RU2118319C1 - Derivatives of thiazolidine, pharmaceutical composition showing hypoglycemic and hypolipidemic activity and inhibiting activity of aldose reductase, and a method of treatment and prophylaxis of diseases in mammals - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: invention proposes derivatives of thiazolidine of the formula (I)

where R¹ and R² are similar of different and each means hydrogen, alkyl with 1-8 carbon atoms; R³ - hydrogen; A and B are similar or different and each means hydrogen or alkyl with 1-8 carbon atoms, or A-B - groups: -C=O, =C=S, -CH₂-CH₂-; X - group W-(CH₂)_m-X′ where W - phenyl that can be unsubstituted or substituted with at least a single substituent taken from alkyl with 1-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, halogen, phenyl and group -NR^a-R^b where R^a and R^b are similar or different and each means hydrogen or alkyl with 1-8 carbon atoms; X¹ - a single bond, oxygen, sulfur or group NR⁴ where R⁴ - alkyl with 1-8 carbon atoms; m = 0-8; Y - group of the formula -(CH₂)_n-Y′- where Y′ - oxygen, sulfur; n = 1-5; Z - group of the formula (II)

Description

 The present invention relates to a number of compounds that can be considered as derivatives of thiazolidine and oxazolidine. The present invention also relates to methods and compositions that use these compounds, as well as to methods for producing these compounds.

 Compounds belonging to this broad class of compounds are disclosed in European Patent Publications NN 008203, 139421, 441605, 208420, 528734, 177353, 306208 and 356214, as well as in WO 92/07850, 92/07839, 91/07107, 92/02520 and 92/03425.

 A brief description of the invention.

 The aim of the present invention is to obtain a series of new chemical compounds that can be considered as derivatives of thiazolidines and oxazolidines or as their derivatives with an open ring.

 Another and more specific objective of the present invention is to provide such compounds, or at least some of them, that can be used to treat and / or prevent one or more diseases, such as hyperlipemia, hyperglycemia, glucose intolerance, insulin resistance and diabetes complications.

 Other objectives and advantages of the present invention will be apparent from the following description.

где
R¹ и R² могут быть одинаковыми или различными и каждый из них представляет атом водорода или алкильную группу, имеющую от 1 до 8 атомов углерода;
R³ представляют атом водорода;
A и B могут быть одинаковыми или различными и каждый представляет атом водорода; алкильную группу, имеющую 1-8 атомов углерода;
A и B, взятые вместе, представляют группы формул:

X представляет собой группу формулы W-(CH₂)_m-X¹-, где W представляет фенильную группу, которая является незамещенной или замещена по крайней мере одним заместителем, выбранным из алкильных групп, имеющих от 1 до 4 атомов углерода, алкокси групп, имеющих от 1 до 4 атомов углерода, атомов галогена, фенильных групп, и групп формулы -NR^aR^b, в которой R^a и R^b являются одинаковыми или различными и каждый представляет атом водорода или алкильную группу, имеющую от 1 до 8 атомов углерода;
X¹ представляет одинарную связь, атом кислорода, атом серы, группу формулы

в которой R⁴ представляет алкильную группу, имеющую от 1 до 8 атомов углерода;
и
m представляет 0 или целое число от 1 до 8,
Y представляет группу формулы: -(CH₂)_n-Y¹,
в которой
Y¹ представляет атом кислорода или атом серы, и
n представляет целое число от 1 до 5;
Z представляет группу формулы (I):

в которой
R⁵ представляет атом водорода
и, кроме того, настоящее изобретение относится к солям, вышеописанных соединений формулы (I).Thus, the present invention relates to compounds of formula (I):

Where
R ¹ and R ² may be the same or different and each of them represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms;
R ³ represents a hydrogen atom;
A and B may be the same or different and each represents a hydrogen atom; an alkyl group having 1-8 carbon atoms;
A and B, taken together, represent groups of formulas:

X represents a group of the formula W- (CH ₂ ) _m —X ¹ -, where W represents a phenyl group which is unsubstituted or substituted by at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups, having from 1 to 4 carbon atoms, halogen atoms, phenyl groups, and groups of the formula —NR ^a R ^b in which R ^a and R ^b are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms ;
X ¹ represents a single bond, an oxygen atom, a sulfur atom, a group of the formula

in which R ⁴ represents an alkyl group having from 1 to 8 carbon atoms;
and
m represents 0 or an integer from 1 to 8,
Y represents a group of the formula: - (CH ₂ ) _n -Y ¹ ,
wherein
Y ¹ represents an oxygen atom or a sulfur atom, and
n represents an integer from 1 to 5;
Z represents a group of formula (I):

wherein
R ⁵ represents a hydrogen atom
and, in addition, the present invention relates to salts of the above compounds of formula (I).

 The present invention also relates to a pharmaceutical composition for the treatment or prevention of diabetes or hyperlipemia and containing an effective amount of an active compound in combination with a pharmaceutically acceptable carrier or diluent, said active compound being selected from the group consisting of compounds of formula (I) as defined above, and salt.

 In addition, the present invention relates to a method for treating or preventing diabetes or hyperlipemia in mammals, including humans, comprising administering to said mammal an effective amount of an active compound selected from the group consisting of compounds of formula (I) as defined above, their salts.

 The present invention also relates to methods for producing compounds of the present invention, described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION
In the compounds of the present invention, the alkyl groups represented by the radicals R ¹ or R ² may have a straight or branched chain and contain from 1 to 8 carbon atoms; however, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbutyl can serve as examples of alkyl groups , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2 , -dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-tr methylbutyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 3,3-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl and 1,1,3,3-tetramethylbutyl groups . Of these, straight or branched alkyl groups having 1 to 6 carbon atoms are preferred, and methyl and ethyl groups are most preferred.

If each of A and / or B, which may be the same or different, represents an alkyl group, then this group may be a straight or branched alkyl group having 1-8 carbon atoms and similar to alkyl groups, examples of which are given above with respect to R ¹ and R ² .

If R ⁵ in the formula for Z represents a hydrogen atom, then the compounds of the present invention can be converted into salts with bases using standard procedures. Examples of such salts are: alkali metal salts such as sodium, potassium or lithium; alkaline earth metal salts such as barium or calcium; salts of other metals, such as magnesium or aluminum; ammonium salts, salts of organic bases such as methylamine, dimethylamine, triethylamine, diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts formed by basic amino acids such as lysine or arginine. Pharmaceutically acceptable salts are preferred.

(где R¹, R², R³, A, B, X, Y и Z определены выше), атом углерода, обозначенный ^*1, всегда является асимметрическим атомом углерода; а атом углерода, обозначенный ^*2, является асимметрическим атомом в том случае, если R¹ и R² представляют разные группы.The compounds of formula (I) of the present invention may exist as various isomers. As shown, for example, in formula (Ia):

(where R ¹ , R ² , R ³ , A, B, X, Y, and Z are defined above), the carbon atom designated ^* 1 is always an asymmetric carbon atom; and the carbon atom designated ^* 2 is an asymmetric atom in the case when R ¹ and R ² represent different groups.

(где R⁵ определен выше), то атом углерода, обозначенный ^*3, также является асимметрическим атомом углерода.In addition, if Z represents a group of formula (Ia):

(where R ^{5 is} defined above), the carbon atom indicated by ^* 3 is also an asymmetric carbon atom.

 Although in the present description all isomers are represented by the same molecular formula (I), the present invention includes the individual isomers, as well as mixtures thereof, including racemates, and in these mixtures the isomers can be present in any ratios. If a stereospecific synthesis technique is used, or optically active compounds are used as starting materials, then individual isomers can be obtained directly; and on the other hand, if a mixture of isomers is obtained as the final product, then individual isomers can be obtained using the conventional separation technique.

а R⁵ представляет атом водорода, то полученные соединения могут образовывать таутомеры, показанные на нижеследующей схеме:

В вышеприведенной формуле (I) все таутомеры и смеси эквивалентных масс или неэквивалентных масс этих таутомеров представлены одной формулой. Поэтому следует отметить, что все указанные изомеры и смеси этих изомеров входят в объем настоящего изобретения.In addition, if Z is a group of formula (i):

and R ⁵ represents a hydrogen atom, the resulting compounds can form tautomers shown in the following scheme:

In the above formula (I), all tautomers and mixtures of equivalent masses or nonequivalent masses of these tautomers are represented by the same formula. Therefore, it should be noted that all of these isomers and mixtures of these isomers are included in the scope of the present invention.

 Moreover, the present invention also includes all solvates (e.g. hydrates) of compounds of formula (I), their salts.

или -CH₂CH₂- ;
X представляет группу формулы W-(CH₂)_m-X¹-, где W представляет фенильную группу, которая является незамещенной или замещенной 1-3 заместителями, выбранными из алкильных групп, имеющих от 1 до 4 атомов углерода, алкокси групп, имеющих от 1 до 4 атомов углерода, атомов галогена, фенильных групп и групп формулы -NR^aR^b, в которой R^a и R^b являются одинаковыми или различными и каждый представляет атом водорода или алкильную группу, имеющую от 1 до 8 атомов углерода,
X¹ представляет простую связь, атом кислорода, атом серы или группу формулы -N(-R⁴), где R⁴ является метильной, этильной или пропильной группой;
m равно нулю или целому числу от 1 до 6;
Y представляет группу формулы -(CH₂)_n-Y' где Y' является атомом кислорода или серы, а n равно целому числу от 1 до 5;
Z представляет группу формулы (V_ii):

Еще более предпочтительными соединениями настоящего изобретения являются такие соединения формулы (I), их соли, в которых:
3) R¹ и R² оба представляют атомы водорода, либо один из них представляет атом водорода, а другой - алкильную группу, имеющую 1-4 атомов углерода;
R³ представляет атом водорода,
A и B являются одинаковыми или различными и каждый представляет атом водорода, метильную, этильную группу; либо A и B, взятые вместе, образуют группу формулы

или -CH₂CH₂-;
X представляет группу формулы W -(CH₂)_m -X₁-, где W представляет фенильную группу, которая является незамещенной или замещенной 1-3 заместителями, выбранными из группы включающей в себя: атом галогена, метильную, этильную, фенильную, амино, диметиламино-, метокси- и этокси-группы;
X¹ - представляет простую связь, атом кислорода, атом серы или группу формулы -N(Me)-;
m равно нулю или целому числу от 1 до 6;
Y представляет группу формулы -(CH₂)_n - Y'-, где Y' представляет атом кислорода или атом серы и n равно целому числу от 1 до 3;
и
Z представляет группу формулы (V_ii):

Еще более предпочтительными соединениями настоящего изобретения являются такие соединения формулы (I), их соли, в которых:
4) R' и R² оба представляют атомы водорода, либо один из них представляет атом водорода, а другой представляет метильную, этильную, пропильную или изопропильную группу;
R³ представляет атом водорода,
A представляет атом водорода, а B представляет атом водорода или метильную, этильную группу; либо A или B, взятые вместе, образуют группу формулы

или

X представляет группу формулы W-(CH₂)_m-X¹, где W представляет галоген-замещенную фенильную, фенилфенильную, метоксифенильную или фенильную группу, X¹ представляет атом кислорода или атом серы, m равно нулю или целому числу от 1 до 6;
Y представляет группу формулы -CH₂O или -(CH₂)₂O-;
и
Z представляет группу формулы (V_ii):

Наиболее предпочтительными соединениями настоящего изобретения являются такие соединения формулы (I), их соли, в которых:
5) R¹ и R² оба представляют атомы водорода, либо один из них представляет атом водорода, а другой представляет метильную или этильную группу;
R³ представляет атом водорода;
A представляет атом водорода, а B представляет атом водорода или метильную группу; либо A и B, взятые вместе, образуют группу формулы

или

X представляет группу формулы W-(CH₂)_m-O-, где W представляет фенильную, 3-хлорфенильную, 4-хлорфенильную, 3-метоксифенильную, 4-метоксифенильную или 4-фенилфенильную группу; и m равно нулю или целому числу от 1 до 6;
Y представляет группу формулы -CH₂O-; и
Z представляет группу формулы (V_ii):

Примеры некоторых соединений настоящего изобретения представлены нижеприведенными формулами (I-1) - (1-7):

В вышеуказанных формулах заместители являются такими, как они определены в таблицах 1-7 соответственно, то есть таблица 1 относится к формуле (I-1), таблица 2 относится к формуле (1-2) и т.д. до таблицы 7, которая относится к формуле (1-7). В указанных таблицах были использованы следующие обозначения:
Ac - ацетил
Boz - бензоил
Bu - бутил
iBu - изобутил
tBu - т-бутил
Bz - бензил
Car - карбамоил
Et - этил
Etc - этоксикарбонил
Hp - гептил
Hx - гексил
Me - метил
Mec - метоксикарбонил
Oc - октил
Ph - фенил
Piv - пивалоил
Pn - пентил
Pr - пропил
iPr - изопропил
Prn - пропионил
Pyr - пиридил
В таблице 7 положение заместителей R³ и Z по отношению к Y указано в скобках после идентификации заместителя.More preferred compounds of the present invention are those compounds of formula (I), their salts, in which:
2) R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group having 1-4 carbon atoms;
R ³ represents a hydrogen atom;
A and B are the same or different and each represents a hydrogen atom, methyl, ethyl, propyl, or A and B taken together form a group of formulas:

or —CH ₂ CH ₂ -;
X represents a group of the formula W- (CH ₂ ) _m —X ¹ -, where W represents a phenyl group which is unsubstituted or substituted by 1-3 substituents selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, phenyl groups and groups of the formula —NR ^a R ^b in which R ^a and R ^b are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms,
X ¹ represents a single bond, an oxygen atom, a sulfur atom or a group of the formula —N (—R ⁴ ), where R ⁴ is a methyl, ethyl or propyl group;
m is zero or an integer from 1 to 6;
Y represents a group of the formula - (CH ₂ ) _n -Y 'wherein Y' is an oxygen or sulfur atom and n is an integer from 1 to 5;
Z represents a group of formula (V _ii ):

Even more preferred compounds of the present invention are those compounds of formula (I), their salts, in which:
3) R ¹ and R ² both represent hydrogen atoms, or one of them represents a hydrogen atom, and the other an alkyl group having 1-4 carbon atoms;
R ³ represents a hydrogen atom,
A and B are the same or different and each represents a hydrogen atom, a methyl, ethyl group; either A and B, taken together, form a group of the formula

or —CH ₂ CH ₂ -;
X represents a group of the formula W - (CH ₂ ) _m -X ₁ -, where W represents a phenyl group which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of: halogen atom, methyl, ethyl, phenyl, amino, dimethylamino, methoxy and ethoxy groups;
X ¹ - represents a single bond, an oxygen atom, a sulfur atom or a group of the formula —N (Me) -;
m is zero or an integer from 1 to 6;
Y represents a group of the formula - (CH ₂ ) _n - Y'-, where Y 'represents an oxygen atom or a sulfur atom and n is an integer from 1 to 3;
and
Z represents a group of formula (V _ii ):

Even more preferred compounds of the present invention are those compounds of formula (I), their salts, in which:
4) R 'and R ² both represent hydrogen atoms, or one of them represents a hydrogen atom, and the other represents a methyl, ethyl, propyl or isopropyl group;
R ³ represents a hydrogen atom,
A represents a hydrogen atom, and B represents a hydrogen atom or a methyl, ethyl group; either A or B taken together form a group of the formula

or

X represents a group of the formula W- (CH ₂ ) _m —X ¹ , where W represents a halogen-substituted phenyl, phenylphenyl, methoxyphenyl or phenyl group, X ¹ represents an oxygen atom or a sulfur atom, m is zero or an integer from 1 to 6;
Y represents a group of the formula —CH ₂ O or - (CH ₂ ) ₂ O—;
and
Z represents a group of formula (V _ii ):

The most preferred compounds of the present invention are those compounds of formula (I), their salts, in which:
5) R ¹ and R ² both represent hydrogen atoms, or one of them represents a hydrogen atom, and the other represents a methyl or ethyl group;
R ³ represents a hydrogen atom;
A represents a hydrogen atom, and B represents a hydrogen atom or a methyl group; either A and B, taken together, form a group of the formula

or

X represents a group of the formula W- (CH ₂ ) _m —O—, where W represents a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl or 4-phenylphenyl group; and m is zero or an integer from 1 to 6;
Y represents a group of the formula —CH ₂ O—; and
Z represents a group of formula (V _ii ):

Examples of certain compounds of the present invention are represented by the following formulas (I-1) to (1-7):

In the above formulas, the substituents are as defined in tables 1-7, respectively, that is, table 1 refers to the formula (I-1), table 2 refers to the formula (1-2), etc. to table 7, which relates to the formula (1-7). The following notation was used in these tables:
Ac - Acetyl
Boz - benzoyl
Bu - butyl
iBu - Isobutyl
tBu - t-butyl
Bz - benzyl
Car - carbamoyl
Et - ethyl
Etc - Ethoxycarbonyl
Hp - Heptyl
Hx - Hexyl
Me - methyl
Mec - methoxycarbonyl
Oc - octyl
Ph - phenyl
Piv - Pivaloyl
Pn - pentyl
Pr - cut
iPr - Isopropyl
Prn - Propionyl
Pyr - pyridyl
In table 7, the position of the substituents R ³ and Z with respect to Y is indicated in parentheses after the identification of the substituent.

 Of the above compounds, compounds NN 1-2, 1-4, 1-48, 1-49, 1-51, 1-64, 1-69, 1-79, 1-91, 1-92, 1- are preferred 93, 1-94, 1-95, 1-128, 1-158, 1-159, 1-160, 1-161, 1-162, 1-163, 1-164, 1-165, 1-166, 1-167, 1-168, 1-169, 1-170, 1-171, 1-173, 1-176, 1-177, 1-179, 1-180, 1-181, 1-184, 1- 186, 1-187, 1-188, 1-189, 1-190, 1-191, 1-192, 1-193, 1-195, 1-197, 1-200, 1-201, 1-204, 1-205, 1-206, 1-207, 1-208 and 1-209, of which compounds NN 1-2, 1-4, 1-51, 1-64, 1-69, 1-79 are more preferred , 1-91, 1-93, 1-94, 1-95, 1-158, 1-159, 1-160, 1-161, 1-162, 1-164, 1-169, 1-170, 1 -173, 1-177, 1-179, 1-180, 1-181, 1-186, 1-187, 1-188, 1-189, 1-190, 1-191, 1-192, 1-193 , 1-195, 1-204, 1-205, 1-206, and 1-209. Even more preferred are compounds NN 1-2, 1-4, 1-64, 1-91, 1-93, 1-94, 1-95, 1-159, 1-161, 1-162, 1-164, 1-173, 1-179, 1-186, 1-191, 1-193, 1-195, 1-205 and 1-206.

The most preferred compounds are the following NN compounds:
1-2. 5- (4- {3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione;
1-93. 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxo-oxazolidin-3-yl) ethoxy] benzyl} thiazolidin-2,4-dione;
1-94. 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxo-oxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione;
1-95. 5- {4- [2- (5-3'-chlorophenoxymethyl-2-thioxo-oxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione;
1-162. 5- {4- [2- (3-6'-phenylhexyloxy-2-hydroxypropyl-amino) propoxy] benzyl} thiazolidine-2,4-dione; and
1-191. 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxo-oxazolidin-3-yl) butoxy] benzyl} thiazolidin-2,4-dione, of which compounds NN 1-2 are particularly preferred, 1-94 and 1-95.

 The compounds of the present invention can be obtained in various ways that are commonly used by specialists to obtain compounds of this type. For example, these compounds may be prepared according to Reaction Schemes A, B, C, and F.

 Reaction Scheme A.

 Below is a General scheme that can be used to obtain any compound of the present invention.

В вышеуказанных формулах X, Y, R¹, R³, A, B и Z являются такими, как они были определены выше.Reaction Scheme A:

In the above formulas, X, Y, R ¹ , R ³ , A, B, and Z are as defined above.

Stage A1
In Step A1, a compound of formula (R-3) is prepared by reacting an amino alcohol of formula (R-1) with a compound of formula (R-2). Compound (R-2) is a known compound and can be prepared by known methods, for example, by reacting a haloacetone and a phenol compound described in Japanese Patent Publication (Kokai) No. Hei-6-25118.

 The reaction of Step A1 can be carried out in the absence or presence of a dehydrating reagent, for example carbonic alkali metal anhydride, such as anhydrous sodium carbonate or anhydrous potassium carbonate; alkali metal sulfuric anhydride such as anhydrous sodium sulfate; alkaline earth metal chloride such as anhydrous calcium chloride; alkaline earth metal sulfuric anhydride, such as anhydrous magnesium sulfate, or molecular sieve.

 The specified reaction is usually and preferably carried out in the presence of a solvent. Any solvent can be used for this purpose, provided that it does not adversely affect the reaction or the reagents used in it, and also provided that the solvent is capable of dissolving, at least to a certain extent, the reagents involved in the reaction. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene, hexane, heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide or sulfolane; or mixtures of any two or more of these solvents.

 The reaction in question can be carried out over a wide range of temperatures, and the exact value of the reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out at an ice cooling temperature up to the temperature of distillation of the solvent. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent used. However, when carrying out the reaction under the preferred conditions outlined above, a period of from 0.5 h to 10 h is generally sufficient.

 This reaction is preferably carried out in a hydrocarbon or alcohol solvent for a period of time from 1 to 5 hours, at a temperature in the range from the temperature of cooling with ice to the temperature of distillation of the solvent. And more preferably, if this reaction is carried out in benzene for 1-3 hours under reflux conditions for the dehydration reaction.

Stage A2
In Step A2, a compound of formula (R-4) is prepared by reducing a compound of formula (R-3).

 This reaction is usually carried out by hydrogenation in the presence of a reducing agent or in the presence of a catalyst.

 If the compound of formula (R-3) is hydrogenated in the presence of a reducing agent, then such an agent may be, for example, a metal hydride such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or diisopropyl aluminum hydride.

 The specified reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or the reagents used in it, and provided that the solvent is capable of dissolving, at least to a certain extent, the reagents involved in the reaction. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixture of two or more of these solvents.

 This reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out in a temperature range ranging from an ice cooling temperature to a heating temperature, for example, using a reflux condenser. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent used. However, when carrying out the reaction under the above preferred conditions, a period of from 0.5 h to several days is generally sufficient.

This reaction is preferably carried out in an alcohol solvent in the presence of sodium borohydride or sodium cyanoborohydride for a period of time ranging from 1 hour to 1 day, under ice cooling or at a temperature in the range from ice cooling to 50 ^° C.

 If the compound of formula (R-3) is subjected to a hydrogenation reaction in the presence of a catalyst, then such a catalyst may be a standard hydrogenation catalyst, for example palladium carbon or platinum oxide.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, in principle, any solvent can be used, provided that it does not have an undesirable effect on the reaction or on the reagents used in it, and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; alcohols such as methanol, ethanol and isopropanol; organic acid esters such as methyl acetate and ethyl acetate; or a mixture of two or more of these solvents.

Stage A3
In Step A3, a compound of formula (R-5) is prepared by alkylation, aralkylation, acylation or carbamoylation of a compound of formula (R-4).

 The alkylation and aralkylation reactions are usually carried out by reacting a compound of formula (R-4) with an alkyl halogen or aralkyl halogen, or with an alkyl or aralkyl ester of alkanesulfonic acid, or with arylsulfonic acid (for example, with methanesulfonic, benzenesulfonic or toluenesulfonic acid) in the absence of sulfonic acid an acid binding agent.

 This reaction is usually and preferably carried out in the presence of a solvent. Any solvent can be used for this purpose, provided that it does not have an undesirable effect on the reaction or on the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane; or mixtures of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role for the present invention. However, in general, this reaction can be carried out in a temperature range from the temperature of ice cooling to the temperature of distillation of the solvent. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent used. However, when carrying out the reaction under the above preferred conditions, a period of from 0.5 h to several days is usually sufficient.

 The acylation reaction is usually carried out in the absence or in the presence of an acid acceptor. Suitable acylating agents are acyl halides and acid anhydrides.

 This reaction is usually and preferably carried out in the presence of a solvent. Any solvent can be used for this purpose, provided that it does not have an undesirable effect on the reaction or on the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane; or mixtures of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role for the present invention. However, basically this reaction can be carried out in a temperature range ranging from the temperature of ice cooling to the temperature of distillation of the solvent. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent used. However, when carrying out the reaction under the above preferred conditions, a period of from 0.5 h to several days is usually sufficient.

 If A and B taken together are a group such as> C = 0,> C = S, then a carbonylating agent (e.g. phosgene, diphosgene, triphosgene, carbonyldiimidazole or chloroformate ester such as ethyl chloroformate); a thiocarbonylating agent (e.g., thiophosgene or thiocarbonyldiimidazole), oxalyl chloride, haloacetyl halide (e.g. chloroacetyl chloride or bromoacetyl bromide), sulfuryl chloride or halide methanesulfonyl halide (e.g. chloromethanesulfonyl chloride).

 This reaction is usually carried out in the absence or in the presence of an acid acceptor. If the reaction is carried out in the presence of an acid acceptor, then such an acid acceptor may be, for example, an organic base such as triethylamine, diisopropylethylamine or pyridine; or an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

 This reaction is usually and preferably carried out in the presence of a solvent. Any solvent can be used for this purpose, provided that it does not have an undesirable effect on the reaction or on the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; urea, such as N, N'-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile and propionitrile; sulfolane; or mixtures of any two or more of these solvents.

This reaction can take place over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role for the present invention. However, in general, this reaction can be carried out in a temperature range ranging from the ice cooling temperature to the distillation temperature of the reaction mixture, and more preferably at the ice cooling temperature or at a temperature in the range from the indicated ice cooling temperature to 50 ^° C. The time required reactions can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of from 0.5 to 50 hours, and more preferably from 5 to 50 hours, is sufficient.

 Reaction Scheme B.

 This scheme provides several methods for preparing representative compounds of the present invention using the same starting materials as used in Reaction Scheme A.

Реакционная схема B2:

Реакционная схема B3:

В вышеуказанных формулах X, A, B, R¹, R²,

и Z определены выше;
R представляет прямую или разветвленную низшую алкильную группу, имеющую предпочтительно 1 - 6 атомов углерода, а более предпочтительно 1 - 4 атомов углерода, например, одну из групп, проиллюстрированных выше для R¹, а в частности, метильную или этильную группу;
Y² представляет атом кислорода или атом серы;
"Halo" означает атом галогена, такой как атом хлора, атом брома или атом иода; и
Z¹ представляет группу формулы (i),
где
R⁵ представляет трифенилметильную группу.Reaction Scheme B1:

Reaction scheme B2:

Reaction Scheme B3:

In the above formulas X, A, B, R ¹ , R ² ,

and Z are defined above;
R represents a straight or branched lower alkyl group having preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms, for example, one of the groups illustrated above for R ¹ , and in particular a methyl or ethyl group;
Y ² represents an oxygen atom or a sulfur atom;
“Halo” means a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; and
Z ¹ represents a group of formula (i),
Where
R ⁵ represents a triphenylmethyl group.

Stage BI
In step BI, a compound of formula (R-6) is prepared by alkylation, aralkylation, acylation or carbamoylation of a compound of formula (R-I). This reaction is carried out mainly in accordance with the procedure described in Step A3 of Reaction Scheme A, using the same reaction conditions and the same reagents.

Stage B2
In Step B2, a compound of formula (R-8) is prepared by reacting a compound of formula (R-6) with a compound of formula (R-7) in the presence or absence of a base. If B is an acyl group or a carbamoyl group, it is preferred that the compound of formula (R-6) is first reacted with a base such as sodium hydride and then the resulting compound is reacted with a compound of formula (R-7).

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not have an undesirable effect on the reaction or on the reagents used and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; sulfolane; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role for the present invention. However, in general, this reaction can be carried out in a temperature range ranging from ice cooling temperature to heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent used. However, in many cases, a period of from 0.5 h to several days is usually sufficient to carry out this reaction.

Stage B3
In Step B3, a compound of formula (R-9) is prepared by reducing a compound of formula (R-8). In principle, any reducing agent commonly used in reactions of this type can be used in this reaction. Examples of reducing agents are metal hydrides such as sodium borohydride, lithium borohydride, lithium aluminum hydride and diisobutylaluminum hydride.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not have an undesirable effect on the reaction or on the reagents used and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out in a temperature range ranging from ice cooling temperature to heating temperature. The time required for the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from 0.5 hours to several days.

 This reaction is preferably carried out in an alcoholic solvent in the presence of lithium borohydride for a period of time from 1 hour to 1 day at a temperature ranging from room temperature to the temperature of distillation of the reaction mixture.

Stage B4
In Step B4, a compound of formula (R-11) is prepared by a Mitsunobu reaction (O. Mitsunobu, Synthesis, p. I (1981)), to which a compound of formula (R-9) and a compound of formula (R-10) are subjected, followed by removal of triphenylmethyl groups.

 The first step of this reaction is usually and preferably carried out in the presence of a solvent. Any solvent can be used in this reaction, provided that it does not have an undesirable effect on the reaction or on the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of any two or more of these solvents.

This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out in a temperature range ranging from an ice cooling temperature to a heating temperature, and more preferably at an ice cooling temperature, or in a temperature range ranging from an ice cooling temperature to 60 ^° C. The time required for the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents used. However, in most cases, the reaction period is from several hours to several days, and more preferably from 5 hours to 3 days.

 The second reaction step is carried out by reacting the obtained compound with an acid, such as acetic acid, trifluoroacetic acid or hydrochloric acid, in the presence or absence of a solvent; or through a catalytic hydrogenation reaction of the obtained compound in the presence of a solvent.

 If this reaction is carried out by reacting the resulting compound with an acid in the presence or absence of a solvent, then this reaction can be carried out in accordance with standard techniques (e.g., JW Grcene, Protective Groups in Organic Synthesis, John Wiley &Sons; JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press).

 If the resulting compound is subjected to a catalytic hydrogenation reaction in the presence of a solvent, then any catalyst commonly used in reactions of this type, for example, palladium carbon, can be used.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not have an undesirable effect on the reaction or on the reagents used and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; alcohols such as methanol, ethanol and isopropanol; acids such as formic acid, acetic acid and propionic acid; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out in the range of from about room temperature to a heating temperature. The time required for the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out this reaction is from several hours to several days, and more preferably from 1 hour to 3 days.

 The specified reaction is usually carried out at atmospheric pressure, or, preferably, at a pressure exceeding atmospheric.

Stage B5
In Step B5, a compound of formula (R-12) is prepared by reacting a compound of formula (R-9) with a 4-fluorobenzaldehyde derivative such as 2-methoxy-4-fluorobenzaldehyde or 3-methyl-4-fluorobenzaldehyde in the presence of a base such like sodium hydride.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent can be used provided that it does not have an undesirable effect on the reaction or on the reagents used in it and has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as demethylacetamide, dimethylformamide and hexamethylphosphoric triamide; or a mixture of any two or more of these solvents.

This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, in general, this reaction can be carried out at a temperature ranging from an ice cooling temperature to a heating temperature, and more preferably at a cooling temperature or at a temperature ranging from an ice cooling temperature to 60 ^° C. The time required for the reaction can also be widely vary depending on many factors, namely the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from several hours to several days, and preferably from 3 hours to 3 days.

Stage B6
In Step B6, a compound of formula (R-13) is prepared by reacting a compound of formula (R-12) with thiazolidine-2,4-dione.

 This reaction can be carried out in the presence or absence of a catalyst. If the reaction proceeds in the presence of a catalyst, then sodium acetate, piperidinium acetate and piperidinium benzoate are examples of suitable catalysts.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not have an undesirable effect on the reaction or on the reagents used and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, mainly this reaction can be carried out by heating. The time required for the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period sufficient to carry out the reaction is from several hours to several days.

Stage B7
In Step B7, a compound of formula (R-14) is prepared by reducing a compound of formula (R-13), for example, by a catalytic hydrogenation reaction or by a reduction reaction using metal hydride.

 If the compound of formula (R-13) is subjected to a catalytic hydrogenation reaction, then any catalyst that is commonly used in reactions of this type, for example palladium carbon, can be used for this purpose.

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used if it does not have an undesirable effect on the reaction or on the reagents used in it and if it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; alcohols such as methanol, ethanol and isopropanol; acids such as formic acid, acetic acid and propionic acid; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from several hours to several days, and preferably from 1 hour to 3 days.

 This reaction is usually carried out at atmospheric pressure or preferably at a pressure higher than atmospheric.

 If the compound of formula (R-13) is subjected to reduction using metal hydride, then this reaction can be carried out by the method described in WO 93/1309.

Stage B8
In Step B8, a compound of formula (R-15) is prepared by reacting a compound of formula (R-12) with hydroxylamine followed by a reduction reaction.

 The reaction of a compound of formula (R-12) with hydroxylamine (hydrochloride) is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not have an undesirable effect on the reaction or on the reagents used therein and is capable of dissolving said reagents, at least to a certain extent. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; amines such as pyridine and triethylamine; or mixtures of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out this reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from several hours to several days, and preferably from 1 hour to 3 days.

 The subsequent reduction reaction is carried out mainly in accordance with the procedures described in Step A2 of Reaction Scheme A; moreover, this reaction can be carried out under the same reaction conditions and using the same reagents.

Stage B9
In Step B9, a compound of formula (R-16) is prepared by reacting a compound of formula (R-15) with trimethylsilyl isocyanate.

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used, provided that it does not have an undesirable effect on the reaction and on the reagents used in it, and if it is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents.

This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from an ice cooling temperature to a heating temperature, and preferably the reaction is carried out at an ice cooling temperature, or at a temperature ranging from an ice cooling temperature to 60 ^° C. The time required to carry out this reactions can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from several hours to several days, and preferably from 1 hour to 3 days.

Stage B10
In Step B10, a compound of formula (R-17) is prepared by reacting a compound of formula (R-15) with chlorocarbonyl isocyanate.

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used if it does not have an undesirable effect on the reaction or on the reagents used in it and if it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents.

This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from an ice cooling temperature to a heating temperature, and preferably at an ice cooling temperature or at a temperature ranging from an ice cooling temperature to 60 ^° C. The time required to carry out this reaction may also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from a few minutes to 1 day.

 Reaction Scheme C.

 The following reaction scheme illustrates an alternative method of obtaining the compounds of formula (R-9) (see, for example, schemes B1 and B2).

В вышеуказанных формулах X, A, B, R¹, R² и

являются такими, как они были определены выше; а Q представляет собой защитную группу для спирта, например т-бутилметилсилильную группу.Reaction Scheme C:

In the above formulas X, A, B, R ¹ , R ² and

are as defined above; and Q represents a protecting group for an alcohol, for example a t-butylmethylsilyl group.

Stage C1
In Step C1, a compound of formula (R-20) is prepared by reacting a compound of formula (R-18) and a compound of formula (R-19).

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents.

This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, this reaction is mainly carried out by heating, and preferably at a temperature of 50 ^° C., or by heating under reflux. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient for the reaction is from several tens of minutes to several days.

Stage C2
In Step C2, a compound of formula (R-21) is prepared by alkylation, aralkylation, acylation or carbamoylation of a compound of formula (R-20). This reaction is mainly carried out in accordance with the procedure of Step A3 of Reaction Scheme A, under the same reaction conditions and using the same reagents.

Stage C3
In Step C3, compounds of formula (R-9) are prepared by removing the protective group Q from a compound of formula (R-21).

 This reaction is carried out by a reaction of a compound of the formula (R-12) with an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid or hydrofluoric acid; or by a reaction of the said compound (R-12) with a compound generating fluorine ions, such as tributylammonium fluoride, in the presence or absence of a solvent; or by a catalytic hydrogenation reaction of said compound in the presence of a solvent.

 A reaction involving the reaction of this compound with an acid or fluoride ion in the presence or absence of a solvent can be carried out by a conventional method (e.g., JW Greene, Protective Groups in Organic Synthesis, John Wiley &Sons; JFW Mc Omie, Protective Groups in Organic Chemistry, Plenum Press).

 If the compound of formula (R-21) is subjected to a catalytic hydrogenation reaction, a catalyst that is commonly used in reactions of this type, for example palladium carbon, can be used in this reaction.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or the reagents used in it and is capable of dissolving, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; alcohols such as methanol, ethanol and isopropanol; acids such as formic acid, acetic acid and propionic acid; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from several hours to several days, and more preferably from 1 hour to 3 days.

 This reaction is usually carried out at atmospheric pressure or preferably at a pressure higher than atmospheric.

 Reaction Scheme C1.

В вышеуказанных формулах R¹, R² и

являются такими, как они были определены выше, а Boc представляет собой т-бутоксикарбонильную группу.The compound of formula (R-19) used in Step C1 can be prepared as shown in Reaction Scheme C1:

In the above formulas, R ¹ , R ² and

are as defined above, and Boc is a t-butoxycarbonyl group.

 So, for example, a compound of formula (R-19) can be obtained by converting a compound of formula (R-22) into an N-t-butoxycarbonylated compound of formula (R-23) followed by O-silylation and obtaining a compound of formula (R-24) and then removing the t-butoxycarbonyl group. These reactions can be carried out by standard methods (see, for example, J.W. Green Protective Groups in Organic Synthesis, John Wiley &Sons; J.F. W. McOmie, Protective Groups in Organic Chemistry. Plenum Press).

 Reaction Scheme D.

 This reaction scheme illustrates a process for preparing a compound of formula (R-27), which is a compound of formula (R-6), in which A and B, taken together, are a carbonyl group and which can then be used as described above in the Reaction scheme B.

В вышеуказанных формулах X и Boc являются такими, как они были определены выше.

In the above formulas, X and Boc are as defined above.

Stage D1
In Step D1, a compound of formula (R-26) is prepared first by reacting a compound of formula (R-25) with sodium hydride, and then by reacting the resulting compound with a compound of formula (R-18).

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used if it does not have an undesirable effect on the reaction or on the reagents used in it and if it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents. Of these, amides are preferred.

 The first reaction step can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from an ice cooling temperature to a heating temperature. The time required for the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from 0.5 to 5 hours.

The second reaction step can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from room temperature to 100 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is usually from 1 hour to several days.

Stage D2
In Step D2, a compound of formula (R-27) is prepared by reacting a compound of formula (R-26) to remove the t-butoxycarbonyl group represented by Boc (e.g., as described by JW Green, Protective Groups in Organic Synthesis, John Wiley &Sons; JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press).

 Reaction Scheme E.

 This reaction scheme illustrates a method for preparing the compound (R-1) used as a starting material in Reaction Schemes A and B (see above).

В вышеуказанных формулах X и Halo являются такими, как они были определены ранее.

In the above formulas, X and Halo are as defined previously.

Stage E1
In Step E1, a compound of formula (R-30) is prepared by reacting a compound of formula (R-29) with a compound of formula (R-28). This reaction is usually carried out in the presence or absence of a base. In this case, any base which is commonly used in reactions of this type can be used. Examples of suitable bases are alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride.

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used if it does not have an undesirable effect on the reaction or on the reagents used in it and if it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate, or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient to carry out the reaction is from several tens of minutes to several days.

Stage E2
In Step E2, a compound of formula (R-1) is prepared by reacting a compound of formula (R-30) with ammonia.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent can be used provided that it does not have an undesirable effect on the reaction and the reagents used in it, and provided that it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as methyl formate, ethyl formate and ethyl acetate; water or a mixture of any of two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient to carry out the reaction is from several tens of minutes to several days.

 This reaction can also be carried out at atmospheric pressure or in a hermetically sealed vessel.

Stage E3
In Step E3, a compound of formula (R-31) is prepared by reacting a compound of formula (R-30) with an alkali metal amide, for example lithium azide, sodium azide or potassium azide.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or the reagents used in it, and provided that it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as methyl formate, ethyl formate and ethyl acetate; water or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient to carry out the reaction is from several tens of minutes to several days.

Stage E4
In Step E4, a compound of formula (R-1) is prepared by reacting a compound of formula (R-31) with lithium aluminum hydride or by the catalytic hydrogenation reaction to which a compound of formula (R-31) is subjected.

 The reaction of a compound of formula (R-31) with lithium aluminum hydride is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or the reagents used in it, and provided that it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from an ice cooling temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient for the reaction is from several tens of minutes to 1 day.

 If a compound of formula (R-31) is hydrogenated in the presence of a catalyst, then standard hydrogenation catalysts, such as, for example, palladium carbon and platinum oxide, can serve as examples of such catalysts.

 This reaction is usually and preferably carried out in the presence of a solvent. In this case, any solvent can be used if it does not have an undesirable effect on the reaction or the reagents used and if it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl format and ethyl acetate; or a mixture of any two or more of these solvents.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature in the range of from about room temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, the period of time sufficient to carry out the reaction is from several tens of minutes to several hours.

 This reaction is usually carried out at atmospheric pressure or preferably at a pressure higher than atmospheric.

 Reaction Scheme F.

 The following reaction scheme illustrates an alternative process for the preparation of compounds of formula (R-36) which relate to compounds of formula (I) of the present invention.

В вышеуказанных формулах X, A, B, R¹, R², R³, y², R,

и Halo являются такими, как они были определены выше.

In the above formulas, X, A, B, R ¹ , R ² , R ³ , y ² , R,

and Halo are as defined above.

Stage F1
In Step F1, a compound of formula (R-32) is prepared by reacting a compound of formula (R-9) with fluoro-4-nitrobenzene in the presence of a base.

 This reaction is usually and preferably carried out in the presence of a solvent. For this purpose, any solvent may be used provided that it does not adversely affect the reaction or reagents used, and provided that it has the ability to dissolve, at least to a certain extent, these reagents. Examples of suitable solvents are: aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixture of two or more of these solvents.

 In this reaction, any base may be used, provided that it does not have an undesirable effect on the reaction; however, such a base can be any base that is commonly used in reactions of this type. Examples of suitable bases are: sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, butyl lithium and lithium diisopropylamide.

 This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. However, a generally suitable temperature for carrying out this reaction is a temperature ranging from an ice cooling temperature to a heating temperature. The time required to carry out the reaction can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents. However, in most cases, a period of time sufficient to carry out the reaction is from 1 hour to several days.

Stage F2
In Step F2, a compound of formula (R-33) is prepared by reducing a compound of formula (R-32).

 This reaction can be carried out by catalytic hydrogenation or by reduction of the nitro group using zinc-acetic acid or tin-hydrochloric acid.

Stage F3
In Step F3, a compound of formula (R-34) is prepared by a Meervain arylation reaction to which a compound of formula (R-33) is subjected. This reaction is usually carried out by the method described in the preliminary publication of Japanese patent (Kokai) N Sho 55-22657, and by S. Oae et al. (Bull. Chem. Soc. Jpn., Vol. 53, p. 1065 (1980)) .

где
Y² представляет собой атом кислорода или атом серы.Stage F4
In Step F4, a compound of formula (R-35) is prepared by reacting a compound of formula (R-34) with a compound of formula

Where
Y ² represents an oxygen atom or a sulfur atom.

 The resulting compound of formula (R-35) can be isolated, but can be used in Step F5 without isolation.

Stage F5
In Step F5, a compound of formula (R-36) is prepared by a catalyzed acid hydrolysis reaction to which a compound of formula (R-35) is subjected. Stage F4 and F5 are usually carried out by the method described in the preliminary publication of Japanese patent (Kokai) N Sho 55-22657.

 After completion of any of the above reactions, the desired compounds obtained in the corresponding steps can be purified by standard methods such as column chromatography, recrystallization, reprecipitation, or any combination thereof. For example, in one suitable isolation procedure, the reaction mixture is extracted by adding a solvent, after which the solvent is evaporated from the extract. Then, the obtained precipitate is introduced into a chromatographic column, for example, with silica gel, and a purified target compound is obtained.

 Biological activity.

 In a test system using animals with congenital diabetes, the compounds of the present invention showed high hypoclycemic activity. Therefore, it is obvious that the compounds of the present invention can be used to treat and / or prevent diabetes; diabetes complications; hyperlipidemia; hypertension associated with obesity; osteoporosis, etc.

 The compounds of the present invention may be administered in various forms depending on the particular disease and condition of the patient. For example, if the compounds are intended for oral administration, they can be made in the form of tablets, capsules, granules, powders or syrups; and if the compounds are intended for parenteral administration, they can be made in the form of injections (intravenous, intramuscular or subcutaneous), drops or suppositories. For the treatment of mucous membranes of the eye, the compounds of the present invention can be administered in the form of eye drops or ointments. These preparations can be made by standard methods, and if necessary, the active ingredient can be mixed with any conventional additive, such as a filler, a binder, a disintegrant, a sizing agent, a corrective agent, a solubilizing agent, a suspending agent, an emulsifying agent or a coating agent. Although the administered dose of the compounds of the present invention may vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disease, the route of administration and the form of the medication intended for the treatment of diabetes, its complications and / or hyperlipemia, however, the daily dose recommended for administration an adult, ranges from 0.01 to 2000 mg of this compound and can be administered in a single dose or divided dose.

 The activity of the compounds of the present invention is illustrated in the experiments below.

Experiment 1. Hypoglycemic activity
As test animals, male mice with hyperglycemia (KK strain) were used, each of which had a body weight of more than 40 g. Each animal was orally administered the test compound in the amount shown in Table 8 below, and then fed as desired for 18 hours After this time, blood was taken from the tail vein of the animal without anesthesia. Blood glucose (BGL) was determined using a blood glucose analyzer (GL-101 manufactured by Mitsubishi Kasei Co. or Gluco oder manufactured by Shino Test Co.).

The level of decrease in blood glucose was calculated by the following equation:
blood glucose lowering level (%) = (BGL _s = BGL _t ) / BGL _s • 100, where BGL _s is BGL for a group of animals that were given only one solvent and no active compound was introduced, and BGL _t is BGL for groups of animals to which the test compound was administered.

 The results obtained are shown in the following table 8, in which each compound of the present invention is indicated by the number of an example in which the preparation of this compound is described.

 As can be seen from table 8, the compounds of the present invention exhibit high hypoglycemic activity.

Experiment 2. Inhibition of aldose reductase
Bovine lens aldose reductase was isolated and partially purified by S. Hyman & JH Kinoshita, y. Biol. Chem., 240, 877 (1965) and K. Inagaki. I. Miwa & J. Okuda, Arch. Biochem. Biophys., 316, 337 (1982) and its activity was determined photometrically by the method of Varma et al. (Biochem. Pharmac., 25, 2505 (1976)). Inhibition of enzyme activity was measured at a concentration of the compounds of the present invention of 5 μg / ml and the results of these measurements are presented in table 9.

Experiment 3. Toxicity
The toxicity of the compounds of the present invention was tested on male rats F344, which were divided into groups of 5 animals. Each animal was orally administered a test compound at a dose of 50 mg per kg body weight for 2 weeks. The compounds of Examples 20, 45 (polar, less polar) and 47 (polar) were used as test compounds. Animals were observed over the next 2 weeks, and during this period of time the animals did not show any deviations that could be attributed to the action of the test compounds. In hematological studies, only a small decrease in the number of red blood cells was found, which could be attributed to the action of the compound of Example 45 (less polar). If the fate is that a significant dose of the compound was administered to each animal, then a zero mortality rate among animals indicates that the compounds of the present invention have low toxicity.

 Thus, the compounds of the present invention have high activity and at the same time very low toxicity, which makes them ideal for therapeutic use.

 The present invention is further illustrated by the following examples, but not limiting the scope of the present invention. In these examples, the compound numbers are the same as the numbers of the compounds shown in tables 1-7 (see above). The preparation of some of the starting materials used in some of these examples is illustrated in the preparations following the examples. Specific values of the angle of rotation were obtained by measurements at room temperature.

Example 1. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxo-oxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-94)
To 330 mg of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (prepared as described in In Preparation 6), 3 ml of trifluoroacetic acid was added under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was neutralized by the addition of aqueous sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. After that, ethyl acetate was removed from the extract by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a mixture of ethyl acetatef and hexane (2: 3 by volume) as the eluent, to give 160 mg of the target compound, with a melting point of 50.9 ^o -52.5 ^o C and R _f = 0.45 (thin layer chromatography on silica gel using a developing solvent of a mixture of ethyl acetate and hexane, 2: 1 by volume).

Example 2. 5- {4- [2- (3-3'-Chlorophenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine -2,4-dione (Compound N 1-92)
To a solution of 100 mg of 3- (3-chlorophenoxy) -2-hydroxypropylamine (prepared as described in Preparation 13) and 139 mg of 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione 3 ml of anhydrous methanol was added 148 mg of sodium cyanoborohydride under ice-cooling. The resulting mixture was stirred at room temperature for 7 hours in a stream of nitrogen gas. After this time, the reaction mixture was left overnight and then poured into water and extracted with ethyl acetate. The resulting extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After that, the solvent was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by thin-layer chromatography on silica gel, using a mixture of ethyl acetate and ethanol (8: 1 by volume) as a developing solvent. Thus, 92 mg of the target compound was obtained having R _f = 0.30 (thin layer chromatography on silica gel using a 10: 1 v / v mixture of ethyl acetate and ethanol as a developing solvent).

Example 3. 5- {4- [2- (3-phenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-16)
The procedure described in Example 2 was repeated, except that 0.98 g of 3-phenoxy-2-hydroxypropylamine (prepared as described in Preparation 15), 3.39 g of 5- [4- (2- oxopropoxy) benzyl] thiazolidine-2,4-dione, 1.11 g of sodium cyanoborohydride and 60 ml of anhydrous methanol. The resulting crude product was purified by column chromatography and silica gel, using a mixture of ethyl acetate and ethanol (10: 1 by volume) as an eluent, to give 1.92 g of the target compound with mp 64-68 ^o C.

Example 4. 5- {4- [2- (5-Phenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-48)
To a solution of 500 mg of 5- {4- [2- (3-phenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared as described in Example 3) in 5 ml of anhydrous dimethylformamide with while cooling with ice, 211 mg of N, N'-carbonyldiimidazole was added and the resulting mixture was stirred at room temperature for 5 hours. After this time, dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure. After adding water to the obtained residue, the mixture was extracted with ethyl acetate. After that, the extract was washed with an aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 1 to 1: 1 by volume) as an eluent, whereby 410 mg of the target compound having so pl. 54 - 56 ^o C.

Example 5. 5- {4- [2- (3-3'-Chlorophenoxy-2-hydroxypropylamino) ethoxybenzyl} thiazolidine-2,4-dione (Compound N 1-91)
The procedure described in Example 2 was repeated, except that 600 mg of 3- (3-chlorophenoxy) -2-hydroxypropylamine (prepared as described in Preparation 13), 800 mg of 5- [4- (2- oxoethoxy) benzyl] thiazolidine-2,4-dione (prepared as described in Preparation 20), 570 mg of sodium cyanoborohydride and 40 ml of anhydrous methanol. Thus, 180 mg of the target compound was obtained having R _f = 0.35 (thin layer chromatography on silica gel using a 1: 4 v / v mixture of ethanol and ethyl acetate as a developing solvent).

Example 6. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-93)
The procedure described in Example 4 was repeated, except that 180 mg of 5- {4- [2- (3-3'-chlorophenoxy-2-hydroxypropylamino) ethoxy] benzyl} thiazolidine-2,4-dione (obtained in accordance with the procedure described in Example 5), 65 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide, resulting in a received 53 mg of the target compound having so pl. 58 - 63 ^o C and R _f = 0.27 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 2: 1 by volume).

Example 7. 5- {4- [2- (3-Phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-2)
500 mg of 3-phenyl-2-hydroxypropylamine (prepared as described in Preparation 17) and 1.0 mg of 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione were suspended in 30 ml of anhydrous benzene and the resulting suspension was heated under reflux for 30 minutes, while removing water. Then, the solvent was removed by evaporation under reduced pressure. The resulting oily product was dissolved in 20 ml of anhydrous methanol, and 670 mg of sodium cyanoborohydride was added to the resulting solution (under ice cooling). After that, the mixture was stirred for 2 hours in a stream of nitrogen gas. Then the reaction mixture was kept overnight, after which the solvent was removed by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed from the extract by evaporation under reduced pressure, and the resulting residue was introduced into a silica gel chromatography column (eluting with a mixture of ethyl acetate and methanol, 5: 1 by volume), after which it was crystallized from ethyl acetate, whereby 590 mg of the target compound was obtained, so pl. . 145 - 152 ^o C.

Example 8. 5- {4- [2- (5-Benzyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-4)
The procedure described in Example 4 was repeated except that 300 mg of 5- {4- [2- (3-phenyl-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in accordance with the description in Example 7), 120 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide. The resulting product was chromatographed on a silica gel column using a mixture of ethyl acetate and hexane (3: 2 by volume) as an eluent, to give 200 mg of the target compound, mp 60 - 70 ^o C.

Example 9. 5- {4- [2- (3-3'-Chlorophenoxy-2-hydroxypropylamino) propylthio] benzyl} thiazolidine-2,4-dione (Compound N 1-158)
The procedure described in Example 2 was repeated, except that 1.0 g of 3- (3-chlorophenoxy) -2-hydroxypropylamine (prepared as described in Preparation 13, 1.5 g of 5- [4- (2-oxopropylthio) benzyl] thiazolidine-2,4-dione (prepared as described in Preparation 18), 940 mg sodium cyanoborohydride and 30 ml anhydrous methanol The resulting crude product was chromatographed on a silica gel column using eluent a mixture of ethyl acetate and ethanol (10: 1 by volume), resulting in a gain of 1.52 mg of the target compound having R _f = 0.44 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and ethanol, 10: 1 by volume).

Example 10. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) propylthio] benzyl} thiazolidine-2,4-dione (Compound N 1-159)
The procedure described in Example 4 was repeated except that 300 mg of 5- {4- [2- (3-3'-chlorophenoxy-2-hydroxypropylamino) propylthio] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 9), 470 mg of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (3: 2 by volume) as an eluent, whereby a more polar diastereomer and a less polar diastereomer were obtained separately. The corresponding diastereomers were purified using high resolution reverse phase preparative liquid chromatography [UMS-Rask ODS-A column (trademark of a product manufactured by UMS Co.); eluent is a mixture of acetonitrile, water, acetic acid and triethylamine, 100: 100: 1: 1 by volume], resulting in 110 mg of the target compound having R _f = 0.15 (thin layer chromatography on silica gel using silica gel using a more polar diastereomer) as a developing solvent, a mixture of ethyl acetate and hexane, 1: 1 by volume), and from a less polar diastereomer, 120 mg of the target compound having R _f = 0.25 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 1 p volume).

Example 11. 5- [4- {2 (R) - [5 (S) - (3-Chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy} benzyl] thiazolidin-2,4-dione (Compound N 1- 94)
The procedure described in Example 1 was repeated, except that 0.96 g of 5- [4- {2 (R) - [5 (S) - (3-chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy was used } benzyl] -3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid. Thus, 0.52 g of the target compound is obtained, having a mp. 48 - 53 ^o C (with softening) and having [α] _D = +54 ^o (methanol, s = 1,000).

Example 12. 5- [4- {2 (S) - [5 (R) - (3-Chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy} benzyl] thiazolidin-2,4-dione (Compound N 1- 94)
The procedure described in Example 1 was repeated, except that 0.73 mg of 5- [4- {2 (S) - [5 (R) - (3-chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy was used } benzyl] -3-triphenylmethylthiazolidine-2,4-dione (obtained as described in Preparation 37), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid, whereby 0.39 g of the target compound having mp . 55-60 ^° C (with softening) and having [α] _D = -52.4 ^° (methanol, s = 0.990).

Example 13. 5- [4- {2 (S) - [5 (S) - (3-Chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy} benzyl] thiazolidin-2,4-dione (Compound N 1- 94)
The procedure described in Example 1 was repeated, except that 0.57 mg of 5- [4- {2 (R) - [5 (R) - (3-chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy was used } benzyl] -3-triphenylmethylthiazolidine-2,4-dione (obtained as described in Preparation 45), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride, resulting in 280 mg of the target compound with a melting point of 52 - 53 ^o C. [α] _D = -39.7 ^° (methanol, s = 0.965).

Example 14. 5- [4- {2 (R) - [5 (R) - (3-Chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy} benzyl] thiazolidin-2,4-dione (Compound N 1- 94)
The procedure described in Example 1 was repeated, except that 0.57 g of 5- [4- {2 (R) - [5 (R) - (3-chlorophenoxymethyl) - 2-oxooxazolidin-3-yl] propoxy was used } benzyl] -3-triphenylmethylthiazolidine-2,4-dione (obtained as described in Preparation 45), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride. Thus was obtained the target compound (280 mg) with so pl. 52 - 53 ^o C.

[α] _D = -39.7 ^° (methanol, s = 0.965).

Example 15. 5- {4- [2- (3-Benzyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-64)
The procedure described in Example 2 was repeated, except that 545 mg of 3-benzyloxy-2-hydroxypropylamine (prepared as described in Preparation 48), 700 mg of 5- [4- (2-oxopropoxy) benzyl] were used thiazolidine-2,4-dione, 470 mg of sodium cyanoborohydride and 60 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography, eluting with a gradient of a mixture of ethyl acetate and ethanol (10: 1 to 5: 1 by volume. In addition, the obtained product was purified using high-resolution reverse phase preparative liquid chromatography (YMC-Pack ODS- A-trademark of a product manufactured by YMC Co.) using a mixture of acetonitrile, water, acetic acid and triethylamine (50: 1: 1 by volume) as an eluent, to give 130 mg of the desired product as a pale yellow glassy hard second substance having R _f = 0,16 (TLC on silica gel using as developing solvent a mixture of ethyl acetate and ethanol, a 10: 1 by volume).

Example 16. 5- {4- [2- (3-5-Phenylpentyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-160)
The procedure described in Example 2 was repeated, except that 820 mg of 3- (5-phenylpentyloxy) -2-hydroxypropylamine (prepared as described in Preparation 51), 840 mg of 5- [4- (2- oxopropyl) benzyl] thiazolidine-2,4-dione, 540 mg of sodium cyanoborohydride and 80 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography, eluting with a gradient of a mixture of ethyl acetate and ethanol (10: 1-5: 1 by volume). After that, the resulting product was purified using high resolution reverse phase preparative liquid chromatography (YMC-Rask ODS-A is a trademark of a product manufactured by YMC Co.) using a mixture of acetonitrile, water, acetic acid and triethylamine as an eluent (50: 50: 1: 1 by volume). Thus, 250 mg of the target compound was obtained in the form of a pale yellow oily substance having R _f = 0.35 (thin layer chromatography on silica gel using a mixture of ethyl acetate and ethanol (5: 1 by volume) as a developing solvent).

Example 17. 5- {4- [2- (3-3'-Phenylpropoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-74)
The procedure described in Example 2 was repeated, except that 720 mg of 3- (3-phenylpropoxy) -2-hydroxypropylamine (prepared as described in Preparation 54), 800 mg of 5- [4- (2- oxopropoxy) benzyl] thiazolidine-2-4-dione, 540 mg of sodium cyanoborohydride and 70 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and ethanol (10: 1-5: 1 by volume) as eluent. The resulting product was then purified using high resolution reverse phase preparative liquid chromatography (YMC-Pack ODS-A is a trademark of a product manufactured by YMC Co.) using a mixture of acetonitrile, water, acetic acid and triethylamine as an eluent (50:50 : 1: 1 by volume), whereby 380 mg of the target compound was obtained as a pale yellow glassy solid having R _f = 0.29 (thin layer chromatography on silica gel using a mixture of ethyl acetate and ethanol as a developing solvent (5: one by volume).

Example 18. 5- {4- [2- (3-2'-Phenylethoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-69)
The procedure described in Example 2 was repeated, except that 0.70 g of 3- (2-phenylethoxy) -2-hydroxypropylamine (obtained in accordance with the procedure described in Preparation 57), 1.00 g of 5- was used [4 - (2-oxopropoxy) benzyl] thiazolidine-2,4-dione, 0.71 g of sodium cyanoborohydride and 20 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using ethyl acetate as eluent. As a result of this procedure, 0.92 g of the target compound was obtained having a melting point of 46 - 49 ^o C (with softening).

Example 19. 5- {4- [2- (3-4'-Phenylbutoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-161)
The procedure described in Example 2 was repeated, except that 1.20 g of 3- (4-phenylbutoxy) -2-hydroxypropylamine (prepared as described in Preparation 60), 1.00 g of 5- [4] were used. - (2-oxopropoxy) benzyl] thiazolidine-2,4-dione, 0.71 g of sodium cyanoborohydride and 20 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using an ethyl acetate-ethanol mixture (8: 1 by volume) as an eluent, to give 1.34 g of the target compound, having a melting point of 32 - 37 ^o C (with softening).

Example 20. 5- {4- [2- (3-6-Phenylhexyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-162)
The procedure described in Example 2 was repeated, except that 864 mg of 3- (6-phenylhexyloxy) -2-hydroxypropylamine (prepared as described in Preparation 63), 800 mg of 5- [4- (2- oxopropoxy) benzyl] thiazolidine-2,4-dione, 540 mg of sodium cyanoborohydride and 50 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and ethanol (1: 0-5: 1 by volume) as an eluent to give 500 mg of the target compound as a pale yellow oily substance having R _f = 0.42 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and ethanol, 5: 1 by volume).

Example 21. 5- {4- [2- (3-8'-Phenyloxythyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-163)
The procedure described in Example 2 was repeated, except that 0.96 g of 3- (8-phenylloctyloxy) -2-hydroxypropylamine (prepared as described in Preparation 66), 0.80 g of 5- was used [4 - (2-oxopropoxy) benzyl] thiazolidine-2,4-dione, 0.54 g of sodium cyanoborohydride and 50 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and ethanol (10: 1-5: 1 by volume) as eluent. As a result of this procedure, 360 mg of the target compound was obtained having R _f = 0.43 (thin layer chromatography on silica gel using a 5: 1 v / v mixture of ethyl acetate and ethanol as a developing solvent).

Example 22. 5- {4- [2- (5-Benzyloxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-164)
The procedure described in Example 4 was repeated, except that 200 mg of 5- {4- [2- (3-benzyloxy-2-hydroxypropylamine) propoxy] benzyl} thiazolidine-2,4-dione (prepared according to the procedure) were used described in Example 15), 73 mg of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography, eluting with a gradient of a mixture of ethyl acetate and hexane (2: 1 to 3: 1 by volume). As a result of this procedure, 160 mg of the target compound was obtained as a pale yellow glassy solid, which is a mixture of a less polar diastereomer having R _f = 0.49 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 3 : 1 by volume), and more polar diastereomer having R _f = 0.38 (thin layer chromatography on silica gel using a 3: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

Example 23. 5- {4- [2- (5-2'-Phenylethoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-165)
The procedure described in Example 4 was repeated, except that 700 mg of 5- {4- [2- (3-2'-phenylethoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (obtained in as described in Example 18), 250 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1: 1 by volume) as an eluent, whereby 650 mg of the target compound was obtained as a mixture (1: 1) of a polar diastereomer having R _f = 0.74 (thin layer chromatography on silica gel using ethyl acetate as eluent), and a less polar diastereomer having R _f = 0.80 (thin layer chromatography on silica gel using ethyl acetate as eluent).

Example 24. 5- {4- [2- (5-3'-Phenylpropoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-166)
The procedure described in Example 4 was repeated, except that 600 mg of 5- {4- [2- (3-3'-phenylpropoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 17), 206 mg of N, N'-carbonyldiimidazole and 60 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and hexane (1: 1 - 3: 2 by volume) as an eluent, resulting in a separate polar diastereomer and less polar diastereomer. The corresponding diastereomers were purified using high resolution reverse phase preparative liquid chromatography (YMC-Pack ODS-A is a trademark of a product manufactured by YMC Co.) using an acetonitrile-water mixture (1: 1 by volume) as eluent. As a result of this procedure, 98 mg of the target compound having R _f = 0.46 (thin layer chromatography on silica gel using a 2: 1 volume mixture of ethyl acetate and hexane as a developing solvent) was obtained from the polar diastereomer, and 189 was obtained from the less polar diastereomer mg of the target compound having R _f = 0.52 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane (2: 1 by volume) as a developing solvent.

Example 25. 5- {4- [2- (5-4'-Phenylbutoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-79)
The procedure described in Example 4 was repeated, except that 550 mg of 5- {4- [2- (3-4'-phenylbutoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 19), 180 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using hexane and ethyl acetate mixtures (2: 1 by volume) as eluent. The product was then purified using high resolution reverse phase preparative liquid chromatography (YMC-Pack ODS-A is a trademark of a product manufactured by YMC Co.) using a mixture of acetonitrile, water, acetic acid and triethylamine as an eluent (100: 100: 1: 1 by volume), resulting in a polar diastereomer and a less polar diastereomer. 170 mg of the target compound having R _f = 0.71 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent) was obtained from the polar diastereomer, and 160 mg of the target compound having R _f = 0.79 (thin layer) was obtained from the less polar diastereomer silica gel chromatography using ethyl acetate as a developing solvent).

Example 26. 5- {4- [2- (5-5'-Phenylpentyloxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-167)
The procedure described in Example 4 was repeated, except that 600 mg of 5- {4- [2- (3-5'-phenylpentyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 16), 194.3 mg of N, N'-carbonyldiimidazole and 60 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 1 by volume) as eluent. As a result of this procedure, 520 mg of the target compound was obtained as a pale yellow oily substance, which is a mixture of a less polar diastereomer having R _f = 0.61 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane (2: 1 by volume) as a developing solvent) and a polar diastereomer having R _f = 0.52 (thin layer chromatography on silica gel using a 2: 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

Example 27. 5- {4- [2- (5-6'-Phenylhexyloxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-168)
The procedure described in Example 4 was repeated, except that 690 mg of 5- {4- [2- (3-6'-phenylhexyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione obtained in as described in Example 20), 217 mg of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 1 to 3: 2 by volume) as an eluent, to give 520 mg of the target compound as a pale yellow oily substance, which is mixture of less polar diastereomer having an R _f = 0,63 (TLC on silica gel using as developing solvent a mixture of ethyl acetate and hexane, 3: 2 by volume) and a polar diastereomer having an R _f - 0,56 (thin layer x omatografiya on silica gel using as developing solvent a mixture of ethyl acetate and hexane, 3: 2 by volume).

Example 28. 5- {4- [2- (5-8'-Phenyloctyloxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-169)
The procedure described in Example 4 was repeated, except that 660 mg of 5- {4- [2- (3-8'-phenyloxyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (obtained in as described in Example 21), 197 mg of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylfomamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 1 by volume) as eluent. As a result of this procedure, 550 mg of the target compound was obtained in the form of a mixture of a polar diastereomer having R _f = 0.58 (thin layer chromatography on silica gel using a 3: 2 by volume mixture of ethyl acetate and hexane as a developing solvent) and a less polar diastereomer having R _f - 0.65 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 3: 2 by volume).

Example 29. 5- {4- [2- (5-7'-Phenylheptyloxymethyl--2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-170)
The procedure described in Example 4 was repeated, except that 590 mg of 5- {4- [2- (3-7'-phenylheptyloxy-2-hydroxypropylamino) propoxy] benzyl] thiazolidine-2,4-dione (obtained in as described in Example 56), 181 mg of N, N'-carbonyldiimidazole and 15 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using an ethyl acetate / hexane mixture (1: 1 by volume) as an eluent to give 383 mg of the target compound as a mixture of a polar diastereomer having R _f = 0.29 (thin layer chromatography on silica gel using as developing solvent a mixture of ethyl acetate and hexane, 1: 1 by volume) and a less polar diastereomer having an R _f = 0,37 (TLC on silica gel using as developing pa -solvent mixture of ethyl acetate and hexane, 1: 1 by volume).

Example 30. 5- {4- [2- (5-3'-Fluorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-171)
The procedure described in Example 1 was repeated, except that 390 mg of 5- {4- [2- (5-3'-fluorophenoxymethyl) -2-oxooxazolidin-3-yl) propoxy] benzyl} - 3-triphenylmethylthiazolidin- was used 2,4-dione (prepared as described in Preparation 74), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride. Thus, 200 mg of the target compound was obtained with a melting point of 50-53 ^o C.

Example 31. 5- {4- [2- (5-4'-Methoxyphenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-173)
(a) The procedure described in Example 1 was repeated, except that 0.68 g of 5- {4- [2-5-4'-methoxyphenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3 was used β-triphenylmethylthiazolidine-2,4-dione (less polar isomer) prepared as described in Preparation 78 (a), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride. Thus, 280 mg of the target compound having a melting point of 49-52 ^° C. was obtained from the less polar diastereomer.

(b) The procedure described in Example 1 was repeated, except that 840 mg of 5- {4- [2- (5-4'-methoxyphenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3- was used triphenylmethylthiazolidine-2,4-dione (polar isomer) prepared as described in Preparation 78 (b), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride. Thus, from the polar diastereomer received 440 mg of the target compound with a melting point of 54-58 ^o C.

Example 32. 5- {4- [2- (3-3'-Dimethylaminophenoxy-2-hydroxypropylamino) propoxy] benzyl} -thiazolidine-2,4-dione (Compound N 1-176)
The procedure described in Example 2 was repeated, except that 1.20 g of 3- (3-dimethylaminophenoxy) -2-hydroxypropylamine (prepared as described in Preparation 81), 1.81 g of 5- [4 - (2-oxopropoxybenzyl] thiazolidine-2,4-dione, 0.96 g of sodium cyanoborohydride and 50 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using ethyl acetate and ethanol (20: 1 each) by volume) After recrystallization from ethanol, 0.74 g of the target compound was obtained, mp 9 2.1-98 ^o C.

Example 33. 5- {4- [2- (5-3'-Dimethylaminophenoxy-methyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-177)
The procedure described in Example 4 was repeated, except that 500 mg of 5- {4- [2- (3-3'-dimethylaminophenoxy-2-hydroxypropylamino] propoxy] benzyl} thiazolidine-2,4-dione (prepared in As described in Example 32), 195 mg of N, N'-carbonyldiimidazole and 5 ml of anhydrous dimethylformamide The obtained crude product was purified by silica gel column chromatography using ethyl acetate and hexane (2: 1 by volume) as an eluent. , resulting in a received 380 mg of the target compound, mp 55.5-57.1 ^o C.

Example 34. 5- {4- [2- (3-4'-Phenylphenoxy-2-hydroxy-propylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-179)
The procedure described in Example 1 was repeated, except that 1.00 g of 3- (4-phenylphenoxy) -2-hydroxypropylamine (prepared as described in Preparation 84), 1.46 g of 5- [4] were used - (2-oxopropoxy) benzyl] thiazolidine-2,4-dione, 0.52 g of sodium borohydride and 40 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and methanol (1: 0-10: 1, v / v) as eluent. Then the obtained product was purified using reverse phase liquid chromatography (eluent is a mixture of acetonitrile and water, 1: 1 by volume) described in Example 10, whereby 174 mg of the target compound was obtained with mp 76.7-80.3 ^o C.

Example 35. 5- {4- [2- (5-4'-Phenylphenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzylthiazolidin-2,4-dione (Compound N 1-180)
The procedure described in Example 4 was repeated, except that 500 mg of 5- {4- [2- (3,4'-phenylphenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 34), 195 mg of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylfomamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (3: 2 by volume) as the eluent, whereby 0.44 g of the target compound was obtained, mp 73.1-75.4 ^° C.

Example 36. 5- {4- [2- (5-4'-Phenylphenoxymethyl-2-thiooxaoxosolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-181)
To a solution of 500 mg of 5- {4- [2- (3-4'-phenylphenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared as described in Example 34) in 10 ml 218 mg of N, N'-thiocarbonyldiimidazole was added to anhydrous methylene chloride, and the resulting mixture was stirred at room temperature for one hour. After this time, water was added to the reaction mixture, and this mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which ethyl acetate was removed by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 3 by volume) as eluent. Then the obtained product was purified using reverse phase liquid chromatography (eluent is a mixture of acetonitrile and water, 60:40 by volume) described in Example 10, whereby 136 mg of the target compound was obtained (mp. 58.7-60, 8 ^o C) from the polar diastereomer and 165 mg of the target compound (mp 177.6 - 180.3 ^o C) from the less polar diastereomer.

Example 37. 5- {4- [2- (3-Phenylthio-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-182)
The procedure described in Example 2 was repeated, except that 2.95 g of 3-phenylthio-2-hydroxypropylamine (obtained as described in Preparation 87), 3 g of 5- [4- (2-oxopropoxy) were used benzyl] thiazolidine-2,4-dione, 1.0 g of sodium cyanoborohydride and 100 ml of anhydrous methanol, resulting in 1.74 g of the target compound, so pl. 176-177 ^o C.

Example 38. 5- {4- [2- (5-Phenylthiomethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -thiazolidin-2,4-dione (Compound N 1-128)
The procedure described in Example 4 was repeated, except that 1.2 g of 5- {4- [2- (3-phenylthio-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared according to with the description given in Example 37), 0.52 g of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide. As a result of this procedure, 1.15 g of the target compound was obtained in the form of a mixture (1: 1) of a polar diastereomer having R _f = 0.30 (thin-layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as a developing solvent) ), and a less polar diastereomer having R _f = 0.38 (thin-layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

Example 39. 5- {4- [2- [3- (N-Methyl-N-phenylamino) -2- hydroxypropylamino] propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-183)
The procedure described in Example 2 was repeated, except that 1.55 g of 3- (N-methyl-N-phenylamino) -2-hydroxypropylamine (obtained as described in Preparation 90) was used, 1.6 g 5- [4- (2-hydroxypropoxy) benzyl] thiazolidine-2,4-dione, 0.4 g of sodium cyanoborohydride and 50 ml of anhydrous methanol, resulting in 1.39 g of the target compound, so pl. 115 - 125 ^o C.

Example 40. 5- {4- [2- [5- (N-Methyl-N-phenylaminomethyl) -2-oxooxazolidin-3-yl propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-184)
The procedure described in Example 4 was repeated, except that 0.9 g of 5- [4- [2- [3- (N-methyl-N-phenylamino) -2-hydroxypropylamino] propoxy] benzyl] thiazolidine-2 was used , 4-dione (prepared as described in Example 39), 0.36 g of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide. Thus, 0.6 g of the target compound was obtained having R _f = 0.24 (thin layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

Example 41. 5- {4- [2- (3-3'-Chlorobenzyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-186)
The procedure described in Example 2 was repeated, except that 3.00 g of 3- (3-chlorobenzyloxy) -2-hydroxypropylamine was used with a purity of 57% (obtained as described in Preparation 93), 5, 00 g of 5- [4- (2-oxopropoxy) benzyl] thiazolidine-2,4-dione, 2.64 g of sodium cyanoborohydride and 100 ml of anhydrous methanol. The resulting crude product was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and ethanol (10: 1-4: 1 by volume) as eluent. This product was then purified by reverse phase column chromatography using a mixture of acetonitrile and water (3: 7 by volume) as eluent, to give 302 mg of the target compound, having a temperature of 52-53 ^° C (with softening).

Example 42. 5- {4- [2- (5-3'-Chlorobenzyloxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl] thiazolidine-2,4-dione (Compound N 1-187)
The procedure described in Example 4 was repeated, except that 300 mg of 5- {4- [2- (5-3'-chlorobenzyloxy-2--hydroxypropylamino (propoxy] benzyl} thiazolidine-2,4-dione (obtained in accordance with the procedure described in Example 41), 115 mg of N, N'-carbonyldiimidazole and 5 ml of anhydrous dimethylformamide The resulting crude product was chromatographed on a silica gel column using a gradient of a mixture of ethyl acetate and hexane (3: 2 - 2: 1, by volume) to give 206 mg of the title compound having R _f = 0,25 (thin layer x omatografiya on silica gel using as developing solvent a mixture of ethyl acetate and hexane, a 2: 1 by volume).

Example 43. 5- {4- [2- (5-3'-Chlorobenzyloxymethyl-2-thiooxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-188)
The procedure described in Example 36 was repeated, except that 300 mg of 5- [4- [2- (3,3'-chlorobenzyloxy) -2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (obtained as described in Example 41), 125 mg of N, N'thiocarbonyldiimidazole and 5 ml of anhydrous methylene chloride. The resulting crude product was purified by silica gel column chromatography, using a mixture of ethyl acetate and hexane (2: 3 by volume) as the eluent, to give 191 mg of the target compound having R _f = 0.35 (thin layer chromatography on silica gel using as a developing solvent, a mixture of ethyl acetate and hexane, 2: 1 by volume).

Example 44. 5- {4- [2- (5-3'-Chlorobenzyloxymethyl-2-thiooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (prepared as described in Example 43) dissolved in 2 ml of methanol, and a solution obtained by diluting 24 mg of sodium methoxide (28% methanol solution) with methanol (1 ml) was added to the resulting solution. After that, the resulting mixture was stirred at room temperature for one hour. After stirring was completed, the solvent was removed by evaporation under reduced pressure to obtain 50 mg of the target compound having a melting point of 238.7 - 240 ^° C (decomposed).

Example 45. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-thiooxooxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-95)
The procedure described in Example 36 was repeated except that 300 mg of 5- {4- [2- (3-3′-chlorophenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 2), 127 mg of N, N'-thiocarbonyldiimidazole and 5 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 3 by volume) as eluent. Then this product was purified using reverse phase column chromatography (eluent is a mixture of acetonitrile and water, 1: 1 by volume) described in Example 10. As a result of this procedure, 87 mg of the target compound having mp 50.3 - 52.8 ^o C, and from a less polar diastereomer received 78 mg of the target compound with so pl. 50.6 - 53.1 ^o C.

Example 46. 5- [4- [2- (3-3'-Chlorophenoxy) -2-hydroxypropylamino) butoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-190)
The procedure described in Example 2 was repeated, except that 1.50 g of (3- (3-chlorophenoxy) -2-hydroxypropylamine (prepared as described in Preparation 13) were used, 2.61 g of 5- [ 4- (2-oxobutoxy) benzyl] thiazolidine-2,4-dione (prepared as described in Preparation 95), 1.40 g of sodium cyanoborohydride and 40 ml of anhydrous methanol. The resulting crude product was purified by column chromatography on silica gel using a gradient of a mixture of ethyl acetate and ethanol (1: 0 - 10: 1 by volume) as the eluent, last why this product was purified using reverse phase column chromatography (eluent is a mixture of acetonitrile and water, 3: 7 by volume) described in Example 1. Thus, 2.97 g of the target compound having a melting point of 49.5 - 52.8 ^o C (with softening).

Example 47. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) butoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-191)
The procedure described in Example 4 was repeated except that 5.48 g of 5- {4- [2- (3-3'-chlorophenoxy-2-hydroxypropylamino) butoxy] benzyl} thiazolidine-2,4-dione ( obtained in accordance with the procedure described in Example 46), 2.11 g of N, N'-carbonyldiimidazole and 60 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography, and a gradient of a mixture of ethyl acetate and hexane (2: 3 - 2: 1 by volume) was used as an eluent. Then this product was purified using reverse phase column chromatography (eluent is a mixture of acetonitrile and water, 9:11 by volume) described in Example 10. As a result of this procedure, 1.91 g of the target compound were obtained from the polar diastereomer (mp. 150.5 - 154.4 ^o C), and from a less polar diastereomer received 1.90 g of the target compound with so pl. 54.4 - 55.4 ^o C (with softening).

Example 48. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-thiooxooxazolidin-3-yl) butoxy] benzyl} thiazolidine-2,4-dione (Compound N 1 -192)
The procedure described in Example 36 was repeated except that 250 mg of 5- {4- [2- (3-3'-chlorophenoxy-2-hydroxypropylamino) butoxy] benzyl} thiazolidine-2,4-dione (prepared in as described in Example 46), 102 mg of N, N'-thiocarbonyldiimidazole and 5 ml of methylene chloride. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 3 by volume) as eluent. This product was then purified by reverse phase column chromatography using an acetonitrile / water mixture (1: 1 by volume) as an eluent, as described in Example 10. As a result of this procedure, 87 mg of the target compound were obtained from the polar diastereomer, mp . 54.1 - 56.0 ^o C, and from the less polar diastereomer received 85 mg of the target compound having so pl. 57.7 - 59.0 ^o C.

Example 49. 5- {4- [2- (5-Phenoxymethyl-2-thioxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-51)
The procedure described in Example 36 was repeated, except that 205 mg of 5- {4 - [2- (3-phenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in accordance with the description given in Example 3), 95 mg of N, N'-thiocarbonyldiimidazole and 5 ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 1 by volume) as eluent. As a result of this procedure, 190 mg of the target compound was obtained, having a mp. 53 - 58 ^o C (with softening).

Example 50. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) pentyloxy] benzyl} thiazolidine-2,4-dione (Compound N 1-193)
(a) The procedure described in Example 1 was repeated, except that 1.58 g of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) pentyloxy] benzyl} was used} -3-triphenylmethylthiazolidine-2,4-dione (no less than the polar isomer obtained as described in Preparation 100), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride. As a result of this procedure, 516 mg of the target compound (mp. 50 - 52 ^° C.) was obtained from the less polar diastereomer.

(b) The procedure described in Example 1 was repeated, except that 1.45 g of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-2,4-yl) pentyloxy] benzyl was used } -3-triphenylmethylthiazolidine-2,4-dione (polar isomer obtained as described in Preparation 100), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride. Thus, 314 mg of the target compound was obtained, having a mp. 53 - 55 ^o C (from the polar diastereomer).

Example 51. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) -3-methylbutoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-195)
(a) The procedure described in Example 1 was repeated, except that 0.92 g of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) -3-methylbutoxy] was used benzyl} -3-triphenylmethylthiazolidine-2,4-dione (less than the polar isomer obtained as described in Preparation 101 (a)), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride. As a result of this procedure, 145 mg of the target compound having a melting point of 145 mg was obtained from the less polar diastereomer. 51 - 53 ^o C.

(b) The procedure described in Example 1 was repeated, except that 1.18 g of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) methylbutoxy] benzyl} was used} -3-trifluorophenylmethylthiazolidine-2,4-dione (polar isomer obtained as described in Preparation 101 (b)), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride, whereby 177 mg of the target compound are obtained (mp. 57 - 58 ^o C) with a polar diastereomer.

 Example 52. 5- {2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) -2-methylpropoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-197).

To 1.5 g of a mixture of 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) -2-methylpropoxy] benzyl} -2-iminothiazolidin-4-one and thiourea (obtained in as described in Preparation III), 4 ml of methanol and 15 ml of 6N were added. aqueous hydrochloric acid. The resulting mixture was heated under reflux for 5 hours. After completion of heating, the reaction mixture was neutralized by adding an aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After that, ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was chromatographed on a column of silica gel (eluent was a 1: 1 by volume mixture of ethyl acetate and hexane). This residue was then purified using high-resolution reverse phase preparative liquid chromatography (YMC-Rask ODS-A product trademark manufactured by YMC Co.) using a mixture of acetonitrile and water (1: 1 by volume) as eluent. As a result of this procedure received 454 mg of the target compound, having so pl. 55 - 58 ^o C.

Example 53. 5- {4- [3- (5-Phenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -thiazolidine-2,4-dione (Compound N 1-49)
The procedure described in Example 1 was repeated, except that 1.98 g of 5- {4- [3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidin-2 were used, 4-dione (obtained as described in Preparation 115), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride, whereby 1.18 g of the target compound are obtained, so pl. 41 - 43 ^o C.

Example 54. 5- {4- [4- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) butoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-200)
The procedure described in Example 1 was repeated, except that 1.42 g of 5- {4- [4- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) butoxy] benzyl} -3-triphenylmethylthiazolidine was used -2,4-dione (obtained as described in Preparation 118), 2 ml of trifluoroacetic acid and 4 ml of methylene chloride, whereby 910 mg of the target compound are obtained, so pl. 40 - 42 ^o C.

Example 55. 5- {4- [2- (2-3'-Chlorophenoxymethylmorpholino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-201)
The procedure described in Example 1 was repeated, except that 1.24 g of 5- {4- [2- (2-3'-chlorophenoxymethylmorpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (obtained as described in Preparation 122), 4 ml of trifluoroacetic acid and 2 ml of methylene chloride, resulting in 181 mg of the target compound having so pl. 51 - 52 ^o C.

Example 56. 5- {4- [2- (3-7'-Phenylheptyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-204)
The procedure described in Example 2 was repeated, except that 836 mg of 3- (7-phenylheptyloxy) -2-hydroxypropylamine (prepared as described in Preparation 69), 800 mg of 5- [4- (2- oxopropoxy) benzyl] thiazolidine-2,4-dione, 540 mg of sodium cyanoborohydride and 50 ml of anhydrous methanol. Thus, 74 mg of the target compound was obtained having R _f = 0.21 (thin layer chromatography on silica gel using a 5: 1 v / v mixture of ethyl acetate and ethanol as a developing solvent).

Example 57. 5- [4- {2- [N- (3,3'-Chlorophenoxy-2-hydroxypropyl) -N-methylamino] propoxy} benzyl] thiazolidine-2,4-dione (Compound N 1-206)
180 mg of paraformaldehyde and 30 mg of p-toluenesulfonic acid were added to 300 mg of 5- {4- [2- (3-3'-chlorophenoxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione (prepared in accordance with the description given in Example 2) in 20 ml of a mixture of toluene and dioxane (1: 1 by volume). The resulting mixture was heated under reflux for 3 hours. After this, the mixture was stirred for 2 days, and then another 180 mg of paraformaldehyde and 30 mg of p-toluenesulfonic acid were added. The resulting mixture was heated for 8 hours under reflux. After this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure. An aqueous sodium bicarbonate solution was added to the resulting residue, after which the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After that, ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified using high resolution reverse phase preparative liquid chromatography (YMC = Rask ODS-A is a trademark of a product manufactured by YMC Co.) using an acetonitrile mixture as eluent and water (1: 1 by volume). Thus, 78 mg of the target compound was obtained, having a mp. 64 - 67 ^o C (with softening).

Example 58. 5- {4- [2- (3-4'-Phenylphenoxy-2-hydroxypropylamino) ethoxy] benzyl} thiazolidine-2,4-dione (Compound N 1-207)
The procedure described in Example 2 was repeated, except that 0.42 g of (3-4-phenylphenoxy) -2-hydroxypropylamine, 10 ml of absolute ethanol, 0.21 g of sodium cyanoborohydride and 0.52 g of 5-4- were used (2-oxoethoxy) benzyl] thiazolidine-2,4-dione. The obtained crude product was purified by silica gel column chromatography (eluent was a gradient of a mixture of ethyl acetate and methanol, 1: 0 - 3: 1 by volume), and then purified by high-resolution reverse phase preparative liquid chromatography (YMC-Rask ODS- column A-trademark), using as a eluent a mixture of acetonitrile and water (3: 7 - 7:13 by volume), resulting in 222 mg of the target compound having mp 83 - 86 ^o C.

Example 59. 5- {4- [2- (5-4'-Phenylphenoxymethyl-2-thiooxooxazolidin-3-yl) ethoxy] benzyl} thiazolidin-2,4-dione (Compound N 1-209)
the procedure described in Example 4 was repeated, except that 50 mg of 5- {4- [2- (3-4'-phenyl-phenoxy-2-hydroxypropylamino) ethoxy] benzyl} thiazolidine-2,4-dione, 1 ml of anhydrous were used methylene chloride and 22 mg of N, N'-thiocarbonyldiimidazole. The resulting crude product was purified using high resolution reverse phase preparative liquid chromatography (YMC-Rask ODS-A) using an acetonitrile-water mixture (1: 1 to 11: 9 by volume) as an eluent, to give 42 mg of the target compounds, mp 68 - 70 ^o C.

Getting 1. 3-Chlorophenoxymethyloxyran
A 50 ml solution of epibromohydrin (40.96 g) in anhydrous dimethylformamide was added dropwise to a mixture of 35.70 g of 3-chlorophenol, 47.67 g of potassium carbonate and 200 ml of anhydrous dimethylformamide. The resulting mixture was heated at a temperature of 62 ^° C. for 3.5 hours. At the end of this time, dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the resulting residue, and the mixture was extracted with ethyl acetate. Then, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a mixture of ethyl acetate and hexane (1: 4 by volume) as an eluent, to give 43.43 g of the target compound having R _f = 0.45 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 4 by volume).

Obtaining 2.5- (3-Chlorophenoxymethyl) -3-t-butoxycarbonyloxazolidin-2-one
2.18 g of sodium hydride (55% dispersion in mineral oil) was washed with hexane, and then 50 ml of dimethylformamide was added. To the resulting mixture was added dropwise (under ice-cooling) a solution of 13.3 g of di-t-butyl iminodicarboxylate in 60 ml of dimethylformamide. After completion of the addition, another 50 ml of dimethylformamide was added to the mixture. The resulting reaction mixture was stirred at the same temperature for 1 hour, and then at room temperature for 2 hours. At the end of this time, 350 ml of dimethylformamide and 9.2 g of 3-chlorophenoxymethyloxirane (prepared as described in Receiving 1). The resulting mixture was stirred for 2 days at room temperature, and then heated for 3 hours at 70 ^o C. After this time, the reaction mixture was acidified with 2 N. aqueous solution of hydrochloric acid to pH 4, while cooling with ice. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the obtained residue, and then the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was then removed from the extract by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient of a mixture of ethyl acetate and hexane (1: 3 - 3: 1 by volume) as an eluent, to give 9.80 g of the target compound, having a melting point of 116.2 - 124.0 ^o C.

Getting 3. 5- (3-Chlorophenoxymethyl) oxazolidin-2-one
To a solution of 1.97 g of 5- (3-chlorophenoxymethyl) -3-tert-butoxycarbonyloxazolidin-2-one (prepared as described in Preparation 2) in 4 ml of anhydrous tetrahydrofuran, 4 ml of trifluoroacetic acid was added under ice cooling, and the resulting the mixture was stirred at room temperature for one hour. After stirring was completed, tetrahydrofuran and trifluoroacetic acid were removed from the reaction mixture by evaporation under reduced pressure to obtain 1.23 g of the target compound having R _f = 0.43 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 4. Ethyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propionate
0.17 g of sodium hydride (55% (w / w) dispersion in mineral oil) was washed with hexane, and then 15 ml of dimethylformamide was added. To the resulting mixture was added dropwise (under ice-cooling) a solution of 1.85 g of 5- (3-chlorophenoxymethyl) oxazolidin-2-one (prepared as described in Preparation 3) in 10 ml of dimethylformamide. Then, another 50 ml of dimethylformamide was added to this mixture. After the addition, the mixture was stirred at room temperature for 2 hours. To the resulting reaction mixture (under ice-cooling) 1.76 g of ethyl 2-bromopropionate in 5 ml of dimethylformamide was added and this mixture was stirred at room temperature for one hour. After this time, dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a mixture of ethyl acetate and hexane (1: 1 by volume) as an eluent, whereby 1.05 g of the target compound having R _f = 0.38 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane as a developing solvent, 1: 1 by volume).

Getting 5. 2- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
(a) To a solution of 2.95 g of ethyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propionate (obtained as described in Preparation 4) in 25 ml of tetrahydrofuran was added 0.4 g of lithium borohydride (with ice cooling). 0.37 ml of methanol and 5 ml of tetrahydrofuran were added to the resulting mixture, after which this mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and an aqueous solution of sodium chloride was added to the resulting residue, after which the mixture extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was recrystallized from ethyl acetate, resulting in 0.93 g of the target compound, so pl. 114 - 115 ^o C.

 (b) To a solution of 152 mg of 3- (2-t-butyldimethylsilyloxy-1-methylethyl) - 5- (3-chlorophenoxymethyl) oxazolidin-2-one (prepared as described in Preparation 11 (in 1 ml of anhydrous tetrahydrofuran (under ice cooling) 1.2 ml of a 26% by weight solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the resulting mixture was stirred at room temperature for 1.5 hours. After this time, a saturated aqueous solution of sodium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. or anhydrous sodium sulfate, then ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a gradient of a mixture of ethyl acetate and ethanol (1: 0 - 20: 1 by volume) as an eluent. 97 mg of the target compound, the physicochemical properties of which were similar to those of the product obtained in accordance with the procedure described in Preparation 5 (a).

Preparation 6. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
A mixture of 344 mg of tributylphosphine, 15 ml of anhydrous benzene, 654 mg of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione and 429 mg of azodicarbonyldipiperidine was stirred at room temperature for 30 minutes. To the resulting mixture was added a solution of 500 mg of 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol (obtained in accordance with the procedure described in Preparation 5) in 10 ml of benzene. This mixture was stirred overnight, after which the solvent was removed from the reaction mixture by distillation under reduced pressure, and the insoluble matters were removed by filtration. The obtained filtrate was evaporated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 3 by volume) as an eluent, whereby 0.33 g of the target compound was obtained, m.p. 90.9 - 94.0 ^o C.

Getting 7. 2-Benzyloxycarbonylaminopropanol
To a solution of 16.9 g of DL-alanine in 100 ml of anhydrous tetrahydrofuran, 31.3 ml of triethylamine were added dropwise under ice-cooling. After that, 100 g of benzyloxycarbonyl chloride (30–35% solution in toluene) was added to the resulting mixture. The resulting reaction mixture was stirred at room temperature overnight. After this time, tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue. Then this mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an ethyl acetate-hexane mixture as an eluent, to obtain 18.07 g of the target compound having a melting point of 52.2 - 56.6 ^o C.

Preparation 8. Benzyl N- (2-t-butyldimethylsilyloxy-1-methylethyl) carbamate
To a mixture of 16.0 g of 2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 7), 12.39 g of imidazole and 150 ml of dimethylformamide (under ice-cooling) was added dropwise a solution of 13.72 g of t-butyldimethylsilyl chloride in 50 ml dimethylformamide. The resulting mixture was stirred at room temperature for 6.5 hours. At the end of this time, dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, after which the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was then removed from the extract by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 6 by volume) as an eluent, to give 23.89 g of the target compound, having a melting point of 68.0 - 70.2 ^o C.

Preparation 9. 2-t-Butyldimethylsilyloxy-1-methylethylamine
A mixture of 4.0 g of benzyl N- (2-t-butylmethylsilyloxy-1-methylethyl) carbamate (prepared according to the procedure described in Preparation 8), 0.80 g of 10% palladium charcoal and 40 ml of ethanol was charged over an hour hydrogen. At the end of this time, hydrogen was replaced with nitrogen, the palladium carbon was removed by filtration from the reaction mixture, and the obtained filtrate was concentrated by evaporation under reduced pressure, whereby 1.88 g of the target compound having R _f = 0.27 (thin layer chromatography on silica gel) were obtained using a developing mixture of ethyl acetate and hexane, 1: 3 by volume).

Preparation 10. 1- (3-Chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1-methylethylamino) ethanol
A mixture of 1.48 g of 2-t-butyldimethylsilyloxy-1-methylethylamine (obtained as described in Obtaining 9), 1.44 g of 3-chlorophenoxymethyloxirane (obtained as described in Obtaining 1) and 16 ml of ethanol heated under reflux for 24 hours. At the end of this time, ethanol was removed from the reaction mixture by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a gradient of a mixture of ethyl acetate and ethanol (1: 0-10: one of volume). As a result of this procedure, 1.53 g of the target compound was obtained having R _f = 0.30 (thin layer chromatography on silica gel using a 10: 1 by volume mixture of ethyl acetate and ethanol as a developing solvent).

Preparation 11. 3- (2-t-Butyldimethylsilyloxy-1-methylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one
To a solution of 300 mg of 1- (3-chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1-methylethylamino) ethanol (prepared as described in Preparation 10) in 5 ml of dimethylformamide was added 146 mg, N, N ′ β-carbonyldiimidazole and the resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 4 by volume) as an eluent, whereby 287 mg of the target compound (mixture of diastereomers) having R _f = 0.30 and 0 was obtained. 17 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 3 by volume).

Preparation 12. 3- (3-Chlorophenoxy) -2-hydroxypropylazide
To 12 ml of a solution of 0.37 g of 3-chlorophenoxymethyloxirane (prepared as described in Preparation 1) in a mixture of methanol and water (8: 1 by volume) was added 0.65 g of sodium azide and 3 ml of methyl formate. The resulting mixture was stirred for 9 hours at a temperature of 50 ^° C. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the obtained residue, and then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed from the extract by evaporation under reduced pressure, whereby 0.40 g of the target compound was obtained as a colorless oily substance having R _f = 0.19 (thin layer chromatography on silica gel using developing solvent mixture of ethyl acetate and hexane, 1: 4 by volume).

Getting 13. 3- (3-Chlorophenoxy) -2-hydroxypropylamine
To a solution of 0.39 g of 3- (3-chlorophenoxy) -2- (hydroxypropylazide (prepared according to the procedure described in Preparation 12) in 5 ml of anhydrous tetrahydrofuran in a nitrogen gas stream, 0.19 g of lithium aluminum hydrate was gradually added under ice-cooling. Under these conditions, the mixture was stirred for one and a half hours, after which the excess lithium aluminum hydrate was decomposed by adding water, insoluble substances were removed from the reaction mixture by filtration through a pad of Celite (trademark), and the obtained filtrate was dried with anhydrous sodium sulfate. Then, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and 0.15 g of the target compound was obtained in the form of white crystals, mp 55-58 ^° C.

Getting 14. 3-Phenoxy-2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 1.00 g of phenoxymethyloxirane, 1.94 g of sodium azide, 10 ml of methyl formate and 45 ml of a mixture of methanol and water (8: 1 by volume) were used, resulting in 1 30 g of the target compound in the form of a pale yellow oily substance having R _f = 0.26 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 4 by volume).

Getting 15. 3-Phenoxy-2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 1.17 g of 3-phenoxy-2-hydroxypropylazide (prepared as described in Preparation 14), 0.46 g of lithium aluminum hydride and 20 ml of anhydrous tetrahydrofuran in resulting in a gain of 1.09 g of the target compound, so pl. 82 - 84 ^o C.

Preparation 16. 3-Phenyl-2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 5 g of (±) - (2,3-epoxypropyl) benzene, 12.1 g of sodium azide, 60 ml of methyl formate and 270 ml of a mixture of methanol and water were used (8: 1 by volume), whereby 6.03 g of the target compound was obtained in the form of a colorless oily substance having R _f = 0.3 (thin layer chromatography on silica gel using a 1: 4 by volume mixture of ethyl acetate and hexane as a developing solvent).

Getting 17. 3-Phenyl-2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 6.0 g of 3-phenyl-2-hydroxypropylazide (prepared as described in Preparation 16), 2.6 g of lithium aluminum hydrate and 300 ml of anhydrous tetrahydrofuran were used, resulting in a received 5.26 of the target compound, so pl. 64 - 66 ^o C.

Preparation 18. 5- [4- (2-Oxopropylthio) benzyl] thiazolidine-2,4-dione
1.28 g of sodium hydride (55 wt.% Dispersion in mineral oil) was washed with toluene, and then 30 ml of dimethylformamide was added. A solution of 3.2 g of 5- (4-mercaptobenzyl) thiazolidine-2,4-dione in 20 ml of dimethylformamide was added dropwise (under ice cooling) to the resulting mixture. This mixture was stirred at room temperature for 30 minutes. After stirring was completed, 1.69 ml of bromoacetone was added to the reaction mixture under ice cooling. Then, the resulting mixture was stirred at room temperature for 2 hours, after which it was kept overnight. Dimethylformamide was removed by evaporation under reduced pressure, and water was added to the resulting residue. The resulting mixture was acidified with 1 N. an aqueous solution of hydrochloric acid until then, until the pH becomes equal to a value in the range from 2 to 3, after which the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography using ethyl acetate and hexane (2: 3 by volume) as an eluent, and 1.68 g of the target compound was obtained, so pl. 96-102 ^o C.

Preparation 19. 5- [4- (2,2-Diethoxyethoxy) benzyl] thiazolidine-2,4-dione
260 mg of sodium hydride (55 wt.% Dispersion in mineral oil) was washed with toluene, and then 5 ml of dimethylformamide was added. To the resulting mixture, 530 mg of 5- (4-hydroxybenzyl) thiazolidine-2,4-dione were added under ice cooling, and the resulting mixture was stirred for 30 minutes at room temperature. After this time, 0.73 ml of diethyl acetal bromoaldehyde was added to the reaction mixture under ice cooling, and the mixture was stirred for 3 hours at a temperature of 50 ^° C. Dimethylformamide was removed by evaporation under reduced pressure, and water was added to the obtained residue. This mixture was acidified with 1 N. an aqueous solution of hydrochloric acid until then, until the pH becomes equal to a value in the range from 2 to 3, after which the mixture was extracted with ethyl acetate. Then, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 2 by volume as the eluent. As a result of this procedure, 600 mg of the target compound having R _f = 0 was obtained , 46 (thin layer chromatography on silica gel using 1: 2 by volume mixture of ethyl acetate and hexane as a developing solvent).

Preparation 20. 5- [4- (2-Oxoethoxy) benzyl] thiazolidine-2,4-dione
10.07 g of 5- [4- (2,2-diethoxyethoxy) benzyl] thiazolidine-2,4-dione (obtained as described in Preparation 19) was dissolved in 80 ml of tetrahydrofuran and 20 ml of 6 was added to the resulting solution n aqueous hydrochloric acid. Then this mixture was left overnight at room temperature. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the obtained residue, and then the mixture was extracted with ethyl acetate. After that, the extract was dried over anhydrous sodium sulfate, and ethyl acetate was removed from the extract by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (2: 3 by volume) as the eluent, to give 5.92 g of the target compound having R _f = 0.37 (thin layer chromatography on silica gel using as a developing solvent a mixture of ethyl acetate and hexane, 2: 1 by volume).

Getting 21. 2- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
To a solution of 152 mg of 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one (obtained as described in Preparation 11) in 1 ml of tetrahydrofuran dropwise (at ice cooling) 1.2 ml of a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, water and sodium chloride were added to the reaction mixture, after which the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then ethyl acetate was removed from the extract by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and ethanol (1: 0 - 20: 1 by volume) as eluent, and 97 mg of the target compound having R _f = 0.28 (thin layer chromatography on silica gel) was obtained using ethyl acetate as a developing solvent).

Getting 22. (S) -3-Chlorophenoxymethyloxyran
To a mixture of 2.57 g of 3-chlorophenol, 7.86 g of triphenylphosphine and 30 ml of anhydrous benzene, 5.22 g of diethyl azodicarboxylate was added dropwise and the mixture was stirred at room temperature for one hour. Thereafter, 2.01 g of (R) -glycidol was added dropwise to the mixture, and the resulting mixture was left at room temperature for 14 hours. At the end of this time, benzene was removed from the reaction mixture by evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 3 by volume) as eluent. As a result of this procedure, 3.11 g of the target compound was obtained having R _f = 0.42 (thin layer chromatography on silica gel using a 1: 3 by volume mixture of ethyl acetate and hexane as a developing solvent).

Getting 23. (R) -2-Benzyloxycarbonylaminopropanol
To a mixture of 5.00 g of D-alanine, 18.49 potassium carbonate, 15 ml of ethyl acetate and 15 ml of water, 11.42 g of benzyloxycarbonyl chloride was added dropwise. Then, the resulting mixture was stirred for 1.5 hours. At the end of this time, the ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. After that, the ethyl acetate layer and the extract were combined, dried with anhydrous sodium sulfate, and then concentrated by evaporation under reduced pressure. The crude crystal precipitate was collected by filtration and washed with hexane, whereby 13.68 g of the target compound was obtained, mp. 78-80 ^o C.

Getting 24. Benzyl N- [2-t-butyldimethyl-silyloxy-1 (R) -methylethyl] carbamate
The procedure described in Preparation 8 was repeated except that 12.54 g of (R) -2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 23), 9.97 g of t-butyldimethylsilyl chloride, 4.90 g were used imidazole and 150 ml of anhydrous dimethylformamide. Thus, 16.43 g of the target compound was obtained having R _f = 0.54 (thin-layer chromatography on silica gel using a 1: 4 by volume mixture of ethyl acetate and hexane as a developing solvent).

Preparation 25. 2-t-Butyldimethylsilyloxy-1 (R) -methylethylamine
The procedure described in Preparation 9 was repeated except that 16.4 g of benzyl N-2- [t-butyldimethylsilyloxy-1 (R) -methylethyl] carbamate (obtained in accordance with the procedure described in Preparation 24) were used, 3 5 g of 10% palladium-carbon and 100 ml of ethanol, whereby 8.55 g of the target compound is obtained having R _f = 0.27 (thin-layer chromatography on silica gel using a 1: 3 mixture of ethyl acetate and hexane as a developing solvent volume) and having [α] _D = -10.1 ^o (methanol, s = 1.155).

Preparation 26. 1 (S) - (3-Chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1 (R) - methylethylamino) ethanol
The procedure described in Preparation 10 was repeated except that 1.48 g of 2-t-butyldimethylsilyloxy-1 (R) -methylethylamine (prepared as described in Preparation 25), 0.72 g (S) were used -3-chlorophenoxymethyloxirane (prepared as described in Preparation 22) and 10 ml of absolute ethanol, resulting in 1.00 g of the target compound with R _f = 0.24 (thin layer chromatography on silica gel using ethyl acetate as developing solvent) and [α] _D = -14.3 ^° (methanol, s = 1.025).

Preparation 27. 3- [2-t-Butyldimethylsilyloxy-1 (R) -methylethyl] -5 (S) - (3-chlorophenoxymethyl) oxazolidin-2-one
The procedure described in Preparation 11 was repeated except that 0.92 g of 1 (S) - (3-chlorophenoxymethyl) -2- [2-t-butyldimethylsilyloxy-1 (R) -methylethylamino] ethanol (prepared according to with the description given in Obtaining 26), 0.48 g of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide. Thus, 0.92 g of the target compound was obtained having R _f = 0.25 (thin layer chromatography on silica gel using a 1: 2 by volume mixture of ethyl acetate and hexane as a developing solvent) and having [α] _D = +34.1 ^o (methanol, s = 0.960).

Preparation 28. 2 (R) - [5 (S) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
The procedure described in Preparation 5 was repeated except that 0.88 g of 3- (2-t-butyldimethylsilyloxy-1 (R) -methylsilyl) -5 (S) - (3-chlorophenoxymethyl) oxazolidin-2-one was used (obtained as described in Preparation 27), 6.6 ml of tetrabutylammonium fluoride (26% solution in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran, resulting in 0.58 g of the target compound having R _f = 0.45 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent) and having [α] _D = +45.6 ^o (methane l, s = 1,000).

Preparation 29. 5- {4- [2 (R) - (5 (S) - (3-Chlorophenoxymethyl-2-oxooxazolidin-3-yl propoxy] benzyl} -3-triphenylmethylthiazolidin-2,4-dione
The procedure described in Preparation 6 was repeated; except that 0.52 g of 2- (R) - [5 (S) - (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol (prepared as described in Preparation 28) was used ), 1.01 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.44 g of tributylphosphine, 0.55 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene. Thus, 1.02 g of the target compound was obtained having R _f = 0.26 (thin layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as a developing solvent) having [α] _D = +35.9 ^o (methanol, s = 1,000).

Getting 30. (R) -3-Chlorophenoxymethyloxyran
The procedure described in Preparation 22 was repeated, except that 5.14 g of 3-chlorophenol, 4.44 g of (S) -glycidol, 15.72 g of triphenylphosphine, 10.44 g of diethylcarboxylate and 50 ml of anhydrous benzene were used in resulting in 6.43 g of the target compound having R _f = 0.42 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 3 by volume).

Getting 31. (S) -2-Benzyloxycarbonyl-aminopropanol
The procedure described in Preparation 7 was repeated, except that 14.55 g of L-alaninol, 126 ml of a 30-35% solution of benzyloxycarbonyl chloride in toluene, 29.6 ml of triethylamine and 100 ml of anhydrous tetrahydrofuran were used, resulting in 8, 15 g of the target compound, so pl. 79-80 ^o C.

Getting 32. Benzyl N- [2-t-butyldimethyl-silyloxy-1 (S) -methylethyl] carbamate
The procedure described in Preparation 8 was repeated, except that 7.00 g of (S) -2-benzyloxycarbonyl-aminopropanol (prepared as described in Preparation 31), 6.03 g of t-butyldimethylsilyl chloride, 5, 45 g of imidazole and 100 ml of anhydrous dimethylformamide, resulting in 10.52 g of the target compound having R _f = 0.48 (thin layer chromatography on silica gel using 1: 7 by volume ethyl acetate and hexane as a developing solvent).

Preparation of 33.2-t-Butyldimethylsilyloxy-1 (S) -methylethylamine
The procedure described in Preparation 9 was repeated except that 10.22 g of benzyl N- [2-t-butyldimethyl-silyloxy-1 (S) -methylethyl] carbamate (obtained in accordance with the procedure described in Preparation 32) were used. , 2.00 g of 10% palladium on charcoal and 80 ml of ethanol, whereby 5.69 g of the target compound is obtained having R _f = 0.27 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1 : 3 by volume) and having [α] _D = +9.7 ^° (methanol, s = 1.040).

Preparation 34. 1 (R) - (3-Chlorophenoxymethyl) -2- [2-t-butyldimethylsilyloxy-1 (S) - methylethylamino] ethanol
The procedure described in Preparation 10 was repeated, except that 1.51 g of 2-t-butyldimethylsilyloxy-1 (S) -methylethylamine (obtained as described in Preparation 33), 0.74 g (R) was used -3-chlorophenoxymethyloxirane (prepared as described in Preparation 30) and 10 ml of absolute ethanol, resulting in 0.88 g of the target compound having R _f = 0.24 (thin layer chromatography on silica gel using ethyl acetate as developing solvent) and having [α] _D = +15.1 ^° (methanol, s = 1.075 )

Preparation 35. 3- [2-t-Butyldimethylsilyloxy-1 (S) -methylethyl] -5 (R) - (3-chlorophenoxymethyl] oxazolidin-2-one
The procedure described in Preparation 11 was repeated except that 0.82 g of 1 (R) - (3-chlorophenoxymethyl) -2- [2-t-butyldimethylsilyloxy-1 (S) -methylethylamino] ethanol (prepared according to with the procedure described in Preparation 34), 0.43 g of N, N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide, whereby 0.85 g of the target compound having R _f = 0.25 (thin layer chromatography on silica gel using as a developing solvent, a mixture of ethyl acetate and hexane, 1: 2 by volume) and having [α] _D = -33.4 ^o (methanol, s = 1.040).

Preparation 36. 2 (S) - [5 (R) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
The procedure described in Preparation 5 was repeated except that 0.78 g of 3- [2-t-butyldimethylsilyloxy-1 (S) -methylethyl] -5 (R) - (3-chlorophenoxymethyl) -oxazolidine-2- was used it (obtained as described in Preparation 35), 5.85 g of a 26% solution of tetrabutylammonium fluoride in tetrahydrofuran and 10 ml of anhydrous tetrahydrofuran, resulting in 0.52 g of the target compound having so pl. 92-94 ^o C and having [α] _D = -47.8 ^o (methanol, s = 0.980).

Preparation 37. 5- {4- [2 (S) -5 [(R) - (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propoxy] benzyl} -3-triphenylmethylthiazolidin-2,4-dione
The procedure described in Preparation 6 was repeated except that 0.46 g of 2 (S) - [5 (R) - (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol (prepared as described) was used shown in Preparation 36), 0.90 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.39 g of tributylphosphine, 0.49 g of azodicarbonylpiperidine and 30 ml of anhydrous benzene, whereby 0.79 g of the target compound having R _f = 0.26 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent a, 1: 1 by volume) and having [α] _D = -35.3 ^o (methanol, s = 1.015).

Preparation 38. 1 (S) - (3-Chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1 (S) -methylethylamino) ethanol
The procedure described in Preparation 10 was repeated, except that 2.00 g of 2-t-butyldimethylsilyloxy-1 (S) -methylethylamine, 1.92 g of (S) -3-chlorophenoxymethyloxirane (prepared as described above) were used in Preparation 22) and 20 ml of ethanol, resulting in 2.22 g of the target compound having R _f = 0.24 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent) and having [α] _D = +14, 7 ^o (methanol, s = 0.995).

Preparation 39. 3- [2-t-Butyldimethylsilyloxy-1 (S) -methylethyl] -5 (S) - (3-chlorophenoxymethyl) oxazolidin-2-one
The procedure described in Preparation 11 was repeated, except that 2.06 g of 1 (S) - (3-chlorophenoxymethyl) -2- [2-t-butyldimethylsilyloxy-1 (S) -methylethylamino] ethanol (prepared according to with the procedure described in Preparation 38), 1.07 g of N, N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide, whereby 2.11 g of the target compound having R _f = 0.18 (thin layer chromatography on silica gel using as a developing solvent, a mixture of ethyl acetate and hexane, 1: 4 by volume) and having [α] _D = +51.7 ^° (methanol, s = 1.03).

Preparation 40. 2 (S) - [5 (S) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
The procedure described in Preparation 5 (b) was repeated except that 2.00 g of 3- [2-t-butyldimethylsilyloxy-1 (S) -methylethyl] -5 (S) - (3-chlorophenoxymethyl) oxazolidine- was used 2-one (obtained as described in Preparation 39), 15 ml of a 26% solution of tetrabutylammonium fluoride in tetrahydrofuran and 20 ml of anhydrous tetrahydrofuran, resulting in 0.85 g of the target compound having so pl. 67-70 ^o C and having [α] _D = +57.0 ^o (methanol, s = 1,055).

Preparation 41. 5- [4- {2 (S) - [5 (S) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propoxy} benzyl] -3-triphenylmethylthiazolidin-2,4-dione
The procedure described in Preparation 6 was repeated except that 405 mg of tributylphosphine, 25 ml of anhydrous benzene, 700 mg of 2 (S) - [5- (S) - (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl were used ] propanol (prepared as described in Preparation 40), 505 mg of azodicarbonyl dipiperidine and 745 mg of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, whereby 340 mg of the target compound having t .pl. 80-84 ^o C and having [α] _D = +25.9 ^o (methanol, s = 0.96).

Preparation 42. 1 (R) - (3-Chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1 (R) -methylethylamino) ethanol
The procedure described in Preparation 10 was repeated except that 3.00 g of 2-t-butyldimethylsilyloxy-1 (R) -methylethylamine, 2.95 g of (R) -3-chlorophenoxymethyloxirane (prepared as described above) were used in Preparation 30) and 30 ml of ethanol, whereby 3.73 g of the target compound is obtained having R _f = 0.23 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent) and having [α] _D = -15, 6 ^o (methanol, s = 0.990).

Preparation 43. 3- [2-t-butyldimethylsilyloxy-1 (R) -methylethyl] -5 (R) - (3-chlorophenoxymethyl) -oxazolidin-2-one
The procedure described in Preparation 11 was repeated except that 3.45 g of 1 (R) - (3-chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1 (R) -methylethylamino) ethanol (prepared according to with the description given in Preparation 42), 1.78 g of N, N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide, whereby 3.52 g of the target compound having R _f = 0.74 (thin layer chromatography on silica gel using as a developing solvent, a mixture of ethyl acetate and hexane, 1: 1 by volume) and having [α] _D = -53.3 ^° (methanol, s = 1.020).

Preparation 44. 2 (R) - [5 (R) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol
The procedure described in Preparation 5 (b) was repeated except that 3.25 g of 3- [2-t-butyldimethylsilyloxy-1 (R) -methylethyl] -5 (R) - (3-chlorophenoxymethyl) oxazolidine- was used 2-one (obtained as described in Preparation 43), 24 ml of a 26% solution of tetrabutylammonium fluoride in tetrahydrofuran and 30 ml of anhydrous tetrahydrofuran, resulting in 2.28 g of the target compound having so pl. 76-78 ^o C and having [α] _D = -65.4 ^o (methanol, s = 1,060).

Preparation 45. 5- [4- {2 (R) - [5 (R) - (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] propoxy} benzyl] -3-triphenylmethylthiazolidin-2,4-dione
The procedure described in Preparation 6 was repeated, except that 526 mg of tributylphosphine, 25 ml of anhydrous benzene, 900 mg of 2 (R) - [5- (R) - (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl were used ] propanol (prepared as described in Preparation 44), 656 mg of azodicarbonyl dipiperidine and 1.21 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, whereby 0.65 g of the expected compounds having so pl. 74-81 ^o C and having [α] _D = -29.0 ^o (methanol, s = 1,000).

Getting 46. Benzyloxymethyloxyran
4.03 g of sodium hydride (55 wt.% Dispersion in mineral oil) was washed with hexane, and then 200 ml of anhydrous dimethylformamide was added. To the resulting mixture, 20 g of anhydrous benzyl alcohol were added dropwise and under ice-cooling. This mixture was then stirred for one hour at room temperature, after which 15.2 ml of epibromohydrin were added dropwise and under ice-cooling. The resulting mixture was stirred for 1.5 hours, and then left overnight. After this time, dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the obtained residue. After that, the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, ethyl acetate was removed from the reaction mixture by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a gradient of a mixture of ethyl acetate and hexane (1: 6 - 1: 5 by volume) as an eluent, whereby 13 g of the target a compound having R _f = 0.39 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 5 by volume).

Getting 47. 3-Benzyloxy-2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 4.92 g of benzyloxymethyloxiran (prepared according to the procedure described in Preparation 46) were used. 160 ml of methanol and water (8: 1 by volume), 9.75 g of sodium azide and 40 ml of methyl formate, resulting in 5.7 g of the target compound in the form of a pale yellow oily substance having R _f = 0.22 ( thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 5 by volume).

Getting 48. 3-Benzyloxy-2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 5.7 g of 3-benzyloxy-2-hydroxypropylazide (prepared as described in Preparation 47), 2.09 g of lithium aluminum hydride and 250 ml of anhydrous tetrahydrofuran were used, resulting in 3.5 g of the target compound (mp. 72-74 ^° C.) in the form of white crystals.

Preparation 49. 5-Phenylpentyloxymethyloxyran
The procedure described in Preparation 46 was repeated except that 5 g of 5-phenyl-1-pentanol, 4.99 ml of epibromohydrin, 1.31 g of sodium hydride (55% by weight dispersion in mineral oil) and 80 ml of anhydrous were used dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 6 by volume) as an eluent, whereby 4.2 g of the target compound was obtained as a colorless oily substance having R _f = 0.49 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 4 by volume).

Getting 50. 3- (5-Phenylpentyloxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 4.0 g of 5-phenylpentyloxymethyloxirane (prepared as described in Preparation 49), 5.9 g of sodium azide, 160 ml of a mixture of methanol and water were used (8: 1 by volume) and 40 ml of methyl formate, whereby 4.5 g of the target compound was obtained in the form of a pale yellow oily substance having R _f = 0.25 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 4 in volume).

Preparation 51. 3- (5-Phenylpentyloxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 4.5 g of 3- (5-phenylpentyloxy) -2-hydroxypropylazide (prepared as described in Preparation 50), 1.3 g of lithium aluminum hydride and 250 were used ml of anhydrous tetrahydrofuran, resulting in 4.3 g of the target compound as a pale yellow oily substance having R _f = 0.09 (thin-layer chromatography on silica gel using a mixture of ethyl acetate, ethanol and triethylamine as a developing solvent, 10: 2 : 1 by volume_.

Getting 52. 3-Phenylpropoxymethyloxyran
The procedure described in Preparation 46 was repeated except that 8 g of 3-phenyl-1-propanol, 9.64 ml of epibromohydrin, 2.56 g of sodium hydride (55% by weight dispersion in mineral oil) and 100 ml of anhydrous were used dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 6 by volume) as eluent, and 7.2 g of the target compound was obtained as a colorless oily substance having R _f = 0.36 ( thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 5 by volume).

Preparation 53. 3- (3-Phenylpropoxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 5.77 g of 3-phenylpropoxymethyloxirane (prepared as described in Preparation 52), 9.75 g of sodium azide, 160 ml of a mixture of methanol and water were used (8: 1 by volume) and 40 ml of methyl formate, whereby 6.6 g of the target compound are obtained in the form of a pale yellow oily substance having R _f = 0.27 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 5 by volume).

Preparation 54. 3- (3-Phenylpropoxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 6.5 g of 3- (3-phenylpropoxy) -2-hydroxypropylazide) (prepared as described in Preparation 53), 2.1 g of lithium aluminum hydride were used, and 250 ml of anhydrous tetrahydrofuran, whereby 6 g of the target compound are obtained in the form of a pale yellow oily substance having R _f = 0.09 (thin-layer chromatography on silica gel using a mixture of ethyl acetate, ethanol and triethylamine as a developing solvent, 10: 2: 1, by volume).

Getting 55. 2-Phenylethoxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 4.28 g of 2-phenylethanol, 1.68 g of sodium hydride (55% by weight dispersion in mineral oil), 4.1 ml of epibromohydrin and 100 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (8: 1 by volume) as an eluent, to give 4.68 g of the target compound as a colorless oily substance having R _f = 0.77 (thin-layer chromatography on silica gel using a developing mixture of hexane and ethyl acetate, 2: 1 by volume).

Getting 56. 30 (2-Phenylethoxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 4.50 g of 2-phenylethoxymethyloxirane (prepared as described in Preparation 55), 8.20 g of sodium azide, 45 ml of methyl formate and 180 ml of a mixture of methanol were used and water (8: 1 by volume). Thus, 5.49 g of the target compound was obtained in the form of a colorless substance with R _f = 0.70 (thin-layer chromatography on silica gel using 2: 1 by volume mixture of hexane and ethyl acetate as a developing solvent).

Getting 57. 3- (2-Phenylethoxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated except that 5.30 g of 3- (2-phenylethoxy) -2-hydroxypropylazide (prepared as described in Preparation 56), 1.85 g of lithium aluminum hydride and 120 were used ml of anhydrous tetrahydrofuran, resulting in 4.47 g of the target compound as a colorless oily substance having R _f = 0.09 (thin-layer chromatography on silica gel using 10: 1 by volume mixture of ethyl acetate and methanol as a developing solvent).

Getting 58. 4-Phenylbutoxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 5.00 g of 4-phenyl-1-butanol, 1.58 g of sodium hydride (55% by weight dispersion in mineral oil), 3.9 ml of epibromohydrin in 110 were used ml of anhydrous dimethylformamide. The resulting crude product was purified by silica gel column chromatography using an ethyl acetate-hexane mixture (8: 1 by volume) as an eluent to give 3.83 g of the target compound (a colorless oily substance) having R _f = 0.77 (thin-layer chromatography on silica gel using a developing mixture of hexane and ethyl acetate, 2: 1 by volume).

Preparation 59. 3- (4-Phenylbutoxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 3.70 g of 4-phenylbutoxymethyloxirane (prepared as described in Preparation 58), 5.83 g of sodium azide, 37 ml of methyl formate and 135 ml of a mixture of methanol were used and water (8: 1 by volume), resulting in 4.46 g of the target compound as a colorless oily substance having R _f = 0.67 (thin-layer chromatography on silica gel using a mixture of hexane and ethyl acetate as a developing solvent, 2: 1 by volume).

Getting 60. 3- (4-Phenylbutoxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 4.30 g of 3- (4-phenylbutoxy) -2-hydroxypropylazide (prepared as described in Preparation 59), 1.31 g of lithium aluminum hydride and 120 were used. ml of anhydrous tetrahydrofuran, resulting in 3.70 g of the target compound in the form of a colorless oily substance having R _f = 0.08 (thin-layer chromatography on silica gel using a 10: 1 v / v mixture of ethyl acetate and methanol as a developing solvent).

Preparation 61. 6-Phenylhexyloxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 5 g of 6-phenyl-1-hexanol, 4.6 ml of epibromohydrin, 1.23 g of sodium hydride (55% by weight dispersion in mineral oil) and 80 ml of anhydrous were used dimethylformamide. The resulting crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1: 7 by volume) as the eluent, and 4.35 g of the target compound having R _f = 0.60 (thin layer chromatography on silica gel using as a developing solvent, a mixture of ethyl acetate and hexane, 1: 5 by volume) as a colorless oily substance.

Preparation 62. 3- (6-Phenylhexyloxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 4 g of 6-phenylhexyloxymethyloxirane (prepared as described in Preparation 61), 5.5 g of sodium azide, 100 ml of a mixture of methanol and water were used (8: 1 by volume) and 25 ml of methyl formate, as a result of which 4.5 g of the target compound were obtained in the form of a pale yellow oily substance having R _f = 0.39 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 5 by volume).

Preparation 63. 3- (6-Phenylhexyloxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 4.5 g of 3- (6-phenylhexyloxy) -2-hydroxypropylazide (prepared as described in Preparation 62), 1.23 g of lithium aluminum hydride and 150 were used. ml of anhydrous tetrahydrofuran, resulting in 3.14 g of the target compound as a pale yellow oily substance with R _f = 0.12 (thin-layer chromatography on silica gel using a 5: 1 mixture of ethyl acetate, ethanol and triethylamine as a developing solvent: 1 by volume).

Preparation 64. 8-Phenyloctyloxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 4 g of 8-phenyl octyl alcohol, 3.18 g of epibromohydrin, 0.85 sodium hydride (55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, resulting which gave 2.42 g of the target compound having R _f = 0.51 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 6 by volume).

Preparation 65. 3- (8-Phenyloctyloxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 2.4 g of 8-phenyloctyloxymethyloxirane (prepared as described in Preparation 64), 2.97 g of sodium azide, 20 ml of methyl formate and 80 ml of a mixture of methanol were used and water (8: 1 by volume), whereby 2.7 g of the target compound is obtained having R _f = 0.29 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 5 by volume).

Preparation 66. 3- (8-Phenyloxythyloxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 2.6 g of 3- (8-phenylloctyloxy) -2-hydroxypropylazide (prepared as described in Preparation 65), 0.65 g of lithium aluminum hydride and 80 ml were used anhydrous tetrahydrofuran, resulting in a gain of 2.11 g of the target compound having so pl. 50 - 54 ^o C.

Preparation 67. 7-Phenylheptyloxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 2 g of 7-phenylheptyl alcohol, 1.7 ml of epibromohydrin, 0.44 g of sodium hydride (55 wt.% Dispersion in mineral oil) and 50 ml of anhydrous dimethylformamide were used, in resulting in 1.15 g of the target compound having R _f = 0.49 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 6 by volume).

Preparation 68. 3- (7-Phenylheptyloxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 1.1 g of 7-phenylheptyloxymethyloxirane (prepared as described in Preparation 67), 1.4 g of sodium azide, 15 ml of methyl formate and 60 ml of a mixture of methanol were used and water (8: 1 by volume), resulting in 1.27 g of the target compound having R _f = 0.45 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane as a developing solvent, 1: 3 by volume).

Preparation 69. 3- (7-Phenylheptyloxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 1.1 g of 3- (7-phenylheptylcosi) -2-hydroxypropylazide (obtained as described in Preparation 68), 0.287 g of lithium aluminum hydride and 50 ml of anhydrous were used tetrahydrofuran. Thus, 0.82 g of the target compound was obtained having R _f = 0.12 (thin-layer chromatography on silica gel using ethyl acetate, ethanol and triethylamine as a developing solvent, 5: 1: 1 by volume).

Getting 70. 3-Fluorophenoxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 4.00 g of 3-fluorophenol, 1.88 g of sodium hydride (55% by weight dispersion in mineral oil), 6.66 g of epibromohydrin and 50 ml of anhydrous dimethylformamide were used, in resulting in 5.33 g of the target compound having R _f = 0.48 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 4 by volume).

Preparation 71. 1- (3-Fluorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1-methylethylamino) ethanol
The procedure described in Preparation 10 was repeated except that 2.00 g of 2-t-butyldimethylsilyloxy-1-methylethylamine, 1.77 g of 3-fluorophenoxymethyloxirane (prepared according to the procedure described in Preparation 70) and 20 ml were used. ethanol, resulting in 2.13 g of the target compound having R _f = 0.17 (thin-layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 72. 3- (2-t-Butyldimethylsilyloxy-1-methylethyl) -5- (3-fluorophenoxymethyl) oxazolidin-2-one
The procedure described in Preparation 11 was repeated except that 2.00 g of 1- (3-fluorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1-methylethylamino) ethanol (prepared according to the procedure described in Preparation) were used. 71), 20 ml of anhydrous dimethylformamide and 1.09 g of N, N'-carbonyldiimidazole, resulting in 0.74 g of the target compound having R _f = 0.29 (thin-layer chromatography on silica gel using ethyl acetate as a developing solvent and hexane, 1: 3 by volume) from the polar diastereomer. 1.03 g of the title compound was obtained from a less polar diastereomer. 54 - 58 ^o C.

Preparation 73. 2- [5- (3-Fluorophenoxymethyl) oxoxoxolidin-3-yl] propanol
The procedure described in Preparation 5 (b) was repeated except that 0.93 g of 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (3-fluorophenoxymethyl) oxazolidin-2-one (obtained in according to the procedure described in Preparation 72), 9 ml of anhydrous tetrahydrofuran and 7.2 ml of a 26% solution of tetrabutylammonium fluoride in tetrahydrofuran, resulting in 0.63 g of the target compound with R _f = 0.18 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 74. 5- {4- [2- (5-3'-Fluorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
The procedure described in Preparation 6 was repeated except that 364 mg of tributylphosphine, 5 ml of anhydrous benzene, 698 mg of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 454 mg of azodicarbonyl dipiperidine and 489 mg 2 were used - [5- (3-fluorophenoxymethyl) -2-oxooxazolidin-3-yl] propanol (obtained as described in Preparation 73), whereby 0.52 g of the target compound is obtained, m.p. 70 - 77 ^o C.

Preparation 75. 1- (4-Methoxyphenoxymethyl-2- (2-t-butyldimethylsilyloxy-1-methylethylamino-ethanol
The procedure described in Preparation 10 was repeated, except that 3.22 g of 2-t-butyldimethylsilyloxy-1-methylethylamine, 3.00 g of 4-methoxyphenoxymethyloxirane and 30 ml of ethanol were used, resulting in 3.58 g of the target compound having R _f = 0.15 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 76. 3- (2-t-Butyldimethylsilyloxy-1-methylethyl) -5- (4-methoxyphenoxymethyl) oxazolidin-2-one
The procedure described in Preparation 11 was repeated except that 3.36 g of 1- (4-methoxyphenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1-methylethylamino) ethanol (prepared as described in Preparation) was used. 75), 1.78 g of N, N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide. Thus, 1.42 g of the target compound having R _f = 0.41 (thin layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent 1: 2 by volume) was obtained from the polar diastereomer, and 1 was obtained from the less polar diastereomer , 62 g of the target compound having a melting point of 81-85 ^o C.

Preparation 77. 2- [5- (4-Methoxyphenoxymethyl) -2-oxooxazolidin-3-yl] propanol
(a) The procedure described in Preparation 5 (b) was repeated, except that 1.52 g of 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (4-methoxyphenoxymethyl) oxazolidin-2-one was used (less than the polar diastereomer obtained as described in Preparation 76), 12 ml of tetrabutylammonium fluoride (26% solution in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran, whereby 1.20 g of the target compound having t. pl. 80-88 ^o C (from a less polar diastereomer).

(b) The procedure described in Preparation 5 (b) was repeated, except that 1.26 g of 3- (2-t-butyldimethylsilyloxy-1-methylethyl) -5- (4-methoxyphenoxymethyl) oxazolidine-2,4 was used -one (polar isomer obtained as described in Preparation 76), 9.6 ml of a 26% solution of tetrabutylammonium fluoride in tetrahydrofuran and 10 ml of anhydrous tetrahydrofuran. Thus, 0.86 g of the target compound was obtained from the polar diastereomer, so pl. 62-67 ^o C.

Preparation 78. 5- {4- [2- (5-4'-Methoxyphenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
(a) The procedure described in Preparation 6 was repeated, except that 800 mg of 2- [5- (4-methoxyphenoxymethyl) -2-oxooxazolidin-3-yl] propanol (less than the polar isomer obtained as described) was used, in Preparation 77 (a)), 688 mg of tributylphosphine, 30 ml of anhydrous benzene, 1.30 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione and 858 mg of azodicarbonyl dipiperidine, resulting in less polar diastereomers received 0.75 g of the target compound with so pl. 60-66 ^o C.

(b) The procedure described in Preparation 6 was repeated, except that 0.85 g of 2- [5- (4-methoxyphenoxymethyl) -2-oxooxazolidin-3-yl] propanol (polar isomer prepared as described) was used in Preparation 77 (b)), 0.73 g of tributylphosphine, 50 ml of anhydrous benzene, 1.68 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione and 0.91 g of azodicarbonyldipiperidine, c resulting in 0.93 g of the target compound (mp. 85-94 ^° C.) from the polar diastereomer.

Getting 79. 3-Dimethylaminophenoxymethyloxy
The procedure described in Preparation 46 was repeated, except that 4.00 g of 3-dimethylaminophenol, 4.5 ml of epibromohydrin, 153 g of sodium hydride (55% by weight dispersion in mineral oil) and 50 ml of dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1: 4 by volume) as an eluent to obtain 4.18 g of the target compound having R _f = 0.36 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 4 by volume).

Getting 80. 3- (3-Dimethylaminophenoxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 2.0 g of 3-dimethylaminophenoxymethyloxirane (prepared as described in Preparation 79), 3.25 g of sodium azide, 20 ml of methyl formate and 90 ml of a mixture of methanol were used and water (8: 1 by volume), resulting in 2.34 g of the target compound having R _f = 0.35 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 4 by volume).

Getting 81. 3- (3-Dimethylaminophenolphenoxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated, except that 2.41 g of 3- (3-dimethylaminophenoxy) -2-hydroxypropylamide (prepared as described in Preparation 80), 0.76 g of lithium aluminum hydride and 50 were used ml of anhydrous tetrahydrofuran, resulting in 1.80 g of the target compound having R _f = 0.9 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and ethanol, 4: 1 by volume).

Getting 82. 4-Phenylphenoxymethyloxyran
The procedure described in Preparation 46 was repeated except that 4.00 g of 4-phenylphenol, 3.97 g of epibromohydrin, 1.27 g of sodium hydride (55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, resulting in 4.43 g of the target compound having a mp of 80.2 - 82.9 ^o C.

Preparation 83. 3- (4-Phenylphenoxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 3.00 g of 4-phenylphenoxymethyloxirane (prepared according to the procedure described in preparation 82), 4.23 g of sodium azide, 15 ml of methyl formate and 90 ml of a mixture of methanol were used and water (8: 1 by volume), resulting in a received 3.09 g of the target compound having so pl. 72.2 - 73.9 ^o C.

Getting 84. 3- (4-Phenylphenoxy) -2-hydroxypropylamine
Hydrogen was introduced into a mixture of 2.94 g of 3- (4-phenylphenoxy) -2-hydroxypropylazide (prepared as described in Preparation 83), 0.3 g of 10% palladium-carbon, and 60 ml of ethanol over 3 hours. Then, insoluble matters were removed by filtration, and the obtained filtrate was concentrated by evaporation under reduced pressure, whereby 2.84 g of the target compound was obtained, mp. 137.7-146.8 ^o C.

Getting 85. Phenylthiomethyloxyran
To a mixture of 6 ml of epibromohydrin, 5.45 g of sodium hydroxide and 30 ml of 1,4-dioxane was added dropwise at room temperature a solution of 5.0 g of thiophenol in 30 ml of 1,4-dioxane, and the resulting mixture was stirred at room temperature for 36 hours. After this time, insoluble solids were removed by filtration, and 1,4-dioxane was evaporated from the filtrate to give a residue. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After that, ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1:10 by volume) as an eluent. As a result of this procedure, 6.78 g of the target compound was obtained in the form of a colorless oily substance having R _f = 0.60 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1:10 by volume).

Getting 86. 3-Phenylthio-2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 7.2 g of phenylthiomethyloxirane (prepared as described in Preparation 85), 14 g of sodium azide, 65 ml of methyl formate and 270 ml of a mixture of methanol and water were used (8: 1 by volume), resulting in 8.33 g of the target compound (colorless oily substance) with R _f = 0.23 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1:10 by volume).

Getting 87. 3-Phenylthio-2-hydroxypropylamine
The procedure described in Preparation 13 was repeated except that 8 g of 3-phenylthio-2-hydroxypropylazide (prepared as described in Preparation 86), 2.9 g of lithium aluminum hydride and 400 ml of anhydrous tetrahydrofuran were used, resulting which received 6.8 g of the target compound, so pl. 57 - 61 ^o C.

Getting 88. N-methyl-N-phenylaminomethyloxy
The procedure described in Preparation 46 was repeated except that 5 g of N-methylaniline, 7.65 ml of epibromohydrin, 2.44 g of sodium hydride (55% by weight dispersion in mineral oil) and 100 ml of anhydrous dimethylformamide were used, resulting whereby 1.67 g of the target compound are obtained in the form of a pale yellow oily substance having R _f = 0.33 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1:10 by volume).

Preparation 89. 3- (N-Methyl-N-phenylamino) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated, except that 1.65 g of N-methyl-N-phenylaminomethyloxirane (prepared as described in Preparation 88), 3.29 g of sodium azide, 15 ml of methyl formate and 63 were used ml of a mixture of methanol and water (8: 1 by volume), whereby 1.9 g of the target compound are obtained in the form of a pale yellow oily substance having R _f = 0.09 (thin layer chromatography on silica gel using a mixture as a developing solvent ethyl acetate and hexane, 1:15 by volume).

Getting 90. 3- (N-Methyl-N-phenylamino) -2-hydroxypropylamine
To a mixture of 1.85 g of 3- (N-methyl-N-phenylamino) -2-hydroxypropylazide (obtained in accordance with the procedure described in Preparation 89), 0.9 g of 10% palladium on charcoal and 30 ml of ethanol for 1 , 5 hours hydrogen was introduced. After this time, hydrogen was replaced with nitrogen, and palladium-carbon from the reaction mixture was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure to obtain 1.6 g of the target compound, mp. 136 ^o C (decomposition).

Preparation 91. 3-Chlorobenzyloxymethyloxyran
The procedure described in Preparation 46 was repeated, except that 5.00 g of 3-chlorobenzyl alcohol, 1.83 g of sodium hydride (55% by weight dispersion in mineral oil), 3.45 ml of epibromohydrin and 60 ml of anhydrous dimethylformamide were used resulting in 5.45 g of the target compound having R _f = 0.31 (thin layer chromatography on silica gel using a 1: 6 by volume mixture of ethyl acetate and hexane as a developing solvent).

Preparation 92. 3- (3-Chlorobenzyloxy) -2-hydroxypropylazide
The procedure described in Preparation 12 was repeated except that 4.73 g of 3-chlorobenzyloxymethyloxirane (prepared as described in Preparation 91), 7.80 g of sodium azide, 24 ml of methyl formate, 135 ml of a mixture of methanol and water (8: 1 by volume) and 10 ml of water, resulting in 5.74 g of the target compound having R _f = 0.29 (thin-layer chromatography on silica gel using a mixture of ethyl acetate and hexane as a developing solvent, 1: 4 by volume).

Preparation 93. 3- (3-Chlorobenzyloxy) -2-hydroxypropylamine
The procedure described in Preparation 13 was repeated except that 6.22 g of 3- (3-chlorobenzyloxy) -2-hydroxypropylazide (prepared as described in Preparation 92), 1.97 g of lithium aluminum hydride and 120 were used. ml of anhydrous tetrahydrofuran, resulting in 3.37 g of the target compound having R _f = 0.03 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 94. 5- [4- (2-Oxobutoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione
A mixture of 7.37 ml of 1-bromo-2-butanone, 20.0 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 21.18 g of cesium carbonate and 200 ml of anhydrous acetone was stirred for 3 h at room temperature. Then, acetone was removed by evaporation under reduced pressure, whereby a residue was obtained. Water was added to this residue, and the mixture was extracted with ethyl acetate. After that, the extract was washed with an aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. After removal of ethyl acetate by evaporation under reduced pressure, the resulting residue was recrystallized from a mixture of ethyl acetate, diethyl ether and diisopropyl ether, whereby 19.36 g of the target compound was obtained, m.p. 155.2 - 156.4 ^o C.

Preparation 95. 5- [4- (2-Oxobutoxy) benzyl] thiazolidine-2,4-dione
To a solution of 19.3 g of 5- [4- (2-oxobutoxy) benzyl] -3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 94) in 100 ml of methylene chloride was added 50 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for one and a half hours. After concentration by evaporation under reduced pressure, a residue was obtained. Water was added to this residue, and the resulting mixture was neutralized by adding sodium bicarbonate, and then extracted with ethyl acetate. After this, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the obtained residue was chromatographed on a silica gel column using a mixture of ethyl acetate and hexane (1: 2 by volume) as an eluent. Recrystallization from a mixture of ethyl acetate and diisopropyl ether gave 9.55 g of the target compound, having a melting point of 141.5 - 145.7 ^o C.

Preparation 96. Ethyl 2- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanoate
The procedure described in Preparation 4 was repeated except that 1.35 g of sodium hydride (55% by weight dispersion in mineral oil), 6.00 g of 5- (chlorophenoxymethyl) oxazolidin-2-one, 100 ml of anhydrous dimethylformamide were used and 6.48 g of ethyl 2-bromovalerate. The resulting crude product was chromatographed on a silica gel column using a mixture of ethyl acetate and hexane (1: 3 by volume) as eluent. As a result of this procedure, a polar diastereomer and a less polar diastereomer were obtained separately. Thus, 4.5 g of the target compound having R _f = 0.58 (thin layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as the developing solvent) was obtained from the polar diastereomer. From a less polar diastereomer, 4.47 g of the target compound are obtained with mp 43 - 49 ^o C.

Preparation 97. 2- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanol
(a) The procedure described in Preparation 5 was repeated, except that 4.38 g of ethyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanoate (less than the polar isomer obtained in accordance with with the procedure described in Preparation 96), 40 ml of anhydrous tetrahydrofuran, 0.39 g of lithium borohydride and 0.29 g of anhydrous methanol, resulting in a 2.22 g of the target compound having a melting point of less polar isomer. 79 - 81 ^o C.

(b) The procedure described in Preparation 5 was repeated, except that 4.31 g of ethyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanoate (polar isomer obtained in accordance with as described in Preparation 96), 40 ml of anhydrous tetrahydrofuran, 0.42 g of lithium borohydride and 0.31 g of anhydrous methanol, whereby 2.03 g of the target compound was obtained (from the polar diastereomer), mp 98 - 102 ^o C.

Preparation 98. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) pentyloxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
(a) The procedure described in Preparation 6 was repeated, except that 1.00 g of 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanol (less than the polar isomer obtained in accordance with the description in Preparation 97 (a)), 1.07 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.74 g of triphenylphosphine, 0.49 g of diethyl azodicarboxylate and 30 ml of anhydrous tetrahydrofuran, resulting from the less polar diastereomer was obtained 1.58 g of the title compound with R _f = 0,6 (thin layer chromatography on silica gel using Single ETS developing solvent ethyl acetate: hexane, 1: 1 by volume).

(b) The procedure described in Preparation 6 was repeated, except that 1.00 g of 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] pentanol (polar isomer prepared as described) was used in Preparation 97 (b), 0.88 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.73 g of triphenylphosphine, 30 ml of anhydrous tetrahydrofuran and 0.49 g of diethyl azodicarboxylate, as a result then from the polar diastereomer was obtained 1.22 g of the title compound having R _f = 0,57 (TLC on silica gel using kaches ve developing solvent ethyl acetate: hexane, 1: 1 by volume).

Preparation 99. Methyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanoate
The procedure described in Preparation 4 was repeated except that 0.92 g of sodium hydride (55% by weight dispersion in mineral oil), 80 ml of anhydrous dimethylformamide, 4.10 g (5- (3-chlorophenoxymethyl) oxazolidine- 2-one and 4.16 g of methyl 2-bromobisobutyrate, whereby a crude product was obtained, which crude product was purified by silica gel column chromatography using an ethyl acetate-hexane gradient gradient (1: 3 - 1: 2 by volume) ). Thus, 1.05 g of the target compound are obtained from the polar diastereomer, and eyuschego R _f = 0,39 (TLC on silica gel using as developing solvent a mixture of ethyl acetate and hexane, 1: 1 by volume), and from the less polar diastereomer was obtained 1.23 g of the title compound having R _f = 0,48 (thin-layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 1 by volume).

Preparation 100. 2- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] methylbutanol
(a) The procedure described in Preparation 5 was repeated, except that 1.14 g of methyl 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanoate (less than the polar isomer, was used, obtained in accordance with the description given in Preparation 99), 144 mg of lithium borohydride, 12 ml of anhydrous dimethylformamide and 105 mg of anhydrous methanol, resulting in 1.02 g of the target compound having R _f = 0.26 (thin layer chromatography on silica gel using as a developing solvent a mixture of ethyl acetate and hexane, 1: 1 by volume) of the less polar diastereomer.

(b) The procedure described in Preparation 5 was repeated, except that 0.93 g of methyl 2- [5- (3-chlorophenoxymethyl) -2-oxoxazolidin-3-yl] -3-methylbutanoate (polar isomer obtained as described in Preparation 99), 118 g of lithium borohydride, 10 ml of anhydrous tetrahydrofuran and 87 mg of anhydrous methanol, whereby 0.47 g of the target compound having R _f = 0.48 (thin layer chromatography) was obtained from the polar diastereomer on silica gel using a mixture of ethyl acetate and g as a developing solvent eksana, 2: 1 by volume).

Preparation 101. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) -3-methylbutoxy] benzyl} -3-triphenylmethylthiazolidin-2,4-dione
(a) The procedure described in Preparation 6 was repeated, except that 800 mg of 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanol (less than the polar isomer obtained in accordance with as described in Preparation 100 (a)), 656 mg of triphenylphosphine, 20 ml of anhydrous tetrahydrofuran, 791 mg of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione and 435 mg of diethyl azodicarboxylate. Thus, 0.92 g of the target compound was obtained from the less polar diastereomer, mp. 60-66 ^o C.

(b) The procedure described in Preparation 6 was repeated, except that 0.90 g of 2- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] -3-methylbutanol (polar isomer obtained in as described in Preparation 100 (b)), 0.76 g of triphenylphosphine, 0.88 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 20 ml of anhydrous tetrahydrofuran and 0.49 g diethyl azodicarboxylate. As a result of this procedure, 1.22 g of the target compound having R _f = 0.55 (thin layer chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and hexane as the developing solvent) was obtained from the polar diastereomer.

Getting 102. 2-Benzyloxycarbonylamino-2-methylpropanol
The procedure described in Preparation 7 was repeated, except that 7.00 g of 2-amino-2-methylpropanol, 13.47 g of benzyloxycarbonyl chloride, 13.13 g of potassium carbonate, 35 ml of ethyl acetate and 35 ml of water were used. Thus, 17.59 g of the target compound are obtained having R _f = 0.72 (thin-layer chromatography on silica gel using a 3: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

Example 103. Gasoline N- (2-t-butyldimethyl-silyloxy-1,1-dimethylethyl) carbamate
The procedure described in Preparation 8 was repeated, except that 10.00 g of 2-benzyloxycarbonylamino-2-methylpropanol, 7.35 g of imidazole, 150 ml of anhydrous dimethylformamide and 8.14 g of t-butyldimethylsilyl chloride were used, resulting in 14 , 68 g of the target compound having R _f = 0.73 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane 1: 4 by volume as a developing solvent).

Preparation 104. 2-t-Butyldimethylsilyloxy-1,1-dimethylethylamine
The procedure described in Preparation 9 was repeated except that 8.00 g of benzyl N- [2-t-butyldimethylsilyloxy-1,1-dimethylethyl] carbamate (prepared as described in Preparation 103) were used, 1, 60 g of 10% palladium on charcoal and 80 ml of ethanol, resulting in 4.02 g of the target compound having R _f = 0.14 (thin layer chromatography on silica gel using ethyl acetate as eluent).

Preparation 105. 1- (3-Chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1,1-dimethylethylamino) ethanol
The procedure described in Preparation 10 was repeated except that 3.36 g of 2-t-butyldimethylsilyloxy-1,1-dimethylethylamine, 3.05 g of 3-chlorophenoxymethyloxirane and 30 ml of ethanol were used, resulting in 4.54 g target compound, mp 70.5-77.3 ^o C.

Preparation 106. 3- (2-t-Butyldimethylsilyloxy-1,1-dimethylethyl) -5- (3-chlorophenoxymethyl) oxazolidin-2-one
The procedure described in Preparation 11 was repeated, except that 5.13 g of 1- (3-chlorophenoxymethyl) -2- (2-t-butyldimethylsilyloxy-1,1-dimethylethylamino) ethanol (prepared as described above) were used. in Preparation 105), 50 ml of anhydrous dimethylformamide and 2.59 g of N, N'-carbonyldiimidazole. Thus, 5.27 g of the target compound was obtained having R _f = 0.33 (thin layer chromatography on silica gel using a 1: 4 v / v mixture of ethyl acetate and hexane as a developing solvent).

Preparation 107. 5- (3-Chlorophenoxymethyl) -3- (2-hydroxy-1,1-dimethylethyl) oxazolidin-2-one
To a solution of 3.84 g of 3- (2-t-butyldimethylsilyloxy-1,1-dimethylethyl) - 5- (3-chlorophenoxymethyl) oxazolidin-2-one (obtained as described in Preparation 106) in 40 ml of acetonitrile 7 ml of a 5% solution of hydrogen fluoride in acetonitrile was added dropwise. The resulting mixture was stirred at room temperature for one hour. Then, the solvent was removed from the reaction mixture by evaporation under reduced pressure, whereby 2.71 g of the target compound was obtained, mp. 81-82 ^o C.

Preparation 108. 5- (3-Chlorophenoxymethyl) -3- [2- (4-nitrophenoxy) -1,1-dimethylethyl] oxazolidin-2-one
To a solution of 200 mg of 5- (3-chlorophenoxymethyl) -3- (2-hydroxy-1,1-dimethylethyl) oxazolidin-2-one and 288 mg of 4-fluoronitrobenzene in 5 ml of dimethylformamide, 35 mg of sodium hydride was added in three portions with ice cooling (55 wt.% Dispersion in mineral oil). After that, the resulting mixture was stirred at the same temperature for 30 minutes. This mixture was then stirred at room temperature for 7 hours, and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. Then, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, after which the residue was purified by silica gel column chromatography, using a mixture of ethyl acetate and hexane (2: 3) by volume as an eluent. As a result of this procedure received 262 mg of the target compound, so pl. 108-112 ^o C.

Preparation 109. 3- [2- (4-Aminophenoxy) -1,1-dimethylethyl] -5- (3-chlorophenoxymethyl) oxazolidin-2-one
To a solution of 2.34 g of 5- (3-chlorophenoxymethyl) -3- [2- (4-nitrophenoxy) -1,1-dimethylethyl] oxazolidin-2-one (obtained as described in Preparation 108) in 70 ml of a mixture of ethyl acetate and t-butanol (9: 1 by volume) was added 6.32 g of tin chloride dihydrate (2). 0.11 g of sodium borohydride was added to the resulting mixture at a temperature of 66 ^° C. in an oil bath. This mixture was then stirred at the same temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, resulting in the formation of a residue. This residue was neutralized by adding an aqueous solution of sodium bicarbonate. Precipitated insoluble matter was removed by filtration, and the obtained filtrate was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After that, ethyl acetate was removed from the extract by evaporation under reduced pressure, whereby 1.96 g of the target compound was obtained having R _f = 0.34 (thin layer chromatography on silica gel using a 4: 1 mixture of ethyl acetate and hexane as a developing solvent) volume).

Preparation 110. Butyl 2-bromo-3- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) -2-methylpropoxy] phenyl} propionate
To a solution of 2.20 g of 3- [2- (4-aminophenoxy) -1,1-dimethylethyl] -5- (3-chlorophenoxymethyl) oxazolidin-2-one in 25 ml of acetone was added dropwise (under ice-cooling), 82 g of a 47% aqueous solution of hydrogen bromide, and then 2 ml of an aqueous solution of 462 mg of sodium nitrite was added to the resulting mixture. The resulting mixture was stirred at the same temperature for 15 minutes, and then 7.18 g of butyl acrylate and 157 mg of copper oxide (1) were added at room temperature. After this, the resulting mixture was stirred at room temperature for 2.5 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, the resulting residue was neutralized by the addition of an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, whereby a residue was obtained. This residue was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and hexane (1: 3 - 1: 1 by volume) as an eluent, to give 2.24 g of the target compound having R _f = 0.44 ( thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 1: 2 by volume).

Preparation 111. 5- {4- [2- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) -2-methylpropoxy] benzyl} -2-iminothiazolidin-4-one
To a solution of 2.07 g of butyl 2-bromo-3- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) -2-methylpropoxy] phenyl} propionate (prepared as described shown in Preparation 110) in 30 ml of methanol was added 0.5 g of thiourea. 0.49 g of sodium acetate was added to the resulting mixture. The resulting mixture was then heated under reflux for 5 hours, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. A saturated aqueous solution of sodium chloride was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography using a gradient of a mixture of ethyl acetate and tetrahydrofuran (1: 0 - 3: 1 by volume) as an eluent. As a result of this procedure, 1.50 g of a mixture of the target compound (R _f = 0.19, thin-layer chromatography on silica gel using ethyl acetate as a developing solvent) and thiourea were obtained.

 Preparation 112. 5-Phenoxymethyloxazolidin-2-one.

To a solution of 500 mg of 3-phenoxy-2-hydroxypropylamine in 5 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole was added under ice-cooling. The resulting mixture was stirred at room temperature overnight. After this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting concentrate. The mixture was then extracted with ethyl acetate and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, whereby a residue was obtained. This residue was purified by silica gel column chromatography (eluent ethyl acetate) to obtain 490 mg of the target compound, mp. 110-111 ^o C.

 Preparation 113. Ethyl 3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propionate.

The procedure described in Preparation 4 was repeated, except that 113 mg of sodium hydride (55% by weight dispersion in mineral oil), 10 ml of anhydrous dimethylformamide, 420 mg of 5-phenoxymethyloxazolidin-2-one (obtained as described recited in Preparation 112) and 471 mg of ethyl 3-bromopropionate. Thus, 463 mg of the target compound was obtained having R _f = 0.34 (thin layer chromatography on silica gel using a 2: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

 Preparation 114. 3- (5-Phenoxymethyl-2-oxooxazolidin-3-yl) propanol.

The procedure described in Preparation 5 (a) was repeated except that 1.64 g of ethyl 3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propionate (prepared according to the procedure described in Preparation 113) were used 15 ml of anhydrous tetrahydrofuran, 244 mg of lithium borohydride and 179 ml of anhydrous methanol, resulting in 1.41 g of the target compound having R _f = 0.28 (thin-layer chromatography on silica gel using ethyl acetate as a developing solvent).

 Preparation 115. 5- {4- [3- (5-Phenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione.

The procedure described in Preparation 6 was repeated, except that 1.29 g of tributylphosphine, 30 ml of anhydrous benzene, 2.98 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 1.61 were used g of azodicarbonyl dipiperidine and 1.33 g of 3- (5-phenoxymethyl-2-oxooxazolidin-3-yl) propanol (prepared as described in Preparation 114). Thus, 2.04 g of the target compound was obtained, mp. 70-73 ^o C.

Preparation 116. Ethyl 4- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] butyrate
The procedure described in Preparation 4 was repeated, except that 0.52 g of sodium hydride (55 wt%, dispersion in mineral oil), 30 ml of anhydrous dimethylformamide, 2.00 g of 5- (3-chlorophenoxymethyl) oxazolidine- were used 2-one and 2.34 g of ethyl 4-bromobutyrate. Thus, 1.50 g of the target compound was obtained having R _f = 0.39 (thin layer chromatography on silica gel using a 2: 1 by volume mixture of ethyl acetate and hexane as a developing solvent).

Preparation 117. Ethyl 4- [5- (3-Chlorophenoxymethyl) -2-oxooxazolidin-3-yl] butanol
The procedure described in Preparation 5 was repeated except that 1.43 g of ethyl 4- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] butyrate (prepared as described in Preparation 116) was used. ), 183 mg of sodium borohydride, 20 ml of anhydrous tetrahydrofuran and 135 ml of anhydrous methanol. As a result of this procedure, 1.26 g of the target compound was obtained having R _f = 0.31 (thin layer chromatography on silica gel using ethyl acetate as a developing solvent).

Preparation 118. 5- {4- [4- (5-3'-Chlorophenoxymethyl-2-oxooxazolidin-3-yl) butoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
The procedure described in Preparation 6 was repeated, except that 647 mg of tributylphosphine, 20 ml of anhydrous benzene, 1.49 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 807 mg of azodicarbonyl dipiperidine and 800 were used mg 4- [5- (3-chlorophenoxymethyl) -2-oxooxazolidin-3-yl] butanol (prepared as described in Preparation 117). The result of this procedure was obtained 1.49 g of the target compound, so pl. 68-72 ^o C.

Preparation 119. 2-Chloroacetamido-1- (3-chlorophenoxymethyl) ethanol
To a solution of 300 mg of 3- (3-chlorophenoxy) -2-hydroxypropylamine in 4 ml of anhydrous tetrahydrofuran was added a solution of 0.24 ml of triethylamine in 1 ml of anhydrous tetrahydrofuran under ice-cooling. Then, 1 ml of a solution of 192 mg of chloroacetyl chloride in anhydrous tetrahydrofuran was added dropwise to the resulting reaction mixture. After that, the reaction mixture was stirred for 3 hours at room temperature. After this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and a residue was obtained. Water was added to this residue, after which the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a mixture of ethyl acetate and hexane (3: 2 by volume) as an eluent. As a result of this procedure, 310 mg of the target compound was obtained having a melting point of 74-77 ^o C.

Getting 120. Ethyl 2- [6- (3-chlorophenoxymethyl) -3-oxomorpholin-4-yl] propionate
To a solution of 2.49 g of sodium hydride (55% by weight dispersion in mineral oil) in 170 ml of dimethylformamide at a temperature of 65 ^° C. in a oil bath was added dropwise a solution of 5.50 g of 2-chloroacetamido-1- (3-chlorophenoxymethyl) ethanol (obtained as described in Preparation 119) in 110 ml of dimethylformamide. After that, the resulting reaction mixture was stirred at the same temperature for one hour. Then, 5.25 g of ethyl 2-bromopropionate was added dropwise to the reaction mixture and under ice-cooling, and this mixture was stirred for one day. After this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, whereby a residue was obtained. Water was added to this residue, and the mixture was extracted with ethyl acetate. Then, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by evaporation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, using a gradient of a mixture of ethyl acetate and hexane (1: 2 - 3: 2 by volume) as an eluent. As a result of this procedure, 4.23 g of the target compound was obtained having R _f = 0.39 (thin layer chromatography using ethyl acetate as a developing solvent).

Preparation 121. 2- [2- (3-Chlorophenoxymethyl) morpholino] propanol
To a suspension of 0.51 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran was added dropwise and under ice-cooling a solution of 1.50 g of ethyl 2- [6- (3-chlorophenoxymethyl) -3-oxomorpholin-4-yl] propionate in 10 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 2.5 hours, after which the excess lithium aluminum hydride was decomposed by adding sodium sulfate decahydrate to the mixture. Insoluble substances were removed from the reaction mixture using a filtration accelerator (Celite ^R , trademark), after which the solvent was removed from the filtrate by evaporation under reduced pressure, whereby 0.97 g of the target compound having R _f = 0.19 (thin layer chromatography on silica gel using a developing mixture of ethyl acetate and hexane, 3: 1 by volume).

Preparation 122. 5- {4- [2- (2-3'-Chlorophenoxymethylmorpholino) propoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione
The procedure described in Preparation 6 was repeated except that 1.21 g of triphenylphosphine, 20 ml of anhydrous tetrahydrofuran, 1.77 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.81 were used g of diethyl azodicarboxylate and 1.32 g of 2- [2- (3-chlorophenoxymethyl) morpholino] propanol (obtained in accordance with the procedure described in Preparation 121). Thus, 1.32 g of the target compound is obtained having a melting point of 48-53 ^o C.

Additional biological data (Hyperlipemic activity)
With hyperlipemia in the blood, the level of triglyceride, which is one of the serum lipids, increases. Accordingly, the degree of hyperlipemia can be estimated by measuring the amount of triglyceride in the blood.

 The experimental animals were male F344 rats. Each group of animals contained 5 animals, and the animals were used for the experiment when they reached the age of 7 weeks. Each test subject was given an oral test compound mixed with a carrier (0.5% CMC) at a dose of 50 mg / mg / day for 2 weeks. At the same time, another group of 5 animals (control group) was given orally only the vehicle. After administration of the test agents to rats for 2 weeks, blood was taken from each rat. Blood serum was separated and triglyceride levels were measured using an automatic analyzer (type 736, manufactured by Hitachi Ltd.). The results are summarized in table. ten.

 As can be seen from the above table. 10 results, compounds of the invention showed a decrease in triglyceride levels.

Claims (1)

 \ \ \ 1 1. Thiazolidine derivatives of the formula I \\\ 6 $$$ \\\ 1 in which R <M ^> 1 <D> and R <M ^> 2 <D> are the same or different and each represents an atom hydrogen or an alkyl group having from 1 to 8 carbon atoms; \\\ 4 R <M ^> 3 <D> - hydrogen atom; \\\ 4 A and B are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms or \\\ 4 A and B together represent a group of the formula \\\ 6 $$$ $$$ or -CH <Mv> 2 <D> CH <Mv> 2 <D> -; \\\ 4 X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 <D> -, \ \\ 1 in which W - a phenyl group which is unsubstituted or substituted by at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, a halogen atom, phenyl groups and groups of the formula \\\ 6 -NR <M ^> a <D> R <M ^> b <D>, \\\ 1 in which R <M ^> a <D> and R <M ^> b <D> are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms; \\\ 4 X <M ^> 1 <D> is a single bond, an oxygen atom, a sulfur atom or a group of the formula >> NR <M ^> 4 <D>, in which R <M ^> 4 <D> is alkyl a group having 1 to 8 carbon atoms; \\\ 4 m - 0 or an integer from 1 to 8; \\\ 4 Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) <Mv> n <D> - Y <M ^> 1 <D> - \\\ 1 in which Y <M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 n - an integer from 1 to 5; \\\ 4 z is a group of formula i \\\ 6 $$$ \ \ \ 1 in which R <M ^> 5 <D> is a hydrogen atom, \\\ 1 and their salts. \\\ 2 2. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are the same or different and each represents a hydrogen atom or an alkyl group having 1 - 6 carbon atoms. \\\ 2 3. The thiazolidine derivative according to claim 1, wherein A and B are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or A or B together represent a group of formulas \\\ 6 $$$ or -CH <Mv> 2 <D> CH <Mv> 2 <D> -. \\ \ 2 4. The thiazolidine derivative according to claim 1, wherein X represents a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 < D> -, \\\ 1 in which W is a phenyl group which is unsubstituted or substituted by 1-3 substituents selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms , phenyl groups and groups of the formula \\\ 6 -NR <M ^> a <D> R <M ^> b <D>, \\\ 1 in which R <M ^> a <D> and R <M ^ > b <D> are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula \\\ 6 -N (-R <M ^> 4 <D>) -, \\\ 1 in which R <M ^> 4 <D> is an alkyl group having 1 to 4 carbon atoms; \\\ 4 m - 0 or an integer from 1 to 8. \\\ 2 5. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; \\\ 4 A and B are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or A or B together form a group of the formula \\\ 6 $$$ or -CH <Mv> 2 <D> CH <Mv> 2 <D> -; \\\ 4 X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 <D> -, \\\ 1 in which W - a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, halogen atoms, phenyl groups and groups of the formula \\\ 6 -NR < M ^> a <D> R <M ^> b <D>, \\\ 1 in which R <M ^> a <D> and R <M ^> b <D> are the same or different and each represents an atom hydrogen or an alkyl group having 1 to 8 carbon atoms; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula \\\ 6 -N (-R <M ^> 4 <D>) -, \\\ 1 in which R <M ^> 4 <D> is an alkyl group having 1 to 4 carbon atoms; \\\ 4 m - 0 or an integer from 1 to 8; \\\ 4 Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) <Mv> n <D> -Y <M ^> 1 <D> -, \\\ 1 in which Y < M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 n - an integer from 1 to 5; \\\ 4 Z is a group of the formula Vii \\\ 6 $$$ \\\ 2 6. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are the same or different and each represents a hydrogen atom or an alkyl group having 1-4 carbon atoms. \\\ 2 7. The thiazolidine derivative according to claim 1, wherein A and B are the same or different and each represents a hydrogen atom or a methyl, ethyl or propyl group, or A and B together form a group of the formula $$$ or -CH <Mv > 2 <D> CH <Mv> 2 <D> -. \\\ 2 8. The thiazolidine derivative according to claim 1, wherein X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 < D> -, \\\ 1 in which W represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, halogen atoms, phenyl groups and groups of the formula \\\ 6 -NR <M ^> a <D> R <M ^> b <D>, \\\ 1 in which R <M ^> a <D> and R <M ^> b <D> are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula \\\ 6 -N (-R <M ^> 4 <D>) -, \\\ 1 in which R <M ^> 4 <D> is a methyl, ethyl or propyl group; \\\ 4 m - 0 or an integer from 1 to 6. \\\ 2 9. The thiazolidine derivative according to claim 1, in which Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) < Mv> n <D> - Y <M ^> 1 <D> -, \\\ 1 in which Y <M ^> 1 <D> is an oxygen atom or a sulfur atom, \\\ 4 n is an integer from 1 up to 5. \\\ 2 10. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are the same or different and each represents a hydrogen atom or an alkyl group, having 1 to 4 carbon atoms; \\ \ 4 A and B are the same or different and each represents a hydrogen atom, a methyl, ethyl or propyl group, or A and B together form a group of the formula \\\ 6 $$$ or -CH <Mv> 2 <D> CH <Mv> 2 <D> -; \\\ 4 X is a group of the formula \ \ \ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 <D> -, \\\ 1 in which W - a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, halogen atoms, phenyl groups, and groups of the formula \\\ 6 -NR <M ^> a <D> R <M ^> b <D>, \\\ 1 in which R <M ^> a <D> and R <M ^> b <D> are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula \\\ 6 -N (-R <M ^> 4 <D>) -, \\\ 1 in which R <M ^> 4 <D> is a methyl, ethyl or propyl group; \ \ \ 4 m - 0 or an integer from 1 to 6; \\\ 4 Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) <Mv> n <D> - Y <M ^> 1 <D> -, \\\ 1 in which Y < M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 n - an integer from 1 to 5; \\\ 4 Z has the meanings defined in paragraph 1. \\\ 2 11. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are both a hydrogen atom or one of them is a hydrogen atom and the other is alkyl a group having 1 to 4 carbon atoms. \\\ 2 12. The thiazolidine derivative according to claim 1, wherein A and B are the same or different and each represents a hydrogen atom, a methyl or ethyl group, or A and B together form a group of the formula \\\ 6 $$$ or CH < Mv> 2 <D> CH <Mv> 2 <D> -. \\\ 2 13. The thiazolidine derivative according to claim 1, wherein X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 < D> -, \\\ 4 in which W is a phenyl group which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen atoms and methyl, ethyl, phenyl, amino, dimethylamino, methoxy and ethoxy groups; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula \\\ 6 -N (Me) -; \\\ 4 m - 0 or an integer from 1 to 6. \\\ 2 14. The thiazolidine derivative according to claim 1, wherein Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) < Mv> n <D> - Y <M ^> 1 <D> -, \\\ 1 in which Y <M ^> 1 <D> is an oxygen atom or a sulfur atom; \\\ 4 n is an integer from 1 to 3. \\\ 2 15. The thiazolidine derivative of claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> both represent an atom hydrogen or one of them represents a hydrogen atom, and the other represents an alkyl group having 1 to 4 carbon atoms; \\\ 4 A and B are the same or different and each represents a hydrogen atom, a methyl or ethyl group, or A and B together form a group of formulas \\\ 6 $$$ or -CH <Mv> 2 <D> CH <Mv> 2 <D> -; \\\ 4 X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 <D> -, \\\ 1 in which W - a phenyl group which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen atoms and methyl, ethyl, phenyl, amino, dimethylamino, methoxy and ethoxy groups; \\\ 4 X <M ^> 1 <D> - a single bond, an oxygen atom, a sulfur atom or a group of the formula -N (Me) -; \\\ 4 m - 0 or an integer from 1 to 6; \\\ 4 Y is a group of the formula \\\ 6 - (CH <Mv> 2 <D>) <Mv> n <D> - Y <M ^> 1 <D> -, \\\ 1 in which Y < M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 n is an integer from 1 to 3; \\\ 4 Z is a group of formula Vii \\\ 6 $$$ \\\ 2 16. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> both are a hydrogen atom or one of them is a hydrogen atom, and the other is a metal, ethyl, propyl or isopropyl group. \\\ 2 17. The thiazolidine derivative according to claim 1, wherein A is a hydrogen atom and B is a hydrogen atom, a methyl or ethyl group, or A and B together form a group of the formula $$$. \\\ 2 18. The thiazolidine derivative according to claim 1, wherein X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 < D> -, \\\ 1 in which W is a halogen-substituted phenyl group, phenylphenyl, methoxyphenyl or phenyl group; \\\ 4 X <M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 m - 0 or an integer from 1 to 6. \\\ 2 19. The thiazolidine derivative according to claim 1, wherein Y is a group of the formula \\\ 6 -CH <Mv> 2 <D> O- or - (CH <Mv> 2 <D>) <Mv> 2 <D> O-. \\\ 2 20. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are both a hydrogen atom or one of them is a hydrogen atom and the other is methyl an ethyl, propyl or isopropyl group; \\\ 4 A is a hydrogen atom and B is a hydrogen atom or a methyl or ethyl group, or A and B together form a group of the formula $$$; \\\ 4 X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> - X <M ^> 1 <D>, \\\ 1 in which W - halogen-substituted phenyl group, phenylphenyl, methoxyphenyl or phenyl group; \\\ 4 X <M ^> 1 <D> - oxygen atom or sulfur atom; \\\ 4 m - 0 or an integer from 1 to 6; \\\ 4 Y is a group of the formula -CH <Mv> 2 <D> O- or - (CH <Mv> 2 <D>) <Mv> 2 <D> O-; \\\ 4 Z is a group of the formula Vii \\\ 6 $$$ \\\ 2 21. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> both are a hydrogen atom or one of them is a hydrogen atom, and the other is a methyl or ethyl group. \\\ 2 22. The thiazolidine derivative according to claim 1, wherein A is a hydrogen atom and B is a hydrogen atom or a methyl group, or A and B together form a group of formulas $$$ \\\ 2 23. The thiazolidine derivative according to claim 1 in which X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D>) <Mv> m <D> -O-, \\\ 1 in which W is phenyl, 3-chlorophenyl, 4- a chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl or 4-phenylphenyl group; \\\ 4 m is 0 or an integer from 1 to 6. \\\ 2 24. The thiazolidine derivative according to claim 1, wherein Y is a group of the formula -CH <Mv> 2 <D> O-. \\\ 2 25. The thiazolidine derivative according to claim 1, wherein R <M ^> 1 <D> and R <M ^> 2 <D> are both a hydrogen atom or one of them is a hydrogen atom and the other is methyl or ethyl group; \\\ 4 R <M ^> 3 <D> - hydrogen atom; \\\ 4 A is a hydrogen atom and B is a hydrogen atom or a methyl group, or A and B together form a group of formulas $$$ \\\ 4 X is a group of the formula \\\ 6 W - (CH <Mv> 2 <D> ) <Mv> m <D> -O- \\ \ 1 in which W is a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl or 4-phenylphenyl group; \\\ 4 m - 0 or an integer from 1 to 6; \\\ 4 Y is a group of the formula: -CH <Mv> 2 <D> O-; \\\ 4 Z is a group of the formula Vii \\\ 6 $$$ \\\ 2 26. The thiazolidine derivative according to claim 1, which is: \\\ 2 5- {4- [2- (3-phenyl-2 β-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione; \\\ 2 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) ethoxy] benzyl} thiazolidine-2,4-dione; \\\ 2 5- {4- [2- (5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) propoxy] benzyl} thiazolidine-2,4-dione; \\ \ 2 5- {4- [2- (5-3'-chlorophenoxymethyl-2-thioxoxoxazolidin-3-yl) propoxy] benzyl} thiazolidin-2,4-dione; \\\ 2 5- {4- [2- (3-6'-phenylhexyloxy-2-hydroxypropylamino) propoxy] benzyl} thiazolidine-2,4-dione and \\\ 2 5- {4- [2- ( 5-3'-chlorophenoxymethyl-2-oxooxazolidin-3-yl) butoxy] benzyl} thiazolidin-2,4-dione, \\\ 1 and their salts. \\\ 2 27. A pharmaceutical composition having hypoglycemic and hypolipemic activity and activity of inhibiting aldose reductase, which comprises an effective amount of the active compound in admixture with a pharmaceutically acceptable carrier or diluent, characterized in that it contains at least one thiazolidine derivative as active compound according to any one of paragraphs. 1 - 26. \\\ 2 28. A method for the treatment or prophylaxis of diseases of mammals subjected to treatment of a compound having hypoglycemic or hypolipemic activity or activity of inhibiting aldose reductase, the method comprising administering to said mammal an effective amount of an active compound, characterized in that the active compound is used according to at least one thiazolidine derivative according to any one of claims 1 to 26.

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