BE1003168A5 - Ethanediol-1,2 derivatives and their salts, production method thereof andcerebral function enhancement agents comprising same - Google Patents

Abstract

Ethanediol-1,2 derivatives and salts of said derivatives, productionmethods of said derivatives and a cerebral function enhancement agentcomprising said derivatives. Said ethanediol-1,2 derivative is representedby the general formula (see fig.) wherein R1, R2, R3, R4, R5 and R6 havevarious significances. The cerebral function enhancement agent according tothe present invention is useful for treating cerebro-vascular dementia,senile dementia, Alzheimer's dementia, damage induced by ischemicencephalopathy and cerebral apoplexia.<IMAGE>

Description

       

  1,2-ETHANEDIOL DERIVATIVES AND THEIR SALTS, THEIR PROCESS

MANUFACTURING. AND IMPROVING AGENTS

BRAIN FUNCTION INCLUDING THEM

  
The present invention relates to 1,2-ethanediol derivatives and their salts, to a process

  
making them, as well as agents for improving brain function

  
understanding. The function improvement agent

  
brain of this invention is useful for the

  
treatment of cerebrovascular dementia,

  
senile dementia, Alzheimer's dementia,

  
sequelae of ischemic encephalopathy and

  
cerebral apoplexy.

  
As 1,2-ethanediol derivatives, it is known,

  
for example, those described in the US patent

  
n [deg.] 2,928,845; J. Pharm. Sci., Vol. 50, pages 769-771

  
(1961); Farmaco Ed. Sci., Vol. 19, pages 1056-1065

  
(1964); etc.

  
These compounds are in use as

  
than local anesthetics. However, we do not know

  
nothing about their use as agents

  
brain function improvement, anti

  
amnesiacs or nootropic agents.

  
International application WO-88/8424 describes

  
that 1,2-ethanediol derivatives can be used

  
as a remedy for Alzheimer's disease and others

  
Degenerative neurological disorders. However, he

  
neither description nor description is given in this request

  
specific example of these derivatives.

  
Drugs such as agents that increase brain metabolism, cerebro-vasodila-

  
tators and the like are in common use as

  
remedy for various dementias, especially

  
  <EMI ID = 1.1> vascular.

  
  <EMI ID = 2.1>

  
an agent for improving brain function which is useful for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, sequelae of ischemic encephalopathy and cerebral apoplexy.

  
An object of the present invention is to provide new 1,2-ethanediol derivatives and their salts.

  
Another object of the present invention is to provide a process for the manufacture of new 1,2-ethanediol derivatives and their salts.

  
Yet another object of the present invention is to provide a new agent for improving brain function, which is useful for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, sequelae of ischemic encephalopathy and cerebral apoplexy and nevertheless has few side effects.

  
The present inventors have conducted a study to solve the problems mentioned above. As a result, it has been discovered that the 1,2-ethanediol derivatives, represented by the following general formula [I], or their salts, exhibit excellent anti-amnesic activity and excellent anti-hypoxic activity and are very useful as agents for improving brain function:

  

  <EMI ID = 3.1>


  
in which : <EMI ID = 4.1> indanyl, indenyl, tetrahydronaphthyl or heterocyclic-, substituted or unsubstituted;

  
R <2> represents a hydrogen atom, a lower alkyl group or a hydroxyl protecting group;

  
R <3> represents a hydrogen atom or a lower alkyl group;

  
  <EMI ID = 5.1>

  
from each other and represent hydrogen atoms or lower alkyl groups; R6 represents an ammonio group or an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group constituted by the pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl groups, pyrazolyle, pyridyle, tétrahydropyridyle, pyrimidinyle, morpholinyle, thiomorpholinyle, quinolyle, quinolizinyle, tétrahydroquinolinyle, tétrahydroisoquinolinyle, quinuclidinyle, thiazolyle, tétrazolyle, thiadiazolyle, pyridinyl, pyridinyle, and

  
n is 0 or is. an integer ranging from 1 to 6; where the substituent on R <1> is selected from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy,

  
  <EMI ID = 6.1>

  
lower alkenyloxy, lower ar-alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, and protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and alkylene groups &#65533; lower xy; alkyl groups

  
  <EMI ID = 7.1> lower, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic

  
  <EMI ID = 8.1>

  
heterocyclic containing nitrogen substituted as R6 each have at least one substituent selected from the group consisting of halogen atoms, protected or unprotected hydroxyl groups, protected or unprotected amino groups, carboxyl groups protected or unprotected, unsubstituted lower alkyl groups, lower alkyl groups substituted with 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, heterocyclic groups, CO- heterocyclic groups, oxo group ,

   lower alkylsulfonyl groups and arylsulfonyl groups; and the amino group substituted as the substituent of R <1> and the amino group substituted as R6 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 carboxyl group or protected or unprotected hydroxyl, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, heterocyclic-CO- groups unsubstituted or substituted by oxo, the adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, provided that the compounds in

  
  <EMI ID = 9.1>

  
optionally be substituted with a halogen atom or with a lower alkyl, lower alkylene dioxy, lower alkoxy or protected or unprotected hydroxyl group and R6 represents
-NR7R8, where R7 represents an ar-lower alkyl or heterocyclic group, and R8 represents an atom <EMI ID = 10.1>

  
and R8 form, when taken with the atom of N,

  

  <EMI ID = 11.1>


  
represents an aryl group or

  
heterocyclic and is 0 or is an integer

  
ranging from 1 to 3,

  

  <EMI ID = 12.1>


  
where R10

  
represents an aryl, heterocyclic group or <EMI ID = 13.1> as

  
cations than those defined above,

  
R12

  
  <EMI ID = 14.1>

  

  <EMI ID = 15.1>


  
  <EMI ID = 16.1>

  
lower carbonyl alkoxy, or

  

  <EMI ID = 17.1>


  
where R <1> <2> at the

  
same meaning as defined above

  
  <EMI ID = 18.1>

  
phenyl unsubstituted or substituted by lower alkyl, and R6 represents a di-alkyl- group

  
lower-amino,

  

  <EMI ID = 19.1>


  
as well as

  
  <EMI ID = 20.1>

H

  
  <EMI ID = 21.1>

  
chosen from the group consisting of heterocyclic groups containing nitrogen mentioned in the definition of R6 and the furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxyl groups -2.3 benzothienyl, 2,3-dihydro-benzopyrrolyle, 2,3-dihydro-4H-thia-l naphthyl, 2,3-dihydro-benzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyle, benzo [ b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl.

  
In this connection, the agent for improving brain function mentioned here designates an agent for improving brain function having not only the effects which conventional agents for improving brain function have, for example, on the after-effects. ischemic encephalopathy and cerebral apoplexy, but also therapeutic or prophylactic effects on amnesia and dementia (for example, cerebrovascular dementia, senile dementia and Alzheimer's dementia).

  
In the present description, the following expressions have the following definitions unless otherwise indicated.

  
The term "halogen atom" means, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the expression "lower alkyl group" means

  
  <EMI ID = 22.1>

  
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like;

  
the expression "lower alkoxy group" means groups (C1-C6 alkyl) -O- - the expression "lower alkylthio group" <EMI ID = 23.1>

  
propenyl, butenyl, pentenyl, hexenyl and the like;

  
the expression "lower alkenyloxy group" means (C2-6 alkenyl) -O- groups
the expression "cycloalkyl group" means C3-6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;

  
the term "aryl group" means phenyl, naphthyl, indanyl and indenyl groups; the term "aryloxy group" means aryl-O- groups;

  
the expression "ar-lower alkyl group"

  
  <EMI ID = 24.1>

  
benzyl, diphenylmethyl, trityl, phenethyl and the like;

  
the expression "ar-lower alkoxy group" means ar- (C1-4 alkyl) groups -0-: the expression "ar-lower alkylthio group" means aryl- (C1-4 alkyl) groups -S- l "lower alkylenedioxy group"

  
  <EMI ID = 25.1>

  
as methylenedioxy, ethylenedioxy and the like; the expression "lower acyl group" means

  
  <EMI ID = 26.1>

  
acetyl, butyryl and the like

  
the expression "aroyl group" means groups

  
  <EMI ID = 27.1>

  
the expression "ar-lower alkylsulfonyl group" <EMI ID = 28.1>
- the expression "arylsulfonyloxy group" means aryl-SO2-0- groups;

  
the expression "lower alkylsulfonylamino group" means groups (C1-C6 alkyl) ¯ SO2-NH-

  
the expression "arylsulfonylamino group" means

  
  <EMI ID = 29.1>

  
the term "di-lower alkyl-amino group" means di- (C1-C6 alkyl) -NH-; and
the expression "ammonio group" means tri-lower alkyl-ammonio groups, such as trimethylammonio, triethylammonio;
- the expression "lower carbonyl alkoxy group" <EMI ID = 30.1>

  
similar.

  
Protective groups of hydroxyl group, carboxyl group and amino group include conventional protective groups of hydroxyl group, carboxyl group and amino group, which are described in "Protective Groups in Organic Synthesis" by Theodra W. Green, 1981, John Wiley & Sons, Inc. In particular, the protecting group for the hydroxyl group specifically includes, for example, lower alkyl, lower acyl and ar-lower alkyl, such as substituted or unsubstituted benzyl or tetrahydropyranyl.

  
The salts of the 1,2-ethanediol derivatives represented by the general formula [I] can be any pharmaceutically acceptable salt. They include, 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, explic acid, fumaric acid, maleic acid, relic 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.

  
When the 1,2-ethanediol derivatives of

  
  <EMI ID = 31.1>

  
included in the present invention. Also, hydrates, solvates and all forms

  
  <EMI ID = 32.1>

  
are included in the present invention.

  
Then gold. describes a manufacturing process

  
  <EMI ID = 33.1>

  
or their salts.

  
The 1,2-ethanediol derivatives of general formula [I] or their = salts can be obtained by methods known per se or their appropriate combinations, for example, by the following manufacturing methods.

  

  <EMI ID = 34.1>
 

  

  <EMI ID = 35.1>
 

  
In the reaction schemes above,

  
  <EMI ID = 36.1>

  
meanings as defined above; R2a represents the same hydroxyl protecting group as in the definition of R <2>

  
R6a represents the same heterocyclic group containing nitrogen, substituted or unsubstituted, as in the definition of R6, provided that the heterocyclic group has a free valence on a carbon atom forming the heterocyclic nucleus;

  
R6b represents the same heterocyclic group containing nitrogen, substituted or unsubstituted, as in the definition of R6, provided that the heterocyclic group containing nitrogen has a free valence on a nitrogen atom forming the nucleus heterocyclic, or a substituted or unsubstituted amino group;

  
R <1> <3> represents the same hydroxyl protecting group as in the definition of R <2>

  
  <EMI ID = 37.1>

  
different, represent halogen atoms; Y represents an eliminable group, such as a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group or the like;

  
  <EMI ID = 38.1>

  
m represents an integer ranging from. 1 to 6.

  
As salts of the compounds of the general formulas [III], [IIIa], [IV], [V], [VII], [IX], [X], [XI], [XII], [XVI], [Ia] , [Ib], [le] and [Id], the same salts may be mentioned as the salts of the compounds of the general formula [I].

  
Each of the above manufacturing processes will now be described.

  
Manufacturing Process 1

  
A compound of general formula [II] is reacted with a compound of general formula [III], or its salt, or a compound of general formula [IIIa], or its salt, in the presence or absence of a base , to obtain a compound of general formula [la] or its salt.

  
The solvent to be used in this reaction can be any solvent unless it has an adverse influence on the reaction. Mention may be made, for example, of aromatic hydrocarbons, such as benzene, toluene, xylene and the like; sulfoxides, such as dimethyl sulfoxide and the like; amides, such as N, N-dimethylformamide and the like; and ethers, such as tetrahydrofuran, dioxane and the like. These solvents can be used alone or as a mixture of two or more. It is also possible to use the compound of general formula [III] or [IIIa] as a solvent.

  
As the base to be used optionally, there may be mentioned, for example, sodium hydride, metallic sodium and potassium tert-butoxide.

  
In the reaction, the compound of general formula [III], or its salt, or the compound of general formula [IIIa] or its salt, is used in an amount of 1-100 moles, preferably 1-10 moles, per mole of the compound of general formula [II].

  
The base as an optional component is used in an amount of 0.01-1.2 moles per mole of the compound of general formula [II].

  
This reaction can usually be carried out at 20-150 [deg.] C, preferably 70-90 [deg.] C, for

  
1 minute to 24 hours, preferably 5 minutes to

  
5 hours.

  
Manufacturing Process 2

  
(1) A compound of general formula [II] is reacted with a compound of general formula [IV], or its salt, in the presence or in the absence of a base, to obtain a compound of general formula [V] , or its salt.

  
This reaction can be carried out in the same way as that described in Manufacturing Process 1.

  
The compound obtained of general formula [V], or its salt, can be used in the subsequent reaction without being isolated.

  
(2) The compound of general formula [V], or its salt, is subjected to a conventional reaction for protecting the hydroxyl group, to obtain a compound of general formula [VI].

  
The compound obtained of general formula [VI] can be used in the subsequent reaction without being isolated.

  
Then, the compound of general formula [VI] is subjected to a reaction for the selective elimination of the hydroxyl protecting group, to obtain a compound of general formula [VII], or its salt.

  
The compound obtained of general formula [VII], or its salt, can be used in the subsequent reaction without being isolated.

  
These reactions can be carried out in accordance with methods known per se, for example, the method described in "Protective Groups in Organic Synthesis" [Theodra W. Green, 1981, John Wiley & Sons, Inc], or a method analogous to this one.

  
The combination of hydroxyl protecting groups (R <1> <3> and R2a) to be used in these reactions can be appropriately chosen.

  
(3) The compound of general formula [VII], or its salt, is reacted with an agent

  
  <EMI ID = 39.1>

  
solvent, in the presence or absence of a base, for

  
  <EMI ID = 40.1>

  
The solvent to be used in the reaction can be any solvent, unless it has an adverse influence on the reaction. Mention may be made, for example, of halogenated hydrocarbons, such as methylene chloride, chloroform and the like; ethers, such as tetrahydrofuran, dioxane and the like; nitriles,

  
  <EMI ID = 41.1>

  
solvents can be used alone or as a mixture of two or more.

  
As the base to be used optionally, there may be mentioned, for example, organic and inorganic bases, such as triethylamine,

  
  <EMI ID = 42.1>

  
  <EMI ID = 43.1>

  
potassium, sodium carbonate, potassium carbonate, sodium hydride and the like.

  
  <EMI ID = 44.1>

  
mention, for example, phosphorus oxychloride, phosphorus oxybromide, trichloride

  
  <EMI ID = 45.1>

  
mention, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.

  
  <EMI ID = 46.1>

  
mole, preferably. 1-2 moles, per mole of the compound of general formula [Vil], or its salt.

  
This = ___-_ ion can usually be carried out at a temperature ranging from -10 [deg.] C to 100 [deg.] C,

  
  <EMI ID = 47.1>

  
hours.

  
The compound obtained of general formula [VIII] can be used *, as such in the subsequent reaction without isolation.

  
  <EMI ID = 48.1>

  
be any solvent, unless it has an adverse influence on the reaction. We can

  
  <EMI ID = 49.1>

  
As a catalyst to be optionally used, there may be mentioned, for example, potassium iodide, sodium iodide and the like.

  
The catalyst is used in an amount of

  
  <EMI ID = 50.1>

[VIII].

  
As a basis for optional use,

  
  <EMI ID = 51.1>

  
those mentioned ___ point (3) of the Manufacturing Process 2.

  
  <EMI ID = 52.1>

  
10 minutes to 20 hours.

  
Manufacturing Process 3

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

  
This reaction can be carried out according to the same method as that mentioned in Manufacturing Process 1.

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

  
The solvent to be used in this reaction can be any solvent, unless it has an unfavorable influence on the reaction. Mention may be made, for example, of the same solvents as those mentioned in point (3) of the Process for Manufacturing 2.

  
As a base to be used optionally, there may be mentioned, for example, the same bases as those mentioned in point (3) of Manufacturing Process 2.

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

  
Each of the sulfonylating agent and the base as an optional component is used in an amount of at least 0.95 moles, preferably 1-2 moles, per mole of the compound of general formula [XI], or of its salt.

  
This reaction can usually be carried out at a temperature of -10 to 100 [deg.] C, preferably from 0 [deg.] C to 40 [deg.] C, for 10 minutes to 30 hours.

  
The compound obtained of general formula [XII], or its salt, can be used in the subsequent reaction without being isolated.

  
(3) The compound of general formula [XII], or its salt, is subjected to a conventional reaction for protecting the hydroxyl group, in order to obtain a compound of general formula [XIII].

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

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

  
(4) A compound of general formula [XII], or its salt, or a compound of general formula [XIII], is reacted with a compound of general formula [IX], or its salt, in the presence or in the absence of a base, to * obtain a compound of general formula [Ic], or its salt.

  
This reaction can be carried out according to the same method as that described in point (4) of Manufacturing Process 2.

  
Manufacturing Process, 4

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

  
The solvent used in this reaction can be any solvent, unless it has an adverse influence on the reaction. Mention may be made, for example, of ethers, such as diethyl ether, tetrahydrofuran, dioxane and the like; and aromatic hydrocarbons, such as benzene, toluene and the like. These

  
  <EMI ID = 53.1>

  
two or more.

  
In this &#65533; &#65533; e reaction, the compound of general formula [XV] is used in an amount of 0.8-100 moles, preferably 0.8-10 moles, per mole of the compound of formula general [XIV].

  
This reaction can usually be carried out at a temperature of -78 [deg.] C to 100 [deg.] C,

  
  <EMI ID = 54.1>

  
hours.

  
The compound obtained of general formula [XVI], or its salt, can be used in the subsequent reaction without being isolated.

  
In this regard, the compound of general formula [XV] to be used in this reaction can be obtained in accordance with a method known per se, for example, the method described in Bull. Soc. Chim. Fr., 1967

  
(5), pages 1533-4C.

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

  
The solvent to be used in this reaction

  
  <EMI ID = 55.1>

  
an adverse influence on the reaction. Mention may be made, for example, of halogenated hydrocarbons, such as methylene chloride, chloroform and the like; harrows, such as tetrahydrofuran, dioxa &#65533; &#65533; e and the like; alcohols, such as ethanol, propanol, butanol and the like; nitriles, such as acetonitrile and the like; and amides, such as NN-dimethylformamide and the like. These solvents can be used alone or in mixture of fires or more.

  
As the base to be used optionally, there may be mentioned, for example, the same bases as

  
  <EMI ID = 56.1>

  
Manufacturing 2.

  
Each appears the compound of general formula [IX], or its salt, e &#65533; base, as an optional component, is used in an amount of at least 1

  
  <EMI ID = 57.1>

  
This reaction can usually be carried out at 10-150 ° C, preferably 20-100 [deg.] C, for
10 minutes to 20 hours.

  
In the above manufacturing processes, the reagents or "- = - can also be used as a solvent, depending on the nature of the reagents or the base.

  
In the manufacturing processes above, when the compounds of general formulas [II],

  
  <EMI ID = 58.1>

  
have isomers (eg, optical isomers, geometric isomers, tautomers), the compounds can be used in any isomeric form. In addition, the compounds can be

  
  <EMI ID = 59.1>

  
When the compounds of the general formulas [II], [III], [IIIa :, [IV], [V], [VI], [VII], [VIII],

  
  <EMI ID = 60.1>

  
to protect these groups beforehand with a conventional protective group and to remove, after the reaction, the protective group if necessary, in accordance with methods known per se.

  
The compounds thus obtained can be subjected to conventional isolation and purification techniques, such as column chromatography, crystallization, distillation, extraction and the like.

  
The 1,2-ethanediol derivatives of the general formula [I], or their salts, can be converted to other 1,2-ethanediol derivatives of the general formula [I], or their salts, by subjecting the first derivatives to an appropriate combination of reactions known per se such as an oxidation reaction, a reduction reaction, an addition reaction, an acylation reaction, an alkylation reaction, a sulfonylation reaction, a deacylation reaction, substitution reaction, dehydration reaction, hydrolysis reaction, and the like.

  
The compounds of the general formula [II], which are the starting materials for obtaining the compounds of the present invention, can be obtained by methods known per se, for example, by the method described in JACS, Vol. 87, page 1353
(1965) and by the method described in Shin Jikken Kagaku Koza, vol. 14, page 579 (1977), Maruzen.

  
The compounds of the present invention, when used as medicaments, can be suitably mixed with excipients, such as a filler, carrier, diluent and the like, and they can be placed under the in the form of tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, injections, etc., in accordance with conventional methods. These drugs can be administered orally or parenterally. The dosage route, dose and number of administrations may vary in an appropriate manner depending on the age, weight and symptoms of the patient, but, <EMI ID = 61.1>

  
composed, per day an adult patient, in one or more fractic - &#65533; .

  
  <EMI ID = 62.1>

  
representative of == present invention will now be described.

  
The numbers of the test compounds used

  
  <EMI ID = 63.1>

  
oral to female ddY mice (5-6 weeks old, each group comprising 10 mice). One hour (or 30 minutes') after administration, each mouse was placed in a glass chamber of

  
  <EMI ID = 64.1>

  
the time elapsed between the moment when we started to pass the g = -: = - through the room until the death of each of the mice.

  
  <EMI ID = 65.1>

  
only.

  
Antihypoxic activity of the test compound

  
  <EMI ID = 66.1>

  

  <EMI ID = 67.1>


  
  <EMI ID = 68.1>

  
Table 1.

  
Table 1
  <EMI ID = 69.1>
 Table 1 (continued)
  <EMI ID = 70.1>
   <EMI ID = 71.1>

  

  <EMI ID = 72.1>


  
  <EMI ID = 73.1>

  
2. Effect of === test poses on amnesia

  
(1) Amnesia induced by electroconvulsive shock

(ECS).

  
An assay co-dissolved in physiological saline was administered intraperitoneally to male ddY mice (5-6 weeks old, each group comprising 10 mice). The passive avoidance task acquisition test was performed 1 hour after administration. Each mouse was placed in the clear compartment of a passive avoidance device of the type passing through two compartments, consisting of a clear compartment and a dark compartment (MPA-100M, manufactured

  
  <EMI ID = 74.1>

  
0.5 seconds, shock impossible to avoid (1.6 mA,

  
3 seconds) was delivered from the bottom. At once

  
  <EMI ID = 75.1>

  
through both eyes of the mouse. At the end of
24 hours, in the retention test, the mouse

  
  <EMI ID = 76.1>

  
the latent state of response for the mouse to enter the dark compartment was measured. If the mouse avoided hushing for more than 300 seconds,

  
  <EMI ID = 77.1>

  
10 mice and expressed by the following symbols: -: 0-60 seconds +: 61-100 seconds

  
++: 101-150 seconds +++: 151-300 seconds.

  
The results are presented in Table 2.

Table 2

  

  <EMI ID = 78.1>
 

  
Table 2 (continued)

  

  <EMI ID = 79.1>


  
(2) Effect of test compounds on amnesia

  
  <EMI ID = 80.1>

  
next was therefore performed.

  
A test = was carried out in accordance with the

  
  <EMI ID = 81.1>

  
Japonica, vol. 89,: ages 243-252 (1987) ".

  
The descent type passive avoidance trainer was used as the test apparatus. It was &#65533; -a black acrylic resin box of 22 cm x 22 cm x II cm (height), the floor part of which consists of: a stainless steel grid and which had one of the corners of the grid

  
  <EMI ID = 82.1> physiological, and injected subcutaneously at a rate of 120 mg / kg into male ddY mice (aged 5-6 weeks, each group comprising 10 mice). In an acquisition test, 15 minutes after administration, each mouse was placed on the platform of the above test apparatus. As soon as the mouse descended from the platform, a current of 2 mA was delivered for 2 seconds, after which the mouse was immediately returned to its refuge cage. A retention test was performed 24 hours after acquisition.

   To each mouse which had been treated with cycloheximide, a test compound dissolved in physiological saline was administered orally; 30 minutes after administration, the mouse was again placed on the platform, and the latent state of response for the mouse to descend was measured. If the mouse avoided descending for more than 300 seconds, a ceiling score of

  
300 seconds was allocated to him.

  
A group of control mice, to which only physiological saline had been administered orally, was also subjected to the measurement of the latent state of response, in the same way.

  
The anti-amnesic activity was considered to be the mean value of the latent states of response of the 10 mice and expressed, by the following symbols
-: 0-60 seconds +: 61-100 seconds

  
++: 101-150 seconds

  
+++: 151-300 seconds.

  
The results are presented in Table 3.

  
Table 3
  <EMI ID = 83.1>
 Table 3 (continued)
  <EMI ID = 84.1>
 Table 3 (continued)

  

  <EMI ID = 85.1>


  
  <EMI ID = 86.1>

  
as substrate was added to a phosphate buffer solution containing dithio-5,5 'bis- (acid

  
  <EMI ID = 87.1>

  
resulting benzoic was measured by photometry at
412 nm.

  
The inhibitory activity === on the acetylcholinesterase of the test compound was expressed by the inhibition (%) when the final concentration of the

  
  <EMI ID = 88.1>

  
The results are presented in Table 4.

Table 4

  

  <EMI ID = 89.1>
 

  
Table 4 (continued)

  

  <EMI ID = 90.1>


  
4. Acute toxicity

  
A test compound dissolved in physiological saline was administered intravenously to a group of 3 male ddY mice (5-6 weeks old), to examine the acute toxicity of the test compound.

  
As a result, the test compounds n [deg.] 1,

  
  <EMI ID = 91.1>

  
46, 52, 53, 54, 65, 67, 70, 71, 112, 119, 120, 126,
132, 147, 151, 159, 160, 170, 176, 178, 182, 190, 194,
209, 219, 220, 221, 229, 235, 236, 240, 251, 256, 279,
283, 309, 312, 313, 315, 316, 319, 325, 327, 337, 360,
368, 369, 375, 377, 385, 390 and 396 did not give any case of death at a dose of 50 mg / kg.

  
The above test results readily show that the compounds of the present invention have

  
  <EMI ID = 92.1>

  
amnesic and inhibitory activity on acetylcholinesterase which are excellent and which have a low toxicity.

  
From the above results it is easily reduced that the brain function enhancers of the present invention are useful for the treatment of cerebrovascular dementia, senile dementia, Alzheimer's dementia, sequelae of ischemic encephalopathy and cerebral apoplexy.

  
The methods of making the compounds of the present invention will now be described in a specific manner with the aid of Manufacturing Examples.

  
In the Manufacturing Examples, the mixing ratio of the eluent is by volume in all cases and, as a column chromatography support, silica gel (Kieselgel 60, Art. 7734) made by Merck Co. was used.

  
The abbreviations used in the Manufacturing Examples have the following meanings:

  
Me methyl,

  
And: ethyl,

  
i-Pr isopropyl,

  
t-Bu tert.-butyle,

  
Ac: acetyl,

  
Ph: phenyl,

  
DPM diphenylmethyl,

  
Bz: benzyl,

  
Tr: trityle,

  
IPA isopropyl alcohol,

  
IPE: diisopropyl ether,

  
PTS p-toluenesulfonic acid.

  
In the following sentences and tables, the substances indicated in square brackets denote solvents used in recrystallization.

  
Manufacturing Example 1

  
(1) A mixture of 10.8 g of (L) -benzoylcystine, 1.6 g of lithium borohydride, 2.4 g of tert.butanol and 180 ml of tetrahydrofuran was brought to reflux for 1 hour, then cooled at -60 [deg.] C. 6.1 g of 4-benzyloxyphenacyl bromide were added thereto. The mixture was stirred for 30 minutes at the same temperature and again for 3 hours at a temperature ranging from -40 [deg.] C to -30 [deg.] C. The reaction mixture was added to a mixture of 100 ml of water and 200 ml of diethyl ether. The organic layer was separated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   The residue thus obtained was purified by column chromatography (eluent: toluene), to obtain 2.8 g of (S) - (4-benzyloxyphenyl) -1 bromo-2 ethanol.

  
(2) 2.8 g of (S) - (4-benzyloxyphenyl) -1 bromo-2 ethanol were dissolved in a mixed solvent of

  
20 ml of methanol and 10 ml of tetrahydrofuran. To the solution was added a solution of 0.8 g of potassium hydroxide dissolved in 4 ml of water, cooled by ice. The mixture was stirred for 5 minutes at the same temperature and again for 10 ninutes at room temperature. The reaction mixture was added to a mixture of
50 ml of diethyl ether and 50 ml of an ice-water mixture. The organic layer has been separated. The aqueous layer was extracted with 25 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate.

   The solvent was removed by distillation under reduced pressure to obtain 1.4 g of (S) - (4-benzyloxyphenyl) -2 oxirane.

  
Melting point: 56-61 [deg.] C

  
  <EMI ID = 93.1>

  
The following compounds were obtained in the same manner.

  

  <EMI ID = 94.1>


  
Manufacturing Example 2

  
(1) A solution of 23 g of (+) - diisopinocamphenylchloroborane dissolved in 30 ml of tetrahydrofuran was cooled to -25 [deg.] C. 12 g of 4-benzyloxyphenacyl bromide were added thereto. The resulting mixture was stirred for 4 hours at a temperature ranging from -20 [deg.] C to -15 [deg.] C. The reaction mixture was added to a mixture of 150 ml of diethyl ether and 100 ml of a water-ice mixture. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent:
hexane: toluene = 1: 2), to obtain 6.8 g of (R) -
(4-benzyloxyphenyl) -1 bromo-2 ethanol.

  
  <EMI ID = 95.1>

  
ethanol were dissolved in a mixed solvent of

  
50 ml of methanol and 25 ml of tetrahydrofuran. A solution of 1.5 g of potassium hydroxide dissolved in 5 ml of water was added thereto, with cooling by ice. The mixture was stirred for 5 minutes at the same temperature and again for 10 minutes at room temperature. The reaction mixture was added to a mixture of

  
100 ml of diethyl ether and 100 ml of an ice-water mixture. The organic layer has been separated. The aqueous layer was extracted with 50 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.7 g of (R) - (4-benzyloxyphenyl) -2 oxirane.

  
Melting point: 58-67 [deg.] C

  
  <EMI ID = 96.1>

  
The following compounds were obtained in the same manner.

  
  <EMI ID = 97.1>

  

  <EMI ID = 98.1>


  
Manufacturing Example 3

  
3.4 g of potassium tert.-butoxide was added to 31 ml of (N, N-dimethylamino) -2 ethanol. The resulting mixture was heated to 80 [deg.] C. 7.7 g of (3-fluoro-phenyl) -2 oxirane were added dropwise over 40 minutes. The mixture was stirred for 3 hours at the same temperature. The rational mixture was added to a 200 ml mixture of a

  
  <EMI ID = 99.1>

  
organic layer has been separated. To the organic layer, 50 ml of water was added. The mixture was adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 100 ml of chloroform. The resulting mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol = 5/1). The resulting oily product was dissolved in 25 ml of acetone. Hydrogen chloride gas was blown into the solution.

   The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 3.1 g of [(N, N-dimethylamino) -2 ethoxy] -2 hydrochloride
(3-fluoro phenyl) -1 ethanol (compound n [deg.] 1).

Melting point: 164-165 [deg.] C [EtOH]

  
The compounds presented in Table 5 were obtained in the same way.

  
In Table 5, R <1>, R <2>, R <3>, R4a, R4b, R6, na and nb each represent a substituent or an integer used in the following formula
  <EMI ID = 100.1>
  <EMI ID = 101.1>
  <EMI ID = 102.1>
 
  <EMI ID = 103.1>
  <EMI ID = 104.1>
 
  <EMI ID = 105.1>
  <EMI ID = 106.1>
 
  <EMI ID = 107.1>
  <EMI ID = 108.1>
 
  <EMI ID = 109.1>
  <EMI ID = 110.1>
 
  <EMI ID = 111.1>
  <EMI ID = 112.1>
 
  <EMI ID = 113.1>
  <EMI ID = 114.1>
 
  <EMI ID = 115.1>
  <EMI ID = 116.1>
 
  <EMI ID = 117.1>
  <EMI ID = 118.1>
 
  <EMI ID = 119.1>
  <EMI ID = 120.1>
 
  <EMI ID = 121.1>
  <EMI ID = 122.1>
 
  <EMI ID = 123.1>
  <EMI ID = 124.1>
 
  <EMI ID = 125.1>
  <EMI ID = 126.1>
 
  <EMI ID = 127.1>
  <EMI ID = 128.1>
 
  <EMI ID = 129.1>
  <EMI ID = 130.1>
 
  <EMI ID = 131.1>
  <EMI ID = 132.1>
 
  <EMI ID = 133.1>
  <EMI ID = 134.1>
 
  <EMI ID = 135.1>
  <EMI ID = 136.1>
 
  <EMI ID = 137.1>
  <EMI ID = 138.1>
 
  <EMI ID = 139.1>
  <EMI ID = 140.1>
 

  
  <EMI ID = 141.1>
  <EMI ID = 142.1>
 
  <EMI ID = 143.1>
  <EMI ID = 144.1>
 
  <EMI ID = 145.1>
  <EMI ID = 146.1>
 
  <EMI ID = 147.1>
  <EMI ID = 148.1>
 
  <EMI ID = 149.1>
  <EMI ID = 150.1>
 
  <EMI ID = 151.1>
  <EMI ID = 152.1>
 
  <EMI ID = 153.1>
  <EMI ID = 154.1>
 
  <EMI ID = 155.1>
  <EMI ID = 156.1>
 
  <EMI ID = 157.1>
  <EMI ID = 158.1>
  <EMI ID = 159.1>
 Manufacturing Example 4

  
A mixture of 5.00 g of 1-benzyl-4-hydroxy piperidine, 1.97 g of potassium tert.-butoxide and

  
  <EMI ID = 160.1>

  
2.10 g of styrene dioxide was added dropwise over 40 minutes. The resulting mixture was stirred for 3 hours at the same temperature. The reaction mixture was added to a mixture of

  
100 ml of a water-ice mixture and 80 ml of ethyl acetate. The mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol
10/1). The resulting oily product was. dissolved in 8 ml of ethanol. To the solution was added 1 ml

  
  <EMI ID = 161.1>

  
20 ml of diethyl ether. The mixture was stirred for 30 minutes at room temperature. The resulting crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to obtain 930 mg of hydrochloride (1-benzyl-piperidinyloxy-4) -2 phenyl-1

  
  <EMI ID = 162.1>

  
Melting point: 193-195 [deg.] C

  
The compounds presented in Table 6 have

  
  <EMI ID = 163.1>

  

  <EMI ID = 164.1>


  

  <EMI ID = 165.1>


  

  <EMI ID = 166.1>
 

  

  <EMI ID = 167.1>


  

  <EMI ID = 168.1>
 

  

  <EMI ID = 169.1>


  

  <EMI ID = 170.1>
 

  

  <EMI ID = 171.1>


  

  <EMI ID = 172.1>
 

  

  <EMI ID = 173.1>


  

  <EMI ID = 174.1>
 

  

  <EMI ID = 175.1>


  

  <EMI ID = 176.1>
 

  

  <EMI ID = 177.1>


  

  <EMI ID = 178.1>
 

  

  <EMI ID = 179.1>


  

  <EMI ID = 180.1>


  

  <EMI ID = 181.1>
 

  
  <EMI ID = 182.1>

  
styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added

  
  <EMI ID = 183.1>

  
The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a hollow solution of 2N sodium hydroxide.

  
The organic layer. been separated, washed with a

  
  <EMI ID = 184.1>

  
dried over anhydrous magnesium sulphate. The. solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluent: toluene, ethyl asiate = 1/1), to

  
  <EMI ID = 185.1>

  
methoxy] -2 ethano = compound n [deg.] 144).

  
The composites presented in Table 7 have

  
  <EMI ID = 186.1>

  
used in the following ferrais:

  

  <EMI ID = 187.1>


  

  <EMI ID = 188.1>


  

  <EMI ID = 189.1>
 

  

  <EMI ID = 190.1>


  

  <EMI ID = 191.1>
 

  
(2) A mixture of 1.00 g of phenyl-1 [(4-benzyl-2-morpholinyl-2) methoxy] -2 ethanol, 500 mg of 5% palladium on charcoal and 10 ml of methanol was subjected to hydrogenation for 4 hours, at temperature

  
ambient and atmospheric pressure. After completion of the reaction, the palladium on carbon was removed by filtration. The solvent has been removed

  
by distillation under reduced pressure. The residue has

  
was purified by column chromatography (eluent:
chloroform / methanol = 10/1), to obtain 450 mg of an oily product. The oily product has been dissolved

  
in 2.5 ml of isopropanol. The solution was mixed with 220 mg of fumaric acid. The mixture was stirred for 1 hour at room temperature. The

  
resulting crystals were collected by filtration,

  
  <EMI ID = 192.1>

  
460 mg of 1/2 phenyl-1 fumarate [(2-morpholinyl) methoxy] -2 ethanol (compound n [deg.] 151).

Melting point: 146.5-147 [deg.] C [EtOH]

  
The compounds shown in Table 8 were obtained in the same manner.

  
In Table 8, R <1>, R <2>, R <3>, R4, R6 and n each represent a substituent or an integer used in the following formula:

  

  <EMI ID = 193.1>


  

  <EMI ID = 194.1>


  

  <EMI ID = 195.1>
 

  
  <EMI ID = 196.1>

  
35 ml of acetone. 2.6 ml of a 5.9N solution of dry hydrogen chloride - ethanol were added, with cooling by ice. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue thus obtained, 50 ml of water and 30 ml of ethyl acetate were added. The aqueous layer was separated and washed with ethyl acetate. We added
50 ml of chloroform. The resulting mixture was adjusted to pH 11 with an aqueous solution of IN sodium hydroxide. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol 5/1), to obtain 1 g of an oily product. The oily product was dissolved in 3 ml of isopropanol. 430 mg of fumaric acid was added thereto. The mixture was stirred for 1 hour at room temperature. The resulting crystals were collected by filtration and dried to obtain 800 mg of 1/2

  
  <EMI ID = 197.1>

  
methoxy] -2 ethanol (compound n [deg.] 155).

  
Melting point: 122-123.5 [deg.] C [EtOH]

  
The compounds shown in Table 9 were obtained in the same manner.

  
  <EMI ID = 198.1>

  
each represent a substituent or an integer used in the following formula:

  

  <EMI ID = 199.1>


  

  <EMI ID = 200.1>


  

  <EMI ID = 201.1>
 

  
Manufacturing example 6

  
(1) 5.1 g of potassium tert.-butoxide was added to 105 ml of ethylene glycol mono-tert.-butyl ether. The mixture was heated to 80 [deg.] C. 35.0 g of (3-chloro-phenyl) -2 oxirane were added dropwise over the course of an hour. The mixture was stirred for 2 hours at the same temperature.

  
The reaction mixture was added to a mixture of

  
  <EMI ID = 202.1>

  
ethyl. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate.

  
The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to a further distillation under reduced pressure, to obtain 37.7 g of (3-chloro-phenyl) -1 (2-tert.-butoxyethoxy) -2 colorless oily ethanol, having a boiling point from 140-146 [deg.] C / 120 Pa (0.9 mmHg).

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

  
  <EMI ID = 203.1>

  
  <EMI ID = 204.1>

  
residue was mixed with 100 ml of toluene. The solvent was further removed by distillation under reduced pressure. residue thus obtained was

  
  <EMI ID = 205.1>

  
reduced pressure. = - concentrated, 100 ml of ethyl acetate were added. The organic layer was separated. The aqueous course has been extracted with 50 ml

  
  <EMI ID = 206.1>

  
organic layer previously separated. The organic layer combined = been washed with a solution

  
  <EMI ID = 207.1>

  
ice, in spar; : one hour. The resulting mixture was stirred for 10 minutes at the same temperature and again for 1 hour at room temperature. The reaction mixture was added to a mixture of
50.0 ml of methylene chloride and 50.0 ml of a water-ice mixture. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to obtain 24.5 g of acetoxy-1 (3-chloro-phenyl) -l
(2-methanesulfonyloxyethoxy) -2 oily ethane.

  
(5) 1.40 g of acetoxy-1 (3-chloro-phenyl) -1
(2-methanesulfonyloxyethoxy) -2 ethane was dissolved in 7 ml of N, N-dimethylformamide. To the solution was added 0.69 ml of N-methylpiperazine and 1.03 g of potassium carbonate. The mixture was stirred for 3 hours at 80 [deg.] C. The reaction mixture was cooled and added to a mixture of 30 ml of a water-ice mixture and 30 ml of diethyl ether. The organic layer has been separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   The residue thus obtained was mixed with 7 ml of methanol and 45 mg of sodium methylate. The mixture was allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 20 ml of ethyl acetate and 10 ml of water were added. The organic layer has been separated. The aqueous layer was extracted with 20 ml of ethyl acetate. The extract was combined with the organic layer <EMI ID = 208.1>

  
used in the = _-; the following:

  

  <EMI ID = 209.1>


  

  <EMI ID = 210.1>


  

  <EMI ID = 211.1>
 

  

  <EMI ID = 212.1>


  

  <EMI ID = 213.1>
 

  

  <EMI ID = 214.1>


  

  <EMI ID = 215.1>


  

  <EMI ID = 216.1>
 

  
Manufacturing Example 7

  
A mixture of 2.0 g of hydrochloride
(4-benzyloxyphenyl) -1 [(N, N-dimethylamino) -2

  
ethoxy] -2 ethanol, 5: 0 mg of 10% palladium on charcoal and 10 ml of methanol was subjected to hydrogenation

  
  <EMI ID = 217.1>

  
atmospheric pressure. After completion of the reaction, the palladium on carbon was removed by filtration. The solvent was removed by distillation under reduced pressure, to obtain 1.4 g of

  
  <EMI ID = 218.1>

  
Melting point: 169.5-170.5 [deg.] C [EtOH]

  
Compounds shown in Table 11

  
  <EMI ID = 219.1>

  
used in the following formula:

  

  <EMI ID = 220.1>


  

  <EMI ID = 221.1>


  

  <EMI ID = 222.1>
 

  

  <EMI ID = 223.1>


  

  <EMI ID = 224.1>
 

  
Manufacturing Example 8

  
0.65 ml of pyridine and 0.99 ml of acetic anhydride were added to 1 g of (3-methylphenyl) -1 [(4-morpholinyl) -2 ethoxy] -2 ethanol. The mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 20 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   The residue was purified by column chromatography (eluent: chloroform / ethanol = 30/1), to obtain 1 g of acetoxy-1
(3-methylphenyl) -1 [(morpholinyl-4) -2 ethoxy] -2 ethane (compound n [deg.] 178).

  
The compounds shown in Table 12 were obtained in the same manner.

  
  <EMI ID = 225.1>

  
each represent a substituent or an integer used in the following formula:

  

  <EMI ID = 226.1>


  

  <EMI ID = 227.1>


  

  <EMI ID = 228.1>
 

  

  <EMI ID = 229.1>


  

  <EMI ID = 230.1>
 

  

  <EMI ID = 231.1>


  

  <EMI ID = 232.1>


  

  <EMI ID = 233.1>
 

  
Manufacturing Example 9

  
50 ml of a 1: 1 mixture of chloroform and water was added to 3.30 g of acetoxy-1 (3-hydroxyphenyl) -l hydrochloride [(N, N-dimethylamino) -2 ethoxy] -2 ethane. To the mixture, we added
750 mg of sodium carbonate with cooling by ice. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of benzene. The mixture was heated to 60 ° C. To the resulting solution, a solution of 870 mg of ethyl isocyanate dissolved in 5 ml of benzene was added dropwise over 10 minutes. The mixture was stirred for 40 minutes at the same temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure.

   The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol: 10/1), to obtain an oily product. The oily product was dissolved in 10 ml of ethanol. Hydrogen chloride gas was blown into the solution. The solvent was removed by distillation under reduced pressure, to obtain 1.90 g of acetoxy-1 hydrochloride [(N-ethylcarbamoyloxy) -3 phenyl] -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethane (compound

  
n [deg.] 189).

Melting point: 111.5-113.5 [deg.] C [Me2C0]

  
Similarly, acetoxy-1 [(3-chloro-phenylcarbamoyloxy) -3 phenyl] -l [(N, N-dimethylamino) -2 ethoxy] -2 ethane hydrochloride was obtained (compound n [deg.] 190).

  
  <EMI ID = 234.1>

  
  <EMI ID = 235.1>

  
within 3 hours, a solution of 34.7 g of

  
  <EMI ID = 236.1>

  
dimethyl sulfoxide. The resulting mixture was stirred for 30 minutes = the same temperature. The reaction mixture was cooled to room temperature and added to a 1 liter mixture of water-

  
  <EMI ID = 237.1>

  
combined was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The

  
  <EMI ID = 238.1>

  
phenyl) -1 (hydroxy-: ethoxy) -2 ethanol.

  
Melting point: 116.5-117 [deg.] C [MeCN].

  
  <EMI ID = 239.1>

  
reaction mixture was added to a mixture of
300 ml of a water-ice mixture and 200 ml of ether

  
  <EMI ID = 240.1> has been separated. The aqueous layer was extracted by
100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with acid

  
  <EMI ID = 241.1>

  
saturated with sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue was purified by column chromatography (eluent: toluene / ethyl acetate: 3/1), to obtain 20.5 g of (4-benzyloxyphenyl) -1 [(p-toluenesulfonyloxy) -2 ethoxy] - 2 ethanol.

  
(3) To a mixture of 20 g of (4-benzyloxyphenyl) -1 [(p-toluenesulfonyloxy) -2 ethoxy] -2 ethanol and 40 ml of methylene chloride containing 8.2 g of 3,4-dihydro-2H -pyranne, 2.3 g of pyridinium p-toluenesulfonate was added at room temperature. The resulting mixture was brought to reflux for 30 minutes. The reaction mixture was cooled to room temperature and added to a mixture of 100 ml of an ice-water mixture and 100 ml of methylene chloride. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to obtain

  
18.6 g of (4-benzyloxyphenyl) -1 (tetrahydropyrannyloxy-2) -1 [(p-toluenesulfonyloxy) -2 ethoxy] -2 light yellow oily ethane.

  
(4) A mixture of 2 g of (4-benzyloxyphenyl) -l
(tetrahydropyrannyloxy-2) -1 [(p-toluenesulfonyloxy) -2 ethoxy] -2 ethane, 5.9 ml of a 40% aqueous solution of methylamine and 20 ml of ethanol was brought to reflux for 2 hours. The reaction mixture was cooled and added to a mixture of 50 ml of a water-ice mixture and 50 ml of diethyl ether. The organic layer has been separated. The aqueous layer was extracted twice each time with 20 ml of diethyl ether. The extracts were combined with the previously separated organic layer. The combined organic layer was mixed with 10 ml of water. The mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The aqueous layer was separated and stirred for 30 minutes at room temperature. 30 ml of chloroform were added thereto.

   The resulting mixture was adjusted to pH 12 with a 5% aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 10 ml of acetone. Hydrogen chloride gas was blown into the mixture with ice cooling. The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 620 ng of (4-benzyloxyphenyl) hydrochloride-1 (2-methylaninoethoxy) -2 ethanol (compound

  
n [deg.] 191).

Melting point: 173-173.5 [deg.] C [EtOH].

  
The compounds shown in Table 13 were obtained in the same manner.

  
In Table 13, R <1>, R <2>, R <3>, R4a, R4b,

  
  <EMI ID = 242.1>

  
integer used in the following formula:

  

  <EMI ID = 243.1>


  

  <EMI ID = 244.1>


  

  <EMI ID = 245.1>
 

  

  <EMI ID = 246.1>


  

  <EMI ID = 247.1>
 

  

  <EMI ID = 248.1>


  

  <EMI ID = 249.1>
 

  

  <EMI ID = 250.1>


  

  <EMI ID = 251.1>
 

  

  <EMI ID = 252.1>


  

  <EMI ID = 253.1>


  

  <EMI ID = 254.1>
 

  
Manufacturing Example 11

  
A mixture of 500 mg of [(imidazolyl-4) methoxy] -2 phenyl --- ethanol, 1.1 ml of pyridine,

  
1.1 ml of triethyl® and 1.1 ml of acetic anhydride was stirred for 1 hour at 100 [deg.] C. The reaction mixture was cooled to room temperature. The solvent was removed by distillation under reduced pressure, the residue was added. 1.1 ml of methyl iodide and 5 ml of acetonitrile. The mixture was allowed to stand at room temperature for 24 hours. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, was added? ml of ethanol and 6.8 ml of a

  
  <EMI ID = 255.1>

  
The resulting mixture was stirred at room temperature for 6 '---- ures. The solvent has been removed

  
  <EMI ID = 256.1>

  
thus obtained, 30 ml of chloroform were added and

  
20 ml of water. The organic layer was separated, washed with water, and tarped over magnesium sulfate

  
  <EMI ID = 257.1>

  
chloroform / ethanc-: 10/1). Diisopropyl ether was added to the resulting white crystals, and the resulting mixture was filtered to obtain 450 mg.

  
  <EMI ID = 258.1>

  
The following compc == was obtained in the same way:

  
(4-Benzyloxy pheny- -1 [(1-methyl-5-imidazolyl) methoxy] -2 etanol compound n [deg.] 215).

  
  <EMI ID = 259.1> Manufacturing Example 12

  
1.23 g of N, N'-dicyclohexylcarbodiimide was added, with ice-cooling, to a solution of 1.08 g of (2-amino ethoxy) -2 phenyl-1 ethanol, 730 mg of nicotinic acid , 810 mg of 1-hydroxy benzotriazole and 0.83 ml of triethylamine dissolved in 5 ml of tetrahydrofuran. The resulting mixture was stirred at the same temperature for

  
5 minutes and again at room temperature for

  
1 hour. To the reaction mixture was added 11 ml of ethyl acetate. Insoluble matter was removed by filtration. To the filtrate, we added

  
5 ml of water and the mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 5 ml of water. The extract was combined with the previously separated aqueous layer. The combined aqueous layer was mixed with 20 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol.
15/1), to obtain 400 mg of (nicotinoylamino-2 ethoxy) -2 phenyl-1 ethanol (compound n [deg.] 216).

  
  <EMI ID = 260.1>

  
Manufacturing Example 13

  
(1) 5 g of (S) -benzyl-4 acetoxymethyl-2

  
  <EMI ID = 261.1>

  
solution, a solution of 1 g of sodium hydroxide dissolved in 5 ml of water was added with ice cooling. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to 50 ml of a water-ice mixture and extracted with 50 ml of chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, in this order,

  
and dried over anhydrous magnesium sulfate. The

  
solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol: 30/1), to obtain 3.6 g of (S) -benzyl-4-hydroxymethyl-2 morpholine.

  
(2) 3.5 g of S-4-benzyl-2-hydroxymethyl-morpholine were dissolved in 5 ml of ethanol. To the solution was added 5 ml of a 5.9N hydrogen chloride-ethanol solution, with cooling by

  
ice. The resulting mixture was stirred for

  
10 minutes at the same temperature. A mixture of 500 mg of 5% palladium on charcoal and 10 ml of methanol was added thereto. The resulting mixture was subjected to hydrogenation for 3 hours at 40 [deg.] C. After completion of the reaction, palladium on carbon was; eliminated by wire &#65533; ration. The solvent was removed by distillation under reduced pressure to obtain a yellow oily product. In the oily product, we have

  
  <EMI ID = 262.1>

  
triethylamine. The resulting mixture was stirred at room temperature for 30 minutes. There was

  
  <EMI ID = 263.1>

  
trityl chloride dissolved in 10 ml of methylene chloride in 20 minutes, cooled by ice. The mixture was stirred at room temperature for 3 hours and added to

  
50 ml of a water-ice mixture. The organic layer has

  
  <EMI ID = 264.1>

  
organic was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain a yellow oily product. The oily product was mixed with 10 ml of diisopropyl ether. The resulting crystals were collected by filtration, to obtain 2.7 g of (S) -trityl-4 hydroxymethyl-2 morpholine.

  
Melting point: 142.0-142.5 [deg.] C [AcOEt-IPE]

  
  <EMI ID = 265.1>

  
The form (2R) having the following properties was obtained in the same way.

  
Melting point: 142.0-142.5 [deg.] C [AcOEt-IPE]

  
  <EMI ID = 266.1>. (3) The same procedure as in point (1) of Manufacturing Example 5 was repeated, except that styrene oxide and 4-benzyl-2-hydroxymethyl-2 morpholine were replaced respectively by the
(S) -phenyl-2 oxirane and (S) -trityl-4 hydroxy- <EMI ID = 267.1>

  
[(4-trityl-morpholinyl-2) methoxy] -2 ethanol (compound n [deg.] 217).

  
(4) In 20 ml of acetone was dissolved

  
  <EMI ID = 268.1>

  
ethanol. To the solution was added, with ice cooling, 7 ml of a 5.9N solution of dry hydrogen chloride - ethanol. The resulting mixture was stirred for 30 minutes at room temperature to carry out the reaction. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue thus obtained was added to a mixture of 30 ml of a water-ice mixture and 30 ml of ethyl acetate. The aqueous layer was separated and washed with 30 ml of ethyl acetate, after which 50 ml of chloroform was added thereto. __ resulting mixture has been adjusted to

  
  <EMI ID = 269.1> Manufacturing Example 14

  
(1) 1.19 g of 4-benzylthio-benzaldehyde was dissolved in 20 ml of tetrahydrofuran. The solution was cooled to -10 [deg.] C. 10 ml of a tetrahydrofuran solution containing 2M 2-chloroethoxymethylmagnesium chloride was added thereto dropwise over 10 minutes. The mixture was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 50 ml of a water-ice mixture, 50 ml of ethyl acetate and 1 g of ammonium chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate.
20/1), to obtain 1.34 g of (4-benzylthio-phenyl) -l
(2-chloro ethoxy) -2 ethanol.

  
Melting point: 49.5-50.5 [deg.] C [hexane-IPE]

  
(2) A mixture of 600 mg of (4-benzylthio-phenyl) -1 (2-chloroethoxy) -2 ethanol, 4 ml of a 50% aqueous dimethylamine solution, 31 mg of potassium iodide and 5 ml ethanol, was brought to reflux for 4 hours. To the reaction mixture was added a further 4 ml of a 50% aqueous dimethylamine solution. The resulting mixture was brought to reflux for 4 hours. The reaction mixture was cooled to room temperature. The. solvent was removed by distillation under reduced pressure.

  
To the residue thus obtained, 30 ml of ethyl acetate and 30 ml of water were added. The resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in
15 ml of acetone. To the solution was added 0.4 ml of a 5N solution of dry hydrogen chloride -ethanol. The resulting crystals were collected by filtration, to obtain 590 mg of hydrochloride.
(4-benzylthio-phenyl) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 222).

Melting point: 173.5-174.5 [deg.] C [EtOH]

  
The compounds shown in Table 14 were obtained in the same manner.

  
  <EMI ID = 270.1>

  
and nb each represent a substituent or an integer used in the following formula: -
  <EMI ID = 271.1>
  <EMI ID = 272.1>
  <EMI ID = 273.1>
   <EMI ID = 274.1>

  
A mixture of 13.2 g of potassium tert.-butoxide and 47.2 L of (N, N-dimethylamino) -2 ethanol

  
  <EMI ID = 275.1>

  
1.5 hours at 80-85 [deg.] C. The reaction mixture was cooled and add a mixture of 100 ml of acetate

  
  <EMI ID = 276.1>

  
organic previously separated. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained &#65533; = been subjected to distillation to obtain a fraction having a boiling point

  
  <EMI ID = 277.1>

  
The insights presented in Table 15 were obtained in the same manner.

  
  <EMI ID = 278.1>

  

  <EMI ID = 279.1>


  

  <EMI ID = 280.1>


  

  <EMI ID = 281.1>
 

  

  <EMI ID = 282.1>


  

  <EMI ID = 283.1>
 

  

  <EMI ID = 284.1>


  

  <EMI ID = 285.1>
 

  

  <EMI ID = 286.1>


  

  <EMI ID = 287.1>
 

  
Manufacturing Example 16

  
(1) A mixture of 6.0 g of 2-hydroxymethyl-4-trityl morpholine, 1.0 g of potassium tert.-butoxide and 6 ml of dimethyl sulfoxide was heated to
80 [deg.] C. Was added dropwise, at 80-85 [deg.] C, over 2 hours, a solution of 2.8 g of
(2-naphthyl) -2 oxirane dissolved in 6 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled and added to a mixture of 60 l of a water-ice mixture and 60 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 9.0 g of
(naphthyl-2) -1 [(trityl-4 morpholinyl-2) methoxy] -2 oily ethanol (compound n [deg.] 254).

  
In the same way, we got the
(naphthyl-1) -1 [(trityl-4 morpholinyl-2) methoxy] -2 ethanol (compound n [deg.] 255).

  
(2) In 50 ml of acetone, 9.0 g of
(naphthyl-2) -1. [(trityl-4 morpholinyl-2) methoxy] -2 ethanol. To the solution was added 3.5 ml of a 5.9N hydrogen chloride-ethanol solution, with cooling by ice. The mixture was stirred for 2 hours at room temperature to carry out the reaction. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue thus obtained, 50 ml of water and 30 ml of ethyl acetate were added. The aqueous layer was. separated and washed with 30 ml of ethyl acetate .: 50 ml of ethyl acetate was added thereto.

   The resulting mixture was adjusted to pH 10.5
  <EMI ID = 288.1>
  <EMI ID = 289.1>
  <EMI ID = 290.1>
 combined organic = been washed with water and a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent:
toluene / ethyl acetate: 1/3), to obtain 8.3 g d / (2-hydroxyethoxy) -2 (naphthyl-1) -1 ethanol.

  
Melting point: 91-92 [deg.] C [IPE]

  
Likewise, (2-hydroxyethoxy) -2 (2-naphthyl) -1 ethanol was obtained.

  
Melting point: 105-106 [deg.] C [AcOEt]

  
  <EMI ID = 291.1>

  
ethanol were dissolved in 50 ml of pyridine. The solution was cooled to -25 [deg.] C. 6.8 g of p-tcluenesulfonyl chloride were added thereto. The resulting mixture was allowed to stand at 0-5 [deg.] C for 24 hours and again at room temperature for 4 hours.

  
  <EMI ID = 292.1>

  
hydrochloric 6N. The organic layer has been separated. The aqueous layer was extracted with 20 ml of ether

  
  <EMI ID = 293.1>

  
organic previously separated. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The

  
  <EMI ID = 294.1>

  
colorless. - <EMI ID = 295.1>

  
anhydrous magnesium. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chlorofo & e / methanol: 5/1), to obtain 1.2 g of an oily product. The oily product was dissolved in 5 ml of isopropanol. To the solution was added 0.5 g of fumaric acid. The mixture was heated to obtain a solution. The solution was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, to obtain 0.9 g of 1/2 (naphthyl-2) -l [(morpholinyl-2) methoxy] -2 fumarate -2

  
  <EMI ID = 296.1>

  
Melting point: 141-144 [deg.] C [EtOH]

  
In the same way, we obtained the

  
  <EMI ID = 297.1>

  
methoxy] -2 amorphous ethanol (compound n [deg.] 257).

  
Manufacturing Example 17

  
(1) A mixture of 4.5 g of potassium tert.-butoxide and 45 ml of ethylene glycol was heated to

  
  <EMI ID = 298.1>

  
(naphthyl-1) -2 oxirane within one hour. The resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled and added to a mixture of 50 ml of ethyl acetate and 50 ml = a water-ice mixture. The organic layer has been separated. The aqueous layer was extracted twice. each time with 20 ml of ethyl acetate. The extracts were combined with the organic layer previously separated. The combined organic layer layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   The residue thus obtained was purified by column chromatography (eluent:
chloroform / ethanol: 10/1), to obtain 3.36 g of [(4-methyl-piperazinyl-1) -2 ethoxy] -2 (naphthyl-1) -l
(tetrahydropyrannyloxy-2) -1 oily ethane, colorless
(compound no [deg.] 258).

  
(5) In 30 ml of acetone, 3.3 g of [(4-methyl-piperazinyl-1) -2 ethoxy] -2 (naphthyl-1) -1 were dissolved.
(tetrahydropyrannyloxy-2) -1 ethane. To the solution was added 3.46 g of p-toluenesulfonic acid monohydrate and 7 ml of water at room temperature.

  
The resulting mixture was stirred at the same temperature for 30 minutes and again at 40 [deg.] C for 1 hour. The reaction mixture was added to a mixture of

  
60 ml of chloroform and 60 ml of a water-ice mixture. The mixture was adjusted to pH 11 with a 10% aqueous sodium hydroxide solution. The organic layer has been separated. The aqueous layer was extracted with 20 ml of chloroform. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 40 ml of acetone. Hydrogen chloride gas was blown into the solution, cooled by ice. The resulting solution was stirred at room temperature for 30 minutes. 40 ml of diethyl ether were added thereto. The resulting mixture was stirred at the same temperature for 30 minutes.

   The resulting crystals were collected by filtration, washed. In the same way, the
(2-naphthyl) -1 [(p-toluenesulfonyloxy) -2 ethoxy] -2 colorless oily ethanol.

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

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

  
(4) A mixture of 7.5 g of (naphthyl-1) -1 (tetra-

  
  <EMI ID = 299.1>

  
ethoxy] -2 ethane, 2.65 ml of N-methylpiperazine,

  
3.96 g of potassium carbonate and 38 ml of N, N-dimethylformamide was stirred for 2 hours at
90-100 [deg.] C. The reaction mixture was cooled to room temperature and added to a mixture of, 100 ml of diethyl ether and 100 ml of a water-ice mixture. The organic layer has been separated. The aqueous layer was extracted twice, each time with 25 ml of diethyl ether. The extracts were combined with the previously separated organic layer., La at 10%. The organic layer has been separated. The aqueous layer was extracted twice, each time with.
10 ml of chloroform. The extracts were combined with the previously separated organic layer. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to obtain

  
1.27 g of an oily product. The oily product was dissolved in 10 ml of acetone. Hydrogen chloride gas was blown into the solution with ice cooling. 10 ml of diethyl ether were added thereto. The resulting crystals were collected by filtration, to obtain 0.72 g of [(N-methylamino) -2 ethoxy] -2 hydrochloride
(naphthyl-1) -1 ethanol (compound n [deg.] 261).

Melting point: 137.5-139 [deg.] C [IPA]

  
The compounds shown in Table 16 were obtained in the same manner.

  
  <EMI ID = 300.1>

  
and nb each represents a substituent or an integer used in the following formula:

  
  <EMI ID = 301.1>

Melting point: 230.5-231.5 [deg.] C [MeOH]

  
Manufacturing Example 18

  
The same procedure as in points (4) and

  
(5) of Manufacturing Example 17 was repeated, except that N-methylpiperazine was replaced by N- (p-fluorobenzoyl) -piperidine, to obtain the

  
  <EMI ID = 302.1>

  
Melting point: 204.5-205.5 [deg.] C [MeOH]

  
Manufacturing Example 19

  
In 20 ml of ethanol, 2 g of

  
  <EMI ID = 303.1>

  
sulfonyloxy) -2 ethoxy] -2 ethane. To the solution was added 6.60 g of an aqueous methylamine solution to
40% at room temperature. The mixture was brought to reflux for 1 hour. The reaction mixture was cooled and added to a mixture of 20 ml of a water-ice mixture and 50 ml of diethyl ether. The

  
  <EMI ID = 304.1>

  
was extracted with 20 μl of diethyl ether. The extract was combined with the previously separated organic layer. To the combined organic layer, we added
15 ml of water and the resulting mixture was adjusted to

  
pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted twice, each time with 10 ml of water. The extracts were combined with the previously separated aqueous layer. The combined aqueous layer was mixed with 2: ml of chloroform and adjusted to pH 11 with an aqueous solution of sodium hydroxide Manufacturing Example 20

  
A mixture of 3.5 g of potassium tert.-butoxide, 9.4 g of N-tritylethanolamine and 50 ml of dimethyl sulfoxide was heated to 85 [deg.] C. 5.3 g of (naphthyl-1) -2 oxirane were added thereto. The resulting mixture was stirred at the same temperature for 5 minutes. The reaction mixture was cooled and added to a mixture of 100 ml of ethyl acetate and 150 ml of a water-ice mixture. The organic layer has been separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

   To the residue thus obtained, 80 ml of a 50% aqueous formic acid solution and 40 ml of tetrahydrofuran were added. The resulting mixture was stirred at 50-60 [deg.] C for 1 hour. The reaction mixture was cooled. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 60 ml of ethyl acetate were added and
60 ml of water. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted twice, each time with 15 ml of water. The extracts were combined with the previously separated aqueous layer. To the combined aqueous layer was added
100 ml of chloroform and the resulting mixture was adjusted to pH 10.5 with potassium carbonate.

   The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 10 ml of diisopropyl ether were added. The resulting crystals have
  <EMI ID = 305.1>
  <EMI ID = 306.1>
  <EMI ID = 307.1>
 oily, 4 ml of ethanol and 0.21 g of maleic acid were added. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried, to obtain

  
0.53 g of (naphthyl-1) -1 ({(pyrimidinyl-2) amino) -2 ethoxy} -2 ethanol maleate -2 ethanol (compound n [deg.] 268).

  
Melting point: 101.5-103 [deg.] C [EtOH-AcOEt]

  
Manufacturing Example 22

  
0.62 g of N, N'-dicyclohexylcarbodiimide was added to a mixture of 0.7 g of (2-amino ethoxy) -2
(naphthyl-1) -l ethanol, 0.37 g of nicotinic acid, 0.41 g of hydroxy-1 benzotriazole, 0.42 ml of triethylamine and 4 ml of tetrahydrofuran with cooling by ice. The resulting mixture was stirred at the same temperature for 5 minutes and again at room temperature for 1 hour. To the reaction mixture was added 6 ml of ethyl acetate. Insoluble matter was removed by filtration. To the filtrate was added 15 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated.

  
The organic layer was extracted twice, each time with 10 ml of water. The extracts were combined with the previously separated aqueous layer. To the combined aqueous layer, 30 ml of chloroform was added and the resulting mixture was adjusted to

  
pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The. solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by chromato-was collected by filtration and dried to obtain

  
  <EMI ID = 308.1>

  
(compound no [deg.] 267).

  
Melting point: 89.5-92 [deg.] C [CHC13-Et20]

  
Manufacturing Example 21

  
7 ml of water and 7 ml of dioxane were

  
  <EMI ID = 309.1>

  
ethanol to obtain a solution. In the solution, we

  
  <EMI ID = 310.1>

  
brought to the noisy reflux 3 hours. We added

  
0.32 g of potassium carbonate and 0.35 g of 2-chloro pyrimidine. The resulting mixture was brought to reflux for 2.5 hours. The reaction mixture was cooled and added to a mixture of 20 ml of acetate

  
  <EMI ID = 311.1>

  
organic has been separated. The aqueous layer has been

  
  <EMI ID = 312.1>

  
been combined with the previously separated organic layer. To the combined organic layer, we added
15 ml of water and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer has been

  
  <EMI ID = 313.1>

  
knocked aqueous layer, 50 ml of chloride were added

  
  <EMI ID = 314.1>

  
20/1), to obtain an oily product. At. product
  <EMI ID = 315.1>
  <EMI ID = 316.1>
  <EMI ID = 317.1>
 column writing (eluent: chloroform / ethanol =
10/1), to obtain an oily product. The oily product was dissolved in 7 ml of acetone. To the solution was added 0.43 ml of a 5N solution of dry hydrogen chloride - ethanol. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 3 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried, to obtain 0.67 g of hydrochloride.
(naphthyl-1) -1 [(nicotinoylamino) -2 ethoxy] -2 ethanol
(compound no [deg.] 269).

  
Melting point: 162.5-163.5 [deg.] C [EtOH-AcOEt]

  
Manufacturing Example 23

  
The same procedure as in point (1) of Manufacturing Example 16 was repeated, except that (naphthyl-2) -2 oxirane and 2-hydroxymethyl-4-trityl morpholine were replaced respectively by ( naphthyl-1) -2 oxirane and diformyl-1,4

  
  <EMI ID = 318.1>

  
piperazinyl-2) methoxy] -2 (naphthyl-1) -l ethanol
(compound no [deg.] 270).

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

  
  <EMI ID = 319.1>

  
each represent a substituent or an integer used in the following general formula:

  

  <EMI ID = 320.1>


  

  <EMI ID = 321.1>


  

  <EMI ID = 322.1>
 

  
Manufacturing Example 24

  
In 1.5 μl of methanol, 250 mg of [(diformyl-1,4? -? Erazinyl-2) methoxy] -2 were dissolved.

  
  <EMI ID = 323.1>

  
1.5 ml of a 5N solution of hydrogen chloride secethanol. The mixture was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration,

  
  <EMI ID = 324.1>

  
methoxy] -2 ethanol (compound n [deg.] 274).

  
Melting point: 199-201 [deg.] C (with decomposition)

  
Manufacturing Example 25

  
The compound obtained was reacted in the same manner as in the paint (1) of Manufacturing Example 16 with gaseous hydrogen chloride in the same manner as in the manufacture of the hydrochloride of Manufacturing Example 22, to obtain the compounds presented in Table 18.

  
  <EMI ID = 325.1>

  

  <EMI ID = 326.1>


  

  <EMI ID = 327.1>


  

  <EMI ID = 328.1>
 

  
Manufacturing Example 26

  
The compounds presented in Table 19 were obtained in the same manner as in point (1) and

  
(2) of Manufacturing Example 16.

  
  <EMI ID = 329.1>

  
each represent a substituent or an integer used in the following general formula:

  
(2) A mixture of 4.5 g of (6-benzyloxy-2-naphthyl) -1 (2-chloroethoxy) -2 ethanol, 1 g of potassium iodide, 10 ml of an aqueous solution of dimethylamine at 50 % and 20 ml of ethanol was brought to reflux for 3 hours. To the reaction mixture was added 10 ml of an aqueous solution of dimethylamine to
50%. The resulting mixture was further refluxed for 6 hours. The reaction mixture was cooled and concentrated to about half its volume under reduced pressure. In the concentrate, we have

  
  <EMI ID = 330.1>

  
mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and a saturated aqueous solution of sodium chloride in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 30 ml of diethyl ether were added. The resulting crystals were collected by filtration and dried, to obtain

  
3.9 g of (6-benzyloxy-2-naphthyl) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 284).

Melting point: 100-100.5 [deg.] C [EtOH-H20]

  
(6-Benzyloxy-2-naphthyl) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol was treated in the same manner as in Manufacturing Example 22, to obtain (benzyloxy hydrochloride -6 naphthyl-2) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol (compound

  
n [deg.] 285).

Melting point: 220-220.5 [deg.] C [EtOH]

  
Manufacturing Example 29

  
In 12 ml of pyridine,

  
  <EMI ID = 331.1> Manufacturing Example 27

  
[(Imidazolyl-5) methoxy] -2 (naphthyl-1) -l ethanol was reacted with methyl iodide to obtain [(1-methyl-imidazolyl-5) methoxy] -2 (naphthyl -l) -l ethanol (compound n [deg.] 283).

  
Manufacturing example 28

  
(1) 6.0 g of 6-benzyloxy-2-naphthaldehyde were dissolved in 6 ml of tetrahydrofuran. - The solution was cooled to -30 [deg.] C. 30 ml of a tetrahydrofuran solution containing 1.6M chloride was added dropwise to it over the course of 10 minutes.

  
  <EMI ID = 332.1>

  
was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 100 ml of ice water, 100 ml of ethyl acetate and 3.6 g of ammonium chloride. The mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water, and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate 20/1) to obtain a solid. To the solid was added 10 ml of diisopropyl ether. The resulting mixture was stirred at room temperature for 1 hour.

   The resulting crystals were collected by filtration and dried to obtain 4.7 g of (6-benzyloxy-2-naphthyl) -1 (2-chloroethoxy) -2 ethanol.

  
Melting point: 86-87.5 [deg.] C [IPE] obtained. The resulting crystals were collected by filtration and dried, to obtain 0.76 g of acetoxy-1 hydrochloride (6-hydroxy-naphthyl-2) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethane ( compound

  
n [deg.] 287).

Melting point: 150.5-151.5 [deg.] C [EtOH]

  
Manufacturing Example 31

  
A mixture of 360 mg of acetoxy-1 hydrochloride (6-hydroxy-naphthyl-2) -1 [(N &#65533; N-dimethylamino) -2 ethoxy] -2 ethane, 10 ml of water and 15 ml of chloroform , was adjusted to pH 9 with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer has been separated. The aqueous layer was extracted twice, each time with 10 ml of chloroform. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 6 ml of benzene. To the solution was added 0.12 ml of ethyl isocyanate. The resulting mixture was stirred for 4 hours at 80 [deg.] C.

   The reaction mixture was cooled. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent:

  
  <EMI ID = 333.1>

  
oily. The oily product was treated in the same manner as in Manufacturing Example 22, to obtain, in the form of an amorphous product, 150 mg of acetoxy-1 hydrochloride [(N-ethylcarbamoyl) oxy-6

  
  <EMI ID = 334.1>

  
(compound no [deg.] 288).

  
  <EMI ID = 335.1>

  
under reduced pressure. To the residue thus obtained, 60 ml were added. ethyl acetate and 60 ml of water. The

  
  <EMI ID = 336.1>

  
was washed with water and a saturated aqueous solution of 3rd sodium chloride, in that order,

  
  <EMI ID = 337.1>

  
solvent was = __ mined by distillation under reduced pressure. 1 detone was added to the residue thus ethoxy] -2 ethanol (compound n [deg.] 290).

  
Melting point: 195-198 [deg.] C (with decomposition) [AcOEt-EtOH]

  
Manufacturing Example 34

  
Triethylamine was added to (8-amino-naphthyl-1) -1 hydrochloride [(N, Ndimethylamino) -2 ethoxy] -2 ethanol. The resulting mixture was reacted with methanesulfonyl chloride to obtain [(N, Ndimethylamino) -2 ethoxy] -2 (methylsulfonylamino-8 naphthyl-1) -l ethanol hydrochloride (compound n [deg.] 291).

  
Manufacturing Example 35

  
The same procedure as in points (1) and

  
(2) of Manufacturing Example 28 was repeated, except that the 6-benzyloxy-naphthaldehyde-2 was replaced by (N, N-dimethylamino) -4 naphthaldehyde-1, to obtain dihydrochloride of [(N, N-dimethylamino) -4 naphthyl-1] -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 292).

  
Manufacturing Example 36

  
13 ml of ethanol were added to 1.3 g of [(N, N-dimethylamino) -4 naphthyl-1] -1 ([N, N-dimethylamino) -2 ethoxy] -2 ethanol dihydrochloride. The resulting mixture was brought to reflux for 1 hour. The reaction mixture was cooled. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, a mixture of 20 ml of ethyl acetate and 20 ml of water was added. The resulting mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with a saturated aqueous chloride solution from Manufacturing Example 32

  
[(N, N-dimethylamino) -2 ethoxy] -2 (8-nitro-naphthyl-1) -l ethanol was obtained in the same manner as in points (1) and (2) of the Manufacturing Example

  
27. This compound was reacted with oxalic acid in the same manner as in point (2) of Manufacturing Example 16, to obtain oxalate of [(N, N-dimethylamino) -2 ethoxy] -2 (8-nitro-naphthyl-1) -l ethanol (compound n [deg.] 289).

  
Melting point: 150-158.5 [deg.] C.

  
Manufacturing Example 33

  
A mixture of 150 mg of [(N, Ndimethylamino) -2 ethoxy] -2 (8-nitro-naphthyl-1) -l ethanol oxalate, 150 mg of 5% palladium on carbon and 3 ml of methanol was subjected to hydrogenation at room temperature for 30 minutes at atmospheric pressure. After completion of the reaction, the palladium-on-carbon was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue thus obtained was added to a mixture of

  
30 ml of a water-ice mixture and 30 ml of chloroform. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 1 ml of ethanol. 0.2 ml of a 5.9 N solution of dry hydrogen chloride - ethanol was added thereto. The resulting crystals were collected by filtration and dried, to obtain 110 mg of dihydrochloride

  
  <EMI ID = 338.1> saturated with sodium chloride, in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate: 15/1), to obtain 6.5 g of formyl-5 (tetrahydropyrannyloxy-2) -1 indane.

  
(3) The same procedure as in points (1) and

  
(2) of Manufacturing Example 28 was repeated, except that 6-benzyloxy-2-naphthaldehyde was replaced by formyl-5 (tetrahydropyrannyloxy-2) -1 indane, to obtain [(N, N-dimethylamino ) -2

  
  <EMI ID = 339.1>

  
ethanol (compound n [deg.] 294).

  
(4) A mixture of 2.5 g of [(N, N-dimethylamino) -2 ethoxy] -2 [tetrahydropyrannyloxy-2) -1

  
  <EMI ID = 340.1>

  
0.64 ml of pyridine, was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 ml of an ice-water mixture and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / methanol: 10/1), to obtain 1.9 g of acetoxy-1 [(N, N-dimethylamino) -2 ethoxy] -2

  
  <EMI ID = 341.1>

  
ethoxy] -2 [(tetrahydropyrannyloxy-2) -1 indanyl-5] -1 ethane was added to 30 ml of a mixed 4: 2: 1 solution of acetic acid, tetrahydrofuran and water. The resulting mixture was stirred at 70 [deg.] C during sodium, and dried over anhydrous magnesium sulfate.

  
The solvent was removed by distillation under reduced pressure to obtain 1.3 g of ethoxy-1 [(N, N-

  
  <EMI ID = 342.1>

  
ethoxy] -2 ethane (compound n [deg.] 293).

  
Manufacturing Example 37

  
(1) 9.6 g of 5-bromo-1-hydroxy indane were dissolved in 100 ml of dry methylene chloride. To the solution was added, at room temperature,

  
570 mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to an ice-water mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate-.

  
15/1), to obtain 13.1 g of bromo-5 (tetrahydropyrannyloxy-2) -1 indane.

  
(2) 8.1 g of bromo-5 (tetrahydropyrannyloxy-2) -1 indane were dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution was added dropwise 20 ml of a 1.5N solution of n-butyllithium -hexane at -65 [deg.] C over 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. 2.3 ml of anhydrous N, K-dimethylformamide were added thereto. The reaction mixture was warmed to room temperature and added to a mixture of 100 ml of a water-ice mixture, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and an aqueous solution under reduced pressure. The residue thus obtained was purified by column chromatography (eluent:
chloroform / methanol: 20/1), to obtain a yellow oily product.

   The oily product was dissolved in 0.1 ml of ethanol. To the solution was added 0.1 ml of a 5.9N solution of dry hydrogen chloride-ethanol at room temperature. The resulting crystals were collected by filtration to obtain 20 mg of

  
  <EMI ID = 343.1>

  
amino) -2 ethoxy] -2 ethanol (compound n [deg.] 298).

  
Melting point: 168-171 [deg.] C (with decomposition) [AcOEt-EtOH]

  
Manufacturing Example 38

  
In the same way as in the manufacture of the hydrochloride in point (5) of Manufacturing Example 37 and in Manufacturing Example 22, we have

  
  <EMI ID = 344.1>

  
[(N, N-dimethylamino) -2 ethoxy] -2 ethanol (compound

  
n [deg.] 299).

  
Melting point: 150-152 [deg.] C [IPA]

  
Manufacturing Example 39

  
[(N, Ndimethylamino) -2 ethoxy] -2 (naphthyl-1) -1 ethanol hydrochloride was reacted with acetic anhydride in pyridine, in the presence of triethylamine, to obtain acetoxy -1 [(N, N-dimethylamino) -2 ethoxy] -2 (naphthyl-1) -l ethane
(compound n [deg.] 300).

  
Manufacturing Example 40

  
The compound obtained from [(methyl-6 naphthyl) -2] -2 oxirane was reacted in the same manner as in point (1) of the Manufacturing Example <EMI ID = 345.1>

  
organic was separated and dried over sulphate

  
  <EMI ID = 346.1>

  
distillation under reduced pressure. The residue thus obtained was purified by column chromatography

  
  <EMI ID = 347.1>

  
same temperature losing overnight. The reaction mixture was scrutinized with a mixture of 50 ml of a water-ice mixture and 50 ml of diethyl ether. The

  
  <EMI ID = 348.1>

  
ethoxy] -2 ethane. -: the solution, 80 mg are added

  
  <EMI ID = 349.1>
  <EMI ID = 350.1>
  <EMI ID = 351.1>
  <EMI ID = 352.1>
 16, with gaseous hydrogen chloride in the same manner as in the manufacture of the hydrochloride in Manufacturing Example 22, to obtain [(N-methyl-2,3-dihydro-pyridine-6H-yl-5) -2 ethoxy] -2 [(6-methylnaphthyl) -2] -l oily ethanol (compound

  
n [deg.] 301).

  
Manufacturing Example 41

  
The compounds presented in Table 20 were obtained in the same manner as in points (1) and (2) of Manufacturing Example 28.

  
  <EMI ID = 353.1>

  
each represent a substituent or an integer used in the following formula:

  

  <EMI ID = 354.1>


  

  <EMI ID = 355.1>
 

  

  <EMI ID = 356.1>


  

  <EMI ID = 357.1>
 

  
The compounds shown in Table 21 were obtained in the same manner.

  
  <EMI ID = 358.1>

  
each represent a substituent or an integer used in the following formula:

  
Manufacturing Example 42

  
1.7 g of potassium tert.-butoxide was added to 31 ml of (N, N-dimethylamino) -2 ethanol. The resulting mixture was heated to 80 [deg.] C. To the solution was added dropwise, at 80-85 [deg.] C, over the course of 1.5 hours, a solution of 5.2 g of (benzo [b] thiophenyl-5) -2 oxirane dissolved in 8 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled and added to a mixture of 60 ml of ethyl acetate and 60 ml of a water-ice mixture. The organic layer has been separated. The aqueous layer was extracted with 30 ml of ethyl acetate. The extract was combined with the organic layer previously separated.

   To the combined organic layer, we added
50 ml of a water-ice mixture and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated, and 50 ml of chloroform was added thereto. The reaction mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The resulting oily product was dissolved in 50 ml of acetone. To the solution was added 4.3 ml of a 5N solution of dry hydrogen chloride-ethanol. The resulting mixture was stirred at room temperature for 1 hour, and 20 ml of diethyl ether was added thereto. The resulting mixture was further stirred for 1 hour. The resulting crystals were collected by filtration and dried, to obtain 3.3 g of (benzo [b] thiophenyl-5) -l [(N, N-dimethylamino) -2 ethoxy] -2 ethanol hydrochloride (compound

  
n [deg.] 312).

  
  <EMI ID = 359.1>
  <EMI ID = 360.1>
  <EMI ID = 361.1>
 
  <EMI ID = 362.1>
  <EMI ID = 363.1>
  <EMI ID = 364.1>
 
  <EMI ID = 365.1>
  <EMI ID = 366.1>
 
  <EMI ID = 367.1>
  <EMI ID = 368.1>
 
  <EMI ID = 369.1>
  <EMI ID = 370.1>
  <EMI ID = 371.1>
 
  <EMI ID = 372.1>
  <EMI ID = 373.1>
 
  <EMI ID = 374.1>
  <EMI ID = 375.1>
  <EMI ID = 376.1>
 Manufacturing Example 43

  
  <EMI ID = 377.1>

  
50 ml of a water-ice mixture and 50 ml of ethyl acetate. The resulting larch was adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated and 30 µl of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 9.5 with potassium carbonates. The organic layer was separated, washed with water and a solution

  
  <EMI ID = 378.1>

  
(compound no [deg.] 339).

  
  <EMI ID = 379.1>

  
Manufacturing Example 44

  
(1) A mixture of 5.7 g of potassium tert.-butoxide and 57 ml of ethylene glycol was heated to
80 [deg.] C. A solution of 18 g of (benzo [b] thiophenyl-5) -2 oxirane dissolved in 30 ml of dimethyl sulfoxide was added thereto over the course of 1.5 hours. The resulting mixture was stirred at the same temperature for

  
30 minutes. The reaction mixture was added to a mixture of 120 ml of a water-ice mixture and 80 ml of ethyl acetate. The organic layer has been separated. The aqueous layer was extracted twice, each time with 30 ml of ethyl acetate. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol:
20/1), to obtain 9.1 g of (benzo [b] thiophenyl-5) -l
(2-hydroxyethoxy) -2 ethanol.

  
Melting point: 119-120.5 [deg.] C [EtOH-AcOEt]

  
(2) In 54 ml of pyridine, 9.0 g of (benzo [b] thiophenyl-5) -1 (2-hydroxyethoxy) -2 ethanol were dissolved. To the solution was added, at -25 ° C., 7.2 g of p-toluenesulfonyl chloride. The mixture was allowed to stand at 0-5 [deg.] C for 24 hours and again at room temperature for 4 hours. The reaction mixture was added to a mixture of

  
103 ml of 6N hydrochloric acid, 50 ml of a water-ice mixture and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer has been separated. The aqueous layer was extracted with 30 ml of ether
  <EMI ID = 380.1>
  <EMI ID = 381.1>
 separate. To the combined organic layer, we added
20 ml of water. The resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid and stirred at room temperature for 20 minutes. The aqueous layer was separated. The organic layer was extracted with 10 ml of water. The extract was combined with the previously separated aqueous layer. To the combined aqueous layer, 30 ml of methylene chloride was added. The resulting mixture was adjusted to pH
11 with an aqueous solution of sodium hydroxide at
10%.

   The organic layer was separated. The aqueous layer was extracted with 15 ml of methylene chloride. The extract was combined with the previously separated organic layer and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 7 ml of acetone. To the solution was added 0.5 ml of a 5N solution of dry hydrogen chloride - ethanol. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 7 ml of diethyl ether. The resulting crystals were collected by filtration to obtain 0.5 g of hydrochloride.
(benzo [b] thiophenyl-5) -1 (N-methylaminoethoxy) -2 ethanol (compound n [deg.] 347).

  
Melting point: 201.5-202.5 [deg.] C [EtQH-Me2CO]

  
The compounds shown in Table 23 were obtained in the same manner.

  
  <EMI ID = 382.1>

  
each represent a substituent or an integer used in the following formula:

  
diethyl. 1 / extract was combined with the layer

  
  <EMI ID = 383.1>

  
combined was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluent: toluene / ethyl acetate:

  
  <EMI ID = 384.1>

  
[(p-toluenesulfonyloxy) -2 ethoxy] -2 oily, colorless ethanol.

  
(3) 0.97 g of pyridinium p-toluenesulfonate was added, at room temperature, to a solution

  
  <EMI ID = 385.1>

  
sulfonyloxy) -2 ethoxy] -2 ethanol and 3.5 ml of 3,4-dihydro-2H-pyr &#65533; &#65533; e dissolved in 40 ml of methylene chloride. The mixture was stirred at the same temperature and again at 40-45 [deg.] C for 30 minutes.

  
  <EMI ID = 386.1>

  
dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure

  
  <EMI ID = 387.1>

  
hydropyrannyloxy-2) -l- [(p-toluenesulfonyloxy) -2 ethoxy] -2 oily ethane, colorless.

  
  <EMI ID = 388.1>

  
solution, 4.9 ml of a 40% aqueous methylamine solution was added. The resulting mixture was worn

  
  <EMI ID = 389.1>

  
organic has been separated. The aqueous layer was extracted with 20 ml: diethyl ether. The extract has been combined with the organic layer beforehand
  <EMI ID = 390.1>
  <EMI ID = 391.1>
 Manufacturing Example 45

  
(1) The same operating mole as in Manufacturing Example 43 was repeated, except that the
(benzo [b] furanyl-5) -2 oxirane and pyridine methanol-3 have been replaced by the
(benzo [b] thiophenyl-5) -2 oxirane and diformyl-1,4 piperazine methanol-2, to obtain (benzo [b] thiophenyl-5) -l [(1,4-diformyl-piperazinyl-2) methoxy ] -2 oily ethanol (compound n [deg.] 354).

  
(2) In 1.5 ml of methanol, 270 mg of (benzo [b] thiophenyl-5) -1 [, (1,4-diformyl-1,4 piperazinyl-2) methoxy] -2 ethanol were dissolved. To the solution was added 1.5 ml of a 5N solution of hydrogen chloride

  
  <EMI ID = 392.1>

  
resulting at room temperature overnight. The resulting crystals were collected by filtration, washed with ethanol, and dried to obtain 150 mg of (benzo [b] thiophenyl-5) -1 [2-pyperazinyl) methoxy] -2 hydrochloride ethanol (compound n [ deg.] 355).

  
Melting point: 216-218 [deg.] C (with decomposition)

  
Example of Fabricaticn 46

  
(1) A mixture of 10 g of (N-tritylamino) -2 ethanol, 3.7 g of potassium tert.-butoxide and 30 ml of dimethyl sulfoxide was heated to 85 [deg.] C. There was

  
  <EMI ID = 393.1>

  
phenyl-5) -2 oxirane dissolved in 10 ml of dimethylsulfoxide. The resulting mixture was stirred at the same temperature for = minutes. The reaction mixture was added to a mixture of 150 ml of an ice-water mixture and 100 ml of ethyl acetate. The organic layer has been separated. The aqueous layer has been

  
  <EMI ID = 394.1> been combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 70 ml of a 50% aqueous formic acid solution and 30 ml of tetrahydrofuran were added. The resulting mixture was stirred at
50-60 [deg.] C, for 1 hour. The solvent was removed by distillation under reduced pressure.

  
  <EMI ID = 395.1>

  
30 ml of water. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer has been separated. The organic layer was extracted twice, each time with 10 ml of water. The extracts were combined with the previously separated aqueous layer. To the combined aqueous layer, 50 ml of methylene chloride was added and adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.2 g of (benzo [b] thiophenyl-5) -l
(2-amino ethoxy) -2 ethanol (compound n [deg.] 356).

  
Melting point: 87-90.5 [deg.] C [EtOH-IPE]

  
(2) 1.1 g of (benzo [b] thiophenyl-5) -1 (2-amino ethoxy) -2 ethanol was dissolved in 10 ml of ethanol. To the solution was added 290 mg of fumaric acid. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 7 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 1.2 g of (benzo [b]

  
  <EMI ID = 396.1> <EMI ID = 397.1>

  
Melting point: 204.5-205.5 [deg.] C [MeOH-EtOH]

  
Manufacturing Example 47

  
The same operating node as in Manufacturing Example 46 was repeated, except that the (N-tritylamino) -2 ethanol was replaced by the (trityl-1 imidazolyl-4) methanol, to obtain the (benzo [ b] thiophenyl-5) -1 [(imidazolyl) methoxy] -2 ethanol (compound n [deg.] 358) having a melting point of 128-129 [deg.] C [AcOEt].

  
In the above name of the compound obtained, the term "(imidazolyl) methoxy" has been used because it has not yet been clarified to which carbon of the carbons in positions 4 and 5 of the imidazolyl group binds the carbon of the methoxy group.

  
Manufacturing Example 48

  
  <EMI ID = 398.1>

  
ethoxy] -2 ethanol was dissolved in a mixture of

  
5 ml of water and 5 ml of dioxane. 0.21 g of sodium carbonate was added thereto. The resulting mixture was heated to 50 [deg.] C. 0.22 g of 2-chloro pyrimidine was added thereto. The resulting mixture was brought to reflux for 3 hours. The reaction mixture was added to a 30 ml mixture of a water-ice mixture and
30 ml of ethyl acetate. The organic layer has been separated. The aqueous layer was extracted with 10 ml of ethyl acetate. The extract was combined with the previously separated organic layer. To the combined organic layer, 20 ml of water was added and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 10 ml of water. The extract was combined with the previously separated aqueous layer.

   To the combined aqueous layer, 50 ml of methylene chloride was added and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol: 20/1), to obtain an oily product. To the oily product, 2 ml of ethanol and 70 g of maleic acid were added. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2 ml of diethyl ether.

   The resulting crystals were collected by filtration and dried to obtain 0.28 g of (benzo [b] thiophenyl-5) -1 ([(2-pyrimidinyl) 2-amino] ethoxy} -2 ethanol 1/2 maleate (compound

  
n [deg.] 359).

  
Melting point: 113.5-114.5 [deg.] C [IPA-AcOEt]

  
Manufacturing Example 49

  
0.39 g of N, N'-dicyclohexylcarbodiimide was added, with ice cooling, to a mixture of 0.45 g of (benzo [b] thiophenyl-5) -1 (2-amino ethoxy) -2 ethanol, 0.23 g of nicotinic acid, 0.26 g of 1-hydroxybenzotriazole, 0.26 ml of triethylamine and 3 ml of tetrahydrofuran. The resulting mixture was stirred at the same temperature for 5 minutes and again at room temperature for 2 hours. To the reaction mixture was added 20 ml of water and 20 ml of ethyl acetate. Insoluble matter was removed by filtration. The filtrate was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted twice, each time with 5 ml of water. The extracts were combined with the previously separated aqueous layer. With the combined aqueous layer, <EMI ID = 399.1>

  
potassium. The organic short was separated, washed with water, and dried over magnesium sulfate

  
  <EMI ID = 400.1>

  
resulting was dissolved in 3 ml of ethanol. 0.24 ml of a 5N solution of dry hydrogen chloride - ethanol was added to the solution. The resulting_mixture has

  
  <EMI ID = 401.1>

  
To the reaction mixture was added 1.5 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried, to obtain 0.31 g of hydrochloride.

  
  <EMI ID = 402.1>

  
ethanol (compound r- 360).

  
Melting point: 152-153 [deg.] C [EtOH-AcOEt]

  
  <EMI ID = 403.1>

  
2-chlorine chloride ethoxymethylmagnesium. The mixture was stirred for 1 hour with cooling.

  
  <EMI ID = 404.1>

  
temperature during: - 5 minutes. The reaction mixture was adjusted to pH with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: toluene / ethyl acetate: 4/1), to obtain 1.3 g of (4-methyl-2-thiazolyl) -1 (2-chloroethoxy) - 2 oily ethanol.

  
(2) A mixture of 1.2 g of (methyl-4 thiazolyl-2) -1 (2-chloroethoxy) -2 ethanol, 3 ml of a 50% aqueous solution of dimethylamine, 0.45 g of potassium iodide and 20 ml of ethanol was brought to reflux for 3 hours. To the reaction mixture was added 3 ml of a 50% aqueous dimethylamine solution. The resulting mixture was brought to reflux for 3 hours. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 30 ml of ethyl acetate and 30 ml of water were added. The resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated and washed with 10 ml of ethyl acetate. 30 ml of ethyl acetate were added thereto. The resulting mixture was adjusted to pH 10.5 with potassium carbonate.

   The organic layer was separated, washed with 10 ml of water and 10 ml of a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 6 ml of ethanol. To the solution was added 0.6 ml of a 5N solution of dry hydrogen chloride -ethanol and 6 ml of diethyl ether. The mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with 2 ml of a 1: 1 mixture of diethyl ether and ethanol, and dried to obtain 390 mg of (4-methyl-2-thiazolyl-2) hydrochloride -1 [( N, Ndimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 361).

  
Melting point: 159-160 [deg.] C [IPA-AcOEt]

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

  
  <EMI ID = 405.1>

  
each represent a substituent or an integer used in the following formula:

  

  <EMI ID = 406.1>


  

  <EMI ID = 407.1>


  

  <EMI ID = 408.1>
 

  

  <EMI ID = 409.1>


  

  <EMI ID = 410.1>
 

  

  <EMI ID = 411.1>


  

  <EMI ID = 412.1>
 

  

  <EMI ID = 413.1>


  

  <EMI ID = 414.1>
 

  

  <EMI ID = 415.1>


  

  <EMI ID = 416.1>
 

  

  <EMI ID = 417.1>


  

  <EMI ID = 418.1>
 

  

  <EMI ID = 419.1>


  

  <EMI ID = 420.1>
 

  

  <EMI ID = 421.1>


  

  <EMI ID = 422.1>
 

  

  <EMI ID = 423.1>


  

  <EMI ID = 424.1>
 

  

  <EMI ID = 425.1>


  

  <EMI ID = 426.1>
 

  

  <EMI ID = 427.1>


  

  <EMI ID = 428.1>


  

  <EMI ID = 429.1>
 

  
  <EMI ID = 430.1>

  
saturated aqueous sodium hydrogencarbonate, the pH of the resilient mixture having been adjusted to 7 with an aqueous solution = - = 40% sodium hydroxide. The resulting mixture was adjusted to pH 10 with a

  
  <EMI ID = 431.1>

  
IN. The resulting mixture was stirred at room temperature for --- hour. In the reaction mixture,

  
  <EMI ID = 432.1> organic layer has been separated and 30 ml of water have been removed

  
been added. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated, and 30 ml of chloroform was added to it

  
added. The resulting mixture was adjusted to pH 11 with a 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 3 ml of methanol and 1 ml of a 5N solution of dry hydrogen chloride -ethanol were added. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 5 ml of ethanol were added. The resulting crystals were collected by filtration and dried to obtain 170 mg of (5-nitro-2-thienyl) -1 [(N, Ndimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 405).

  
Melting point: 189-191.5 [deg.] C (with decomposition)

  
Manufacturing Example 52

  
(1) In 10 ml of pyridine, 3.4 g were dissolved

  
of [(N, N-dimethylamino) -2 ethoxy] -2 (6-benzyloxy benzo [b] furanyl-2) -l ethanol. To the solution was added 1.8 ml of acetic anhydride. The resulting mixture was stirred at room temperature for 17.5 hours. The solvent was removed by distillation under reduced pressure. To the residue thus obtained, 40 ml of ethyl acetate and 40 ml of water were added. The resulting mixture was adjusted to pH 7 with sodium hydrogencarbonate. The organic layer has been separated. The aqueous layer was extracted with 20 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous solution of <EMI ID = 433.1>

  
magnesium sulphate = = anhydrous. The solvent was removed by distillation under reduced pressure. The

  
  <EMI ID = 434.1>

  
(compound no [deg.] 406).

  

  <EMI ID = 435.1>


  
(2) A mixture of 3.2 g of acetoxy-1 (benzyloxy-6 benzo [b] furanyl-2) -l [(N, N-dimethylamino-2 ethoxy] -2

  
  <EMI ID = 436.1>

  
ambient and at atmospheric pressure, for 1.5 hours. After completion of the reaction, the

  
  <EMI ID = 437.1>

  
sodium. The organic layer has been separated. The aqueous layer was extracted with 10 ml of chloroform.

  
  <EMI ID = 438.1>

  
previously separated. The combined organic layer has

  
  <EMI ID = 439.1>

  
  <EMI ID = 440.1>

  
n [deg.] 407).

  

  <EMI ID = 441.1>
 

  
(3) In 3.5 ml of benzene, 0.65 g of acetoxy-1 (6-hydroxy benzo [b] furanyl-2) -1 [(N, Ndimethylamino) -2 ethoxy] -2 ethane was dissolved. . To the solution was added 0.33 ml of ethyl isocyanate. The resulting mixture was stirred for 30 minutes at 80 [deg.] C. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform / ethanol: 6/1), to obtain an oily product. The oily product was treated with dry hydrogen chloride according to an ordinary method to obtain 0.58 g of acetoxy-1 hydrochloride
(N-ethylcarbamoyloxy-6 benzo [b] furanyl-2) -1 [(N, Ndimethylamino) -2 ethoxy] -2 ethane (compound n [deg.] 408).

  
  <EMI ID = 442.1>

  
The present invention will now be described specifically by way of Examples. However, this invention is in no way limited to these Examples.

  
Example 1 (Tablets)

  
Tablets each containing 50 mg of (4-benzyloxyphenyl) hydrochloride-1 [(N, Ndimethylamino) -2 ethoxy] -2 ethanol (compound n [deg.] 48) were prepared using the following formulation , according to the following method:

  

  <EMI ID = 443.1>
 

  

  <EMI ID = 444.1>


  
  <EMI ID = 445.1>

  
aqueous solution containing 8% polyvinylpyrrolidone K-90. The kneaded product was dried at 40 [deg.] C and mixed

  
  <EMI ID = 446.1>

  
shaped into round tablets, each weighing 175 mg and having a diameter of 8 mm.

Example 2 (Capsules)

  
Capsules each containing 50 mg of [(N, N-dimethylamino) -2 ethoxy] -2 hydrochloride

  
  <EMI ID = 447.1>

  
have been prepared using the following formulation according to the following method:

  
Per capsule:

  

  <EMI ID = 448.1>


  
  <EMI ID = 449.1>

  
aqueous solution containing 8% polyvinylpyrrolidone K-90. The kneaded product was dried at 40 [deg.] C and mixed

  
  <EMI ID = 450.1>

  
introduced into gelatin capsules n [deg.] 3 in an amount of 150 mg per capsule, in order to obtain capsules.

Example 3 (Liquid)

  
A liquid containing 25 mg of [(N, N-dimethylamino) -2 ethoxy] -2 (trifluoromethyl-3 phenyl) -1 ethanol hydrochloride -1 ethanol (compound n [deg.] 42) was prepared using the formulation following, according to the following method:

  
Per bulb:

  

  <EMI ID = 451.1>


  
The above components were dissolved in physiological solution, and the total volume of the solution was brought to 1 ml. The solution was aseptically filtered and introduced into an ampoule to obtain a liquid.

  
Example 4 (Solution for injection)

  
A solution for injection containing 25 mg of [(N, N-dimethylamino) -2 ethoxy] hydrochloride -2

  
  <EMI ID = 452.1>

  
prepared using the following formulation, according to the following method:

  

  <EMI ID = 453.1>
 

  
The above components were dissolved in 1.5 ml of distilled water prepared for injection. The solution was aseptically filtered, introduced into a 3 ml mini-ampoule, and lyophilized, in order to obtain a solution for injection.

  
Example 5 (Fine granules)

  
Fine granules each containing 50 mg of

  
  <EMI ID = 454.1>

  
the following formulation, in accordance with the following method:

  

  <EMI ID = 455.1>


  
  <EMI ID = 456.1>

  
granulation with stirring at high speed with an aqueous solution containing 8% of polyvinylpyrrolidone K-90. The granules obtained were sieved to

  
  <EMI ID = 457.1>

  
(32 mesh) and dried, in order to obtain fine granules.

  
Example 6 (Tablets)

  
  <EMI ID = 458.1>

  
phenyl) -l ethanol compound n [deg.] 215), hydrochloride of [(N, N-dimethylamin: -2 ethoxy] -2 (naphthyl-1) -l ethanol

  
  <EMI ID = 459.1> amino) -2 ethoxy] -2 (naphthyl-2) -1 ethanol (compound

  
n [deg.] 229), hydrochloride of [(N, N-dimethylamino) -2 ethoxy] -2 (benzo [b] thiophenyl-5) -l ethanol (compound

  
n [deg.] 312), [(N-methyl 1H-tetrahydro-1,2,5,6 pyridinyl-3) methyl] -2 (benzo [b] thiophenyl-5) -1 ethanol
(compound n [deg.] 345), fumarate of (2-amino ethoxy) -2
(benzo [b] thiophenyl-5) -l ethanol (compound n [deg.] 357), hydrochloride of [(N, N-diethylamino) -2 ethoxy] -2
(benzo [b] thiophenyl-5) -1 ethanol (compound n [deg.] 388) and hydrochloride of [(4-benzyl-piperazinyl-1) -2 ethyl] -2 (benzo [b] furanyl-5) - ethanol (compound

  
n [deg.] 394) were treated as in Example 1, in order to obtain tablets each containing 50 mg of one of the above compounds.

Example 7 (Capsules)

  
[(N, N-dimethylamino) -2 ethoxy] -2 (3-methylphenyl) -1 ethanol hydrochloride (compound n [deg.] 15), [(1-methyl-5-imidazolyl) methoxy] -2 (4-benzyloxyphenyl) -l ethanol (compound n [deg.] 215), hydrochloride of [(N, N-dimethylamino) -2 ethoxy] -2 (naphthyl-1) -l ethanol
(compound n [deg.] 228), hydrochloride of [(N, N-dimethylamino) -2 ethoxy] -2 (naphthyl-2) -1 ethanol (compound n [deg.]
229), hydrochloride of [(N, N-dimethylamino) -2 ethoxy] -2 (benzo [b] thiophenyl-5) -l ethanol (compound

  
n [deg.] 312), of [(N-methyl 1H-tetrahydro-1,2,5,6

  
  <EMI ID = 460.1>

  
[(N, N-diethylamino) -2 ethoxy] -2 hydrochloride
(benzo [b] thiophenyl-5) -1 ethanol (compound n [deg.] 388), and dihydrochloride of [(4-benzyl-piperazinyl-1) -2 ethyl] -2 (benzo [b] furanyl-5) -l ethanol (compound

  
n [deg.] 394) were treated as in Example 2, in order to obtain capsules each containing 50 mg of one

  
  <EMI ID = 461.1>


    

Claims (1)

1 - Ethanediol-1,2 derivative represented by the following general formula, or salt of this derivative:  <EMI ID = 462.1> where: <EMI ID = 463.1> indanyl, indenyl, tetrahydronaphthyl or heterocyclic, substituted or unsubstituted; - R <2> represents a hydrogen atom, a lower alkyl group or a protective group hydroxyl; - R <3> represents a hydrogen atom or a lower alkyl group; - the nR4 and nR5 are identical or different from each other and represent atoms hydrogen or lower alkyl groups; - R6 represents an ammonio group or an amino or heterccyclic group containing nitrogen, substituted or ncn-substituted, the group nitrogen containing heterocyclic being chosen in the group made up of the groups pyrrolyle, pyrrolidinyle, pipéridyle, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyricyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinclinyl, tetrahydroisoquinol inyl, quinuclidinyl, thiazolyl, tetrazolyl thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl :, pyrazolinyl, pyrazolidinyl, purinyl and iiazolyl; and n is 0 or es = an integer ranging from 1 to 6; where the substituent s :: r R <1> is chosen from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, protected amino groups, protected or unprotected hydroxyl groups, nitro group, group oxo and lower alkylenedioxy groups;  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 or arylsulfonylamino or heterocyclic <EMI ID = 464.1> substituted nitrogen containing heterocyclic as R6 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, aryl groups unsubstituted or substituted by halogen, aroyl groups unsubstituted or substituted by halogen, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocyclic groups, hetero groups  <EMI ID = 465.1> lower sulfonyl and arylsulfonyl groups; and the amino group substituted as the substituent of  <EMI ID = 466.1> <EMI ID = 467.1> 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 , heterocyclic groups, heterocyclic-CO- groups unsubstituted or substituted by  <EMI ID = 468.1> lower and the arylsulfonyl groups, provided that the compounds in  <EMI ID = 469.1> optionally be substituted by a halogen atom or by a lower alkyl, lower alkylene dioxy, lower alkoxy or  <EMI ID = 470.1> -NR7R8, where R7 represents an ar-lower alkyl or heterocyclic group, and R8 represents an atom <EMI ID = 471.1> and R8 form, when taken with the atom of N,  <EMI ID = 472.1>  <EMI ID = 473.1> heterocyclic and is 0 or is an integer ranging from 1 to 3,  <EMI ID = 474.1>  <EMI ID = 475.1> represents an aryl, heterocyclic or <EMI ID = 476.1> group where R <1> <2> represents a carboxyl group or a lower carbonyl alkoxy group, or  <EMI ID = 477.1> where R <1> <2> has the same meaning as defined above  <EMI ID = 478.1> phenyl unsubstituted or substituted by alkyl lower, and R6 represents a di-lower alkyl group- amino,  <EMI ID = 479.1> as well as the compounds in vs which R represents an unsubstituted phenyl group and R  <EMI ID = 480.1> selected from the group consisting of nitrogen containing heterocyclic groups mentioned in the definition of R6 and the furyl, thienyl, benzothienyl, pyrannyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxyl groups -2.3 benzothienyl, 2,3-dihydro-benzopyrrolyle, 2,3-dihydro-4H-thia-1 naphthyl, 2,3-dihydro-benzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [ b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, izoindolyl and isoquinolyl. 2 - Ethanediol-2 derivative, or salt of this derivative, according to claim 1, in which: <EMI ID = 481.1> substituted; - R <2> represents a hydrogen atom or a hydroxyl protecting group: - the nR4 are identical or different from each other and represent hydrogen atoms or lower alkyl groups; - the nR5 represent hydrogen atoms; and - R6 represents an ammonio group or an amino (other than di- (lower alkyl) amino) or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group consisting of pyrrolyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl and thiadiazolyl groups. 3 - Ethanediol-2 derivative, or salt of this derivative, according to claim 1, in which: <EMI ID = 482.1> unsubstituted; - R <2> represents a hydrogen atom or a hydroxyl protecting group; - the nR4 are identical or different from each other and represent hydrogen atoms or lower alkyl groups; - the nR5 represent hydrogen atoms: and - R6 represents an ammonio group or an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl groups , pyrazolyle, pyridyle, pyrimidinyle, morpholinyle, quinolyle, quinolizinyle, tétrahydroquinolinyle, quinuclidinyle, thiazolyle et thiadiazolyle. 4 - A 1,2-ethanediol derivative, or salt of this derivative, according to claim 1, in which R <1> represents a substituted or nonsubstituted heterocyclic group. 5 - 1,2-Ethanediol derivative, or salt of this derivative, according to claim 1, in which  <EMI ID = 483.1> tetrahydronaphthyl, which may be optionally substituted with a halogen atom or a lower alkyl group; R <2> represents a hydrogen atom - R <3> represents a hydrogen atom the nR4 and nR5 represent hydrogen atoms; R6 represents a morpholinyl group which has a free valence on a carbon atom forming the nucleus, a pyridyl group, an imidazolyl group, a piperazinyl group substituted by a phenyl- (C1-4alkyl) group or an amino group which may be optionally substituted with a lower alkyl group or a cycloalkyl group; and n represents an integer ranging from 1 to 4. 6 - A 1,2-ethanediol derivative, or salt of this derivative, according to claim 1, in which <EMI ID = 484.1> benzofuranyl or 2,3-dihydro benzothienyl; - R <2> represents a hydrogen atom; - R <3> represents a hydrogen atom; - nR4 and nR5 represent hydrogen atoms; - R6 represents a pyridyl group, a piperidinyl group which may be optionally substituted by a lower alkyl group, a 1,2,5,6-tetrahydro group pyridyl which may be optionally substituted by a lower alkyl group, an imidazolyl group, a group piperazinyl substituted with a phenyl group (C1-4alkyl) or an amino group which may be optionally substituted by a lower alkyl group or a cycloalkyl group; and - n represents an integer ranging from 1 to 4.  <EMI ID = 485.1> amino) -2 ethoxy] -2 ethanol, or salt of this compound. 8 - (4-Benzyloxyphenyl) -1 [(methyl-1 imidazolyl-5) methoxy] -2 ethanol, or salt of this compound. 9 - (Imidazolylmethoxy) -2 (naphthyl-1) -l ethanol, or salt of this compound. 10 - (1-Methyl imidazolylmethoxy-5) -2 (naphthyl-1) -l ethanol, or salt of this compound. 11 - (Benzo [b] thiophenyl-5) -1 [(N, Ndimethylamino) -2 ethoxy] -2 ethanol, or salt of this compound. 12 - (Benzo [b] thiophenyl-5) -1 [(N, Ndimethylamino) -3 propoxy] -2 ethanol, or salt of this compound. 13 - (Benzo [b] thiophenyl-5) -1 (imidazolylmethoxy) -2 ethanol, or salt of this compound. 14 - (Benzo [b] thiophenyl-5) -1 [(1-methyl-tetrahydro-1,2,5,6 pyridinyl-3) methoxy] -2 ethanol, or salt of this compound. 15 - (Benzo [b] furanyl-5) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol, or salt of this compound. 16 - Process for the manufacture of a 1,2-ethanediol derivative represented by the following general formula, or of a salt of this derivative:  <EMI ID = 486.1> in which : R <1> represents a phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, substituted or unsubstituted; R <3> represents a hydrogen atom or a lower alkyl group; - the nR4 and nR5 are identical or different from each other and represent hydrogen atoms or lower alkyl groups; R6 represents an ammonio group or an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group constituted by the pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl groups, pyrazolyle, pyridyle, tétrahydropyridyle, pyrimidinyle, morpholinyle, thiomorpholinyle, quinolyle, quinolizinyle, tétrahydroquinolinyle, tétrahydroisoquinolinyle, quinuclidinyle, thiazolyle, tétrazolyle, thiadiazolyle, pyridinyl, pyridinyle, and n is 0 or is an integer ranging from 1 to 6; where the substituent on R <1> is chosen from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and lower alkylenedioxy groups;  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 or arylsulfonylamino or heterocyclic  <EMI ID = 487.1> substituted nitrogen containing heterocyclic as R6 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, heterocyclic groups, heterocyclic-CO- groups, the oxo group,  lower alkylsulfonyl groups and arylsulfonyl groups; and the amino group substituted as the substituent of  <EMI ID = 488.1> each at least one substituent chosen from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, lower alkyl groups substituted by a protected or unprotected carbcxyl or hydroxyl group, cycloalkyl groups, aryl groups, groups lower acyl, ar-lower alkyl groups, heterocyclic groups, heterocyclic-CD- groups unsubstituted or substituted by  <EMI ID = 489.1> lower and arylsulfonyl croups, provided that composites are excluded in  <EMI ID = 490.1> optionally be substituted by a halogen atom or by a lower alkyl, lower alkylene dioxy, lower alkoxy or  <EMI ID = 491.1> - NR &#65533; R &#65533;, where R7 represents an ar-lower alkyl group <EMI ID = 492.1>  <EMI ID = 493.1> and R8 form, when taken with the atom of N,  <EMI ID = 494.1>  where R9 represents an aryl group or heterocyclic and i is 0 or is an integer ranging from 1 to 3,  <EMI ID = 495.1>  <EMI ID = 496.1> represents an aryl, heterocyclic group or -N-heterocyclic and R8 and i have the same meanings R8 <EMI ID = 497.1> lower carbonyl alkoxy, or  <EMI ID = 498.1> where R <1> <2> has the same meaning as defined above  <EMI ID = 499.1> phenyl unsubstituted or substituted by lower alkyl, and R6 represents a di- (lower alkyl) group  <EMI ID = 500.1> selected from the group consisting of nitrogen containing heterocyclic groups mentioned in the definition of R6 and the furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxyl groups -2.3 benzothienyl, 2,3-dihydro-benzopyrrolyle, 2,3-dihydro-4H-thia-1 naphthyl, 2,3-dihydro-benzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [ b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl, which comprises the reaction of a compound represented by the general formula:  <EMI ID = 501.1>  <EMI ID = 502.1> those defined above, with a compound represented by the following general formula, or a salt of this compound:  <EMI ID = 503.1> in which : mR4 and mR5 are the same or different from each other and represent hydrogen atoms or lower alkyl groups; R6 has the same meaning as that defined above; and m represents an integer ranging from 1 to 6, or a compound represented by the following general formula, or a salt of this compound:  <EMI ID = 504.1>  <EMI ID = 505.1> nitrogen containing heterocyclic, substituted or unsubstituted, only in the definition of R6, provided that the heterocyclic group has a free valence on a carbon atom forming the heterocyclic nucleus. 17 - Process for the manufacture of a 1,2-ethanediol derivative represented by the following general formula, or salt of this derivative:  <EMI ID = 506.1> in which : - R <1> represents a phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, substituted or unsubstituted; - R2a represents a hydroxyl protecting group; - R <3> represents a hydrogen atom or a lower alkyl group; - mR4 and mR5 are the same or different from each other and represent hydrogen atoms or lower alkyl groups;  and - R6b represents an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen having a free valence on a carbon atom forming the heterocyclic nucleus and being chosen from the group consisting of pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolixinyle, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl; and - m is an integer ranging from 1 to 6; Where the substituent on R <1> is chosen from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio , lower alkenyl, lower alkenyloxy, ar-lower alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and lower alkylenedioxy groups;  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 or arylsulfonylamino or heterocyclic substituted as the substituent of R <1> and the heterocyclic group containing nitrogen, substituted, as R6b each have at least one substituent selected from the group consisting of halogen atoms, protected hydroxyl groups or unprotected, 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,  aryl groups unsubstituted or substituted by halogen, aroyl groups, unsubstituted or substituted by halogen, unsubstituted lower alkoxy groups, lower alkoxy groups substituted by a lower alkoxy group, lower acyl groups, ar-alkyl groups lower, ar-lower alkenyl groups, heterocyclic groups, heterocyclic-CO- groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups; and the amino group substituted as the substituent of <EMI ID = 507.1> each at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, lower alkyl groups. substituted with a protected or unprotected carboxyl or hydroxyl group, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, heterocyclic-CO- groups unsubstituted or substituted by oxo, adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, provided that the compounds in  <EMI ID = 508.1> optionally be substituted by a halogen atom or by a lower alkyl, lower alkylenedioxy, lower alkoxy or hydroxyl group  <EMI ID = 509.1> represents an ar-lower alkyl or heterocyclic group, and R8 represents a hydrogen atom or a lower alkyl group, or else R7 and R8 form, when taken with the atom of N,  <EMI ID = 510.1> where R9 represents an aryl group or heterocyclic and i is 0 or is an integer ranging from 1 to 3,  <EMI ID = 511.1>  <EMI ID = 512.1> represents an aryl, heterocyclic group or <EMI ID = 513.1> where R <1> <2> represents a carboxyl group or a group lower alkoxycarbonyl, or  <EMI ID = 514.1> where R <1> <2> has the same meaning as defined above  <EMI ID = 515.1> phenyl unsubstituted or substituted by alkyl lower, and R6b represents a di- (lower alkyl) group  <EMI ID = 516.1>  <EMI ID = 517.1>  <EMI ID = 518.1> H all the heterocyclic groups above were chosen from the group consisting of the heterocyclic groups containing nitrogen mentioned in the definition of R6b and the furyl, thienyl, benzothienyl, pyranyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl groups , benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydro-benzothienyl, 2,3-dihydro-benzopyrrolyl, 2,3-dihydro-4H-thia-l naphthyl, 2,3-dihydro-benzofuranyl, benzo [b] dioxanyl, imidazo [ 2,3-a] pyridyle, benzo [b] pipérazinyle, chroményle, isothiazolyle, isoxazolyle, oxadiazolyle, pyridazinyle, isoindolyle et isoquinolyle, which comprises the reaction of a compound represented by the general formula:  <EMI ID = 519.1> where: <EMI ID = 520.1> meanings as defined above; and - Y represents an eliminable group, with a compound represented by the following general formula, or a salt of this compound: H-R6b in which R6b has the same meaning as that defined above. 18 - Use of a 1,2-ethanediol derivative represented by the following general formula, or of a salt of this derivative, for the preparation of a medicament for the treatment of cerebrovascular dementia, of senile dementia, Alzheimer's dementia, sequelae of ischemic encephalopathy or cerebral apoplexy in a patient:  <EMI ID = 521.1> in which : R <1> represents a phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group, substituted or unsubstituted; R <2> represents a hydrogen atom, a lower alkyl group or a hydroxyl protecting group; - R <3> represents a hydrogen atom or a lower alkyl group - the nR4 and nR5 are identical or different from each other and represent hydrogen atoms or lower alkyl groups; <EMI ID = 522.1> amino or heterocyclic nitrogen-containing, substituted or unsubstituted, the heterocyclic group containing nitrogen being 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 pyidolidinyl pyridininyl, pyridinyl) and - n is 0 or is an integer ranging from 1 to 6; where the substituent on R <1> is chosen from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and lower alkylenedioxy groups;  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 or arylsulfonylamino or heterocyclic <EMI ID = 523.1> substituted nitrogen containing heterocyclic as R6 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, heterocyclic groups, heterocyclic-CO- groups , the oxo group,  lower alkylsulfonyl groups and arylsulfonyl groups; the amino group substituted as the substituent of R <1> and the amino group substituted as R6 each have at least one substituent selected from the group consisting of protected or unprotected hydroxyl groups, unsubstituted lower alkyl groups, alkyl groups lower substituted with a protected or unprotected carboxyl or hydroxyl group, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, heterocyclic groups -CO- unsubstituted or substituted by oxo , the adamantyl group, the lower alkylsulfonyl groups and the arylsulfonyl groups, provided that the compounds in  <EMI ID = 524.1> optionally be substituted by a halogen atom or by a lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group and R6 represents -NR R R &#65533;, where R7 represents a group ar-lower alkyl or heterocyclic, and R8 represents a hydrogen atom or a lower alkyl group, or else R7 and R8 form, when taken with the atom of N,  <EMI ID = 525.1>  <EMI ID = 526.1> <EMI ID = 527.1> from  <EMI ID = 528.1>  <EMI ID = 529.1> -N-heterocycliqu = and R8 and i have the same signifiR8  <EMI ID = 530.1>  <EMI ID = 531.1>  <EMI ID = 532.1>  <EMI ID = 533.1> where R <1> <2> has the even significant as that defined above;  <EMI ID = 534.1> nitrogen containing heterocyclics mentioned in the definition of = and the furyl, thienyl,  <EMI ID = 535.1> R <1> represents .-. == a substituted or unsubstituted phenyl group; R <2> represents a hydrogen atom or a hydroxyl protecting group; nR4 are the same or different from each other and represents hydrogen atoms or lower alkyl groups; the nR5 represent hydrogen atoms; and R6 represents an ammonio group or an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl , pyrazolyle, pyridyle, pyrimidinyle, morpholinyle, quinolyle, quinolizinyle, tétrahydroquinolinyle, quinuclidinyle, thiazolyle et thiadiazolyle. 20 - Use of a 1,2-ethanediol derivative or a salt of this derivative, according to claim 18, in which:  <EMI ID = 536.1> unsubstituted;  <EMI ID = 537.1> hydroxyl protector; nR4 are the same or different from each other and represents hydrogen atoms or lower alkyl groups; the nR5 represent hydrogen atoms; and <EMI ID = 538.1> amino or heterocyclic nitrogen-containing, substituted or unsubstituted, the heterocyclic group containing nitrogen being selected from the group consisting of pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, morpholinyl, quinolyle, quinolizlnyle, tétrahydroquinolinyle, quinuclidinyle, thiazolyle et thiadiazolyle. 21 - Use of a 1,2-ethanediol derivative, or a salt of this derivative, depending on the  <EMI ID = 539.1> substituted or unsubstituted heterocyclic group. 22 - Use of a 1,2-ethanediol derivative or a salt of this derivative, according to claim 18, in which:  <EMI ID = 540.1> indanyl, tetrahydronaphthyl, furyl, thienyl, pyridyl, quinolyl, benzothienyl, 2,3-dihydro-2,3 benzofuranyl, indolyl, benzofuranyl, 2,3-dihydro-benzothienyl, 1,2,3,4-quinolinyl or imidazolyl, substituted or unsubstituted; R6 represents an ammonio group or an amino or heterocyclic group containing substituted or unsubstituted nitrogen, the heterocyclic group containing nitrogen being chosen by the group consisting of the pyrrolinyl, piperidyl, piperazinyl, imidazolyl, pyridyl, morpholinyl groups , thiomorpholinyl, tetrahydropyridyl, quinuclidinyl and tetrazolyl,  <EMI ID = 541.1> consisting of halogen atoms; lower alkyl groups; lower alkenyl groups; phenyl groups which may be optionally substituted by a halogen atom or a lower alkyl or lower alkoxy group; phenyl groups (C1-4 alkyl); lower alkoxy groups which may be optionally substituted by a pyridyl, furyl or thienyl group; phenyl groups (C1-4 alkoxy) which may be optionally substituted by a halogen atom or a lower alkyl, hydroxyl or lower alkoxy group: the phenoxy group; the phenylaminocarbonyloxy group which may be optionally substituted by a halogen atom the lower alkyl-amino-carbonyloxy groups; lower alkylthio groups; the phenylsulfonylamino group; amino groups which may be optionally substituted with a lower alkyl group; the hydroxyl group; the nitro group; the oxo group;  phenyl- (C1-4alkylthio) groups; phenyl- (C1-4 alkylsulfonyl) groups; thienyl group, pyridyl group; and lower alkylenedioxy groups: the substituent on R6, when R6 represents a substituted amino group, being chosen from the group consisting of lower alkyl groups which may be optionally substituted with a hydroxyl group; lower acyl groups; cycloalKyle groups; phenyl- (C1-4alkyl) groups; the pyrimidinyl group; the pyridinecarbonyl group and the adamantyl group; and the substituent on R6, when R6 represents a substituted heterocyclic group containing nitrogen, being selected from the group consisting of halogen atoms; the hydroxyl group; lower alkyl groups which may be optionally substituted with a hydroxyl group; the amino group; lower acyl groups which may be optionally substituted with a pyrrolidinyl group;  phenyl- (C1-4alkyl) groups; phenyl groups (C2-4 alkenyl); aroyl groups which are substituted by a halogen atom; the pyridyl group and the oxo group; provided that the compounds in  <EMI ID = 542.1> optionally substituted by a halogen atom or a lower alkyl, lower alkoxy, lower alkylenedioxy or hydroxyl group and R6 represents -NR7R8, where R7 represents a phenyl- (alkyl in  <EMI ID = 543.1>  <EMI ID = 544.1>  <EMI ID = 545.1>  <EMI ID = 546.1>  where R9 represents a phenyl group and i is 0 or an integer ranging from 1 to 3. 23 - Use of a 1,2-ethanediol derivative, or of a salt of this derivative, according to claim 22, in which: <EMI ID = 547.1> optionally substituted with a halogen atom;  <EMI ID = 548.1> 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> represents a hydrogen atom; - R <3> represents a hydrogen atom; - nR4 and nR5 represent hydrogen atoms; - R6 represents a morpholinyl group which has a free valence on a carbon atom forming the nucleus, a pyridyl group, an imidazolyl group which can be optionally substituted by a lower alkyl group, or an amino group which can be optionally substituted by a group lower alkyl or cycloalkyl. 24 - Use of a 1,2-ethanediol derivative, or of a salt of this derivative, according to claim 22, in which: R <1> represents a naphthyl, indanyl or tetrahydronaphthyl group which may be optionally substituted by a halogen atom or a lower alkyl group - R <2> represents a hydrogen atom; R <3> represents a hydrogen atom; nR4 and nR5 represent hydrogen atoms; R6 represents a morpholinyl group which has a free valence on a carbon atom forming the nucleus, a pyridyl group, an imidazolyl group, a piperazinyl group substituted by a phenyl- (C1-4alkyl) group or an amino group which may be optionally substituted with a lower alkyl group or a cycloalkyl group; and - n represents an integer ranging from 1 to 4. 25 - Use of a 1,2-ethanediol derivative, or a salt of this derivative, according to claim 22, in which: <EMI ID = 549.1> benzofuranyl or 2,3-dihydro-benzothienyl; - R <2> represents a hydrogen atom; - R <3> represents a hydrogen atom; - nR4 and nR5 represent hydrogen atoms; - R6 represents a pyridyl group; a piperidinyl group which may be optionally substituted by a lower alkyl group; a 1,2,5,6-tetrahydro pyridyl group which may be optionally substituted with a lower alkyl group; an imidazolyl group; a piperazinyl group substituted with a phenyl- (C1-4alkyl) or an amino group which may be optionally substituted by a lower alkyl group or a cycloalkyl group; and n represents an integer ranging from 1 to 4. 26 - Use of a 1,2-ethanediol derivative, or a salt of this derivative, according to claim 18, in which the derivative or the salt is (4-benzyloxyphenyl) -1 [(N, N-dimethylamino) -2 ethoxy] -2 ethanol, or a salt of this compound. <EMI ID = 550.1> Claim 18, in which the derivative or the salt is (benzylox & = -. phenyl) -1 [(methyl-1-imidazolyl-5) methoxy] -2 ethanc = or a salt of this compound. 28 - Use of an ethane derivative-  <EMI ID = 551.1> a salt of this compound. 29 - Use of an ethane derivative-  <EMI ID = 552.1> claim 18, wherein the derivative or salt is (1-methyl-iridazolylmethoxy-5) -2 (naphthyl-1) -l  <EMI ID = 553.1> 30 - Use of an ethane derivative-  <EMI ID = 554.1>  <EMI ID = 555.1> 31 - Use of an ethane derivative-  <EMI ID = 556.1>  <EMI ID = 557.1> propoxy] -2 ethane: or a salt of this compound. 32 - Use of an ethane derivative-  <EMI ID = 558.1> 1,2-diol, or a salt thereof, according to claim 18, wherein the derivative or salt is (benzo [b] furanyl-5) -l [(N, N-dimethylamino) -2 ethoxy] -2 ethanol, or a salt of this compound. 35 - Use of a 1,2-ethanediol derivative, or a salt of this derivative, according to claim 18, in which the derivative or salt is [(N, N-dimethylamino) -2 ethoxy] -2 (3-methylphenyl) -1 ethanol, or a salt of this compound. 36 - Agent for improving brain function comprising a 1,2-ethanediol derivative, represented by the following general formula, or a salt of this derivative:  <EMI ID = 559.1> in which :  <EMI ID = 560.1> indanyl, indenyl, tetrahydronaphthyl or heterocyclic, substituted or unsubstituted; R <2> represents a hydrogen atom, a lower alkyl group or a hydroxyl protecting group; R <3> represents a hydrogen atom or a lower alkyl group; nR4 and nR5 are the same or different from each other and represent hydrogen atoms or lower alkyl groups; R6 represents an ammonio group or an amino or heterocyclic group containing nitrogen, substituted or unsubstituted, the heterocyclic group containing nitrogen being chosen from the group constituted by the pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl groups, pyrazolyle, pyridyle, tétrahydropyridyle, pyrimidinyle, morpholinyle, thiomorpholinyle, quinolyle, quinolizinyle, tétrahydroquinolinyle, tétrahydroisoquinolinyle, quinuclidinyle, thiazolyle, tétrazolyle, thiadiazolyle, pyridinyl, pyridinyle, and n is 0 or is an integer ranging from 1 to 6; the substituent on R <1> being chosen from the group consisting of halogen atoms, amino groups, lower alkyl, aryl, ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, alkenyl lower, lower alkenyloxy, lower ar-alkylthio, lower aralkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic, substituted or unsubstituted, protected amino groups, protected or unprotected hydroxyl groups, nitro group, oxo group and groups lower alkylenedioxy:;  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 or arylsulfonylamino or heterocyclic  <EMI ID = 561.1> heterocyclic containing nitrogen substituted as  <EMI ID = 562.1> 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, substituted lower alkyl groups with 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 with lower alkoxy group, lower acyl groups, ar-lower alkyl groups, ar-lower alkenyl groups, heterocyclic groups, heterocyclic-CO- groups, oxo group, lower alkylsulfonyl groups and arylsulfonyl groups;  and the amino group substituted as the substituent of  <EMI ID = 563.1> each at least one substituent chosen from the group consisting of protected or unprotected hydroxyl groups, lower alkyl groups. unsubstituted, lower alkyl groups substituted by a protected or unprotected carboxyl or hydroxyl group, cycloalkyl groups, aryl groups, lower acyl groups, ar-lower alkyl groups, heterocyclic groups, heterocyclic-CO- unsubstituted groups or substituted by oxo, the adamantyl group, the lower alkylsulfonyl groups and the arylsulfonyl groups, provided that the compounds in  <EMI ID = 564.1> optionally be substituted by a halogen atom or by a lower alkyl, lower alkylenedioxy, lower alkoxy or protected or unprotected hydroxyl group and R6 represents -NR7R8, where R7 represents an ar-lower alkyl group <EMI ID = 565.1> of hydrogen or a lower alkyl group, or else R7 and R8 form, when taken with the atom of N,  <EMI ID = 566.1> where R9 represents an aryl group or a heterocyclic group and i is worth 0 or is a number <EMI ID = 567.1>  <EMI ID = 568.1> where R10 represents an aryl group, a heterocyclic group or a group -N-b = terocyclic and R8 and i have the R [pound] meanings at = - those defined above,  <EMI ID = 569.1>  <EMI ID = 570.1>  <EMI ID = 571.1>  <EMI ID = 572.1>  <EMI ID = 573.1>  <EMI ID = 574.1> where R <1> <2> has the even significant- as that defined above,  <EMI ID = 575.1> selected from the group consisting of heterocyclic nitrogen-containing groups mentioned in the definition of = and furyl, thienyl, benzothienyl, p & n65, isobenzofuranyl, oxazolyl,  <EMI ID = 576.1>