added to a mixture of 100 ml of ethyl acetate and 150 ml of ice-water. The organic layer is separated and the aqueous layer extracted with 50 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. To the residue obtained are added 80 ml of a 50% aqueous formic acid solution and 40 ml of tetrahydrofuran. The resulting mixture is stirred for 1 h at 50 to 60 ⁰ C and cooled, the reaction mixture. The solvent is removed by distillation under reduced pressure. To the obtained residue are added 60 ml of ethyl acetate and 60 ml of water and the pH of the resulting mixture is adjusted to 2 with 6N hydrochloric acid. The aqueous layer is separated and the organic layer extracted twice with 15 ml of water. The extracts are combined with the previously separated aqueous layer. To the combined aqueous layer is added 100 ml of chloroform and the pH of the resulting mixture is adjusted to 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. D: isungsmittel removed by distillation under reduced pressure. 10 ml of diisopropyl ether are added to the residue obtained. The resulting crystals are collected by filtration and dried; 1.8 g of 2- (2-aminoethoxy) -1- (1-naphthyl) ethanol (Compound No. 267) are obtained; M.p. 98.5 to 92 ° C [CHCl-Et ₂ O].

Production Example 21

7 ml of water and 7 ml of dioxane are added to 0.7 g of 2- (2-aminoethoxy) -1- (1-naphthyl) -ethanol to form a solution. To the solution is added 0.32 g of potassium carbonate and the resulting mixture is heated to 50.degree. 0.35 g of 2-chloropyrimidine are added and the resulting mixture is refluxed for 3 hours. 0.32 g of potassium carbonate and 0.35 g of 2-chloropyrimidine are added. The resulting mixture is refluxed for 2.5 hours. The reaction mixture is cooled and added to a mixture of 20 ml of ethyl acetate and 20 ml of ice-water. The organic layer is separated and the aqueous layer extracted with 10 ml of ethyl acetate. The extract is combined with the previously separated organic layer. To the combined organic layer is added 15 ml of water and the pH of the resulting mixture is adjusted to 1.5 with 6 N hydrochloric acid. The aqueous layer is separated. The organic layer is extracted with 10 ml of water. The extract is combined with the previously separated aqueous layer. The combined aqueous layer is mixed with 50 ml of methylene chloride and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 20/1); an oily product is obtained, which is mixed with 4 ml of ethanol and 0.21 g of maleic acid. The reIuitierende mixture is stirred for 1 h at room temperature. To the reaction mixture is added 2 ml of diethyl ether and the resulting mixture is stirred for 1 h at the same temperature. The resulting crystals are collected by filtration and dried; 0.53 g of 1- (1-naphthyl) -2- [2 - [(pyrimidin-2-yl) amino] ethoxy] ethanol maleate (Compound No. 268) is obtained; Mp. 101.5 to 103 ⁰ C [EtOH-AcOEt].

Hortensbelsplol 22

With ice-cooling, 0.62 g of N, N'-dicyclohexylcarbodiimide are added to a mixture of 0.7 g of 2- (2-aminoethoxy) -1- (1-naphthyl) ethanol, 0.37 g of nicotinic acid, 0.41 g of 1-hydroxybenzotriazole, 0.42 ml of triethylamine and 4 ml of tetrahydrofuran. The resulting mixture is stirred for 5 minutes at the same temperature and further for 1 hour at room temperature. To the reaction mixture is added 6 ml of ethyl acetate and insoluble matters are removed by filtration. To the filtrate are added 15 ml of ethyl acetate and 20 ml of water, and the pH of the resulting mixture is adjusted to 2 with 6N hydrochloric acid. The aqueous layer is separated and the organic layer extracted twice with 10 ml of water. The extracts are combined with the previously separated aqueous layer. To the combined aqueous layer is added 30 ml of chloroform and the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1). An oily product is obtained, which is dissolved in 7 ml of acetone. 0.43 ml of a 5 N dry hydrogen chloride-ethanol solution is added to the solution, and the resulting mixture is stirred for 1 hour at room temperature. To the reaction mixture is added 3 ml of diethyl ether and the resulting mixture is stirred for 1 h at the same temperature. The resulting crystals are collected by filtration and dried; 0.67 g of 1- (1-naphthyl) -2- (2- (nicotinoylamino) -ethoxy) -ethanol hydrochloride (compound no. 269) are obtained; Mp. 162.5 to 163.5 ⁰ C [EtOH-AcOEtI.

Production Example 23 Repeating the process described in (1) of Preparation Example 16, but using instead of 2- (2-naphthyl) -

oxirane and 2-hydroxymethyl-4-tritylmorpholine 2- (1-naphthyl) oxirane and 1,4-diformyl-2-piperazinylmethanol, respectively

Oily 2 - ((1,4-diformyl-piperazin-2-yl) -methoxy] -1- (1-naphthyl) -ethanol (Compound No. 270).

In the same way, the compounds listed in Table 17 are obtained. In Table 17, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and η each show a substituent or an integer, as in the following general Formula used:

U-I

it - ο

H H Φ

CN

κ it υ -ο

• · _ _ QJ r. W σ -Ρ Σ (U ο M H H H O in I r ¹ ° ι υ • 4y OO << + J η W σ »· - in w r ^ O 1-1 co O I υ (O)- ι υ CN ι < / \ η ι < Γ »* - ' β (Ο) 00 '-' = _ < from OS Γ- (N ^ CS = η OS = CN it rh it TJ •H& (Ο) η U 'Φ CN (N (N

Production Example 24

toff-ethanol solution. The mixture is left overnight at room temperature

ifi "Strr ^KriSta " o Τ * ⁶ " ^dehydration 9 is ^collected - washed ^with ethanol and dried; man - (1-naphthyl) -2 - [(piperazin-2-yl) -methoxy] -ethanoldihydrochloride (precursor No. 274); Fp.199bis201 ^<> C (Zers.).

Herstellungsbelspie! 25

The compound obtained in the same manner as in (1) of Production Example 16 is reacted with hydrogen chloride gas in the same manner as described in the preparation of the hydrochloride of Preparation Example 22; the compounds listed in Table 18 are obtained.

UiiS ^{12 3 4 6} " ^{] eWeilS a substituent or a} Sanze number, as in the following, general

R ³

1 '6

R - CH - CH - O - t - CH - h - R

I 1 ⁿ

2 '4

OR R

Table 18 Formula used:

Connect. No. R ¹ R ² R ³ R ⁴ R ⁶ Br " η AcI di t i ο η s - salt Pp. Cc) 275 H H H -O 1 HCl 162-164 [EtOH-Et ₂ O] 276 Il Il ti It Il ti 143-146 277 Il 11 Il - O It 151.5-154 [EtOH-Et ₂ O] 278 Il Il Il H 1 Il 154-156 [EtOH-IPA]

IO (D (D

Production Example 26

The compounds listed in Table 19 are synthesized in the same manner as in (1) and (2) of Production Example 16

receive.

Formula used:

5 !. ^{n Rl} ' * ^{R3 <R </ R6 and n Each part has a substituent} "° ^d * r *" β a ^ e number, as in the following, general

R I CH - CH

2 OR

- 0 - (- CHH- R

Table 19

Connection "No. R ¹ me R ² R ³ R ⁴ R ⁶ η Additi cs a s. ζ - Mp ( ⁰ C) 279 H H H 1 - oily 280 11 Il Il Il Il  ι 1/2 fumaric acid 167.5-170 [EtOH] 281 Il It Il It Il - 122-123 [Me ₂ CO-AcOEt] 282 Il Il 11 11 Il 138-139 [Me ₂ CO-AcOEt]

Production Bolts 27 2- (1-imidazol-5-yl) -methoxy-1- (1-naphthyl) ethanol is reacted with methyl iodide to give oily 2- (1-methylimidazol-5-yl)

methoxy-1- (1-naphthyl) -ethanol (Compound No. 283).

Manufacturing Bills 28

(1) Dissolve 6.0 g of 6-benzyloxy-2-naphthaldehyde in 60 ml of tetrahydrofuran and cool the solution to -30 ° C. To this is added dropwise within 10min 30ml of a tetrahydrofuran solution containing 1.6M 2-chloroethoxy-methylmagnesium chloride. The resulting mixture is stirred for 1 hour under ice cooling. The reaction mixture is added to a mixture of 100 ml of ice-water, 100 ml of ethyl acetate and 3.6 g of ammonium chloride. The mixture is adjusted to pH 2 with 6 N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium chloride. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by column chromatography (elution ratio: toluene / ethyl acetate = 20/1); This gives a solid which is mixed with 10 ml of diisopropyl ether. The resulting mixture is stirred for 1 h at room temperature. The resulting crystals are collected by filtration and dried; obtained 1.7 g of 1- (6-benzyloxy-2-naphthyl) -2- (2-chloroethoxy) ethanol; Fp.8e-87.5 ⁰ C | IPEl.

(2) A mixture of 4.5 g of 1- (6-benzyloxy-2-naphthyl) -2- (2-chloroethoxy) ethanol, 1 g of potassium iodide, 10 ml of a 50% aqueous dimethylamine solution and 20 ml of ethanol is refluxed for 3 hours. To this is added 10 ml of a 60% aqueous dimethylamine solution and the resulting mixture is refluxed for 6 h. The reaction mixture is cooled and concentrated under reduced pressure to about half of its volume. 100 ml of ethyl acetate and 100 ml of water are added to the concentrate and the pH of the mixture is adjusted to 10.5 with potassium carbonate.

The organic layer is separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is mixed with 30 ml of diethyl ether. The resulting crystals are collected by filtration and dried; obtained 3.9 g of 1- (6-benzyloxy-2-naphthyl) -2- (2- (N, N-dimethylamino) -ethoxy] ethanol (Compound # 284), mp 100 to 100.5 ⁰ C. IEtOH-H ₂ O).

1- (6-Benzoxyoxy-2-naphthyl) -2- (2- (N, N-dimethylamino) -thoxy] -ethanol is treated in the same manner as in Preparation 22 to give 1- (6-benzyloxy-2- naphthyl) -2- | 2- (N, N-dimethylamino) -ethoxy) -ethanol hydrochloride (Compound No. 285); Mp 220-220.5 ° C (EtOH).

Manufacturing Bills 29

3.0 g of 1 (e-benzyloxy-2-naphthyl) -2- [2- (N, N-dimethylamino) -ethoxy] -ethanol are suspended in 12 ml of pyridine and the suspension is treated with 1.6 ml of acetic anhydride. The resulting mixture is stirred for 24 h at room temperature. After completion of the reaction, the solvent is removed by distillation under reduced pressure. The resulting residue is combined with 60 ml of ethyl acetate and 60 ml of water and the pH of the mixture is adjusted to 10.5 with potassium carbonate. The organic layer is separated and the aqueous layer extracted with 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 30 ml of acetone. 1.5 ml of a 5 N dry hydrogen chloride-ethanol solution are added to the solution and the resulting mixture is stirred for 1 h at room temperature. The resulting crystals are collected by filtration and dried; 2.6 g of 1-acetoxy-1- (6-benzyloxy-2-naphthyl) -2- (2- (N, N-dimethvlamino) -ethoxy) -ethane hydrochloride (Compound No. 286) are obtained, mp 157-158 ⁰ C (MeCN].

Manufacturing label 30

A mixture of 2.0 g of 1-acetoxy-1- (6-benzyloxy-2-naphthyl) -2- (2- (N, N-dimethylamino) -ethoxy] -ethane hydrochloride, 0.5 g of 5% palladium on carbon and 40 ml of ethanol is hydrogenated under atmospheric pressure at room temperature After completion of the reaction, palladium on carbon is removed by filtration, the solvent is removed by distillation under reduced pressure, acetone is added to the obtained residue, and the resulting crystals are collected by filtration and dried 0.76 g of 1-acetoxy-1- (6-hydroxy-2-naphthyl) -2- (2- (N, N-dimethylamino) -thoxy] -ethane hydrochloride (Compound No. 287); mp 150, 5-151.5 ° C (EtOH).

Herstellungsbeliplel31

A mixture of 360mg 1Acetoxy-1-) e-hydroxy-2-naphthyl) -2- (2- (N, N-dimethylamirole) -ethoxy] -ethane hydrochloride, 10 mL water and 15 mL chloroform is added with saturated aqueous sodium bicarbonate solution The organic layer is separated and the aqueous layer is extracted twice with 10 ml each of chloroform The extracts are combined with the previously separated organic layer The combined organic layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. the solvent is removed by distillation under reduced pressure, and the residue obtained is dissolved in 6 ml benzene. to the solution are 0,12ml ethyl isocyanate and the resulting mixture is stirred for 4 h at 8O ⁰ C. the reaction mixture is cooled, the solvent by distillation under reduced pressure and the residue obtained was purified by column chromatography (eluent: chloroform / Ethanol = 20/1) to yield an oily product which is treated the same orphan as in Preparation 22; 150 mg of 1-acetoxy-1- (6- (N-ethylcarbamoyl) -oxy-2-naphthyl-2- [2- (N, N-dimethylamino) -ethoxy] -ethane hydrochloride in amorphous form (Compound No. 288) are obtained. ,

Manufacturing label 32

2- [2- (N, N-Dimethylamino) -ethoxy] -1- (8-nitro-1-naphthyl) -ethanol is prepared in the same manner as in (1) and (2) of

Production example 27 obtained. This compound is reacted with oxalic acid in the same manner as in (2) of Preparation Example 16

implemented; there is obtained 2- (2- (N, N-di-diethylamino) -ethoxyM- (8-nitro-1-naphthyl) -ethanol oxalate (Compound No. 289);

Mp 150-158.5 ⁰ C.

Herttelli plum 33

A mixture of 160 mg of 2- (N, N-dimethylmethyl) -ethoxy) -i- (8-nitro-1-naphthyl-ethanoloxalate, 160 mg of 6% palladium-on-charcoal and 3 ml of methanol becomes 3Om under atmospheric pressure After completion of the reaction, palladium on carbon is removed by filtration, and the filtrate is distilled under reduced pressure to remove the solvent.

The residue obtained is added to a mixture of 30 ml of ice-water and 30 ml of chloroform. The mixture is adjusted to pH 11 with 2N aqueous sodium hydroxide solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 1 ml of ethanol. To this is added 0.2 ml of a 5.9 N dry hydrogen chloride-ethanol solution. The resulting crystals are collected by filtration and dried; 110 mg of 1- (8-amino-1-naphthyl) -2- | 2- (N, N-dimethylamino) ethoxy | -ethanol · dihydrochloride (Compound No. 290) are obtained; Mp. 195-198 ⁰ C (dec.) (AcOEt-EtOHI.

Manufacturing label 34

Triethylamine is added to 1- (8-amino-1-naphthyl) -2- [2 (N, N-dimethylaminol-ethoxyl-ethanol-hydrochloride.) The resulting mixture is treated with methanesulfonyl chloride to give oily 2- [2- (N, N Dimethylamino) -ethoxyl-1- (8-methylsulfonylamino-1-naphthyl) -ethanol hydrochloride (Compound No. 291).

Herttellungtboliplel 35

The procedure as in (1) and (2) of Preparation Example 28 is repeated, except that the 6-benzyloxy-2-naphthaldehyde is replaced by 4- (N, N-dimethylamino) -1-naphthaldehyde; Oily 1- [4- (N, N-dimethylamino) -1-naphthyl-2- [2- (N, N-dimethylamino) -ethoxy) -ethanol dihydrochloride (Compound No. 292) is obtained.

Manufacturing Belief 36

13 ml of ethanol are added to 1.3 g of 1- | 4- (N-dimethylamino) -1-naphthyl] -2- (2- (N, N-dimethylamino) -ethoxy) -ethanoldihydric chloride and the resulting mixture is refluxed for 1 h. The reaction mixture is cooled and the solvent removed by distillation under reduced pressure. The residue obtained is treated with a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture is adjusted to pH 10 with potassium carbonate. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; This gives 1.3 g of oily 1-ethoxy-1- | 4 (N, N-dimethylamino) -1-naphthyl-2- | 2-N, N-dimethylamino) -ethoxy) -othane (Compound No. 293).

Manufacturing label 37

(1) Dissolve 9.6 g of 5-8rom-1-hydroxyindane in 100 ml of dry methylene chloride and the solution is admixed at room temperature with 570 mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran. The resulting mixture is stirred for 3 hours at the same temperature and the reaction mixture is added to ice-water. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 15/1); 13.1 g of oily 5-bromo-1- (tetrahydropyran-2-yl-oxy) -indane are obtained.

(2) 8.1 g of 5-bromo-1-tetrahydropyran-2-yl-oxy) -indane are dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution is added dropwise within 10 min at -05 ⁰ C 20ml of a 1.5 N n-butyllithium-hexane solution. The resulting mixture is stirred for 5 minutes at the same temperature and then treated with 2.3 ml of anhydrous Ν, Ν-dimethylformamide. The reaction mixture is warmed to room temperature and added to a mixture of 100 ml of ice-water, 100 ml of diethyl ether and 2 g of ammonium chloride.

The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 15/1); This gives 6.5 g of 5-formyl-1- (tetrahydropyran-2-yl-oxy) -indan.

(3) The procedure as in (1) and (2) of Production Example 28 is repeated except that the 6-benzyloxy-2-naphthaldehyde is replaced with 5-formyl-1- (tetrahydropyran-2-yl-oxy) -indone is replaced; Oily 2- (N, N-dimethylamino) -ethoxy-1 - [1- (tetrahydropyran-1-yl-oxy) -indan-S-yl-ethanol (Compound No. 294) is obtained.

(4) A mixture of 2.5 g of 2- | 2- (N, N-dimethylamino) -ethoxy] -1- [1- (tetrahydropyran-2-yl-oxy) -indan-5-yl] -ethanol, 8 mL Acetic anhydride and 0.64 ml of pyridine are stirred at room temperature for 1 h. The reaction mixture is added to a mixture of 50 ml of ice-water and 50 ml of diethyl ether. The organic layer is then separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by column chromatography (elutlon solvent: chloroform / methanol = 10/1); 1.9 g of oily 1-acetoxy-2- [2- (N, N-dimethylmethyl) -ethoxy] -1- [(tetrahydropyran-2-yl-oxy) -ndan-6-yl] -ethane ( Compound No. 295).

(5) Mpn is 1,8g1-acetoxy-2- | 2- (N, N-dimethylamino) -ethoxy-1-H- (tetrahydropyran-2-yl-oxy) -indan-5-yl) -ethane at 30% 4: 2 1 mixed solution of acetic acid, tetrahydrofuran and water. The resulting mixture is stirred for 2 h at 70 ° C, the reaction mixture was cooled and charged with a mixture of 100 ml of water and 100 ml of diethyl ether. The resulting mixture is adjusted to pH 8.5 with potassium carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1); 1.0 g of oily 1-acetoxy-1 - [(1-hydroxy) -indan-5-yl] -2- | 2- (N, N-dimethylamino) -ethoxy) -ethane (Compound No. 266) is obtained.

(6) In 5 ml of pyridine, 1.0 g of 1-acetoxy-1 - ((1-hydroxy) -indan-5-yl] -2- [2- (N, N-dimethylamino) -ethoxy) -ethane is dissolved and treated the solution at room temperature with 0.3 ml of methanesulfonyl chloride. The resulting mixture is stirred overnight at the same temperature and the reaction mixture is added to a mixture of 50 ml of ice-water and 50 ml of diethyl ether. The resulting mixture is adjusted to pH 8.5 with potassium carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / methanol = 10/1); This gives 80 mg of oily 1-acetoxy-1- (1H-inden-e-yl) -2- | 2- (N, N-dimethylamino) -ethoxy] -ethane (Compound No. 207).

(7) In 0.5 ml of methanol is dissolved 80 mg of 1-acetoxy-1- (1H-inden-6-yl) -2- | 2- (N, N-dimethylamino) -othoxy) -ethane.

To the solution are added 80 mg of a 28% sodium hydrogen-methanol solution under ice-cooling. The resulting mixture is stirred for 20 minutes at room temperature.

The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / methanol = 20/1); an oily product is obtained which is dissolved in 0.1 ml of ethanol. At room temperature, 0.1 ml of a 5.9 N dry hydrogen chloride-ethanol solution is added to the solution. The resulting crystals are collected by filtration; 20 mg of 1- (1H-inden-6-yl) -2- [2- (N, N-dimethylamino) ethoxylethanol hydrochloride (Compound No. 298) are obtained; Mp 168 to 171 "C (dec.) (AcOEt-EtOH).

Manufacturing label 38

In the same manner as described in the preparation of the hydrochlorides in (5) of Preparation Example 37 and Preparation Example 22, 1 - ((1-hydroxy) -indan-5-yl) -2- | 2- (N, N-dimethylamino ) -ethoxy) -ethanol hydrochloride (Compound No. 299); Mp 150 to 152 ^° C (IPA).

Herstollungsbelsplel 39

2- [2- (N, N-dimethylamino) -ethoxy] -1- (1-naphthyl) -ethanol hydrochloride is reacted with acetic anhydride in pyridine in the presence of triethylamine; Oily 1-acetoxy-2- [2- (N, N-dimethylamino) ethoxy] -1- (1-naphthyl) ethane (Compound No. 3OO) is obtained.

Manufacturing Balls 40

The compound obtained from 2- [2- (6-methylnaphthyl)] - o): ir6n in the same manner as in (1) of Production Example 16 is treated with hydrogen chloride gas in the same manner as in the preparation of the hydrochloride in the Example 1! 22 described implemented; Oily 2- [2- (N-methyl-2,3-dihydropyridin-6H-5-yl) methoxy] -1- [2- (6-mothylnaphthyl)] ethanol (Compound No. 301) is obtained.

Production Plan 41 The compounds listed in Table 20 are prepared in the same manner as in (1) and (2) of Preparation Example 28

receive.

In Table 20, R ¹ , R ² , R ³ , R ⁴ , R ^e and η each show a substituent or an integer, as in the following formula

used:

pi

υ

Pi-U

CN

K Pi

ο - ο

CAJ

O) HH Q)

"α

EH

I - Ö * Ή * 00 «Κ H in - CN r. υ (Λ Cl 01 ' οι H M 0 C CN t, K H ^ -, r- «-. I O CN 4J -J O I φΟ ¹ ^ N + · I < CN M • r ro C-M σ \ Η I CO • r- N CN · - · I. f ^ w * ft!  σ ι- XJ (O CC (Λ H H β O U H K U CN K pi CN • sr = pi CN = η N = "γ pi I CD CN O a) Q) SS \ / a I pi I I el) I ⁼ pi K = ^{= =} = ⁼ K \ / \ / (O) V / (2) in CN η O O O Cl η η O η

O r-. a) r-ι U - O it O + J ro / CS +) S to in O β * ro η υ WHERE H W \ / • ü I H < υ ^ - \ ^ - v I O Z ο < • Η Κ I i r * · dl ) - ( cn υ I *? I \ / in χ co I (O) H ι < r-i X Z • O cn I O I H 4J I O O I th cn 4-> rH W from 4-) ro ro ro W co W B = • Η · - HCl = 7 \ / (CY) γ x (U O) \ / \ / S S <@) Z \ / VO , I O = I ro ₌ (O • ρ U = \ s O CVI (U H H Ui .Q "EH co O ro

r- \ Ρ (D fey O (D S W υ (Ο / in O (Ο) CM / - \ • υ ο α) (Ο) H < η ο S ι-Η VO I in I Γ0 H ffi ^ i ί-L-i I O I O O -P σ> -P vo ω  * W HCl CM = α) ω 2 2 \ / _ I = co t K O B O CVj (D at α EH

^ιΓ: ν ^ ¹

Production Bolts 42 One gives 1.7 g of potassium tert-butoxld to 31 ml of 2- (N, N-Dlmethylamino) ethanol and the resulting mixture heated to 8O ⁰ C. To

The solution is added dropwise at 80 to 85 ° C within 1.5 h, a solution of 5.2 g of 2- (benzo [b] -thlophen-5-yl) -oxirane, dissolved in 8ml

Dlmethylsulfoxid. The resulting mixture is stirred for 1 h boi at the same temperature, the reaction mixture is cooled and

Add it to a mixture of 60 ml of ethyl acetate and 60 ml of I: is-water. The organic layer is separated and the aqueous

Layer extracted with 30 ml of ethyl acetate. The extract is combined with the previously separated organic layer. To the

50 ml of ice-water are added to the combined organic layer and the pH of the resulting mixture is adjusted to 1.5 with 6 N hydrochloric acid. The aqueous layer is separated and mixed with 60 ml of chloroform. The resulting

Mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated, washed with water and

dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the resulting oily product is dissolved in 50 ml of acetone. To the solution is added 4.3 ml of 5N dry hydrogen chloride.

Ethanol solution. The resulting mixture is stirred for 1 h at room temperature and treated with 20 ml of diethyl ether. Man stirs

the resulting mixture for another hour. The resulting crystals are collected by filtration and dried to recover 3.3 g of 1- (benzolb] thiophene-5-yl) -2- (2- (N, N-dimethylamino) -ethoxy) -ethanol hydrochloride (compound no. 312);

Mp. 191.5 to 192.5 ⁰ C (EtOH-Me ₂ OH). In the same way, the compounds listed in Table 21 are obtained. In Table 21, R ', R ² , R ³ , R ⁴ , R ⁶ and η each show a substituent or an integer, as in the following formula

used:

O CM CM I Oi a) K U - O ell I & rc O

¹ ι H W ro O νο ο \ \ O VO (Λ * 3 * H VO CM η ιΗ C H η VO -P H K H Π U O I CTv γη ω I O η + J O • f- m ι ι  ** W + -> • r- N in κ Η ^ -> in K • σ ι- • ο in + J • O 00 4Y <C (Λ νο W CM W G ι. H Η'- ' i-l U VO U K Oi CM H ^ Pi U m (N = W ci Q) Q) CN pi \ / = = = iH pi I r # r • H U = K ⁼ = = Q) X ⁼ = ζ ιη ⁼ C- H η H η

in rtj O / OO in in <-ι in * Pm ro = \ • + J • in η H O ro VO r- W OO I OO J ro from O VD CN Hr-, I * C VO (U r-i Ü H I O in -P H ro H I < I co W H -· in I in <-> U K U φ VD (U co Cm r \ sa VO H VO H U K CN = ^ W H = U K CN (D (U Σ Σ = \ / = I = K ⁼ = S co - t O th pn \ (5) S CVJ - / 5) Φ H / ν ). H CJ), Q (O) (O) CD r- H I V fcH ro J ro H CN ro O η ro

O e'en

cn νο

• P + J in W CJN O • O co υ cn υ νο < I i HI in a I < • O OO P4 co -P VO H :O oo W

CS

Γ "r- ·

σ \ νο

CS

φ φ

a a /

H H Φ .α

CSes m

it

ιη

νο

CS

in O • U VD I Q) ι Γ in • O VO + J VO ω

bO

H ^! 9

cn from H I in

r *

VO

bO

• A

:O

ac

r> 4

U W (N

(N

(U S

(U

Φ (U X S

SG

(N

co

(N

cn

(N

ο m η

ο ι-ι CN ft, et] η bO = ιη ιη ιΗ O CO • Η η 00 (N H H cn υ H - η ι I r- I i γ- »= *! : 0 ιη in K in S HI • • O • O ι << H Γ- -P ο -P 00 ο W cn W Γ- H = I (N · - ' Η - H U J ν η K α) <υ (N = = ¹ Σ Σ αϊ <D \ / Σ Σ I \ / \ = I ω κ ₌ w • μ - ₌ U ο pn ) ^ / γ- a: CM Φ H \ v / S H Φ, α (Ο) (Ο) CD νο EH Lr ω η CO η - η η η

Table 21 (cont.)

337 U H ( H H -N ^X Me 4 HCl 105-107 [EtOH-AcOEt] 338 ^DH , Me ^ ° -r <Me Me Fumaric acid 123-124.5 [EtOH-AcOEt] [OJ

Comment:

+: This compound can be obtained by calling Compound No. 328

a conventional hydrogenation reaction subjects

Production sheet 43 A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoxide is heated to 80 ° C. and added

2.4 g of 2- (benzo [b] furan-5-yl) -oxirane. Dio resulting mixture is stirred for 15min at 85 ° C ⁰ QO. You give that

Reaction mixture to a mixture of 50ml ice-water and 50ml ethylacotate and adjust the pH of the resulting Mix with 6N hydrochloric acid to 1. The aqueous layer is separated and versetvt with 30ml Ethyiacetat, Die

resulting mixture is adjusted to pH 9.5 with potassium carbonate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in the following order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained by

Purified by column chromatography (eluent: chloroform / ethane, ol = 50/1); 0.56 g of 1- (ßenzo | b] furan-5-yl) -2- are obtained.

(pyridin-3-yl-methoxy) -ethanol (Compound No. 339); Mp. 85-86 ⁰ C (IPE EtOHI.

The compounds listed in Table 22 are obtained in the same manner. In Table 22, R ¹ , R ² , R ³ , R ⁴ , R ^e and η each show a substituent or an integer as in the following formula

used:

pi ►J-i - U CN CM CM T ac pi CO O U-O H H I ! q ro K Ph pi - U I

• 'I in - ·> bO = I \ CS C • M Ή (P) * ^ * O O H :O CJ • r HI cn O  r- N I 4J H T3 ι- in w υ OJ et IO • O rc N C να υ O rij CQ I VD I r = pi "" ¹ Pi ⁼ ro _- = pi ° Ρ5 H = r-l ⁼ pi I ⁰ J - B (O) Ή ·· ac O O) H * 3 * η O "ST m

ιη cn m W - OO ι-. O CN * Ot <r> + J υ ι CTi H IN THE in «J I 4J CN I in o OO I in W H K • υ H K • O I O in < I O .π υ r- -P cn ^ H -P CN rij CN « co W • Η I / \ Q) CJ = Z O / \ Q) = = I W th ζ = = -H c * Z = r \ OJ ₌ (0 r · r- φ - in , Q η r VC  ^ ·

Manufacturing label 44

(1) A mixture of 5.7 g of potassium tert-butoxide and 57 ml Ethylonglykol auf8O ⁰ C and are within 1.5 hours to a solution of 18g of 2- (benzo |! B] thiophene-5-yl ) -oxirane dissolved in 30 ml of dimethylsulfoxide. The resulting mixture is stirred for 30 minutes at the same temperature and the reaction mixture is added to a mixture of 120 ml of ice-water and 80 ml of ethyl acetate. The organic layer is separated and the aqueous layer extracted twice with 30 ml of ethyl acetate. The extracts are combined with the previously separated organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography (eluent: chloroform / ethanol = 20/1); 9.1 g of 1- (bonozolb) thlophen-5-yl) -2- (2-hydroxyethoxy) ethanol are recovered; Mp. 119 to 120.5 ⁰ C IEtOH-AcOEt).

(2) In 54ml of pyridine is dissolved 9.0 g of 1- (benzo [b) thiophen-5-yl) -2- (2-hydroxyethoxy) ethanol and added to the solution at -25 ⁰ C with 7.2 g p-toluenesulfonyl chloride , The mixture is allowed to stand for 24 h at 0 to 5 ⁰ C and a further ⁴ h at room temperature. The reaction mixture is added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice-water and 100 ml of diethyl ether. The resulting mixture is adjusted to pH 2.0 with 6 N hydrochloric acid. The organic layer is separated and the aqueous layer extracted with 30 ml of diethyl ether. Dor extract is combined with the previously separated, organic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by column chromatography (eluent: toluene / ethylacotate = 10/1); This gives 7.7 g of colorless, oily 1- (benzo [b] thiophen-5-yl) -2- | 2- (p-toluenesulfonyloxy) -ethoxy] -ethanol.

(3) At room temperature, 0.97 g of pyridinium p-toluenesulfonate are added to a solution of 7.6 g of l (benzo [b] thiophene-5-yl) -2- [2- (p-toluenesulfonyloxyethoxylethanol and 3, 5ml of 3,4-dihydro-2 H-pyran is dissolved in 40ml MethylencMorid. the mixture is stirred at the same temperature and another 30 minutes at 40 to 45 ⁰ C. the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. the solvent removed by distillation under reduced pressure to give 8.7 g of colorless, oily 1- (benzo [b] thiophene-5-yl) -1- (2-tetrahydropyranyloxy) -2- [2- (p-toluenesulfonyloxy) -ethoxy]. ethane.

(4) 1.5 g of 1- (benzo [b] thiophene-5-yl) -1- (2-tetrahydropyranyloxy) -2-I2- (p-toluenesulfonyloxy) ethoxy) ethane are dissolved in 15 ml of ethanol, and the Solution with 4.9 ml of 40% aqueous methylamine solution. The resulting mixture is refluxed for 1 h, and the reaction mixture is added to a mixture of 20 ml of ice-water and 20 ml of diethyl ether. The organiscl layer is separated and the aqueous layer extracted with 20ml diethyl ether. The extract is combined with the previously separated organic layer. Add 20ml of water to the combined organic layer. The resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid and stirred at room temperature for 20 minutes, the aqueous layer is separated, and the organic layer is extracted with 10 ml of water The extract is combined with the previously separated aqueous layer aqueous layer is added 30 ml of methylene chloride and the pH of the resulting mixture with 10% aqueous sodium hydroxide solution to 11. The organic layer is separated and the aqueous layer extracted with 15ml of methylene chloride The extract is combined with the previously separated, organic layer and The combined organic layer is dried over anhydrous magnesium sulfate, the solvent is removed by distillation under reduced pressure, and the resulting residue is dissolved in 7 ml of acetone To the solution is added 0.5 ml of a 5N dry hydrogen chloride-ethanol solution, and the resulting mixture 1 is stirred h at room temperature R. To the reaction mixture is added 7 ml of diethyl ether and the resulting crystals are mixed with 7 ml of diethyl ether. The resulting crystals are collected by filtration; 0.5 g of 1- (benzo [b] thiophene-5-yl) -2- (N-methylaminoethoxy) -ethanol hydrochloride (Compound No. 347) is obtained; Mp 201.5-202.5 ° C | EtOH-Me, CO].

In the same way, the compounds listed in Table 23 are obtained. In Table 23, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and η each show a substituent or an integer, as in the following formula

uses:>

ps -υ ι

CS

K PS

α-o

to

CAJ

"υ

H H

<υ cd

EH

• i · in O CO ι- »O W • υ υ o r ^ it ro CS it υ * - * α> σν Q) ω CS ι < O Ha • ^ «a ι ι O I i CO I m W ι «- · m K CSW • O • O I O cn -μ ¹ η vo-P it Q) H W CS »- '' £ cn W Η · · · co a (N «- < I H ο H H υ • ι- , U υ K W • ι-N CS -σ r- = β CS Q) a O = O φ νο Pi J I O PS K = ΓΟ S PS K ⁼ CS ^s PS ⁼ PS W (O ο cn in ro co

4J in IO + J - CS γ- to = ro • W in Η O r-IO ro ro o υ r ^ υ (N υ σ * «J H «<I I it rij = η i in " in K I O • O • O OO +> ο +> (S +> ro W r "W CNW (S '-' .1 ©, H ζ (U P X: cd HCl JJ (O (O (N = ro (D M • in \ / ro I > / -χ w S (O t K O W K = (Λ CM Q) H \ H Q), η (O) CD I ^ H cn

Production Example 45

(1) The ancestor of Preparation Example 43 is repeated except that 2- (benzo [b] furan-5-yl-oxirane and 3-pyr'-dimethanol are replaced by 2- (benzene-3-thiophene-5-yl) -oxirai, w 4-diformyl-2-piperazine-methanol to give oily 1- (benzo [b] thiophen-5-yl) -2 - ((1,4-diformyl-piperazin-2-yl) -methoxy] -ethanol (Compound No 354).

(2) Dissolve in 1.5 ml of methanol 270 mg of 1- (benzo (b] -thiophene-5-yl) -2 - [(1,4-dilformyl-piperazin-2-yl) -methoxy] -ethanol and treat the solution with 1.5 ml of a 5N dry hydrogen chloride-ethanol solution, the resulting mixture is allowed to stand overnight at room temperature, the resulting crystals are collected by filtration, washed with ethanol and dried to recover 150 mg of 1- (benzolblethiophene-5-yl). 2-l (piperazinyl-2-yl) -methoxy] -ethanol dihydrochloride (Compound No. 355); mp 226-218 ° C (dec.).

Manufacturing Belsplel 4S

(1) A mixture of 10 g of 2- (N-tritylamhol) ethanol, 3.7 g of potassium tert-butoxide and 30 ml of dimethyl sulfoxide is heated to 85 ° C. To this is added a solution of 5.8 g of 2- (benzo [thiophene-1/1] oxirane dissolved in 10 ml of dimethylsulfoxide, the resulting mixture is stirred for 5 minutes at the same temperature, the reaction mixture is added to a mixture of 150 ml of ice-water and 100 The organic layer is separated and the aqueous layer is extracted with 30 ml of ethyl acetate The extract is combined with the previously separated organic layer The combined organic layer is washed with water and saturated aqueous sodium chloride solution in that order and transferred anhydrous magnesium sulfate. the solvent is removed by distillation under reduced pressure and the resulting residue with 70 ml of 50% aqueous formic acid solution and 30 ml of tetrahydrofuran. the resulting mixture is stirred for 1 h at 50 to 60 ⁰ C. the solvent is removed by distillation under diminished) pressure and the residue obtained mi 50 ml of ethyl acetate and 30 ml of water are added. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated and the organic layer extracted twice with 10 ml of water. The extracts are combined with the previously separated aqueous layer. To the combined aqueous layer is added 50 ml of methylene chloride and the pH is adjusted to 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; obtained 1.2 g of 1- (benzo (b) thiophe> -5-yl) -2- (2-amlnoethoxy) ethanol (Compound no. 356, Fp.87 to 90.5 ⁰ C (EtOH-IPE].

(2) Dissolve 1.1 g of 1- (benzo [b] thiophene-5-yl) -2- (2-aminethoxy) ethanol in 10 ml of ethanol and add 290 mg of fumaric acid to the solution. The resulting mixture is stirred for 30 minutes at room temperature and the reaction mixture is mixed with 7 ml of diethyl ether. The resulting mixture is stirred for 1 h at the same temperature. The resulting crystals are collected by filtration and dried; 1.2 g of 1- (benzo (b) thiophene-5-yl) -2- (2-aminoethoxy) ethanol-1/2 · fumarate (Compound No. 377) are obtained; Fp.204,5 to 2 ^ 5.5 ⁰ C IMeOH-EtOH].

Manufacturing Label 47

The procedure of Preparation 46 is repeated except that the 2- (N-tritylamino) ethanol is replaced by (1-tiitylimidazol-4-yl) -methanol; 1 - (benzo [b] thiophene-5-yl) -2 - [(imidazolyl) -methoxy] -ethanol is obtained

(Compound No. 358); Mp. 128 to 129 ⁰ C (AcOEt].

In the designation of the compound obtained above, the term "(imidazolyl) methoxy" was used because it is not fully understood to which carbon atom of the carbons of the imidazolyl group at the 4- and 5-positions the carbon atom of the

Methoxy group is bound.

Manufacturing Label 48

0.46 g of 1- (benzo [b] thiophene-5-yl) -2- (2-aminoethoxy) ethanol are dissolved in a mixture of 5 ml of water and 5 ml of dioxane. To this is added 0.21 g of sodium carbonate and the resulting mixture is heated to 50.degree. 0.22 g of 2-chloropyrimidine are added and the resulting mixture is refluxed for 3 h. The reaction mixture is added to a mixture of 30 ml of ice-water and 30 ml of ethyl acetate. The organic layer is separated and the aqueous layer extracted with 10 ml of ethyl acetate. The extract is combined with the previously separated organic layer. 20 ml of water are added to the combined organic layer and the resulting mixture is adjusted to pH 1.5 with 6 N hydrochloric acid. The aqueous layer is separated and the organic layer extracted with 10 ml of water. The extract is combined with the previously separated aqueous layer. To the combined aqueous layer is added 50 ml of methylene chloride and the pH of the resulting mixture is adjusted to 10.5 with potassium carbonate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 20/1). This gives an oily product, which is mixed with 2ml of ethanol and 70mg of maleic acid. The resulting mixture is stirred for 1 h at room temperature. To the reaction mixture. oh give 2 ml of diethyl ether. The resulting crystals are collected by filtration and dried; 0.28 g of 1- (benzo (3-thiophene-5-yl) -2 - ([2- (pyrimidin-2-yl) -amino) -ethoxy] -ethanol-1-maleate (compound no. 359); mp 113.5 to 114.5 ⁰ C UPA-AcOEt).

Production Example 49

0.39 g of N, N'-dicyclohexylcarbodiimide are added, with ice-cooling, to a mixture of 0.45 g of 1- (benzo [b] thiophene-5-yl) -2- (α-aminoethoxy-ethanol, 0.23 g of nicotinic acid, 0, 26 g of 1 -H / hydroxybenzotriazole, 0.26 ml of triethylamine and 3 ml of tetrahydrofuran The resulting mixture is stirred at room temperature for 5 minutes and at room temperature for a further hour The reaction mixture is admixed with 20 ml of water and 10 ml of ethyl acetate. Insoluble matters are filtered off. The filtrate is adjusted to pH 1.5 with 6N hydrochloric acid, the aqueous layer is separated and the organic layer is extracted twice with 5 ml of water each time The extracts are combined with the previously separated aqueous layer The combined aqueous layer is washed with 30 ml Chloroform and the resulting mixture is adjusted to pH 10.5 with potassium carbonate, the organic layer is separated, washed with water and dried over anhydrous magnesium sulfate d removed by distillation under reduced pressure and the residue obtained by säulenchromatoyraphie purified (eluent: chloroform / ethanol = 10/1). Dissolve the resulting oily product in 3 ml

Ethanol and the solution is mixed with 0.24 ml of a 5 N dry hydrogen chloride-ethanol solution. The resulting mixture is stirred for 1 h at room temperature and the reaction mixture is mixed with 1.5 ml of diethyl ether. The resulting mixture is stirred for 1 h at the same temperature. The resulting crystals are collected by filtration and dried; is obtained 0.31 g of 1- (benzo | b] thiophon-5-yl) -2- (2- (nlcotinoylamlno) -ethoxy] ethanol hydrochloride (Compound Ranked # 360), mp 152-153 ⁰ C IEtOH. -AcOEt].

Production Example 50

(1) Dissolve 1.6 g of 4-methyl-2-formylthiazole in 30 ml of tetrahydrofuran and the solution is cooled to -30 ° C from. 10 ml of a tetrahydrofuran solution containing 1.6M 2-chloroethoxymethylmagnesium chloride are added dropwise within 10 minutes. The mixture is stirred for 1 h while cooling with ice. The reaction mixture is added to a mixture of 50 ml of ice-water, 50 ml of ethyl acetate and 2 g of ammonium chloride. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid and stirred for 5 min at the ε! Eichen temperature, the reaction mixture is adjusted to pH 6 with saturated aqueous sodium bicarbonate solution. The organic layer is filtered off, washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 4/1); 1.3 g of oily 1- (4-methyl-2-thiazolyl) -2- (2-chloroethoxy) ethanol are obtained.

(2) A mixture of 1.2 g of 1- (4-methyl-2-thiazolyl) -2- (2-chloroethoxy) ethanol, 3 ml of 50% aqueous dimethylamine solution, 0.45 g of potassium iodide and 20 ml of ethanol is refluxed for 3 hours. The reaction mixture is mixed with 3 ml of 50% aqueous dimethylamine solution and the resulting mixture is refluxed for 3h. The solvent is removed by distillation under reduced pressure and the residue obtained is mixed with 30 ml of ethyl acetate and 30 ml of water. The resulting Gemis: h is adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer is separated and evolved with 10 ml of ethyl acetate. To this is added 30 ml of ethyl acetate and the pH of the resulting mixture with Kaliumcarboant to 10.5. The organic layer is separated, washed with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 6 ml of ethanol. To the solution are added 0.6 ml of a 5 N dry hydrogen chloride-ethanoi solution and 6 ml of diethyl ether. The mixture is stirred for 1 h at room temperature. The resulting crystals are collected by filtration, washed with 2 ml of a 1: 1 mixture of diethyl ether and ethanol and dried; 390 mg of 1- (4-methyl-2-thiazolyl) -2- [2- (N, N-dimethylamino) -ethoxy] -ethanol hydrochloride (Compound No. 361) are obtained; Mp 159-160 ° C [IPA-AcOEt).

In the same way, the compounds listed in Table 24 are obtained. In Table 24, R ', R ² , R ³ , R ⁴ , R ⁶ and η each show one, substituent or integer as in the following formula

used:

VD Oi

-υ

ο ι

οί -ο

(N

U-O I

di

I ho _v TP • - ro hO (/) Öli Ui from office C 2 2 -E- < in o - :O O O VD fi, O <N OO I / \ ^^ • r- N ι VO C) rH K X) I O r-4 I e X) TC in -O oo ω • a: <λ C VD CN H di (U O) O a a CN \ / ro 2 I di " (N r = Oi rh Oi ac ΐΐ • erbi] Nr Z-W > from office

bO ν in O \ bO etj / OO ) V νο υ <Fo> • Η ro o VO (- \ (O) ro H co υ ro : θ ή te / \ : ο I i ι ο 2 W in x - \ ι Ι --- / m + J Y tH U O γ-ω ω th rs + ι ( (N H -J Σ (N OO W Vh α) υ * S U r-H \ / υ VO 2 th VO ⁼ U I ζ η " r th = ⁼ - th : = W  Ρ U O CsI α> H H , Q EH f ~ VD η

ω • Ρ U ο fa

H H Q)

R-O (D U • r-, • = U S in o W CN O υ O Q) ) - \ CTi rij υ ro r- a VPJ ⁵ t- I VO «g Γ HI O in ι I ^ N 2 -m Η H SJ I O H K I I O I O CN O VO 4J r- W in - »J  Η W in W ₁ γΗ  H '-' H '-' I U S U Q) th S (N cd U - g yy CN fa W = CN S = (DQ) _ CN \ / _ 2 2 I I EC = = B = ι Ο J = ( \ _ / ² P (Ti VO cn

H H Φ .Ω

_ CTV l-l U 'S * • Ρ O) = / co = ro VO ω H 33 \ / ω (Λ vo • "e r- ο I O / Λ ro in O \ / / Η ι-I ro υ νο O) ti o υ 2 / γλ \ I < η VO ι < R 2 rH I-I Q) ro rtj I CN Oi (μ Ο CO I σ \ ι VO H H ^ - ' C 2 U H 33 I O I O in s M * 4- · = ΓΟ 4J CO PQ γΗ <-J Ch ^ ro = r-4 O O) Q) K s 2 2 (N \ / CN : 2 Q) (D. = I 2 2 r \ / S 2 I 2 ro [- γο

Table 24 (cont.)

377 MeNH N '"^ Cl H H H / Me Me ti 2 HCl 153.5-154 [iPAJ 378 H Il » Et "Κ Et Il 2HCl 176-179 379 It ti Il MeMe Il - oily 380 H Il ti   1 ti ti It I

ιη > Γ γΗ CJ -. rH Γ-I O) \ ιη ο υ ιη U : U CTI χ ω X S ι χ O Οι H (N ο η ω \ / (O) »3 · = σ \ υ , I I υ I O 2 ft ι ΓΟ < • Η ιη cn »j I L- r \ X H ι , / ι ι O KU I O I χ 2 χ  Η> - · CO IT 4J ιη O I α \ \ / ο I ΓΟ ω \ / • 4J 2 ΓΟ I 2 VO ω - I W ro = ΓΟ I ro 1 I X I H X = < X = Ι \ Γ> X X r \ 00 C ΓΟ H ΓΟ to 00 00 • μ ΓΟ U ο ν- ' CM Φ / H H Φ , α cd ^ i !)

ιη ι-ι 4J U ω ω < a ₍ ιη Γ? / ιη V = Γ 1 ζ. \ = Λ 00 V • ω Σ > φ οο ω - \ • W ro ι / ο; ro W ro ο \ / ro cn O O σ \ O = { \ <τ \ O σ> ο Γ- U / ro ϋ CO -o υ ^ H < χ H ⁼ rH λ: I ι Z I i Βζθ " I I ι ι ro I ιη χ VD ιη in K CTv ιΗ O O 00 " O O 4J M 4J r ^ J 00 -0 γ- ω r -H ι-I ro W ι ι ro W : = (N -M 4J ω ω _ \ / ζ ι ζ • "" "Ν CO - = • Ρ U O ^{= =} CM ω ) β11 λ- <cd (H 03 00 ro

U _H / / -S α) CO ιη \ O * n \ r> W I t / l η 'ι-ι σ " V-λ in r-1 in O / cn (2) (NJ * ^ M {Ο) th υ \ / • ζ I η \ νο C in ( ' I O ^ T ft, I ft) CN yy * tC in 4-> OO I in X O I ® 0 \ cn in ω • Η tC Q) O Q) / rH.-ι I O co a: in "^^? * ** 4y VO · -I - j -j  Η co M rh σ> S r- \ 1 U ro I : CN υ η CN ^x - { N I CN Q) Q) 03 CD S 2 I I \ / 2 I O = I = "* - '-Ν • r cn • Ρ = U ο CVI Φ H H CN Φ cn IH η

r ~ ι I X ω > (ό ro in I «Η CJ a -1 -P ω \ / ro r I I -I U cn X : ω in w Z I in W Gi \ / ro CN : O O I ro r Gi H ro (N υ O 0 : (N : H in I (N N co d. : in = t 2 I I ra I ri I = f " Γ-- Gi I X I 4 VD H ro I CTI O co Gi \ / L I X (N ro O) r ^ H VO in X S ιη (Tl VD I I (Tv ro ο ro ü) ω χ S = / / \\ C <\ J / z /

Table 24 (Forts.J H H me It 3 - 81.5-83 397 H 11 Il - ^K v 2 HCl IPA IPE 398 · ti It , -N-Me Me ti It 196-198 [EtOH-AcOEt] 399 ISJ It ti Il I * 1/2 1,5 ^ naphthalenyl disulphonic acid 190-192.5 [EtOH-AcOEtJ 400 pi It Amorphous Il Il

(O CJ)

Table 24 (Cont.) H H .me 2 HCl oily 4Ox ac Il Il 1 - ti 402 H Il ti I Tr Il 1/2 maleic acid 110-117 403 11 Ό H Sr M

Remarks:

+1: This compound can be obtained by subjecting Compound No. 362 to a hydrolysis reaction using hydrochloric acid. 2: This compound can be obtained by dissolving Compound No. 364 of a Hydrochloric acid.

3: This compound can be obtained by subjecting Compound No. 374 to a conventional hydrogenation reaction

Herstollingbolsplel 51

(1) A mixture of 9.2 g of 1- (2-thionyl) -2- [2- (N, N-dimethylamino) -ethoxy] -ethanol and 18 ml of acetic anhydride is refluxed for 10 min. The reaction mixture is added dropwise to a mixture of 7.8 ml of concentrated nitric acid and 27 ml of acetic anhydride over 30 min at ⁰ ° C. The resulting mixture is stirred for 2 hours at the same temperature. The reaction mixture is added to a saturated sodium hydroxycarbonate solution, the pH of the resulting mixture being adjusted to 7 with 40% aqueous sodium hydroxide solution. The resulting mixture is adjusted to pH 10 with 40% aqueous sodium hydroxide solution and mixed with 300 ml of chloroform. The organic layer is separated and mixed with 300 ml of water. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated and mixed with 300 ml of chloroform. The resulting mixture is adjusted to pH 10 with 40% aqueous sodium hydroxide solution. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 10.4 g of oily 1-nitro-nitro-thienyl-1-acetoxy-1-N-dimethylaminol-oxy-ethoxylated olefin (Compound No.404) are obtained.

(2) In 10 ml of methanol is dissolved 320 mg of O-miiro ^ -thienyD-i-acetoxy ^ - ^ - IN, N-dimethylaminolethoxy-ethane and the solution is treated with 1.27 ml of 1 N aqueous solution of sodium hydroxide. The resulting mixture is stirred for 1 h at R JU.ntempeiatur. and the reaction mixture with 40ml of chloroform and 40ml of water. The organic layer is separated and mixed with 30 ml of water. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer is separated and mixed with 30 ml Chlorofr rm. The resulting mixture is adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solution center! is removed by distillation under reduced pressure and the residue obtained admixed with 3 ml of methanol and 1 ml of a 5N dry hydrogen chloride-ethanol solution. The solvent is removed by distillation under reduced pressure and the residue obtained is mixed with 5 ml of ethanol. The resulting crystals are collected by filtration and dried; 170 mg of 1- (5-nitro-2-thienyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol (Compound No.405) are obtained; Mp. 183-191.5 ⁰ C (Zers.).

Manufacturing Example 52

(1) In10 ml of pyridine-soln3,4p 2- [2- (N, N-dimethylamino) -ethoxy] -1- (β-benzyloxybenzoylb) furan-2-yl) -ethanol, and the solution is treated with 1.8 ml of acetic anhydride. The resulting mixture is stirred at room temperature for 17.5 hours. The solvent is removed by distillation under reduced pressure. 40 ml of ethyl acetate and 40 ml of water are added to the residue obtained, and the pH of the resulting mixture is adjusted to 7 with sodium bicarbonate. The organic layer is separated and the aqueous layer extracted with 20 ml of ethyl acotate. The extract is combined with the previously separated oiganic layer. The combined organic layer is washed with water and saturated aqueous sodium chloride solution in this order and dried over non-aqueous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 1/1); 3.25 g of oily 1-acotoxy-1- (6-benzyloxybenzo (b] furan-2-yl) -2- | 2- (N, N-dimethylamino) -ethoxy) -ethane (Compound No.406) are obtained.

IR (pure) cm "': v _c .o 1740.

(2) A mixture of 3.2 g of 1-acetoxy-1- (6-benzyloxybenzo [blfuran-2-yl) -2-I2- (N, N-dimethylamino) -ethoxyl-ethane, 0.6 g of 5% palladium on carbon, 0.67 ml of concentrated hydrochloric acid and 30 ml of methanol is hydrogenated for 1.5 hours under atmospheric pressure at room temperature. After completion of the reaction, palladium on carbon is removed by filtration and the solvent is distilled off under reduced pressure. The residue obtained is mixed with 20 ml of chloroform and 20 ml of water. The pH of the resulting mixture is adjusted to 7 with sodium bicarbonate. The organic layer is separated and the aqueous layer extracted with 10 ml of chloroform. The extract is combined with the previously separated organic layer. The combined organic layer is washed with 5 ml of water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / methanol = 7/1); This gives 1.57 g of oily 1-acetoxy-1- (6-hydroxybenzo (b] furan-2'yl) -2- | 2- (N, N-dimethylamino) ethoxy] -ethane (Compound No.407 IR (in) cm " ¹ : v _c = o 1740.

(3) In 3.5 ml of benzene is dissolved 0.65 g of 1-acetoxy-1- (6-hydroxybenzo [blfuran-2-yl) -2- [2- (N, N-dimethylamino) -ethoxy] -ethane and added the solution with 0.33 ml of ethyl isocyanate. The resulting mixture is stirred for 30 min at 8O ⁰ C and the solvent removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 6/1); an oily product is obtained which is treated with dry hydrogen chloride according to a customary procedure; 0.58 g of oily 1-acetoxy-i- (6-N-ethylcarbamoyloxyben-o [b] furan-2-yl) -2- | 2- (N, N-dimethylamino) -ethoxy] -ethane hydrochloride ( Connection No.408). IR (pure) cm " ¹ : Vc-o 1730.

The following examples illustrate the invention without limiting it.

Example 1 (tablets)

Each containing 50 mg of 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] -ethanol hydrochloride (Compound No. 48)

Tablets are prepared using the following recipe according to the following procedure:

(D

(2)

Per tablet: mg Connection No. 48 50 lactose 20 Kollidon CL (product of BASF) 15 corn starch 30 AVICEL PH101 (product of Asahi Kasei) 50 Polyvinylpyrrolidone K-90 5 light silica 3 magnesium stearate CM a total of 175

Components (1) are kneaded with an aqueous solution containing 8% polyvinylpyrrolidone K-90. The kneaded product is getrockiiet at 4O ⁰ C and mixed with the components (2). The resulting mixture is made into round tobacco weighing 175mg each and 8mm in diameter.

Example 2 (Kapieln)

Each of S0mg2-l2-N, N-dimethylamino) -thethoxy) -1- (4- (4-phenyloxy) -phenyl] -ethanol hydrochloride (Compound No. 54) is added to capsules using the following recipe Process produced.

Per capsule: mg (1) Connection No. 54 50 lactose 20 corn starch 53 Kollidon CL (product of BASF) 2 Polyvinylpyrrolidone K-90 5 (2) AVICEL PH 302 (product of Asahi Kasei) 18 magnesium stearate 2 total 150

The components (1) are kneaded with an aqueous solution containing 8% polyvinylpyrrolidone K-90. The kneaded product is dried at 40 ° C and mixed with the components (2). The resulting mixture is filled in No. 3 gelatin capsules in an amount of 150 mg per capsule.

Example 3 (Liquid)

A liquid containing 25 mg of 2- [2- (N, N-dimethylamino) ethoxy] -1- (3-trifluoroethylthiopropyl) -1-ethanol hydrochloride (Compound No. 42) is prepared using the following Recipe according to the following procedure:

Per ampoule:

Pre-tie no.42 25mg

Methyl paraoxybenzoate 1 mg

Total 26mrj

The above components are dissolved in physiological saline and the total volume of the solution is brought to 1 ml. The solution is filtered aseptically and filled into an ampoule. A liquid drug is obtained.

Example 4 (injection preparation)

An injection preparation containing 25 mg of 2- | 2- (N, N-dimethylamino) ethoxy) -1- (3-fluorophenyl) ethanol hydrochloride (Compound

No. 1) is prepared by using the following recipe according to the following procedure:

Compound No. 1 25mg

Manitol 75mg

Total 100mg

The above components are dissolved in 1.5 ml of distilled water prepared for injection. The solution is filtered aseptically, filled in 3 ml mini-vials and freeze-dried. A preparation for injection is obtained.

Example 5 (fine granules)

A fine granule containing 50 mg of 2- (1-benzylpiperidin-4-yloxy) -1-phenylethanol hydrochloride (Compound No. 112)

prepared according to the following recipe according to the following procedure

(1)

The components (1) are stirred at high speed with an aqueous solution containing 8% polyvinylpyrrolidone K-90 and granulated. The resulting granules are sieved through a 32 mesh / 2.5 cm sieve and dried. This gives a fine granules.

Example 6 (tablets)

2- [2- (N, N-Dimethylamino) -ethoxy] - (3-methylphonyl) ethanol hydrochloride (Compound No. 15), 2- (1-methylimidazol-5-yl) -methoxyl-1- ( 4-benzyloxyphenyl) ethanol (Compound No. 215), 2- [2- (N, N-dimethylamino) -ethoxy] -ethoxy] -1- (1-naphthoxyethanol hydrochloride (Compound No. 228), 2 2- [N, N-dimethylamino) -ethoxy] -1- (2-naphthyl) -ethanol hydrochloride (Compound No. 229), 2-I2- (N, N-dimethylamino) -ethoxyl-1- ( benzo [blothiophene-5-yl) -othanol hydrochloride (Compound No. 312), 2- (N-methyl-H '1,2,5,6-tetrahydropyridin-3-yl) methyl] -1- (benzoIb] -thiophene-5-yl) -ethanol (Compound No. 345), 2- (2-aminoethoxy) -1- (benzo [b] thiophene-5-yl) -ethanolfumarate (Compound No. 377), 2- 2- (N, N -diethylamino) ethoxy) -1- (benzo (3-thiophene-5-yl) -ethanol hydrochloride (Compound No. 338) and 2- [2- (4-benzylpiperazin-1-yl) - ethyl] -1 - (benzolb] furan-5-yl) -cctane dihydrochloride (Compound No. 394) was processed as in Example 1 to give tablets each containing 50 mg of one of the above compounds.

(1) Connection No. 112 50 mg α-starch 200mg purified sucrose 250 mg lactose 470 mg Polyvinylpyrrolidone K-90 30 mg A total of lOOOmg

Example 7 (Capsules)

aia-IN.NDimethylamino-ethoxyl-10-aminopropyltriethanol hydrochloride (precursor 15), 2-l (1-methylimidaiol-5-yl) -methoxy] -1- (4-benzyloxyphenyl) -ethanol (precursor No. 215 ), 2- | 2- (N, N-dimethylamino) ethoxy-1- (1-naphthyl) -othanol · hydrochloride (compound # 228), 2- | 2- (N _l N-Dimothylamino) -elhoxy) - 1- (2-naphthyl) -ethanol-hydrochloride (Prec. No. 229), 2-l2- (N, N-dimethylamino) -othoxy) -1- (ben2oIb] thiophon-5-yl) -othanol hydrochloricl (Vorbii ) No. 312), 2 - [(N-Molhyl-1H-1,2,5,6-tetrahydropyridin-3-yl) -methyl) -1- (bonzolb) thlophon-5-yl) -ethanol (Binding no. 345), 2- (2-amino-thoxy-1- (benzo [b] thiophon-5-yl) ethanol (umarate (Compound No. 377), 2-l2- (N, N-diethylamino) ethoxy) - 1- (benzenebis) thiophon-5-yl) -ethanol-hydrochloric chloride (Binding No. 388) and 2- | 2- (4-8-oncylpipota * in-1-yl) ethyl] -1- (bo.TZo (bUurQn) 5-yl) -othanoldihydrocbloride (Compound No. 394) are processed as in Example 2. Capsules each containing 50 mg of one of the above compounds are obtained.

Claims (35)

1. Process for the preparation of a 1,2-ethane! 3ο * 3rd of the following general formula or salt thereof,
R ³ R ⁴ R'-CHCH-O-IC- ^ R ⁶ OH R ⁵ wherein R ^{1 represents} a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocycle group; R ^{2 represents} a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group; R ^{3 is} a hydrogen atom or a lower alkyl group; nR ⁴ radicals and nR ⁶ radicals are identical or different and represent hydrogen atoms or lower alkyl groups; R ^{6 represents} an ammonio group or represents a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing!) Heterocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazoM, pyrazolyl, pyridyl , Tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, Pyrazolidinyl, purinyl and indazolyl groups; and η is 0 or an integer from 1 to 6, wherein the substituent on R ^{1 is} selected from the group consisting of halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, Ar lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, Ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocycle groups, protected amino groups, protected or unprotected hydroxyl groups, nitro groups , Oxo group and lower alkylenedioxy groups; the substituted lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkyltnio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino , Arylsulfonylamino or heterocycle groups as the substituent of R ¹ and the substituted nitrogen-containing heterocycle group as R ⁶ each have at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxyl groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted ones Lower alkyl groups, lower alkyl groups substituted by a protected or unprotected hydroxyl group, unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower acyl groups, Ar-lower alkyl groups, Ar-lower alkenyl groups, heterocycle groups. Heterocycle CO groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups; and the substituted amino group as the substituent of R ¹ and the substituted amino group as R ⁶ each have at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected carboxyl or hydroxyl group, cycloalkyl groups , Aryl groups, lower acyl groups, ar-lower alkyl groups, heterocycle groups, unsubstituted or oxo-substituted heterocycle-CO groups, adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, provided that the compounds are excluded where R ^{1 is} a phenyl group which may be optionally substituted by the halogen atom or the lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected Hydroxylgruppa and R ^{6 is} -NR ⁷ R ⁸ , wherein R ^{7 is} an Ar-lower alkyl or heterocycle and R ^{8 is} a water R ⁷ urrd R ⁸ together with the N atom form the following structures: in which R ^{9 is} an aryl or heterocycle group and i is 0 or an integer from 1 to 3, 10 where R ^{10 is} an aryl, heterocycle or N-heterocycle group and fl ⁸ and i are the same R ⁸ Meanings have wiö above, -N from R ^iJ · in which R ^{11 is} an arylgiuppe; _R 12 wherein R ^{12 represents} a carboxyl group or a lower alkoxycarbonyl group, or 12 in which R ^{12 has} the same meaning as above, and the compounds in which R ^{1 is} an unsubstituted or lower alkyl-substituted phenyl group and R ^{6 is} a di-lower alkylamino group, -N , -N) or -NO; where all above heterocycle groups are selected from the group consisting of the nitrogen-containing heterocycle groups mentioned in the definition of R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl , Benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzcthienyl, 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, pyridazinyl, isoindolyl and isoquinolyl groups, characterized in that a compound the general formula, O 1 A 3 R-CHCHR wherein 3 ¹ and R ^{3 have} the meanings given above, with a compound of the following general formula or a salt thereof: R ⁵ wherein mR ⁴ radicals and mR ⁵ radicals are identical or different and represent hydrogen atoms or Neraleralkylgruppen, R ^{6 has} the meaning given above and m is an integer from 1 to 6, or with a compound of the following general formula or a salt the same: HO-R ^6a wherein R ⁶ "represents the same substituted or unsubstituted nitrogen-containing heterocycle group as in the definition of R ⁸ , provided that the heterocycle group has a free valence at a carbon atom of the heterocyclic ring. 2. The method according to claim 1, characterized in that oin 1,2-Ethandiolderivat or a salt thereof is prepared, wherein R ^{1 is} a substituted or unsubstituted phenyl group; R ^{2 is} a hydrogen atom or a hydroxyl-protecting group; nR ⁴ radicals are the same or different and denote hydrogen atoms or lower alkyl groups; nR ⁵ radicals for hydrogen atoms steven; and R ^{6 is} an ammonio group or is a substituted or unsubstituted amino (excluding di-lower alkylamino) or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl , Pyrimidinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups. 3. The method according to claim 1, characterized in that one prepares a 1,2-ethanol derivative or a salt thereof, in which R ^{1 is} a substituted or unsubstituted naphthyl group; R ^{2 is} a hydrogen atom or dine hydroxyl protecting group; nR ⁴ radicals are the same or different and represent hydrogen atoms or lower alkyl groups; nR ⁶ radicals represent hydrogen atoms; and R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl , Pyrimidinyl, morpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups. 4. The method according to claim 1, characterized in that one prepares a 1,2-Ethandiolderivat or a salt thereof, in which R ^{1 represents} the substituted or unsubstituted heterocycle group. 5. The method according to claim 1, characterized in that one prepares a 1,2-Ethandiolderivat or a salt thereof, bai the R ¹ for a naphthyl, indanyl or Tetrahydronaphthylgruppe steli, may optionally be substituted by a halogen atom or a halogenoalkyl group 'pe; R ^{2 is} a hydrogen atom; R ^{3 is} a hydrogen atom; nR ⁴ radicals and nR ⁵ radicals represent hydrogen atoms; R ^{6 represents} a morpholinyl group having a free valence on a carbon atom of the ring, a pyridyl group, an imidazolyl group, a phenyl C 1-4 alkyl group-substituted fiperazinyl group or an amino group which may be optionally substituted by a lower alkyl group or a cycloalkyl group; and η is an integer of 1 to 4. 6. The method according to Ansprucn 1, characterized in that one prepares a 1,2-Ethandiolderivat or a salt thereof, in which R ^{1 is} a benzothienyl, benzofuranyl or 2,3-Dihydrobenzothienylgruppe; R ^{2 represents} a hydrogen atom; R ^{3 is} a hydrogen atom; nR ⁴ radicals and nR ⁵ radicals denote hydrogen atoms; R ^{6 is} a pyridyl group, a piperidinyl group which may be optionally substituted by a lower alkyl group, a 1,2,5,6-tetrahydropyridyl group which may be optionally substituted by a lower alkyl group, an imidazolyl group, a phenyl-C 1-8 alkyl group-substituted one Piperazinyl group or an amino group which may be optionally substituted by a lower alkyl group or cycloalkyl group; and η is an integer from 1 to 4. 7. The method according to claim 1, characterized in that one produces 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof. 8. The method according to claim 1, characterized in that one produces 1- (4-benzyloxyphenyl) -2 - [(1-methyl-5-imidazolyl) methoxy] ethanol or oin salt thereof. 9. Process according to Claim 1, characterized in that 2- (imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof is prepared. 10. The method according to claim 1, characterized in that one prepares 2- (1-methyl-5-imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof. A process according to claim 1, characterized in that 1- (benzo [b] thiophene-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof is prepared. 12. Process according to Claim 1, characterized in that 1- (benzo [b] thiophen-5-yl) -2- [3- (N, N-dimethylamino) -propoxy] ethanol or a salt thereof is prepared. 13. The method according to claim 1, characterized in that one produces 1- (benzo [b] thiophene-5-yl) -2- (imidazolylmethoxy) ethanol or a salt thereof. A process according to claim 1, characterized in that 1- (benzene-b) thiophen-5-yl) -2 - [(1-methyl-1,2,5,6-tetrahydropyridin-3-yl) -methoxy] -ethanol or a Salt thereof produces. A process according to claim 1, characterized in that 1- (benzo [b] iuran-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol or a salt thereof is prepared. 16. A process for producing a 1,2-ethanediol derivative of the following general formula or a salt thereof, R3 R < R'-CHCH-O-fC-fR ⁸¹¹ 1.1 "OR ^2a R ⁵ wherein R ^{1 represents} a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocycle group; R ^{2a is} a hydroxyl protecting group; R ^{3 is} a hydrogen atom or a lower alkyl group; mR ⁴ radical and TiR ⁵ radicals are the same or different and represent hydrogen atoms or lower alkyl groups; and R ^{eb represents} a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocyclic group has a free valence on a carbon atom of the heterocyclic ring and is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl , Imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinucidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, And imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups; and m is an integer from 1 to 6 wherein the substituent on R ^{1 is} selected from the group consisting of halogen, substituted or unsubstituted amino, Lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenylox Y, Ar-lower alkylthio, Ar-lower alkylsulfonyl, arylsulfonyl, lower alkyl- ^p- sulfonylamino, arylsulfonylamino and heterocycle groups, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and lower alkylenedioxy groups; the substituted lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino -, Arylsulfoi.ylamino- or heterocycle groups as the substituents of R ¹ and the substituted nitrogen-containing heterocycle as R ^6b each have at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxyl groups, protected or unprotected amino groups, protected or unprotected carboxyl groups unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected hydroxyl group, unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower Acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocycle groups, heterocyclic-CO groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups; and the substituted amino group as the substituent of R ¹ and the substituted amino group as R ^6b each have at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected carboxyl or hydroxyl group, Cycloalkyl groups, aryl groups, lower acyl groups, Ar-lower alkyl groups, heterocycle groups, unsubstituted or oxo-substituted heterocycle-CO groups, adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, provided that the compounds are excluded where R ^{1 is} a phenyl group which may be optionally substituted may be represented by the halogen atom or the lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group and R ^{6b is} -NR ⁷ R ⁰ wherein R ^{7 is} an ar-lower alkyl or heterocycle group and R ^{8 is} a Wa or R ⁷ and R ⁸ together with the N atom form the following structures: -N N-4-CH-WR ⁹ in which R ^{9 is} an aryl or heterocycle group and i is 0 or an integer from 1 to 3, .10 -N NHCH ₀ H where R ^{10 is} an aryl, heterocyclic or N-heterocycle group and R ⁸ and i are the same R ^{8 has} meaning as above, / - \
-NV ^0H _R Jl wherein R ^{11 is} an aryl group; R ¹² -N in which R ^{12 is} a carboxyl group or a lower alkoxycarbonyl group or R ¹² in which R ^{12 has} the same meaning as above, and the compound in which R ^{1 is} an unsubstituted or lower alkyl-substituted phenyl group and R ^{6b is} a di-lower alkylamino group, r ~ \ -N or _n ο stands; wherein all the above heterocycle groups are selected from the group consisting of the nitrogen-containing heterocycle groups mentioned in the definition of R ^6b and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl , Benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl - imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and! sochinolyl groups, characterized in that a compound of the general Formula, R ¹ -CHCH-O-4C4-Y il ^m _R 2e _R 5 wherein R ¹ , R ^2a , R ³ , R ⁴ , R ⁵ and m have the meanings given above and Y represents a removable group, with a compound of the following general formula or a salt thereof: HR ^6b
wherein R ^{6b has} the meaning given above. Use of a 1,2-ethanediol derivative of the following general formula or a salt thereof for the manufacture of a medicament for the treatment of cerebrovascular dementia, dementia dementia, Alzheimer's dementia, morbid conditions of ischemic encephalopathy or cerebral apoplexy in a patient: Π ³ R ⁴ R'-CHCH-O-fC- ^ R ³ (J) R ¹ R ⁵ " wherein R ^{1 represents} a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocycle group; R ^{2 represents} a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group; R ^{3 is} a hydrogen atom or a lower alkyl group; nR ⁴ radicals and nR ° radicals are identical or different and represent hydrogen atoms or niaderalkyl groups; R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing helocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, Tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl , Purinyl and indazolyl groups; and η is 0 or an integer from 1 to 6, wherein the substituent on R ^{1 is} selected from the group consisting of halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, Ar lower alkoxy, aryloxy, carbamoyloxy, niaderalkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocycle groups, protected amino groups, protected or unprotected hydroxyl groups, nitro group, Oxo group and lower alkylenedioxy groups which are substituted lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl , Lower alkylsulfonylamino, arylsulfonylamino or heterocycle groups as the substituent of R ¹ and the substituted nitrogen-containing heterocycle group as R ^6, respectively s have at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxyl groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected hydroxyl group, unsubstituted or halo-substituted aryl groups, unsubstituted or halogen-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocycle groups, heterocyclic-CO groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups; and the substituted amino group as the substituent of R ¹ and the substituted amino group as R ⁶ each have at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, etc. Native alkyl groups substituted by a protected or unprotected carboxyl or hydroxyl group, Cycloalkyl groups, aryl groups, lower acyl groups, lower aralkyl groups, heterocycle groups, unsubstituted or oxo-substituted heterocyclic-CO groups, adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, provided that those compounds are excluded where R ^{1 is} a phenyl group which may be optionally substituted may be represented by the halogen atom or the lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group and R ^{6 is} -NR ⁷ R ⁸ wherein R ^{7 is} an Ar-lower alkyl or heterocycle group and R ^{8 is} a represents hydrogen atom or a lower alkyl group or R ⁷ and R ⁸ together with the N atom form the following structures: in which R ^{9 is} an aryl or heterocycle group and i is 0 or an integer from 1 to 3, where R ^{10 is} an aryl, heterocycle or N-heterocycle group and R ⁸ and i are the same R ^{8 have} meanings as above, -N wherein R ^{11 is} an aryl group; R ¹² -N in which R ^{12 is} a carboxyl group or a lower alkoxycarbonyl group or R ¹² in which R ^{12 has} the same meaning as above; wherein all of the above heterocycle groups are selected from the group consisting of the nitrogen-containing hoterocycle groups mentioned in the definition of R ⁶ and furyl, thien ·, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl , Benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl , Benzo (b) dioxanyl, imidazo [2,3-a] pyridy!, Benzo [b] piperazinyl, chromenyl, isothiazolyl, isoAa ^ uiyi-, oxadiazolyl, pyridazinyl, isoindolyl, and isoquinolyl groups. 18. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 17, characterized in that R ^{1 represents} a substituted or unsubstituted phenyl group; R ^{2 is} a Wassei atom or a hydroxyl protecting group; nR ⁴ radicals are the same or different and denote hydrogen atoms or lower alkyl groups; nR ⁶ radicals are hydrogen atoms; and R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl , Pyrimidinyl, morpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiaciazolyl groups. 19. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 17, characterized in that R ^{1 represents} a substituted or unsubstituted naphthyl group; R ^{2 is} a hydrogen atom or a hydroxyl-protecting group; nR ⁴ radicals are the same or different and represent hydrogen atoms or lower alkyl groups; nR ⁵ radicals mean water stoichioms; and R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl , Pyrimidinyl, morpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups. 20. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 17, characterized in that R ^{1 represents} the substituted or unsubstituted heterocycle group. 21. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 17, characterized in that R ^{1 represents} a substituted or unsubstituted phenyl, naphthyl, indanyl, tetrahydronaphthyl, furyl, thienyl, pyridyl, quinolyl Benzothienyl, 2,3-dihydrobenzofuranyl, indolyl, benzofuranyl, 2,3-dihydrobenzothienyl, 1,2,3,4-tetrahydroquinolinyl or imidazolyl group; R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocyclic group, where the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolinyl, piperidyl, piperazinyl, imidazolyl, pyridyl, morpholinyl , Thiomorpholinyl, Tetrahydropyridyl, quinuclidinyl and tetrazolyl groups, the substituent on R ^{1 is} selected from the group consisting of halogen atoms; lower alkyl; Nioderalkenylgruppen; Phenyl groups which may optionally be substituted by a halogen atom or a lower alkyl or lower alkoxy group; Phenyl-C ^ -alkyl groups; Lower alkoxy groups which may optionally be substituted by a pyridyl, furyl or thienyl group; Phenyl C 1-4 alkoxy groups which may optionally be substituted by a halogen atom or a lower alkyl, hydroxyl or lower alkoxy group; a phenoxy group; Phenylaminocarbonyloxy groups which may be optionally substituted by a halogen atom; Niederalkylaminocarbonyloxygruppgn; lower alkylthio; a phenylsulfonylamino group; Amino groups which may optionally be substituted by a lower alkyl group; a HyJroxylgrup ^; a nitro group; an oxo group; Phenyl-C ^ alkylthio; Phenyl-C ^ alkylsulfonyl; a thienyl group; a pyridyl group; and Nioderalkylenedioxy groups; and the substituent on R ⁶ , when R ^{6 is} a substituted amino group, is selected from the group consisting of lower alkyl groups which may optionally be substituted by a lower acyl group; cycloalkyl groups; Phenyl-C ^ -alkyl groups; a pyrimidinyl group; a pyridinecarbonyl group and an adamantyl group; and the substituent on R ⁶ , when R ^{6 is} a substituted nitrogen-containing heterocycle group, is selected from the group consisting of halogen atoms; hydroxyl group; Lower alkyl groups which may be optionally substituted by a hydroxyl group; an amino group; lower acyl groups which may optionally be substituted by a pyrrolidinyl group; , _4-alkyl, phenyl-C; Phenyl-C ₂ -4 alkenyl groups; Aroyl groups which are optionally substituted by a halogen atom; a pyridyl group and an oxo group; with the proviso that the compounds are excluded in which R ^{1 is} a phenyl group which may be optionally substituted by the halogen atom or the lower alkyl, lower alkoxy, lower alkylenedioxy or hydroxyl group and R ^{6 is} -NR ⁷ R ⁸ , wherein R ^{7 represents} a phenyl-C ^ -alkyl or pyrimidinyl group and R ^{8 represents} a hydrogen atom or a lower alkyl group or R ⁷ and R ⁸ form the following structure together with the N atom in which R ^{9 represents} a phenyl group and i is 0 or an integer from 1 to 3. 22. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 21, characterized in that R ^{1 represents} a phenyl group which may optionally be substituted by a halogen atom; a phenyl-C 1-4 alkoxy group; a thienyl group; a phenoxy group which may be optionally substituted by a halogen atom or a lower alkoxy group; or a lower alkoxy group which may be optionally substituted by a thienyl group; R ^{2 is} a hydrogen atom; R ^{3 is} a hydrogen atom; nR ⁴ radicals and nR ⁵ radicals represent hydrogen atoms; R ^{6 represents} a morpholinyl group which has a free valence at a carbon atom of the ring, or a pyridyl group, an imidazolyl group, Ίιβ may optionally be substituted by a lower alkyl group, or an amino group which may be optionally substituted by a lower alkyl or a cycloalkyl group , Use of a 1,2-ethanediol derivative or a salt thereof according to claim 21, characterized in that R ^{1 represents} a naphthyl, indanyl or tetrahydronaphthyl group which may optionally be substituted by a halogen atom or a lower alkyl group; R ^{2 is} a hydrogen atom; R ^{3 is} a hydrogen atom; nR ⁴ and nR ⁵ radicals represent hydrogen atoms; R ^{6 represents} a morpholinyl group having a free valence on a carbon atom of the ring, a pyridyl group, an imidazolyl group, a phenyl-C 1-4 -alkyl group-substituted piperazinyl group or an amino group which may be optionally substituted by a lower alkyl group or a cycloalkyl group; and η is an integer from 1 to 4. 24. Use of a 1,2-ethanediol derivative or a salt thereof according to claim 21, characterized in that R ^{1 represents} a benzothienyl, benzofuranyl or 2,3-Dihydrobenzothienylgruppe; R ^{2 is} a hydrogen atom; R ^{3 is} a hydrogen atom; nR ⁴ and nR ⁵ radicals represent hydrogen atoms; R ^{6 is} a pyridyl group; a piperidinyl group which may be optionally substituted by a lower alkyl group; a 1,2,5,6-tetrahydropyridyl group optionally substituted by a lower alkyl group may be substituted; imidazolyl; a phenyl-C 1-4 -alkyl group-substituted piperazinyl group or an amino group which may be optionally substituted by a lower alkyl group or a cycloalkyl group; and η is an integer from 1 to. 25. Use according to claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (4-benzyloxy) phenyl) -2- [2- (N, N-dimethylamino) ethoxyethanol or a salt thereof. 26. Use according to claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (4-benzyloxyphenyl) -2 - [(1-methyl-5-imiclazolyl) -methoxyethanol or a salt thereof is. Use according to Claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 2- (imidazolylmethoxy) -1- (1-naphthyl) -ethanol or a salt thereof. 28. Use according to claim 17, characterized in that it is the 1,2-Ethandioldorivat or its salt is 2- (1-methyl-5-imidazolylmethoxy) -1- (1-naphthyl) ethanol or a salt thereof , 29. Use according to claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (benzo [b] thiophene-5-yl) -2- [2- (N, N-dimothylamino) -ethoxy-ethanol or a salt thereof. 30. Use according to claim 17, characterized in that it is in the 1,2-Ethandiolderivat or its SaI. is 1- {benzo (b) thiophene-5-yl) -2- [3- (N, N-dimethylamino) -propoxy] ethanol or a salt thereof. Use according to Claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (benzo (b) thiophene-5-yl) -2- (imidazolylmethoxy) -ethanol or a salt of the same acts. 32. Use according to claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (benzo [b] thiophen-5-yl) -2 - [(1-methyl-1,2, 5,6-tetrahydropyridin-3-yl) methoxy] ethanol or a salt thereof. 33. Use according to claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 1- (benzo [b] furan-5-yl) -2- (2- (N, N-dimethylamino) -ethoxy-ethanol or a salt thereof. Use according to Claim 17, characterized in that the 1,2-ethanediol derivative or its salt is 2- (2- (N, N-dimethylamino) ethoxyl-1- (3-methylphenyl) -ethanol or a Salt thereof. 35. An agent for improving cerebral function, comprising a 1,2-ethanediol of the following general formula or a salt thereof, R3 R * R ^{1 is} -CHCH-O-4C4-R ⁶ I " OR ² R ⁶ wherein R ^{1 represents a} monosubstituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaph'hyl or heterocycle group; R ^{2 represents} a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group; R ^{3 is} a hydrogen atom or a lower alkyl group; nR ⁴ radicals ur.d nR ⁵ radicals are identical or different and represent hydrogen atoms or lower alkyl groups; R ^{6 is} an ammonio group or is a substituted or unsubstituted amino- or nitrogen-containing heterocycle group, wherein the nitrogen-containing heterocycle group is selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, Tetrahydropyridyl, pyrimidinyl, morpholinylthiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, jhinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, Purinyl and indazolyl groups; and η is 0 or an integer from 1 to 6, wherein the substituent on R ^{1 is} selected from the group consisting of halogen, substituted or unsubstituted amino, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, Ar lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulphonyl, arylsulphonyl, Nioderalkylsulfonylamino, arylsulfonylamino and heterocycle groups, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group 3 and lower alkylenedioxy groups; the substituted lower alkyl, aryl, ar-lower alkyl, lower; alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, Ai-lower alkylthio, ar-lower alkylsulfonyl, arylsulfony !, lower alkylsulfonylamino, arylsulfonylamino or heterocycle groups as the substituent of R ¹ and the substituted nitrogen-containing heterocycle group as R ^{6 in} each case have at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxy groups, protected or unprotected amino groups, protected or unprotected carboxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected hydroxyl group, unsubstituted or halo-substituted aryl group, unsubstituted or halo-substituted aroyl groups, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower acyl groups, Ar-lower alkyl groups, Ai-lower alkenyl groups, Hete cycloalkyl groups, heterocycle CO groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups; and the substituted amino group as the substituent of R ¹ and the substituted amino group as R ⁶ each have at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, lower alkyl group subc / substituted by a protected or unprotected carboxyl group. or hydroxyl group, cycloalkyl groups, aryl groups, lower acyl groups, Ar-lower alkyl groups, heterroryl group, unsubstituted or oxo-substituted heterocycle CO groups, adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, with the proviso that the compounds are excluded in which R ^{1 is} a phenyl group which may optionally be substituted by the halogen atom or the lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group and R ^{6 is} -NR ⁷ R ⁸ , where R ^{7 is} an Ar-lower alkyl or heterocycle group and R ³ a Wa or R ⁷ and R ⁸ together with the N atom form the following structures: in which R ^{9 is} an aryl or heterocycle group and i is 0 or an integer from 1 to 3, COR ¹⁰ where R ' ^{0 is} an aryl, heterocycle or N-heterocycle group and R ⁸ and i are the same R ^{8 have} meanings as above, -N V wherein R ^{11 is} an aryl group; R ¹² in which R ^{12 is} a carboxyl group or a lower alkoxycarbonyl group or _R 12 in which R ^{12 has} the same meaning as above; wherein all of the above heterocycle groups are selected from the group consisting of the nitrogen-containing heterocycle groups mentioned in the definition of R ⁶ and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, Oxazolyl, benzofuranyl, indolyl, benzimidazolyl, bonzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobonzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl , 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo (2,3-alpyridyl, benzo | b) piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups , and pharmaceutically acceptable excipients and additives. Field of application of the invention The invention relates to 1,2-Fththiolc! Urivato and their Salzo, ancestors for Horstollung dorsolben sowio Mittol for improving the Cerobralfunktion with a content thereof. The agents according to the invention for improving cleroborax function are useful for the treatment of cerebrovascular dementia, senilor domontia, Alzheimer's oomontia, soquelao of ischemic encephalopathy and cerobralor apoplexy.