Connection asola, methods for their preparation, intermediate compounds, methods for their preparation, pharmaceutical composition having antifungal activity

 

(57) Abstract:

Describes the new connection Azola General formula I, where the values A, R1- R3, W, X, Y, Z, m specified in paragraph (1 formulas that exhibit antifungal activity and can be used in the treatment of ringworm, visceroptosis. Also describes the method of production thereof, intermediate compounds, and a pharmaceutical composition having anti-fungal activity. 26 C. and 5 C.p. f-crystals, 6 PL.

Background of the invention.

a) the Scope of the invention

The present invention relates to an antifungal agent. In particular, the present invention relates to an antifungal agent used to treat ringworm, visceroptosis and the like. More specifically, the present invention relates to a derivative containing 5-membered heterocyclic ring or a condensed ring, and its salts of addition of the acid, which are used as antifungal agents. Further, the present invention relates to a method for producing such a derivative and a salt of addition of acid and pharmaceutical compositions containing the derivative and its pharmaceutically acceptable salt.

b) description of the prior art

In the field of antifungal agents amphoteric or the like is used, for example, in the treatment of mycosis profundus. However, recently opened synthetic antifungal agents azole type. Even in these agents azole type, however, there is an urgent need for the development of more effective antifungal agent from the point of view of their effect on patients with suppressed immune function.

For example, Japanese open patent publication (KOKAI) N 70885/1982 describes triazole compound as azole antifungal agent type. In addition, Japanese open patent publication (KOKAI) N 224689/1985 describes derived (1,2,4-triazole-1-yl)methylcarbamate.

The present invention provides an antifungal agent, is more efficient than known anti-fungal agents, and its intermediate products.

The essence of the invention.

Autorizovana, represented by the General formula:

< / BR>
where R1and R2the same or different from each other and represent each a halogen atom or a hydrogen atom;

R3means a hydrogen atom or a lower alkyl group;

l, r and m can be the same or different from each other and represent each 0 or 1;

A represents N or CH;

W denotes an aromatic ring or a condensed ring which may have one or more heteroatoms and may have one or more substituents; or denotes an aromatic ring or condensed ring, where part or all of the aromatic ring or the condensed ring which may have one or more heteroatoms, and may have one or more substituents are saturated;

X represents an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, alkadienes group which may have one or more substituents, arkendale group which may have one or more substituents, or allinternal group which may have one or more substituents;

Y represents a group represented by-S-, or -(CH2-4; and

Z denotes a hydrogen atom, halogen atom, lower alkyl group, halogenated lower alkyl group, lower CNS group, halogenated lower CNS group, hydroxyl group, thiol group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents, a phenoxyl group, which may have one or more substituents, imidazolidinyl group which may have one or more substituents, triazolyl group which may have one or more substituents, tetrazolyl group which may have one or more substituents, or an amino group, which may have one or more substituents, except for the case when W is a thiazole ring, R3is a methyl group and Z is a hydrogen atom when l = 1 and r = m = 0,

or its salt.

II. A method of obtaining optically active (2S,3R)-3-(2,4 - differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1 - yl)butyronitrile, which includes the interaction of optically active (2R,3S)-2-(2,4-differenl)-3-methyl-2-(1H-1,2,4-triazole - 1-yl)methyloxirane with cyanide diethylaluminum.

III. A method of obtaining optically active (2S,3R)-3-(2,4 - d is active (2R,3S)-3-(2,4-differenl)-3-methyl-2-(1H-1,2,4-triazole - 1-yl)methyloxirane with cyanide ytterbium.

IV. The way stereoselective obtain optically active (2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4 - triazole-1-yl)butyronitrile, which includes the interaction of optically active (2R, 3S)-3-(2,4-differenl)-3-methyl-2- (1H-1,2,4-triazole-1-yl)methyloxirane with acetonecyanohydrin.

V. Method of obtaining the compound represented by formula

< / BR>
where W denotes a substituted triazole ring, and

A, R1, R2, R3X, Y, Z, r and m are defined above,

or its salts of addition of the acid, which includes the interaction of the compounds represented by the formula:

< / BR>
where A, R1, R2and R3defined above, with a compound represented by the formula:

< / BR>
where Hal represents Br or Cl, and X, Y, Z, r and m are defined above.

VI. The method of obtaining the compound represented by the formula:

< / BR>
where A, R1, R2, R3X, Y, Z, r and m are defined above and means a substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring or a condensed ring;

or its salts of addition of the acid, which includes the interaction of the compounds represented by the formula:

< / BR>
where A, R1and R2defined above,

with the connection, PR is ASEE 5-membered heterocyclic ring or a condensed ring, and

Z is hydrogen or CH3.

VII. The method of obtaining the compound represented by the formula:

< / BR>
where W denotes a substituted or unsubstituted 5-membered heterocyclic or condensed ring,

A, R1, R2, R3X, Y, Z, r and m are defined above,

or its salts of addition of the acid, which includes the interaction of the compounds represented by the formula:

< / BR>
with a compound represented by the formula:

< / BR>
where R3X, Y, Z, r and m are defined above.

VIII. The method of obtaining the compound represented by the formula:

< / BR>
where A, R1, R2, R3, W, X, Y, Z, r and m are defined above,

or its salts of addition of the acid, which includes the interaction of the compounds represented by the formula:

< / BR>
where A, R1, R2, R3, W, X, Y, Z, r and m are defined above,

with meta-chloroperbenzoic acid and then with sodium 1,2,4-triazole or sodium 1,3-imidazole.

IX. The pharmaceutical composition containing the compound represented by the General formula:

< / BR>
where R1and R2the same or different from each other and represent each a halogen atom or a hydrogen atom;

R3denotes a hydrogen atom Il is th 0 or 1;

A is N or CH;

W denotes an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, or its condensed ring;

X represents an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, alkadienes group which may have one or more substituents, arkendale group which may have one or more substituents, or allinternal group which may have one or more substituents;

Y represents a group represented by-S-, or -(CH2)j-, in which R6means a hydrogen atom or a lower alkyl group, and j represents an integer of 1-4;

Z denotes a hydrogen atom, halogen atom, lower alkyl group, halogenated lower alkyl group, lower CNS group, halogenated lower CNS group, hydroxyl group, thiol group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents, a phenoxyl group, which may have one or more substituents, imidazolidinyl the group to which stitely, tetrazolyl group which may have one or more substituents, or an amino group which may have one or more substituents, except for the case when W is a thiazole ring, R3is a methyl group and Z denotes a hydrogen atom when r = m = 0,

or its salt of the addition of acid and pharmaceutically acceptable salt.

X. Method of obtaining derivative represented by the General formula:

< / BR>
where A is =CH - or =N-;

L and M are the same or different from each other and represent each a halogen atom or a hydrogen atom;

R1means a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy; or a condensed ring of a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring;

or its salts of addition of the acid, which includes obtaining a derivative or its salts of addition of the acid by d>/BR>L and M are defined above;

the compound containing 5-membered heterocyclic ring, or a condensed ring, or a partially or fully saturated condensed ring, in the presence of n-alkylate, for their interaction and then adding 1,2,4-triazole and sodium hydride to the obtained reaction product to their interaction.

XI. The method of obtaining derivative represented by the General formula:

< / BR>
where A is =CH - or =N-;

L and M are the same or different from each other and represent each a halogen atom or a hydrogen atom;

R1denotes a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy; or a condensed ring of a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring;

or its salts of addition of the acid, which includes obtaining a derivative or its salts of addition of acid vzaimode also, with sodium azide and triethylamine hydrochloride.

XII. The method of obtaining derivative represented by the General formula:

< / BR>
where A is =CH - or =N-;

L and M are the same or different from each other and represent each a halogen atom or a hydrogen atom;

R1means a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy; or a condensed ring of a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring;

moreover, these derivatives substituted alkyl group at the 3 - or 4-position tetrazole ring, or its salts of addition of the acid, which includes obtaining a derivative or its salts of addition of the acid by the interaction of its corresponding derivative containing tetraselenafulvalene 5-membered heterocyclic ring, with alkylhalogenide.

XIII. The method of deriving, predstavlennoj which means each halogen atom or a hydrogen atom;

R1means a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy; or a condensed ring of a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring;

moreover, these derivatives substituted alkyl group at the 3 - or 4-position tetrazole ring, or its salts of addition of the acid, which includes obtaining a derivative or its salts of addition of the acid by the interaction of its corresponding derivative containing halogenopyrimidines 5-membered heterocyclic ring, 1,2,4-tetrazole and sodium hydride.

XIV. The method of obtaining derivative represented by the General formula:

< / BR>
where A is =CH - or =N-;

L and M are the same or different from each other and represent each a halogen atom or a hydrogen atom;

R1means a 5-membered heterocyclic ring which may contain one or bilateralism ring, which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring;

moreover, these derivatives substituted alkyl group at the 3 - or 4-position tetrazole ring, or its salts of addition of the acid, which includes obtaining a derivative or its salts of addition of the acid by the interaction of its corresponding derivative containing (1,2,4-tetrazol-1-yl)ethanol.

XV. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group; a represents a protective group for hydroxyl group; and a represents a leaving group;

or its salt, which includes the introduction of protection for the hydroxyl group of compounds represented by the General formula:

< / BR>
where R means the same group as defined above, and

R1denotes a hydrogen atom or a protective group for carboxyl groups by introducing protective groups to obtain the compound represented by the General formula:

< / BR>
where R, R1and Pr, each, oznaczenia, represented by the General formula (2) to obtain the compound represented by the General formula:

< / BR>
where R and Pr, each means the same group as defined above,

and then the interaction of the compounds represented by the General formula (3), with the compound represented by the formula: LH, where L means the same group as described above.

XVI. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group;

X are identical or different from each other and represent each a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R and Pr, each mean the same groups as defined above,

L denotes a leaving group,

with a compound represented by the General formula:

< / BR>
where X, each mean the same groups as defined above, and

Y represents a chlorine atom, bromine or iodine,

or its reactive derivative.

XVII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are Odin is tnou group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr, each mean the same groups as defined above, with triphenylphosphane matilida obtained from methyltriphenylphosphonium, methyltriphenylphosphonium or methyltriphenylphosphonium, or trimethylsilylmethylamine chloride, trimethylsilylmethylamine bromide or trimethylsilylmethylamine.

XVIII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr, each mean the same groups as defined above,

with peroxyketal.

XIX. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for R>
< / BR>
where R, X and Pr, each mean the same groups as defined above,

with chloromethylation obtained from chloromethane or bremgarten, or dimethylsulfoxide, dimethylsulfonium, diethylsulfoxide or diethylaluminium.

XX. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr, each mean the same groups as defined above,

with an oxidizing agent.

XXI. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

R2means a lower alkyl group,

R3denotes methyl or lower CNS group,

or Sol which means those same groups, as defined above,

with alkoxycarbonylmethyl halogen or dialkoxybenzene halogen.

XXII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr each mean the same groups as defined above,

R2means a lower alkyl group,

R3denotes methyl or lower CNS group,

with peroxynitrate in the presence of a base.

XXIII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

A denotes CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X ptx2">

XXIV. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen and

Pr represents a protective group for hydroxyl group, and means a leaving group,

or its salt, which comprises halogenoalkane, alkylsulfonate or arylsulfonate compounds represented by the General formula:

< / BR>
where R, X and Pr, each mean the same groups as defined above.

XXV. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

Pr represents a protective group for hydroxyl group,

A denotes CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr, each mean the same groups as defined above,

L is a leaving group,

with 1,2,4-triazole or imidazole or its salt.

XXVI. The method of obtaining the compound represented by the General formula:
A denotes CH or a nitrogen atom,

or its salt, which comprises removing the Pr, which is a protective group for the hydroxyl group of compounds represented by the General formula:

< / BR>
where R, X and A, each mean the same groups as defined above,

Pr is a protecting group for a hydroxyl group.

XXVII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

A denotes CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and A, each mean the same groups as defined above,

with an oxidizing agent.

XXVIII. The method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen,

A denotes CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and A, each means the same groupdelay connection, represented by the General formula:

< / BR>
where R1and R2the same or different from each other and represent each a halogen atom or a hydrogen atom;

R3means a hydrogen atom or a lower alkyl group;

l, r and m can be the same or different from each other and represent each 0 or 1;

A is N or CH;

W denotes an aromatic ring or a condensed ring which may have one or more heteroatoms and may have one or more substituents, or

W denotes an aromatic ring or condensed ring, where part or all of the aromatic ring or the condensed ring which may have one or more heteroatoms and may have one or more substituents are saturated,

X represents an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, alkadienes group which may have one or more substituents, arkendale group which may have one or more substituents, or allinternal group which may have one or more substituents; a represents a group represented by-S-, or -(CH2)j<>/BR>Z denotes a hydrogen atom, halogen atom, lower alkyl group, halogenated lower alkyl group, lower CNS group, halogenated lower CNS group, hydroxyl group, thiol group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents, a phenoxyl group, which may have one or more substituents, imidazolidinyl group which may have one or more substituents, triazolyl group which may have one or more substituents, tetrazolyl group which may have one or more substituents, or an amino group, which may have one or more substituents, except for the case when W is a triazole ring, R3is a methyl group and Z is a hydrogen atom when l = 1 and r = m = 0,

or its salt of the addition of acid and pharmaceutically acceptable salt.

Detailed description of the invention and preferred options for implementation.

The present invention relates to derivative represented by the General formula (I)

< / BR>
where A is =CH - or =N-,

L and M are the same or different from each other and the seat is th may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy; or condensed ring a 5-membered heterocyclic ring which may contain one or more other heteroatoms in addition to the sulfur atom and has a Deputy with the aromatic ring, which may contain one or more heteroatoms and may have a Deputy, or fully or partially saturated condensed ring,

or its salts of addition of the acid, which has excellent antifungal properties.

Derivatives according to the present invention can be obtained by different ways of synthesis. Some of them are shown in the examples below.

Process A:

2-Chloro-2',4'-defloration added to 4-(2,4-differenl)the triazole in the presence of n-utillity. After treatment of the reaction product added 1,2,4-triazole and sodium hydride and get 1-(2,4-differenl)-1-(4-(2,4-differenl)thiazol-2-yl)- 2-(1H-1,2,4-triazole-1-yl)ethanol.

Process B:

(1) 2-Chloro-2', 4'-defloration added to 6-cyanobenzoate in the presence of n-utility to obtain 1-(2,4-differenl)-1- (6-cyanobenzoate-2-yl)-2-chloroethanol.

(2) 1,2,4-Triazole is added to a suspension of sodium hydride in dimethylformamide. To this suspension is added 1-(2,4-differenl)- 1-(6-tianamen is 1,2,4,triazole-1-yl)ethanol.

Process C:

1-(2,4-Differenl)-1-(4-(4-cyanophenyl)thiazol-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol interacts with sodium azide and triethylamine hydrochloride to obtain 1-(2,4-differenl)-1- [4-[(4-(5-tetrazole)phenyl)thiazol]-2-yl] -2-(1H-1,2,4-triazole-1 - yl)ethanol.

Process D:

Methyliodide interacts with 1-(2,4-differenl)-1-[4-[(4- (5-tetrazole)phenyl)thiazol] -2-yl] -2-(1H-1,2,4-triazole-1 - yl)ethanol obtained in the above process C, with the receipt of two isomers, in which a methyl group substituted at the 3 - and 4-positions tetrazole rings.

Process E:

1-(2,4-Differenl)-1-(2-(4-forfinal)thiazol-5-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol interacts with 1,2,4-triazole and sodium hydride to obtain 1-(2,4-differenl)-1-[2-[(4-(1-1H - 1,2,4-triazole)phenyl)thiazole]-5-yl)-2-(1H-1,2,4-triazole-1 - yl)ethanol.

Process F:

1-(2,4-Differenl)-1-(6-thiocarbamoylation-2-yl)-2- (2-(1H-1,2,4-triazole-1-yl)ethanol interacts with sodium bicarbonate and bromoacetone to obtain 1-(2,4 - differenl)-1-(6-(3-methylthiazole-1-yl)benzothiazole-2-yl)-2-(2-(1H-1,2,4 - triazole-1-yl)ethanol.

Process G:

1-(2,4-Differenl)-1-(6-cyanobenzoate-2-yl)-2-(2- (1H-1,2,4-triazole-1-yl)ethanol and triethylamine dissolved in dimethylformamide. In the resulting solution Mgr)-2-(2-(1H-1,2,4-triazole-1-yl)ethanol.

The process H:

1-(2,4-Differenl)-1-(6-thiocarbamoylation-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol is subjected to interaction with dimethylacetal of bromoacetaldehyde to obtain 1-(2,4 - differenl)-1-(6-thiazol-1-yl)benzothiazole-2-yl-2-(1H-1,2,4-triazole-1 - yl)ethanol.

Process I:

(1) 1-(2,4-Differenl)-1-(4-thiocarbamoylation-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol is subjected to interaction with barometerbarometric acid to obtain 1-(2,4 - differenl)-1-(4-ethoxycarbonylmethyl-2-yl)thiophene-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol (A).

(2) thus Obtained compound (A) is dissolved in saturated methanolic ammonia solution and the resulting solution was allowed to stand for passage of interaction between the compound (1) and ammonia to obtain 1-(2,4-differenl)-1-(4-(4- carbamoylmethyl-2-yl)thiophene-2-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol (B).

Process J:

The compound (V) obtained in stage (2) of the above process 1, is dissolved in pyridine and subjected to interaction with phosphorus oxychloride to obtain 1-(2,4-differenl)-1-(4-(4- cenotesa-2-yl)thiophene-2-yl)-2-(1H-1,2,4-triazole-1 - yl)ethanol.

As examples of solvents used in the present invention, can be mentioned lower alcohols, tone, methyl ethyl ketone, diethylketone and cyclohexanone, ethers, such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol and 1,2-dimethoxyethane; NITRILES, such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, butyl acetate and diethylphthalate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromatic compounds such as benzene, toluene, xylene, monochlorobenzene, nitrobenzene, indole, pyridine, quinoline, kallidin and phenol; hydrocarbons, such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum ether and petroleum benzine; amines, such as ethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine and toluidine; amides, such as formamide, N-organic, N,N-dimethylimidazole, N, N-dimethylacetamide and N,N-dimethylformamide; amides of phosphoric acid, such as triamide hexamethylphosphoric acid triamide and hexamethylphosphoric acid; organic acids such as formic acid, acetic acid, DIPEROXY acid, triperoxonane acid and Chloroacetic acid; sulfoxidov, appropriate solvents. These solvents can be simple solvents or mixtures of two or three solvents. There are no particular limitations on the ratio between miscible solvents.

As pharmaceutically acceptable salts, derivatives, salts of addition of the acid according to the present invention include salts.

Exactly, as examples of inorganic salts, you can specify the alkali metal salts, such as salts of sodium and potassium salts; ammonium salts, salts of tetraethylammonium, Quaternary ammonium salts such as salts of betaine; salts of alkaline earth metals such as calcium salts and magnesium salts; and salts of inorganic acids, such as hydrochloride, hydrobromide, sulphates, carbonates and bicarbonates.

On the other hand, as examples of organic salts can be specified organic carboxylates such as acetates, maleate, lactates and tartratami; organic sulfonates such as methanesulfonate, hydroxyethanesulfonic, hydroxyethanesulfonic, salt cabrinovic acids, benzosulfimide and toluensulfonate; salts of amino acids such as arginine salt, lysine, serine, aspartate, glutamate and glycine chelates; amine salts such as salts of triethylenediamine, salt, N-methylglucamine, diethanolamine salt, triethanolamine salt, Tris salt(hydroxymethylamino)methane and salt venetiancasino.

Further, the present invention relates to a compound represented by the General formula (I)

< / BR>
where R1and R2the same or different from each other and represent each a halogen atom or a hydrogen atom;

R3means a hydrogen atom or a lower alkyl group;

r and m can be the same or different from each other and represent each 0 or 1;

A is N or CH;

W denotes an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, or its condensed ring;

X represents an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, alkadienes group which may have one or more substituents, arkendale group which may have one or more substituents, or allinternal group which may have one or more substituents;

Y represents a group represented by-S-, or -(CH2)j-, in which R6means the atom is alogena, lower alkyl group, halogenated lower alkyl group, lower CNS group, halogenated lower CNS group, hydroxyl group, thiol group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents, a phenoxyl group, which may have one or more substituents, imidazolidinyl group which may have one or more substituents, triazolyl group which may have one or more substituents, tetrazolyl group which may have one or more substituents, or an amino group which may have one or more substituents, except for the case when W is a triazole ring, R3is a methyl group and Z denotes a hydrogen atom when l = 1 and r = m = 0,

or its salt of the addition of acid, which has excellent antifungal properties.

Compounds according to the present invention can be obtained by different ways of synthesis. Some of them are shown in the examples below.

I path:

The compound of the formula:

< / BR>
where A, R1, R2and R3defined above

subjected to interaction with the connection Togo connection represented by the formula:

< / BR>
where W is a group containing a substituted azole, and

A, R1, R2, R3X, Y, Z, r and m are defined above.

II path:

The compound of the formula:

< / BR>
where A, R1and R2defined above,

subjected to interaction with the compound of the formula:

< / BR>
where D is a group containing a substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring or a condensed ring, and

Z is hydrogen or CH3,

with getting through this connection represented by the formula:

< / BR>
where W is a substituted or unsubstituted nitrogen-containing 5-membered heterocyclic ring or a condensed ring, and

A, R1, R2, R3X, Y, Z, r and m are defined above.

III path:

The compound of the formula:

< / BR>
where A, R1and R2defined above,

subjected to interaction with the compound of the formula:

< / BR>
where R3X, Y, Z, r and m are defined above,

with getting through this connection represented by the formula:

< / BR>
where W is a group containing a substituted or unsubstituted 5-membered heterocyclic ring or a condensed Cali:

< / BR>
where R1, R2, R3, W, X, Y, Z, r and m are defined above,

subjected to interaction with meta-chloroperbenzoic acid and then with sodium 1,2,4-triazole or sodium 1,3-imidazole with getting through this connection represented by the formula:

< / BR>
where A, R1, R2, R3, W, X, Y, Z, r and m are defined above.

The acid forming the salt of the added acid compounds in accordance with the present invention, can be used inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and citric acid. Preferred acids are hydrochloric and acetic acid.

As examples of solvents used in the present invention, may be mentioned lower alcohols such as methanol, ethanol, propanol and butanol; polyhedrality, such as ethylene glycol; ketones, such as acetone, methyl ethyl ketone, diethylketone and cyclohexanone; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol and 1,2-dimethoxyethane; NITRILES, such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, isoprop enclarity carbon, 1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromatic compounds such as benzene, toluene, xylene, monochlorobenzene, nitrobenzene, indole, pyridine, quinoline, kallidin and phenol; hydrocarbons, such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine and petroleum ether; amines, such as ethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine and toluidine; amides, such as formamide, N-organic, N, N-dimethylimidazole, N, N-dimethylacetamide and N,N-dimethylformamide; amides of phosphoric acid, such as triamide hexamethylphosphoric acid triamide and hexamethylphosphoric acid; organic acids such as formic acid, acetic acid, DIPEROXY acid, triperoxonane acid and Chloroacetic acid; sulfoxidov, such as dimethyl sulfoxide; carbon sulfides such as carbon disulfide; water and other commonly used solvents. These solvents can be simple solvents or mixtures of two or three solvents. There are no particular limitations on the mixing ratio of the mixed solvents.

As pharmaceutically acceptable salts, derivatives, the examples of inorganic salts, you can specify the alkali metal salts, such as salts of sodium and potassium salts; ammonium salts; salts of tetraethylammonium; Quaternary ammonium salts such as salts of betaine; salts of alkaline earth metals such as calcium salts and magnesium salts; and salts of inorganic acids, such as hydrochloride, hydrobromide, sulphates, carbonates and bicarbonates.

On the other hand, as examples of organic salts can be specified organic carboxylates such as acetates, maleate, lactates and tartratami; organic sulfonates such as methanesulfonate, hydroxyethanesulfonic, hydroxyethanesulfonic, salt cabrinovic acids, benzosulfimide and toluensulfonate; salts of amino acids such as arginine salt, lysine salt, serine salt, aspartate, glutamate and glycine chelates; amine salts, such as salts, triethylamine salts of trimethylamine, pyridine salts, salts of procaine, picoline salts, salts dicyclohexylamine, salts of N,N-dibenziletilendiaminom, salt, N-methylglucamine, salts diethanolamine, triethanolamine salt, Tris salt(hydroxymethylamino)methane and salt venetiancasino.

Further, the present invention relates to a method for producing a compound represented on auxillou group, and

L represents a leaving group,

or its salt, which includes the introduction of protection for the hydroxyl group of compounds represented by the General formula:

< / BR>
where R means the same group as defined above, and

R1denotes a hydrogen atom or a protective group for carboxyl group,

by introducing a protective group to obtain compounds represented by the General formula:

< / BR>
where R, R1and Pr, each mean the same groups as defined above, respectively,

removing the protective group of carboxyl group in the formula (2) to obtain the compound represented by the formula:

< / BR>
where R and Pr have the same groups as defined above, respectively,

and the interaction of this compound of the formula (3) with the compound represented by the formula: LH, where L is a leaving group;

to a method for producing compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen, and

Pr represents a protective group for hydroxyl group,

or their salts, which comprises the interaction of compounds, predstavlepy,

with a compound represented by the General formula:

< / BR>
where X are the same group as defined above, and

Y represents a chlorine atom, bromine or iodine, respectively.

or its reactive derivative;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

with triphenylphosphonium obtained from methyltriphenylphosphonium, methyltriphenylphosphonium or methyltriphenylphosphonium, or trimethylsilylmethylamine, trimethylsilylmethylamine or trimethylsilylmethylamine;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr is protect the unity, represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

with peroxisomal;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X in Pr have the same groups as defined above,

with chloromethylation obtained from chlorodimethyl or bremgarten, or dimethylsulfone Metricom or dimethylsulfoxide matilida;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and represent each a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

with ocil ACHAT lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom,

Pr represents a protective group for hydroxyl group,

R2represents a lower alkyl group, and

R3represents a methyl group or a lower CNS group, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

with alkoxycarbonylmethyl halogen or dialkoxybenzene halogen;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom,

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

R2represents a lower alkyl group, and

R3represents a methyl group or a lower CNS group,

with peroxynitrate in the presence founded kilou group

X are identical or different from each other and denote a hydrogen atom or halogen atom,

Pr represents a protective group for hydroxyl group and

A denotes CH or nitrogen atom, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above,

with 1,2,4-triazole or imidazole or its salt;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom,

Pr represents a protective group for hydroxyl group, and

L is a leaving group, respectively,

or its salt, which comprises halogenoalkane, alkylsulfonate or arylsulfonate compounds represented by the General formula:

< / BR>
where R, X and Pr have the same groups as defined above;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom,
or its salt, which comprises the interaction of the compounds represented by the formula:

< / BR>
where R, X and Pr have the same groups as defined above, and

L is a leaving group,

with 1,2,4-triazole or imidazole or its salt;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom,

Pr represents a protective group for hydroxyl group and

A denotes CH or nitrogen atom, respectively,

or its salt, which comprises removing the Pr, which is a protective group for the hydroxyl group of compounds represented by the General formula:

< / BR>
where R, X, Pr and A have the same group as defined above, respectively,

or its salts;

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

A denotes CH or nitrogen atom, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula

the method of obtaining the compound represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

A denotes CH or nitrogen atom, respectively,

or its salt, which comprises the interaction of the compounds represented by the General formula:

< / BR>
where R, X and A have the same group as defined above, respectively,

with hydroxylamine-O-sulfonic acid.

These methods include methods of producing intermediate products of synthesis for the preparation of an antifungal agent.

This invention further relates to the following compounds or their salts, which are used as intermediate products of the synthesis. Thus, the present invention relates to compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

Pr means a protective group for hydroxyl group, and

L represents a leaving group, respectively,

or their salts;

the compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are the same or different from droopy, and

Q represents an oxygen atom or CH2accordingly,

or their salts;

the compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group, respectively,

or their salts;

the compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group, and

M represents a hydroxyl group or a leaving group, respectively,

or their salts; and

the compounds represented by the General formula:

< / BR>
where R means a lower alkyl group,

X are identical or different from each other and denote a hydrogen atom or halogen atom, and

Pr represents a protective group for hydroxyl group, and

A represents CH or nitrogen atom, respectively,

or their salts.

Then given a detailed explanation of this invention and used terminamos or branched chain, containing 1-6 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, isopentyl group, tert-pentelow group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexoloy group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyloxy group and the like. A preferred group includes methyl group, ethyl group, through the group, etc.

R1denotes a halogen atom or a protective group for carboxyl group.

Used here is a protective group for a carboxyl group may be any group commonly used in organic C is for the carboxyl group include, for example, a lower alkyl group with straight chain or branched chain containing 1-6 carbon atoms, such as methyl group, ethyl group, isopropyl group and a tert-boutelou group; halogenated lower alkyl groups such as 2-iodation group and 2,2,2-trichlorethylene group; lower alkoxyalkyl groups, such as methoxymethyl group, ethoxymethyl group and isobutoxide group; lower aliphatic aryloxyalkyl groups, such as acetoxymethyl group, propionylthiocholine group, butyrylcholine group and pivaloyloxymethyl group; lower alkoxycarbonylmethyl groups, such as methoxycarbonylmethyl group, 1-methoxycarbonylethyl group, ethoxycarbonylmethylene group, 1-ethoxycarbonylmethylene group and 2-methoxycarbonylmethylene group; kalkilya groups such as benzyl group, p-methoxybenzyl group, nitrobenzyl group and p-nitroaniline group; benzydamine group and felicilda group; (5-methyl-2-oxo-1,3-dioxo-4-yl)-methyl group and the like.

Removing the protective group of the carboxyl group can be carried out in the usual way, such as hittnau group for hydroxyl group.

Used here, the protective group for hydroxyl group can be any group that is used in organic synthesis as a protective group for hydroxyl group, and not particularly limited. Examples of protective groups for the hydroxyl group include, for example, lower alkylsilane groups, such as trimethylsilyl group, tert-butyldimethylsilyl group and so forth; the lower alkylarylsulfonate group, such as tert-butyldiphenylsilyl group and so forth; the lower alkoxymethyl groups, such as methoxymethyl group, 2-methoxyethoxymethyl group, etc. such as tetrahydropyranyl group; kalkilya groups such as benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, nitrobenzyl group, p-nitrobenzyl group, triticina group, methoxytrityl group, dimethoxytrityl group and so forth; acyl groups such as formyl group, acetyl group, etc.,; the lower alkoxycarbonyl group, such as tert-butoxycarbonyl group, 2-iodoxybenzene group, 2,2,2-trichlorocarbanilide group and so forth; altneratively groups such as 2-propanecarboxylate group, 2-chloro-2-propanecarboxylate gruppenarbeit group, cinnamoylcocaine group and so forth; aracelikarsaalyna groups, such as benzyloxycarbonyl group, p-methoxybenzenesulfonyl group, nitrobenzisoxazole group, p-nitrobenzisoxazole group, etc.

Removing the protective group of hydroxyl group can be carried out in the usual way, such as hydrolysis, restoration or the like, depending on the type of the protective group.

L represents a leaving group.

Used here leaving group may be any group that is used in organic synthesis as leaving groups, and not particularly limited. Examples of leaving groups include, for example, halogen atoms such as chlorine atom, bromine atom, iodine atom, etc., allylthiourea, such as methylthiourea, ethylthiourea, PropertyGroup etc.; aristocraty, such as phenylthiourea, tolylthiourea, 2-pyridylthio etc., alkylsulfonates, such as methyloxirane, triftormetilfullerenov, econsultancy, propanesulfonate etc.; arylsulfonate, such as benzolsulfonate, tailorshop etc.; alkanoyloxy, such as acetoxy is.; alkylamino, such as methylaminopropyl, atramentaria, propylamino, butylamino etc.; dialkylamines, such as dimethylaminopropyl, diethylaminopropyl, dipropylamino, methylaminopropyl, ethylpropylamine, methylpropylamine and so on; and substituted phosphoryloxy, such as diphenoxyethane, etc. Respectively activating reagent used in reactions of this invention include, for example, the anhydrides of the acids, such as triperoxonane anhydride, methanesulfonyl anhydride, triftormetilfullerenov anhydride, p-toluensulfonyl anhydride, etc.; acid anhydrides, such as methanesulfonate, p-toluensulfonate, diphenylchlorophosphine etc., and moreover includes 2-mercaptopyridine, oxalicacid, thionyl chloride, thienylboronic and the like.

X are identical or different from each other and denote a hydrogen atom or a halogen atom. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

Y represents a chlorine atom, a bromine atom or an iodine atom.

The reactive derivative of the compound represented by the General formula:

< / BR>
which means a chlorine atom, a bromine atom or an iodine atom, respectively,

can be obtained, for example, by activating Y metal, such as Mg, with the formation of the halide of magnesium (-MgY), thereby obtaining the Grignard reagent.

Used here peroxynitrate can be any commonly used in organic synthesis, and are not particularly limited. Examples of leaving groups include, for example, organic peroxyacids, such as meta-chloroperbenzoic acid (m-HPBC), peracetic acid, etc., and aqueous hydrogen peroxide. Metachlorobenzoic acid is preferred.

Used here, the oxidizing agent can be any commonly used as an oxidizing agent in organic synthesis, and are not particularly limited. Examples of the oxidizing agent include, for example, osmium tetroxide, potassium permanganate, and the like.

Alkoxycarbonylmethyl halide means dimethyltrimethylene halide, substituted alkoxygroup corresponding to the lower alkyl group described above and, in particular, includes methoxydibenzoylmethane chloride,

methoxydibenzoylmethane bromide,

amoxicillinonline chloride,

amoxicilline chloride,

propeciaonlineorder.info bromide,

isopropoxybenzonitrile bromide, etc.

Dialkoxybenzene halide means methylselenocysteine halide, substituted alkoxygroup corresponding to the lower alkyl group described above, and in practice includes dimethoxymethylsilane chloride,

dimethoxymethylsilane bromide,

diethoxymethylsilane chloride,

diethoxymethylsilane bromide,

dibromochloromethane chloride,

dibromochloromethane bromide,

debutante.multicellular chloride,

debutante.multicellular bromide, etc.

Used here may be any generally known as a base in organic synthesis, and are not particularly limited. Examples of the base include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydride, potassium hydride, tert-butoxylate, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0] undeca-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, Isom nitrogen.

R2represents a lower alkyl group. The lower alkyl group has the same values as described above.

R3represents methyl or lower CNS group.

Lower CNS group corresponds to the above-described lower alkyl group and is, in particular, CNS group with a straight or branched chain containing 1-6 carbon atoms, and includes, for example, metaxylene group, ethoxyline group, n-propoxyphenyl group, isopropoxyphenyl group, n-butoxyl group, isobutoxy group, sec-butoxyphenyl group, tert-butoxyl group, n-pentoxil group, isopentenyl group, sec-pentoxil group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropyl group, 1,2-dimethylpropylene group, n-hexyloxyphenyl group, isohexadecane group, 1-methylpentanediol group, 2-methylpentanediol group, 3-methylpentanediol group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutanol group, 2-ethylbutanol group, 1,1,2-trimethylspiro the optimum group, etc.

Q represents an oxygen atom or CH2.

M represents a hydroxyl group or a leaving group.

This group has the same values as specified above.

Used salt is not limited in type and include, for example, salts of addition of acid, such as hydroptere, hydrochloride, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, Hydrobromic, hydroiodide, etc; salts of addition organoboronic acids, such as acetate, maleate, fumarate, oxalate, lactate, citrate, triptorelin etc.; salt addition organosulfur acids, such as methanesulfonate, triftorbyenzola, aconsultant, hydroxyethanesulfonic, hydroxyethanesulfonic, bansilalpet, toluensulfonate, salt, taurine, etc; salts of addition of amine, such as salt, triethylamine salt of trimethylamine, salt, pyridine salt of procaine, picoline salt, salt dicyclohexylamine, salt N, N-dibenziletilendiaminom, salt, N-methylglucamine, diethanolamine salt, triethanolamine salt, salt of Tris(hydroxymethylamino)methane and salt penicillamine; salts of addition of alkali metal such as sodium salt, potassium salt, etc; salts of addition of the alkali earth metal, such as salt l glycine, salt aspartamus acid, salt of glutamic acid and the like.

Pharmaceutically acceptable salt means a salt that is commonly used to obtain drugs.

Used here hydroxylamine derivative may be any compound which is generally applicable in organic synthesis for the conversion to a cyano formyl group and is not particularly limited, and includes, for example, hydroxylamine-O-sulfonic acid, etc.

Methods of obtaining, in accordance with the present invention, which are represented by the following General scheme described below (scheme, see the end of the description).

Path A-1 is the path by which the hydroxyl group of the compound represented by formula (101) [in which R and R1each mean the same groups as described above. They will be used next] is protected. The compound represented by formula (102) [where Pr means the same group as described above. It will be used next], a hydroxyl group which is protected by this method, can be obtained by protecting a hydroxyl group in accordance with the method known in the art. Hydroxyl groups, protected various protective g is science Publication Co. ,)".

Path A-2 is the path by which the protective group for the carboxyl group of the compound represented by formula (102) is subjected to removal. As with the path A-1, in this way the compound represented by formula (103), can be obtained according to the method of removing the protective group for the carboxyl group in accordance with the conventional manner, for example by hydrolysis or by catalytic regeneration with acid or base. More specifically, removing the protection can be carried out by the interaction of the compounds of formula (102) with hydrochloric acid, triperoxonane acid, acetic acid, hydrogen bromide, formic acid, tosic acid, hydrogen peroxide, trimethylsilylpropyne, tert-piperonyl potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, potassium carbonate, sodium carbonate, boron TRIFLUORIDE, aluminum halide, tetrabutylammonium fluoride, etc. in a solvent that does not inhibit the reaction.

Path A-3 is the path by which the leaving group (L) is attached to the compound represented by formula (103). The compound represented by the formula (104), can be obtained by the interaction of the compounds represented by formula (103), to activate triftormetilfullerenov anhydride or p-toluensulfonyl anhydride; the anhydrides of the acids, such as methanesulfonate, p-toluensulfonate, diphenylchlorophosphine, oxalicacid or thionyl chloride; or 2-mercaptopyridine. If desirable, can be used condensing agent, such as disclocation (DCC), in accordance with the reactivity of the used reagent.

On the way B-1 compound of the formula (105), in which the leaving group L in formula (104) are replaced with a disubstituted phenyl group, can be obtained by the interaction of the compounds represented by the formula (104), with the compound represented by formula

< / BR>
[in which X and Y each represent the same groups as described above. They will be used next] or its reactive derivative, for example a Grignard reagent, in which Y denotes-MgCl, -MgBr or MgI, activated metallic magnesium.

In C-1 olefin compound represented by the formula (106), can be obtained by the interaction (the so-called Wittig reaction) compounds represented by the formula (105), with triphenylphosphane Metricom, which is obtained by processing methyltriphenylphosphonium chloride, methyltriphenylphosphonium bromide or methyltriphenylphosphonium iodide base, such as butyldimethylchlorosilane with intermediate salelologa alcohol, and subjecting the intermediate silloway alcohol to remove the group salelologa alcohol with the help of a complex of boron TRIFLUORIDE or the like.

Path D-1 is the path by which the olefinic compound represented by the formula (106), epoxidized. There are no specific restrictions on the reagent for the epoxidation, as it is a reagent capable of epoxydecane double bond. However, as examples, you can specify organic peroxyacids, such as metachlorobenzoic acid (mjpbk), and peracetic acid, and aqueous hydrogen peroxide. Epoxysilane represented by the formula (107) was obtained, preferably, by interacting with metallocarboranes acid.

Epoxysilane represented by the formula (107) can also be obtained in the following way E-1. Namely, epoxysilane can be obtained by the coupling of compounds of formula (105) with chloromethylation obtained from chloromethane or bromomethane using a base, such as utility, or dimethylsulfoxide matilida, diethylsulfoxide Metricom or diethylsulfide matilida.

The path F-1 refers to reactions in which epoxysilane, presents formulationa, represented by the formula (108) [in which A denotes a nitrogen atom or CH. It will also be used hereinafter] , can be obtained by the interaction of epoxysilane represented by the formula (107), with alkali metal salt of imidazole or 1,2,4-triazole, which is obtained by mixing the alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride, with imidazole or 1,2,4-triazole in a solvent.

The way G-1 is the path by which the protective group for hydroxyl group is subjected to removal. This protective group for a hydroxyl group may be removed by a method known in the art. For example, it can be carried out by the method described by Green in the literature above.

The path H-1 is the path by which the olefinic compound oxidizes 1.2-diglycol using an oxidizing agent. The compound represented by the formula (110), can be obtained by treating compound represented by the formula (106), an oxidizing agent such as osmium tetroxide or potassium permanganate.

Path I-1 is the path by which the compound represented by the formula (105), is converted into the compound represented by the formula (110). This way the connection represented by ParameterName a halide or dialkoxybenzene the halide with the connection, represented by the General formula

< / BR>
[in which R2means a lower alkyl group and R3denotes a methyl or a lower alkyl group. They will be used next], and then by the interaction of the thus obtained compound with peroxynitrate in the presence of a base.

The way J-1 is the path by which the primary hydroxyl group of the compound represented by the formula (110) is replaced by a leaving group L. This process can be carried out in accordance with the path a-3. The compound represented by the formula (111) can be obtained by the interaction of the compounds represented by the formula (110), preferably the acid chloride of the acid, such as methanesulfonate, p-toluensulfonate, diphenylchlorophosphine, oxalicacid or thionyl chloride.

On the way J-2 leaving group L of the compound represented by the formula (111) can be replaced imidazolidines or 1,2,4-triazoline group conducting the engagement in accordance with the by F-1.

The path K-1 is the path by which the primary hydroxyl group of the compound represented by the formula (109), is oxidized to a formyl group. Oxidation of this primary hydroxyl group can be osula, such as chromium, manganese, or silver, or an organic oxidizing agent, typical of dimethyl sulfoxide. As reagents can be used, for example, a complex of chromic acid - pyridine, pyridine chlorproma or pyridine dichromate. An alternative commonly used method of oxidation with DMSO, using oxalicacid.

Path L-1 is the path by which the primary hydroxyl group of the compound represented by the formula (112), is substituted by cyano. The compound represented by the formula (113), can be obtained by the interaction of the compounds represented by the formula (112), with a derivative of hydroxylamine, such as hydroxylaminopurine acid.

Path M-1 and N-1 are ways to get antifungal agent, which is the final compound and represented by the formula (115). These paths can be obtained the compounds having excellent antifungal activity and represented by the formula (115), by adding hydrogen sulfide to the compound represented by the formula (113), with the formation of compounds represented by the formula (114), and then by the interaction of the thus obtained compound with 2-bromo-4'-methylthiazolidine.

Reacts The P>C, preferably from -40oC to 50oC, more preferably from -20oC to 25oC.

No particular limit is imposed on the solvent used in the present invention, therefore, they should not impede the reaction, and are typically used in organic syntheses. However, as shown in the examples, you can specify lower alcohols, such as methanol, ethanol, propanol and butanol; polyhedrality, such as ethylene glycol and glycerin; ketones such as acetone, methyl ethyl ketone, diethylketone and cyclohexanone; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol and 1,2-dimethoxyethane; NITRILES, such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, isopropylacetate, butyl acetate and diethylphthalate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromatic compounds such as benzene, toluene, xylene, monochlorobenzene, nitrobenzene, indole, pyridine, quinoline, kallidin and phenol; hydrocarbons, such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine and petroleum ether; amines, tan, benzylamine and toluidine; amides, such as formamide, N-organic, N,N-dimethylimidazole, N,N-dimethylacetamide and N,N-dimethylformamide; amides of phosphoric acid, such as triamide hexamethylphosphoric acid triamide and hexamethylphosphoric acid; organic acids such as formic acid, acetic acid, DIPEROXY acid, triperoxonane acid and Chloroacetic acid; sulfoxidov, such as dimethyl sulfoxide; carbon sulfides such as carbon disulfide; water and other commonly used solvents. These solvents can be simple solvents or mixtures of two or three solvents. There are no particular limitations on the ratio between miscible solvents.

Along the path indicated above, the products obtained can be purified, known in the art, such as column chromatography on silica gel or the like, if necessary, and they can be subjected to a reaction for removing the protective groups, if desired. Removing the protective groups can be performed by subjecting the products to restore, such as catalytic reduction or solvolysis.

In addition, compounds represented by the following formula

< / BR>
or their salts, the compounds represented by the General formula

< / BR>
or their salts, and compounds represented by the General formula

< / BR>
or their salts [in the formula (116) - (120) R, Pr, L, X, Q, M and A, each mean the same groups, the above] used in the methods of manufacturing of the present invention and the synthesis of compounds with excellent antifungal activity.

For compounds and methods of obtaining, in accordance with the present invention there are stereometry having asymmetric carbon atom in the molecule and having the S-configuration or R-configuration. In addition, for those compounds which have a double bond, there are geometrical isomers of type E or z To confirm the description describes one configuration. However, the present invention covers both compounds and their mixtures. Compounds according to the present invention is not limited presents in the formula described for illustration. The optical isomers can be separated by conventional methods for optical separation, while the diastereomers can be separated using the method of separation such as chromatography.

When it is assumed polostei with their respective methods of obtaining of the present invention.

From the point of view of the antifungal activity of sterically it is preferable to use a method of obtaining, where optically active (S)-methylhydroxy-2-methylpropionate used as compounds of General formula (101) or the original product in the implementation of the method described above for formation of compounds of General formula (113), supporting stereostructure, with getting through this optically active (2S,3R)-3-(2,4 - differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)- butyronitrile as compounds of General formula (113) and intermediate products with this stereostructure.

According to the present invention, for example, can be obtained compound represented by the General formula:

< / BR>
where X are the same or different from each other and represent each a hydrogen atom or halogen;

R4means a hydrogen atom or a lower alkyl group;

r and m can be the same or different from each other and represent each 0 or 1;

A is N or CH;

W denotes an aromatic ring which may have one or more substituents and may contain one or more heteroatoms selected from N, S and O, or its condensed ring;

G represents a group represented by-S-, or -(CH2)j-, in which R5means a hydrogen atom or a lower alkyl group, and j represents an integer of 1-4; and

Z denotes a hydrogen atom, halogen atom, lower alkyl group, halogenated lower alkyl group, lower CNS group, halogenated lower CNS group, hydroxyl group, thiol group, a nitrogroup, cyano, lower alkanoyloxy group, a phenoxyl group, which may have one or more substituents, imidazolidinyl group which may have one or more substituents, triazolyl group which may have one or more substituents, tetrazolyl group which may have one or more substituents, or an amino group which may have one or more substituents,

or their salts.

Some examples will be given hereinafter to describe the invention in more detail. However, the present invention but ogranichennoi Varian Company.

In addition, Tr, Ms, MOM, TBDPS and Bn denote the next group of trail, mesyl, methoxymethyl, tert-butyldiphenylsilyl and benzyl, respectively.

Examples.

The present invention is hereinafter described in the examples, experimental examples and formulation examples more specifically. However, the present invention is not limited to only these examples, experimental examples and formulation examples

Example 1:

Synthesis of 1-(2,4-differenl)-1-(4-(2,4-differenl)thiazol-2-yl)- 2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
After dissolving 4-(2,4-differenl)thiazole (330 mg) in diethyl ether (3 ml) and cooling the resulting solution to -78oC in an atmosphere of nitrogen was added 1.6 M solution of 1.06 ml) n-utility in hexane and the resulting mixture is stirred for about 10 minutes. After adding to the mixture dropwise solution of 2-chloro-2',4'- defloration (306 mg) in tetrahydrofuran liquid reaction mixture is heated to -20oC for the addition of an aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is dissolved in dimethylformamide (3 ml) to obtain rastriya (135 mg). Solution (B) was added to a solution of (a), and the mixture is heated at 60oC for 6 hours. Then the liquid reaction mixture are added ethyl acetate and water and the organic layer washed for some time with water, the solvent is distilled off. The residue is subjected to column chromatography on silica gel to recrystallization fraction containing the desired compound from diethyl ether to obtain through this specified in the title compound (390 mg). Its physical properties are shown in table 1.

Example 2.

(1) Synthesis of 1-(2,4-differenl)-1-(6-cyanobenzoate-2-yl)-2 - chloroethanol

< / BR>
After dissolving 6-cyanobenzoate (1.60 g) in tetrahydrofuran (80 ml) and cooled to -98oC in nitrogen atmosphere are added dropwise within 10 minutes of 1.6 M solution (5,9 ml) n-utility in hexane and the resulting mixture stirred for 5 minutes. To this mixture is added dropwise a solution of 2-chloro-2',4'-defloration (2.85 g) in tetrahydrofuran (20 ml). After heating the liquid reaction mixture to -10oC it added to an aqueous solution of ammonium chloride. After heating the reaction mixture to room temperature, the organic layer is separated, the solvent is distilled off under reduced pressure. Aq the content of inorganic fillers layer washed with water and then with saturated salt solution, dried over magnesium sulfate and then distilled under reduced pressure. The residue is subjected to column chromatography on silica gel (solvent: hexane/ethyl acetate = 20/1, then hexane/ethyl acetate = 5/1) to obtain by this means the desired compound (1,49 g).

(2) Synthesis of 1-(2,4-differenl)-1-(6-cyanobenzoate-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol

< / BR>
Sodium hydride (440 mg) is suspended in dimethylformamide (10 ml) and added 1,2,4-triazole (948 mg) to a suspension, to which is added 1-(2,4-differenl)-1-(6-cyanobenzoate-2-yl)-2 - chloroethanol (1,49 g) in dimethylformamide (10 ml). The mixture is heated at 60oC for 4 hours. After cooling, the liquid reaction mixture to room temperature, thereto was added ethyl acetate and water. The separated organic layer is washed three times with water and then dried over magnesium sulfate and the solvent is distilled off. The residue is recrystallized from dichloroindophenol ether to give the desired compound (1,17 g). Melting point: 170-172oC.

Example 3.

Synthesis of 1-(2,4-differenl)-1-[4-[(4-(5- tetrazole)phenyl)thiazol]-2-yl]-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(4-(4-cyanophenyl)thiazol-2-yl)-2-(1H - 1,2,4-triazole-1-yl)ethanol (melting point 195-198alumina (404 mg). The resulting mixture was heated overnight (12 hours) at 100oC. After removal of insoluble material by filtration and distillation of the solvent the residue is dissolved in a small quantity (each about 2 ml) of acetone and ethyl acetate. To the solution was added water and the pH of the solution set about 4 with concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried, thus obtaining specified in the title compound (380 mg). Melting point: 252-254oC. Its physical properties are shown in table 2.

Example 4.

Synthesis of 1-(2,4-differenl)-1-[4-[(4-(5-(3-methyl)tetrazol)- phenyl]thiazol] -2-yl-2-(1H-1,2,4-triazole-1-yl)ethanol [structural formula A] and 1-(2,4-differenl)-1-[4-[(4-(5-(4- methyl)tetrazole)phenyl)thiazole] -2-yl-2-(1H-1,2,4-triazole-1-yl)ethanol [structural formula B]

The structural formula of A

< / BR>
The structural formula B

< / BR>
1-(2,4-Differenl)-1-[4-[(4-(5-tetrazole)phenyl)thiazol] -2 - yl] -2-(1H-1,2,4-triazole-1-yl)ethanol (320 mg) obtained in example 3, was dissolved in dimethylformamide (3 ml). To the solution was added cesium carbonate (231 mg) and the mixture was stirred at 60oC for 30 minutes and then cooled to room temperature. Add methyliodide (0,048 ml) and poluchaetsya. After removal of the solvent under reduced pressure from the extract, the residue is subjected to column chromatography on silica gel with getting through this connection [melting point: 188-191oC] structural formula A by elution with 1% methanol-chloroform and then obtaining compounds [dual melting point: 110-115oC and 185-187oC] (60 mg) structural formulas In the elution with 2% methanol-chloroform. Its physical properties are shown in table 2.

Example 5.

Synthesis of 1-(2,4-differenl)-1-[2-(4-1-1H-1,2,4 - triazole)phenyl)thiazol-5-yl)]-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
A solution of 1-(2,4-differenl)-1-(2-(4-forfinal)-1-(2-(4- forfinal)thiazol-5-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol in dimethylformamide (3 ml) is added dropwise to the solution in dimethylformamide (3 ml), obtained from 1H-1,2,4-triazole (168 mg) and 60% sodium hydride (81 mg). The resulting mixture was heated at 100oC for 30 hours. After cooling, the liquid reaction mixture to room temperature there was added water and extracted with ethyl acetate. The solvent is distilled off from the extract and the resulting residue is subjected to column chromatography on silica gel (elution with 3% methanol-ethyl acetate) to obtain through this, is specified in the header is terphenyl)-1-(6-thiocarbamoylation-2-yl)- 2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(6-cyanobenzoate-2-yl)-2-(1H-1,2,4 - triazole-1-yl)ethanol (418 mg) and triethylamine (500 mg) dissolved in dimethylformamide (4 ml). After cooling, ice water, the resulting solution is injected hydrogen sulfide for 5 minutes. After keeping for more than 6 hours at room temperature to the solution was added water and ethyl acetate to separate liquid layers. The organic layer is washed twice with water and then with saturated salt solution and dried over magnesium sulfate. The solvent is distilled to give the desired compound (437 mg). Its physical properties are shown in table 2.

Example 7.

Synthesis of 1-(2,4-differenl)-1-(6-(3-methylthiazole-1-yl) benzothiazole-2-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(6-thiocarbamoylation-2-yl)-2- (1H-1,2,4-triazole-1-yl)ethanol (219 mg) was dissolved in ethanol (2 ml) and to the solution was added sodium bicarbonate (42 mg) and bromoacetone (46 l). The resulting mixture is heated at 60oC for 3 hours. The ethyl acetate and water added to the liquid reaction mixture to separate liquid layers. The organic layer was washed with saturated salt solution and then dried and the solvent is distilled off. The residue is subjected to column chromatography on silica gel (LWIR the melting point: 213-215oC.

Example 8.

Synthesis of 1-(2,4-differenl)-1-(6-thiazol-1-yl)benzothiazole-2-yl)- 2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(6-thiocarbamoylation-2-yl)-2-(1H - 1,2,4-triazole-1-yl)ethanol (181 mg) and dimethylacetal of bromoacetaldehyde (256 g) dissolved in ethanol (2 ml). To the solution was added three drops of concentrated sulphuric acid and boiled under reflux for 2.5 hours. After cooling, the liquid reaction mixture there was added water and a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and then with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off. To the residue was added hexane for planting the reaction product, which is then collected by filtration and washed with hexane to obtain through this, the desired compound (168 mg). Melting point: 162-166oC.

Example 9.

(1) Synthesis of 1-(2,4-differenl)-1-(4-(4-ethoxycarbonylmethyl-2 - yl)thiophene-2-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(4-thiocarbamoylation-2-yl)-2-(1H-1,2,4 - triazole-1-yl)ethanol (1.6 g) dissolved in dimethylformamide (10 ml) and to the solution add-brometalia water is added and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with a saturated solution of salt. The residue is subjected to column chromatography on silica gel (chloroform: methanol = 80:1) to obtain by means of this oily product (1.78 g).

(2) Synthesis of 1-(2,4-differenl)-1-(4-(4-carbamoylmethyl-2 - yl)thiophene-2-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(4-(4-ethoxycarbonylmethyl-2-yl)- thiophene-2-yl)-2-(1H-1,2,4-triazole-1-yl)ethanol (1.7 g) obtained in stage (1), dissolved in a saturated methanol solution (35 ml) of ammonia and the resulting solution is kept for 23 hours at room temperature. After removal of the solvent under reduced pressure to obtain crystals (1.2 g) from dichloromethane-ether melting Point: 112-115oC.

Example 10:

Synthesis of 1-(2,4-differenl)-1-(4-(4-cenotesa-2-yl)thiophene-2 - yl)-2-(1H-1,2,4-triazole-1-yl)ethanol

< / BR>
1-(2,4-Differenl)-1-(4-(4-carbamoylmethyl-2-yl)thiophene-2 - yl)-2-(1H-1,2,4-triazole-1-yl)ethanol (1.2 g) dissolved in pyridine (7,1 ml). The solution is cooled in an ice bath and to it add phosphorus oxychloride (0,29 ml). The resulting mixture was stirred for 30 minutes. After the interaction to the reaction mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer is washed once with 6 N from the site of salt. After drying the thus obtained organic layer over magnesium sulfate, the solvent is distilled off and the residue is purified column chromatography on silica gel. Recrystallization from dichloromethane solution in ether then yields a solid product (800 mg). Melting point: 172-173oC.

Examples 11-17.

Compounds represented by the General formula (II):

< / BR>
in which A, M, and L replaced, as shown in table 1, receive the same manner as in example 1.

In the tables below are given the following notation:

mp. - So pl.

1N. M.R. -1H NMR

Hz - Hz

brd - user. D. (broadened doublet)

brs - user. C. (broadened singlet)

d - d (doublet)

dd - DD (double doublet)

m - m (multiplet)

s - s (singlet)

td - TD (triple doublet)

Examples 18-87.

The target compounds obtained in the same manner as in examples 1-10, the total shown in table 2.

Experimental example 1.

Groups of five mice ICR infect through their tail veins with a strain of Candida albicans MCY 8622 (2 x 106 SOY/mouse) (SFU - SOY, interiorsbysha unit). After 1 hour connection [represented by the General formula (III)], is shown in t is the period of 7 days to calculate the average number of days of survival for each group. This is the average number used as an index indicating the antifungal activity in vivo.

General formula (III) is as follows:

< / BR>
Preparative example 1:

The raw product 1: (2S,3R)-3-(2,4-differenl)-3 - hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyronitrile

The structural formula is:

< / BR>
To a solution of 5 g (20.0 mmol) of optically active (2R,3S)-2-(2,4-differenl)-3-methyl-2-(1H-1,2,4-triazole-1 - yl)methyloxirane dissolved in 40 ml of toluene, add 80 ml of diethylammonium (1.0 M toluene solution) under nitrogen atmosphere. The mixture is heated at 50oC for 12 hours and added dropwise sequentially added 10 ml of water and 120 ml of 1 HCl. The resulting mixture is stirred for 2 hours at room temperature, filtered through filter Florisil and then subjected to extraction with ethyl acetate. The obtained organic layer is washed 4 times with liquid obtained by mixing water and saturated salt solution at a ratio of 1:1, and finally with a saturated solution of salt. After removal of the solvent under reduced pressure the residue was washed with diisopropyl ether to obtain 3.15 g (56,6%) of optically active (2S,3R)-3-(2,4-differenl)-3 - hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyronitrile. Physical the ) of 1.17 (3H, d, J=7,2 Hz), 3,29 (1H, q, J=7.2 Hz), 4,82 (1H, d, J=14,0 Hz), equal to 4.97 (1H, d, J=14,0 Hz), 5,44 (1H, d, J=0.8 Hz), 6,74-PC 6.82 (2H, m), 7,39-7,46 (1H, m), 7,83 (1H, s), to 7.84 (1H, s).

MS: MH+= 279.

Preparative example 2:

Obtaining a crude product of 1 another method:

The uranyl chloride ytterbium in the amount of 388 mg (1 mmol) is left for 6 hours at 120oC under reduced pressure. This compound is suspended in 10 ml of tetrahydrofuran under nitrogen atmosphere and the suspension cooled to -78oC. To this suspension is added dropwise 1.9 ml p-nitroethylene (1,63 M solution in hexane) and the resulting mixture stirred for 5 minutes at room temperature and then cooled to -78oC. To this mixture is carefully added dropwise 0.8 ml of trimethylsilylacetamide. The resulting mixture was stirred for 10 minutes at -78oC and then for 5 minutes at room temperature, cooled to -78oC. To this mixture was added dropwise a solution of 128 mg (0.5 mmol) of optically active (2R,3S)-2-(2,4-differenl)-3-methyl-2-(1H-1,2,4-triazole - 1-yl)methyloxirane dissolved in 1 ml of tetrahydrofuran, and the temperature of the mixture immediately raise to room temperature. To this mixture was added a saturated aqueous solution of ammonium chloride followed by extraction e of the solvent under reduced pressure the residue is recrystallized from diethyl ether to obtain through this 81 mg (58,2%) of optically active (2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H - 1,2,4-triazole-1-yl)butyronitrile.

Preparative example 3:

Obtaining a crude product of 1 another method:

The lithium hydride in the number of 48 mg (60,0 mmol) is added to a cooled with ice to a solution (50 ml) of tetrahydrofuran to full suspension. After 10 minutes the suspension is added dropwise to 5.4 g (63.5 mmol) of acetonecyanohydrin [(CH3)2C(OH)CN], followed by continued stirring additional 1.5 hours at room temperature. To this mixture was added 5 g (20.0 mmol) of optically active (2R,3S)-2-(2,4-differenl)-3-methyl-2- (1H-1,2,4-triazole-1-yl)methyloxirane. To the resulting reaction solution was added 100 ml of ethyl acetate and then washed with 100 ml of water and 50 ml of sodium chloride solution. Next, dried over magnesium sulfate. The resulting solution was then filtered. The filtrate is concentrated under reduced pressure. To the concentrate is added 50 ml of diisopropyl ether. The resulting solution was subjected to filtration with the receipt of 4.2 g (76,0%) of optically active (2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H - 1,2,4-triazole-1-yl)butyronitrile.

Preparative example 4:

Obtaining the crude product 2:

Getting 2-(2,4-differenl)-3-thioamide-1-(1H-1,2,4-triazole-1 - yl)-2-butanol

The structural formula is:

< / BR>
To the racemic metil-4-(1H-1,2,4-triazole-1-yl)butyronitrile (14 g), add 14 ml of water in the O,O-diethyldithiophosphate (73 ml) and the resulting mixture is heated and refluxed for 30 minutes. The liquid reaction mixture is again cooled to room temperature, add water and subjected to extraction with AcOEt. Received AcOEt layer was washed with water and saturated aqueous NaCl and dried over magnesium sulfate. The solvent is then distilled off. The resulting residue is purified by chromatography on silica gel (SiO2: 300 g, elution with 1% solution of MeOH in CH2Cl2a 2% solution of MeOH in CH2Cl2and 3% solution of MeOH in CH2Cl2sequentially) and then recrystallized from methylene chloride-isopropyl ether to obtain by this means the desired product (8.1 g). In addition, when an optically active substance crude product 1 is used instead of the racemic modification of the raw material 1 can be obtained similarly optically active crude product 2.

The physical properties of this product are described below.

So pl. 164-167oC.

NMR: solvent CDCl3) a 1.11 (3H, d, J=7,1 Hz), 3,69-and 3.72 (1H, m), 4,55 (1H, d, J=14,3 Hz), to 5.08 (1H, d, J=14,3 Hz), of 6.71-to 6.80 (2H, m), 7,42-of 7.48 (1H, m), 7,80 (1H, user. C) 7,94 (1H, s), to 8.41 (1H, user. C).

MS: MH+= 313.

Premrna formula:

< / BR>
4'-Cyanoacetate (10 g) is dissolved in 100 ml of chloroform and the resulting solution was added dropwise 48% HBr (3,7 ml) in chloroform at room temperature. After stirring for 2 hours at room temperature to the liquid reaction mixture was added saturated aqueous solution of NaHCO3for its neutralization. The chloroform layer is washed with water and saturated aqueous NaCl and dried over magnesium sulfate. Then the chloroform is distilled off. The obtained solid product is recrystallized from AcOEt-n-hexane to obtain through this target compounds (3,49 g). The physical properties of this product are described below.

So pl. 82-84oC.

NMR: solvent CDCl3) of 4.44 (2H, s), 7,81-to 7.84 (2H, m), of 8.09 (1H, d, J=8 Hz), 8,23 (1H, d, J=8 Hz).

Preparative example 6:

Obtaining a crude product of 4:

Getting 2-ethyl-4-chlorobenzothiazole

The structural formula is:

< / BR>
2-Amino-5-chlorothiophenol (2,618 g) dissolved in N-organic (6 ml) and the solution added propionate (1,57 ml) followed by heating at 130oC for 1.5 hours. To the liquid reaction mixture was added ethyl acetate and an aqueous solution of sodium bicarbonate for separating a mixture layers. Organice silica gel (hexane: ethyl acetate = 20: 1) to obtain through this 2-ethyl-6-chlorobenzothiazole (2.3 g). The physical properties of this product are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.47 (3H, t, J=7.4 Hz), 3,14 (2H, q, J=7.4 Hz), 7,40 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,81 (1H, d, J=2.0 Hz), 7,86 (1H, d, J=8,8 Hz).

Preparative example 7:

Obtaining a crude product of 5:

Getting 2-ethyl-6-(1,2,3-triazole-2-yl)benzothiazole

The structural formula is:

< / BR>
1H-1,2,3-Triazole (10.0 g) is dissolved in dimethylformamide (280 ml) and to the solution was added 60% dispersion of sodium hydride (5,79 g) in mineral oil for more than 10 minutes. To this mixture was added dropwise a solution of 4-peritrabecular (18.6 g) at room temperature and the resulting mixture is heated and stirred at 50oC for 9 hours. The reaction mixture is poured into 400 ml of a saturated aqueous solution of ammonium chloride and there poured 200 ml of water. This mixture is subjected to extraction with ethyl acetate (400 MLH, 200 MLH) and an ethyl acetate layer is washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure and purified by chromatographytandem on a column of silica gel (hexane: ethyl acetate = 2:1 _ 1:1) to obtain by means of this 4-(1,2,3-triazole-2-yl)nitrobenzene (11.5g).

4-(1,2,3-Triazole-2-yl)aniline (5.0 g) obtained in the previous reaction is dissolved in 55 ml of acetic acid and to the solution was added ammonium thiocyanate (6.0 g). The resulting mixture was stirred under cooling with ice water. To this mixture was added dropwise a solution of bromine (of 1.62 ml) in 20 ml of acetic acid over 30 minutes. The mixture is then warmed to room temperature, stirred at this temperature for 4 hours.

The reaction mixture is cooled with ice water and added dropwise concentrated ammonia solution with achievement thus pH 6. The resulting precipitates are filtered, washed with water and then with cold ethanol and dried under reduced pressure with Petworth in N,N-dimethylformamide (60 ml) and to the solution was added soliditet (8,66 ml) followed by stirring for 20 minutes at 65oC. the Reaction mixture was poured into 100 ml of water and subjected to extraction with ethyl acetate (100 ml x 3). The obtained organic layer was washed with water and then with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained oily product was then purified by chromatographytandem on a column of silica gel (dichloromethane) to give 6-(1,2,3-triazole-2-yl)benzothiazole (1.1 g).

6-(1,2,3-Triazole-2-yl)benzothiazole (1.1 g) is suspended in ethanol (90 ml) and to the suspension was added 12 ml of hydrazinoacetate. The resulting mixture is heated and refluxed for 2 hours. After concentrating the reaction mixture under reduced pressure, add 20 ml of water and set to pH 7 with acetic acid. Thus obtained mixture 3 times subjected to extraction with ethyl acetate and the resulting organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2-amino-5-(1,2,3-triazole-2-yl)thiophenol (2.3 g). This product is used in subsequent reactions without purification.

2-Amino-5-(1,2,3-triazole-2-yl)thiophenol (2.3 g) is dissolved in N-organic (8 ml) and the solution added th mixture was poured into saturated aqueous sodium hydrogen carbonate solution and subjected to extraction with dichloromethane. The resulting organic layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then purified on a column of silica gel (hexane-ethyl acetate = 4:1 _ 1:1) to obtain the target compound, 2-ethyl-6-(1,2,3-triazole-2 - yl)benzothiazole (940 mg). The physical properties of this product are described below.

Condition: solid product.

NMR; solvent CDCl3) 1,49 (3H, t, J=7,7 Hz), 3,17 (2H, q, J=7,7 Hz), 7,83 (2H, s), 8,03 (1H, d, J=8,8 Hz), to 8.20 (1H, DD, J=8,8 Hz, 3.2 Hz), 8,55 (1H, d, J=8,8 Hz).

Example 88.

Obtaining compounds of the structural formula:

< / BR>
2-(2,4-Differenl)-3-thioamide-1-(1H-1,2,4-triazole-1-yl)-2 - butanol (crude product 2) (156 mg) was dissolved in EtOH (2 ml) and to the solution was added 2-bromo-4'-cyanoacetate (crude product of 3) (224 mg), followed by heating and boiling under reflux for 1 hour. The liquid reaction mixture is neutralized with a saturated solution of aqueous sodium carbonate and subjected to extraction with AcOEt. After washing the extract with water and then saturated NaCl solution and drying over anhydrous magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on silica gel (SiO2: 20 g, elution methylene chloride and then a 1% solution of MeOH in methylene chloride), and ZAT is soedineniya described below.

So pl. 196-197oC.

NMR: solvent CDCl3) of 1.23 (3H, d, J=8.0 Hz), 4.09 to (1H, q, J=8.0 Hz), 4.26 deaths (1H, d, J=14,3 Hz) to 4.92 (1H, d, J=14,3 Hz), 5,74 (1H, s), 6,78-6,85 (2H, m), of 7.48-rate of 7.54 (1H, m), of 7.64 (1H, s), of 7.69 (1H, s), of 7.75 (1H, d, J= 8.1 Hz), the 7.85 (1H, s), 8,03 (1H, d, J=8,1 Hz).

MS: MH+= 483.

Example 89.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-4'-medicineaccutane. The physical properties of this compound is described next. Condition: solid product.

NMR: solvent CDCl3) of 1.23 (3H, d, J = 7,2 Hz), of 2.54 (3H, s), of 4.05 (1H, q, J = 7.2 Hz), 4,28 (1H, d, J = 14.4 Hz), 4,88 (1H, d, J = 14.4 Hz), 6,13 (1H, s), 6.75 in - 6,85 (2H, m), 7,33 (2H, user. d, J = 8,4 Hz), 7,42 (1H, s), 7,46 - rate of 7.54 (1H, m), 7,66 (1H, s), 7,82 (2H, user. d, J = 8,4 Hz), 7,92 (1H, s).

MS: MH+= 459.

Example 90.

Obtaining the compounds represented by the structural formula:

_

The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-2', 4'-defloration. The physical properties of this compound are described below.

MS: MH+= 449.

Example 91.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-4'-methylacetophenone. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) of 1.23 (3H, d, J = 7,1 Hz) to 2.41 (3H, s), Android 4.04 (1H, d, J = 7,1 Hz), 4,28 (1H, d, J = 14,3 Hz), 4,88 (1H, d, J = 14,3 Hz), 6,24 (1H, s), 6,76 - 6,84 (1H, s), 7,27 (2H, d, J = 8,3 Hz), 7,40 (1H, s), 7,47 - 7,53 (1H, m), the 7.65 (1H, s), 7,80 (2H, d, J = 8,3 Hz), 7,94 (1H, s).

MS: MH+= 427.

Example 92.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-4'-methoxyacetophenone. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) of 1.23 (3H, d, J = 7,1 Hz), 3,88 (3H, s), Android 4.04 (1H, kV(2H, d, J = 8,2 Hz), 7,94 (1H, s).

MS: MH+= 443.

Example 93.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-4'-nitroacetophenone. The physical properties of this compound are described below.

So pl. 180 - 182oC.

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7,1 Hz), 4,11 (1H, d, J = 7,1 Hz), 4,27 (1H, d, J = 14,2 Hz), 4,94 (1H, d, J = 14,2 Hz), 5,70 (1H, s), 6,79 - 6,85 (2H, m), 7,43 - of 7.55 (1H, m), of 7.70 (1H, s), 7,71 (1H, s), a 7.85 (1H, s), 8,08 (2H, d, J = 9.0 Hz), 8,32 (2H, d, J = 9.0 Hz).

MS: MH+= 458.

Example 94.

Obtaining the compounds represented by the structural formula:

< / BR>
To a suspension 1,570 g of 60% sodium hydride in 30 ml of DME was added 5 g of 4-portifino and the resulting mixture was stirred at room temperature for 5 minutes. To this mixture was added 4.9 g of 4-fortetienne, followed by stirring for 3.5 hours at 80oC. To this mixture, poured water and extracted with ethyl acetate. The extract is washed with water and then with saturated salt solution and the solvent is distilled off under reduced pressure to obtain through the structural formula:

< / BR>
receive in accordance with the same manner as described in preparative example 4. The target connection then receive in accordance with the same manner as described in example 88, except that this compound is used instead of 2-bromo-4'-cyanoazobenzene. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.22 (3H, d, J = 7,0 Hz), of 4.05 (1H, q, J = 7.0 Hz), 4.26 deaths (1H, d, J = 14.6 Hz), 4,88 (1H, d, J = 14.6 Hz), 6,04 (1H, s), 6,76 - 6,85 (2H, m), 7,07 (2H, user. DD, J = 8,4, and 8.4 Hz), 7,32 (2H, user. d, J = 8,4 Hz), 7,44 (1H, user. C), 7,44 (2H, user. DD, J = 8,4, and 8.4 Hz), 7,45 - rate of 7.54 (1H, m), 7,66 (1H, s), 7,82 (2H, user. d, J = 8,4 Hz), 7,89 (1H, s).

MS: MH+= 539.

Example 95.

Obtaining the compounds represented by the structural formula:

< / BR>
In 4 ml of N-methylpyrrolidone dissolve 400 mg of the compound obtained in example 88, and to the solution was added 123 mg NaN3and 260 mg Et3N HCl. The resulting mixture was heated for 6.5 hours at an external temperature of 100oC in the oil bath and the solution is further added 31 mg NaN3and 65 mg Et3N HCl to the reaction for 20 hours at 90oC. To the resulting mixture are added methylene chloride and the resulting mixture is removed by filtration positivley to stand for planting solids. This solid product is separated by filtration to obtain 390 mg of the target compound. The physical properties of this compound are described below.

So pl. 166 - 169oC.

NMR: solvent CDCl3) to 1.14 (3H, d, J = 7,3 Hz), 4,11 (1H, q, J = 7,3 Hz), 4,37 (1H, d, J = 14.6 Hz), to 4.87 (1H, d, J = 14.6 Hz), between 6.08 (1H, s), 6,91 - of 6.96 (1H, m), 7.18 in - to 7.25 (1H, m), 7,27 - 7,34 (1H, m), a 7.62 (1H, s), 8,11 (2H, d, J = 8.5 Hz), to 8.20 (2H, d, J = 8.5 Hz), by 8.22 (1H, s), 8,29 (1H, s).

MS: MH+= 481.

Example 96.

Obtaining the compounds represented by the structural formula:

< / BR>
In water (4 ml) suspended 800 mg of the compound obtained in example 88, and to the suspension was added to 2.6 ml (16,479 mmol) of the compound represented by the structural formula:

< / BR>
followed by heating and boiling under reflux for 30 minutes. To the liquid reaction mixture was added water and the mixture is subjected to extraction with AcOEt. After washing the extract with water and then with saturated aqueous NaCl solution and drying over magnesium sulfate AcOEt is distilled off. The obtained residue without purification was dissolved in 10 ml of acetone and to the solution was added to 0.45 ml of CH3I followed by stirring at 40oC for 40 minutes. To the obtained liquid reaction mixture was added water and the mixture is subjected to extract onaut AcOEt. The obtained residue without purification was dissolved in 10 ml of EtOH and the solution was added 220 mg NH2NHCHO, of 0.26 ml Et3N and one drop of sulfuric acid followed by heating and boiling under reflux for 1 hour. To the obtained liquid reaction mixture was added water and subjected to extraction with AcOEt. After washing the extract with water and then with saturated aqueous NaCl solution and drying over magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on a column of silica gel (SiO2: 50 g, elution methylene chloride and then a 1% solution of MeOH in methylene chloride and then a 2% solution of MeOH in methylene chloride) to obtain through this, 369 mg of the target compound. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,1 Hz), 4,08 (1H, q, J = 7,1 Hz), 4,34 (1H, d, J = 14.4 Hz), 4,91 (1H, d, J = 14.4 Hz), x 6.15 (1H, s), 6,79 - 6,85 (1H, s), 7,52 - 7,56 (2H, m), 7,69 (1H, s), 7,97 - to 7.99 (3H, m) to 8.14 (2H, d, J = 8,2 Hz), of 8.25 (1H, s).

MS: MH+= 480.

Example 97.

Obtaining the compounds represented by the structural formula:

< / BR>
In 3 ml of dimethylformamide was dissolved 250 mg of the compound obtained in example 95, and to the solution was added 174 mg CsC 0.05 ml of CH3I followed by stirring for 30 minutes at room temperature. To the liquid reaction mixture are added water and subjected to extraction with AcOEt. After washing the extract with water and then with saturated aqueous NaCl solution and drying over magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on a column of silica gel (SiO2: 30 g, elution methylene chloride and then a 1% solution of MeOH in methylene chloride and then a 2% solution of MeOH in methylene chloride) to obtain through this 125 mg of the target compound. The physical properties of this compound are described below.

So pl. 191 - 193oC.

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7.0 Hz), 4.09 to (1H, q, J = 7.0 Hz), the 4.29 (1H, d, J = 14 Hz), 4,33 (3H, s) to 4.92 (1H, d, J = 14 Hz), 6,01 (1H, s), 6,77 - 6,85 (2H, m), 7,49 - of 7.55 (1H, m), 7,58 (1H, s), to 7.67 (1H, s), to $ 7.91 (1H, C) of 8.04 (2H, d, J = 8,2 Hz), 8,24 (2H, d, J = 8,2 Hz).

MS: MH+= 495.

Example 98.

Obtaining the compounds represented by the structural formula:

_

In 5 ml of acetone is dissolved 200 mg of the compound obtained in example 96, and to the solution was added to 60.6 mg of potassium carbonate and 0.03 ml of methyl chloride. The resulting mixture was stirred for 19 hours at room temperature. To the liquid reaction mixture probabl the drying over magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on a column (SiO2: 40 g, elution methylene chloride and then with 0.5% solution of MeOH in methylene chloride and then a 1% solution of MeOH in methylene chloride) to give 142 mg of the target compound. The physical properties of this compound are described below.

Condition: solid product.

NMR: _ solvent CDCl3) of 1.13 (1H, d, J = 6.0 Hz), 1,25 (2H, d, J = 7,1 Hz), 4,01 is 4.13 (4H, m), 4,27 (2/3H, d, J = 14 Hz), 4,29 (1/3H, d, J = 14 Hz), 4,91 (1H, d, J = 14 Hz), the 5.45 (1/3H, s), between 6.08 (2/3H, s) 6,70 - 6,84 (2H, m), 7,50 - of 7.55 (2H, m), to 7.67 - 7.68 per (4/3H, m), 7,79 - 7,81 (2/3H, m), to 7.93 (1H, s), of 7.96 (1H, s), 7,98 (1H, s), 8,10 (1H, s), 8,19 (2H, d, J = 8,4 Hz).

Example 99.

Obtaining the compounds represented by the structural formula:

< / BR>
To a solution of 138 mg of the compound obtained in example 89, dissolved in 3 ml of chloroform, was added 215 mg of meta-chloroperbenzoic acid, followed by stirring at room temperature. After the disappearance of the raw material to the liquid reaction mixture was added water, followed by extraction with ethyl acetate. The obtained organic layer was washed with 50% saturated aqueous sodium bicarbonate, water and saturated salt solution. After removal of the solvent under reduced pressure the residue is purified chromate is of this to 98.5 mg of target compound. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,2 Hz), to 3.09 (3H, s), 4.09 to (1H, q, J = 7.2 Hz), 4,27 (1H, d, J = 14.4 Hz), 4,91 (1H, d, J = 14.4 Hz), 5,78 (1H, s), 6,78 - 6,85 (2H, m), 7,47 - of 7.55 (1H, m), to 7.67 (1H, s), of 7.69 (1H, s), 7,87 (1H, C) 8,02 (2H, user. d, J = 8,4 Hz), 8,10 (2H, user. d, J = 8,4 Hz).

MS: MH+= 491.

Example 100.

Obtaining the compounds represented by the structural formula:

< / BR>
The target compound is obtained from the compound obtained according to example 7, in accordance with the same method as in example 99. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.22 (3H, d, J = 7,2 Hz), 4,07 (1H, q, J = 7.2 Hz), 4,23 (1H, d, J = 14.4 Hz), the 4.90 (1H, d, J = 14.4 Hz), 5,73 (1H, s), 6,77 - 6,84 (2H, m), 7,20 (2H, user. DD, J = 8,4, and 8.4 Hz), 7,46 - 7,53 (1H, m), 7,63 (1H, s), to 7.68 (1H, s), 7,83 (1H, s), 7,97 - 8,07 (6H, m).

MS: MH+= 571.

Example 101.

Obtaining derivatives represented by the structural formula:

< / BR>
< / BR>
and

< / BR>
Compounds I, II and III in accordance with this example receive according to the same method as in example 88, except that 4-cyanoaniline part of the crude product 3 was replaced with the VA of these compounds are described below.

(I)

So pl. 149 - 151oC.

NMR: solvent (DMSO-d6) of 1.13 (3H, d, J = 7,1 Hz), 4,07 (1H, q, J = 7,1 Hz), 4,36 (1H, d, J = 14,3 Hz), a 4.86 (1H, d, J = 14,3 Hz), 6,07 (1H, s), 6,91 - of 6.96 (1H, m), 7.18 in - 7,24 (1H, m), 7,27 was 7.36 (2H, m), to 7.61 (1H, s), 7,88 (1H, t, J = 8 Hz), 8,11 (1H, d, J = 8 Hz), by 8.22 (1H, s), of 8.28 (1H, s), 8,60 - to 8.62 (1H, m).

MS: MH+= 414.

(II)

So pl. 148 - 149oC.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,1 Hz), 4.09 to (1H, q, J = 7,1 Hz), 4,27 (1H, d, J = 14,3 Hz) to 4.92 (1H, d, J = 14,3 Hz), of 5.84 (1H, user. C) 6,77 - 6,85 (2H, m), 7,40 (1H, DDD, J = 7,8, 4,8, 0,92 Hz), of 7.48 - 7,56 (1H, m), 7,58 (1H, s), to 7.68 (1H, s), 7,88 (1H, s), 8,21 (1H, DDD, J = 7,8, 2,2, 1,6 Hz), 8,61 (1H, DD, J = 4,8, 1,6 Hz) to 9.15 (1H, DD, J = 2,2, 0,92 Hz).

MS: MH+= 414.

(III)

Condition: Solid product.

NMR: solvent CDCl3) 1,24 (3Hx4/5, d, J = 7,1 Hz), 1,68 (3Hx1/5, d, J = 6.2 Hz), 4,08 - to 4.15 (1H, m), 4,25 (4/5H, kV, J = 14,5 Hz), 4,73 (1/5H, d, J = a 13.9 Hz), 4.92 in (1/5H, d, J = a 13.9 Hz), 4.95 points (4/5H, d, J = 14,5 Hz), 5,77 (4/5H, user. C) 5,88 (1/5H, user. C) of 6.49 - 6,55 (1/5H, m), 6,66 - 6,72 (1/5H, m), 6,76 - 6,85 (1H, m), 7,07 - 7,14 (4/5H, m), 7,26 (1/5H, s), 7,44 (1/5H, s), 7,47 - 7,55 (4/5H, m), to 7.61 - to 7.64 (1/5H, m), 7,69 (4/5H, s), 7,73 (4/5H, C), 7,78 - 7,81 (4/5H, m), 7,87 (4/5H, s), 8,03 (1/5H, s), 8,64 - 8,66 (4/5H, m), 8,69 - 8,72 (1/5H, m).

MS: MH+= 414.

Example 102.

Obtaining the compounds represented by the structural formula:

< / BR>
In 7 ml of AcOEt and 5 ml of tetrahydrofuran was dissolved 700 mg is the missing stirring for 1 hour at room temperature and then added 227 mg (0,882 mmol) mjpbk. The resulting mixture was stirred for 1 hour. To the liquid reaction mixture was added an aqueous solution of sodium sulfite, stirred for 5 minutes and subjected to extraction with AcOEt. After washing the extract with an aqueous solution of sodium sulfite, aqueous sodium hydrogen carbonate solution, water and then aqueous NaCl solution and drying over magnesium sulfate the solvent is distilled off. The residue is crystallized from CH2Cl2-Ice with getting through this intermediate N-oxide. The compound is dissolved in 5 ml of CH2Cl2to the solution was added 0,49 ml of TMS-CN at room temperature. After 5 minutes add 0,34 ml Me2NCOCl and the mixture is heated and refluxed for 1.5 hours. Then add 0.25 ml of TMS-CN and 0.17 ml, Me2NCOCl and the resulting mixture is heated and refluxed for 2.5 hours. To the liquid reaction mixture was added an aqueous solution of sodium bicarbonate and the mixture is subjected to extraction with AcOEt. After washing the extract with water and saturated aqueous NaCl solution and drying over magnesium sulfate the solvent is distilled off. The residue is purified by chromatography on silica gel (SiO2: 40 g, elution methylene chloride and then a 1% solution of MeOH in methylene chloride and then with a 2% solution of Mehedinti described below.

So pl. 197 - 200oC.

NMR: solvent (DMSO-d6) to 1.14 (3H, d, J = 7,0 Hz), 4,07 - 4,11 (1H, m), 4,47 (1H, q, J = 14,3 Hz), 4,84 (1H, d, J = 14,3 Hz), 6,10 (1H, s), 6,91 - of 6.96 (1H, m), 7.18 in - 7,22 (1H, m), 7.23 percent - 7,33 (2H, m), to 7.61 (1H, s), 7,98 (1H, d, J = 7,7 Hz), to 8.14 (1H, t, J = 7,7 Hz), 8,21 (1H, s), 8,40 (1H, d, J = 7,7 Hz), 8,44 (1H, s).

MS: MH+= 439.

Example 103.

Obtaining the compound (I) represented by the structural formula:

< / BR>
and another compound (II) represented by structural formula is:

< / BR>
In 16 ml of EtOH was dissolved 1.6 g of 2-(2,4-differenl)-3-thioamide-1- (1H-1,2,4-triazole-1-yl)butane-2-ol (156 mg) and to the solution is added to 0.71 ml ethylbromoacetate (ethyl ether bronirovochnoy acid). The resulting mixture is heated and refluxed for 5 hours. The liquid reaction mixture is again cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate solution and subjected to extraction with AcOEt. After washing the extract with water and then aqueous NaCl solution and drying over magnesium sulfate the solvent is distilled off. The residue is purified by chromatography (SiO2: 150 g, elution CH2Cl2and then a 1% solution of MeOH in CH2Cl2and then a 2% solution of MeOH in CH2Cl2with getting through this 435 mg of 2-(2,4-gift the Oia and the solution slowly added to 5.1 ml of a 1 M toluene solution of DIBAL at -78oC. for 40 minutes, then added to 2.3 ml of a 1 M toluene solution of DIBAL at the same temperature. After 1 hour, the liquid reaction mixture was added an aqueous solution of MH4Cl at -78oC. the Reaction mixture is again heated to room temperature, add water and subjected to extraction with AcOEt. Then the extract is washed with water and dried over magnesium sulfate, the solvent is distilled with getting through this 989 mg of 2-(2,4-differenl)-3- (4-formilleza-2-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol as a crude product.

To 5 ml of THF was added 60% NaH (109 mg) under cooling with ice water and to the mixture was added dropwise a solution of (Et2O)2P(=O)CH2CN (of 0.44 ml) in 5 ml of THF. After stirring the mixture for 1 hour to the mixture is slowly added a solution of 989 mg videolooking product, dissolved in 10 ml of THF. After stirring the mixture for 30 minutes at room temperature to the liquid reaction mixture was added water, followed by extraction with AcOEt. After washing the extract with water and then with saturated aqueous NaCl solution and drying over magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on silica gel (SiO2: 60 g, elution CHCl3and then a 1% solution of MeOH in CHCl3and inane II geometric isomer in the form of the second eluate. Physical properties of these compounds are described below.

to 1.19 (3H, d, J = 7,1 Hz), was 4.02 (1H, q, J = 7,1 Hz), 4,16 (1H, d, J = 14,3 Hz), 4,91 (1H, d, J = 14,3 Hz), vs. 5.47 (1H, s), 6,33 (1H, d, J = 16.0 Hz), 6,77 - 6,84 (2H, m), 7,33 (1H, d, J = 16.0 Hz), 7,46 (1H, s), 7,47 - 7,51 (1H, m), 7,72 (1H, s), 7,82 (1H, s).

MS: MH+= 388.

of 1.20 (3H, d, J = 7,0 Hz), of 4.05 (1H, q, J = 7.0 Hz), of 4.45 (1H, d, J = 14,0 Hz), 4,89 (1H, d, J = 14,0 Hz) to 5.56 (1H, d, J = 11,9 Hz), 5,78 (1H, s), 6.75 in - PC 6.82 (2H, m), 7,17 (1H, d, J = 11,9 Hz), 7,50 - to 7.59 (1H, m), of 7.60 (1H, s), of 7.75 (1H, s), 8,10 (1H, s).

MS: MH+= 388.

Example 104.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 88, except that instead of 2-(2,4-differenl)-3-thioamide-1-(1H-1,2,4-triazole-1-yl)butane-2-ol using 2-(2,4-differenl)-3-thioamide-1-(1H-1,2,4-triazole-1-yl) propan-2-ol. The physical properties of this compound are described below.

So pl. 148 - 149oC.

NMR: solvent CDCl3) to 3.38 (1H, d, J = 15.2 Hz), a 3.87 (1H, d, J = 15.2 Hz) and 4.65 (1H, d, J = 14,0 Hz), 4,71 (1H, d, J = 14,0 Hz), 5,97 (1H, s) 6,70 - 6,76 (1H, m), 6,77 - 6,83 (1H, m), 7,42 (1H, m), 7,47 - 7,41 (1H, m), 7,69 - 7,72 (2H, m), 7,86 (1H, s), 7,86 - of 7.90 (2H, m), 8,18 (1H, s).

MS: MH+= 424.

Example 105.

Obtaining the compounds represented by the structural formula:
m, instead of 2-bromo-4'-cyanoazobenzene using 2-bromo-4'-peracetate. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 3.34 (1H, d, J = 15,4 Hz), a-3.84 (1H, d, J = 15,4 Hz), to 4.62 (1H, d, J = 14,0 Hz), 4,71 (1H, d, J = 14,0 Hz), and 6.25 (1H, s), 6,82 - 6,69 (2H, m), 7,13 - was 7.08 (2H, m), 7,17 (1H, s), 7,47 - 7,40 (1H, m), 7,76 - 7,72 (2H, m), the 7.85 (1H, s), 8,21 (1H, s).

MS: MH+= 417.

Example 106.

Receiving compound I represented by the structural formula:

< / BR>
and another compound II, which is a diastereoisomer of compound I.

After adding dropwise n-utility (1.6 M hexane solution; 313 ml) to Diisopropylamine (840 l) in 15 ml of tetrahydrofuran at -65oC the mixture is cooled to 4oC with holding thus the reaction for 15 minutes to obtain a solution diisopropylamide lithium. After cooling the solution to -63oC to the amide solution was sequentially added tertrahydrofuran ring solution (10 ml) of 2-ethyl-6-chlorobenzothiazole (988 ml) obtained in preparative example 5, and tertrahydrofuran ring solution (12 ml) of 1-(1H-1,2,4-triazole-1-yl)-2,4-defloration (there were 1,227 g) when the internal temperature of not higher than -60oC. After the reaction for 15 the offer is subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and then with saturated salt solution, dried and evaporated to dryness under reduced pressure. The residue is purified on a column of silica gel (dichloromethane : methanol = 100:1). Thus obtained mixture of diastereomers is passed through a column of silica gel (dichloromethane : ethyl acetate = 10:1 5:1) to obtain through this, 442 mg of compound I in the form nizkovoltnoy faction and 66 mg of compound II, which is its diastereoisomer in the form of a highly polar fractions. The physical properties of this compound are described below.

I

So pl. 187oC

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7.0 Hz), 4.09 to (1H, q, J = 7.0 Hz), 4,27 (1H, d, J = 14.4 Hz), is 4.93 (1H, d, J = 14.4 Hz), 5,80 (1H, s), 6,85 - of 6.78 (2H, m), of 7.48 (1H, DD, J = 8,8 Hz, 2.4 Hz), 7,49 - of 7.55 (1H, m), to 7.67 (1H, s), 7,87 (1H, C) of 7.90 (1H, d, J = 2.4 Hz), 7,94 (1H, d, J = 8,8 Hz).

MS: MH+= 421.

II

So pl. 127 - 130oC

NMR: solvent CDCl3) 1,68 (3H, d, J = 6.8 Hz), of 4.13 (1H, q, J = 6.8 Hz), 4,71 (1H, d, J = 14 Hz), 4,94 (1H, d, J = 14 Hz), by 5.87 (1H, s), 6,46 - 6,50 (1H, m), to 6.43 - 6,69 (1H, m), 7,09 - 7,16 (1H, m), 7,38 (1H, DD, J = 2.0 Hz, 8,8 Hz), of 7.69 (1H, s), 7,72 (1H, d, J = 2.0 Hz), 7,80 (1H, d, J = 8,8 Hz), of 8.04 (1H, s).

MS: MH+= 421.

Example 107.

Obtaining the compounds represented by the structural formula:

< / BR>
Mix 2-3 hours in 300 ml of N-methylpyrrolidone. After cooling the mixture to room temperature, thereto was added 150 ml of water, set to pH 3 using concentrated hydrochloric acid and twice subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated salt solution and dried. The solvent is distilled off and the remaining solvent is then distilled off by azeotropic distillation with toluene to obtain through this 2-ethyl-6-(tetrazol-5-yl)benzothiazole (1.86 g). This compound is dissolved in dimethylformamide (20 ml) and to the solution was added cesium carbonate (3,06 g) followed by heating at 80oC for 1.5 hours. Then to the reaction mixture of 1.17 ml iodomethane while cooling with ice. Mixture is allowed to reach room temperature and stirred for 7 hours. Add water and ethyl acetate to separate the mixture into layers, and the organic layer washed with water and dried. The residue is purified through a column of silica gel (hexane : ethyl acetate = 4:1) to obtain through this 2-ethyl-6-(2-methyltetrazol-5-yl)benzothiazole (930 mg). Using the thus obtained compound, receive the same manner as in example 106, the target connection. The physical properties of this compound are described below.

So pl. 184 - 185oC

NMR: - ,86 (2H, m), 7,50 - 7,58 (1H, m), to 7.67 (1H, s), 7,89 (1H, s), 8,13 (1H, DD, J = 0.4 Hz, 8,8 Hz), 8,30 (1H, DD, J = 1,6 Hz and 8.8 Hz), a total of 8.74 (1H, DD, J = 0.4 Hz, 1.6 Hz).

Example 108.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive the same manner as in example 106, except that instead of 2-bromo-6-chlorobenzothiazole use 2-ethyl-6-fermentation. The physical properties of this compound are described below.

So pl. 151 - 153oC.

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7,1 Hz), 4,08 (1H, q, J = 7,1 Hz), 4,28 (1H, d, J = 14.4 Hz), is 4.93 (1H, d, J = 14.4 Hz), of 5.83 (1H, s), 6,77 - 6,85 (2H, m), 7.23 percent - 7,29 (1H, m), 7,49 - 7,56 (1H, m), 7,58 to 7.62 (1H, m), to 7.67 (1H, s), 7,87 (1H, s), of 7.96 - 8,00 (1H, m).

MS: MH+= 405.

Example 109.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive the same manner as in example 106, except that instead of 2-bromo-6-chlorobenzothiazole use 2-ethyl-6-cyanobenzoate. The physical properties of this compound are described below.

So pl. 186 - 188oC.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,2 Hz), 4,16 (1H, q, J = 7.2 Hz), 4,24 (1H, d, J = 14,0 Hz), 4,96 (1H, d, J = 14,0 Hz), 5,67 (1H, s), 6,79 - 6,86 (2H, m), 7,49 - 7,56 (1H, m), 7,69 (1H, s), to 7.77 (1H, DD, J = 1,6 Hz and 8.4 Hz), 7,83 (1H, C), 8, is placed, represented by the structural formula:

< / BR>
The compound (506 mg) obtained in example 109, suspended in methanol (10 ml) and the suspension sequentially added and 0.37 ml of a 1N aqueous solution of sodium hydroxide and 30% hydrogen peroxide (0,42 ml). The resulting mixture is stirred for 2 hours at room temperature and for carrying out the extraction of added water and ethyl acetate. The obtained organic layer was washed with water, dried with subsequent distillation. The residue is purified on a column of silica gel (dichloromethane : methanol = 50:1 20:1) to obtain by this means the desired compound (311 mg). The physical properties of this compound are described below.

So pl. 112 - 117oC.

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7,0 Hz), of 4.13 (1H, q, J = 7.0 Hz), the 4.29 (1H, d, J = 14.4 Hz), 4,94 (1H, d, J = 14.4 Hz), of 5.82 (1H, s), ceiling of 5.60 and 6.25 (2H, usher.), 6,78 - 6,86 (2H, m), 7,50 - 7,56 (1H, m), to 7.67 (1H, s), 7,87 (1H, s), of 7.90 (1H, DD, J = 1,6 Hz and 8.4 Hz), 8,08 (1H, DD, J = 1,6 Hz and 8.4 Hz), 8,48 (1H, DD, J = 0.6 Hz, 1.6 Hz).

MS: MH+= 430.

Example 111.

Obtaining the compounds represented by the structural formula:

< / BR>
The compound (507 mg) obtained in example 109, and one drop of triethylamine are dissolved in dimethylformamide (5 ml) and the solution saturated with gaseous hydrogen sulfide at room shall have an aqueous solution of sodium bicarbonate and ethyl acetate to separate into layers. The obtained organic layer was washed with water, dried and concentrated. The residue is purified on a column of silica gel (solvent for elution: dichloromethane : methanol = 50: 1) to obtain the target compound (538 mg). The physical properties of this compound are described below.

So pl. 157 - 160oC.

NMR: solvent CDCl3) of 1.23 (3H, d, J = 7,2 Hz), of 4.13 (1H, q, J = 7.2 Hz), 4,27 (1H, d, J = 14,0 Hz), 4,94 (1H, d, J = 14,0 Hz), of 5.81 (1H, s), 6,78 - 6,85 (2H, m), 7.24 to 7,30 (1H, user. c), 7,39 - 7,56 (1H, m), to 7.67 (1H, s), 7,66 - 7,72 (1H, user. c) 7,86 (1H, s), 7,95 (1H, DD, J = 2.0 Hz, 8,8 Hz), 8,02 (1H, d, J = 8,8 Hz), 8,59 (1H, d, J = 2.0 Hz).

MS: MH+= 446.

Example 112.

Obtaining compounds (mixture of 1: 1 diastereomers) represented by the structural formula:

< / BR>
The compound (2.67 g) obtained in example 111, suspended in 130 ml of acetone and the suspension is added to 1.12 ml iodomethane with heating and boiling under reflux the mixture at 40oC for 8 hours. The solvent is distilled off to obtain an intermediate compound represented by the structural formula:

< / BR>
This intermediate compound (548 mg) was dissolved in ethanol (5.8 ml) and the solution added aminotetrazole (174 l) with heating and boiling under reflux Poluchenie under reflux for 1 hour. To the liquid reaction mixture was added an aqueous solution of sodium bicarbonate and ethyl acetate to separate into layers. The obtained organic layer was washed with water, dried and evaporated to dryness. The residue is purified on a column of silica gel (dichloromethane : methanol = 100:1 to 10:1) to obtain by means of this target compound in the form of 1:1-mixture of diastereomers.

Condition: solid product.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,2 Hz), at 1.73 (3H, d, J = 7,2 Hz), 4,10 (1H, q, J = 7.2 Hz), is 4.15 (1H, q, J = 7.2 Hz), 4,32 (1H, d, J = 14,0 Hz), to 4.73 (1H, d, J = 14,0 Hz), 4,94 (1H, d, J = 14,0 Hz), of 4.95 (1H, d, J = 14,0 Hz), of 5.92 (1H, s), 5,98 (1H, s), 6,44 - 6,50 (1H, m), 6,63 - 6,70 (1H, m), 6,77 - 6,84 (2H, m), 7,12 - 7,17 (1H, m), 7,17 (1H, user. C), 7,22 (1H, user. C) 7,50 - EUR 7.57 (1H, m), 7,66 (1H, s), of 7.69 (1H, s), to 7.84 (1H, DD, J = 1,6 Hz and 8.4 Hz), 7,89 (1H, s), to $ 7.91 (1H, d, J = 8,4 Hz), 7,93 (H, DD, J = 1,6 Hz and 8.4 Hz), with 8.05 (1H, d, J = 8,4 Hz), of 8.06 (1H, s), of 8.27 (1H, d, J = 1,6 Hz), 8,46 (1H, d, J = 1.6 Hz).

Example 113.

Obtaining the compounds represented by the structural formula:

< / BR>
The intermediate compound (1,17 g) from example 112 was dissolved in ethanol (12 ml) and the solution successively added formylhydrazine (240 mg), triethylamine (250 l) and one drop of concentrated sulfuric acid while conducting interaction for 40 minutes at room temperature and then for 1.5 si added ethyl acetate and water to conduct extraction. The obtained organic layer was washed with water, dried and concentrated. The residue is purified on a column of silica gel (dichloromethane : methanol = 20:1) to obtain the target compound (742 mg). The physical properties of this compound are described below.

So square 138 - 140oC.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,2 Hz), of 4.13 (1H, q, J = 7.2 Hz), 4,33 (1H, d, J = 14,2 Hz), of 4.95 (1H, d, J = 14,2 Hz), 5,96 (1H, s), 6,78 - 6,86 (2H, m), 7,51 - EUR 7.57 (1H, m), to 7.67 (1H, s), to $ 7.91 (1H, s), 8,10 (1H, d, J = 8,4 Hz), of 8.25 (1H, d, J = 8,4 Hz), 8,32 (1H, s), 8,69 (1H, s).

MS: MH+= 472.

Example 114.

Obtaining the compounds represented by the structural formula:

< / BR>
The compound (264 mg) obtained in example 111, dimethylacetal of bromoacetaldehyde (390 l) and one drop of concentrated sulfuric acid is heated and refluxed for 1 hour in ethanol. Then add dimethylacetal of bromoacetaldehyde (390 l) with heating and boiling under reflux for 1 hour, the liquid reaction mixture are added ethyl acetate and water to separate the mixture into layers. The obtained organic layer is washed with water and dried and the solvent is distilled off. To the residue was added hexane and the precipitate collected by filtration to obtain the target link is actuarial (CDCl3) of 1.28 (3H, d, J = 7,2 Hz), of 4.12 (1H, q, J = 7.2 Hz), or 4.31 (1H, d, J = 14,2 Hz), 4,96 (1H, d, J = 14,2 Hz), of 5.89 (1H, s), 6,78 and 6.25 (2H, m), 7,40 (1H, d, J = 3,4 Hz), 7,66 (1H, s), 7,89 (1H, s), 7,92 (1H, d, J = 3,4 Hz), of 8.09 (1H, d, J = 0.4 Hz), 8,10 (1H, d, J = 1.6 Hz), the rate of 8.75 (1H, DD, J = 0.4 Hz, 1.6 Hz).

MS: MH+= 470.

Example 115.

Obtaining compounds represented by structural formula A:

< / BR>
and structural formula B:

< / BR>
The compound (453 mg) obtained in example 113, dissolved in acetone (4.5 ml) and to the solution was added powdered potassium carbonate (138 mg) and itmean (62 l). The resulting mixture was stirred overnight at room temperature. The mixture is subjected to extraction with ethyl acetate-water. The obtained organic layer is washed with water and dried, the solvent is distilled off. The residue is purified on a column of silica gel (dichloromethane : methanol = 50:1 30: 1) and then isolated and purified by ODS column with methanol : water = 60:40 65: 35) to give the compound of structural formula A (192 mg) and the compound of structural formula B (52 mg). Physical properties of these compounds are described below.

A

So pl. 180 - 190oC.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,0 Hz) to 4.01 (3H, s), 4,11 (1H, q, J = 7.0 Hz), 4,32 (1H, d, J = 14,0 Hz), 4,94 (1H, d, J = 14,0 Hz), of 5.99 (1H, s), 6,77-6,86 (2H, m), 7,50 - EUR 7.57 (1H, s), the 7.65 (1H, s), to $ 7.91 (1H, s), 8,08 (1H, d, J = 8,4 Hz), UP>C.

NMR: solvent CDCl3) of 1.29 (3H, d, J = 7,2 Hz), 4,07 (3H, s) to 4.15 (1H, q, J = 7.2 Hz), 4,30 (1H, d, J = 14,2 Hz), equal to 4.97 (1H, d, J = 14,2 Hz), of 5.82 (1H, s), 6,79 - 6,86 (2H, m), 7,50 - 7,58 (1H, m), 7,68 (1H, s), 7,82 (1H, DD, J = 1.8 Hz, and 8.4 Hz), 7,87 (1H, s), to 7.99 (1H, s), 8,16 (1H, d, J = 8,4 Hz), of 8.28 (1H, d, J = 1,8 Hz).

Example 116.

Obtaining the compounds represented by the structural formula:

< / BR>
The target compound (120 mg) receive the same manner as described in example 106, except that instead of 2-bromo-6-chlorobenzothiazole use 2-ethyl-6-(1,2,3-triazole-2-yl)benzothiazole (529 mg), which is crude product 5, obtained in preparative example 7. The physical properties of this compound are described below.

Condition: oily product.

NMR: solvent CDCl3) of 1.29 (3H, d, J = 7,1 Hz), of 4.12 (1H, q, J = 7,1 Hz), 4,32 (1H, d, J = 14,2 Hz), equal to 4.97 (1H, d, J = 14,2 Hz), by 5.87 (1H, user. C), 6,79 - 6,83 (2H, m), 7,50 - 7,58 (1H, m), to 7.67 (1H, s), 7,87 (2H, s), 7,89 (1H, s) to 8.12 (1H, d, J = 9.0 Hz), 8,30 (1H, DD, J = 8,8, 2.2 Hz), 8,65 (1H, d, J = 2.2 Hz).

Example 117.

Obtaining compounds (mixture of 1: 1 diastereomers) represented by the structural formula:

< / BR>
2-Ethyl-6-methoxycarbonylbenzyl receive in accordance with the same manner as described in preparative example 7. This compound is dissolved in 1 ml of diethyl what E. stirring the mixture at room temperature was added a saturated aqueous solution of ammonium chloride and subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and then with saturated salt solution and the solvent is distilled off under reduced pressure. Thus obtained crude product is purified on a column of silica gel to obtain (2 methyl-2-(2-ethylbenzothiazoline-6-yl)ethanol) (138 mg). The target compound (mixture of 1:1 diastereomers) receive, in accordance with the same manner as described in example 99, except that this product is double the amount compared to example 116 instead of 2-ethyl-6-chlorobenzothiazole use 2-ethyl-6-chlorobenzothiazole and n-utillity. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) 1,25 (1,5 H, d, J = 7,2 Hz), 1,60 (3H, s) to 1.67 (3H, s), 1,80 (1,5 H, d, J = 8,4 Hz), 4,05 - 4,17 (1H, m), 4,27 (0.5 H, d, J = 14.4 Hz), 4,71 (0.5 H, d, J = 14,0 Hz), 4,90 - of 4.95 (1H, m), 6,02 (0.5 H, s), 6,13 (0.5 H, d, J = 1,6 Hz), 6,44 - 6,51 (0.5 H, m), 6,63-6,70 (0.5 H, m), 6,63 - 6,70 (0.5 H, m), 6,76 - 6,85 (1H, m), 7,10 - 7,17 (0.5 H, m), 7,50 - 7,56 (1H, m), to 7.61 - 7,65 (0.5 H, m), of 7.64 (0.5 H, s), 7,66 (0.5 H, s), 7,84 (0.5 H, d, J = 8,8 Hz), 7,89 (0.5 H, s), to $ 7.91 (0.5 H, d, J = 1.6 Hz), 8,00 (0.5 H, d, J = 8,8 Hz), 8,06 (0.5 H, s), 8,10 (0.5 H, d, J = 1.6 Hz).

MS: MH+= 445.

Example 118.

Obtaining compounds (mixture of 1: 1 diastereomers) represented by the structural formula:

< / BR>
The same 2-ethyl-6-methoxycarbonylbenzyl the thief added 1N aqueous NaOH (8 ml) followed by heating and boiling under reflux for 4.5 hours. To the reaction mixture was added 8 ml of 1N HCl and then regular salt is subjected to extraction with ethyl acetate. Then the extract was washed with saturated salt solution, the solvent is distilled under reduced pressure to get through this 6-carboxy-2-ethylbenzothiazoline (642 mg). This product (1,957 g) dissolved in xylene (50 ml) without purification, and to the solution was added 2-amino-2-methyl-1-propanol (6 ml). The resulting mixture is heated and refluxed for 3 days with a nozzle Dean-stark. The solvent is distilled off from the liquid reaction mixture under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the intermediate compounds represented by the structural formula:

< / BR>
Using the intermediate obtain the target compound in accordance with the same method as in example 106. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) 1,27 (1,5 H, d, J = 6,8 Hz) to 1.38 (3H, s) of 1.42 (3H, s), 1.70 to (1,5 H, d, J = 6.8 Hz), 4,08 - 4,18 (1H, m), 4,12 (1H, s), 4,18 (1H, s), 4,29 (0.5 H, d, J = 14.4 Hz), 4,74 (0.5 H, d, J = 14 Hz), 4,94 (0.5 H, d, J = 14.4 Hz), 4.95 points (0.5 H, d, J = 14 Hz), 5,90 (0.5 H, s) 5,94 (0.5 H, d, J = 1.6 Hz), to 6.43 - of 6.49 (0.5 H, m), 6,62 - 6,69 (0.5 H, m), 6,77 - 6,85 (1H, is), 8,05 (0.5 H, s), 8,10 (0.5 H, DD, J = 1,6, and 8.4 Hz), 8,35 (0.5 H, d, J = 1.6 Hz), 8,53 (0.5 H, d, J = 1.6 Hz).

MS: MH+= 484.

Example 119.

Obtaining the compound (I) represented by the structural formula:

< / BR>
and another compound (II), which is its diastereoisomer.

2-Ethyl-6-methyldibenzothiophene receive in accordance with the same manner as described in preparative example 7, a mixture of diastereomers, which is the target compounds produced in accordance with the same manner as described in example 106, except that they use this product. The mixture is subjected to chromatography on silica gel with separation of the compounds (I) and compound (II), which is its diastereoisomer.

(I)

Condition: solid product.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,0 Hz), to 2.57 (3H, s) 4,06 (1H, q, J = 7.0 Hz), 4,27 (1H, d, J = 14,2 Hz) to 4.92 (1H, d, J = 14,2 Hz), to 5.93 (1H, s), 6,76 - 6,84 (2H, m), 7,42 (1H, DD, J = 2.0 a, and 8.4 Hz), 7,47 - of 7.55 (1H, m), the 7.65 (1H, C) 7,76 (1H, d, J = 2.0 Hz), 7,88 (1H, s), 7,92 (1H, d, J = 8,4 Hz).

MS: MH+= 433.

(II)

Condition: solid product.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,0 Hz), to 2.57 (3H, s) 4,06 (1H, q, J = 7.0 Hz), 4,27 (1H, d, J = 14,2 Hz) to 4.92 (1H, d, J = 14,2 Hz), to 5.93 (1H, s), 6,76 - 6,84 (2H, m), 7,42 (1H, DD, J = 2.0 a, and 8.4 Hz), 7,47 - of 7.55 (1H, m), 7 Obtaining the compound (I), represented by the structural formula:

< / BR>
and another compound (II), which is its diastereoisomer.

The above compound (I) and the compound (II), which is its diastereoisomer is obtained from the compound obtained in example 119 and its diastereoisomer, respectively, according to the same method as described in example 99. Physical properties of these compounds are described below.

(I)

Condition: solid product.

NMR: solvent CDCl3) of 1.29 (3H, d, J = 7,2 Hz), 3,13 (3H, s), 4,18 (1H, q, J = 7.2 Hz), 4,24 (1H, d, J = 14,12 Hz), to 4.98 (1H, d, J = 14,2 Hz), of 5.68 (1H, s), 6,79 - 6,86 (2H, m), 7,49 - 7,56 (1H, m), of 7.70 (1H, s), to 7.84 (1H, s), of 8.06 (1H, DD, J = 2.0 a, 8,8 Hz), 8,19 (1H, d, J = 8,8 Hz), 8,58 (1H, d, J = 2.0 Hz).

MS: MH+= 465.

(II)

Condition: solid product.

NMR: solvent CDCl3) 1,71 (3H, d, J = 6.8 Hz), is 3.08 (3H, s), 4,22 (1H, q, J = 6.8 Hz), to 4.73 (1H, d, J = 14,0 Hz), to 4.98 (1H, d, J = 14,0 Hz), 5,72 (1H, s), 6,47 - is 6.54 (1H, m), 6,64 - of 6.71 (1H, m), 7,12 - 7,19 (1H, m), 7,72 (1H, s), of 7.96 (1H, DD, J = 1,7, 8,8 Hz), 8,02 (1H, s), of 8.04 (1H, d, J = 8,8 Hz), to 8.41 (1H, user. d, J = 1.7 Hz).

MS: MH+= 465.

Example 121.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 106, excluded is the same way, as described in preparative example 6. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 1.24 (3H, d, J = 7,2 Hz), 4,07 (1H, q, J = 7.2 Hz), 4.26 deaths (1H, d, J = 14.4 Hz), to 4.92 (1H, d, J = 14.4 Hz), of 5.84 (1H, s), 6,76 - 6,84 (2H, m), 7,06 (2H, user. DD, J = 8,6, 8.6 Hz), 7,39 - 7,44 (3H, m), 7,47 one-7,55 (1H, m), 7,66 (1H, c), to 7.77 (1H, d, J = 1.6 Hz), 7,86 (1H, c), to 7.93 (1H, d, J = 8,8 Hz).

MC: MH+= 513.

Example 122.

Obtaining the compound (I) represented by the structural formula:

and another compound (II) represented by structural formula is:

< / BR>
A mixture of the above compounds is obtained from the compound obtained in example 121 according to the same method as described in example 99. The mixture is subjected to chromatography on silica gel with split connections and getting through this individual compounds. Physical properties of these compounds are described below.

(I)

Condition: solid product.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,2 Hz), 4,22 (1H, d, J = 14.4 Hz), 4,63 (1H, q, J = 7.2 Hz), 5,11 (1H, d, J = 14.4 Hz), 6,56 (1H, user. C) 6,76 - 6,87 (2H, m), 7.23 percent (2H, user. DD, J = 8,4, and 8.4 Hz), 7,46 - rate of 7.54 (1H, m), 7,68 (1H, s), 7,92 (1H, s), 7,99 - of 8.04 (2H, m) to 8.12 (1H, DD, J = 1,6, and 8.4 Hz), 8,32 (1H, d, J = 8,4 Hz), 8,51 (1H, user. d, J = 1.6 Hz).

MS: MH+Il. DD, J = 8,6, 8.6 Hz), 7,47 - rate of 7.54 (1H, m), 7,68 (1H, s), 7,81 (1H, s), 7,98 - 8,03 (1H, m) to 8.12 (1H, d, J = 8,8 Hz), 8,58 (1H, d, J = 2.0 Hz).

MC: MH+= 545.

Example 123.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 106, except that instead of 2-ethyl-6-chlorobenzothiazole use 2-ethyl-4-chlorobenzothiazole. The physical properties of this compound are described below.

Condition: oily product.

NMR: solvent CDCl3) of 1.26 (3H, d, J = 8.0 Hz), 4,19 (1H, q, J = 8.0 Hz), 4,34 (1H, d, J = 15.2 Hz), 4,96 (1H, d, J = 15.2 Hz), of 5.92 (1H, user. C), 6,78 - 6,84 (2H, m), 7,34 - 7,40 (1H, m), 7,50 - 7,58 (2H, m), 7,68 (1H, s), 7,78 - 7,58 (2H, m), 7,68 (1H, s), 7,78 - a 7.85 (1H, m), 7,92 (1H, s).

Example 124.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 109, except that instead of 2-ethyl-6-cyanobenzoate use 2-ethyl-4-cyanobenzoate. The physical properties of this compound are described below.

Condition: oily product.

NMR: solvent CDCl3) of 1.26 (3H, d, J = 7,1 Hz) to 4.15 (1H, q, J = 7,1 Hz), 4,22 (1H, d, J = 14,2 Hz), to 4.98 (1H, d, J = 14,2 Hz), 5,63 (1H,>Example 125.

Obtaining the compounds represented by the structural formula:

< / BR>
2-Ethyl-6-chloro-7-azobenzene (3,16 g) and thiamethoxam sodium (1,67 g) interact for 1 hour at 90oC in N-organic (9 ml). After cooling, the reaction mixture thereto are added water and ethyl acetate to separate the mixture into layers. The obtained organic layer is washed with water and dried and the solvent is distilled off. The residue is purified on a column of silica gel (hexane : ethyl acetate = 10:1) to obtain by means of this intermediate compound, 2-ethyl-6-dimethoxy-7-usebestmail (2.25 mg). Using this intermediate connection, the target connection receive according to the same method as in example 106. The physical properties of this compound are described below.

So pl. 185 - 186oC.

NMR: solvent CDCl3) to 1.25 (3H, d, J = 7,2 Hz), 2,65 (3H, s), a 4.03 (1H, q, J = 7.2 Hz), 4,30 (1H, d, J = 14,2 Hz), 4,94 (1H, d, J = 14,2 Hz), of 5.75 (1H, s), 6,77 - 6,85 (2H, m), 7,31 (1H, d, J = 8,4 Hz), of 7.48 - of 7.55 (1H, m), 7,68 (1H, s), 7,86 (1H, s), 8,02 (1H, d, J = 8,4 Hz).

Example 126.

Obtaining the compounds represented by the structural formula:

< / BR>
The compound (400 mg) obtained in example 125, dissolved in dichloromethane (4 ml) and to the solution was added meta-chloroperbenzoic kmaway sequentially with an aqueous solution of sodium bicarbonate, to which are added dichloromethane and water and dried. The solvent is distilled off to obtain the target product (452 mg). The physical properties of this compound are described below.

So pl. 211 - 214oC.

NMR: solvent CDCl3) of 1.30 (3H, d, J = 7,0 Hz), 3,32 (3H, s), 4,14 (1H, q, J = 7.0 Hz), 4,23 (1H, d, J = 14.4 Hz), free 5.01 (1H, d, J = 14.4 Hz), 5,59 (1H, s), 6,80 - 6,86 (2H, m), of 7.48 - 7,56 (1H, m), 7,72 (1H, s), 7,82 (1H, s), of 8.25 (1H, d, J = 8,4 Hz), of 8.47 (1H, d, J = 8,4 Hz).

MS: MH+= 466

Example 127.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 125, except that intermediate compound using 2-ethyl-6-chloro-7-asiansuite. The physical properties of this compound are described below.

So pl. 177 - 178oC.

NMR: solvent CDCl3) of 1.27 (3H, d, J = 7,2 Hz), 4,07 (1H, d, J = 7,2 Hz), 4,27 (1H, d, J = 14,0 Hz), 4,96 (1H, d, J = 14,0 Hz), 5,63 (1H, s), 6,78 - 6,85 (2H, m), 7,47 (1H, d, J = 8,4 Hz), of 7.48 - of 7.55 (1H, m), of 7.70 (1H, s), 7,83 (1H, s), 8,19 (1H, d, J = 8,4 Hz).

Example 128.

Obtaining the compounds represented by the structural formula:

< / BR>
2-Ethyl-7-asiansuite (2,95 g) dissolved in dichloromethane (30 ml) and to the solution at room temperature was added Armenia reaction, the reaction mixture is treated with an aqueous solution of sodium sulfite while cooling with ice water. Thus obtained reaction mixture is diluted with dichloromethane and the resulting organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated saline solution in this order and dried. The solvent is distilled to obtain 2-ethyl-7-asiansuite-7-oxide (2,69 g). This compound is added to dichloromethane (27 ml) and sequentially adds dimethylaminocarbonylmethyl (4,16 g), trimethylsilyl cyanide (5,69 ml) and triethylamine (6.3 ml) to the reaction for 8 hours at room temperature. Next was added trimethylsilyl cyanide (2.5 ml) and dimethylaminocarbonylmethyl (2.5 ml). After the reaction for 2 days at room temperature to the reaction mixture was added aqueous sodium bicarbonate, followed by stirring for 1 hour. The reaction mixture was subjected to extraction with ethyl acetate and the resulting organic layer was washed with water, dried and evaporated. After cleaning residue on a column of silica gel (elution with dichloromethane : methanol = 200: 1), recrystallized from dichloromethane-isopropyl ether leads to the formation of 2-ethyl-6-cyano-7-usebestmail (1,37 g). The target connection receive according to the same method as in example 106, except h which I described below.

So pl. 170 - 173oC.

NMR: solvent CDCl3) of 1.30 (3H, d, J = 7,0 Hz), 4,13 (1H, apt d, J = 7,0 Hz, 0.8 Hz), 4,25 (1H, d, J = 14,0 Hz), to 4.98 (1H, d, J = 14,0 Hz), 5,59 (1H, d, J = 0.8 Hz), 5,59 (1H, d, J = 0.8 Hz), 6,79 - 6,86 (2H, m), 7,49 - 7,56 (1H, m), 7,72 (1H, C), 7,81 (1H, s), to 7.84 (1H, d, J = 8,4 Hz), 8,35 (1H, d, J = 8,4 Hz).

MS: MH+= 413

Example 129.

Obtaining the compounds represented by the structural formula:

_

The target compound is obtained from the compounds obtained according to example 128, in accordance with the same manner as described in example 111. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) of 1.30 (3H, d, J = 7,2 Hz), of 4.12 (1H, q, J = 7.2 Hz), 4,28 (1H, d, J = 14.4 Hz), 5,00 (1H, d, J = 14.4 Hz), the 5.65 (1H, s), to 6.80 - 6.87 in (2H, m), 7,49 - 7,56 (1H, m), of 7.70 (1H, s), 7,70 - 7,76 (1H, user. C), 7,80 (1H, s), with 8.33 (1H, d, J = 8,8 Hz), 8,91 (1H, d, J = 8,8 Hz), to 9.32 is 8.38 (1H, user. C).

Example 130.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same method described in example 127, except that instead of 1-(1H-1,2,4-triazole-1-yl)-2', 4'-defloration using 1-(1H-1,2,4-triazole-1-yl)-2'-chloroacetophenone. The physical properties of this compound are described below.

, is in, J = 7,2 Hz), of 5.55 (1H, s), ceiling of 5.60 (1H, d, J = 14.4 Hz), 7.18 in - 7,22 (2H, m), 7,34 - 7,38 (1H, m), 7,46 (1H, d, J = 8,8 Hz), 7,68 (1H, s), 7,69 - 7,73 (1H, s), 7,81 (1H, s), to 8.20 (1H, d, J = 8,8 Hz).

Example 131.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 106, except that instead of 2-ethyl-6-chlorobenzothiazole using 2-methyl-6-chlorobenzothiazole. The physical properties of this compound are described below.

Condition: solid product.

The NMR solvent (CDCl3) 3,43 (1H, d, J = 15.2 Hz), 3,88 (1H, d, J = 15.2 Hz) and 4.65 (1H, d, J = 14,2 Hz), 4,70 (1H, d, J= 14,2 Hz), 6,03 (1H, s), 6,69 - 6,74 (1H, m), 6,76 - for 6.81 (1H, m), 7,40 (1H, DD, J = 8,8 Hz, 2.0 Hz), 7,42 - 7,50 (1H, m), of 7.75 (1H, DD, J = 2.0 Hz), 7,82 (1H, d, J = 8,8 Hz), the 7.85 (1H, s), 8,18 (1H, s).

Example 132.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 131 except that instead of 2-methyl-6-chlorobenzothiazole using 2-methyl-6-cyanobenzoate. The physical properties of this compound are described below.

So pl. 176 - 178oC.

NMR: solvent CDCl3) to 3.52 (1H, d, J = 15,4 Hz), 3,95 (1H, d, J = 15,4 Hz), 4,69 (2H, s), by 5.87 (1H, s) of 6.71 - PC 6.82 (1H, m), 7,51 - p 133.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same method described in example 127, except that instead of 2-ethyl-6-chloro-7-asiansuite using 2-methyl-6-chloro-7-asiansuite. The physical properties of this compound are described below.

So pl. 145 - 147oC.

NMR: solvent CDCl3) 3,47 (1H, d, J = 15.2 Hz), 3,90 (1H, d, J = 15.2 Hz), 4,69 (2H, s), USD 5.76 (1H, s) 6,70 - 6,83 (2H, m), 7,39 (1H, d, J = 8,4 Hz), 7,42 - 7,49 (1H, m), 7,86 (1H, s), 8,08 (1H, d, J = 8,4 Hz), 8,13 (1H, s).

Example 134.

Obtaining the compounds represented by the structural formula:

< / BR>
Hydrochloride 3-nitro-4-chloropyridine (2038 mg) is dissolved in ethanol (42 ml) and to the solution was added sodium hydrosulfide (2148 mg), followed by stirring for 40 minutes at room temperature. To this reaction mixture was added an aqueous solution of sodium hydrosulfide in (6.67 g) and the resulting mixture is heated and stirred at 80oC for 12 hours. After separation of nerastvorimogo material by filtration the solution is concentrated. The concentrate was dissolved in methanol-water and the solution is mixed with silica gel and dried under reduced pressure. Then hold elution with 5:1 chloroform: what this product was added 7 ml of ethyl acetate and molecular sieve 4A, and the resulting mixture is heated and refluxed for 20 minutes in nitrogen atmosphere. The reaction mixture was dried under reduced pressure and dissolved in methanol. The solution is subjected to adsorption with silica gel. This solution elute 50:1 chloroform-methanol to obtain through this, 590 mg of 2-methyl-5-asiansuite. The target connection receive in accordance with the same manner as described in example 131 except that instead of 2-methyl-6-chlorobenzothiazole use the above 2-methyl-5-asiansuite. The physical properties of this compound are described below.

So pl. 137 - 148oC.

NMR: solvent (CD3OD) of 3.69 (1H, d, J = 14,8 Hz), 4,08 (1H, d, J = 14,8 Hz), of 4.77 (1H, d, J = 14.4 Hz), to 4.87 (1H, d, J = 14.4 Hz), of 6.71 - 6,84 (1H, m), 6,92? 7.04 baby mortality (1H, m), 7,32 - 7,46 (1H, m), 7,83 (1H, s), of 7.97 (1H, d, J = 5,2 Hz), of 8.37 (1H, d, J = 5.8 Hz), of 8.37 (1H, s), 9,06 (1H, s).

Example 135.

Obtaining the compounds represented by the structural formula:

< / BR>
Sodium azide (2301 mg) dissolved in dimethyl sulfoxide (60 ml) and to this solution was added 2-bromo-4'-dimethylacetophenone (3000 mg), followed by stirring for 20 minutes at room temperature. The reaction mixture is poured into 200 ml of ice water and then subjected to extraction with ethyl acetate (200 ml x 5). The extract is dried over anhydrous magnesium sulfate, concentrated under reduced pressure and satom this 2-azide-4'-dimethylacetophenone (2155 mg). After cooling to -78oC solution Diisopropylamine lithium in 47 ml of tetrahydrofuran obtained from Diisopropylamine (1.75 ml) and 1.6 M hexane solution (7.8 ml) utility, are added dropwise tertrahydrofuran ring solution (19 ml) 2-azide-4'-dimethylacetophenone (2155 mg) over 5 minutes, followed by stirring at -78oC for 1 hour. Then added dropwise propionate (1,81 ml) and the resulting mixture allowed to stand at -78oC for 10 minutes, warmed to room temperature and stirred for 10 minutes at room temperature. The reaction mixture was poured into ice water and subjected to extraction with ether (300 ml x 3). The extract is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained oily substance is purified by chromatography on a column of silica gel (hexane _ hexane : ethyl acetate = 10:1) to obtain through this 2-azide-1-(4'-dimethylphenyl)finalproject (1.98 g). This product is dissolved in cyclohexane (38 ml) and to the solution was added ether phosphoric acid. The resulting mixture was stirred for 1 hour at room temperature in a nitrogen atmosphere and then for 20 hours at 90oC when heated. The reaction mixture was clean chromatometer)oxazole (630 mg). Using this connection instead of 2-ethyl-6-chlorobenzothiazole, get the target connection in accordance with the same manner as described in example 106. The physical properties of this compound are described below.

Condition: oily product.

NMR: solvent CDCl3) of 1.55 (3H, d, J = 8.0 Hz), 2,50 (3H, s), 3,88 (1H, q, J = 8.0 Hz), 4,69 (1H, d, J = 13.3 Hz), to 4.98 (1H, d, J = 13.3 Hz), to 5.56 (1H, user. C), 6,60 - 6,72 (2H, m), 7,20 - 7,26 (2H, m), 7,22 - 7,34 (1H, m), 7,27 (2H, s), 7,33 - 7,38 (2H, m), of 7.70 (1H, s), 8,30 (1H, s).

Example 136.

Obtaining the compounds represented by the structural formula:

< / BR>
The product (77 mg) of example 135 was dissolved in dichloromethane (6.0 ml) and cooled with ice water to the solution was added meta-chloroperbenzoic acid (156 mg). After heating the mixture to room temperature it is stirred for 1 hour. To the reaction mixture was added saturated aqueous sodium thiosulfate solution and a saturated aqueous solution of sodium bicarbonate. To the mixture was added dichloromethane (10 ml) to separate the mixture into layers. The resulting aqueous layer is subjected to further extraction with dichloromethane (10 ml x 2). The organic layers are combined, washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under pony is LEM (hexane-ethyl acetate = 4:1 _ dichloromethane-methanol = 10:1) to obtain by means of this target compound. The physical properties of this compound are described below.

Condition: oily product.

NMR: solvent CDCl3) to 1.60 (3H, d, J = 7,2 Hz), of 3.07 (3H, s), 3,91 (1H, q, J = 7,1 Hz), 4,71 (1H, d, J = 14.1 Hz), 5,00 (1H, d, J = 14.1 Hz), 5.40 to - 5,50 (1H, user. C) 6,62 - 6,72 (2H, m), 7,26 - 7,33 (1H, m), 7,31 (1H, s), 7,60 - to 7.64 (2H, m), 7,73 (1H, s), 7,92 - of 7.97 (2H, m), with 8.05 (1H, s).

MS: m/e FAB 475 (MH+).

Example 137.

Obtaining the compounds represented by the structural formula:

< / BR>
and its diastereoisomer;

A solution of 2-ethyl-4-cyano-5-trimethylsilylimidazole (1,58 g) in 10 ml of tetrahydrofuran are added dropwise to 20 ml of tertrahydrofuran ring solution Diisopropylamine lithium (obtained from 1,40 ml Diisopropylamine and 3.2 ml utility (1.6 M hexane solution) at -65oC. and Then added dropwise to 10 ml of tertrahydrofuran ring solution of (1H-1,2,4-triazole-1-yl)-2,4-diferentiation at -65oC. After stirring the mixture for 1.5 hours to give an aqueous solution of ammonium chloride and the resulting mixture was separated with ethyl acetate and water on the liquid. The obtained organic layer is washed with water and dried and the solvent is distilled off. The residue is dissolved in 20 ml of tetrahydrofuran and the solution was added 20 ml of tertrahydrofuran ring solution (1.0 M) tetrabutyl the traditional divide the mixture with ethyl acetate and water layers, the obtained organic layer was washed with water, dried and concentrated to dryness. The residue is purified by chromatography on a column of silica gel (dichloromethane : methanol = 200:1) getting through this one diastereomeric the compound (I) (464 mg). The fraction containing the other diastereoisomer and (1H-1,2,4-triazole-1-yl)-2,4-defloration, treated with sodium borohydride in methanol and subjected to separation on a column of silica gel with getting through this 564 mg other diastereomer of compound (II). The physical properties of this compound are described below.

(I)

So pl. 198 - 205oC.

NMR: solvent CDCl3) of 1.20 (3H, d, J = 7,1 Hz) 4,06 (1H, q, J = 14.4 Hz), 4,08 (1H, q, J = 7,1 Hz), 4,96 (1H, d, J = 14.4 Hz), 5,41 (1H, s), 6,77 - 6,83 (2H, m), 7,42 - 7,49 (1H, m), of 7.75 (1H, s), 7,80 (1H, s), with 8.05 (1H, s).

MS: MH+= 362

(II)

So pl. 191 - 194oC.

NMR: solvent CDCl3) to 1.61 (3H, d, J = 7,1 Hz), 4,08 (1H, q, J = 7,1 Hz), of 4.66 (1H, d, J = 14,0 Hz), to 4.98 (1H, d, J = 14,0 Hz), lower than the 5.37 (1H, s), 6,58 - 6,70 (2H, m), 7,12 - to 7.18 (1H, m), of 7.75 (1H, s), 7,79 (1H, s), of 7.97 (1H, s).

MC: MH+= 362

Example 138.

Obtaining the compounds represented by the structural formula:

< / BR>
In 2 ml of N-methylpyrrolidone dissolved 150 mg of the compound obtained in example 137, and to the solution add the>
C in the oil bath. To the liquid reaction mixture are added water and subjected to 3 times of extraction with AcOEt. After the extraction was washed with water and then saturated aqueous NaCl and dried over magnesium sulfate. AcOEt is distilled off. To the residue was added 2 ml of acetone, 4 ml of EtOH and 10 ml of water. The resulting mixture was adjusted to pH 3 with 1N aqueous HCl and allowed to stand. The result is a solid product. The solid product is separated by filtration to obtain 82 mg of the target compound. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent (DMSO - d6) of 1.13 (3H, d, J = 7,0 Hz), 4,11 - to 4.14 (1H, m), 4,34 (1H, d, J = 14,2 Hz), 4,80 (1H, d, J = 14,2 Hz), 6,16 (1H, s), 6,93 - 6,98 (1H, m), 7.18 in - 7,24 (1H, m), 7,28 - 7,33 (1H, m), to 7.61 (1H, s), by 8.22 (1H, s), to 8.45 (1H, user. C).

MC: MH+= 405.

Example 139.

Obtaining the compounds represented by the structural formula:

< / BR>
In 1 ml of dimethylformamide was dissolved 80 mg of the compound obtained in example 138, and to the solution was added 65 mg Cs2CO3followed by heating for 30 minutes at an external temperature of 60oC in the oil bath. Next, to the reaction mixture of 0.02 ml of CH3I followed by stirring for 30 minutes at to the of xtracta water and then with saturated aqueous NaCl solution and drying over magnesium sulfate AcOEt is distilled off. The resulting residue is purified by chromatography on a column of silica gel (SiO2: 20 g, elution CH2Cl2and then a 1% solution of MeOH in CH2Cl2and then a 2% solution of MeOH in CH2Cl2) to obtain 58 mg of the target compound. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) 1,22 (0,9 H, d, J = 7,1 Hz), 1,25 (2,1 H, d, J = 7,1 Hz), 4,08 - is 4.21 (2H, m), 4,45 (0,9 H, s), 4,49 (2,1 H, s), 4.95 points (0,7 H, d, J = 14,2 Hz), 5,00 (0,3 H, d, J = 14,8 Hz), 5.40 to (0,7 H, c) of 5.53 (0,3 H, s), 6,76 - 6,84 (2H, m), 7,45 - 7,52 (1H, m), 7,72 (0,3 H, C) 7,75 (0,7 H, s), 7,78 (0,7 H, s), 7,81 (0,3 H, s), 8,14 (0,3 H, s), 8,35 (0,7 H, C).

MC: MH+= 419

Example 140.

Obtaining the compound (I) represented by the structural formula:

< / BR>
and it diastereomers of compound (II):

The corresponding target compounds receive in accordance with the same manner as described in example 137 except that instead of 2-ethyl-4-cyano-5-trimethylsilylimidazole use 2-ethyl-4-(4'-forfinal)-5-trimethylsilylimidazole. The physical properties of this compound are described below.

(I)

So pl. 122 - 124oC.

NMR: solvent CDCl3) to 1.67 (3H, d, J = 7,0 Hz), 4,08 (1H, q, J = 7.0 Hz), to 4.73 (1H, d, J = 13,8 Hz), is 4.93 (1H, d, J = 13,8 Hz), 6,14 (1H, d, J = 1.7 Hz), 6.48 in - 6,54 (1H, m), 6,66 - 6 is ritel (CDCl3) of 1.23 (3H, d, J = 7,1 Hz) 4,06 (1H, q, J = 7,1 Hz), 4,28 (1H, d, J = 14.4 Hz), 4,89 (1H, d, J = 14.4 Hz), 6,04 (1H, s), 6,77 - 6,85 (2H, m), 7,13 - 7,17 (1H, m), 7,41 (1H, s), 7,47 - of 7.55 (1H, m), to 7.67 (1H, s), the 7.85 - a 7.92 (2H, m), of 7.90 (1H, s).

Example 141.

Obtaining the compound (I) represented by the structural formula:

< / BR>
and it diastereomers of compound (II).

The corresponding target compounds receive in accordance with the same manner as described in example 137 except that instead of 2-ethyl-4-cyano-5-trimethylsilylimidazole use 2-ethyl-4-(4'-chlorophenyl)-5-trimethylsilylimidazole. The physical properties of this compound are described below.

(I)

So pl.: 132 - 133oC.

NMR: solvent CDCl3) to 1.67 (3H, d, J = 7,0 Hz), 4,10 (1H, q, J = 7.0 Hz), to 4.73 (1H, d, J = a 13.9 Hz), is 4.93 (1H, d, J = a 13.9 Hz), 6,09 (1H, s), 6,46 - 6,55 (2H, m), 7,65 - of 6.73 (1H, m) 7,05 - 7,13 (1H, m), 7,17 (1H, s), 7,35 - 7,40 (2H, m), the 7.65 of 7.70 (2H, m), of 8.04 (1H, s).

(II)

So pl.: 162 - 164oC.

NMR: solvent CDCl3) of 1.23 (3H, d, J = 7,1 Hz) 4,06 (1H, q, J = 7,1 Hz), 4,27 (1H, d, J = 14.4 Hz), 4,89 (1H, d, J = 14.4 Hz), 5,97 (1H, s), 6,76 - 6,85 (2H, m), 7,40 - of 7.55 (4H, m), to 7.67 (1H, s), 7,72 - to 7.77 (2H, m), 7,89 (1H, s).

Example 142.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same method, ottiano-5-trimethylsilylimidazole. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) 3,44 (1H, d, J = 15,0 Hz), 3,81 (1H, d, J = 15,0 Hz), 4,58 (1H, d, J = 14,2 Hz), 4,74 (1H, d, J = 14,2 Hz), of 5.48 (1H, s), 6,74 - PC 6.82 (2H, m), 7,40 - 7,46 (1H, m), a 7.85 (1H, s), 7,87 (1H, s), 8,07 (1H, s).

MC: MH+= 348.

Example 143.

Obtaining the compounds represented by the structural formula:

< / BR>
The target connection receive in accordance with the same manner as described in example 137 except that instead of 2-ethyl-3-cyano-5-trimethylsilylimidazole using 2-methyl-4-(4'-chlorophenyl)-5-trimethylsilylimidazole. The physical properties of this compound are described below.

Condition: solid product.

NMR: solvent CDCl3) to 3.34 (1H, d, J = 15.3 Hz), 3,85 (1H, d, J = 15.3 Hz), to 4.62 (1H, d, J = 14,2 Hz), 4,71 (1H, d, J = 14,2 Hz), 6,21 (1H, s), 6,69 - 6,83 (2H, m), 7,27 (1H, s), of 7.36 - 7,46 (3H, m), 7.68 per - 7,73 (2H, m), a 7.85 (1H, s), to 8.20 (1H, s).

Example 144.

Obtaining the compounds represented by the structural formula:

< / BR>
To a suspension of AlCl3(5,88 g) in CH2Cl2(50 ml) was added differental (5,77 g) and then to the mixture was added dropwise a solution of 2-(4-cyanophenyl)acetylchloride (5,28 g) in CH2Cl2(30 ml). Then the mixture is heated and codwithout column chromatography (SiO2) with an elution CH2Cl2-hexane (1:1) to obtain by means of this 4-(2-(2,4-differenl)-2-oxo)-ethylbenzonitrile (2,45 g).

To a solution of this compound in EtOH (12 ml) was added 50% NaOH (0,67 g) and then added dropwise MeI (0,46 ml). The resulting mixture is stirred for 4 hours at room temperature. Then to the mixture was added ethyl acetate and washed with water, the residue obtained by evaporation of the organic layer, purify by chromatography on a column (SiO2; hexane-CH2Cl2= 3:1 _ 1:1) to obtain through this, 0.5 g of the compound, 4-(2-(2,4-differenl)-1-methyl-2-oxo)ethylbenzonitrile.

1.0 M ethereal solution (3.9 ml) TMSCH2MgCl cooled to -78oC and added dropwise an ethereal solution (5 ml) of the above compound (0.5 g). After that, the mixture is heated to 0oC and stirred for 10 minutes. To the mixture was added saturated aqueous solution of ammonium chloride followed by extraction with AcOEt. The obtained organic layer is evaporated to dryness and add CH2Cl2(10 ml) and BF3-OEt2(of 0.24 ml) at 0oC, followed by stirring for 1.5 hours at the same temperature. Then to the mixture was added AcOEt and washed with aqueous solution of hydrogen is in column (SiO2; hexane-CH2Cl2= 3:1 _ 1:1) to obtain by means of this compound, 4-(2-(2,4-differenl)-1-methyl-2-propenylbenzene (0.2 g).

To a solution of this compound (200 mg) in chloroform (4 ml) was added meta-chloroperbenzoic acid (490 mg) under cooling with ice water and the resulting mixture left to stand overnight. After rinsing liquid reaction mixture is diluted with sodium carbonate and then with water to the residue obtained by evaporation of the obtained organic layer, add 5 ml of dimethylformamide. Thus obtained mixture was added to a solution of sodium 1,2,4-triazole in dimethylformamide (3 ml), which is derived from 1,2,4-triazole (272 mg) and 60% NaH (141 mg). After the reaction for 2 hours at 90oC to the reaction mixture was added ethyl acetate, followed by washing with water. The solvent is distilled off and the obtained residue is subjected to chromatography on a column (SiO2; hexane-CH2Cl2= 1:1 _ 1:2) to obtain through this 50 mg of the target compound. The physical properties of this compound are described below.

So pl. 208 - 209oC.

NMR: solvent CDCl3) of 1.13 (3H, t, J = 7,1 Hz) to 3.38 (1H, q, J = 7,1 Hz), with 3.79 (1H, d, J = 14,5 Hz), 4,79 (1H, d, J = 14,5 Hz), to 4.98 (1H, d, J = 1.5 Hz), 6,74 - 7,81 (2H, m), 7,44 the tion, represented by the structural formula A:

< / BR>
and compounds represented by structural formula B:

< / BR>
i) the Compound (625 mg) obtained in example 144, dissolved in N,N-dimethylformamide (2 ml) and the solution is heated together with NaN3(345 mg) and Et3N HCl (731 mg) for 7 hours at 100oC. After removal of the undissolved product is filtered, the solvent is distilled off under reduced pressure and the obtained residue was added a small amount of ethanol and water. Then the mixture is brought to pH 2 using HCl. Loose produce a solid product by filtration, washed with water and then dried. Output: 539 mg

ii) the Above solid product (514 mg) was dissolved in N,N-dimethylformamide (5 ml) and to this solution was added Cs2CO3(422 mg) and MeI (0,089 ml) followed by heating for 4 hours at room temperature. Add ethyl acetate and the resulting organic layer is washed 3 times with water. After that, the solvent is distilled off and the residue is purified by chromatography on a column (SiO2; CH2Cl2:EtOA = 4:1) to obtain by means of this compound (333 mg) structural formula A and a compound (93 mg) structural formula B. Physical properties of these compounds are described below.

d, J = 14,3 Hz) to 4.41 (3H, s), a 4.83 (1H, d, J = 14,3 Hz), a 4.83 (1H, d, J = 1.5 Hz), 6,74 - for 6.81 (2H, m), 7,44 - rate of 7.54 (1H, m), of 7.64 (2H, d, J = 8,4 Hz), 7,71 (1H, s), of 7.75 (1H, s) to 8.14 (2H, d, J = 8,4 Hz).

B

So pl. 169 - 171oC.

NMR: solvent CDCl3) of 1.17 (3H, d, J = 7,1 Hz), 3,42 (1H, q, J = 7,1 Hz), 3,88 (1H, d, J = 14.1 Hz), 4,22 (3H, s), a 4.83 (1H, d, J = 14.1 Hz), of 4.95 (1H, d, J = 1.5 Hz), 6.75 in - PC 6.82 (2H, m), 7,44 - of 7.55 (1H, m), 7,70 for 7.78 (6H, m).

Example 146.

Receiving compound A represented by the structural formula:

< / BR>
and it diastereomeric connection B.

The target connection receive in accordance with the same manner as described in example 144 except that instead of 2-(4-cyanophenyl)acetylchloride using 2-(4-(1,2,3-triazole-2-yl)phenyl)acetylchloride. The physical properties of this compound are described below.

A

So pl. 198 - 199oC.

NMR: solvent CDCl3) to 1.16 (3H, d, J = 7,1 Hz), 3,39 (1H, q, J = 7,1 Hz) to 3.89 (1H, d, J = 14.1 Hz), a 4.83 (1H, d, J = 14.1 Hz), is 4.85 (1H, s), 6,72 - to 6.80 (2H, m), 7,44 - of 7.55 (1H, m), of 7.64 (2H, d, J = 8.6 Hz), 7,72 (1H, s), 7,76 (1H, s), 7,83 (2H, s), 8,08 (2H, d, J = 8.6 Hz).

B

Condition: solid product.

NMR: solvent CDCl3) was 1.58 (3H, d, J = 7,0 Hz), of 3.46 (1H, q, J = 7.0 Hz), of 4.67 (1H, d, J = a 13.9 Hz), is 4.85 (1H, d, J = 1.3 Hz), to 5.03 (1H, d, J = a 13.9 Hz), 6.42 per - 6,48 (1H, m), 6,61 is 6.67 (1H, m), 6,93 - 6,99 (1H, m), 7,14 (2H, user. d, J = 8.6 Hz), of 7.75 (2H, s) is th ICR infect through their tail veins with a strain of Candida albicans MCY 8622 (2 x 106 SOY/mouse) (SFU - SOY, entityarray unit). After 1 hour, the compounds shown in table 4, is administered orally at a dose of 2.5 or 10 mg per kg of body weight of the mouse to the appropriate groups of mice. Observations should be performed within 7 days to calculate the average number of days of survival for each group. This is the average number used as an index indicating the antifungal activity in vivo (see tab. 4).

Example 147.

< / BR>
In 33 ml of pyridine is dissolved and 6.6 ml (60 mmol) of (S)-methyl hydroxy-2-methylpropionate. To the resulting solution was added to 18.1 g (1.5 equivalent) triphenylmethane followed by heating for 1 hour at 80oC. the Reaction mixture is cooled to room temperature and then slowly added to 350 ml of water. The precipitated crystals are collected by filtration, washed with water and dried. Thus obtained product is recrystallized from ethanol to obtain 18.3 g (yield: 85%) of target compound (203).

C24H24O3MH+= 360

Calculated,%: H = of 6.71, C = 79,97, N = 0

Found,%: H = 6,76, C = 79,77, N = 0,05

The melting point of the crystals: 84 - 85oC.

1H-NMR ( , CDCl3): to 1.15 (3H, d, J = 7,1 Hz), 2,69 - 2,77 (1H, m), 3,17 (1H, DD, J = 5.6 Hz, 8,8 Hz), 3,29 (1H, DD, J = 5.6 Hz, 8,8 Hz), 3,70 (3H, s), 7,20 - 7,44 (15H, m)FL (203). While cooling with ice water to the resulting solution was added dropwise over 15 minutes with stirring 54 ml of an aqueous solution 2,52 g (2 equivalents) of the monohydrate of lithium hydroxide. After heating the resulting mixture to room temperature and stirring for 4 hours add 3.6 ml of glacial acetic acid and the organic solvent is distilled off under reduced pressure. After extraction with ethyl acetate, the extract washed with water, dried and concentrated to obtain 10.4 g of target compound (204). By recrystallization from dichloromethane-hexane get the pattern for the (quantitative) analysis.

C23H22O3MH+= 347

Calculated,%: C = 79,74 H = 6,47 N = 0

Found,%: C = 79,59 H 6,47 N = 0,07

The melting point of the crystals: 99 - 102oC.

1H-NMR ( , CDCl3): of 1.18 (3H, d, J = 7,2 Hz), 2,69 - 2,78 (1H, m) of 3.25 (1H, DD, J = 5.6 Hz, 8,8 Hz), 3,32 (1H, DD, J = 5.6 Hz, 8,8 Hz), 7,15 was 7.45 (15H, m).

< / BR>
In 50 ml of dichloromethane is dissolved 10.3 g (29,8 mmol) of the compound (204). While cooling with ice water to the obtained solution are added successively to 3.64 g (1.1 equivalent) of 2-mercaptopyridine, of 3.64 g (0.1 equivalent) of 4-dimethylaminopyridine and 6.76 g (1.1 equivalent) dicyclohexylcarbodiimide. The resulting mixture paravauxite the precipitate was separated by filtration. Then, the filtrate is diluted with ethyl acetate, washed twice with water and saturated salt solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure.

The residue is purified on a column of silica gel (elution with hexane : ethyl acetate = 9:1) to obtain through this, 11.9 g (yield 91%) of target compound (205) as a yellow oil.

1H-NMR ( , CDCl3): to 1.21 (3H, d, J = 7,2 Hz), 2,99 - to 3.09 (1H, m), 3,21 (1H, DD, J = 5.6 Hz, 9,2 Hz), 3,44 (1H, DD, J = 7,6 Hz and 9.2 Hz), 7,21 - 7,33 (10H, m), 7,43 - 7,47 (6H, m), 7,63 (1H, d, J = 8.0 Hz), 7,73 (1H, t, J = 8.0 Hz), 8,63 (1H, d, J = 4,8 Hz).

Example 148.

< / BR>
7.8 ml of tetrahydrofuran suspended 780 mg (1.2 equivalents relative to the compound (205)] the magnesium powder, activated by stirring overnight at 120oC in nitrogen atmosphere. To this suspension was added one drop of 2,4-diversamente and one piece of crystal iodine and stirred the mixture, to which are added dropwise to 3.67 ml [1.2 equivalents relative to the compound (205)] 2,4-diversamente dissolved in 17 ml of tetrahydrofuran while maintaining the internal temperature at 40 - 60oC. Then add 20 ml of tetrahydrofuran, the mixture was cooled to an internal temperature of -30oC. Solution of the Institute of internal temperature -25 - -30oC. Then the resulting mixture is stirred for 15 minutes at -30oC and 2 hours at room temperature, the reaction mixture was added saturated aqueous solution of ammonium chloride, followed by stirring for 15 minutes. To the mixture are added ethyl acetate and water to separate an organic layer. The organic layer is washed twice with water and once with saturated salt solution and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified on a column of silica gel (elution with hexane : ethyl acetate = 9:1) and then recrystallized from methanol to obtain through this 7,46 g (yield 62%) of target compound (206).

C29H24F2O2MH+= 442

Calculated,%: H = 5,47 C = 78,7 N = 0

Found,%: H = 5,48 C = seen at the level 78.73 N = 0

The melting point of the crystals: 94 - 97oC.

1H-NMR ( , CDCl3): to 1.21 (3H, d, J = 6.8 Hz), 3,21 (1H, DD, J = 5,2 Hz and 8.8 Hz), 3,42 (1H, DD, J = 6,4 Hz and 8.8 Hz), of 3.56 (1H, m), to 6.80 (1H, m) 6,94 (1H, m), 7,17 - 7,31 (15H, m), to 7.77 - 7,83 (6H, m).

Example 149.

< / BR>
In 64 ml of tetrahydrofuran is suspended to 6.43 g [1.2 equivalents relative to the compound (206)] methyltriphenylphosphonium bromide in a stream of nitrogen. To this suspension is added dropwise to 11.2 ml [1.2 EQ is. the donkey heat the mixture again to room temperature and then stirring for 2 hours was added dropwise a solution of 6,63 g (15.0 mmol) of the compound (206) in 30 ml of tetrahydrofuran. To the liquid reaction mixture was added 500 ml of hexane and 300 ml of water and nerastvorim product removed by filtration.

The organic layer is separated and washed 3 times with water and once with saturated salt solution and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified on a column of silica gel (elution hexane : ethyl acetate = 50:1) to obtain through this, is 5.4 g (yield 85%) of oily product (207).

1H-NMR ( , CDCl3):

of 1.16 (3H, d, J = 7,0 Hz), 2,81 - 2,89 (1H, m), 2,97 - a 3.01 (1H, DD, J = 6,0 Hz and 9.2 Hz), 3.04 from - is 3.08 (1H, DD, J = 6,0 Hz and 9.2 Hz), 5,11 (1H, s), a total of 5.21 (1H, s), 6,68 to 6.75 (2H, m), 7,00 - 7,06 (1H, m), 7.18 in - 7,28 (9H, m), 7,35 - 7,39 (6H, m).

Example 150.

< / BR>
In 25 ml of dichloromethane is dissolved 2.70 g (6,14 mmol) of the compound (207). While cooling with ice water to the solution was added 1,46 g (1.1 equivalent) meta-chloroperbenzoic acid (purity 80%), followed by stirring for 12 hours at 4oC. To the reaction mixture was added meta-chlorbenzoyl acid number of 290 mg (0.34 equivalent) will be followed by the sodium sulfite followed by extraction with ethyl acetate. The obtained organic layer is washed successively with water, saturated sodium hydrogen carbonate solution, water and saturated salt solution and then dried over magnesium sulfate and the solvent is distilled off under reduced pressure to get through this 2,813 g of oily product (208). According to proton NMR analysis it was found that this compound is a mixture of 2:1 of the desired isomer (a) and its diastereoisomer (208).

1H-NMR ( , CDCl3) of 0.93 (3H, d, J = 8,8 Hz) <a>, and 0.98 (3H, d, J = 8,8 Hz)<b>, 2,04 - 2,12 (1H, m)<b>, 2,20 - of 2.28 (1H, m)<a>,

was 2.76 (1H, d, J = 5,2 Hz)<a>, was 2.76 (1H, d, J = 5,2 Hz)<b> is 2.88 (1H, DD, J = 7,2 Hz and 9.2 Hz)<a>, 2,96 (1H, DD, J = 7,2 Hz and 9.2 Hz)<b> 3,00 - of 3.06 (1H, m)<a+b>, to 3.02 (1H, d, J = 5,2 Hz)<a>, 3,11 (1H, d, J = 5,2 Hz)<b>, 6,61 - of 6.73 (2H, m)<a+b>, 7,12 - to 7.50 (16H, m)<a+b>.

Example 151.

< / BR>
(Alternate method)

1.6 M hexane solution of utility added dropwise to 221 mg of the compound (206) and 44 liters (1.2 equivalent) chloromethane in tetrahydrofuran (2.2 ml) at -70oC by injecting nitrogen. The resulting mixture was stirred for 5 minutes at this temperature and then heated to achieve an internal temperature as room temperature and stirring for 1 hour. To the mixture sequentially added an aqueous solution Sydenham salt solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (elution with hexane : ethyl acetate = 9:1) to obtain through this 219 mg (yield 96%) of the compound (208). According to proton NMR analysis found that this compound is diastereomers a mixture containing the compound (208a) and (208b) in the ratio of 1:2,5.

Example 152.

< / BR>
8.5 ml of dimethylformamide are suspended 370 mg [1.5 equivalent relative to the compound (208)] sodium hydride (60% dispersion in mineral oil) and to the suspension was added 851 mg (2 equivalents relative to the compound (208)] 1,2,4-triazole. After stirring for 15 minutes at room temperature to the suspension was added a solution of 2,813 g (6,17 mmol) of the compound (208) (diastereomer mixture <a> : <b> = 2:1), dissolved in 22 ml of dimethylformamide and the resulting mixture was stirred for 8.5 hours at 80oC. After cooling to room temperature, to the mixture are added water and ethyl acetate to separate into layers. The obtained organic layer was washed with saturated salt solution and then dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (elution with dichloromethane : methanol = 200:1) pornosu, and 867 mg of the mixture of both compounds in the form of a white solid product.

1NMR ( , CDCl3) of 0.87 (3H, d, J = 7,6 Hz), 2,37 at 2.45 (1H, m), 3,40 (1H, DD, J = 3.2 Hz, 10.0 Hz), 3,55 (1H, DD, J = 5.6 Hz, 10.0 Hz), 4,19 (1H, d, J = 14.4 Hz) and 4.65 (1H, d, J = 14.4 Hz), 4,88 (1H, s), 6,64 - 6,72 (2H, m), 7,22 - 7,30 (6H, m), 7,32 - 7,37 (6H, m), 7,46 is 7.50 (6H, m), of 7.64 (1H, s), to 7.84 (1H, s)

< / BR>
Cm. description connection (209a). The solid product.

1H-NMR ( , CDCl3): to 1.48 (3H, d, J = 7,6 Hz), 2,47 - of 2.56 (1H, m), of 2.92 (1H, DD, J = 3.2 Hz, 9.6 Hz), 3,19 (1H, DD, J = 3.2 Hz, 9.6 Hz), 4,56 (1H, d, J = 14,0 Hz), 4,69 (1H, DD, J = 14,0 Hz), 4,78 (1H, s), of 6.49 - of 6.61 (2H, m), 7,01 - to 7.09 (1H, m), 7,16 - 7,37 (15H, m), 7,63 (1H, s), 7,88 (1H, s).

Example 153.

< / BR>
7.4 ml of methanol is dissolved 740 mg (1,41 mmol) of the compound (209a) and to the resulting solution was added 295 mg (1.1 equivalent) of toluenesulfonic acid monohydrate, followed by stirring for 1 hour at room temperature. To the mixture was added 295 mg (1.1 equivalent) of toluenesulfonic acid monohydrate, followed by stirring for 3 hours at room temperature. To the mixture was added water and a saturated solution of sodium bicarbonate and ethyl acetate to separate into layers. The obtained organic layer was washed with water and then with saturated salt solution and dried over magnesium sulfate and the solvent is distilled PR the mixtures of dichloromethane and methanol in ratios of 100:1, 50:1 and 25:1) to obtain through this 246 mg of crude product. The product is recrystallized from a mixed solvent of dichloromethane and isopropyl ether to obtain 190 mg (yield 48%) of target compound (210) in the form of the pure product.

C13H15F2N3O2MH+= 284

Calculated,%: H = 5,34 C = 55,12 N = 14,83

Found,%: H = 5,33 C = 55,09 N = 14,93

The melting point of the crystals: 134 - 135oC.

1H-NMR ( , CDCl3): 0,84 (3H, d, J = 7,2 Hz), 2,30 - 2,39 (1H, m), 2,67 - 2,77 (1H, user. C) a 3.83 (1H, DD, J = 5.4 Hz, 11.2 Hz), 3,99 (1H, DD, J = 3.2 Hz, 11.2 Hz), was 4.76 (1H, d, J = 14,0 Hz), equal to 4.97 (1H, d, J = 14,0 Hz), 5,28 (1H, s), 6,69 - of 6.78 (2H, m), of 7.36 - the 7.43 (1H, m), of 7.75 (1H, s), to $ 7.91 (1H, s).

Example 154.

< / BR>
In a mixed solution of 5 ml of water and 2.5 ml of acetone is dissolved 144 mg N-methylmorpholine oxide (50% aqueous solution) and the resulting solution was sequentially added 36 l of osmium tetroxide (4% aqueous solution) and a solution of 247 mg of the compound (207) 2.54 ml of acetone. After stirring overnight at room temperature, to the mixture was added 100 l of osmium tetroxide (4% aqueous solution), followed by stirring for 24 hours at room temperature. To the mixture was added 10% aqueous Hydrosulphite solution of sodium followed by extraction with ethyl the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (elution successively with mixtures of hexane and ethyl acetate in ratios of 10:1 and 4:1) to obtain through this 153 mg of the main product (211a) in solid form, and 23 mg of its diastereoisomer (211b), having a high polarity.

1H-NMR ( ,CDCl3): of 0.75 (3H, d, J = 8,8 Hz), 1,80 (1H, DD, J = 5,2 Hz and 8.4 Hz), 2,44 of $ 2.53 (1H, m), 2,77 (1H, DD, J = 5,6 Hz and 8.4 Hz), 3,21 (1H, DD, J = 8,4, of 14.0 Hz), 3,32 (1H, DD, J = 2,8 Hz, of 14.0 Hz), 3,63 (1H, DD, J = 8,4 Hz, 11.2 Hz), of 3.96 (1H, DDD, 2,8 Hz, 5.6 Hz, 11.2 Hz), 4,39 (1H, s), 6,69 - 6,76 (1H, m), 6,79 - 6,84 (1H, m), 7,22 - 7,30 (3H, m), 7,32 - 7,37 (6H, m), 7,43 - 7,47 (6H, m), 7,52 - 7,58 (1H, m).

< / BR>
See the description of the compounds (211a). The solid product.

1H-NMR ( , CDCl3) to 1.35 (3H, d, J = 7,2 Hz), 2,34 is 2.44 (1H, m), with 2.93 (1H, DD, J = 3,6 Hz, 9.6 Hz), 3,19 (1H, DD, J = 3,6 Hz, 9.6 Hz), 3,82 (1H, DD, J = 6,8 Hz, a 10.6 Hz), of 3.96 (1H, DD, J = 5,2 Hz, a 10.6 Hz), 4,50 (1H, s), 6,57 - only 6.64 (1H, m), 6,70 to 6.75 (1H, m), 7.18 in - 7,31 (15H, m), 7,39 was 7.45 (1H, m).

Example 155.

< / BR>
3.3 ml of dichloromethane is dissolved in 96 g (2.2 equivalents in relation to the matter) oxalicacid and to the resulting solution at -60oC in a stream of nitrogen was added 185 g (4.8 equivalent with respect to the substance) of dimethylsulfoxide in dichloromethane (0.9 ml). After stirring for 5 minutes, added dropwise a solution of 142 mg (0.005 mmol the substance) of triethylamine. The resulting mixture was warmed to room temperature. To the mixture was added water, followed by extraction twice with dichloromethane. The obtained organic layer is washed twice with water and once with saturated salt solution and then over magnesium sulfate, and the solvent is then distilled off under reduced pressure. The residue is purified on a column of silica gel (elution with dichloromethane-methanol = 50:1) to obtain through this 106 mg (75% yield) of the desired product (212).

C13H13F2N3O2MH+= 262

Calculated,%: H = 4,66 C = 55,52 N = 14,94

Found,%: H = 4,68 C = 55,44 N = 14,96

The melting point of the crystals: 140 - 144oC.

1H-NMR ( , CDCl3) a 1.01 (3H, d, J = 7,2 Hz), 2,96 - 3,03 (1H, m), to 4.62 (1H, d, J = 14,0 Hz), the 4.90 (1H, d, J = 14,0 Hz), 5,16 (1H, s), 6.73 x - for 6.81 (2H, m), 7,37 - 7,44 (1H, m), 7,79 (1H, s), 7,86 (1H, s), 9,85 (1H, d, J = 3.2 Hz).

Example 156.

< / BR>
In 0,36 ml of water is suspended 36 mg (0,128 mmol) of the compound (212) and to the suspension was added 17 mg (1.2 equivalents) gidroksiiminobetulonovoi acid followed by heating for 1.5 hours at 50oC. To the mixture was added 21 mg gidroksiiminobetulonovoi acid followed by heating for 40 minutes. To the liquid reaction mixture was added ethyl acetate and asystem salt solution and then dried over magnesium sulfate and the solvent is then distilled off under reduced pressure. The residue is purified on a column of silica gel (elution with dichloromethane : methanol = 100:1) to obtain through this 12 mg of the target product (202).

C13H12F2N4O MH+= 279

Melting point: 181 - 182oC.

1H-NMR ( , CDCl3): of 1.17 (3H, d, J = 7,2 Hz), 3,29 (1H, q, J = 7.2 Hz), 4,82 (1H, d, J = 14,0 Hz), equal to 4.97 (1H, d, J = 14,0 Hz), 5,44 (1H, d, J = 0.8 Hz), 6,74 - PC 6.82 (1H, m), 7,39 - 7,46 (1H, m), 7,83 (1H, s), to 7.84 (1H, s).

Example 157.

< / BR>
1.1 ml of methanol was dissolved 110 mg of the compound (206) and to the solution was added 53 mg (1.1 equivalent) of the monohydrate of p-toluenesulfonic acid, followed by stirring for 20 minutes at 40oC. To the mixture are added water and ethyl acetate to perform the extraction. The obtained organic layer was washed with saturated salt solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 32 mg (yield 58%) of target compound (213) in the form of oil. The optical purity of this compound evaluate liquid chromatography high resolution using a chiral column. Optical purity is 99.0%. Conditions of the analysis are described next.

Column: Chiral Cell OB (inner 1H-NMR ( , CDCl3): of 1.18 (3H, d, J = 6.8 Hz), 2,50 (1H, t, J = 6.0 Hz), 3.45 points - of 3.54 (1H, m), 3.72 points - with 3.79 (1H, m), 3,84 - to 3.92 (1H, m), 6,82 - to 6.88 (1H, m), 6,92 - 6,98 (1H, m), 7,83 - of 7.90 (1H, m).

Example 158.

< / BR>
In 5 ml of dichloromethane is dissolved 472 mg (2.36 mmol) of the compound (213) and to the solution was added 448 g (2.5 equivalents) of chloromethyl methyl ether, 822 g (2 equivalents) of diethylethanolamine and a catalytic amount of 4-dimethylaminopyridine, followed by stirring overnight at room temperature. To the mixture was added dichloromethane and water to perform the extraction. The obtained organic layer was washed with water and saturated salt solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified on a column of silica gel (elution with hexane : ethyl acetate = 10:1) to obtain through this, 485 mg (yield 84%) of the target product (214) in the form of an oily product.

1H-NMR ( , CDCl3): to 1.22 (3H, d, J = 6.8 Hz), 3,29 (3H, s), 3,85 - 3,68 (2H, m), a 3.87 - of 3.94 (1H, m), 4,56 (1H, d, J = 8,4 Hz), 4,59 (1H, d, J = 9.4 Hz), 6,84 - 6,91 (1H, m), 6,94 - 6,99 (1H, m), a 7.85 - a 7.92 (1H, m).

Example 159.

< / BR>
The target connection (215) in the form of oil are as diastereomer a mixture of 1:1 in accordance with an alternative way of connection (208).

< 3,09 (1H, d, J = 5,2 Hz) to 3.33 (1H, s)<a>, to 3.36 (1H, s)<b> 3,19 - to 3.38 (1H, m)<a+b>, 3,45 - of 3.54 (1H, m)<a+b> of 4.57 (2H, s)<a>, br4.61 (1H, s)<b>, 6,75 - to 6.88 (2H, m)<a+b>, 7,32 was 7.45 (1H, m)<a+b>.

Example 160.

< / BR>
In 2.5 ml of dimethylformamide is dissolved 500 mg of the compound (213) and to the solution sequentially added 715 mg of imidazole and 715 l tert-butyldiphenylsilyl, followed by stirring for 2.5 hours at room temperature. To the reaction mixture are added ethyl acetate and water to perform the extraction. The obtained organic layer was washed with water and saturated salt solution and dried over magnesium sulfate. The product was then purified on a column of silica gel (elution with hexane : ethyl acetate = 9:1) to obtain through this 939 mg of the target product (216) in solid form.

1H-NMR ( , CDCl3): of 0.94 (9H, s) to 1.19 (3H, d, J = 10.0 Hz), to 3.58 (1H, m in), 3.75 (1H, DDD, J = 10.0 Hz, 5.2 Hz, 0.8 Hz), of 3.94 (1H, DDD, J = 10.0 Hz, 6.8 Hz, 1.6 Hz), PC 6.82 - 6.87 in (1H, m), 6,92 - 6,98 (1H, m), 7,29 - 7,44 (6H, m), 7,49 - 7,52 (2H, m), EUR 7.57 - to 7.61 (2H, m), 7,79 - a 7.85 (1H, m).

Example 161.

< / BR>
A solution of 438 mg (1.00 mmol) of the compound (216) 4.4 ml of diethyl ether are added dropwise to 3.0 ml of 1.0 M solution trimethylamine chloride in diethyl ether at room temperature in a stream of nitrogen, followed by stirring Teese it is subjected to extraction with ethyl acetate. The extract is washed with water and saturated salt solution and then dried over magnesium sulfate. Azeotropic distillation with toluene gives 524 mg of solid product.

Product number 262 mg dissolved in 2.5 ml of dichloromethane and to the solution are added dropwise 69 l complex triphoridae-diethyl ether while cooling with ice water. After stirring for 10 minutes to the reaction mixture was added a saturated solution of sodium bicarbonate, followed by extraction with dichloromethane. The extract is washed with water and saturated salt solution and dried over magnesium sulfate and the solvent is then distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (elution with hexane : ethyl acetate = 20:1) to obtain through this 174 mg of the target product (217) in the form of an oily product.

1H-NMR ( , CDCl3): of 1.02 (9H, c) of 1.17 (3H, d, J = 6.8 Hz), 2,72 is 2.80 (1H, m), 3,50 (1H, DD, J = 6,4 Hz, 10.0 Hz), to 3.64 (1H, DD, J = 5,2 Hz, 10.0 Hz), 5,13 (1H, s), 5,23 (1H, s) of 6.71 - of 6.78 (2H, m),? 7.04 baby mortality - 7,11 (1H, m), 7,31 - the 7.43 (6H, m), 7,58 - 7,63 (4H, m).

Example 162.

< / BR>
Carry out the synthesis of the compound (208). According to proton NMR analysis found that the ratio of diastereomers in oily product (218) is 1:2.

1

Example 163.

< / BR>
(Alternate method)

In 2 ml of tetrahydrofuran is dissolved 72 mg (0.16 mmol) of the compound (216) and 3.2 l (0.18 mmol) chloridometer. The resulting solution was cooled to -78oC in a stream of nitrogen. To this solution are added dropwise to 0.12 ml (0,17 mmol) of 1.5 M solution in diethyl ether complex motility-lithium bromide. The resulting mixture was stirred for 1 hour while heating to room temperature. To the reaction mixture was added a saturated solution of aqueous ammonium chloride followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated salt solution, dried and then concentrated under reduced pressure to get through this 86 mg oily compounds (218). According to proton NMR analysis found that the ratio of the diastereoisomers of the product is 1:1.

Example 164.

< / BR>
Connection (213) (233 mg, 0,507 mmol) dissolved in 5.0 ml of toluene and to the solution was added 141 mg (0,609 mmol) of silver oxide and 84 l (0,710 mmol) benzylbromide with subsequent premesis is at washed with ether. The filtrate is concentrated and then purified through column chromatography with silica gel (elution with hexane and then hexane : ethyl acetate = 12:1) to give 66 mg (yield 44%) of compound (219) in the form of a colorless oily product.

1H-NMR ( , CDCl3): to 1.21 (3H, d, J = 7,0 Hz), of 3.54 (1H, DD, J = 8,8 Hz, 5.5 Hz), 3,60 - 3,70 (1H, m), 3,82 (1H, DD, J = 8,8 Hz, 3.6 Hz), 4,47 (1H, d, J = 11,9 Hz), of 4.54 (1H, d, J = 11,9 Hz), 6,80 - 6,98 (2H, m), 7,20 - 7,40 (5H, m), 7,82 - 7,88 (1H, m).

Example 165.

< / BR>
In 2 ml of anhydrous tetrahydrofuran was dissolved 66 mg (0.23 mmol) of the compound (219) and 18 l (0.25 mmol) chloridometer. The resulting solution was cooled to -78oC. To this solution are added dropwise 0.16 ml (0.24 mmol) of 1.5 M solution in diethyl ether complex motility-lithium bromide. The resulting mixture was warmed to room temperature and stirred for 2.5 hours. To the reaction mixture was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to get through this 60 mg (yield 86%) of compound (220) in the form of an oily product.

Unexpectedly, compound (22)<b>, 2,14 - to 2.18 (1H, m)<a>, 2,20 - of 2.28 (1H, m)<b>, 2,77 is 2.80 (2H, m)<a+b> 3,07 - 3,10 (2H, m)<a+b>, 3,24 - of 3.32 (2H, m)<a+b>, 3,38 - of 3.46 (2H, m)<a+b>, 4,40 - to 4.52 (4H, m)<a+b> 6,75 - 6,84 (4H, m)<a+b>, 7,26 - 7,40 (12H, m)<a+b>.

Preparative examples.

Preparative examples of compounds (202) to the final compounds described below.

Preparative example 8.

< / BR>
To 33 g of the compound (202) was added 33 ml of water and 172 ml of O,O-diethyldithiophosphate and the mixture is heated and refluxed for 30 minutes. The reaction mixture is again cooled to room temperature and added with water, followed by extraction with ethyl acetate. Received an ethyl acetate layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off. To the obtained residue, add 70 ml of diethyl ether to form crystals. Thus obtained crystals are collected by filtration to obtain the target compound (35 g) as a crude product. The crude product (13,9 g) dissolved in ethyl acetate and the solution washed with 5% aqueous sodium carbonate solution and the solvent is then distilled off. The obtained residue is recrystallized from diethyl ether and diisopropyl ether to obtain through this 7-NMR ( , CDCl3): a 1.11 (3H, d, J = 7,1 Hz), 3,71 (1H, q, J = 7,1 Hz), 4,55 (1H, d, J = 14,3 Hz), to 5.08 (1H, d, J = 14,3 Hz), of 6.71 - to 6.80 (2H, m), 7,42 - of 7.48 (1H, m), 7,80 (1H, user. C) 7,94 (1H, s), to 8.41 (1H, user. C).

Preparative example 9.

< / BR>
Connection (221) (15,02 g) is dissolved in the standard (150 ml) and add 2-bromo-4'-methylthiazolidine (14.97 mg) followed by heating and boiling under reflux for 4 hours. The liquid reaction mixture is cooled to 0oC and then neutralized with an aqueous solution of bicarbonate, followed by extraction with ethyl acetate. The extract is washed with water and then with saturated salt solution and dried over anhydrous magnesium sulfate and the ethyl acetate is distilled off. The residue is purified by chromatography on silica gel (SiO2the elution dichloromethane and then 1% solution of methanol in dichloromethane) to obtain by means of this target compound (222) (10,19 g) as a solid product.

MH+= 459

1H-NMR ( , CDCl3): of 1.23 (3H, d, J = 7,2 Hz), of 2.54 (3H, s), of 4.05 (1H, q, J = 7.2 Hz), 4,28 (1H, d, J = 14.4 Hz), 4,88 (1H, d, J = 14.4 Hz), 6,13 (1H, s), 6.75 in - 6,85 (2H, m), 7,33 (2H, user. d, J = 8,4 Hz), 7,42 (1H, s), 7,46 - rate of 7.54 (1H, m), 7,66 (1H, s), 7,82 (2H, user. d, J = 8,4 Hz), 7,92 (1H, s).

Preparative example 10.

< / BR>
To a solution of compound (222) (10,19 g), dissolved in 150 ml of chloroform, is ishodovanja crude product to the liquid reaction mixture was added water, followed by extraction with chloroform. The obtained organic layer was washed with 50% aqueous solution of sodium bicarbonate, water and then saturated salt solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is purified by chromatography on a column of silica gel with getting through this target compound (223) (8,2 g) as a solid product.

MH+= 491

1H-NMR ( , CDCl3): of 1.24 (3H, d, J = 7,2 Hz), to 3.09 (3H, s), 4.09 to (1H, q, J = 7.2 Hz), 4,27 (1H, d, J = 14.4 Hz), 4,91 (1H, d, J = 14.4 Hz), 5,78 (1H, s), 6,78 - 6,85 (2H, m), 7,47 - of 7.55 (1H, s), to 7.67 (1H, s), of 7.69 (1H, s), 7,87 (1H, C) 8,02 (2H, user. d, J = 8,4 Hz), 8,10 (2H, user. d, J = 8,4 Hz).

Experimental example 3.

Groups of five mice ICR infect through their tail veins with a strain of Candida albicans MCY 8622 (2 x 106 COE/mouse) (SFU - COE, entityarray unit). After 1 hour, the compounds according to this description, is administered orally at a dose of 2.5 or 10 mg per kg of body weight of the mouse to the appropriate groups of mice. Observations should be performed within 7 days to calculate the average number of days of survival for each group. This is the average number used as an index indicating the antifungal activity in vivo.

Results

The result of the experiment shown in the table. 5.

As is clear from these donnabritney, has excellent antifungal activity and is therefore useful for the prevention and treatment of various fungal infectious diseases.

Examples preparative forms of the pharmaceutical composition

Example I

Two grams of the compound of example 99 of the present invention is dissolved in ethanol in a 500 ml flask, then add 6 g of polyvinylpyrrolidone and dissolve. The solvent is evaporated and the residue is collected, ground in a mill and then sieved through sieves with openings 32 mesh with obtaining granulated composition.

Example II

Two grams of the compound of example 49 of the present invention is dissolved in ethanol in a 500 ml flask, then add water to obtain 85% ethanol solution. Added to a solution of 6 g of hydroxypropylmethylcellulose, then the solvent is evaporated. The residue is collected, ground in a mill and then sieved through sieves with openings 32 mesh with obtaining granulated composition.

The use of phthalate hydroxypropylmethylcellulose or hydroxypropylcellulose also provides granular composition.

Example III

Five grams of the compound of example 99 of the present invention is the thief added 15 g of hydroxypropylmethylcellulose and 100 g of crystalline cellulose (trade name XXX, is Asahi Chemical Industry Co., a particle size of from 200 to 300 μm) to obtain a suspension, and then the solvent is evaporated. The residue is collected, ground in a mill and then sieved to separate the granules which pass through a sieve with openings 32 mesh and do not pass through a sieve with openings 48 mesh. Thus obtained granulated composition.

Data on the biological activity

1. Determination of the minimum concentration of antibiotic (µa)

The minimum concentration of the antibiotic was determined by the method based on twice the dissolved agar agar Saburo with dextrose (SDA: Difco Laboratories, Detroit, Mich.). The yeast is grown on SDA when 30oC for 24 hours and diluted to a final concentration of 105cells/ml sterilized saline solution.

Filamentous fungi grown on potato agar with dextrose (PDA: Eiken Chemical Co., Tokyo, Japan) at 30oC for 1 week and dilute to a final concentration of 105cells/ml of sterilized physiological saline containing 0.05% Tween 80. Five microlitres each suspension fungi deal with multinodular Replicator (Microplanar: Sakuma Seisakusho, Tokyo, Japan) on a plate of agar, which contains incubatee at 30oC. ICA is defined as the lowest drug concentration at which see some inhibition of fungus growth compared to control fungal growth.

The results obtained are presented in table. 6.

Investigated the activity against C. albicans MYC 8622.

2. Data on the toxicity of the inventive compounds

The compound of example 104 (200 mg/kg) administered orally 4 rats daily for 7 days. All rats were still alive at day 8 and was not observed any toxic effect.

The same result was observed when the test compound of example 127.

1. Connection Azola represented by the General formula 1

< / BR>
where R1and R2are the same or different and each represents a halogen atom or a hydrogen atom;

R3represents a hydrogen atom or a lower alkyl group;

r and m may be the same or different, each represents 0 or 1;

A represents N or CH;

W represents phenyl, oxazole, thiazole, or thienyl, or a group represented by the formula

< / BR>
where Q is S or O;

T is =CH-, =N - or =N+O-;

ring E is a 6-membered aromatic number is from phenyl, morpholinyl or methyl;

X represents phenyl which may be substituted by fluorine, thiazole or pyridine, landiolol group which may be substituted stands, or alkantiolsul group;

Y represents a group selected from-S -,- O - or -(CH2)j- where j is an integer from 1 to 4;

Z represents a hydrogen atom, halogen atom, halogenated lower alkyl group, lower CNS group, a hydroxyl group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents selected from fluorine, chlorine or 2,6-dimethylmorpholine, imidazolidinyl group, triazolyl group which may be substituted thiazole, tetrazolyl group which may be substituted by stands or amino group, oxazoline, which can be replaced by stands, except when W is a thiazole ring, R3is a methyl group and Z is a hydrogen atom when r = m = 0 and when W is phenyl, R3is hydrogen; Z is hydrogen, halogen, halogenated lower alkyl or lower alkoxygroup, when r = m = 0,

or its salt.

2. The compound or its salt accession SUP>+
-O-;

ring E is a 6-membered aromatic ring which may contain 1 or 2 nitrogen atom.

3. The compound or its salt accession acid on p. 2, where the group represented by formula

< / BR>
is a group represented by the following formula:

< / BR>
< / BR>
< / BR>
4. Connection asola, having the structural formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and their salts accession acids.

5. A method of obtaining optically active (2S, 3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl) butyronitrile, which includes the interaction of optically active (2R, 3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)-methyl]oxirane with cyanide diethylaluminum.

6. A method of obtaining optically active (2S, 3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl) butyronitrile, which includes the interaction of optically active (2R, 3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)-methyl]oxirane with cyanide ytterbium.

7. The way stereoselective obtain optically active (2S, 3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl) butyronitrile, which includes the interaction of the optical asset is b obtain compounds of asola, represented by the formula

< / BR>
where W, A, R1, R2, R3X, Y, Z, r and m are defined in paragraph 1,

or its salt accession acid, which includes the interaction of the compounds represented by formula

< / BR>
where A, R1, R2and R3defined above,

with the compound represented by formula

< / BR>
where Hal represents Br or Cl;

X, Y, Z, r and m are defined above.

9. The method of obtaining compounds of asola represented by the formula

< / BR>
where A, R1, R2, R3X, Y, Z, r and m are defined in paragraph 1,

W represents a thiazole,

or its salt accession acid, which includes the interaction of the compounds represented by formula

< / BR>
where A, R1and R2defined in paragraph 1,

with the compound represented by formula

< / BR>
where D is a group of the formula-W-(X)r(Y)m-Z;

Z' is hydrogen or CH3.

10. The method of obtaining compounds of asola represented by the formula

< / BR>
where W represents a thiazole;

A, R1, R2, R3X, Y, Z, r and m are defined in paragraph 1,

or its salt accession acid, which includes the interaction of the compounds represented by formula

< / BR>
with the connection, presti asola, represented by the formula

< / BR>
where A, R1, R2, R3, W, X, Y, Z, r and m are defined in paragraph 1,

or its salt accession acid, which includes the interaction of the compounds represented by formula

< / BR>
where A, R1, R2, R3, W, X, Y, Z, r and m are defined above,

with metallocarboranes acid and then with sodium 1,2,4-triazole or sodium-1,3-imidazole.

12. Pharmaceutical composition having anti-fungal activity that contains the connection Azola represented by the General formula 1

< / BR>
where R1and R2are the same or different and each represents a hydrogen atom or a halogen atom;

R3represents a hydrogen atom or a lower alkyl group;

r and m may be the same or different and each represents 0 or 1;

A is N or CH;

W represents phenyl, oxazole, thiazole, or thienyl, or a group represented by the formula

< / BR>
where Q is S or O;

T is =CH-, =N - or =N+O-;

ring E is a 6-membered aromatic ring which may contain 1 or 2 nitrogen atom;

W can have one or more substituents selected from phenyl, morpholinyl or methyl;

Y represents a group selected from-S -,- O-, or -(CH2)j- where j is an integer from 1 to 4;

Z represents a hydrogen atom, halogen atom, halogenated lower alkyl group, lower CNS group, a hydroxyl group, a nitrogroup, cyano, lower alkanoyloxy group, phenyl group which may have one or more substituents selected from fluorine, chlorine or 2,6-dimethylmorpholine, imidazolidinyl group, triazolyl group which may be substituted thiazole, tetrazolyl group which may be substituted by stands or amino group, oxazoline, which can be replaced by stands, except when W is a thiazole ring, R3is a methyl group and Z denotes a hydrogen atom when r = m = 0, when W is phenyl, R3represents a hydrogen atom and Z represents hydrogen, halogen, halogenated lower alkyl group or lower alkoxygroup, when r = m = 0,

or its salt.

13. The compound or its salt under item 1, where W represents phenyl, oxazole, thiazole or benzothiazole.

14. The compound or its salt under item 1, where W represents phenyl, oxazole, thiazole or benzothiazole or W p is UP>;

ring E is a 6-membered aromatic ring which may contain 1 or 2 nitrogen atom;

W can have one or more substituents selected from phenyl, morpholinyl or methyl.

15. The compound or its salt accession acid on p. 1, where the halogen is chlorine, bromine, iodine or fluorine.

16. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

Pr represents a protective group for hydroxyl group;

L represents a leaving group,

or its salt, which includes the introduction of protection for the hydroxyl group of compounds represented by the General formula

< / BR>
where R represents a group as defined above;

R1represents a hydrogen atom or a protective group for carboxyl group,

by introducing a protective group to obtain the compound represented by General formula 2

< / BR>
where R, R1and Pr each represent groups defined above,

with the subsequent removal of the protective group of the carboxyl group of the compound represented by General formula 2, to obtain the compound represented by General formula 3

< / BR>
where R and Pr each made the connection, represented by the formula

LH,

in which L represents a group specified above.

17. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R and Pr each represent groups defined above;

L represents a leaving group,

with a compound represented by the General formula

< / BR>
where each X represents a group as defined above;

Y represents chlorine, bromine or iodine,

or its reactive derivative.

18. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and Pr each Prichard, methyltriphenylphosphonium or methyltriphenylphosphonium, or trimethylsilylmethylamine, trimethylsilylmethylamine or trimethylsilylmethylamine.

19. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and Pr each represent groups defined above,

with peroxyketal.

20. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and Pr each represents the groups defined above,

with chloromethylation obtained from chloromethane or bremgarten, or demersum.

21. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and Pr each represents the groups defined above,

with an oxidizing agent.

22. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

A represents CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and Pr each represents the groups defined above,

with 1,2,4-triazole, or imidazole, or its salt.

23. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and ka is the first involves removing the Pr, which is a protective group for the hydroxyl group of the compound represented by the General formula

< / BR>
where R, X and A each represents a group defined above;

Pr is a protecting group for a hydroxyl group.

24. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

A represents CH or a nitrogen atom,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and A each represents a group defined above;

with an oxidizing agent.

25. The method of obtaining the compound represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

A represents a nitrogen atom or CH,

or its salt, which comprises the interaction of the compounds represented by the General formula

< / BR>
where R, X and A each represents a group defined above;

with hydroxylamine derivative.

26. The connection represented by the La hydroxyl group;

L represents a leaving group,

or its salt.

27. The connection represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group;

Q represents an oxygen atom or CH2,

or its salt.

28. The connection represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group,

or its salt.

29. The connection represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents a hydrogen atom or halogen;

Pr represents a protective group for hydroxyl group;

M represents a hydroxyl group,

or its salt.

30. The connection represented by the General formula

< / BR>
where R represents a lower alkyl group;

X are identical or different and each represents at is CH or a nitrogen atom,

or its salt.

31. The pharmaceutical composition according to p. 12, useful as antifungal agent.

Priorities for items:

07.02.94 on PP.1 - 3;

05.07.94 on PP.4 - 6;

10.08.94 on p. 7;

09.12.94 on PP.16 - 31.

 

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< / BR>
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