RU2117668C1 - Oxazolidone derivative or its pharmacologically acceptable salts, pharmaceutical composition, method of treatment - Google Patents

Abstract

FIELD: chemistry of heterocyclic compounds, organic chemistry and technology, biochemistry. SUBSTANCE: invention relates to derivatives of oxazolidone of the formula (I) R¹ where A and B each means nitrogen, sulfur or oxygen atom at condition that at least one of their must be nitrogen atom. R² and

Description

 The invention relates to oxazolidone derivatives having an excellent medical effect.

 We can say that at present for 20 - 30 people in the usual state there is one suffering from depression. In addition, most patients have a depressive state, which is a consequence of brain damage, etc. Thus, depression and depression can be considered modern diseases.

 Tricyclic antidepressants such as imipramine and amitriptyline have previously been used to relieve depression and depression. However, antidepressants are not so preferable, as they are not effective for ~ 40% of patients and have side effects, especially for patients aged, such as tachycardia, low blood pressure, headache, finger tremor, constipation, and urination disorder.

 On the other hand, it has long been known that monoamine oxidase inhibitors (hereinafter referred to as MAO) have an antidepressant effect and it is shown that their effect is wider than that of tricyclic antidepressants. However, hydrazide MAO inhibitors are not currently used, as it has been found that they cause liver disorders. Non-hydrazide MAO inhibitors are also barely used, as their inhibitory effect of MAO is irreversible.

 Additional studies have shown that MAO is classified into two types, type A and type B, and that unpleasant side effects such as low blood pressure, headache and dizziness, as well as the so-called “cheese effect,” when the drug interacts with food having a high content of tyramine, causes attacks of hypertension, due mainly to the inhibitory effect of MAO-B.

 The inventors conducted extensive research to find a way that provides a reversible inhibitory effect, and at the same time free from serious side effects or interaction with food, and also effective for patients in a wide range. For this, the inhibitory effect of MAO-A and compounds with a similar effect were studied.

 As a result of such studies, the inventors found that the object of the invention can be oxazolidone derivatives, which are described below. The present invention is made based on this finding.

 Despite the fact that the derivatives of oxazolidone used as medications are described, for example, in patents in Japan N 40428/1985, 5391/1988, 54710/1988, 63671/1988, 56071/1989, 37354/1990, 61465/1990 and 9106/1991 and Japanese Patent No. 63671/1988, they differ in structure from the compounds of the present invention.

 US 5011849 discloses oxazole carboxamide derivatives having monoamine oxidase inhibitory activity, as well as pharmaceutical compositions containing these derivatives or their pharmaceutically acceptable salts as an active agent and a pharmaceutically acceptable excipient.

 However, the structure described in US patent 5011849 is significantly different from the structure of the compounds of the present invention.

где
A и B каждый представляет собой атом азота, атом серы или атом кислорода, с условием, что по крайней мере один из A и B должен быть азотом;
R¹ представляет собой атом водорода, атом галогена, цианогруппу, низший алкил, циклоалкил, гидроксиалкил, алкоксиалкил, цианоалкенил группы, группу, соответствующую формуле:

(в которой
n и m каждый представляет собой 0 или целое число от 1 до 4 и R³ и R⁴ могут быть одинаковыми или разными и каждый представляет собой атом водорода, гидроксил, низший алкил, низший алкоксил группы или группу, соответствующую формуле

(в которой
R⁷ и R⁸ могут быть одинаковыми или разными и каждый представляет собой атом водорода или низший алкил или R⁷ и R⁸ могут вместе с атомом азота образовывать кольцо и кольцо может быть замещенным), группу, соответствующую формуле:

(в которой
p и g каждый представляет собой 0 или целое число от 1 до 4 и X является атомом кислорода, атомом серы или группой, соответствующей формуле: =N-OR⁹ (R⁹ - атом водорода или низший алкил), группу, соответствующую формуле:

(в которой
R⁵ и R⁶ могут быть одинаковыми или разными и каждый представляет собой атом водорода, низший алкил или цианоалкил группу или R⁵ и R⁶ могут образовывать вместе с атомом азота, с которым они связаны, кольцо и кольцо может быть замещенным), группу, соответствующую формуле:
NC-(CH₂)_r-Y-(CH₂)_s-
(в которой
r и s каждый представляет собой 0 или целое число от 1 до 4 и Y является атомом кислорода, атомом серы, группой формулы: -NH-), арил группу, которая может быть замещенной, арилалкил группу, которая может быть замещенной, гетероарил группу, которая может быть замещенной, гетероарилалкил группу, которая может быть замещенной, карбамоилалкил группу или цианоалкилкарбамоил группу;
R² представляет собой атом азота или низший алкил и связь, представленная

, соответствует простой или двойной связи).The present invention relates to oxazolidone derivatives corresponding to the general formula (1) or their pharmacologically acceptable salts:

Where
A and B each represents a nitrogen atom, a sulfur atom or an oxygen atom, with the proviso that at least one of A and B must be nitrogen;
R ¹ represents a hydrogen atom, a halogen atom, a cyano group, lower alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl groups, a group corresponding to the formula:

(wherein
n and m each represents 0 or an integer from 1 to 4 and R ³ and R ⁴ may be the same or different and each represents a hydrogen atom, hydroxyl, lower alkyl, lower alkoxyl group or a group corresponding to the formula

(wherein
R ⁷ and R ⁸ may be the same or different and each represents a hydrogen atom or lower alkyl, or R ⁷ and R ⁸ together with a nitrogen atom form a ring and the ring may be substituted), a group corresponding to the formula:

(wherein
p and g each represents 0 or an integer from 1 to 4 and X is an oxygen atom, a sulfur atom or a group corresponding to the formula: = N-OR ⁹ (R ⁹ is a hydrogen atom or lower alkyl), a group corresponding to the formula:

(wherein
R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, a lower alkyl or cyanoalkyl group, or R ⁵ and R ⁶ may form together with the nitrogen atom to which they are attached, the ring and ring may be substituted), a group, corresponding to the formula:
NC- (CH ₂ ) _r -Y- (CH ₂ ) _s -
(wherein
r and s are each 0 or an integer from 1 to 4 and Y is an oxygen atom, a sulfur atom, a group of the formula: —NH—), an aryl group which may be substituted, an arylalkyl group which may be substituted, a heteroaryl group, which may be substituted, a heteroarylalkyl group, which may be substituted, a carbamoylalkyl group or a cyanoalkylcarbamoyl group;
R ² represents a nitrogen atom or lower alkyl and a bond represented by

corresponds to a single or double bond).

 The present invention also provides a preparation for the prophylaxis and treatment of diseases against which monoamine oxidase inhibitors are effective, comprising, as an active ingredient, an oxazolidone derivative of the general formula (I) above and / or a pharmacologically acceptable salt thereof.

 Further, the present invention provides: a medicament comprising an effective dose of an oxazolidone derivative of the general formula (I) and / or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient; the use of an oxazolidone derivative of the general formula (I) or a pharmacologically acceptable salt thereof for the manufacture of a medicament against diseases against which monoamine oxidase inhibitors are effective; a method of treatment according to which a patient suffering from diseases against which monoamine oxidase inhibitors are effective is administered an effective dose of an oxazolidone derivative of the general formula (I) and / or a pharmacologically acceptable salt thereof.

 The present invention is suitable for the treatment of diseases against which monoamine oxidase A inhibitors are effective, especially those against which the administration of antidepressants is effective.

Lower alkyl groups in R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ in the above general formula (I) are straight chains or branched alkyl groups having 1 - 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl, 1 2-dimethylpropyl; hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl and octyl groups. Most preferred among them are methyl, ethyl, propyl and isopropyl groups.

The lower alkoxy groups in R ³ and R ⁴ are straight or branched alkoxy groups containing from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy and hexyloxy groups. Among them, methoxy and ethoxy groups are most preferred.

Alkoxyalkyl groups of R ¹ are the above lower alkyl groups.

Aryl groups Aryl groups which, by definition, R ¹ may be substituted, include phenyl, naphthyl, tolyl and xylyl groups.

Arylalkyl groups Arylalkyl groups which, by definition, R ¹ may be substituted, are groups derived from the aryl groups described above.

Heteroaryl groups Heteroaryl groups, which R ¹ may be substituted by definition, are saturated or unsaturated 5- to 7-membered rings containing 1 or 2 nitrogen, sulfur or oxygen atoms.

Heteroarylalkyl groups of heteroarylalkyl groups which, by definition, R ¹ may be substituted, are groups derived from the above heteroaryl groups.

 The substituents on “aryl groups which may be substituted”, “arylalkyl groups which may be substituted”, “heteroaryl groups which may be substituted”, and “heteroarylalkyl groups which may be substituted” include hydroxyl, lower alkyl, cyano lower alkoxy, amino, nitro, carboxyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl and cyanoalkenyl groups.

Hydroxyalkyl groups in R ¹ are the lower alkyl groups described above, which furthermore have one or two hydroxyl groups attached to any of their carbon atoms.

Alkenyl groups of cyanoalkenyl groups in the definition of R ¹ correspond to the lower alkyl groups presented above, which have one or more double bonds between their two carbon atoms. A cyano group may be bonded to any carbon atom of an alkenyl group.

Carbamoylalkyl groups in R ¹ are groups that are derived from the lower alkyl groups described above.

Cyanoalkylcarbamoyl groups in the definition of R ¹ are groups derived from the above cyanoalkyl groups.

The halogen atoms in R ¹ include fluoro, chloro, bromo and iodo.

Cycloalkyl groups in R ¹ include groups containing from 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups.

The term “can form a ring together with the nitrogen atom to which they are attached” in the definitions of R ⁵ and R ⁶ or R ⁷ and R ⁸ refers, in particular, to piperidino and pyrrolidino groups and to piperidino and morpholino groups that additionally contain nitrogen atoms oxygen or sulfur.

 Hydroxyl, cyano, carboxyl, amino, nitro, lower alkyl, lower alkoxyl, hydroxyalkyl, cyanoalkyl and cyanoalkenyl groups are used as their substituents.

 Pharmacologically acceptable salts of the present invention include inorganic acid salts such as hydroxychloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; amino acid salts such as aspartate and glutamate.

 Some of these compounds can form salts with metals, such as Na, K, Ca and Mg, which are also included in the pharmacologically acceptable salts of the present invention.

 The compounds of the present invention can form geometric and optical isomers depending on the substituents, and these isomers are included in the present invention.

 Preferred examples of the compounds of the present invention will be given below, in particular, to facilitate the explanation of the present invention, which in no way limit the invention.

(где
R², R³, R⁴ n и m являются группами, определенными выше). R² является желательно атомом водорода или метил, этил или пропил группой, среди которых более желательны атом водорода и метил группа, причем из них более предпочтительна метил группа.Examples of the most suitable compounds are compounds corresponding to the basic formula (A) and their pharmacologically acceptable salts:

(Where
R ² , R ³ , R ⁴ n and m are groups as defined above). R ² is preferably a hydrogen atom or a methyl, ethyl or propyl group, among which a hydrogen atom and a methyl group are more desirable, of which methyl group is more preferred.

R ³ and R ⁴ may be the same or different and each represents a hydrogen atom or a hydroxyl or lower alkyl group, among which a hydrogen atom or a hydroxyl, methyl, ethyl, propyl, butyl or tert-butyl group is more desirable, with an atom being more preferred hydrogen or hydroxyl or methyl group.

The most desirable combination of the values of R ³ and R ⁴ , comprising a hydrogen atom and a hydroxyl group. A further desired combination thereof includes a hydroxyl group and a lower alkyl group. The following desired combination includes two hydrogen atoms.

 n and m are independently 0 or an integer from 1 to 4. Desirable combinations of n and m include n = 3 and m = 0; n = 2 and m = 1; n is 1 and m is 2; n is 0 and m is 3; n = 2 and m = 0; n = 1 and m = 1; n = 0 and m = 2, among which the combination of n = 3 and m = 0 is more desirable; and n = 2 and m = 0, the most preferred combination includes n = 2 and m = 0.

(где
R², R⁵ и R⁶ имеют значения, представленные выше). R² является желательно атомом водорода или метил, этил или пропил группой, среди которых более желательны - атом водорода и метил группа, причем наиболее предпочтительна метил группа.Examples of the following most preferred compounds are compounds corresponding to the general formula (B) and their pharmacologically acceptable salts:

(Where
R ² , R ⁵ and R ⁶ have the meanings given above). R ² is preferably a hydrogen atom or a methyl, ethyl or propyl group, among which a hydrogen atom and a methyl group are most desirable, with a methyl group being most preferred.

R ⁵ and R ⁶ may preferably be the same or different and each represents a hydrogen atom or a cyanoalkyl group, or the case where R ⁵ and R ⁶ form a ring together with the nitrogen atom to which they are bonded, however, it is preferred that R ⁵ and R ⁶ form a ring together with the nitrogen atom to which they are attached, the ring, in particular, is a piperidino or pyrrolidino group. The ring may preferably have one or two substituents, more preferably one substituent. Preferred examples of substituents are cyano, hydroxyl and carboxyl groups.

(где
R², X, p и q имеют значения, представленные выше).Examples of the following most preferred compounds are compounds corresponding to general formula (C) and pharmacologically acceptable salts thereof:

(Where
R ² , X, p and q have the meanings given above).

R ² is preferably a hydrogen atom or a methyl, ethyl or propyl group, among which a hydrogen atom and a methyl group are most desirable, with a methyl group being most preferred.

 X is preferably a sulfur or oxygen atom, more preferably an oxygen atom.

 p and q are independently 0 or an integer from 1 to 4. Desirable combinations of p and q include p = 3 and q = 0; p = 2 and q = 1; p = 1 and q = 2; p = 0 and q = 3; p = 2 and q = 0; p = 1 and q = 1; p = 0 and q = 2, among which p-3 and q = 0 are more desirable; p = 2 and q = 0 and most preferably a combination of p = 2 and q = 0.

Among the compounds of the present invention, compounds having a particularly excellent inhibitory activity to monoamine oxidase are the following compounds or pharmacologically acceptable salts thereof:
1) 3- [2- (1-hydroxy-3-cyanopropyl) benzthiazolol-6-yl] - 5-methoxymethyl-2-oxazolidinone,
2) 3- [2- (3-cyanopropyl) benzthiazol-6-yl] -5- methoxymethyl-2-oxazolidinone,
3) 3- [2- (1-hydroxy-4-cyanobutyl) benzthiazol-6-yl] -5-methoxymethyl-2-oxazolidinone and
4) 3- [2- (4-cyanobutyl) benzthiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.

 Typical methods for preparing the compounds of the present invention are presented below.

(где
A и B имеют значения, описанные выше, R_a ¹ представляет собой группу, выбранную из тех же групп, которые описаны для R¹, исключая атомы галогена и группу формулы:

(где
R³, R⁴, m и n имеют значения, представленные выше) и Hal представляет собой атом галогена).Production Method 1
(first stage)

(Where
A and B have the meanings described above, R _a ¹ represents a group selected from the same groups as described for R ¹ , excluding halogen atoms and a group of the formula:

(Where
R ³ , R ⁴ , m and n have the meanings given above) and Hal represents a halogen atom).

 Namely, a compound of general formula (II) is reacted with a compound of general formula (III) in the presence or absence of a base to form a compound of general formula (IV). Any type can be used as a base. Examples of preferred bases are alkali metal salts such as potassium carbonate and sodium bicarbonate; alkali metal hydrides such as sodium hydride and potassium hydride; amines such as triethylamine.

 The reaction solvent is any organic solvent that is not involved in the reaction. The use of alcohols as solvents, such as ethanol, is preferred; esters such as tetrahydrofuran and dioxane; and dimethylformamide.

The reaction temperature ranges from 0 ^° C. to the boiling point of the solvent.

(где
A, B и R_a ¹ имеют значения, указанные выше).(second stage)

(Where
A, B and R _a ¹ have the meanings indicated above).

 Namely, the compound of general formula (IV) obtained in the first step is nitrated in the usual manner to form a compound of general formula (V).

(где
A, B и R_a ¹ имеют значения, указанные выше).(third step)

(Where
A, B and R _a ¹ have the meanings indicated above).

 Namely, the compound of general formula (V) obtained in the second step is reduced by conventional catalytic hydrogenation to form a compound of general formula (VI).

 Preferred catalysts include, for example, palladium on carbon, platinum oxide, Raney nickel and rhodium alumina.

 As the solvent for the reaction, any organic solvent is used. Preferred solvents are alcohols, such as methanol; hydrocarbons such as toluene; esters such as tetrahydrofuran; N, N-dimethylformamide; and ethyl acetate.

The reaction temperature ranges from about 0 ^° C. to the boiling point of the solvent.

(где
R_a ¹, R², A и B имеют значения, описанные выше).(Fourth stage)

(Where
R _a ¹ , R ² , A and B have the meanings described above).

 Namely, the compound of general formula (VI) obtained in the third step is converted with glycidol derivatives of general formula (VII) in the usual manner to form a compound of general formula (VIII).

 Compound (VIII) can be obtained in high yield using magnesium perchlorate, sodium perchlorate or lithium perchlorate according to the procedure described in Tetrahedron Letters Vol. 31, N 32, pp. 4661-4664 (1990).

 The reaction solvent may be any organic solvent commonly used for organic synthesis and not participating in the reaction. Alcohols such as methanol, ethanol, propanol, isopropanol and butanol are preferably used as solvents for reactions with non-perchlorate compounds; acetonitrile is preferably used for reactions with perchlorates.

The reaction temperature ranges from about 0 ^° C. to the boiling point of the solvent.

 This stage, depending on the circumstances, can be carried out in an airtight vessel.

(где
R_a ¹, R², A и B имеют значения, описанные выше).(Fifth stage)

(Where
R _a ¹ , R ² , A and B have the meanings described above).

 Namely, the compound of general formula (VIII) obtained in the fourth step is reacted with a symmetric carbonyl compound, such as N, N-carbonyldiimidazole or diethyl carbonate, to produce the desired compound (IX) containing a cyclic urethane residue.

 As the reaction solvent, any organic solvent not participating in the reaction is used. Preferred solvents are esters, such as tetrahydrofurans.

The reaction temperature ranges from about 0 ^° C. to the boiling point of the solvent.

If R ¹ is a halogen atom, then the desired compound (1) can be obtained using the starting materials from the second stage.

(где
R_a ¹ и R² имеют значения, указанные выше), то оно может быть получено также следующим способом:
Первая стадия

(где
R_a ¹ имеет значения, описанные выше).The method of obtaining 2
If the desired compound is a compound of the following general formula (X):

(Where
R _a ¹ and R ² have the meanings indicated above), then it can also be obtained in the following way:
First stage

(Where
R _a ¹ has the meanings described above).

 Namely, o-aminothiophenol (XI) is reacted with a carboxylic acid or its reactive derivative (XII) according to the usual method to form a benzthiazole derivative of the general formula (XIII).

 Examples of reactive derivatives of carboxylic acids include acid chlorides, esters and nitriles.

 The reaction is carried out in any organic solvent that is not involved in the reaction. Preferred solvents are benzene, tetrahydrofuran, pyridine and chloroform.

The reaction temperature varies from about -20 ^{° C.} to the boiling point of the solvent.

 The resulting benzothiazole compound (XIII) can be converted according to the methods described for the second to fifth stages in the method of obtaining 1 with the formation of the desired compound (X).

(где
A, B и R² имеют значения, представленные выше), то оно может быть получено синтезом соединения общей формулы (XV):

по способу получения 2 с последующей обработкой по методам 1 или 2:

(Метод 1)
Соединение (XV) восстанавливают с комплексом гидрида металла, таким как три-трет-бутоксиалюмогидрид лития или триэтоксиалюмогидрид лития для восстановления только кетогруппы в лактонной группе до образования лактольного соединения (XVI). Хотя температура реакции может изменяться от температуры при охлаждении льдом до температуры кипения растворителя, наиболее предпочтительна комнатная температура. В реакции используют любой органический растворитель, пригодный для органического синтеза и инертный к реакции. Примеры особенно предпочтительных растворителей включают тетрагидрофуран, диэтиловый эфир и 1,2-диметоксиэтан.The method of obtaining 3
If the desired compound is a compound according to the general formula (XIV):

(Where
A, B and R ² have the meanings given above), then it can be obtained by synthesis of a compound of general formula (XV):

according to the method of obtaining 2, followed by processing according to methods 1 or 2:

(Method 1)
Compound (XV) is reduced with a metal hydride complex such as lithium tri-tert-butoxyaluminum hydride or lithium triethoxyaluminum hydride to restore only the keto group in the lactone group to form lactol compound (XVI). Although the reaction temperature may vary from temperature with ice cooling to the boiling point of the solvent, room temperature is most preferred. Any organic solvent suitable for organic synthesis and inert to the reaction is used in the reaction. Examples of particularly preferred solvents include tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane.

 The lactol compound (XVI) reacts with hydroxylamine hydrochloride in a solvent to form oxime (XVII). Although the reaction temperature may vary from temperature with ice cooling to the boiling point of the solvent, room temperature is most preferred. A solvent suitable for organic synthesis and inert to the reaction is used in the reaction. Examples of particularly preferred solvents include pyridine, water, methanol and ethanol. Solvents can be used either singly or in a mixture of two or more solvents.

 Oxime (XVII) is reacted with 1- (trifluoroacetyl) imidazole in a solvent to form the desired compound (XIV). Although the reaction temperature may vary from an ice cooling temperature to a boiling point of a solvent, an ice cooling temperature is preferred. Any solvent suitable for organic synthesis and inert to the reaction is used in the reaction. Examples of particularly preferred solvents include liquid ammonia, methanol, ethanol, propanol and isopropanol.

(Method 2)
Compound (XV) reacts with ammonia to produce amide (XVIII). Although the reaction temperature may vary from ice cooling to the boiling point of the solvent, room temperature is preferred. Any solvent suitable for organic synthesis and inert to the reaction is used. Examples of particularly preferred solvents include tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane.

 Amide (XVIII) is reacted with trifluoroacetic anhydride in a solvent and then treated with sodium bicarbonate to form the desired compound (XIV). Although the reaction temperature may vary from ice cooling to the boiling point of the solvent, room temperature is most preferred. Any solvent suitable for organic synthesis and inert to the reaction is used in the reaction. Examples of particularly preferred solvents include 1,4-dioxane, tetrahydrofuran and pyridine. The solvent may be used alone, a mixture of solvents, two or more may be used.

 Although the basic methods for preparing the compounds of the present invention are described above, the compounds of the present invention can also be obtained by various modifications of the above production methods, wherein the nitro group is introduced into the benzene ring and then the substituent is introduced into the second position.

 The substituent in the 2-position can be replaced using conventional methods such as oxidation, reduction or condensation.

 The following experimental examples illustrate the results of the present invention.

 Examples.

Determination of MAO inhibitory activity using rat forebrain:
The inhibitory activity of MAO was determined by the method of Prada et al. (J. Pharmacol. Exp. Ther., 248, 400-414 (1989)).

The enzymatic reaction was carried out in 300 μl of a solution having the following composition:
enzyme source - 20 μl
¹⁴ C-labeled enzymatic substrate - 80 μl
test compound - 200 μl
in total - 300 μl
A suspension of 1 part of the forebrain volume of male Wistar rats with 5 parts of 0.1M potassium phosphate buffer (pH 7.4) was used as an enzyme source. The enzyme source was mixed with the test compound and the mixture was kept for 10 minutes at 37 ^° C, then an enzymatic substrate was added to start the reaction, after 10 minutes 200 μl of 2N hydrochloric acid was added to complete the reaction.

Labeled ¹⁴ C MAO-A and MAO-B, 5-HT (serotonin) and PEA (β-phenylethylamine) were used as substrates. The specific radioactivity of 5-HT and PEA was regulated to 11.1 MBq / mmol and 29.6 MBq / mmol, respectively , and their concentration in the reaction is 200 μM and 20 μM, respectively.

 The test compound was dissolved in distilled water to obtain the concentration necessary in the reaction. If the test compound is not soluble in water, then it was dissolved in dimethyl sulfoxide to a concentration of 10%.

 Diethyl ether and n-heptane were used as radioactive metabolites formed by MAO-A and MAO-B, respectively. After the completion of the enzymatic reaction, 3 ml of solvent was added to the reaction mixture, shaken for 10 minutes. After centrifugation for 10 minutes at 3000 rpm, the lower aqueous layer was frozen with a dry ice / acetone mixture. The upper organic layer was separated by decantation and its radioactivity was determined using a liquid scintillation counter.

The results are shown in table. 1 and 2. The inhibitory activity of the tested compounds to MAO-A and MAO-B is given at concentrations of 10 ^-7 M and 10 ^-6 M or using IC ₅₀ values (see table. 1.2).

 From the above experimental examples, it can be seen that the compounds of the present invention are capable of selectively inhibiting MAO-A. Thus, oxazolidone derivatives, which are compounds of the present invention, are effective in the treatment of diseases requiring MAO inhibition, especially MAO-A inhibition. Examples of such diseases include depression, depressive neurosis, and a depressive state due to the effects of brain damage. In addition, the compounds of the present invention have an excellent antireserpine effect, which improves the therapeutic effect in the treatment of the diseases described above.

 Additionally, the compounds of the present invention have reduced toxicity and high safety, so from this point of view the invention is very valuable.

 The compounds of the present invention are used in the form of tablets, powder, granules, capsules, syrup or inhalation in the treatment or prevention of these diseases. The dose varies depending on symptoms, age, type of disease, etc., and is usually 0.1 to 1000 mg, preferably 1 to 500 mg, more preferably 1 to 100 mg, and most preferably 5 to 50 mg per day for an adult , and with a single injection or with the introduction of several servings per day.

 Formulations containing compounds are prepared by conventional methods with conventional pharmaceutical excipients.

 Namely, solid oral formulations are prepared by adding an excipient and, if necessary, a binding agent, a disintegrator, a lubricant, a color additive, a drug modifier, etc., to the active ingredient and molding the resulting mixture into tablets, coated tablets , granules, powder or capsules.

 Excipient polymers include lactose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose, and silicon dioxide. Examples of binding agents are polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxymethyl cellulose, calcium citrate, dextrin and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and vegetable grease. As color additives use additives approved for use in medicine. As drug modifiers include cocoa powder, methanol, aromatic powder, menthol oil, borneol and cinnamon powder. Such tablets and granules may be coated with sugar, gelatin or other similar materials.

 Injections for subcutaneous, intramuscular or intravenous administration are obtained by conventional methods, by adding to the active ingredient, if necessary, a pH regulator, buffer, stabilizer, etc.

Examples
The following examples further illustrate the present invention, but the invention is not limited to them.

 Examples of the preparation of starting compounds used for the synthesis of the desired compounds are also given below.

 In the examples, the designations "Me" and "Et" represent a methyl group and an ethyl group, respectively.

60 г 2-аминотиофенола и 36,6 г гликолевой кислоты нагревают в течение 12 часов при 130^oC в герметичном сосуде. Продукт реакции растворяют в этилацетате, сушат над сульфатом натрия, растворитель упаривают в вакууме, остаток перекристаллизовывают из диизопропилового эфира и получают 55 г названного соединения в форме белых кристаллов.Examples of the preparation of starting compounds
Example 1
2-hydroxymethylbenzothiazole

60 g of 2-aminothiophenol and 36.6 g of glycolic acid are heated for 12 hours at 130 ^° C. in a sealed vessel. The reaction product was dissolved in ethyl acetate, dried over sodium sulfate, the solvent was evaporated in vacuo, the residue was recrystallized from diisopropyl ether to obtain 55 g of the title compound in the form of white crystals.

¹ H-NMR (CDCl ₃ ) δ:
3.54 (1H, t), 5.08 (2H, t), 7.38 (1H, t), 7.47 (1H, t), 7.88 (1H, d), 7.97 (1H, d).

К 41 г 2-гидроксиметилбензотиазола, полученного в Примере 1, в 55 мл концентрированной серной кислоты, прибавляют по каплям 24 мл концентрированной азотной кислоты (удельный вес: 1.42), поддерживая температуру реакции при 40^oC или ниже, перемешивают 1 час, выливают в смесь лед-вода и экстрагируют этилацетатом. Экстракт сушат над сульфатом натрия, упаривают в вакууме и получают твердый осадок, который перекристаллизовывают из этилацетата и получают 15 г названного соединения.Example 2
6-nitro-2-hydroxymethylbenzothiazole

To 41 g of 2-hydroxymethylbenzothiazole obtained in Example 1, in 55 ml of concentrated sulfuric acid, 24 ml of concentrated nitric acid (specific gravity: 1.42) was added dropwise, maintaining the reaction temperature at 40 ^° C. or lower, stirred for 1 hour, poured into ice-water mixture and extracted with ethyl acetate. The extract was dried over sodium sulfate, evaporated in vacuo to give a solid precipitate, which was recrystallized from ethyl acetate to give 15 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
2.37 (1H, s), 5.07 (2H, s), 8.05 (1H, d), 8.35 (1H, dd), 8.86 (1H, d).

К раствору 15 г 6-нитро-2-гидроксиметилбензотиазола, полученного в Примере 2, и 11 мл триэтиламина в тетрагидрофуране при 10^oC прибавляют по каплям 9 мл бензоилхлорида, перемешивают 1 час при комнатной температуре, прибавляют воду и экстрагируют этилацетатом. Экстракт сушат над сульфатом натрия, упаривают в вакууме. Остаток хроматографируют на колонке с силикагелем (растворитель: дихлорметанол/метанол) и получают 10 г названного соединения.Example 3
6-nitro-2-benzoyloxymethylbenzothiazole

To a solution of 15 g of 6-nitro-2-hydroxymethylbenzothiazole obtained in Example 2 and 11 ml of triethylamine in tetrahydrofuran at 10 ^° C., 9 ml of benzoyl chloride are added dropwise, stirred for 1 hour at room temperature, water is added and extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column (solvent: dichloromethanol / methanol) to obtain 10 g of the title compound.

10 г 6-нитро-2-бензоилоксиметилбензотиазола, полученного в Примере 3, в растворе смеси этилацетата и этанола (1 : 1) гидрируют в течение 10 часов в присутствии 1 г катализатора (палладия на углероде). После окончания реакции катализатор отфильтровывают через целит, фильтрат упаривают в вакууме и получают 8,7 г названного соединения.Example 4
6-amino-2-benzoyloxymethylbenzothiazole

10 g of 6-nitro-2-benzoyloxymethylbenzothiazole obtained in Example 3 in a solution of a mixture of ethyl acetate and ethanol (1: 1) is hydrogenated for 10 hours in the presence of 1 g of a catalyst (palladium on carbon). After completion of the reaction, the catalyst was filtered off through celite, the filtrate was evaporated in vacuo to give 8.7 g of the title compound.

Смесь 8.7 г 6-амино-2-бензоилоксиметилбензотиазола, полученного в Примере 4, и 3 г метилового эфира глицидной кислоты кипятят 3 часа в этаноле, упаривают в вакууме, хроматографируют на колонке с силикагелем (растворитель: дихлорметан/метанол) и получают 6.2 г названного соединения.Example 5
N- (2-Benzoyloxymethylbenzothiazol-6-yl) -2-hydroxy-3-methoxypropylamine

A mixture of 8.7 g of 6-amino-2-benzoyloxymethylbenzothiazole obtained in Example 4 and 3 g of glycidic acid methyl ester is boiled for 3 hours in ethanol, evaporated in vacuo, chromatographed on a silica gel column (solvent: dichloromethane / methanol) to obtain 6.2 g of the titled connections.

Хлорангидрид, полученный при обработке (S)-(+)-5-оксо-2-тетрагидрофуранкарбоновой кислоты тионилхлоридом, прибавляют по каплям при охлаждении льдом к раствору 600 г 2-аминотиофенола в 1500 мл пиридина, перемешивают 3 часа при комнатной температуре, выливают в лед/воду, образовавшийся осадок отфильтровывают, промывают водой, затем эфиром, перекристаллизовывают из ацетона и диизопропилового эфира и получают 504 г названного соединения.Example 6
2- (5-Oxotetrahydrofuran-2-yl) benzothiazole

The acid chloride obtained by treating (S) - (+) - 5-oxo-2-tetrahydrofurancarboxylic acid with thionyl chloride is added dropwise under ice-cooling to a solution of 600 g of 2-aminothiophenol in 1500 ml of pyridine, stirred for 3 hours at room temperature, poured into ice / water, the precipitate formed is filtered off, washed with water, then with ether, recrystallized from acetone and diisopropyl ether and 504 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
2.6 ~ 2.9 (4H, m), 5.8 ~ 5.9 (1H, m), 7.45 (1H, t), 7.52 (1H, t), 7.95 (1H, d), 8.04 (1H, d).

К раствору 504 г 2-(5-оксотетрагирдофуран-2-ил)бензотиазола, полученного в Примере 6, в 2000 мл концентрированной серной кислоты прибавляют по каплям при -5 - 0^oC 188 мл концентрированной азотной кислоты, перемешивают 30 минут в этих условиях, 2 часа при 0^oC, реакционную смесь выливают в приблизительно 30 л лед/вода. Образовавшийся осадок отфильтровывают, промывают водой, затем этанолом, сушат и получают 488 г названного соединения.Example 7
6-Nitro-2- (5-oxotetrahydrofuran-2-yl) benzothiazole

To a solution of 504 g of 2- (5-oxo-tetrahydrofuran-2-yl) benzothiazole obtained in Example 6 in 2000 ml of concentrated sulfuric acid, 188 ml of concentrated nitric acid is added dropwise at -5 - 0 ^° C, and stirred for 30 minutes under these conditions , 2 hours at 0 ^o C, the reaction mixture is poured into approximately 30 l of ice / water. The precipitate formed is filtered off, washed with water, then with ethanol, dried and 488 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
2.6 ~ 3.0 (4H, m), 5.8 ~ 6.0 (1H, m), 8.13 (1H, d), 8.40 (1H, dd), 8.88 (1H, d).

Суспензию 388 г 6-нитро-2-(5-оксотетрагирдофуран-2-ил)бензотиазола, полученного в Примере 7, в 6000 мл диоксана гидрируют в течение 48 часов в присутствии 30 г 10% палладия на углероде при комнатной температуре при атмосферном давлении. Катализатор отфильтровывают, растворитель упаривают, полученный твердый остаток перекристаллизовывают из ацетона и диизопропилового эфира и получают 300 г названного соединения.Example 8
6-amino-2- (5-oxotetrahydrofuran-2-yl) benzothiazole

A suspension of 388 g of 6-nitro-2- (5-oxotetrahydrofuran-2-yl) benzothiazole obtained in Example 7 in hydrogen 6000 ml of dioxane is hydrogenated for 48 hours in the presence of 30 g of 10% palladium on carbon at room temperature at atmospheric pressure. The catalyst is filtered off, the solvent is evaporated, the obtained solid residue is recrystallized from acetone and diisopropyl ether and 300 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
2.6 ~ 2.9 (4H, m), 5.8 ~ 5.9 (1H, m), 7.08 (1H, dd), 7.58 (1H, d), 7.85 (1H, d).

К 300 г 2-хлорбензотиазола в 1500 мл концентрированной серной кислоте прибавляют по каплям при 0^o - 10^oC 134 мл концентрированной азотной кислоты, перемешивают 1 час, выливают в лед/воду. Образовавшийся осадок отфильтровывают, промывают водой, затем ацетоном, сушат и получают 380 г названного соединения.Example 9
2-chloro-6-nitrobenzothiazole

To 300 g of 2-chlorobenzothiazole in 1500 ml of concentrated sulfuric acid, 134 ml of concentrated nitric acid is added dropwise at 0 ^° - 10 ^° C, stirred for 1 hour, poured into ice / water. The precipitate formed is filtered off, washed with water, then with acetone, dried and 380 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
8.07 (1H, d), 8.39 (1H, dd), 8.76 (1H, d).

К смеси 68 г 2-хлор-6-нитробензотиазола, полученного в Примере 9, 50 г этил изонипекотата в 300 мл этанола и 300 мл тетрагидрофурана прибавляют 50 г бикарбоната натрия, кипятят 3 часа, выливают в лед/воду и экстрагируют этилацетатом. Экстракт промывают водным солевым раствором, упаривают в вакууме, остаток хроматографируют на колонке и получают 106 г названного соединения.Example 10
Ethyl N- (6-nitrobenzothiazol-2-yl) isonipecotate

To a mixture of 68 g of 2-chloro-6-nitrobenzothiazole obtained in Example 9, 50 g of ethyl isonipecotate in 300 ml of ethanol and 300 ml of tetrahydrofuran were added 50 g of sodium bicarbonate, boiled for 3 hours, poured into ice / water and extracted with ethyl acetate. The extract was washed with aqueous saline, evaporated in vacuo, the residue was chromatographed on a column to obtain 106 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
1.27 (3H, t), 1.8 ~ 2.0 (2H, m), 2.0 ~ 2.1 (2H, m), 2.6 ~ 2.7 (1H, m), 3.3 ~ 3.4 (2H, m), 4.1 ~ 4.2 (2H, m) ), 4.18 (2H, q), 7.50 (1H, d), 8.20 (1H, dd), 8.50 (1H, d).

К 106 г этил N-(6-нитробензотиазол-2-ил)изонипекотата, полученного в Примере 10, в 300 мл этанола прибавляют 150 мл 5 М водного раствора гидроокиси натрия, нагревают 3 часа, выливают в разбавленную соляную кислоту. Образовавшийся осадок отфильтровывают, промывают водой, затем эфиром, сушат и получают 96 г названного соединения.Example 11
N- (6-nitrobenzothiazol-2-yl) isonipecotinic acid

To 106 g of ethyl N- (6-nitrobenzothiazol-2-yl) isonipecotate obtained in Example 10, 150 ml of 5 ml of 5 M aqueous sodium hydroxide solution are added to 300 ml of ethanol, heated for 3 hours, and poured into dilute hydrochloric acid. The precipitate formed is filtered off, washed with water, then with ether, dried and 96 g of the title compound are obtained.

:
1.6 ~ 1.8 (2H, м), 1.9 ~ 2.1 (2H, м), 2.5 ~ 2.7 (1H, м), 3.2 ~ 3.5 (2H, м), 4.0 ~ 4.2 (2H, м), 7.47 (1H, м), 8.13 (1H, дд), 8.70 (1H, д). ¹ H-NMR (CDCl ₃ )

:
1.6 ~ 1.8 (2H, m), 1.9 ~ 2.1 (2H, m), 2.5 ~ 2.7 (1H, m), 3.2 ~ 3.5 (2H, m), 4.0 ~ 4.2 (2H, m), 7.47 (1H, m ), 8.13 (1H, d), 8.70 (1H, d).

К суспензии 90 г N-(6-нитробензотиазол-2-ил)изонипекотиновой кислоты, полученной в Примере 11, в 500 мл тетрагидрофурана и 1000 мл диметилформамида добавляют 100 мл триэтиламина и прибавляют по каплям при -20^oC 45 мл изобутилхлоркарбоната, перемешивают 20 минут, вносят 100 мл концентрированного водного аммиака при -40^oC, перемешивают 20 минут. Реакционную смесь выливают в лед/воду, образовавшийся осадок фильтруют, промывают водой, затем эфиром, сушат и получают 75 г названного соединения.Example 12
N- (6-Nitrobenzothiazol-2-yl) isonipecotamide

To a suspension of 90 g of N- (6-nitrobenzothiazol-2-yl) isonipecotinic acid obtained in Example 11 in 500 ml of tetrahydrofuran and 1000 ml of dimethylformamide, 100 ml of triethylamine was added and 45 ml of isobutyl chlorocarbonate was added dropwise at -20 ^° C, and stirred 20 minutes, add 100 ml of concentrated aqueous ammonia at -40 ^o C, mix for 20 minutes. The reaction mixture was poured into ice / water, the precipitate formed was filtered, washed with water, then with ether, dried and 75 g of the title compound were obtained.

¹ H-NMR (d ₆ -DMCO) δ:
1.5 ~ 1.7 (2H, m), 1.9 ~ 2.0 (2H, m), 2.5 ~ 2.7 (1H, m), 3.2 ~ 3.4 (2H, m), 3.9 ~ 4.1 (2H, m), 7.47 (1H, d ), 8.13 (1H, d), 8.78 (1H, d).

К 75 г N-(6-нитробензотиазол-2-ил)изонипекотамида, полученного в Примере 12, в 700 мл диметилформамида прибавляют 50 г п-толуолсульфонилхлорида, нагревают 20 минут при 110^oC, выливают в лед/воду, нейтрализуют гидроокисью натрия. Образовавшийся осадок отфильтровывают, промывают водой и затем эфиром, сушат и получают 60 г названного соединения.Example 13
N- (6-Nitrobenzothiazol-2-yl) -4-cyanopiperidine

To 75 g of N- (6-nitrobenzothiazol-2-yl) isonipecotamide obtained in Example 12, in 50 ml of dimethylformamide, 50 g of p-toluenesulfonyl chloride are added, heated for 20 minutes at 110 ^° C., poured into ice / water, and neutralized with sodium hydroxide. The precipitate formed is filtered off, washed with water and then with ether, dried, and 60 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
2.0 ~ 2.2 (4H, m), 3.0 ~ 3.1 (1H, m), 3.7 ~ 3.8 (2H, m), 3.9 ~ 4.0 (2H, m), 7.52 (1H, d), 8.20 (1H, dd), 8.50 (1H, d).

Смесь 60 г N-(6-нитробензотиазол-2-ил)-4-цианопиперидина, полученного в Примере 13, и 2000 мл диоксана гидрируют 2 часа в присутствии 3 г 10% палладия на углероде при комнатной температуре и атмосферном давлении. Катализатор отфильтровывают, раствор упаривают в вакууме и получают 51 г названного соединения.Example 14
N- (6-Aminobenzothiazol-2-yl) -4-cyanopiperidine

A mixture of 60 g of N- (6-nitrobenzothiazol-2-yl) -4-cyanopiperidine obtained in Example 13 and 2000 ml of dioxane is hydrogenated for 2 hours in the presence of 3 g of 10% palladium on carbon at room temperature and atmospheric pressure. The catalyst was filtered off, the solution was evaporated in vacuo to give 51 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
1.9 ~ 2.1 (4H, m), 2.8 ~ 3.0 (1H, m), 3.5 ~ 3.6 (2H, m), 3.70 (2H, m), 3.7 ~ 3.9 (2H, m), 6.70 (1H, dd), 6.95 (1H, d); 7.37 (1H, d).

Смесь 6.2 г N-(2-бензоилоксиметилбензотиазол-6-ил)-2-гидрокси- 3-метоксипропиламина, полученного в Примере 5, и 4 г карбонилдиимидазола кипятят 3 часа в тетрагидрофуране, прибавляют по каплям 0.5 мл воды, раствор кипятят дополнительно 1 час, выливают в лед/воду, экстрагируют этилацетатом. Экстракт сушат над сульфатом натрия, раствор упаривают в вакууме, остаток хроматографируют на колонке с силикагелем (растворитель: н-гексан/этилацетат) и получают 4 г названного соединения.Example 1
3- (2-Benzoyloxymethylbenzothiazol-6-yl) -5-methoxymethyl-2-oxazolidinone

A mixture of 6.2 g of N- (2-benzoyloxymethylbenzothiazol-6-yl) -2-hydroxy-3-methoxypropylamine obtained in Example 5 and 4 g of carbonyldiimidazole are boiled for 3 hours in tetrahydrofuran, 0.5 ml of water is added dropwise, the solution is boiled for an additional 1 hour , poured into ice / water, extracted with ethyl acetate. The extract was dried over sodium sulfate, the solution was evaporated in vacuo, the residue was chromatographed on a silica gel column (solvent: n-hexane / ethyl acetate), and 4 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ ) δ:
3.45 (3H, s), 3.68 (2H, d), 4.03 (1H, dd), 4.14 (1H, t), 4.80 (1H, m), 5.73 (2H, s), 7.49 (2H, m), 7.62 (2H, m), 8.08 (1H, d), 8.13 (2H, m), 8.28 (1H, d).

К раствору 4.7 г 3-(2-бензоилоксиметилбензотиазол-6-ил)-5- метоксиметил-2-оксазолидинона, полученного в примере 1, в метанола/диоксане (1:1) прибавляют 7.5 мл 2 N NaOH водного раствора, перемешивают 2 часа, метанол упаривают в вакууме и экстрагируют этилацетатом. Экстракт сушат, раствор упаривают в вакууме и получают 3.25 г названного соединения.Example 2
3- (2-Hydroxymethylbenzothiazol-6-yl) -5-methoxymethyl-2-oxazolidinone

To a solution of 4.7 g of 3- (2-benzoyloxymethylbenzothiazol-6-yl) -5-methoxymethyl-2-oxazolidinone obtained in Example 1 in methanol / dioxane (1: 1) 7.5 ml of 2 N NaOH aqueous solution was added, stirred for 2 hours , methanol was evaporated in vacuo and extracted with ethyl acetate. The extract was dried, the solution was evaporated in vacuo to give 3.25 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
3.44 (3H, s), 3.68 (2H, d), 4.02 (1H, dd), 4.14 (1H, t), 4.80 (1H, m), 5.06 (2H, d), 7.52 (1H, dd), 7.90 (1H, d), 8.21 (1H, d).

Смесь 0.6 г 3-(2-гидроксиметилбензотиазол)-6-ил)-5- метоксиметил-2-оксазолидинона, полученного в Примере 2, 0.15 мл бромацетонитрила и 1.5 мл 2 N водного раствора гидроокиси натрия перемешивают 3 часа при комнатной температуре, добавляют воду и экстрагируют этилацетатом. Экстракт сушат над сульфатом натрия, раствор упаривают в вакууме, хроматографируют на колонке с силикагелем (растворитель: гексан/этилацетат) и получают 0.35 г названного соединения.Example 3
3 - [(2-Cyanomethyloxymethylbenzothiazole) -6-yl] -5-methoxymethyl-2-oxazolidinone

A mixture of 0.6 g of 3- (2-hydroxymethylbenzothiazole) -6-yl) -5-methoxymethyl-2-oxazolidinone obtained in Example 2, 0.15 ml of bromoacetonitrile and 1.5 ml of a 2 N aqueous sodium hydroxide solution was stirred for 3 hours at room temperature, water was added and extracted with ethyl acetate. The extract was dried over sodium sulfate, the solution was evaporated in vacuo, chromatographed on a silica gel column (solvent: hexane / ethyl acetate), and 0.35 g of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ:
3.45 (3H, s), 3.68 (2H, d), 4.02 (1H, dd), 4.14 (1H, t), 4.46 (2H, s), 4.80 (1H, m), 5.03 (2H, s), 7.60 (1H, dd), 8.00 (1H, d), 8.28 (1H, d).

Смесь 0.6 г 3-(2-гидроксиметилбензотиазол-6-ил)-5-метоксиметил- 2-оксазолидинона, полученного в примере 2, и 0.47 г пятиокиси фосфора перемешивают 1 час при охлаждении льдом, выливают в лед/воду и экстрагируют этилацетатом. Органический слой промывают водой, сушат над сульфатом натрия, упаривают в вакууме и получают маслообразный остаток, который растворяют в диметилформамиде. К раствору добавляют 0.21 г цианометиламина гидрохлорида и 0.61 мл триэтиламина, нагревают 24 часа при 60^oC, охлаждают, вносят воду и экстрагируют этилацетатом. Органический слой упаривают, хроматографируют на колонке с силикагелем (растворитель: дихлорметан/метанол) и получают 0.2 г названного соединения.Example 4
3 - [(2-Cyanomethylaminomethylbenzothiazole) -6-yl] -5- methoxymethyl-2-oxazolidinone

A mixture of 0.6 g of 3- (2-hydroxymethylbenzothiazol-6-yl) -5-methoxymethyl-2-oxazolidinone obtained in Example 2 and 0.47 g of phosphorus pentoxide are stirred for 1 hour under ice-cooling, poured into ice / water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, evaporated in vacuo to give an oily residue, which was dissolved in dimethylformamide. To the solution was added 0.21 g of cyanomethylamine hydrochloride and 0.61 ml of triethylamine, heated for 24 hours at 60 ^° C., cooled, water was added and extracted with ethyl acetate. The organic layer was evaporated, chromatographed on a silica gel column (solvent: dichloromethane / methanol), and 0.2 g of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ:
3.45 (3H, s), 3.68 (2H, d), 3.78 (2H, d), 4.03 (1H, dd), 4.16 (1H, t), 4.37 (2H, d), 4.81 (1H, m), 7.56 (1H, dd), 7.97 (1H, d), 8.28 (1H, d).

Example 5
3- [2- (5-Oxotetrahydrofuran-2-yl) benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone
A mixture of 300 g of 6-amino-2- (5-oxotetrahydrofuran-2-yl) benzothiazole obtained in the Starting materials. Example 8 in 200 ml of ethanol and 146 g of (S) - (-) - glycidic acid methyl ester is boiled for 10 hours, the solvent is evaporated off under vacuum, 8 L of ethyl acetate is added to the residue. The resulting solution was passed through a column of silica gel, the eluate was evaporated in vacuo and an oily residue was obtained, which was dissolved in 2500 ml of tetrahydrofuran, 166 g of 1,1'-carbonyldiimidazole were added, boiled for 2 hours, water was carefully added, boiled for 1 hour, evaporated in vacuo to 1/3 of the original volume, poured into ice / water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, aqueous sodium bicarbonate, aqueous saline, dried over magnesium sulfate, evaporated, the residue was chromatographed on a silica gel column (methylene chloride / ethanol) to obtain 166 g of the title compound.

¹ NMR (CDCl ₃ ) δ:
2.6 ~ 2.9 (4H, m), 3.43 (3H, s), 3.68 (2H, d), 4.0 ~ 4.2 (2H, m), 4.7 ~ 4.9 (1H, m), 5.8 ~ 5.9 (1H, m), 7.88 (1H, m), 8.00 (1H, d), 8.24 (1H, m).

К 2.1 мл метилового эфира (S)-(-)-глицидной кислоты в 25 мл ацетонитрила прибавляют 5.2 г перхлората магния, перемешивают 10 минут при комнатной температуре, добавляют 5 г 6-амино-2-(5-оксотетрагидрофуран-2-ил)-бензотиазола, полученного в Исходные. Примере 8, перемешивают 30 минут при комнатной температуре, выливают в воду и экстрагируют этилацетатом. Органический слой промывают насыщенным водным солевым раствором, сушат, растворитель упаривают и получают 6.5 г маслообразного остатка. Остаток растворяют в 30 мл тетрагидрофурана, прибавляют 4.3 г 1,1'-карбонилдиимидазола, кипятят 1 час, охлаждают, упаривают в вакууме. Остаток обрабатывают метиленхлоридом, промывают водой, сушат, растворитель упаривают в вакууме, остаток хроматографируют на колонке с силикагелем, перекристаллизовывают из ацетона/изопропилового эфира и получают 3.8 г названного соединения.Example 5

Example 6
3- [2- (5-Oxotetrahydrofuran-2 (S) -yl) benzothiazol-6-yl] - 5 (R) -methoxymethyl-2-oxazolidinone

5.2 g of magnesium perchlorate are added to 2.1 ml of (S) - (-) - glycidic acid methyl ester in 25 ml of acetonitrile, stirred for 10 minutes at room temperature, 5 g of 6-amino-2- (5-oxotetrahydrofuran-2-yl) is added -benzothiazole obtained in the source. Example 8, stirred for 30 minutes at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous saline, dried, the solvent was evaporated, and 6.5 g of an oily residue was obtained. The residue is dissolved in 30 ml of tetrahydrofuran, 4.3 g of 1,1'-carbonyldiimidazole are added, boiled for 1 hour, cooled, evaporated in vacuo. The residue was taken up in methylene chloride, washed with water, dried, the solvent was evaporated in vacuo, the residue was chromatographed on a silica gel column, recrystallized from acetone / isopropyl ether to give 3.8 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
2.6 ~ 2.9 (4H, m), 3.43 (3H, s), 3.68 (2H, d), 4.0 ~ 4.2 (2H, m), 4.7 ~ 4.9 (1H, m), 5.8 ~ 5.9 (1H, m), 8.00 (1H, d), 8.24 (1H, m).

К раствору 160 г 3-[2-(5-оксотетрагидрофуран-2-ил)бензотиазол- 6-ил]-5-метоксиметил-2-оксазолидинона, полученного в примере 5, в 3000 мл тетрагидрофурана прибавляют по каплям 900 мл 1 M раствора три-трет-бутоксиалюмогидрида лития в тетрагидрофуране, перемешивают 2 часа при комнатной температуре, выливают в лед/воду, нейтрализуют разбавленной соляной кислотой и экстрагируют этилацетатом. Экстракт промывают водным бикарбонатом натрия, затем водным солевым раствором, сушат над сульфатом магния и упаривают в вакууме. Остаток хроматографируют на колонке с силикагелем (метиленхлорид/этанол) и получают 72 г названного соединения.Example 7
3- [2- (5-Hydroxytetrahydrofuran-2-yl) benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone

To a solution of 160 g of 3- [2- (5-oxo-tetrahydrofuran-2-yl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone obtained in Example 5, in 900 ml of tetrahydrofuran, 900 ml of a 1 M solution are added dropwise. lithium tri-tert-butoxyaluminohydride in tetrahydrofuran, stirred for 2 hours at room temperature, poured into ice / water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, then with aqueous saline, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column (methylene chloride / ethanol) to give 72 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
2.0 ~ 2.8 (4H, m), 3.44 (3H, s), 3.68 (2H, d), 4.0 ~ 4.2 (2H, m) 4.7 ~ 4.9 (1H, m), 5.42 (1 / 2H, t), 5.60 (1 / 2H, q), 5.73 (1 / 2H broad s), 5.85 (1 / 2H, broad s), 7.5. ~ 7.6 (1H, m), 7.9 ~ 8.0 (1H, m), 8.2 ~ 8.3 (1H, m).

К раствору 72 г 3-[2-(5-гидрокситетрагидрофуран-2-ил)бензотиазол- 6-ил] -5-метоксиметил-2-оксазолидинона, полученного в примере 7, в 150 мл пиридина прибавляют 18.6 г гидрохлорида гидроксиламина, перемешивают 10 минут при комнатной температуре, выливают в лед/воду, экстрагируют этилацетатом. Экстракт промывают разбавленной соляной кислотой, водным раствором бикарбоната натрия, водным солевым раствором, сушат над сульфатом натрия и упаривают в вакууме. Остаток перекристаллизовывают из ацетона/диизопропилового эфира и получают 73 г названного соединения.Example 8
3- [2- (1-Hydroxy-4-hydroxyiminobutyl) benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone

To a solution of 72 g of 3- [2- (5-hydroxytetrahydrofuran-2-yl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone obtained in Example 7, 18.6 g of hydroxylamine hydrochloride are added in 150 ml of pyridine, stirred 10 minutes at room temperature, poured into ice / water, extracted with ethyl acetate. The extract is washed with dilute hydrochloric acid, aqueous sodium bicarbonate, aqueous saline, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from acetone / diisopropyl ether to give 73 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ:
2.0 ~ 2.3 (2H, m), 3.42 (3H, s), 3.6 ~ 3.8 (2H, m), 4.0 ~ 4.2 (2H, m), 4.8 ~ 4.9 (1H, m), 5.0 ~ 5.1 (1H, m) ), 5.85 (1 / 4H, d), 6.00 (3 / 4H, d), 7.5 ~ 7.7 (1H, m), 7.90 (1H, d), 8.20 (1H, d), 10.05 (3/4, s ), 10.40 (1/4, m).

К раствору 73 г 3-[2-(1-гидрокси-3-гидроксииминопропил)бензотиазол- 6-ил] -5-метоксиметил-2-оксазолидинона, полученного в примере 8, в 800 мл тетрагидрофурана прибавляют по каплям при охлаждении льдом 90 г трифторацетилимидазола, перемешивают 4 часа при комнатной температуре, выливают в водный раствор бикарбоната натрия и экстрагируют этилацетатом. Экстракт промывают водным солевым раствором, сушат над сульфатом магния, упаривают в вакууме, полученный остаток перекристаллизовывают из ацетона/воды и получают 51 г названного соединения.Example 9
3- [2- (1 (S) -Hydroxy-3-cyanopropyl) benzothiazol-6-yl] - 5 (R) -methoxymethyl-2-oxazolidinone

To a solution of 73 g of 3- [2- (1-hydroxy-3-hydroxyiminopropyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone obtained in Example 8 in 800 ml of tetrahydrofuran 90 g are added dropwise under ice-cooling trifluoroacetylimidazole, stirred for 4 hours at room temperature, poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with aqueous saline, dried over magnesium sulfate, evaporated in vacuo, the obtained residue was recrystallized from acetone / water, and 51 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ ) δ:
2.1 ~ 2.4 (2H, m), 2.5 ~ 2.7 (2H, m), 3.42 (3H, s), 3.6 ~ 3.7 (2H. M), 3.9 ~ 4.1 (2H, m), 3.60 (1H, d), 4.7 ~ 4.9 (1H, m), 5.1 ~ 5.2 (1H, m), 7.50 (1H, dd), 7.83 (1H, d), 8.15 (1H, d). so pl. 74 - 75 ^o C.

К 50 мл жидкого аммиака в герметичном сосуде при -78^oC прибавляют 2.9 г 3-[2-(5-гидрокситетрагидрофуран-2-ил)бензотиазол- 6-ил] -5-метоксиметил-2-оксазолидинона, герметизируют, перемешивают 3 часа при комнатной температуре, аммиак медленно упаривают. К остатку добавляют ацетон, выпавшие кристаллы отфильтровывают, сушат и получают 2,6 г названного соединения.Example 10
3- [2- (1 (S) -Hydroxy-3-carbamoylpropyl) benzothiazol-6-yl] - 5 (R) -methoxymethyl-2-oxazolidinone

2.9 g of 3- [2- (5-hydroxytetrahydrofuran-2-yl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone are added to 50 ml of liquid ammonia in a sealed vessel at -78 ^° C, sealed, stirred for 3 hours at room temperature, ammonia is slowly evaporated. Acetone was added to the residue, the precipitated crystals were filtered off, dried, and 2.6 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ ) δ:
1.90 (1H, m), 2.20 (3H, m), 3.35 (3H, s), 3.60 (2H, m), 3.85 (1H, t), 4.20 (1H, t), 4.80 ~ 4.90 (2H, m) 6.25 (1H, d), 6.80 (1H, s), 7.30 (1H, s), 7.75 (1H, d), 7.90 (1H, d), 8.20 (1H, s).

so pl. 170 - 171 ^o C.

К суспензии 2.0 г 3-[2-(1(S)-гидрокси-3-карбамоилпропил)- бензотиазол-6-ил]-5(R)-метоксиметил-2-оксазолидинона в смеси 20 мл 1.4-диоксана и 3.6 мл пиридина прибавляют по каплям в течение 20 минут при охлаждении льдом 2.0 мл ангидрида трифторуксусной кислоты, перемешивают 2 часа при комнатной температуре, реакционную смесь прибавляют к насыщенному водному раствору бикарбоната натрия и экстрагируют этилацетатом. Органический слой промывают разбавленной соляной кислотой, затем насыщенным солевым водным раствором и сушат. Растворитель упаривают, остаток кристаллизуют из ацетона/воды и получают 1.6 г названного соединения.Example 11
3- [2- (1 (S) -Hydroxy-3-cyanopropyl) benzothiazol-6-yl] - 5 (R) -methoxymethyl-2-oxazolidinone

To a suspension of 2.0 g of 3- [2- (1 (S) -hydroxy-3-carbamoylpropyl) -benzothiazol-6-yl] -5 (R) -methoxymethyl-2-oxazolidinone in a mixture of 20 ml of 1.4-dioxane and 3.6 ml of pyridine 2.0 ml of trifluoroacetic acid anhydride are added dropwise over 20 minutes under ice-cooling, stirred for 2 hours at room temperature, the reaction mixture is added to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, then with saturated brine, and dried. The solvent was evaporated, the residue was crystallized from acetone / water to give 1.6 g of the title compound.

К раствору 3,48 г 3-[2-(5-оксотетрагидрофуран-2- ил)бензотиазол-6-ил]-5-метоксиметил-2-оксазолидинона, полученного в примере 5 в 20 мл безводного тетрагидрофурана при -50^oC прибавляют по каплям 30 мл 1.0 М раствора диизобутилалюмогидрида в тетрагидрофуране, перемешивают 30 минут, обрабатывают по обычной методике и после перекристаллизации получают 2.8 г 3-[2-(1.4-дигидроксибутил)бензотиазол-6-ил)-5-метоксиметил-2- оксазолидинона.Example 12
3- [2- (1-hydroxy-4-cyanobutyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone

To a solution of 3.48 g of 3- [2- (5-oxo-tetrahydrofuran-2-yl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone obtained in Example 5 in 20 ml of anhydrous tetrahydrofuran at -50 ^° C was added dropwise 30 ml of a 1.0 M solution of diisobutylaluminohydride in tetrahydrofuran, stirred for 30 minutes, treated in the usual manner and after recrystallization, 2.8 g of 3- [2- (1.4-dihydroxybutyl) benzothiazol-6-yl) -5-methoxymethyl-2-oxazolidinone are obtained.

¹ H-NMR (CDCl ₃ ) δ:
1.80 (2H, m), 2.00 (2H, m), 3.40 (3H, s), 3.60 ~ 3.80 (4H, m), 3.95 (1H, t), 4.10 (1H, t), 4.80 (1H, m) 5.10 (1H, m), 7.50 (1H, dd), 7.80 (1H, d), 8.05 (1H, d).

so pl. 137 - 138 ^o C
To 2.8 g of 3- [2- (1.4-dihydroxybutyl) -benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone thus obtained, 1 ml of anhydrous triethylamine is added to 20 ml of anhydrous methylene chloride, 0.6 0.6 slowly added with ice-cooling ml of methanesulfonyl chloride, stirred for 30 minutes, add 100 ml of ether, filtered and evaporated. The residue is dissolved in 15 ml of dimethyl sulfoxide, 1.5 g of potassium cyanide are added, heated for 3 hours at 80 ^o C, cooled, treated in the usual manner, purified and 1.5 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ:
1.90 (2H, m), 2.0 ~ 2.2 (2H, m), 2.40 (2H, t), 3.40 (3H, s), 3.65 (2H, m), 4.00 (1H, t), 4.15 (1H, t) , 4.80 (1H, m), 5.10 (1H, m), 7.50 (1H, m), 7.90 (1H, t), 8.20 (1H, m).

Смесь 22 г N-(6-аминобензотиазол-2-ил)-4-цианопиперидина, полученного в Исходные. Примере 14, и 11.2 мл (R)-(-)-глициновой кислоты метилового эфиров 400 мл этанола, кипятят 10 часов, этанол упаривают в вакууме, вносят 300 мл тетрагидрофурана, затем 17 г 1,1'-карбонилдиимидазола кипятят 30 минут, добавляют 50 мл воды, кипятят 30 минут, упаривают до 1/3 начального объема, выливают в лед/воду и экстрагируют этилацетатом. Экстракт промывают водой, сушат над сульфатом магния, растворитель упаривают в вакууме и очищают хроматографией на колонке с силикагелем (растворитель метиленхлорид/этанол) и получают 6.2 г названного соединения (свободного).Example 13
(R) -3- [2- (4-Cyanopiperidino) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone hydrochloride

A mixture of 22 g of N- (6-aminobenzothiazol-2-yl) -4-cyanopiperidine obtained in the Starting materials. Example 14 and 11.2 ml of (R) - (-) - glycinic acid methyl esters 400 ml of ethanol, boiled for 10 hours, ethanol was evaporated in vacuo, 300 ml of tetrahydrofuran were added, then 17 g of 1,1'-carbonyldiimidazole were boiled for 30 minutes, added 50 ml of water, boiled for 30 minutes, evaporated to 1/3 of the initial volume, poured into ice / water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, the solvent was evaporated in vacuo and purified by silica gel column chromatography (methylene chloride / ethanol solvent) to obtain 6.2 g of the title compound (free).

 The product is treated with methanol containing hydrogen chloride to give the title compound (hydrochloride).

¹ H-NMR (free, CDCl ₃ ) δ:
1.9 ~ 2.1 (4H, m), 2.9 ~ 3.0 (1H, m), 3.42 (3H, s), 3.6 ~ 3.7 (4H, m), 3.8 ~ 4.1 (4H, m), 4.7 ~ 4.8 (1H, m ), 7.25 (1H, d), 7.50 (1H, d), 8.08 (1H, d).

Examples 14 to 52
The compounds listed in tables 3 to 9, receive the same methods as in examples 1 to 13.

Claims (17)

1. Derived oxazolidone of General formula I

where A and B are each nitrogen, sulfur or oxygen, provided that at least one of A and B must be nitrogen;
R ¹ is hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl, cyanoalkenyl groups, a group of the general formula;

in which n and m = 0 - 4, an integer;
R ³ and R ⁴ are the same or different and each is hydrogen, hydroxyl, lower alkyl group or a group of the general formula

in which R ⁷ and R ⁸ , the same or different, and each is hydrogen, a lower alkyl group, or R ⁷ and R ⁸ can together with the nitrogen atom to which they are attached form a ring that can be substituted,
group of the general formula

in which p and q = 0 - 4, an integer;
X is oxygen or a group of the general formula
= N - OR ⁹ ,
where R ⁹ is hydrogen or lower alkyl,
or a group of the general formula

in which R ⁵ and R ⁶ , the same or different, and each is hydrogen, a lower alkyl or cyanoalkyl group, or R ⁵ and R ⁶ can together with the nitrogen atom to which they are attached form a ring that can be substituted,
or a group of the general formula
NC - (CH ₂ ) _r - Y - (CH ₂ ) _s -
in which r and s = 0 - 4, an integer;
Y is oxygen or a group of the formula - NH-, aryl group, cyanoalkylcarbamoyl group, alpha-benzoyloxymethyl, 5-oxo-tetrahydrofuran-2-yl, 5-oxo-tetrahydrofuran-2- (S) -yl, 5-hydroxytetrahydrofuran-2-yl, 1- hydroxy-4-hydroxybutyl, 4-hydroxy-4-hydroxyiminobutyl, 1-hydroxy-3-carbamoylpropyl, 1-oxo-3-cyanopropyl;
R ² is hydrogen or a lower alkyl group;
connection

- single or double bond,
or its pharmacologically acceptable salts.  2. The derivative according to claim 1, characterized in that A is sulfur, B is nitrogen.  3. The derivative according to claim 1, characterized in that A is nitrogen, B is sulfur.  4. The derivative of claim 1, wherein the compound of general formula I is 3- [2- (1-hydroxy-3-cyanopropyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.  5. The derivative of claim 1, wherein the compound of general formula I is 3- [2- (3-cyanoproyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.  6. The derivative of claim 1, wherein the compound of general formula I is 3- [2- (1-hydroxy-4-cyanobutyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.  7. The derivative of claim 1, wherein the compound of general formula I is 3- [2- (4-cyanobutyl) benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.  8. The derivative of claim 1, inhibiting monoamine oxidase.  9. The derivative of claim 1, inhibiting monoamine oxidase A.  10. The derivative of claim 1 as an antidepressant.  11. A pharmaceutical composition that inhibits monoamine oxidase containing an active agent and a pharmaceutically acceptable excipient, characterized in that the active agent contains the oxazolidone derivative and / or its pharmacologically acceptable salt according to claim 1 in an effective amount.  12. The composition according to p. 11, used to treat diseases against which monoamine oxidase inhibitors are effective.  13. The composition according to p. 11, used to treat diseases against which monoamine oxidase A inhibitors are effective.  14. The composition according to claim 11, used to treat depressive conditions.  15. A method of treating diseases against which monoamine oxidase inhibitors are effective, comprising administering monoamine oxidase inhibitors to a patient, characterized in that the oxazolidone derivative according to claim 1 or a pharmacologically acceptable salt thereof in an effective amount is administered as monoamine oxidase inhibitors.  16. The method according to clause 15, wherein monoamine oxidase inhibitors A are used as monoamine oxidase inhibitors.  17. The method according to clause 15, wherein the disease is a depressive state.

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