Derivatives of oxazolidine, or their pharmaceutically acceptable salts, or esters and method of production thereof

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with hypoglycemic activity. The essence of the invention: derivatives of oxazolidine formulae 1; where R is C1-C8-alkyl, X Is S or O, Y is H or a group-A-COOW where A-C1-C6-alkylen, W-H or C1-C6-alkyl, Ar-aryl group containing 6-10 carbon atoms in the ring, possibly substituted with halogen, halo/ C1-C4/ by alkyl, hydroxy-group, C1-C4-alkyl, C1-C4-alkoxy group, or their salts or esters. Method for obtaining compounds of formula I. 2s. and 19 C. p. F.-ly, 6 ill., table 4.

The present invention relates to a series of new derivatives of oxazolidine that are valuable anti-inflammatory properties and action against obesity and include compounds suitable for use in the treatment or prevention of hyperlipidemia and hyperglycemia and, due to the inhibiting action alsoreported, can be effective in the treatment and prevention of complications of diabetes. They are also effective for the treatment and prevention of obesity-related hypertension and osteoporosis. The invention also provides methods for obtaining Aetna derivative of thiazolidine, are structurally related to the compounds of the present invention are effective for reducing blood sugar. Such compounds are described, for example, in the patent application of Japan Kokai No. Sho 55-22636 (Tokyo No. Sho 62-42903); in the application to the Japan patent Kokai No. Sho 60-51189 (Tokyo No. Hei 2-31079); Kawamafsu et al. Chem. Pharm. Bull. 30, (1982) 3580-3600 and in the publication of the European patent N 441605.

Publication of the European patent N 294995 and the application for the patent cooperation Treaty PCT WIPO 92/07838, which, as acknowledged by all, represent the latest in technology, reveal connections that structure similar to the compounds of the present invention. The connection of these two documents, reflecting the level of technology, which are thought to be structurally similar to the compounds of the present invention of formulas (M) and (N) below. The compound of formula (M), which is a 3-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenyl] -1-methylethyl} -5-(3-chlorophenyl)oxazolidin-2-it is described in the published European patent N 294995. The compound of formula (N), which is a 3-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] ethyl} -5-phenyloxazolidine-2-it is described in the application for the patent cooperation Treaty PCT WIPO 92/07838.

We have now discovered a restrictive number of new derivatives of oxazolidine, which have valuable anti-inflammatory activity and action against obesity, being also suitable for the treatment of conditions associated with obesity and diabetes, and which have low toxicity.

Therefore, the aim of the present invention is to provide a series of compounds of this type.

Another and more specific objective of the present invention to provide such compounds which possess antidiabetic activity and action against obesity and, preferably, have a low toxicity.

Another objective of the present invention is to provide methods and compositions in which these compounds are used.

Other objectives and advantages will become clear in the course descriptions.

Compounds of the present invention are compounds of formula (I)

< / BR>
in which

R represents an alkyl group containing from 1 to 8 carbon atoms;

X represents an oxygen atom or a sulfur atom;

Y represents a hydrogen atom or a group of the formula A-COOH, in which A represents alkylenes group, containing what about the 10 ring carbon atoms, or substituted aryl group which contains 6 to 10 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents (a);

said substituents (a) are selected from the group consisting of halogen atoms; halogenating groups in which the alkyl part contains 1 to 4 carbon atoms; hydroxyl groups; alkyl groups containing from 1 to 4 carbon atoms; and alkoxygroup containing from 1 to 4 carbon atoms; and their pharmaceutically acceptable salts and esters.

The invention also provides a pharmaceutical composition for the treatment or prevention of diabetes, obesity, hyperlipemia, hyperglycemia, diabetic complications, obesity-related hypertension and osteoporosis, and this composition contains an effective amount of the active compound in a mixture with a pharmaceutically acceptable carrier or diluent, in which the active compound selected from the group consisting of compounds of the formula (I)and their pharmaceutically acceptable salts and esters.

The invention also provides a method of treatment or prevention of diabetes, obesity, hyperlipemia, hyperglycemia, diabetic complications, obesity-related gidani said mammal an effective amount of an active compound, which are selected from the group consisting of compounds of the formula (I) and their pharmaceutically acceptable salts and esters.

The invention also provides methods for producing compounds of the present invention, which are hereinafter described in more detail.

In the compounds of the present invention, in which R represents an alkyl group, this alkyl group may be an alkyl group with straight or branched chain, containing from 1 to 8 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 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-trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 3,3-dimethylpentyl, octyl, 1-methylheptan, 2-ethylhexyl 1,1,3,3-TETRAMETHYLBUTYL. When P represents an alkyl group, such a group preferably is an alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, and more predpochtitel is, in particular, a methyl or ethyl group.

When And represents alkylenes group, it may be Allenova group with a straight or branched chain, containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of such groups are methylene, ethylene, utilizinga, trimethylene, propylidene, 1-metilidinovy, 2-metilidinovy, tetramethylene, 1-methyltrienolone, 2-methyltrienolone, 3-methyltrienolone, isopropylidene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, pentamethylene, 1-mediterraneita, 2-metiluratilovaya, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-methyl-2-ethylethylene, 1,2,2-trimethylethylene, 1-propylethylene, hexamethylene, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentanediol, 5-methylpentadiene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 1,4-dimethyltrimethylene, 1-atinternational, 2-atinternational, 1-methyl-2-ethyldimethylamine, 2-methyl-2-ethyldimethylamine, 2-propertiesfilename, 1,1-diethylethylene, 1,2-diethylethylene or 1-methyl-2-propylethylene group.

When the a is aryl group, containing from 6 to 10 carbon atoms; more preferably, when such a group represents a phenyl, 1-naftalina or 2-naftalina group; and more preferably, when such a group is phenyl or 2-naphthyl. When Ar represents a substituted aryl group, which is substituted by at least one Deputy, selected from the group consisting of substituents (a), preferably, when such aryl group substituted by one to five mentioned substituents, and most preferably, when she replaced one of the three mentioned substituents. When ariannol group there is more than one substituent, these substituents may be the same or different.

When the substituent (a) represents an alkyl group, this may be an alkyl group with straight or branched chain, containing from 1 to 4 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

When the substituent (a) represents alkoxygroup, it may be alkoxygroup straight or branched chain, containing from 1 to 4 carbon atoms. Examples of such groups are methoxy, ethoxy-, propoxy-, isopro the t halogenating group, the alkyl component may represent a straight or branched chain and contain from 2 to 4 carbon atoms, in particular 1 to 2 carbon atoms, and preferably contains from 1 to 3 halogen atoms that can be the same or different. Examples of such groups are trifluoromethyl, trichloromethyl, deformity, dichloromethyl, dibromomethyl, 2,2,2-trichloroethyl, 2-foretel, 2,2-dibromoethyl, 3-chloropropyl, 3,3,3-cryptochromes and 4-terbutyl, of which preferred are alkyl groups containing from 1 to 3 carbon atoms, which is substituted by 1 to 3 halogen atoms (and, when atoms of halogen 2 or 3, they are the same), more preferably, when it is a methyl or ethyl group substituted by 1 to 3 fluorine atoms or chlorine; special, the most preferred group is triptorelin group.

When the substituent (a) represents a halogen atom, this may be a fluorine atom, a chlorine, iodine or bromine, preferably chlorine atom or fluorine.

Examples of Ar groups, when it is a (C6-C10)-aryl group, substituted by 1 to 5 substituents, which are identical or different, are 2-chlorophenyl, 3-chlorophenyl, 3-tert-butylphenyl, 3-isopropylphenyl, 3-ativan Anil, 3-bromophenyl, 4-forfinal-forfinal, 2-forfinal, 3-were, 4-isopropylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,5-acid, 2,5-acid, 3,4,6-trimetilfenil, 3-fluoro-4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3,4-dioxyphenyl, 2,5-dimethyl-4-methoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 5-bromo-2-ethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3-triptoreline, 4-triptoreline, 2,5-dimethoxy-3,4,6-trimetilfenil and 2-methoxy-1-naphthyl.

When Y represents a group of formula A-COOH, the compound of the present invention inevitably contains a carboxyl group. These compounds are acids, and, thus, can form salts or esters. There are no restrictions regarding the nature of such salts and esters, with the proviso that, when they are intended for therapeutic use, they must be "pharmaceutically acceptable", which means, as is well known to specialists that they should not have reduced (or not reduced) activity, or increased toxicity (or undesirable increased toxicity compared to the free acids. When connection is soedinenii to obtain other compounds then do not apply even these restrictions.

Examples of complex ester groups are groups comprising alkyl groups containing from 1 to 20 carbon atoms, still preferably from 1 to 7 carbon atoms, and most preferably from 1 to 5 carbon atoms such as the groups described as examples when considering alkyl groups which may be represented by R, and higher alkyl groups such well known in the art, as nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, monodecyl and icosyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl, but the most preferred groups are methyl, ethyl and tertbutyl;

cycloalkyl group containing from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group;

kalkilya groups in which the alkyl part contains from 1 to 3 carbon atoms and the aryl part is a carbocyclic aromatic group containing from 6 to 14 carbon atoms which may be substituted or unsubstituted, and, if it is substituted, has at least one of substituents (a),dpochitaet such kalkilya group, which generally contain from 7 to 9 carbon atoms; examples of such Uralkalij groups are benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, benzhydryl /i.e. diphenylmethyl/ triphenylmethyl, bis-(o-nitrophenyl)methyl, 9-antimetal, 2,4,6-trimethylbenzyl, 4-bromobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl and piperella group;

alkeneamine group containing from 2 to 10 carbon atoms, preferably from 3 to 10 carbon atoms, and more preferably from 3 to 5 carbon atoms, such as vinyl, allyl, 2-methylallyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1 nonanal and 1-decenyl, of which preferred are vinyl, allyl, 2-methylallyl, 1-propenyl, Isopropenyl and butenyl, and most preferred are allyl and 2-methylallyl;

galogensoderjasimi alkyl group having from 1 to 6, preferably from 1 to 4, carbon atoms in which the alkyl part is as defined above for the alkyl groups, and there are examples, and the halogen atom is the atom gloyna, triptoreline, dichlorethylene, deformational, 2,2,2-trichlorethylene, 2-halogenation (for example, 2-chloraniline, 2-florachilena, 2-brometalia or 2-idalina), 2,2-dibromoethylene and 2,2,2-tribromaniline group;

substituted serialkiller groups in which the alkyl part has a value (and examples) are given above, and the silyl group has up to 3 substituents, selected from alkyl groups containing from 1 to 6 carbon atoms, and phenyl groups which are unsubstituted or have at least one Deputy, selected from substituents (a), values, and examples of which are given above, for example, 2-trimethylsilylethynyl group;

phenyl group, which phenyl group is unsubstituted or substituted, preferably at least one alkyl group containing from 1 to 4 carbon atoms, or allmineral, for example, fenilalanina or benzamidophenyl group;

phenyl group which may be unsubstituted, or may contain at least one of substituents (a), values, and examples of which are given above, for example, the very penicilina group or p-brompheniramine group;

cyclic and acyclic terpinolene group, for example, geranyl, nil, pentenyl, campanil and norbornene;

alkoxymethyl groups in which the CNS portion contains from 1 to 6, preferably from 1 to 4, carbon atoms, and can itself be substituted by a single unsubstituted alkoxygroup, such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and methoxyethoxymethyl;

aliphatic aryloxyalkyl groups in which the acyl group preferably represents alkanoyloxy group, and more preferably alkanoyloxy group containing from 2 to 6 carbon atoms, and the alkyl portion contains from 1 to 6, preferably from 1 to 4 atoms of carbon, such as acetoxymethyl, propionylacetate, butyraldoxime, isobutyrylacetate, pivaloyloxymethyl, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-isobutyrylacetate, 1-pivaloyloxymethyl, 2-methyl-1-pivaloyloxymethyl, 2-pivaloyloxymethyl, 1-isobutyrylacetate, 1-isobutyryloxy, 1-acetoxypropionyl, 1-acetoxy-2-methylpropyl, 1-propionylacetate, 1-propionyloxy, 2-acetoxypropionyl and 1-butyrylacetate;

cycloalkylation aliphatic aryloxyalkyl groups in which the acyl group preferably represents alkanoyloxy group, and more preferred is up to 7 carbon atoms, and the alkyl portion contains from 1 to 6, preferably from 1 to 4, carbon atoms, such as cyclohexylacetate-methyl, 1-(cyclohexyloxy)ethyl, 1-(cyclohexylmethoxy)-propyl, 2-methyl-1-(cyclohexyloxy)propyl, cyclopentylmethyl, 1-(cyclopentyloxy)ethyl, 1-(cyclopentyloxy)propyl and 2-methyl-1-(cyclopentyloxy)propyl;

alkoxycarbonylmethyl groups, especially 1-(alkoxycarbonyl)ethyl group, in which CNS portion contains from 1 to 10, preferably from 1 to 6, and more preferably from 1 to 4, carbon atoms, and the alkyl portion contains from 1 to 6, preferably from 1 to 4, carbon atoms, such as 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-second-butoxycarbonylmethyl, 1-tertbutoxycarbonyl, 1-(1-ethylpropylamine)ethyl and 1-(1,1-dipropylenetriamine)ethyl, and other alkoxycarbonylmethyl group, in which alkoxygroup, and the alkyl group contains from 1 to 6, preferably from 1 to 4, carbon atoms, such as 2-methyl-1-(isopropoxycarbonyl)propyl, 2-(isopropoxycarbonyl)propyl, ISO is ethyl;

cycloalkylcarbonyl group and cycloalkylcarbonyl groups in which cycloalkyl group contains from 3 to 10, preferably from 3 to 7 carbon atoms is mono - or polycyclic and optionally substituted by at least one (and preferably only one) alkyl group containing from 1 to 4 carbon atoms (e.g. selected from those alkyl groups, examples of which are given above) and the alkyl portion contains from 1 to 6, preferably from 1 to 4 carbon atoms (e.g. selected from those alkyl groups, examples of which are given above), and most preferably represents methyl, ethyl or propyl, for example, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, cyclopentanecarboxylate, cyclopentanecarboxylate, 1-cyclohexyloxycarbonyloxy, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclopentanecarboxylate, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, 2-methyl-1-(1-methylcyclohexanecarboxylic)propyl, 1-(1-methylcyclohexanecarboxylic)propyl, 2-(1-methylcyclo is enciclopedicanyfile)propyl, 1-(1-methylcyclopentadienyl)propyl, 2-(1-methylcyclopentadienyl)propyl, 1-(cyclopentanecarbonyl)propyl, 2-(cyclopentanecarbonyl)propyl, 1-(1-methylcyclopentadienyl)ethyl, 1-(1-methylcyclopentadienyl)propyl, adamantanecarboxylic, adamantankarboksilato, 1-adamantanemethylamine and 1-adamantankarboksilato;

cycloalkylcarbonyl groups in which the CNS group has one cycloalkenyl Deputy, and cycloalkenyl Deputy contains from 3 to 10, preferably from 3 to 7, carbon atoms and is a mono - or polycyclic, for example, cyclopropanedicarboxylic, cyclobutanedicarboxylate, cyclopentanetetracarboxylic, cyclohexyloxycarbonyloxy, 1-(cyclopropylmethoxy)ethyl, 1-(cyclobutanedicarboxylate)ethyl, 1-(cyclopentanecarbonyl)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl;

technicianlocation and trainingsecuritysmall groups in which terpinolene group is such, examples of which are given above, and preferably is circular terminalno group, for example, 1-(methyloxycarbonyl)ethyl, 1-(3-pennicornis)ethyl, 3-piniactannevimemea and 3-pennicarpenter;

5-alkyl or 5-phenyl in which the phenyl group may be substituted by at least one of (Deputy) (a), values, and examples of which are given above, (2-oxo-1,3-dioxolan-4-yl)alkyl groups in which each alkyl group (which may be the same or different) contains from 1 to 6, preferably from 1 to 4, carbon atoms, for example, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)-methyl, (5-tert-butyl-2-oxo-1,3-dioxolan-4-yl)methyl and 1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)ethyl; and

other groups, especially groups that are easily removed in vivo, such as phthalidyl, indanyl and 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxole-4-yl.

Especially preferred are complex alkylamine, especially those in which the alkyl group contains from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, butyl and isobutyl esters.

Compounds of the present invention in which Y represents a hydrogen atom or a group of the formula A-COOH, can also form salts. Examples of the same is such as magnesium, barium or calcium; salts of other metals, such as aluminum; ammonium salts, salts of organic bases, such as the axis of methylamine, dimethylamine, trimethylamine, Diisopropylamine, guanidine, aminoguanidine or dicyclohexylamine; and salts of amino acids such as lysine or arginine.

Compounds of the present invention may exist in the form of various stereoisomers, as shown by the formula (A)

< / BR>
in which R, Ar, X and Y have the foregoing significance. There are three asymmetric carbon atom in the formula (A), which marked *1,*2 and*3. Although they are all depicted here as a single equation, the present invention includes as a separate, isolated isomers and mixtures (in which the number of isomers may be the same or different), including the racemates. When using stereospecific synthesis technique, or use as a starting material an optically active compounds can be directly obtained individual isomers; on the other hand, if you get a mixture of isomers, the individual isomers can be obtained by the usual techniques of separation.

Of the compounds of the invention preferred are those isomers in which the asymmetric carbon atoms, marked represent a hydrogen atom, may also exist as tautomers. The ratio between the tautomers shown in Fig. 1, where R, X and Ar have the foregoing significance.

Although all these compounds is depicted here as a single equation, the present invention includes as a separate, isolated isomers and mixtures (in which the number of isomers can be equal or different).

(1) the Preferred compounds of the present invention are those compounds of formula (I) and their salts, in which

R represents an alkyl group containing from 1 to 6 carbon atoms;

X represents the atoms of oxygen or sulfur atom;

Y represents a hydrogen atom or a group of the formula A-COOH, in which A represents alkylenes group containing from 1 to 4 carbon atoms;

Ar represents an aryl group containing from 6 to 10 ring carbon atoms, or aryl group containing from 6 to 10 ring carbon atoms, substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of substituents (a), values, and examples of which are given above; and

when Y represents a group of formula A-COOH, (C1-C4-alkylether.

(2) Balearic

R represents an alkyl group containing from 1 to 4 carbon atoms;

X represents an oxygen atom or a sulfur atom;

Y represents a hydrogen atom or a group of the formula A-COOH, in which A represents a methylene or ethylene group; and

Ar represents an unsubstituted phenyl group, unsubstituted naftalina group, or phenyl or naftalina group substituted by 1 to 5 substituents, which may be the same or equal, selected from the group consisting of substituents (a), values, and examples of which are given above; and Y represents a group of formula-A-COOH, (C1-C4-alkylether.

(3) Even more preferred compounds of the present invention are those compounds of formula (I), in which

R represents an alkyl group containing from 1 to 4 carbon atoms;

X represents an oxygen atom or sulfur;

Y represents a hydrogen atom or a group of formula-CH2-COOH;

Ar represents an unsubstituted phenyl group, unsubstituted naftalina group or a phenyl group substituted by 1 to 5 substituents that are the same or different, selected from the group consisting of C is uppy, hydroxyl group, alkyl groups containing from 1 to 4 carbon atoms, and CNS group containing 1 or 2 carbon atoms; and

when Y represents a group of formula-CH2-COOH, (C1-C4-alkylether.

(4) the Most preferred compounds of the present invention are those compounds of formula (I), in which

P represents a methyl or ethyl group;

X represents an oxygen atom or sulfur;

Y represents a hydrogen atom or a group of formula-CH2-COOH;

Ar represents phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-forfinal, 3-triptoreline, 3-were, 3-methoxyphenyl, 3,5-dichlorophenyl, 3,5-di-tertbutyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-fluoro-phenyl, 2,5-dimethoxy-3,4,6-trimetilfenil, 3,5-dimethyl-4-hydroxyphenyl or 2-naphthyl; and

when Y represents a group of formula-CH2COOH, methyl and ethyl esters.

Typical examples of the compounds of the present invention are such compounds of formula (1 1) and formulas (1 2) in which the substituents have the values corresponding to the values in the table. 1 and table. 2 below, i.e., PL. 1 relates to formula (1 1), and table. 2 from the tert-butyl

Bu sec-butyl

Et ethyl

Me methyl

MeO methoxy

Np naphthyl

Ph phenyl

Pr drunk

Pr isopropyl

Pn of pencil

Tfm trifluoromethyl

< / BR>
Of compounds, examples of which are given in table. 1, 2 are preferred NN 5, 6, 7, 11, 12, 13, 19, 20, 27, 35, 48, 105, 106, 107, 111, 112, 113, 119, 120, 127, 135, and their pharmaceutically acceptable salts.

More preferred compounds are compounds NN 5, 7, 12, 13, 19, 27, 48, 105, 107, 112, 113, 119, 127 and 148 and their pharmaceutically acceptable salts.

Most preferred are the following compounds:

5) 3-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1-methylethyl} -5-(3-chlorophenyl)oxazolidin-2-he;

7) 3-{ 2-[4-(3-methoxycarbonylmethyl-2,4-dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl}-5-(3-chlorophenyl)oxazolidin-2-he;

105) 3-{ 2-[4-(2,4 dioxothiazolidine-5-ylmethyl)-phenoxy] -1-methylethyl}-5-(3-chlorophenyl)oxazolidin-2-tion; and

107) 3-{ 2-[4-(3-methoxycarbonylmethyl 2,4-dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl}-5-(3-chlorophenyl)oxazolidin tion;

and their pharmaceutically acceptable salts.

Compounds of the present invention can be obtained in various ways, well known for producing compounds of this type. For example, in the General case is set out above values, and y1represents any of the groups, which represent the y, and the values of which are set out above, or a group protecting the amino group) with Carboniferous or thiocarbanilide substance; and

(b) if desirable, the removal of the protective group from the resulting compound; and

(c) if desirable, the implementation of hydrolysis, get salt or esterification of the obtained compound to obtain the compound of formula (I) or its salt or ester.

More specifically, the compounds of the present invention can be obtained by any of methods 1 through 5, which are described below.

In shown in Fig. 2 the formulas Ar, R, X, Y1and Z1have installed the above values. When y1represents a protecting group, this protecting group can be, for example, triphenylmethyl group (trityl).

Stage 1

At this stage amerosport formula (II) [Collins, J. Med. Chem. 13(1970) 674 enter into interaction with the compound of the formula (III). The connection of the formula (III) can be obtained using conventional techniques, for example by reaction galogensoderjasimi derivative of acetone with phenol connection.

The reaction amerosport f as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate, or in the presence of molecular sieves, or the reaction can be performed in the absence of such substances. The reaction is normally and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that the solvent has no harmful effect on the reaction or on the participating agents, and that it can dissolve the reagents, at least partially. Examples of suitable solvents are hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; alcohols, such as methanol or ethanol; sulfoxidov, such as dimethyl sulfoxide; sulfolane; or a mixture of any two or more of these solvents. It is preferable to perform the reaction in the presence of a hydrocarbon or alcohol solvent, and most preferably in the presence of Leicester parameter for the invention. Generally found convenient to carry out the reaction at a temperature of from a temperature under cooling with ice to the boiling temperature under reflux used solvent (if used), and preferably when heated to the boiling temperature under reflux. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out in the above-described preferred conditions, the reaction time is from 0.5 to 10 h, preferably from 1 to 5 h, and most preferably from 1 to 3 o'clock

Stage 2

The resulting compound of formula (IV) then restore to obtain the compounds of formula (V).

The reduction can be carried out by conducting in contact with the compounds of formula (IV) with a suitable reducing agent, or by hydrogenation of compounds of formula (IV) in the presence of a catalyst.

When the reaction is carried out in the presence of a reducing agent, restrictions on the nature used in this reaction, the reductant is missing. Examples of particularly suitable reducing agents VD sodium; or nutritionrelated and alumoweld lithium or diisobutylaluminium, of which preferred are borohydride sodium and cyanoborohydride sodium. The amount of reducing agent is not critical for the reaction, though, to save, it is preferable that this number would be at least equimolar with respect to the compound of formula (IV). In General, the reaction normally occurs when using from 1 to 50 moles, and preferably with a large excess of reducing agent per mole of the compounds of formula (IV). The reaction is normally and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the participating agents, and that it can dissolve the reagents, at least partially. Examples of solvents include hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; alcohols such as methanol, ethanol or isopropanol; or a mixture of any Dublin core can take place in a wide temperature range, and the precise reaction temperature is not critical to the invention. Generally found convenient to carry out the reaction at a temperature between the temperature of the cooling with ice and some heated, preferably between temperature cooling with ice, and 50oC. the Time required for the reaction may also vary widely, depending on many factors, especially the reaction temperature, nature of reactants and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, sufficient time may be generally from 30 min to several days, preferably from 1 h to 1 day.

When the recovery is carried out by hydrogenation in the presence of catalyst used, the catalyst may be any catalyst, usually for catalytic reduction, and the nature of the catalyst is not critical to the present invention. Examples of preferred catalysts are palladium on charcoal or platinum oxide. Usually the reaction is carried out preferably in the presence of a solvent, the nature of which is not critical, provided that the solvent does not okazyvaemyh solvents include ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides as dimethylformamide or dimethylacetamide; alcohols such as methanol, ethanol or isopropanol; esters of organic acids, such as metallotect or ethyl acetate; and mixtures of any two or more of the solvents described above. When using the palladium catalyst, the catalytic hydrogenation is carried out, preferably, at a pressure of from moderate to strong, preferably from 5 kg/cm2. When using a platinum catalyst, the hydrogenation performed, preferably, at atmospheric pressure. The reaction will take place in a wide temperature range, and the exact choice of temperature is not critical for the invention. In General, it is found that the reaction is conveniently carried out at a temperature in the range from room temperature to 50oC. It is also preferably performed in the presence of alcoholic solvents, especially methanol or ethanol.

Stage 3

The compound of formula (I) can be obtained by reaction of compounds of formula (V) with Carboniferous substance or thiocarbanilide substance. The reaction of the compound of formula (V) with Carboniferous substance results in a product in which X represents product, in which X represents a sulfur atom. There is not particular limitation on the nature Carboniferous or thiocarbanilide substances used in such reactions, and examples of such substances include phosgene, diphosgene; triphosgene; carbonyldiimidazole; esters of Harborview acid, such as ethylchloride; tietgen and thiocarbonyldiimidazole. If desired, the reaction can be carried out in the presence of a base, in order to remove the acid formed during the reaction. When such a base is used, the nature of the base is not critical to the present invention. It is generally preferable to use the base as organic bases triethylamine, diisopropylethylamine or pyridine; and inorganic bases such as sodium carbonate or potassium carbonate. The reaction is normally and preferably performed in the presence of a solvent, the nature of which is not essential to the present invention, provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include hydrocarbons, such as benzene, toluene, xylene, Gex the rod; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; urea derivatives, such as N, N'-dimethylimidazolidine; sulfoxidov, such as dimethyl sulfoxide; NITRILES, such as acetonitrile or propionitrile; sulfolane; or a mixture of any two or more of these solvents. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. In General, it is found that the reaction is conveniently carried out at a temperature between the temperature of the cooling with ice and the boiling point under reflux solvent used, preferably at a temperature between the temperature of the cooling with ice, and 50oC. the Time required for the reaction may also vary widely, depending on, for example, the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out in the preferred conditions outlined above, sufficient time will be the period from 30 minutes to 50 hours, preferably from 5 to 50 hours

When the compound of the formula (II) represents the optical is in the compound of formula (A), stereochemical integrity can be preserved in the compound of formula (I). Moreover, in stage 2, when it can be done the usual reaction asymmetric hydrogenation of compounds of formula (I) can be obtained in the form of a stereoisomer having an asymmetric carbon atom at the position marked with a*2 in the General formula (A).

In shown in Fig. 3 the formula Ar, R, X, and Y1have installed the above values; L represents alkylsulfonyl group, such as methanesulfonyl, econsultancy propanesulfonyl or butanesulfonyl; or arylsulfonyl group, such as toluensulfonyl or naphthalenesulfonyl, preferably p-toluenesulfonyl; V represents a halogen atom, e.g. chlorine atom, bromine or iodine; Z is a protective for the amino group, for example alkoxycarbonyl group or aryloxyalkyl group, such as tert-butoxycarbonyl group or benzyloxycarbonyl group; and M represents an alkaline metal such as sodium or potassium.

Stage 4

At this stage, the compound of formula (X) are obtained by the interaction of the protected N amerosport formula (VI) with a phenyl compound of the formula (VII). This reaction is (1981)] in General, the reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as chlorophora, methylene chloride or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxide; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; and mixtures of any two or more of the solvents described above. The reaction may proceed in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. In General it is found that the reaction is conveniently carried out at temperatures from the temperature bath of ice water to some heated, preferably to the temperature of the cooling with ice up to 60oC. the Time required for the reaction may also vary widely, zavisimogo provided the reaction is carried out in the preferred conditions outlined above, will be sufficient time from several hours to several days, preferably from 5 h to 3 days.

Stage 5

The compounds of formula (VIII) can be obtained by alkanolammonium or arylsulfonamides, preferably by metilirovaniem or totalrevenues, the compounds of formula (VI).

The reaction, if desired, can be carried out in the presence of a base to remove the acid formed during the reaction, the nature of which is not critical to the present invention. On the other hand, the reaction can be carried out in the absence of base. Examples of suitable bases include carbonates of alkali metals such as sodium carbonate, sodium bicarbonate, potassium carbonate; triethylamine and pyridine. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents ASD as chloroform, methylene chloride or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide; or a mixture of any two or more of the above-mentioned solvents. The reaction may proceed in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. In General it is found that the reaction is conveniently carried out at a temperature from temperature cooling with ice to a temperature of small heating, preferably at a temperature from temperature cooling with ice up to 60oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in a preferred conditions, educated in General terms above, will be sufficient reaction period of from 1 h to several days, for example, from 1 h to 1 day.

The reaction preferably takes place in the presence of triethylamine at a temperature from temperature cooling with ice up to 60oC and for a time from 1 h uly (VIII) with the compound of the formula (IX).

The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a mixture of any two or more of these solvents. The reaction can be performed in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. In General it is found that the reaction is conveniently carried out at a temperature between the temperature of the cooling with ice and a small heated, preferably to the temperature of the cooling with ice up to 60oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvents. However, provided that the reaction OSShD is from 1 h to several days, preferably from 1 h to 1 day.

The reaction preferably takes place in the presence of a solvent at a temperature from temperature cooling with ice up to 60oC for a time from 1 h to 1 day.

Stage 7

The compound of formula (XI) can be obtained by removal of the protective group Z of the compounds of formula (X), and, if desired, by removal of the protective group Y1. The removal of the protective group can be carried out by any conventional technique, such as, for example, which corresponds to the procedure described in J. W. Green, "Protective Groupsin Organic Synfhesis", John Wiley Sons; and in J. F. W. McOnue "Protective Groups in Organic Chemisfry", Plenum Press, and these works are included in this link.

The compound of formula (V) is produced by interaction of gelegenheden formula (XII) with aminoguanidinium formula (XI).

The reaction can be carried out, if desired, in the presence of a base, the nature of which is not critical to the present invention. Alternatively, the reaction can be carried out in the absence of base. Examples of suitable bases present in the reaction mixture to remove the acid formed during the reaction, include carbonates of alkali metals such as sodium carbonate, bicarbonate NAT who I am. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; ethers, such as diethyl ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; alcohols such as methanol, ethanol or isopropanol; sulfoxidov, such as dimethyl sulfoxide; or a mixture of any two or more of the above-mentioned solvents. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. In General it is found that it is convenient to perform the reaction at room temperature or with slight heating, preferably at a temperature from room temperature to 60oC. the Time required for the reaction may also vary within wide five. However, provided that the reaction is carried out in the preferred conditions outlined above, a sufficient reaction time will be the period from 1 h to several days, especially from 3 hours to 3 days. The reaction is preferably carried out in the presence of a solvent selected from the group consisting of alcohols, amides and sulfoxidov, at a temperature from room temperature up to 60oC during the time from 3 hours to 3 days.

Stage 8

The compound of formula (I) can also be obtained by the coupling of compounds of formula (V) with Carboniferous or thiocarbanilide substance, as described above.

When the compound of the formula (VI) represents an optically active compound, due to the presence of an asymmetric carbon atom in position, put*2 in the compound of formula (A), the stereochemical integrity can be preserved in the compound of formula (XI). In addition, when the compound of the formula (XII) represents an optically active compound, due to the presence of an asymmetric carbon atom at the position marked with*1 in the formula (A compound of the formula (I) can be saved stereochemical integrity at the asymmetric carbon atoms*1 and*2.


The compound of formula (V) can be obtained by the interaction of epoxysilane formula (XIII) with aminoguanidinium formula (XI).

The reaction can be carried out, if desired, in the presence of an acid catalyst. Alternatively, the reaction can be carried out without catalyst. Although the exact nature of the catalyst is not critical to the present invention, it is found that suitable catalysts are, in particular, such catalysts as inorganic, for example mineral acids, for example, hydrogen chloride and sulfuric acid; and a Lewis acid such as boron TRIFLUORIDE, aluminum chloride and aluminum oxide. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents, and that it can dissolve the reagents, at least partially. Examples of such solvents include hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; ethers, such emailforwarding; alcohols, such as methanol, ethanol or isopropanol, sulfoxidov, such as dimethyl sulfoxide; NITRILES such as acetonitrile; water; and a mixture of any two or more of these solvents. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. Generally found convenient to carry out the reaction or under ice cooling, or heating. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, a sufficient period of time from 1 h to several days.

The reaction preferably takes place in the presence of a solvent at a temperature of from 30oWith up to 120oC for a time from 1 h to 1 day.

The compound of formula (Y) can then be converted into a compound of formula (I) by interacting with Carboniferous or thiocarbanilide agent in the same way as described above for stage 3.

When compounds of formulas (XI) and (XIII) are optically active connection of the unity of formula (A), in the compound of formula (I) can be saved stereochemical integrity.

In shown in Fig. 5 formulas Ar, R, X, Y and Y1have the meanings defined above, R1represents a lower alkyl group such as methyl or ethyl group; Z1represents a hydrogen atom or a group protecting the hydroxyl group, such as the heterocyclic group, for example, tetrahydropyranyl or tetrahydrofuranyl; alkoxyalkyl group, in which CNS portion and the alkyl portion each contain from 1 to 4 carbon atoms, such as methoxymethyl, 1-methoxyethyl, 1-ethoxypropan, 1-methoxypropyl or 1-methoxybutyl; aracelio group, values and examples of which are given above for the group of esters, in particular benzyl, diphenylmethyl and triphenylmethyl; trehzameshchenny silyl group in which the substituents are the three alkyl groups, which may be the same or different and each contains from 1 to 4 carbon atoms, or 1 or 2 such alkyl groups and, respectively, 2 or 1 phenyl groups, for example trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

Stage 10

The compound of formula (XV) can be p is Anna in Organic Syubbesis, 1, 336, which is included in this link.

The reaction can be carried out in the interaction of the compounds of formula (XIV) with hydrogen cyanide or a combination of trimethylsilylacetamide with iodine zinc, obtaining cyanohydrin, and subsequent hydrolysis with the participation of an acid catalyst. Although the first part of this reaction may be carried out in a wide temperature range, generally it is preferable to perform it with ice cooling or heating. It is preferable, however, to carry out the reaction at a temperature of from room temperature to 100oC. the Time required for the reaction may also vary widely, depending on, for example, the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out in the preferred conditions outlined above, will be sufficient time from 30 minutes to one day, preferably from 1 h to 10 h

Hydrolysis involving acid catalyst, comprising the second part of the stage 10, is typically carried out using an acid, the nature of which is not critical to the present invention. Examples of suitable acids include inorganic acids such as hydrogen chloride or CEM way flows in the presence of excess water and although the precise reaction temperature is not implemented for the present invention found that it is convenient to perform the reaction at a temperature between room temperature and the boiling temperature of the reaction mixture under reflux, preferably at temperatures up to boiling under reflux. The time required for the reaction may also vary widely and depends on many factors, particularly the reaction temperature and periods of reagents. However, when followed by the preferred conditions outlined above, will be sufficient time lag of a few tens of minutes to several tens hours, in particular from 30 minutes to 10 o'clock

The reaction preferably takes place at temperatures up to boiling under reflux in the presence of hydrogen chloride or sulfuric acid for a time of 30 min to 10 h

Stage 11

This stage involves obtaining the compounds of formula (XVI) esterification compounds of the formula (XV).

Esterification the compounds of formula (XV) may be performed using any of the accepted methods. It is found that suitable methods are, in particular, esteri etani halogenated alkyl compounds with alkali.

Esterification involving acid catalyst can be carried out in the interaction of the compounds of formula (XV), for example, with an excess of alcohol, in the presence or in the absence of solvent, and preferably in the presence of inorganic acids such as hydrogen chloride or sulfuric acid, or organic acids such as p-toluensulfonate, at suitable temperatures, for example from room temperature to heating, during the relevant time, for example from several hours to several days.

Esterification using diazoalkane preferably carried out in the presence of a solvent, for example in the presence of alcohol, such as methanol or ethanol; hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; or a mixture of any two or more of the solvents described above. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. In General it is found that it is convenient to perform the reaction at a temperature from temperature cooling with ice to nugget to vary within wide limits, depending on many factors, particularly the reaction temperature and the nature of the factors and solvent.

When the esterification reaction using alkali and alkylhalogenide examples of bases that can be used include carbonates of alkali metals such as potassium carbonate or sodium carbonate. The reaction is preferably carried out in the presence of a solvent. Do not carry special restrictions regarding the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include alcohols, such as methanol or ethanol; ethers, such as diethyl ether, tetrahydrofuran or dioxane; hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; and mixtures of any two or more of the solvents described above. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. In General it is found that conveniently carried out which also may vary within wide limits, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in a preferred conditions, educated in General terms above, a suitable period of time will be from several hours to several days.

Stage 12

Hydroxyl group of the thus obtained compounds of formula (XVI) protect, using the usual protection of the hydroxyl group, and obtain the connection formula (XVII). Examples of protective groups for hydroxyl group, which can be used include tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, for example as described in T. W. Green.Protective Groups in Organic Synffesis, John Wiley Sons, and J. F. W. McOmce. Protective Groups in Organic Chemistry. Plenum Press. This reaction can be carried out using the procedure described Green.

Stage 13

The compound of formula (XVIII) can be obtained by reduction of compounds of formula (XVII). The reaction is carried out in a suitable manner, entering into contact with the compound of formula (XVII) with an appropriate reducing agent. Examples of suitable reducing agents include hydrates of metals such as al the I reaction although, to save, it is preferable that this number would be at least an equimolar amount relative to the compound of formula (XVII). In General, the reaction is usually performed using from 1 to 5 moles, preferably a large excess of reducing agent per mole of the compounds of formula (XVII). The reaction is normally and preferably carried out in the presence of a solvent. There is not any special restrictions on the nature of the solvent used provided that the solvent will not have a harmful effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least partially. Examples of suitable solvents include ethers, such as diethyl ether, tetrahydrofuran or dioxane; and hydrocarbons, such as benzene, toluene, xylene, hexane and heptane. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. Generally found convenient to carry out the reaction at a temperature of from 60oC to 50oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the used re what s in General terms above, sufficient time will be from 30 minutes to 24 hours

Stage 14

The compound of formula (XIX) can be obtained from compounds of formula (XVII) in the usual way, for example, the interaction with diisobutylaluminium, in a solvent, as a rule, in a hydrocarbon solvent such as hexane, heptane, benzene, toluene or xylene. The reaction may proceed in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. Generally found convenient to carry out the reaction by cooling the reaction mixture, for example in a bath of dry ice with acetone, although the reaction may also take place in the interval from -100oC and 0oC. the Time required for the reaction may also vary widely, depending on, for example, the reaction temperature and the nature of participating reactants and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, a sufficient reaction time will usually be from 1 h to 5 h

Stage 15

The compound of formula (XIX) can be obtained by oxidation of compounds of formula (XVIII). The reaction is carried out using conventional oxidation, such as oxidation with Sposobem oxidation, described in Mancuso. Huaug Sweri. J. Org. Chem. Vol. 43, No. 12, (1978) 2480.

More specifically, it is found that the reaction proceeds adequately when using the oxidant described Sweri af al. quoted above. The exact temperature at which the reaction is not critical for the invention, and the reaction may proceed in a wide temperature range. Generally found convenient to carry out the reaction at a temperature of from -100oC to 100oC, preferably from -75oC to 50oC. the Time required for the reaction may also vary widely, depending on, for example, the reaction temperature and the nature of participating in the reaction of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, a sufficient reaction time will usually be from 1 min to 3 h, preferably from 5 min to 1 h

Stage 16

The compound of formula (XXI) can be obtained by the interaction of the carbonyl compounds of the formula (XIX) with aminoguanidinium formula (XI). The reaction can be carried out in the same manner as described above in stage 1.

Stage 17

The compound of formula (XXI) can be obtained by reduction of compounds of formula (XX). Z1in the compound of formula (XXI) is a group protecting the hydroxyl group, the compound of formula (I) can be obtained by cleavage of the protective group from compounds of formula (XXI) using conventional procedures at the first stage and the second stage introduction in the interaction of the resulting compound with Carboniferous or thiocarbanilide agent, as described above for stage 3. Cleavage of the protective group can be carried out using known techniques, for example in accordance with the methods described in T. W. Green. Protective Groups in Organic Syuffesis. Johu Wiley Sons; and in J. F. W. McOmie. Orofesfive Groups in Organic Hemisfry. Plenum Press.

When the compound of the formula (XIX) and (XI) are optically active compounds, due to the presence of asymmetric carbon atoms at positions marked with*1 and*2 in the compound of formula (A), the compound of formula (I) can be saved stereochemical integrity.

Alternatively, racemic compounds of formula (XV) can be, if desired, separated to obtain the individual isomers, i.e., [(R) (XY)] and [(S) (XY)] using optically active amines typically used for traditional optical separation. Examples of such amines in the foregoing values, R2is a (C1-C5)-alkyl group such as methyl or ethyl group; R3is a (C6-C10)-aryl group such as phenyl, p-tolyl or naphthyl; (C6-C10)-aryl group, which contains at least one Deputy, selected from the group consisting of substituents (a), values, and examples of which are given above, for example, p-bromophenyl, 2-methoxyphenyl or 3-were; unsubstituted (C1-C5)-alkyl group such as methyl or ethyl group; or (C1-C5)-alkyl group, which contains at least one halogen Deputy, for example triptorelin group; and R4represents the balance of ester, the definition of which is given above.

Stage 19

The compound of formula (XXIII) can be obtained by the coupling of compounds of formula (II) with the compound of the formula (XXII), and recovering the resulting compound in accordance with the procedure described above for stages 1 and 2.

Stage 20

The compound of formula (XXIV) can be obtained by treating the compounds of formula (XXIII) carbonyliron or thiocarbanilide agent, in accordance with the procedure, opolaskivanija formula (XXIV) with sulfonylureas agent in the presence of a base to remove the acid, formed during the reaction.

There is no special limitation on the nature sulfonylurea agent used in this reaction. Examples of such suitable sulfonylurea agents include arylsulfonate, such as benzosulphochloride, p-toluensulfonate or naphthalenesulfonate; arylsulfonate, which contains at least one halogen Deputy, such as p-bromobenzonitrile; unsubstituted (C1-C5-alkanesulfonyl, such as methanesulfonate, acanaloniidae, butanesulfonate; or alkanesulfonyl, which contains at least one halogen Deputy, such as triftormetilfullerenov; and unsubstituted anhydride (C1-C5-alkanesulfonyl, such as the anhydride of methansulfonate; or substituted anhydride (C1-C5-alkanesulfonyl, such as the anhydride of triftoratsetata. The nature of the base used in this reaction also is not critical to the present invention, provided that it can remove any acid formed during the reaction. Examples of suitable bases include organic bases, such as triethylamine as sodium carbonate or potassium carbonate. The reaction is usually carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used, provided that the solvent has no harmful effect on the reaction or on the participating agents, and that it can dissolve the reagents, at least partially. Examples of suitable solvents are hydrocarbons, or aromatic, or aliphatic, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; NITRILES, such as acetonitrile or propionitrile; sulfoxidov, such as dimethyl sulfoxide; or a mixture of any two or more of the above-mentioned solvents. The reaction will take place in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. Generally found convenient to carry out the reaction under cooling or with heating, preferably at a temperature from temperature cooling with ice up to 50oC. the Time required for dccii and from the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, sufficient time will usually be from 30 min to 1 day, in particular from 1 to 15 hours

The reaction is preferably carried out using as solvent a simple ether, halogenated hydrocarbon, nitride or amide, at a temperature from temperature cooling with ice up to 50oC, and for 1-15 hours is More preferable to carry out the reaction in tetrahydrofuran, methylene chloride or acetonitrile at a temperature from temperature cooling with ice to room temperature.

Stage 22

The compound of formula (XXVI) can be obtained by the coupling of compounds of formula (XXV) with thiourea. The exact amount of thiourea used in this reaction is not essential for the present invention, although preferably thiourea was attended by in excess relative to the compound of formula (XXV), preferably thiourea was attended by at least 1.2-5 times the amount, and most preferably 1.5 to 3 times the amount to the compound of formula (XXV). The reaction is normally and preferably carried out in the presence of solvent is the solvent has no harmful effect on the reaction or on the involved reagents, at least partially. Examples of such solvents include alcohols, such as methanol, ethanol or onomatology ether of ethylene glycol; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide; sulfolane; or a mixture of any two or more of these solvents. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. In General, however, found to be eligible to carry out the reaction at a temperature between room temperature and the boiling temperature of the reaction mixture under reflux, preferably at temperatures up to boiling under reflux. The time required for the reaction, izmenaet widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, sufficient time will usually range from 30 min to 20 h, in particular from 1 to 5 o'clock

The reaction is preferably carried out by heating in monopetalum ether of ethylene glycol at boiling point with oracletm the compounds of formula (XXVI), preferably, in the presence of an acid catalyst. This hydrolysis can be carried out directly after obtaining the compounds of formula (XXVI) and without releasing the connection, or after separation of the connection, for example, as described below.

The nature of the catalyst is not essential for the present invention. Examples of such catalysts include inorganic acids such as hydrogen chloride, hydrogen bromide, phosphoric acid or sulfuric acid; and organic acids such as p-toluensulfonate, methanesulfonate, triftoratsetata or triperoxonane acid. When the hydrolysis is carried out without isolating the compounds of formula (XXVI), the reaction is preferably carried out in the presence of a large excess of water per mole of thiourea used at the stage 22. When the hydrolysis is carried out with a compound of formula (XXVI), which is selected, the reaction is preferably carried out in the presence of a large excess of water per mol of compound of formula (XXVI). The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent used, provided that the solvent does not okazuya least partially. Examples of suitable solvents include alcohols, such as methanol, ethanol or onomatology ether of ethylene glycol; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxidov, such as dimethyl sulfoxide; sulfonyl; or a mixture of any two or more of the above solvents. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. Generally found convenient to carry out the reaction at the boiling point under reflux. The time required for the reaction also varies widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, will be sufficient time from 30 min to 10 h, in particular from 1 to 5 o'clock

The reaction preferably takes place by heating in monopetalum ether of ethylene glycol at the boiling point under reflux for 1-5 hours

Stage 24

The compound of formula (XXVIII) can be obtained by transformation of a compound of formula (XXVII) in salt, preferably in Solda V, A and R4have installed the above values).

Each of these two reactions are performed, preferably, in the presence of a solvent. There is no special limitation on the nature of the solvent used, provided that the solvent has no harmful effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least partially. Examples of suitable solvents include amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; urea derivatives, such as N, N'-dimethylimidazolidine; sulfoxidov, such as dimethyl sulfoxide; Sultan; or a mixture of any two or more of these solvents. The nature of the salt-forming agent in the first stage, this stage is not essential to the invention. Examples of suitable reagents include sodium hydride, potassium hydride, sodium methoxide, ethoxide sodium tert-piperonyl potassium. The reaction can occur in a wide range of temperatures, and the precise reaction temperature is not critical for the invention. Generally found convenient to carry out the reaction at a temperature between the temperature of the cooling with ice and a small heated, preferably with tamponade depending on many factors, including the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, sufficient time will usually range from 30 min to 10 h, preferably from 1 to 6 o'clock

Preferably, the first stage of complete reaction was carried out using sodium hydride in amide as solvent at a temperature from temperature cooling with ice to room temperature within 1 to 6 hours

Salt of an alkali metal obtained by this procedure, then, preferably, is injected into the interaction, without prior isolation from the reaction mixture with a compound of formula V-A-COOR4(where V, A and R4have installed the above values) for 1 6 h under ice cooling or heating. It is preferable to carry out this reaction at a temperature from temperature cooling with ice to room temperature.

Stage 25

The compound of formula (XXIX) can be obtained by hydrolysis of compound (XXVIII). This reaction can be carried out using conventional techniques hydrolysis of ether carboxylic acids, for example, in the presence of water and acid or osnovne special restrictions regarding the nature of an acid catalyst, used, provided that it has no harmful effect on the reaction. Examples of suitable acids include inorganic acids such as hydrogen chloride, sulfuric acid, phosphoric acid and hydrogen bromide. When the reaction is carried out in the presence of a basic catalyst, does not particular restrictions on the nature of the basic catalyst used, provided that it has no adverse effect on the reaction. Examples of suitable bases include carbonates of alkali metals such as sodium carbonate or potassium carbonate; hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide; or a concentrated solution of ammonia in methanol. The hydrolysis is preferably carried out in a solvent. There is no special limitation on the nature of the solvent used provided that the solvent has no harmful effect on the reaction or on the reagents and that it can dissolve the reagents, at least partially. Solvents that are typically used in such reactions of hydrolysis, equally can be used in this reaction. Examples of suitable solvents include water; alcohols such as methanol, this is a quiet solvents with water.

The reaction can occur in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. Generally found convenient to carry out the reaction at a temperature of from 0oC to 150oC. the Time required for the reaction may also vary widely, depending on many factors, such as the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined outlined above, sufficient time will usually be from 1 to 10 hours

After completing any of the reactions described above, the desired compounds can be extracted from the reaction mixture by conventional means. For example, one suitable recovery is the extraction of compounds from the reaction mixture by adding a suitable solvent; and releasing extracts from the solvent by distillation. The resulting product is then, if desired, may be further purified by conventional means, for example, by recrystallization, presidenial or various chromatographic techniques, especially column chromatography, preferably on silica gel.

The biological activity of the compounds of the present invention is illustrated by the following further experiments, in which the compounds are number one of the examples, the following, which describes how to obtain them.

Experiment 1

The ability of compounds of the Yan content of sugar in the blood was measured in mice, as described later.

The male KK mice with elevated blood sugar, each of which weighs more than 40 g, enter, each, 50 mg/kg of compounds which have, in a mixture of polyethylene glycol 400 in a ratio of 1:1 by volume and 0.5% (weight/volume) of carboxymethyl cellulose in an aqueous solution of sodium chloride, and then left for 18 hours without food restrictions. At the end of this period take blood samples from the tail. The level of blood sugar (BSL) is determined with a glucose analyzer (GL-101, Mitsubishi Kasei, Co.). Degree (R) to which the test compound reduces blood sugar level, calculated in accordance with the following equation:

< / BR>
in which

B: the level of blood sugar in the group, which was introduced solvent

A: the Level of blood sugar in the group that was administered the test compound.

The results are presented in table. 3.

As clearly shown in the table. 3, all of the compounds that were tested, have good activity in reducing the sugar level in the blood.

Experiment 2

Hypoglycemic effect when the load of glucose

Hypoglycemic effect of compounds of the present sabretech months each one weighs between 28-30 g do not feed during the night, and then administered orally 1 mg/kg or 10 mg/kg intended for testing the connections in the carboxymethyl cellulose (CMC), or carboxymethylcellulose with a control connection. After 60 min, injected subcutaneously 1.2 g/kg D-glucose. Then, after 60 and 120 min after subcutaneous injection of glucose, take samples and blood glucose levels determined by the analyzer, glucose (GL-101, production Mifsubishi Kasei, Co.). The degree of hypoglycemia (R) of the tested compounds at the load of glucose is calculated in accordance with the following equation:

R=[I-(B/A) 100]

in which

A: the level of glucose in blood in the group, which was introduced CMC

B: the level of glucose in blood in the group that was administered the test sample.

The results are presented in table. 4.

As clearly shown in the table. 4, all tested compounds show an excellent hypoglycemic effect.

Experiment 3

Toxicity

The toxicity of the compounds of the present invention have male ddY mice, divided into groups of 3 individuals. The test compound is administered orally to each test animal at a dose of 300 mg per kg of body weight. Test the week after administration of the compounds, and during this period they showed no deviations from normal behavior that can be linked to the experimental compounds. At the end of the observation period all animals were still alive.

Taking into account the fact that each animal entered a significant dose-zero coefficient of deaths indicates that the compounds of the present invention have very low toxicity.

Compounds of the present invention can be administered in various forms, depending on the patient and the desired route of administration. Suitable formulations for oral administration include tablets, capsules, granules, powders or syrups; and suitable formulations for parenteral administration include formulations for injection (which may be intravenous, intramuscular or subcutaneous), drops and suppositories. These various preparations can be obtained in the usual way, in which the active compound is mixed with any known additives that are commonly used in the manufacture of pharmaceutical preparations, such as carriers, binders, dispersing agents, lubricants, corrigentov, soljubilizatory, suspendresume agents and vedaste and forms of the drug. However, for the average adult patient, the daily dose is generally from 0.01 mg to 2000 mg, which can be entered at one time or in multiple doses.

Obtaining the compounds of the present invention is further illustrated by the following examples which are not limiting, and gaining some raw materials shown in the following preparative examples.

Example 1

3-{ 2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy] -1-methyl-ethyl-5-(3-chlorophenyl)oxazolidin-2-on (compound No. 5)

.

Add 360 mg carbonyldiimidazole to a solution of 640 mg 5-(4-{ 2-[2-(3-chlorophenyl)-2-hydroxyethylamino] propoxy} benzyl-thiazolidin-2,4-Dion-1/2 ethyl acetate) [obtained as described in preparative example 10] in 5 ml of dimethylformamide, and the mixture is left to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with saturated aqueous sodium chloride, and then extracted with ethyl acetate. Extract three times washed with saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. The ethyl acetate is then removed from the dried extract by distillation under reduced pressure, and the obtained residue to o " em as eluent, and get called in the header connection. Named in the title compound obtained as two mixtures of isomers that elute from the column separately: (i) a first fraction consisting of 150 mg of the mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), and the mixture is melted at a temperature of from 56oC to 59oC; and (ii) a second fraction consisting of 150 mg of the mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively, *1 and*2 in the above formula (A), and the mixture is melted at a temperature of from 58oC to 66oC.

Example 2

3-{ 2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy] -I-methyl-ethyl}-5-(3-chlorophenyl)oxazolidin-2-tion (compound N 105)

< / BR>
Follow a procedure similar to that described above in example 1, but using 0,41 g thiocarbonyldiimidazole and 1.0 g 1/2 ethyl acetate 5-(4-{2-[2-3-chlorophenyl)-2-hydroxy-ethylamino propoxy} benzyl] thiazolin-2,4-dione[obtained as described in preparative example 10] in a mixture of 2 ml of dimethylformamide and 2 ml of methylene chloride. Thus obtained crude product is purified column chromatography on silica is in the title compound in the form of mixtures of isomers, which elute from the column separately: (i) a first fraction consisting of 0.2 g of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above-mentioned formula (A), and a mixture of Rf(the flow rate)/ 0,56(thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 2:3 by volume); and (ii) a second fraction consisting of 0.2 g of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), the mixture has a Rf of 0.47( thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 2:3 by volume).

Example 3

3-{ 2-[4-(3-Methoxycarbonylmethyl-2,4-dioxothiazolidine-5-ylmethyl(phenoxy] -1-methylethyl}-5-(3-chlorophenyl)oxazolidin-2-on (compound N7)

< / BR>
Add 0,094 g 55% (W/V) dispersion of sodium hydride in mineral oil to a solution of 0.9 g 3-{2-[4-(2,4-dioxothiazolidine-5 - ylmethyl)phenoxy]-1-methylethyl}-5-(3-chlorophenyl)oxazolidin-2-[obtained as described in example 1 above] in 15 ml of dimethylformamide, and the mixture is stirred at Cabramatta. The reaction mixture was then allowed to stand at room temperature for three days, after which it is treated in accordance with the procedure described above in example 1, the thus Obtained crude product is purified column chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate in the ratio of 1:1 by volume, and get named in the title compound in the form of mixtures of isomers that elute from the column separately: (i) a first fraction containing 0.35 g of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), the mixture has a Rf of 0.56 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane with ethyl acetate in the ratio of 2:3 by volume); and (ii) a second fraction consisting of 0.3 g of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), and the mixture has an Rf of 0.35 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 2:3 by volume).

Example 4

3-{ 2-[4-(2,4-blowing procedure described above in example 1, but using 390 mg 5-(4-{ 2-[2-(2-naphthyl)-2-hydroxyethylamino propoxy}benzyl]thiazolidin - 2,4-dione [obtained as described in preparative example 5] 20 ml of acetonitrile and 460 mg of thiocarbonyldiimidazole get named in the title compound in crude form. The crude product is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume, and receive 250 mg named in the preparation of a compound that softens at a temperature of from 75oC to 85oC.

Example 5

3-{2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl}-5-(2,5-dimethoxy-3,4,6-trimetilfenil)oxazolidin-2-he

(connection N19)

< / BR>
Follow a procedure similar to that described above in example 1, but using 160 mg 5-(4-{2-[2-(2,5-dimethoxy-3,4,6 trimetilfenil) -2-hydroxyethylamino] -propoxy} -benzyl)thiazolidine-2,4-dione [obtained as described in preparative example 1] 6 ml of methylene chloride and 192 mg of carbonyldiimidazole, and get named in the title compound as crude product. This crude product is then purified column chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate in the ratio is from the column into two fractions (i) a first fraction, consisting of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 *2 in the above formula (A), the mixture has Bf0,52 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 1:2 by volume); and (ii) a second fraction consisting of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), and the mixture is Rf0,44 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 1:2 by volume).

Example 6

3-{ 2-[4-(2,4-Dioxothiazolidine-5 - ylmethyl)phenoxy]-1(R) -methylethyl}-5(R)-(3-chlorophenyl)oxazolidin-2-on (compound No. 5)

< / BR>
Follow the procedure described above in example 1, but using 13 g 5-(4-{ 2 -[2(R)-(3-chlorophenyl)-2 - hydroxyethylamino]-propoxy} benzyl)thiazolidine-2,4-dione [obtained as described in preparative example 4] a 4.86 g carbonyldiimidazole and 100 ml of dimethylformamide, to obtain 10.4 g named in the title compound, melting between 144oC and 149oC.

[]Phenoxy] -1(R)-methylethyl} -5(R)-(3-chlorophenyl)oxazolidin-2-tion (compound N 105)

< / BR>
Follow the procedure described above in example 1, but using 13 g of 5 -(4-{2(R)-[2(R)-(3-chlorophenyl) -2 - hydroxyethylamino]-propoxy} benzyl)thiazolidine-2-,4-dione [obtained as described in preparative example 4] 5.35 g of thiocarbonyldiimidazole and 100 ml of dimethylformamide, get 10,56 g named in the title compound, melting between 164oC and 173oC.

[]2D3+25,6 (c 0,995, chloroform).

To a mixture of 100 mg of the above compound with 1 ml of methanol add to 40.4 μl of 28% (V/V) solution of sodium methylate in methanol. The resulting mixture is moved at room temperature for 5 minutes after which time the methanol is removed by distillation under reduced pressure and to the residue is added ethyl acetate, to cause the formation of crystals. The resulting crystals are removed by filtration, and dried, to obtain 100 mg of the sodium salt monohydrate named in the title compound, melting between 216 and 218oC.

Example 8

3-{2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl}-5-(3-trifloromethyl)oxazolidin-2-tion (compound No. 112)

< / BR>
Follow the procedure described above in example 1, but using 1.0 g 5-(4-{2-[2-(3-triptoreline)-2-hydro is l of dimethylformamide and 380 mg of thiocarbonyldiimidazole, get named in the title compound in crude form. This crude product is purified column chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate in the ratio 3:2 by volume, and get named in the title compound as a mixture of two isomers that elute from the column separately: (i) the first fraction, which elute consists of 210 mg of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A); and the mixture has an Rf0,35 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio 3: 2 by volume); and (ii) the second fraction, which elute, consists of 180 mg of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), and the mixture is Rf0,25 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio 3:2 by volume).

Example 9

3-{2-[4-(3-Methoxycarbonylmethyl - 2,4-dioxothiazolidine-5-ylmethyl)phenoxy]-1(R)-methylethyl}-5(R)-(3-chloro is 2.0 g 3-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1 - methylethyl}-5-(3-chlorophenyl)oxazolidin-2 - it is obtained as described in example 6, 20 ml of dimethylformamide, 227 mg, 55% (V/V) dispersion of sodium hydride in mineral oil and 0.6 ml of methylpropanoate get named in the title compound as crude product. This crude product is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume, and get to 1.87 g named in the title compounds having Rf0,28 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume).

[]2D5+6,5o(c 1,002, chloroform).

Example 10

3-{ 2-[4-(3-Methoxycarbonylmethyl-2,4-dioxothiazolidine-5-ylmethyl phenoxy] -1(R)-methylethyl}-5(R)-(3-chlorophenyl)oxazolidin-2-tion (compound N 107)

< / BR>
Follow the procedure described above in example 3, but using 2.0 g 3-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1(R)-methylethyl} -5(R)-(3-chlorophenyl)oxazolidin-2-thione [obtained as described in example 7] 20 ml of dimethylformamide, 220, mg, 55% (V/V) dispersion of sodium hydride in mineral oil and of 0.58 ml of methylpropanoate, get named sagalowsky as eluent a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume, and get 1,03 g named in the title compounds having Rf0,25 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of etichetta and hexane in a ratio of 1:2 by volume).

[]2D5+28,2o(c 1,000, chloroform).

Example 11

3-{ 2[4-(3-tert-Butoxycarbonylmethyl-2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1(R)-methylethyl} -5(R)-(3-chlorophenyl)oxazolidin-2 - tion (compound N 108)

< / BR>
Follow the procedure described above in example 3, but using 250 mg 3-{ 2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] - 1(R)-methylethyl} -5(R)-(3-chlorophenyl)oxazolidin-2-thione [obtained as described in example 7] 10 ml of dimethylformamide, 23 g of 55% (W/V) dispersion of sodium hydride in mineral oil and 0,088 ml of tert-butylbromide get named in the title compound in crude form. This crude product is then purified column chromatography on silica gel, using as eluate a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume, and obtain 229 mg named in the title compound with Rf=0,26 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume).

< / BR>
Follow the procedure described above in example 1, but using 125 mg of 5-(4{ 2(R)-[2(R)-(3-chlorophenyl) -2 - hydroxyethylamino] -4-methylpentanoic}benzyl)thiazolidine-2,4-dione [obtained as described in preparative example 19] of 57.5 mg carbonyldiimidazole and 10 ml of dimethylformamide, get named in the title compound in crude form. This crude product is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume, and obtain 105 mg of the named header compounds having Rf=0,46 (thin layer chromatography on silica gel, as a releasing solvent mixture of ethyl acetate and hexane in a ratio of 1:1 by volume).

Example 13

3-{ -2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy] - 1(R)-isobutylether} -5(R)-(3-chlorophenyl)oxazolidin-2-tion (compound N 151)

< / BR>
Follow the procedure described above in example 1, but using 12 mg of 5-(4-{ 2(R)-2(R)-(3-chlorophenyl)-2-hydroxyethylamino] -4-methylpentanoic} benzyl)thiazolidine-2,4 dione [obtained as described in preparative example 19] 6,8 mg thiocarbonyldiimidazole and 2 ml of dimethylformamide, and get named in the title compound in crude form. This crude product is then purified teenie 1:1 by volume, and get to 11.9 mg named in the title compounds having Rf=0,54 (thin layer chromatography on silica gel, as a releasing solution using a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume).

Example 14

3-{ 2-[4-(3-Ethoxycarbonylethyl-2,4-dioxothiazolidine-5-ylmethyl)-phenoxy] -1(R)-methylethyl}-5(R)-(3-chlorophenyl)oxazolidin-2-tion (connection N152)

< / BR>
To a solution of 150 mg 3-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1(R)-methylethyl} -5(R)-3-chlorophenyl)oxazolidin-2-thione (obtained as described in example 7) in 10 ml of dimethylformamide added 13 mg of 55% (W/V) dispersion of sodium hydride in mineral oil, and the mixture is stirred at room temperature for 1 h At the end of this period, with ice cooling is added slowly to 0.04 ml of ethyl-3-bromopropionate. The mixture was then stirred at room temperature for 4 h, after which it was allowed to stand overnight at the same temperature. Then add to 0.22 g of potassium carbonate and 0.2 ml of ethyl-3-bromopropionate, and the mixture is heated at 60oC for 4 h and Then to the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. The resulting extract is then dried over anhydrous sodium sulfate, and the solvent is removed by distillation E. eluent mixture of ethyl acetate and hexane in a ratio of 1:2 by volume, receive 25 mg named in the title compounds having Rf=0,45 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:1).

Example 15

3-{ 2-[4-(2,4-Dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl} -5-(3,5-dimethyl-4-hydroxyphenyl)oxazolidin-2-on (compound No. 17)

< / BR>
Follow the procedure described above in example 1, but using 250 mg 5 -[4-{ 2-(2-[3,5-dimethyl-4-hydroxyphenyl-2 - hydroxyethylamino)propoxy}benzyl, thiazolidin-2,4-dione (obtained as described in preparative example 22), 95 mg of carbonyldiimidazole and 3 ml of dimethylformamide, get named in the title compound in crude form. This crude product is then purified column chromatography on silica gel, using as eluent SMEs ethyl acetate and hexane in a ratio of 1:1 by volume, and get named in the title compound in the form of two isomeric compounds, which elute from the column separately: (i) a first fraction consisting of 55 mg of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively,*1 and*2 in the above formula (A), and the mixture is Rf= 0,53 (thin layer chromatography n the volume) and (ii) a second fraction, consisting of 50 mg of a mixture of isomers having the configuration at the asymmetric carbon atoms marked, respectively, *1 and*2 in the above formula (A), and the mixture is Rf= 0,41 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 2: 1 by volume).

Preparative example 1

5-(4-{ -2-[2-(2,5-Dimethoxy-3,4,6-trimetilfenil)-2 - hydroxyethylamino] propoxy}benzyl)thiazolidine-2,4-dione

A solution of 1.23 g of 2-amino-1-(2,5-dimethoxy-3,4,6-trimetilfenil)ethanol [obtained as described in preparative example 14] and 3.0 g of 5-[4-(2-oxopropoxy)benzyl] -3-triphenyl-methylthiazolidine-2,4-dione [obtained as described in preparative example 20] in 300 ml of benzene is heated at the boiling point under reflux for about 4 h, during which the water formed during the reaction is distilled off in the form of an azeotrope with benzene. The reaction mixture is then freed from the benzene by distillation under reduced pressure. The residue is dissolved in a mixture of 100 ml of absolute methanol and 100 ml of absolute ethanol, and then to the solution was added 8.5 g of sodium borohydride. The resulting mixture was then heated PI boiling point with the inverse reduced pressure. The residue is then mixed with water, and then extracted with ethyl acetate. An ethyl acetate layer is then washed twice with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and to the residue is added, while cooling with ice, 50 ml triperoxonane acid. The resulting mixture was then stirred at room temperature for one hour. At the end of this time triperoxonane acid is distilled off under reduced pressure, and the residue is mixed with water. Thus obtained aqueous mixture was then neutralized with an aqueous solution of potassium carbonate and then extracted with ethyl acetate. The extract is washed twice with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed by distillation at reduced pressure, then the residue purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and ethanol in a ratio of 5: 1 by volume, receive 160 mg named in the title compounds having Rf=0,3 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and utensil}thiazolidin-2,4-dione

(2A) 5-4-2(P)-tert-Butoxycarbonylamino benzyl-3 - triphenyltetrazolium-2,4-dione

To a solution of 20.7 g of triphenylphosphine in 300 ml of benzene under ice cooling, is added dropwise to 13.2 g of diethylazodicarboxylate. The mixture was then stirred at room temperature for 30 min, then added to 35.0 g of 5-(4-hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione[obtained as described in preparative example 11] the mixture is Then stirred at room temperature for 1 h, then added to the mixture of 13.2 g of 2-tert-butoxycarbonylamino-1-propanol, and the mixture is left to stand overnight at the same temperature. Then add to the mixture one by one, and in 3 or 4 admission, of 40.9 g of triphenylphosphine, 23,68 ml of diethylazodicarboxylate and 33 g of 2-tert-butoxycarbonylamino-1 - propanol, and the mixture is stirred for 2 days. At the end of this time the reaction mixture is freed from benzene by distillation under reduced pressure. The residue is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:3 by volume, obtain 30.0 g of 5-{4-[2(R)-tert-butoxycarbonylamino-I-propoxy] benzyl} -3-triphenyltetrazolium-2,4-dione, melting between 153oC and 157
To a solution of 85.5 g of 5-{4-[2-tert - butoxycarbonylamino]benzyl}-3-triphenyltetrazolium-2,4-dione [obtained as described above in stage (a)] in 700 ml of methylene chloride under ice cooling is added dropwise to 500 ml triperoxonane acid, and the mixture is stirred at room temperature for 4 hours after this time the reaction mixture is freed from methylene chloride and triperoxonane acid by distillation under reduced pressure. The residue is then proscout with a mixture of benzene and a small amount of ethyl acetate, and the crystals that fall, collected by filtration. These crystals precrystallization from a mixture of methanol and ethyl acetate, get 36,9 named in the title compound, melting between 162oC and 166oC.

-13,0o(c=0,885, methanol).

Preparative example 3

5-{ 4-[2(R)-(3-Chlorophenyl)-2 - tert-butyldimethylsilyloxy] propoxy]benzyl}thiazolidine-2,4-dione

A mixture of 36.5 trifenatate 5-{4- [2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione [obtained as described in preparative example 2] to 98.4 g --(tert-butyldimethylsiloxy)-a-(3-chlorophenyl)-acetaldehyde [obtained as described in preparative example 12] and 400 ml of absolute methanol paramashiva mixture is added 29.0 g lamborginid sodium, small portions, and the mixture is left to stand overnight at room temperature. At the end of this time the methanol is distilled off under reduced pressure, the residue is mixed with water and ethyl acetate, and an ethyl acetate layer is separated from the mixture. Then an ethyl acetate layer was washed with saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 2:1 by volume, get 46,5 g named in the connection header.

[]2D3-26,3o(c=0,988, chloroform).

Preparative example 4

5-(4-{ 2(R)-[2(R)-(3-Chlorophenyl)-2 - hydroxyethylamino] propoxy} -benzyl)thiazolidine-2,4-dione

To a solution of 46.2 g of 5-(4-{2(R)-[2(R)-(3-chlorophenyl) -2-tert-butyldimethylsilyloxy] propoxy} benzyl)thiazolidine - 2,4-dione [obtained as described in preparative example 3] in 500 ml of tetrahydrofuran added, with ice cooling, 88 g of tetrabutylammonium, and the mixture is stirred at room temperature for 15 hours At the end of this time, the tetrahydrofuran is distilled off under reduced with rastvorom sodium chloride, and dried over anhydrous sodium sulfate, then the solvent is distilled off under reduced pressure. The residue is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and ethanol in a ratio of 5:1 by volume, get named in the title compound in the form of crude crystalline product. These crystals are then recrystallized from a mixture of ethyl acetate and ethanol, and get 27,1 g named in the title compound, melting between 100oC and 112oC.

[]2D3-4,4o) (c=1,005, methanol).

Preparative example 5

5-(4-{ 2-[2-(2-Naphthyl)-2-hydroxyethylamino] propoxy} benzyl) -capsaicin-2,4-dione

Follow the procedure described in preparative example 10, but using 520 mg of 2-amino-1-(2-naphthyl)ethanol [obtained as described in preparative example 8] 650 mg of 5 - 4-(2-oxopropoxy)benzyl, thiazolidin-2,4-dione [obtained as described in preparative example 9] 150 ml of benola, 100 ml of absolute methanol and 1.25 g of sodium borohydride get named in the workpiece connection in raw form. This crude product is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and ethanol with o
C.

Preparative example 6

5-(4-{ 2-[2-(3-Triptoreline)-2 - hydroxyethylamino] propoxy} -benzyl)thiazolidine-2,4-dione

Follow the procedure described in preparative example 10, but using 5,88 g 2-amino-1-(3-triptoreline)-ethanol [obtained as described in preparative example 13] 8 g of 5-[4-(2-about isopropoxy)benzyl]-thiazolidine-2, 4-dione [obtained as described in preparative example 9] 200 ml of benzene, 150 ml of absolute methanol and 5.4 g of cyanoborohydride sodium, get named in the title compound in crude form. This crude product is then purified column chromatography on silica gel, using as eluent ethyl acetate receive 4,05 g named in the harvesting of compounds, melting between 100oC and 105oC.

Preparative example 7

2-Amino-1-(3-chlorophenyl)ethanol

To a mixture of 112 g of trimethylsilylmethyl and 0.1 g of iodine zinc is added dropwise 140 g of 3-chlorobenzaldehyde, and the resulting mixture is heated on an oil bath and maintained at a temperature of 90oC for 2.5 hours At the end of this time the reaction mixture is added dropwise to a mixture of 50 g of lithium aluminum hydride and 1200 ml of tetrahydrofuran, and the mixture is then heated at a temperature of keel 15% (W/volume) aqueous solution of sodium hydroxide and 150 ml of water, in the order as listed. The insoluble matter is filtered off and the filtrate is concentrated by evaporation under reduced pressure. The concentrate is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate, ethanol and triethylamine in the ratio 10:4:1 by volume, and subsequently distilled in vacuo, and receive 66 g named in the title compound in the form of a liquid, boiling at 140-141oC (2.5 mm RT.article 333 PA).

Preparative example 8

2-Amino-1-(2-naphthyl)ethanol

A mixture of 7.4 g of 2-naphthaldehyde, to 9.93 g trimethylsilylmethyl and catalytic amount of iodine zinc is heated on an oil bath with a temperature of 90oC for 2 hours after this time the reaction mixture is added dropwise and under ice cooling to a mixture of 5.7 g of lithium aluminum hydride and 500 ml of tetrahydrofuran, and the resulting mixture was then heated at boiling temperature under reflux for 3 hours To the mixture in the order listed, to 5.7 ml of water and 5.7 ml of 15% (W/volume) aqueous solution of sodium hydroxide and 17.1 ml of water, dropwise. The insoluble matter is filtered off and the filtrate is concentrated by evaporation under reduced pressure. The crystals obtained from concentrate,istalol, melting at between 113oC and 116oC.

Preparative example 9

5-[4-(2-Oxopropoxy)benzyl]thiazolidin-2,4-dione

9 (a) 1-(4-Aminophenoxy)propane-2-he hydrochloride

A stream of hydrogen is passed through a mixture of 19.6 g of 1-(4-nicotinate)propane-2-it, 300 ml of methanol, 30 ml of concentrated aqueous hydrochloric acid and 4 g of 10% (in volume) of palladium on charcoal at room temperature for 5 hours after which time the catalyst is filtered off and the filtrate is concentrated by evaporation under reduced pressure to obtain 20 g of the named header connection. This connection directly, without further purification, is used in the next stage.

9 (b) Ethyl-2-chloro-3-[4-(2-oxopropoxy)phenyl]propionate

To a mixture of 20 g of 1-(4-aminophenoxy)propane-2-it, hydrochloride [obtained in the above stage (a)] and 400 ml of acetone are added 50 ml of 35% (W/volume) aqueous hydrochloric acid, and then to the resulting mixture dropwise and with cooling with ice add a solution of 12 g of sodium nitrite in 20 ml of water; the mixture is then stirred at the same temperature for 20 minutes At the end of this time to a mixture of parts added 130 g of acrylate and then 3.2 g of copper oxide, and received in rezvanian under reduced pressure and the concentrate is mixed with water and ethyl acetate. An ethyl acetate layer is separated, washed with water and dried over anhydrous sodium sulfate; the solvent is then removed by distillation under reduced pressure. The resulting residue is purified column chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate in the ratio of 5:1 by volume, and obtain 11.3 g named in the title compounds having Rf0,31 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of hexane and ethyl acetate in the ratio of 5:1 by volume).

9(c) 5-[4-(2-Oxopropoxy)benzyl]thiazolidin-2,4-dione

A mixture containing 12 g of ethyl-2-chloro-3-[4 - (2-oxopropoxy)-phenyl]propionate [obtained as described above in stage (b)] 5 g of thiourea and 30 ml of sulfolane is heated at 90oC for 3 h, and then to the mixture was added 100 ml of nanometrology ether of ethylene glycol and then heated for 4 hours At the end of this time the reaction mixture is added 40 ml of water and 20 ml of aqueous concentrated hydrochloric acid, and the resultant mixture heated for 4.5 hours at an oil bath at 100oC. After that the reaction mixture is mixed with water and ethylacetate, and then an ethyl acetate layer is separated, p is the pressure. The resulting residue is purified columnar chromatography on silica gel using the method of gradient elution with mixtures of hexane and ethyl acetate in a ratio lying in the range from 3:2 to 2:3 by volume as the eluent, followed by crystallization from a mixture of ethyl acetate and hexane, and get to 4.2 g named the title compound as crystals, melting at 158 159oC.

Preparative example 10

1/2 ethyl Acetate 5-[4-{2-2-(3-chlorophenyl)-2-hydroxyethylamino]- propoxy} benzyl, thiazolidin-2,4-dione

A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol [obtained as described in preparative example 7] and 3.58 g of 5-[4-(2-oxopropoxy)benzyl] thiazolidin-2,4-dione [obtained as described in preparative example 9] in 50 ml of benzene is heated at the boiling point under reflux for 1.5 hours while the water formed during the reaction is continuously removed. At the end of this time used the benzene is removed by distillation under reduced pressure. The resulting residue is dissolved in 100 ml of absolute methanol, and then the resulting solution was added 3 g of sodium borohydride. The reaction mixture is left to stand at room temperature is Oh. The resultant aqueous mixture is extracted with ethyl acetate, and the extract is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the resultant residue purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and ethanol in a ratio of 10: 1 by volume. The product is recrystallized from ethyl acetate, to obtain 0.74 g named the title compound as crystals, melting between 100oC and 125oC.

Preparative example 11

5-(4-Hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione

11(a) 5-(4-Acetoacetanilide)thiazolidin-2,4-dione

A mixture containing 200 g of p-hydroxybenzaldehyde, 229 g thiazolidin-2,4-Dinga, 280 g of sodium acetate and 660 ml of dimethylacetamide, and stirred at 150oC for 1 h the Mixture was then cooled and to it was added 540 ml of dimethylacetamide and 370 ml of acetic anhydride. The resulting mixture was then stirred at 50oC for 1.5 h, after which it was poured into water. A solid substance that falls, is collected by filtration, washed with water and dried over anhydrous sodium sulfate, and obtain 390 g named in the title compound, melting between 238Liden)thiazolidin-2,4-dione obtained, (as described above in stage (a)] in 80 ml of acetic acid, and the mixture hydronaut, passing through a solution of hydrogen at atmospheric pressure at 90oC for 5 h in the presence of 2.0 g of 10% (in volume) of palladium on charcoal. At the end of this time the catalyst is filtered off and the filtrate is diluted with toluene. The solvent acetic acid is then removed by distillation in the form of an azeotropic mixture with toluene. The crystals, which are allocated by adding to the concentrate of toluene and hexane, collected by filtration and dried, to obtain 1.8 g named in the title compound, melting between 115oC and 117oC.

11(c) 5-(4-Acetoxyphenyl)-3-triphenyltetrazolium-2,4-dione

To a solution of 9.0 g of 5-(4-acetoxyphenyl)thiazolidin-2,4-dione [obtained as described above in stage (b)] in 70 ml of methylene chloride add 3,43 g of triethylamine, and the resulting mixture is added dropwise a solution of 9.45 g of triphenylmethylchloride in 30 ml of methylene chloride. The mixture was then stirred at room temperature for 1 h, after which it was allowed to stand overnight at the same temperature. At the end of this time the reaction mixture is mixed with water and ethyl acetate, and the organic layer was separated, washed nassen the reduced pressure, and the crystals formed are washed with a mixture of hexane and ethyl acetate and dried, get 7,86 g named in the title compound, melting between 152oC and 156oC.

11(d) 5-(4-Hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione

The solution to 2.99 g of 28% (in volume) of methanol solution of sodium methoxide in 10 ml of methanol is added dropwise under ice cooling to a solution 7,86 g of 5 -(4-acetoxyphenyl)-3-triphenyltetrazolium-2,4-dione [obtained as described above in stage (c)] in 70 ml of toluene, and the resulting mixture was stirred at room temperature for 1 h, after which it was allowed to stand overnight at the same temperature. The pH value of the reaction mixture is then brought to 4 by adding 1N aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is then removed by distillation under reduced pressure, and the crystals which have appeared in the residue is collected, washed with hexane and dried, to obtain 6.0 g named in the title compound, melting between 158oC and 160oC.

Preparative example 12

(R)--tert-Butyldimethylsilyloxy-a-(3-chlorophenyl)acetal-Devid

12(a) 3-Charmingalina the th of zinc is heated at 90oC for 2 h under stirring. The reaction mixture is cooled with ice, and add 350 ml of concentrated aqueous hydrochloric acid. The resulting mixture was then heated at boiling temperature under reflux for 1 h, after which it is mixed with water and ethyl acetate. An ethyl acetate layer is separated and mixed with 30% (W/volume) aqueous solution of sodium hydroxide. The aqueous layer was separated, washed three times with ethyl acetate and then acidified with concentrated hydrochloric acid, whereupon the mixture is extracted with ethyl acetate. The extract is washed with water, and dried over anhydrous sodium sulfate. The solvent is then removed by distillation under reduced pressure, and get 172 g named the title compound as crystals, melting between 110oC and 114oC.

12(b) (R)-3-Charmingalina acid and (S)-3-charmingalina acid

A mixture of 100 g of 3-harmondale acid [obtained as described above in stage (a)] and 32.7 g -(+)-1-phenethylamine dissolved in a mixture of methanol and diethyl ether and recrystallized from it. The resulting crystals are collected by filtration, precrystallization three times from a mixture of methanol and diethyl ether, and mixed with aqueous hydrochloric Extract is dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure, obtain 11.4 g of 3-harmondale acid in the form of crystals, melting between 102oC and 105oC.

[]2D3-153,7o(c 1,026, chloroform).

To the filtrate obtained as described above, add hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The resulting residue is mixed with 32,7 g -(-)-1 - phenethylamine and three times recrystallized from a mixture of methanol with diethyl ether, to obtain 11.2 g of 3-harmondale acid in the form of crystals, melting between 101oC and 104oC.

[]2D3+151,9o(c 1,008, chloroform).

12 (c) Methyl-(R) -3 - chloromandelic

To a solution of 28 g-3-harmondale acid [obtained as described above in stage (b)] in a mixture of 300 ml of methanol and 700 ml of benzene is added dropwise to 18.3 ml of 10% (W/volume) solution trimethylsilyldiazomethane in hexane and the resulting mixture is stirred for 1 h At the end of this time the solvent is removed by distillation under reduced pressure to obtain 28.6 g named in the title compound, having []2D3119,3o(c and 1.00, chloroform) and Rf 0,36 (tonkas the>

12(c) Methyl-(R) - tert-butyldimethylsilyloxy-3-chlorophenylacetic

A solution of 31.6 g of tert-butyldimethylsilyloxy in 200 ml of dimethylformamide under ice cooling is added dropwise to a solution of 28 g of methyl-3-chloromandelic[obtained as described above in stage (c)] and 28.5 imidazole in 300 ml of dimethylformamide, and the resulting mixture was stirred at the same temperature for 30 min, after which it was allowed to stand overnight at 40oC. after this time the reaction mixture is concentrated by evaporation under reduced pressure and the residue is mixed with water and ethyl acetate. An ethyl acetate layer is separated and dried over anhydrous sodium sulfate and then the solvent is removed by distillation under reduced pressure. The resulting residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1-15 volume, and get to 42.2 g named the title compound as crystals, melting between 36oC and 38oC.

[]2D3-39,1o(c 1,014 registered, chloroform).

12 (e) (R) - tert-Butyldimethylsilyloxy - a -(3-chlorophenyl)-acetaldehyde

A solution of 26 g of methyl - tert, butyldimethylsilyloxy-3-chlorophenyl is cooled to -60oC, and then cooled solution is added dropwise 124 ml of a 1M solution of diisobutylaluminium in hexane. The resulting mixture was stirred at the same temperature for 3 h, after which there was added 10 ml of water, and the temperature of the mixture was allowed to gradually rise to room temperature. The reaction mixture is then mixed with water and ethyl acetate, after which it is stirred for 30 minutes, the Insoluble matter is filtered off using a Celite filter (trade mark), and an ethyl acetate layer separated from the filtrate and dried over anhydrous sodium sulfate. The solvent ethyl acetate is removed by distillation under reduced pressure, and the residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:60 by volume, and get named in the title compound having Rf 0,36 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:60 by volume).

Preparative example 13

2-Amino-1-(3-triptoreline)ethanol

Using a procedure similar to that described in preparative example 7, but using 25 g of 3 triftormetilfullerenov, 15,71 g trimate the m purifying the reaction product column chromatography on silica gel with a mixture of ethyl acetate and benchmark in the ratio 2:1 by volume as the eluent, get 25,2 g named the title compound as crystals, melting at 72oc, and having an Rf of 0.25 (thin layer chromatography on silicagel, as a releasing solvent, a mixture of ethyl acetate, ethanol and triethylamine in the ratio 10:3:1 by volume).

Preparative example 14

2-Amino-1-(2,5-dimethoxy-3,4,6 trimetilfenil)ethanol

Following the procedure similar to that described in preparative example 7, but using 67 g of 2,5-dimethoxy-3,4,6 trimethylbenzaldehyde, 51 ml of trimethylsilylacetamide, 50 mg iodine zinc, 36,63 g alumiweld lithium and 2 l of tetrahydrofuran, and then purifying the reaction product by recrystallization from a mixture of ethyl acetate and hexane, get 56,2 g named the title compound as crystals, melting between 110oC and 112oC.

Preparative example 15

2(R)-tert-Butoxycarbonylamino-4-methylpentanol

To a solution of 10 g of (R)-(-)-leucinol in 100 ml of dioxane and 50 ml of tetrahydrofuran while cooling with ice add 11,83 ml of triethylamine. Then to the reaction mixture is added dropwise a solution of 18.6 g of di - tert-BUTYLCARBAMATE in 50 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 3 h, after which it will dissolve the oil, with Rfof 0.5 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume).

Preparative example 16

5-{ 4-[2(R)-tert-Butoxycarbonylamino - 41-methylpentylamino]benzyl}-3-triphenyltetrazolium-2,4-dione

To a mixture of 2.28 g of 1,1'-azodicarbonamide, 3,34 ml tributylphosphine and 100 ml of anhydrous benzene is added 2.1 g of 5 -(4 - hydroxybenzyl)-3-triphenyltetrazolium-2,4-dione [obtained as described in preparative example 11] the resulting mixture is stirred at room temperature for 1.5 hours, then add 2 g 2(P)-tert-butoxycarbonylamino-4-methylpentanol [obtained as described in preparative example 15] The mixture was then stirred for 5 h at the same temperature. At the end of this time, insoluble matter is filtered off and the filtrate concentrated. The resulting residue is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:4 by volume, and gain of 1.05 g named in the title compounds having Rf0,54 (thin layer chromatography on silica gel, the quality of the Preparative example 17

5-{4-[2(R)-Amino-4 - methylpentylamino]benzyl}thiazolidine-2,4-dione, triptorelin

Follow a procedure similar to that described in preparative example 2, but use of 1.03 g of 5-{4-[2(R)- tertbutoxycarbonyl-4-methylpentylamino] benzyl} -3-triphenyltetrazolium-2-, 4-dione [obtained as described in preparative example 16] 10 ml of methylene chloride and 10 ml triperoxonane acid. After completion of the reaction, the methylene chloride and triperoxonane acid is removed by distillation under reduced pressure, and the residue is washed with toluene, to obtain 640 mg of the named header connection.

Preparative example 18

5-(4-{ 2(R)-[2(R)-(3-Chlorophenyl)-2 - tert-butyldimethylchlorosilane] -4-methylpentanoic}benzyl)thiazolidine-2,4-dione

Follow a procedure similar to that described in preparative example 3, but using 540 mg of 5 -{4-[2)R)-amino-4 - methylpentylamino]benzyl}thiazolidine-2,4-dione of triptoreline [obtained as described in preparative example 17] 630 mg of (R) -a-(tert-butyldimethylsilyloxy) a-(3-chlorophenyl)-acetaldehyde [obtained as described in preparative example 12] 614 mg cyanoborohydride of sodium and 10 ml of absolute methanol, and you get named in the title compound in crude form. This crude product is a ratio of 1:3 by volume, and obtain 420 mg of the named header compounds having Rf0,70 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume).

Preparative example 19

5-(4-{ 2(R)-[2(R)-(3-Chlorophenyl)-2 - hydroxyethylamino]-4-methylpentanoic} benzyl)thiazolidine-2,4-dione

Follow a procedure similar to that described above in preparative example 4, but using 350 mg of 5-(4-{2(R)-[2(R)-(3-chlorophenyl) -2-tert-butyldimethylsilyloxy-4 - methylpentanoic} benzyl] thiazolidin-2,4-dione [obtained as described in preparative example 18] 1.39 g of tetrabutylammonium and 10 ml of tetrahydrofuran, and get named in the title compound in crude form. This crude product is then purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume, and get 180 mg named in the title compounds having Rf0,28 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:1 by volume).

Preparative example 20

5-[4-(2-Oxopropoxy)benzyl]-3-triphenylimidazole,2 g of 5 -(4-hydroxybenzyl)-3 - triphenyltetrazolium [received so as described in preparative example 11), and the mixture is stirred at room temperature until, until you added to dissolve the connection. Then to the mixture in an ice bath, is added dropwise 4 g bromoacetone, and then the mixture is left to stand at room temperature overnight. At the end of this time the reaction mixture, while cooling with ice, add 2.2 g of tert-butoxide potassium and 10 g of bromoacetone. The resulting mixture was then stirred at room temperature for 2 h, after which the reaction mixture is concentrated by evaporation under reduced pressure. Then to the residue add saturated aqueous solution of sodium chloride. The resulting mixture is extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The ethyl acetate is then removed by evaporation under reduced pressure, and the resulting residue is purified column chromatography on silica gel, using as eluent a mixture of etelaat and hexane in a ratio of 2:5 by volume, and get named in the title compound with Rf0,46 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and hexane in a ratio of 1:2 by volume 3,5-Dimethyl-4-methoxysalicylaldehyde

A solution of 9.0 g of 3,5-dimethyl-4-hydroxybenzaldehyde in 20 ml of dimethylformamide is added dropwise and under ice cooling to a suspension of 3.14 g of 55% (W/V) dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture was then stirred for 20 min, then cooling with ice add 5.8 g methylchlorosilanes ether. The resulting mixture was then stirred at room temperature for 1 h after this time the reaction will smeet water is added and the mixture extracted with ethyl acetate. The extract is then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed and then distillation under reduced pressure and get 11,0 g named in the connection header.

21(b) 2-Amino-1-(3,5-dimethyl-4-methoxyethoxymethyl)ethanol

Follow a procedure similar to that described above in preparative example 7, but using 11 g of 3,5-dimethyl-4-methoxy-methoxybenzaldehyde [obtained as described above in stage (a)] 14,05 g trimethylsilylmethyl, a catalytic amount of iodine zinc, 6,47 g of lithium aluminum hydride and 120 ml of tetrahydrofuran, and get 12,67 g named in the title compound, melting between 62oC and 65oC.

21 (c) 2-Amino-canola [received so as described above in stage (b)] in 200 ml of 4 N solution of hydrogen chloride in dioxane was stirred at room temperature for 18 hours the Solvent is then removed by distillation in vacuo under reduced pressure, and get 10,45 g named in the title compound, melting between 170oC and 172oC.

Preparative example 22

5-[4-{ 2-(2-[3,5-Dimethyl-4-hydroxyphenyl] -2-gidroksietilimino)- propoxy}benzyl]thiazolidin-2,4-dione

To a solution of 2.18 g of the hydrochloride of 2-amino-1-(3,5-dimethyl-4-hydroxyphenyl)ethanol [obtained as described in preparative example 21] in 100 ml of ethanol under ice cooling type of 1.93 g of 28% (V/V) solution of sodium methylate in methanol. Then the solvent is removed by distillation under reduced pressure and the mixture is concentrated to obtain a residue. Follow a procedure similar to that described above in example 10, using the remainder of the 2-amino-1- (3,5-dimethyl-4-hydroxyphenyl)ethanol, obtained above, 2.8 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidin-2,4-dione [obtained as described in preparative example 9] 50 ml of benzene, 2.5 g of sodium borohydride and 80 ml of absolute methanol, and get named in the title compound in crude form. This crude product is then purified column chromatography on silikatnogo in the title compound, with Rf=0,48 (thin layer chromatography on silica gel, as a releasing solvent, a mixture of ethyl acetate and ethanol in the ratio of 4:1 by volume).

Example 16

3-(2-(4-(3-carboxymethyl-2,4-dioxothiazolidine-5-yl-methyl)-phenoxy)-1(R)-methylethyl)-5(R)-(3-chlorophenyl)oxazolidin-2-tion (compound 106)

< / BR>
A mixture of 460 - g 3-(2-(4-(3-butoxycarbonylmethyl-2,4-dioxothiazolidine-5-yl-methyl)phenoxy)-1(R)-methylethyl)-5(R)-(3 - chlorophenyl)oxazolidin-2-thione obtained in example 11 and 20 ml of 4n HCl in dioxane is stirred at room temperature for 3 h and then at 50oC for 4 h then the solvent is evaporated under reduced pressure and the resulting residue purified by HPLC method: stationary phase ODS; mobile phase a mixture of acetonitrile-water in the ratio 6:4, receiving 40 g of target compound with so pl. 140-170oC.

1. Derivatives of oxazolidine formula I

< / BR>
where R1WITH8is an alkyl group;

X is an oxygen atom or sulfur;

Y is a hydrogen atom or a group of formula-A-W,

where a1WITH6-Allenova group;

W is a hydrogen atom or a C1WITH6is an alkyl group;

Ar is unsubstituted aryl group containing from 6 to 10 ring atoms coal least one Deputy, selected from the group consisting of substituents AND'moreover , the mentioned substituents AND'selected from the group consisting of halogen atoms, halogenating groups in which the alkyl part contains 1 to 4 carbon atoms, hydroxyl groups, alkyl groups containing from 1 to 4 carbon atoms, and alkoxygroup containing from 1 to 4 carbon atoms,

or their pharmaceutically acceptable salts, or esters.

2. Derived oxazolidine under item 1, where Y is a hydrogen atom or a group of formula-A-W, where a has the value specified in paragraph 1, and W is a hydrogen atom or a C1WITH6is an alkyl group.

3. Derived oxazolidine under item 1, where R1- C6is an alkyl group.

4. Derived oxazolidine under item 1, where R1- C4is an alkyl group.

5. Derived oxazolidine under item 1, where R is a methyl or ethyl group.

6. Derived oxazolidine under item 1, where a1- C4-Allenova group.

7. Derived oxazolidine under item 1, where a methylene or ethylene group.

8. Derived oxazolidine under item 1, where AG aryl group containing 6 to 10 ring carbon atoms, or an aryl group containing 6 to 10 atoms wasteaway of deputies AND'whose values are specified in paragraph 1.

9. Derived oxazolidine under item 1, where AG unsubstituted phenyl group, unsubstituted naftalina group or phenyl or naftalina group substituted by 1-5 substituents which can be the same or different, selected from the group consisting of substituents AND'whose values established in paragraph 1.

10. Derived oxazolidine under item 1, where Ar is unsubstituted phenyl group, unsubstituted naftalina group or phenyl group substituted by 1 to 5 substituents that are the same or different, selected from the group consisting of substituents AND'moreover , the mentioned substituents AND'selected from the group consisting of halogen atoms, triptoreline groups, hydroxyl groups, alkyl groups containing 1 to 4 carbon atoms, and alkoxygroup containing 1 or 2 carbon atoms.

11. Derived oxazolidine under item 1, where Ar1phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-forfinal, 3-triptoreline, 3-were, 3-methoxyphenyl, 3,5 - dichlorophenyl, 3,5-di-tertbutyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-forfinal, 2,5-dimethoxy-3,4,6-trimetilfenil, 3,5-dimethyl-4-hydroxyphenyl or 2-naphthyl.

m is hydrogen or a group of formula-COOH, where a1WITH4-Allenova group; AG - aryl group containing 6 to 10 ring carbon atoms, or an aryl group containing 6 to 10 carbon atoms in the ring is substituted by 1 to 5 substituents, which may be the same or different, selected from substituents AND'whose values are specified in paragraph 1, or when the Y group of formula-COOH, WITH1WITH4-alkylether,

or its pharmaceutically acceptable salt.

13. Derived oxazolidine under item 1, where R1- C4is an alkyl group; X is an oxygen atom or sulfur; Y is a hydrogen atom or a group of formula-COOH, where a methylene or ethylene group; Ar is unsubstituted phenyl group, unsubstituted naftalina group or phenyl or naftalina group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of substituents AND'whose values are specified in paragraph 1, or when the Y group of formula-COOH, (1WITH4-alkylether,

or its pharmaceutically acceptable salt.

14. Derived oxazolidine under item 1, where R1- C4is an alkyl group; X is an oxygen atom or a sulfur atom; Y is a hydrogen atom or a group of formula-CH2COOH; Ar is unsubstituted phenyl, equal or different, selected from substituents AND'mentioned substituents AND'selected from the group consisting of halogen atoms, triptoreline groups, hydroxyl groups, alkyl groups containing 1 to 4 carbon atoms, and CNS groups containing 1 or 2 carbon atoms, or when the Y group of formula CH2COOH, WITH1WITH4-alkylether,

or its pharmaceutically acceptable salt.

15. Derived oxazolidine under item 1, where R is a methyl or ethyl group; X is an oxygen atom or sulfur; Y is a hydrogen atom or a group of formula-CH2COOH; Ar is a group selected from the group consisting of phenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 3-bromophenyl, 3-ftoheia, 3-triptoreline, 3-methylphenyl, 3-methoxyphenyl, 3,5-dichlorophenyl, 3,5-di-tert.butyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-ftoheia, 2,5-dimethoxy-3,4,6-trimetilfenil, 3,5 - dimethyl-4-hydroxyphenyl and 2-naphthyl, or when the Y group of formula-CH2COOH, its methyl or ethyl ester or its pharmaceutically acceptable salt.

16. Derived oxazolidine under item 1, selected from the group consisting of 3-{ 2-[4- (2,4-dioxothiazolidine-5-ylmethyl)phenoxy] -1-methylethyl}-5-(3-chlorophenyl)-oxazolidin-2-it or its pharmaceutically receiving arboletes-2,4-dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl} -5-(3 - chlorophenyl)oxazolidin-2-it or its pharmaceutically acceptable salts.

18. Derived oxazolidine under item 1, selected from the group consisting of 3-{ 2-[4- (2,4-dioxothiazolidine-3-ylmethyl)phenoxy]-1-methylethyl} -5-(3-chlorophenyl)-oxazolidin-2-thione or its pharmaceutically acceptable salts.

19. Derived oxazolidine under item 1, selected from the group consisting of 3-{ 2-[4- (3-methoxycarbonylmethyl-2,4-dioxothiazolidine-5-ylmethyl)phenoxy]-1-methylethyl} -5-(3 - chlorphenyl)oxazolidin-2-thione or its pharmaceutically acceptable salts.

20. Derived oxazolidine on PP. 1 14 having hypoglycemic activity.

21. The method of obtaining derivatives of oxazolidine formula I under item 1 or their pharmaceutically acceptable salts, or esters, characterized in that the compound of formula V

< / BR>
where Ar and R have the meanings specified in paragraph 1, and Y'any of the groups, which are represented by formula V in paragraph 1, or a group protecting the amino group,

subjected to interaction with Carboniferous or thiocarbanilide agent and, if desired, otscheplaut protective group from the resulting compound and, if desired, hydrolyzing form a salt or esterificated the resulting compound to obtain the compound of formula I, or its salt or its ester.

 

Same patents:

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to new benzanilide derivatives, processes for their preparation and the pharmaceutical compositions

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

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