Derived oxazolidine or its pharmacologically acceptable salts, pharmaceutical composition, method of treatment

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with inhibiting the monoamine oxidase activity. Disclosed are derivatives of oxazolidone formula I, where A and B each represents an atom of nitrogen, sulfur or oxygen, provided that at least one of them must be a nitrogen atom, R1and R2have different meanings indicated in the description, as well as a pharmaceutical composition and method of treatment based on them. 3 S. and 14 C.p. f-crystals, 9 PL.

The invention relates to derivatives of oxazolidone with excellent medical effect.

We can say that currently, 20 to 30 people in the normal state, there is one suffering from depression. In addition, most patients have depressive condition which is a consequence of brain damage, and so on, Thus depression and depression can be considered modern diseases.

To alleviate depression and depressive state prior to this used tricyclic antidepressants, such as imipramine and amitriptyline. However, antidepressants are not so preferred, as they are not effective for ~ 40% of patients is the pressure, headache, tremor of the fingers, constipation, problems with urination.

On the other hand it is well known that inhibitors of monoamine oxidase (hereinafter referred to as MAO) have antidepressant effect and shows that their action is wider than the tricyclic antidepressants. However, hydrazide MAO inhibitors currently not used, since discovered that they cause liver disorders. Neherenia MAO inhibitors also barely used, because of their inhibitory effect irreversible MAO.

Additional studies have shown that MAO is classified in 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", where the interaction of the drug with food with a high content of tiramina causes bouts of hypertension, primarily due to the inhibiting effect of MAO-B.

The inventors conducted extensive research to find a way in which a reversible inhibitory effect, and at the same time free from serious side effects or interact with food and is also effective for patients in a wide range. To do this, the research by the inventors found, the object of the present invention may be derived oxazolidone, which are described below. The present invention is made on the basis of this discovery.

Despite the fact that the derivatives of oxazolidine, used as medical drugs 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 the Japan patent N 63671/1988, they differ in structure from the compounds of the present invention.

In the patent US 5011849 disclosed oxazolidinone derivatives possessing inhibiting the monoamine oxidase activity, as well as pharmaceutical compositions containing these derivative or its pharmaceutically acceptable salt as an active agent and a pharmaceutically acceptable filler.

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

The present invention relates to derivatives of oxazolidine corresponding to the General formula (1) or their pharmaceutically acceptable salts:

< / BR>
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;

R1present cyanoacetyl group, the group corresponding to the formula:

< / BR>
(in which

n and m each represents 0 or an integer from 1 to 4 and R3and R4may be the same or different and each represents a hydrogen atom, hydroxyl, lower alkyl, lower alkoxyl group or a group corresponding to the formula

< / BR>
(in which

R7and R8may be the same or different and each represents a hydrogen atom or lower alkyl, or R7and R8can together with the nitrogen atom to form a ring and the ring may be substituted), a group corresponding to the formula:

< / BR>
(in which

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-OR9(R9is a hydrogen atom or lower alkyl), the group corresponding to the formula:

< / BR>
(in which

R5and R6may be the same or different and each represents a hydrogen atom, lower alkyl or cianelli group, or R5and R6may form together with the nitrogen atom to which they are bound, a ring and the ring may be substituted), a group corresponding to the formula:

NC-(CH2)r-Y-(CH2)s-
the om sulfur, a group of the formula: -NH-), an aryl group which may be substituted, arylalkyl group which may be substituted, heteroaryl group which may be substituted, heteroaromatic group which may be substituted, carbamoylethyl group or cyanoacrylate group;

R2represents a nitrogen atom or a lower alkyl and the bond represented corresponds to a simple or double bond).

The present invention also provides a drug for prevention and treatment of diseases against which effective monoamine oxidase inhibitor comprising as an active ingredient derived oxazolidone General formula (I) above, and/or its pharmacologically acceptable salt.

Further, the present invention provides: a drug product, including its composition effective dose derived oxazolidone General formula (I) and/or its pharmacologically acceptable salt and pharmaceutically acceptable excipient; application of the derived oxazolidone General formula (I) or its pharmacologically acceptable salt for a drug against a disease against which an effective monoamine oxidase inhibitors; treatment soglasnoplanu dose derived oxazolidone General formula (I) and/or its pharmacologically acceptable salt.

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

The lower alkyl group in R1, R2, R3, R4, R5, R6, R7, R8and R9in the above General formula (I) are straight chain or branched alkyl group having 1 to 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 group. Most preferred among these are methyl, ethyl, propyl and isopropyl groups.

Lower alkoxy group, R3and R4are straight or branched alkoxy groups containing from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-nutrient are methoxy, ethoxy group.

Alkoxyalkyl group, R1are the above groups are lower alkyl.

The aryl group of the aryl groups which R1may be substituted include phenyl, naphthyl, tolyl and xylyl group.

Arylalkyl group arylalkyl groups, which by definition R1may be substituted, represent a group derived from the above-described aryl groups.

Heteroaryl group heteroaryl groups, which by definition R1may be substituted, represent a saturated or unsaturated 5 - to 7-membered ring containing 1 or 2 nitrogen atom, sulfur or oxygen.

Heteroaromatic group heteroaromatic groups, which by definition R1may be substituted, represent a group derived from the above heteroaryl groups.

The substituents in the aryl groups which may be substituted", "arylalkyl groups which may be substituted", "heteroaryl groups which may be substituted", and "heteroaromatic groups which may be substituted" include hydroxyl, lower alkyl, cyano, lower alkoxy, amino, nitro, carboxyl, hydroxyalkyl, alkoxyalkyl, cianelli and cyanoacetyl group.

Alkenyl group cyanoacetyl groups in the definition of R1corresponds to the above lower alkyl groups which have one or more double bonds between two carbon atoms. Cyano group can be linked to any carbon atom alkenylphenol group.

Carbamoylethyl group in R1represent a group derived from the above lower alkyl groups.

Cyanoacrylate group in the definition of R1represent a group derived from the above cianelli groups.

The halogen atoms in R1include fluorine, chlorine, bromine and iodine.

Cycloalkyl group in R1include groups containing from 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii and cyclodecyl group.

The concept of "can form a ring together with the nitrogen atom to which they relate" in the definitions of R5and R6or R7and R8applies, in particular, to piperidine and pyrrolidine group and piperidino, morpholino groups, which additionally contain nitrogen atoms, oxygen or sulfur.

In kachestvenii, cianelli and cyanoacetyl group.

Pharmacologically acceptable salt in the present invention include salts of inorganic acids, such as hydroxychloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, bansilalpet and toluensulfonate; salts of amino acids 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 pharmaceutically acceptable salts of the present invention.

Compounds of the present invention can form the 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 explanation of the present invention, which in no way limit the invention.

Examples of the most suitable compounds are compounds corresponding to the basic formula (A) and their pharmacologically acceptable salt:

< / BR>
(where

R2, R3, R4n and m are the groups defined above). R2the C and methyl group, among them, more preferred methyl group.

R3and R4may be the same or different and each represents preferably a hydrogen atom or a hydroxyl or lower alkyl groups, among which the more desirable a hydrogen atom or a hydroxyl, methyl, ethyl, propyl, butyl or tert-butyl group, and more preferred hydrogen atom or hydroxyl, or methyl group.

The most desirable combination of values of R3and R4comprising a hydrogen atom and a hydroxyl group. Next the desirable combination includes a hydroxyl group and a lower alkyl group. The following desirable combination includes two hydrogen atoms.

n and m represent independently from each other 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=1 and m=2; n= 0 and m=3; n=2 and m=0; n=1 and m=1; n=0 and m=2, among which more preferably a combination of n= 3 and m=0; and n=2 and m=0, the most preferred combination includes n=2 and m=0.

Examples the following most preferred compounds are compounds corresponding to General formula (B) and their pharmacologically acceptable salt:

< / BR>
(where

R2, R5and R6have values represented lately - a hydrogen atom and methyl group, and most preferred methyl group.

R5and R6may preferably be the same or different and each represents a hydrogen atom or cianelli group, or the case when R5and R6form a ring together with the nitrogen atom to which they relate, however, preferably, when R5and R6form a ring together with the nitrogen atom to which they are bound, a ring, in particular, is piperidino or pyrrolidino group. The ring may be preferably one or two substituent, more preferably one substituent. Preferred examples of the substituents are cyano, hydroxyl and carboxyl group.

Examples the following most preferred compounds are compounds corresponding to the General formula (C) and their pharmacologically acceptable salt:

< / BR>
(where

R2, X, p and q have the values given above).

R2is preferably a hydrogen atom or a methyl, ethyl or propyl group, among which the more desirable is a hydrogen atom and methyl group, and most preferred methyl group.

X is preferably a sulfur atom or oxygen, more W is 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 the more desirable - p-3 and q=0, 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 particularly excellent inhibitory activity for monoamine oxidase, are the following compounds or their pharmacologically acceptable salt:

1) 3-[2-(1-hydroxy-3-cyanopropyl)benzothiazole-6-yl] - 5-methoxymethyl-2-oxazolidinone,

2) 3-[2-(3-cyanopropyl)benzothiazol-6-yl]-5 - methoxymethyl-2-oxazolidinone,

3) 3-[2-(1-hydroxy-4-cyanomethyl)benzothiazol-6-yl] -5 - methoxymethyl-2-oxazolidinone and

4) 3-[2-(4-cyanomethyl)benzothiazol-6-yl]-5 - methoxymethyl-2-oxazolidinone.

Typical methods of producing compounds of the present invention are presented below.

The method of obtaining 1

(the first stage)

< / BR>
(where

A and B have the meanings described above, Ra1represents a group selected from the same groups as described for R1excluding the atoms of halogen and a group of the formula:

< / BR>
(where

R3, R4, m and n have the meanings given above and Hal represents a halogen atom).

Namely, the connection OEM compounds of General formula (IV). As the base can be used any type. Examples of preferred bases are alkali metal salts, such as potassium carbonate and sodium hydrogen; hydrides of alkali metals, such as sodium hydride and potassium hydride; amines, such as triethylamine.

The solvent for the reaction is any organic solvent which does not participate in the reaction. Preferably used as solvents, alcohols, such as ethanol; ethers such as tetrahydrofuran and dioxane; and dimethylformamide.

The reaction temperature ranges from 0oC to the boiling point of the solvent.

(second stage)

< / BR>
< / BR>
(where

A, B, and Ra1have the values specified above).

Namely, the compound of General formula (IV) obtained in the first stage, nitrous usual method with the formation of compounds of General formula (V).

(the third step)

< / BR>
(where

A, B, and Ra1have the values specified above).

Namely, the compound of General formula (V) obtained in the second stage, restore normal catalytic hydrogenation with the formation of compounds of General formula (VI).

P is camping aluminum.

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

The reaction temperature varies from about 0oC to the boiling point of the solvent.

(Fourth stage)

< / BR>
(where

Ra1, R2A and B have the meanings described above).

Namely, the compound of General formula (VI) obtained in the third step turn with derivatives glycidol General formula (VII) in the usual way with the formation of compounds of General formula (VIII).

The compound (VIII) can be obtained with high yield by using magnesium perchlorate, sodium perchlorate or lithium perchlorate according to the method described in "Tetrahedron Letters", Vol. 31, N 32, p 4661-4664 (1990).

The reaction solvent may be any organic solvent generally used for organic synthesis and not participating in the reaction. For reactions with non-perchlorate compounds are preferably used as solvents, alcohols, such as methanol, ethanol, propanol, isopropanol and butanol, for the range of approximately 0oC to the boiling point of the solvent.

This stage, depending on the circumstances, may be carried out in a sealed vessel.

(Fifth stage)

< / BR>
(where

Ra1, R2A and B have the meanings described above).

Namely, the compound of General formula (VIII) obtained in the fourth stage, reacts with symmetric carbonyl compound, such as N,N-carbonyldiimidazole or diethylcarbamyl, with the formation of the desired compound (IX) containing a cyclic urethane residue.

As the reaction solvent use any organic solvent not participating in the reaction. Preferred solvents are ethers, such as tetrahydrofurane.

The reaction temperature varies from about 0oC to the boiling point of the solvent.

If R1is a halogen atom, the desired compound (1) can be obtained by using the original from the second stage.

The method of obtaining 2

If the desired compound is a compound of the following General formula (X):

< / BR>
(where

Ra1and R2have the values specified above), it can also be obtained as>/P>Namely, aminothiophenol (XI) is reacted with carboxylic acid or its reactive derivative (XII) according to conventional methods education benzthiazole derivative of General formula (XIII).

Examples of reactive derivatives of the carboxylic acid include acid anhydrides, esters and NITRILES.

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

The reaction temperature varies from about -20oC to the boiling point of the solvent.

Formed benzthiazole compound (XIII) can be transformed 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).

The method of obtaining 3

If the desired compound is a compound corresponding to General formula (XIV):

< / BR>
(where

A, B, and R2have the meanings given above), it can be obtained by synthesis of compounds of General formula (XV):

< / BR>
method for producing 2 with the following processing methods 1 or 2:

< / BR>
(Method 1)

The compound (XV) establish complainonline only ketogroup in the lactone group to education lactolose compound (XVI). Although the reaction temperature may vary from a temperature under cooling with ice to the boiling point of the solvent, the preferred room temperature. In the reaction using any organic solvent suitable for organic synthesis and inert to the reaction. Examples of particularly preferred solvents include tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane.

Lactaline compound (XVI) is reacted with hydroxylamine hydrochloride in a solvent to form the oxime (XVII). Although the reaction temperature may vary from a temperature under cooling with ice to the boiling point of the solvent, the preferred room temperature. In the reaction using a solvent suitable for organic synthesis and inert to the reaction. Examples of particularly preferred solvents include pyridine, water, methanol and ethanol. The solvents can be used as one, and a mixture of two or more solvents.

The oxime (XVII) is reacted with 1-(TRIFLUOROACETYL)imidazole in a solvent to form the desired compound (XIV). Although the reaction temperature may vary from the temperature of the cooling with ice to the boiling point of the solvent, preference is synthesis and inert to the reaction. Examples of particularly preferred solvents include liquid ammonia, methanol, ethanol, propanol and isopropanol.

(Method 2)

The compound (XV) is reacted with ammonia amide (XVIII). Although the reaction temperature may vary from the temperature of the cooling with ice to the boiling point of the solvent, preferably room temperature. Use any solvent suitable for organic synthesis and inert to the reaction. Examples of particularly preferred solvents include tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane.

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

Deputy in the 2-position can be replaced using conventional methods, such as oxidation, recovery or condensation.

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

Examples.

Determination of inhibitory activity of MAO with the use of the rat forebrain:

Inhibitory MAO activity 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:

source enzymes - 20 ál

14C-labeled enzyme substrate 80 ál

test connection - 200 ál

in the amount of 300 μl

As a source of enzymes used a suspension of 1 part of volume of the forebrain of male Wistar rats with 5 parts of 0.1 M potassium phosphate buffer (pH 7.4). The source of enzyme was mixed with the test compound and the mixture was stirred for 10 minutes at 37oC, then added the enzymatic substrate to start the reaction, 10 minutes was added 200 μl of 2N hydrochloric acid to complete the reaction.

As substrates arranged 5-HT and PEA regulated to 11.1 MBq/mmol and 29.6 MBq/mmol, respectively, and their concentration in the reaction - 200 μm and 20 μm, respectively.

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

Diethyl ether and n-heptane was used as the radioactive metabolites formed MAO-A and MAO-B, respectively. After the enzymatic reaction, the reaction mixture was added 3 ml of solvent, was dissolved in 10 minutes. After centrifugation for 10 minutes at 3000 revolutions/minute, the bottom water layer froze the mixture of dry ice/acetone. The upper organic layer was separated by decantation and determined its radioactivity using a liquid scintillation counter.

The results are shown in table. 1 and 2. Inhibiting activity of the test compounds for MAO-a and MAO-b are shown at concentrations of 10-7M and 10-6M or with IC50values (see tab. 1,2).

From the examples above experiment shows that the compounds of the present invention may selectively inhibit MAO-A. Thus the derivatives of oxazolidine, avlasaren inhibition of MAO-A. Examples of such diseases include depression, depressive neurosis, depressive state due to the effects of brain damage. In addition, the compounds of the present invention have excellent antirestenotic effect, which improves therapeutic effect in the treatment of the above diseases.

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

Compounds of the present invention is used in the form of tablets, powder, granules, capsules, syrups or inhalations in the treatment or prevention of these diseases. The dose varies depending on symptoms, age, type of illness, etc. and usually ranges from 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 adult, and with an introduction or introduction to a few servings per day.

Preparative form containing compounds receive conventional methods with conventional pharmaceutical excipients.

Namely, a solid formulation for oral administration obtained by adding excipient and, if necessary, the light is in, and so on, the active ingredient, and forming the resulting mixture into tablets, coated tablets, granules, powder or capsules.

The polymers excipient include lactose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose and silicon dioxide. Examples of binding agents are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, Arabian gum, tragakant, gelatin, shellac, hydroxypropylcellulose, hydroxymethylcellulose, calcium citrate, dextrin and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silicon dioxide and vegetable grease lubrication. As color additives used additives permitted for use in medicine. As modifiers of drug substances include cocoa powder, methanol, aromatic powder, menthol oil, borneol and cinnamon powder. These tablets and granules may be coated with sugar, gelatin or other similar materials.

Injections for subcutaneous, intramuscular or intravenous receive conventional methods, adding to the active ingredient, if necessary, the pH Adjuster, buffer, stabilizer, etc.

Examples get the source compounds used for the synthesis of the desired compounds are also provided below.

In the examples mean "Me" and "Et" represents a methyl group and ethyl group, respectively.

Examples get the source connections

Example 1

2-Hydroxymethylbenzene

< / BR>
60 g of 2-aminothiophenol and 36.6 g of glycolic acid are heated for 12 hours at 130oC in a sealed vessel. The reaction product is dissolved in ethyl acetate, dried over sodium sulfate, the solvent is evaporated in vacuum, the residue is recrystallized from diisopropyl ether and obtain 55 g of the above compound in the form of white crystals.

1H-NMR (CDCl3) :

3.54 (1H, t), 5.08 (2H, d), 7.38 (1H, t), 7.47 (1H, t), 7.88 (1H, d), of 7.97 (1H, d).

Example 2

6-Nitro-2-hydroxymethylbenzene

< / BR>
To 41 g of 2-hydroxymethylimidazole obtained in Example 1 in 55 ml of concentrated sulphuric acid are added dropwise 24 ml of concentrated nitric acid (specific gravity: 1.42), maintaining the reaction temperature at 40oC or below, stirred for 1 hour, poured into a mixture of ice-water and extracted with ethyl acetate. The extract is dried over sodium sulfate, evaporated in vacuum and.

1H-NMR (CDCl3) :

2.37 (1H, c), 5.07 (2H, s), 8.05 (1H, d), 8.35 (1H, DD), 8.86 (1H, d).

Example 3

6-Nitro-2-benzyloxybenzoate

< / BR>
To a solution of 15 g of 6-nitro-2-hydroxymethylimidazole obtained in Example 2, and 11 ml of triethylamine in tetrahydrofuran at 10oC added dropwise 9 ml of benzoyl chloride, stirred for 1 hour at room temperature, added water and extracted with ethyl acetate. The extract is dried over sodium sulfate, evaporated in vacuum. The remainder chromatographic on a column of silica gel (solvent: dichloromethane/methanol) and receive 10 g of the named compound.

Example 4

6-Amino-2-benzyloxybenzoate

< / BR>
10 g of 6-nitro-2-benzyloxybenzoate obtained in Example 3, a solution of a mixture of ethyl acetate and ethanol (1 : 1) hydronaut for 10 hours in the presence of 1 g of catalyst (palladium on carbon). After the reaction the catalyst is filtered off through celite, the filtrate evaporated in vacuum and obtain 8.7 g of the named compound.

Example 5

N-(2-Benzoyloxymethyl-6-yl)-2-hydroxy - 3-methoxypropylamine

< / BR>
A mixture of 8.7 g of 6-amino-2-benzyloxybenzoate obtained in Example 4, and 3 g of methyl EPE is(solvent: dichloromethane/methanol) and obtain 6.2 g of the named compound.

Example 6

2-(5-Oxitetraciclina-2-yl)benzothiazole

< / BR>
The acid chloride obtained in the processing of (S)-(+)-5-oxo-2-tetrahydrofuranate acid with thionyl chloride, are added dropwise with 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 is filtered off, washed with water, then ether, recrystallized from acetone and diisopropyl ether and receive 504 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 7

6-Nitro-2-(5-oxitetraciclina-2-yl)benzothiazole

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

1H-NMR (CDCl3) :

2.6 ~ 3.0 (4H, m), 5.8 ~ 6.0 (1H, m), 8.13 (1H, d), 8.40 (1H, DD), 8.8 and Jethro-2-(5-oxitetraciclina-2-yl)benzothiazole, obtained in Example 7, in 6000 ml of dioxane hydronaut within 48 hours in the presence of 30 g of 10% palladium on carbon at room temperature under atmospheric pressure. The catalyst is filtered off, the solvent evaporated, the resulting solid residue is recrystallized from acetone and diisopropyl ether and receive 300 g of the named compound.

1H-NMR (CDCl3) :

2.6 ~ 2.9 (4H, m), 5.8 ~ 5.9 (1H, m), 7.08 (1H, DD), 7.58 (1H, d), 7.85 (1H, d).

Example 9

2-Chloro-6-nitrobenzothiazole

< / BR>
To 300 g of 2-chlorobenzothiazole in 1500 ml of concentrated sulfuric acid are added dropwise at 0o- 10oC 134 ml of concentrated nitric acid, stirred for 1 hour, poured into ice/water. The formed precipitate is filtered off, washed with water, then with acetone and dried, yielding 380 g of the named compound.

1H-NMR (CDCl3) :

8.07 (1H, d), 8.39 (1H, DD), 8.76 (1H, d).

Example 10

Ethyl N-(6-nitrobenzothiazole-2-yl)isonipecotate

< / BR>
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 was added 50 g of sodium bicarbonate, boiled for 3 hours, poured into ice/water and extracted with ethyl acetate. The extract is washed woodiana.

1H-NMR (CDCl3) :

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).

Example 11

N-(6-nitrobenzothiazole-2-yl)isonicotinate acid

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

1H-NMR (CDCl3) :

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, DD), 8.70 (1H, d).

Example 12

N-(6-Nitrobenzothiazole-2-yl)isonipecotamide

< / BR>
To a suspension of 90 g of N-(6-nitrobenzothiazole-2-yl)isonicotinate acid obtained in Example 11, in 500 ml of tetrahydrofuran and 1000 ml of dimethylformamide was added 100 ml of triethylamine and added dropwise at -20oC 45 ml isobutylparaben, stirred for 20 minutes, make 100 ml of concentrated aqueous ammonia at -40oC, stirred for 20 minutes. The reaction mixture was poured into ice/water, the precipitate is filtered, washed with water, then ether, and dried produces the .4 (2H, m), 3.9 ~ 4.1 (2H, m), 7.47 (1H, d), 8.13 (1H, DD), 8.78 (1H, d).

Example 13

N-(6-Nitrobenzothiazole-2-yl)-4-cyanopiperidine

< / BR>
To 75 g of N-(6-nitrobenzothiazole-2-yl)isonipecotamide obtained in Example 12, in 700 ml of dimethylformamide was added 50 g of p-toluensulfonate, heated for 20 minutes at 110oC, poured into ice/water, neutralized with sodium hydroxide. The formed precipitate is filtered off, washed with water and then ether and dried, yielding 60 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 14

N-(6-Aminobenzothiazole-2-yl)-4-cyanopiperidine

< / BR>
A mixture of 60 g of N-(6-nitrobenzothiazole-2-yl)-4-cyanopiperidine obtained in Example 13, and 2000 ml of dioxane hydronaut 2 hours in the presence of 3 g of 10% palladium on carbon at room temperature and atmospheric pressure. The catalyst is filtered off, the solution evaporated in vacuum and obtain 51 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 1

3-(2-Benzoyloxymethyl-6-yl)-5-methoxymethyl-2 - oxazolidinone

< / BR>
A mixture of 6.2 g of N-(2-benzoylacetate 3 hours in tetrahydrofuran, added dropwise 0.5 ml of water, the solution is boiled for an additional 1 hour, poured into ice/water, extracted with ethyl acetate. The extract is dried over sodium sulfate, the solution is evaporated in vacuo, the residue chromatographic on a column of silica gel (solvent: n-hexane/ethyl acetate) and get 4 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 2

3-(2-Hydroxymethylbenzene-6-yl)-5-methoxymethyl-2 - oxazolidinone

< / BR>
To a solution of 4.7 g of 3-(2-benzoyloxymethyl-6-yl)-5 - methoxymethyl-2-oxazolidinone obtained in example 1 in methanol/dioxane (1:1) was added 7.5 ml of 2 N NaOH aqueous solution, stirred for 2 hours, the methanol is evaporated in vacuo and extracted with ethyl acetate. The extract is dried, the solution is evaporated in vacuum and obtain 3.25 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 3

3-[(2-Cyanometallates)-6-yl]-5-methoxymethyl-2 - oxazolidinone

< / BR>
A mixture of 0.6 g of 3-(2-hydroxymethylbenzene)-6-yl)-5 - methoxymethyl-2-oxazolidinone received Note is mperature, add water and extracted with ethyl acetate. The extract is dried over sodium sulfate, the solution is evaporated in vacuum, chromatographic on a column of silica gel (solvent: hexane/ethyl acetate) and obtain 0.35 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 4

3-[(2-Cyanometallates)-6-yl] -5 - methoxymethyl-2-oxazolidinone

< / BR>
A mixture of 0.6 g of 3-(2-hydroxymethylbenzene-6-yl)-5-methoxymethyl - 2-oxazolidinone obtained in example 2, and 0.47 g of phosphorus pentoxide is stirred for 1 hour while cooling with ice, poured into ice/water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, evaporated in vacuum and get an oily residue which is dissolved in dimethylformamide. To the solution was added 0.21 g of cyanomethylene hydrochloride and 0.61 ml of triethylamine is heated for 24 hours at 60oC, cooled, bring water and extracted with ethyl acetate. The organic layer is evaporated, chromatographic on a column of silica gel (solvent: dichloromethane/methanol) and obtain 0.2 g of the named compound.

1H-NMR (CDCl3) :

3.45 (3H, s), 3.68 (trihydrogen-2-yl)benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone

A mixture of 300 g of 6-amino-2-(5-oxitetraciclina-2-yl)benzothiazole obtained in the Original. Example 8 in 200 ml of ethanol and 146 g of methyl ester of (S)-(-)-glycidol acid is boiled for 10 hours, the solvent is evaporated in vacuo, to the residue add 8 l of ethyl acetate. The resulting solution was passed through a column of silica gel, and the eluate evaporated in vacuum and get an oily residue which is dissolved in 2500 ml of tetrahydrofuran, was added 166 g of 1,1'-carbonyldiimidazole, boiled for 2 hours, carefully add water, boil for 1 hour, evaporated in vacuo to 1/3 the original volume, poured into ice/water and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate, evaporated, the residue chromatographic on a column of silica gel (methylene chloride/ethanol) and get 166 g of the named compound.

1NMR (CDCl3) :

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).

Example 5

< / BR>
Example 6

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

< / BR>
To 2.1 ml methyl ester (S)-(-)-perature, add 5 g of 6-amino-2-(5-oxitetraciclina-2-yl)-benzothiazole obtained in the Original. Example 8, stirred for 30 minutes at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried, the solvent evaporated and obtain 6.5 g of oily residue. The residue is dissolved in 30 ml of tetrahydrofuran, was added 4.3 g of 1,1'-carbonyldiimidazole, boiled for 1 hour, cooled, evaporated in vacuum. The residue is treated with methylene chloride, washed with water, dried, the solvent evaporated in vacuo, the residue chromatographic on a column of silica gel, recrystallized from acetone/isopropyl ether and obtain 3.8 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 7

3-[2-(5-Hydroxymitragynine-2-yl)benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone

< / BR>
To a solution of 160 g of 3-[2-(5-oxitetraciclina-2-yl)benzothiazol - 6-yl]-5-methoxymethyl-2-oxazolidinone obtained in example 5, in 3000 ml of tetrahydrofuran are added dropwise to 900 ml of 1 M solution of tri-tert-butoxylated lithium in tetrahydrofuran, stirred for 2 hours at cetecom. The extract was washed with aqueous sodium bicarbonate, then water, saline solution, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on a column of silica gel (methylene chloride/ethanol) and obtain 72 g of the named compound.

1H-NMR (CDCl3) :

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, HF), 5.73 (1/2H Shire. s), 5.85 (1/2H, Shir. C) 7.5. ~ 7.6 (1H, m), 7.9 ~ 8.0 (1H, m), 8.2 ~ 8.3 (1H, m).

Example 8

3-[2-(1-Hydroxy-4-hydroxyaminobutyryl)benzothiazol-6-yl] - 5-methoxymethyl-2-oxazolidinone

< / BR>
To a solution of 72 g of 3-[2-(5-hydroxymitragynine-2-yl)benzothiazol - 6-yl] -5-methoxymethyl-2-oxazolidinone obtained in example 7, in 150 ml of pyridine was added 18.6 g of hydroxylamine hydrochloride, stirred for 10 minutes at room temperature, poured into ice/water, extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated in vacuum. The residue is recrystallized from acetone/diisopropyl ether and obtain 73 g of the named compound.

1H-NMR (CDCl3) :

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 isothiazol-6-yl] - 5(R)-methoxymethyl-2-oxazolidinone

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

1H-NMR (CDCl3) :

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 - 75oC.

Example 10

3-[2-(1(S)-Hydroxy-3-carbamoylmethyl)benzothiazol-6-yl] - 5(R)-methoxymethyl-2-oxazolidinone

< / BR>
To 50 ml of liquid ammonia in a sealed vessel at -78oC added 2.9 g of 3-[2-(5-hydroxymitragynine-2-yl)benzothiazol - 6-yl] -5-methoxymethyl-2-oxazolidinone, pressurized, stirred for 3 hours at room temperature, ammonia is slowly evaporated. To the residue add acetone, the precipitated crystals filtered off and dried, yielding 2.6 g is(1H, t), 4.80 ~ 4.90 (2H, m), 6.25 (1H, d), 6.80 (1H, Shir s), 7.30 (1H, Shir s), 7.75 (1H, d), 7.90 (1H, d), 8.20 (1H, s).

so pl. 170 - 171oC.

Example 11

3-[2-(1(S)-Hydroxy-3-cyanopropyl)benzothiazol-6-yl] - 5(R)-methoxymethyl-2-oxazolidinone

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

Example 12

3-[2-(1-hydroxy-4-cyanomethyl)benzothiazol-6-yl] -5 - methoxymethyl-2-oxazolidinone

< / BR>
To a solution of 3.48 g of 3-[2-(5-oxitetraciclina-2 - yl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone obtained in example 5 in 20 ml of anhydrous tetrahydrofuran at -50oC added dropwise 30 ml of a 1.0 M solution of diisobutylaluminium in tetrahydrofuran, per the butyl)benzothiazol-6-yl)-5-methoxymethyl-2 - oxazolidinone.

1H-NMR (CDCl3) :

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 - 138oC

To 2.8 g of 3-[2-(1.4-dihydroxybutyl)-benzothiazol-6-yl]-5 - methoxymethyl-2-oxazolidinone, thus obtained, 20 ml of anhydrous methylene chloride was added 1 ml of anhydrous triethylamine, slowly while cooling with ice, add 0.6 ml of methanesulfonanilide, stirred for 30 minutes, make 100 ml of ether, filtered and evaporated. The residue is dissolved in 15 ml of dimethyl sulfoxide, contribute 1.5 g of potassium cyanide, heated 3 hours at 80oC, cooled, treated in the usual manner, purify and obtain 1.5 g of the named compound.

1H-NMR (CDCl3) :

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).

Example 13

(R)-3-[2-(4-Cyanopiperidine)benzothiazol-6-yl]-5-methoxymethyl-2 - oxazolidinone hydrochloride

< / BR>
A mixture of 22 g of N-(6-aminobenzothiazole-2-yl)-4-cyanopiperidine obtained in the Original. Example 14, and 11.2 ml (R)-(-)-glycine acid methyl esters 400 ml of ethanol is boiled for 10 hours, the ethanol is evaporated in vacuum, make 300 ml of tetrahydrofuran, and then 17 g of 1,1'-carbonyldiimidazole key is tracerout with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, the solvent was evaporated in vacuum and purified by chromatography on a column of silica gel (solvent methylene chloride/ethanol) and obtain 6.2 g of the above compound (free).

The product is treated with methanol containing hydrogen chloride, and get a named connection (hydrochloride).

1H-NMR (free, CDCl3) :

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, DD), 7.50 (1H, d), 8.08 (1H, d).

Examples 14 - 52

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

1. Derived oxazolidone General formula I

< / BR>
where A and B each is a nitrogen, sulfur or oxygen, provided that at least one of A and B must be nitrogen;

R1is hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl, cyanoacrylate group, a group of the General formula;

< / BR>
in which n and m = 0 - 4, integer;

R3and R4the same or different and each is hydrogen, hydroxyl, lower alkyl group or a group of the General formula

< / BR>
in which R7and R8the same or different and each is hydrogen, a lower alkyl group, or R substituted,

a group of General formula

< / BR>
in which p and q = 0 - 4, integer;

X is oxygen or a group of the General formula

= N - OR9,

where R9is hydrogen or lower alkyl,

or a group of the General formula

< / BR>
in which R5and R6the same or different and each is hydrogen, lower alkyl or cyanoaniline group, or R5and R6can together with the nitrogen atom to which they are linked, form a ring which may be substituted,

or a group of the General formula

NC - (CH2)r- Y - (CH2)s-

in which r and s = 0 - 4, integer;

Y is oxygen or a group of the formula - NH- , aryl group, cyanoacetylurea group, alpha benzoyloxymethyl, 5-oxitetraciclina-2-yl, 5-oxitetraciclina-2-(S)-yl, 5-hydroxymitragynine-2-yl, 1-hydroxy-4-hydroxybutyl, 4-hydroxy-4-hydroxyaminobutyryl, 1-hydroxy-3-carbamoylmethyl, 1-oxo-3-cyanopropyl;

R2is hydrogen or a lower alkyl group;

communication - simple or double bond,

or its pharmacologically acceptable salt.

2. Derived under item 1, wherein A is sulfur, B is nitrogen.

3. Derived under item 1, wherein A is nitrogen, B is sulfur.

4. Derived under item 1, dimetil-2-ox - azelizinom.

5. Derived under item 1, characterized in that the compound of General formula I is 3-[2-(3-cyanopropyl)-benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.

6. Derived under item 1, characterized in that the compound of General formula I is 3-[2-(1-hydroxy-4-cyanomethyl)-benzothiazol-6-yl] -5-methoxymethyl-2-OK - stolicinaia.

7. Derived under item 1, characterized in that the compound of General formula I is 3-[2-(4-cyanomethyl)-benzothiazol-6-yl] -5-methoxymethyl-2-oxazolidinone.

8. Derived under item 1, inhibiting the monoamine oxidase.

9. Derived under item 1, inhibiting the monoamine oxidase A.

10. Derived under item 1 as an antidepressant.

11. The pharmaceutical composition inhibiting the monoamine oxidase containing the active agent and a pharmaceutically acceptable excipient, wherein the active agent contains a derivative of oxazolidone and/or its pharmacologically acceptable salt p. 1 in an effective amount.

12. The composition according to p. 11 used for the treatment of diseases against which effective inhibitors of monoamine oxidase.

13. The composition according to p. 11 used for the treatment of diseases against which the efficiency is of Taani.

15. A method of treating diseases against which an effective monoamine oxidase inhibitors, including introduction to the patient monoamine oxidase, characterized in that as monoamine oxidase inhibitors injected derived oxazolidone under item 1 or its pharmacologically acceptable salt in an effective amount.

16. The method according to p. 15, characterized in that as monoamine oxidase inhibitors use inhibitors of monoamine oxidase A.

17. The method according to p. 15, wherein the disease is depression.

 

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,

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< / BR>
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< / BR>
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