Derivatives carbapenem and method of production thereof


C07D477/10 - with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
C07D477/06 - from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

 

(57) Abstract:

Usage: in medicine as antimicrobial agents. The inventive Products: derivatives carbapenem formula I, where R1is hydrogen or methyl, R2is hydrogen or unsubstituted C1-C6-alkyl, R3- COOH or COO-, Q represents a group of formula 2-4, where R4-R9, R11, R12- C1-C6-alkali, R10- carnemolla group, n is 0 or 1, n1is 0, 1, 2, m1is 0 or 1, the Z group of formula 5 and 6. Reagent 1: compound of formula 7, where RL- sulfonyloxy, phosphoryloxy, R3P- carboxyamide group. Reagent 2: compound of formula 8. Conditions of reactions: in a medium of an organic solvent at minus 20 to plus 40oC. 2 C. and 18 h.p. f-crystals, 14 PL.

The invention relates to a series of new derivatives carbapenem having excellent antimicrobial activity and which, owing to their high resistance to inactivation under dehydropeptidase I have a greater value in the treatment and prevention of infectious diseases. The invention also provides methods of obtaining these compounds, and methods of obtaining compositions and formulations on the basis of these modifications is to penicillins, used or proposed for use as antibiotics. They usually have a structure that can be represented by formula (A):

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In this formula we have outlined the important rooms for connections carbapenem position, using the numbering scheme commonly used in this area and adopted in the nomenclature of the compounds of the invention. According to the recommendations of the International Union of Pure and Applied Chemistry (IUPAC, Commission on Nomenclature of Organic chemical compounds referred to in the invention, received policestations name, the structure above carbapenem is used as a generic name.

Antibiotics on the basis of carbapenem not having substituents in position-1 potentially represent a very useful series of compounds with extraordinary antibacterial activity. But they, unfortunately, are chemically unstable and, moreover, sensitive to the action of dehydropeptidase I in vivo. Dehydropeptidase I is an enzyme gidrolizuemye-lactam ring of antibiotics on the basis of carbapenem and which is present in mammalian tissues, for example in the cortical substance of the kidney. This enzyme is responsible is the first number of a man, in the result of reducing their effect. Despite these shortcomings antibiotics on the basis of carbapenem find increasing use in the treatment of bacterial infections.

The metabolism of antibiotics in vivo can be demonstrated on the example of low (insignificant) highlight the connection (unlike its metabolites) in the urine, which is confirmed for thienamycin (H. Kropp and other Antimicrob. Agents chemother. 22, 62 (1982) and S. R. Norby et. al. there, 23, 300 (1983)).

Although found that the compounds carbapenem having a substituent in position 1 (usually 1-methyl group) are not as susceptible to dehydropeptidase 1 in vivo, many of the compounds of this type are open to the present time, does not have sufficient activity. Thus, it is highly desirable, to consider the presence of this antibiotic on the basis of carbapenem that combines good activity thienamycin with resistance to dehydropeptidase 1 in vivo.

Many connections carbapenem already known. Some of them are described, for example, in European patent publications N 126587, 333175, 442497, 443883, 508682 and 518588. European patent publication N 333175 reveals the connection that tierralinda group and C the response of the present invention, however, that there is no binding of the carbonyl group. Compounds disclosed in European Patent publication 126587, on the other hand, represent carboxyl thio-pyrrolidine beta-lactam compounds. However, I believe that the closest prototype of the compounds of the invention are compounds presented in European Patent publication N 508682 and 518558, both patents were published after the priority dates of the present application. Compounds of the invention showed better activity than other compounds prototypes.

Thus, the compounds of the invention are compounds of formula (I) and pharmaceutically acceptable salts and esters of this compound

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in which R1represents a hydrogen atom or methyl group; R2represents a hydrogen atom, unsubstituted alkyl having from 1 to 6 carbon atoms, substituted alkyl having from 1 to 6 carbon atoms and which has at least one Deputy, selected from the group consisting of substituents A, below, alkylamino group having from 2 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, or provided that O does not contain a Quaternary nitrogen atom, a group of the formula-C/= NH/R0, W is the UPP formula (Q-I, (Q-II), (Q-III), (Q-IV), (Q-V), (Q-VI), (Q-VII), (Q-(VIII), (Q-IX), (Q-X), (Q-XI), (Q-XII) and (Q-XIII)(see end of text)

in which R4represents a hydrogen atom, unsubstituted alkyl having from 1 to 6 carbon atoms, or substituted alkyl having from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B, defined below; R5and R6independently selected from the group consisting of unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms, and each of which is substituted by at least one Deputy, selected from the group consisting of substituents B, defined below, or R4and R5together represent a group of the formula -(CH2)m-, in which m is 2 or 3; R7, R8and R9independently selected from the group consisting of unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms and which have at least one Deputy, selected from the group of substituents, defined below; R10represents a hydrogen atom, karbamoilnuyu group, unsubstituted alkyl group having from 1 to 6 ATO is", selected from the group consisting of substituents B, defined below; or R7and R8together represent a group of the formula -(CH2)p-/W/w-/CH2/qin which p is 0, 1, 2 or 3, q is 0, 1, 2 or 3, w represents an oxygen or sulfur atom, w is 0 or 1, provided that (p+q+w) is a factor lying in the range from 2 to 6, or R7and R10together represent a group of the formula -(CH2)p-/W/w'-/CH2/q'-, in which p' is 0, 1, 2 or 3, q' is 0, 1, 2 or 3, w represents an oxygen or sulfur atom, and w is 0 or 1; n is 0 or 1; Z represents a group of the formula (Z-I) (Z-II), (Z-III), (Z-IV), (Z-V), (Z-VI), (Z-VII) or (Z-VIII);< / BR>
< / BR>
in which R11and R12independently selected from the group consisting of unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups which have from 1 to 6 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B, described below; and R13, R14and R15independently selected from the group consisting of carbamoyl groups, unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms and which are substituted at the end is n' is 0, 1 or 2, provided that (m'+n') is greater than 0;

R16represents an unsubstituted alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B, defined below; R18represents an unsubstituted alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 8 carbon atoms, and which has at least one Deputy, selected from the group consisting of substituents B, defined below; X represents a sulfur atom or a group of the formula in which R17represents an unsubstituted alkyl group having from 1 to 6 carbon atoms; n2is 1 or 2; R19represents an unsubstituted alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B, defined below; Y represents a group of the formula or R20, R21and R22independently selected from the group consisting of hydrogen atoms and unsubstituted alkyl groups having from 1 until SUB>/s-/W/w'-/CH/tin which s is 0, 1, 2 or 3, t is 0, 1, 2 or 3, w represents the atoms of oxygen or sulfur, and w' is 0 or 1; R23and R24independently selected from the group consisting of hydrogen atoms, halogen atoms, unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms, and which have substituents, at least one Deputy, selected from the group consisting of substituents C, defined below, carbamoyl groups, amino groups, cyano groups and carbamoyloximes; n3is 1, 2 or 3.

R25represents a hydrogen atom, an unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having from 1 to 6 carbon atoms and which may be substituted by at least one Deputy, selected from the group consisting of substituents C, defined below, alkenylphenol group having from 2 to 6 carbon atoms, or alkylamino group having from 2 to 6 carbon atoms, or alkylamino group having from 2 to 6 carbon atoms; R26represents a hydrogen atom, a halogen atom, an unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having is, ostoja of substituents C, defined below, hydroxy-group, carboxypropyl, carbamoyl group, amino group, ceanography or carbamoyloximes; n4is 0, 1 or 2; p2is 0 or 1; R27represents a hydrogen atom or an unsubstituted alkyl group having from 1 to 6 carbon atoms; R28and R29independently selected from the group consisting of hydrogen atoms, unsubstituted alkyl group having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents C, defined below; p3is 1 or 2; R30represents a hydrogen atom, an unsubstituted alkyl group having from 1 to 6 carbon atoms and which may be substituted by at least one Deputy, selected from the group consisting of substituents D, defined below, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or a group of the formula-C/=NH/R33in which R33represents a hydrogen atom, an unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having from 1 to 6 carbon atoms and is her E, defined below, cycloalkyl group having from 3 to 6 carbon atoms in the ring or cycloalkenyl group, in which cycloalkyl part has from 3 to 6 carbon atoms in the ring, and the alkyl part has from 1 to 6 ring carbon atoms; R31represents a hydrogen atoms, unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents (F, defined below, alkenylphenol group having from 2 to 6 carbon atoms, or alkylamino group having from 2 to 6 carbon atoms; R32represents a hydrogen atom, a halogen atom, an unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents (F, defined below, hydroxy-group, carbamoyl, group, amino group, ceanography or carbamoyloximes; R34represents a hydrogen atom or an unsubstituted alkyl group having from 1 to 6 carbon atoms; R35represents a hydrogen atom, unsubstituted alkyl is Aya substituted by at least one Deputy, selected from the group consisting of substituents G, defined below, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, or a group of the formula-C/=NH/R33in which the value of R33defined above; and U is imidazolidinyl group, tetrazolyl or tetrazolyl group.

Substituents And are selected from the group consisting of hydroxy-group, carboxypropyl, carbamoyl groups, carbamoyloximes, cyano groups, halogen atoms, oxygen atoms (to form a carbonyl group), alkoxygroup having from 1 to 6 carbon atoms, amino groups, alkylamino having from 1 to 6 carbon atoms, and dialkylamino in which each alkyl radical has from 1 to 6 carbon atoms.

The deputies are selected from the group consisting of cyano groups, hydroxy groups, carboxypropyl, sulfo, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, alkanolamines having from 1 to 6 carbon atoms, alkanoyloxy having from 1 to 6 carbon atoms, alkaloida groups, carbamoyl groups, alkylcarboxylic groups having 2 to 7 carbon atoms, dialkylammonium groups having in each alkyl group of 1 to 6 carbon atoms, carbamoyloximes, alkylcarboxylic in which each alkyl group has from 1 to 6 carbon atoms, amino groups, alkylamino having from 1 to 6 carbon atoms, dialkylamino in which each alkyl group has from 1 to 6 carbon atoms, sulfamoyl groups and oxygen atoms (to form oxopropanoic).

The alternates are selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, cyano groups, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, and amino groups.

Deputy D is chosen from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, carbamoyloximes, cyano groups, sulfamoyl groups, urednik groups, sulfo, alkoxygroup having from 1 to 6 carbon atoms, alkoxycarbonyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 6 carbon atoms, alkanolamines having from 1 to 6 carbon atoms, alkanoyloxy having from 1 to 6 carbon atoms, halogen atoms, aminopropyl groups, having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, dialkylamino in which each alkyl group has from 1 to 6 carbon atoms; alkylcarboxylic groups having 2 to 7 carbon atoms, dialkylammonium groups in which each alkyl group has from 1 to 6 carbon atoms, alkylcarboxylic groups in which each alkyl group has from 1 to 6 carbon atoms.

Deputy E are selected from the group consisting of halogen atoms and CNS groups having from 1 to 6 carbon atoms.

Deputy F is chosen from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms or amino groups.

The substituents G are selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, carbamoyloximes, cyano groups, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, and amino groups.

The invention also provides a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent or filler/thickener mixture with an effective amount of an antibiotic composition, in which LASS="ptx2">

The invention also provides a method of treatment or prevention of bacterial infections in a mammal, which may be people, which consists in the introduction of the said mammal an effective amount of an antibiotic that is selected from compounds of formula (I) and pharmaceutically acceptable salts and esters of the compound.

The invention also provides methods of obtaining these compounds, which will be described hereafter in more detail.

Compounds of the invention may contain viewy ion (i.e., the nitrogen atom of the Quaternary ammonium group) groups of the formula (Q-I), (Q-II), (Q-IV), (Q-V) and (Q-VI). In this case, preferably, R3would negatively charged ion (i.e. a group of the formula COO-should be in position-3 carbapenem), in order to balance the positively charged viewy ion. However, if R3is, for example, ester group, in this case, it is necessary that the compound contained a negatively charged ion to neutralize the positively charged Navaho ion. This negative ion can serve as anionic part of any of the acids, which will be described here below.

To connect the/SUP>, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35each represents alkyl group having from 1 to 6 carbon atoms, such may be an alkyl group branched or unbranched chain of 6 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, VT. -butyl, tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl. Among these substituents, preferred alkyl groups having 1-4 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, W.-butyl and tert.-butyl, and most preferred methyl and ethyl.

In those cases where R0and R2represent an alkyl group having from 1 to 6 carbon atoms, it can be alkyl branched or unbranched chain of 1-6 carbon atoms, preferably from 1-4 carbon atoms, and examples Eyeopener, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl. Among these, we prefer those alkyl groups which have from 1 to 3 carbon atoms, preferably methyl, ethyl and propyl, and most preferred methyl.

In those cases where R2, R25, R30, R31or R35is alkenylphenol group, it may be a group of branched or unbranched chain of carbon atoms, having from 2 to 6 carbon atoms, preferably 3-4 carbon atoms, examples of such groups include vinyl, allyl, 2-methylallyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and 3-hexenyl. Among these groups are vinyl, allyl, 2-methylallyl, 1-propenyl, Isopropenyl and butenyl preferred allyl and 2-methylallyl most preferred.

In those cases where R2, R25, R30, R31or R35are alkylamino group, it may be branched or non-branched chain, containing from 2 to 6, preferably 3-4 carbon atom and 3-hexenyl, among the listed examples PROPYNYL and 2-methylpropenyl preferred.

In those cases where R33is cycloalkyl group which has a ring of 3-6 carbon atoms, it may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, including cyclopropyl and cyclopentyl preferred.

In those cases where R33is cycloalkylcarbonyl group cycloalkyl part has a ring of 3-6 carbon atoms and the alkyl part has from 1-6 of the ring atoms are carbon. Examples of such Akilov can be unbranched or branched chains of carbon atoms that are already given above in connection with R4and examples cycloalkyl part above in connection with R33. Specific examples of such cycloalkenyl groups include cyclopropylmethyl, 1 - and 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 3-cyclopropylmethyl, 4-cyclopentylmethyl, 3-cyclopropylmethyl, 6-cyclobutylmethyl, 2-cyclopropylmethyl and 2-cyclopropylmethyl, listed among cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclopentylmethyl preferred.

In those cases where R2represents a substituted alkyl group, Alki the participating unsubstituted alkyl group, and the substituents are selected from the group consisting of substituents As, for example hydroxy-group, carboxypropyl, carbamoyl group, carbamoyloximes, ceanography; halogen atoms such as fluorine, chlorine, bromine or iodine, preferably fluorine atoms, chlorine or bromine; an oxygen atom (to form a carbonyl group); alkoxygroup having from 1 to 6 carbon atoms, which may be unbranched or branched chain, and examples include methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, W.-butoxy, tert. -butoxy-, pentyloxy, neopentylene, isopentane and hexyloxy, among which we prefer group having 1-3 carbon atoms, preferably methoxy, ethoxy or propoxylate; amino; alkylamino having from 1 to 6 carbon atoms in which the alkyl part may be represented by the examples above in connection with R2examples of amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino-, W. -butylamino, tert. -butylamino, pentylamine, isopentylamine, neopentylene, and hexylamino, among them we preferred methylamino, ethylamino and propylamino; and dialkylamino, in which each alkali etc. examples of dialkylamino include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diphenhydamine, digoxigenin, methylethylamine, methylpropylamine-among which we prefer dimethylamino, diethylamino-dipropylamino.

In those cases where R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18or R19represent a substituted alkyl group having from 1 to 6 carbon atoms, which may be any alkyl group described above in connection with the unsubstituted alkyl groups represented by these symbols. The substituents can be selected from the group consisting of substituents In, for example, ceanography, hydroxy-group, carboxypropyl, sulfopropyl, reenie groups carbamoyl group, carbamoyloximes, amino, sulfamoyl group, and oxygen atoms (to form a carbonyl group); halogen atoms, alkoxygroup, alkylamino and dialkylamino, they can all be represented by the examples given above in relation to substituents A;

ancilliary having from 1 to 6 carbon atoms, in which alkyl Citigroup methylthio-, ethylthio or PropertyGroup, alkylsulfonyl group having from 1 to 6 carbon atoms in which the alkyl part may be represented by the examples above in connection with R2etc. preferred methylsulfinyl, ethylsulfinyl or propylsulfonyl group; alkylsulfonyl group having from 1 to 6 carbon atoms in which the alkyl part may be represented by the examples above in connection with examples R2etc. preferred methylsulfonyl, ethylsulfonyl or propylsulfonyl group;

alkanolamines having from 1 to 6 carbon atoms, which may be unbranched or branched chain; examples of such groups include formamido, propionamido, butyramide, isobutyramide, Valeriano, isovaleramide, paulolino, and exonerating, among which preferred acetamido - and propionamidoxime, alkanoyloxy having from 1 to 6 carbon atoms which may have 1 to 6 carbon atoms, represents an unbranched or branched chain, and examples of such groups include formyloxy-, acetoxy-, propionyloxy, butyryloxy, isobutyryloxy, valeriote-, isovalerianic, pivaloyloxy,group, having 1-6 carbon atoms, which may be represented by a branched or unbranched chain; examples of such groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl, among them the preferred acetyl and propionyl;

alkoxycarbonyl group having 2 to 7 carbon atoms, and CNS part has from 1 to 6 carbon atoms, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethanol, W.-butoxycarbonyl, tert. -butoxycarbonyl, ventilatsioonile and hexyloxymethyl group, among which preferred the CNS groups which have from 1 to 3 carbon atoms, more preferred methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl group;

alkylcarboxylic group having 2 to 7 carbon atoms, the alkyl part of which has from 1 to 6 carbon atoms, and examples of which include methylcarbamoyl, propellerblades, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric, W.-butylcarbamoyl, tert.-butylcarbamoyl, intelceremony, isopentanol, neopentylene profilirovannuju group;

dialkylanilines groups in which each alkyl portion has 1-6 carbon atoms; examples include dimethylcarbamoyl, diethylcarbamoyl, dipropylamino, diisopropylamino, dibutylamino, dimetilkarbamida, dihexylfluorene, methylethylcarbinol and methylpropionamidine group, among which we preferred dimethylcarbamoyl, diethylcarbamoyl and dipropylamine group;

alkylcarboxylic having 2-7 carbon atoms, in which the alkyl portion has 1-6 carbon atoms, and examples of which include methylcarbamoyl, isopropylcarbamate, isobutylbarbituric, W.-butylcarbamoyl, tert. -butylcarbamoyl, intercorporate, isobutylbarbituric, neopentanoate, and hexylberberine group, among which we prefer methylcarbamoyl, ethylcarbamate, propylgallate group; and dialkylammonium in which each alkyl portion has 1-6 carbon atoms, and examples of which include dimethylcarbamoyl, diethylcarbamoyl, dipropylamine, diisopropylcarbodiimide, dibutylbarbituric, dimetilkarbamida, dihexylfluorene, methylation is bamileke, dipropylamino group.

As for the substituents C, D, E, F and G, examples of groups and atoms which include these substituents include those described in connection with equivalent groups and atoms for the substituents of type Century.

In those cases where R3is carboxyamide group, preferably, it was a group capable of forming ester groups to carboxylic acid. Examples of these ester groups include alkyl groups having 1-20 carbon atoms, more preferred C1-C6alkali, such as described in connection with the substituent R4and higher alkyl groups, well known to experts in this field, such as heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, pentadecyl, octadecyl, Needell, and icosyl, but the preferred group having 1-4 carbon atoms, and most preferred methyl, ethyl and tert.-butyl;

cycloalkyl group having 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;

kalkilya groups in which the alkyl portion has 1-3 carbon atoms, and the aryl group represents a carbocyclic aromatic group having 6-14 carbon atoms, which can be zamestitel from the group H, defined and illustrated by examples below, although the unsubstituted groups are preferred; examples of such Uralkalij groups include benzyl, phenethyl, 1-phenylethyl, 3-phenylethyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)-ethyl, 2-(2-naphthyl)-ethyl, benzhydryl, namely diphenylmethyl, bis/ortho-nitrophenyl/methyl, 9-antimetal, 2,4,6-trimethylbenzyl, 4-bromobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl, and piperonyl; among which preferred benzyl, benzhydryl, 4-nitrobenzyl and 2-nitrobenzyl;

alkeneamine group having 2-6 carbon atoms, and halogenated alkeneamine group having 2-6 carbon atoms, such as vinyl, allyl, 2-methylallyl, 2-chloroallyl, 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, among which preferred is vinyl, allyl, 2-methylallyl, 1-propenyl, Isopropenyl and butenyl, most preferred 2-chloroallyl and 2-methylallyl, halogenated alkyl groups having 1-6, preferably 1-4 carbon atoms in which the alkyl part corresponds to the definitions and examples given above in connection with alkyl groups, halogen atom is ethyl (for example, 2-chloroethyl, 2-bromoethyl, 2-toroidal or 2-iodoethyl), 2,2-dibromoethyl and 2,2,2-tribromoaniline groups, among them the preferred 2,2,2-tri-trichloroethyl, 2,2-dibromoethyl and 2,2,2-tribromoethyl;

substituted killkenny groups in which the alkyl part corresponds to the definitions and examples given above, and the silyl group has up to 3 substituents, selected from alkyl groups having from 1 to 6 carbon atoms, and phenyl groups which are unsubstituted or have at least one Deputy, substituents selected from H, defined and illustrated by examples, which will be given below, for example 2-trimethylsilylethynyl group;

phenyl group, which phenyl group is unsubstituted or preferably substituted by at least one alkyl group having from 1 to 4 carbon atoms, or allmineral, for example, it may be phenyl, tolyl and benzamidophenyl; fenceline group that may be unsubstituted or substituted, or to have at least one of the substituents H, which are defined and illustrated by examples below, for example, it may be penicilina group itself or the p-bromopinacolone group; cyclic or acyclic terpinolene group, nl, nobinary, norbornyl, pentenyl, campanil and norbornene;

alkoxymethyl groups in which the CNS part is 1-6, preferably 1-4 carbon atoms, and may itself be substituted by a single unsubstituted alkoxy group, such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl, methoxyethoxymethyl;

aliphatic aryloxyalkyl groups in which the acyl group is preferably alkanoyl and more preferably this alkanoyl having 2-6 carbon atoms and the alkyl portion has 1-6 carbon atoms and preferably 1-4 carbon atoms, such as acetoxymethyl, propionoxy, butyryloxy, isobutylacetate, pivaloyloxymethyl, 1-pivaloyl-oxyethyl, 1-acetoxyethyl, 1-isobutyrylacetate, 1-pivaloyloxymethyl, 2-methyl-1-pivaloyloxymethyl, 2-pivaloyloxymethyl, 1-isobutyrylacetate, 1-isobutyryloxy, 1-acetoxymethyl, 1-acetoxymethyl, 1-propionylacetate, 1-propionyloxy, 2-acetoxypropionyl and 1-butyrylacetate, among which preferred pivaloyloxymethyl, isobutyrylacetate, 1-isobutyrylacetate, acetoxymethyl or 1-acetoxyethyl;

cycloalkyl-substituted aliphatic aryloxyalkyl groups in which the acyl Gilly Deputy has 3-7 carbon atoms, and the alkyl portion has 1-6 carbon atoms, preferably 1-4 carbon atoms, this group such as (cyclohexylmethoxy) methyl, 1-(cyclohexyloxy)ethyl, 1-(cyclohexyloxy)propyl, 2-methyl-1-(cyclohexyloxy)propyl, (cyclopentyloxy)methyl, 1-(cyclopentyloxy)ethyl, 1-(cyclopentyloxy)-propyl and 2-methyl-1-(cyclopentyloxy)propyl;

alkoxycarbonylmethyl groups, in particular 1-(alkoxycarbonyl)ethyl group, in which CNS part is 1-10, preferably 1-6, and preferably 1-4 carbon atoms, the alkyl portion has 1-6, preferably 1-4 carbon atoms, such groups as so-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-W.-butoxycarbonylmethyl, 1-so-butoxycarbonylmethyl, 1-(1-ethylpropylamine)ethyl and 1-(1,1-dipropylenetriamine)-ethyl, and other alkoxycarbonylmethyl group in which the alkoxy and alkyl groups have from 1 to 6, preferably 1-4 carbon atoms include 2-methyl-1-(isopropoxycarbonyl)-propyl, 2-(isopropoxycarbonyl)propylacetate, among these groups - tert.butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-isopropoxycarbonyloxymethyl and 1-tert-butoxycarbonylmethyl preferred;

cycloalkylcarbonyl and cycloalkylcarbonyl groups in which cycloalkyl group has from 3 to 10, preferably 3 to 7 carbon atoms and is mono - or polycyclic group, and possibly substituted by at least one, and preferably only one Deputy

alkyl group having from 1 to 4 carbon atoms (e.g. selected from those alkyl groups which are illustrated by the above examples), and the alkyl part has from 1 to 6 carbon atoms, more preferably 1-4 carbon atoms (e.g. selected from those alkyl groups, which is illustrated by the examples above), and among the most preferred methyl, ethyl or propyl, for example, the 1-methylcyclohexanecarboxylic, cyclopentanecarboxylate, cyclopentanecarboxylate, 1-cyclohexyloxycarbonyloxy, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclopentanecarboxylate, 1-cyclohexyloxycarbonyloxy, 1 cyclohexenyltrichlorosilane)propyl, 1-(1-methylcyclohexanecarboxylic)-propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 2-(cyclohexyl-carbonyloxy)propyl, 2-methyl-1-(1-methylcyclopentadienyl)propyl, 1-(1-methylcyclopentadienyl)propyl, 2-(1-methylcyclopentadienyl)-propyl, 1-(cyclopentanecarbonyl)propyl, 2-(cyclopentanecarbonyl)-propyl, 1-(1-methylcyclopentadienyl)ethyl, 1-(1-methylcyclopentene)-carbonyloxy, adamantanecarboxylic, adamantankarboksilato, 1-adamantanecarboxylic and 1-adamantankarboksilato, among these groups, preferred 1-cyclohexylcarbodiimide or 1-cyclopentanecarboxylate;

cycloalkylcarbonyl group, in which alkoxygroup has one cycloalkenyl Deputy, cycloalkenyl substituent has from 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms and a mono - or polycyclic group, for example, this cyclopropanedicarboxylic, cyclobutanedicarboxylate, cyclopentanetetracarboxylic, cyclohexyloxycarbonyloxy, 1-(cyclopropylmethoxy)ethyl, 1-(cyclobutanedicarboxylate)ethyl, 1-(cyclopentanecarbonyl)ethyl and 1-cyclohexylmethoxy is that terpinolene group is a group, which is illustrated by the examples above, and preferably is circular terpinolene group, for example 1-(methoxycarbonylamino)-ethyl, 1-(methylcarbonate)ethyl, methyloxycarbonyl, methylcarbamoylmethyl, 1-(3-penetrationsexy)ethyl, 1-(3-pinalalabas)ethyl, 3-penetratability and 3-finalinerrordirectory;

5-alkyl or 5-phenyl which may be substituted by at least one of substituents C, defined and illustrated by the examples above, (2-oxo-1,3-dioxolan-4-yl)alkyl groups in which each alkyl group (which may be the same or different from each other) has from 1 to 6 carbon atoms, preferably 1-4 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 (5-methyl-2-oxo-1,3-dioxolan-4-yl)ethyl; and

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

Among the above groups, we particularly prefer those groups which can easily be removed in vivo, PU), allyloxycarbonyl groups (in particular 1-isopropoxycarbonyloxymethyl), cycloalkylcarbonyl groups (in particular 1-methylcyclohexanecarboxylic and 1-cyclohexyloxycarbonyloxy), phthalidyl group, and (5-substituted 2-oxo-1,3-dioxolan-4-yl(methyl group), in particular (5-methyl-2-oxo-1,3-dioxolan-4-or methyl.

Typically, in the compounds of the present invention R1can represent a hydrogen atom or methyl, preferably methyl.

Compounds of the present invention may form a salt. Examples of such salts include salts of alkali metals such as sodium, potassium or lithium, salts of alkaline-earth metals such as barium or calcium, salts of other metals, such as magnesium or aluminum; ammonium salts; salts of organic bases, such as salts with triethylamine, Diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts with basic amino acids such as lysine or arginine. Also, in cases where the compound of the present invention contains a basic group in its molecule, it can form acid salts of accession.

Examples of such salts accession acids include salts with reorganize estomatologia acid, itestosterone acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, phosphoric acid; salts with lower alkylsulfonyl acids, such as methanesulfonate, trifluromethanesulfonate or econsultation; salt arylsulfonate, such as benzosulfimide or n-toluensulfonate; salts with organic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid, and salts with amino acids, such as glutamic acid or aspartic acid.

Compounds of the present invention must contain at least one, and possibly several asymmetric carbon atoms in their molecules and, therefore, can form optical isomers. Although they represent the same molecular formula, the present invention includes as an individual, isolated isomers and mixtures of isomers, including racemic mixtures. In those cases, when using methods stereospecific SYN may be obtained directly, in those cases, if you get a mixture of isomers, the individual isomers can be isolated by standard methods. Isomers preferably include compounds in which R' is methyl, and the position-1 has the R-configuration; compounds in which position -5 and -6, respectively, we have (5S, 6S) configuration, which is similar to a configuration that has thienamycin, and alpha-position with a hydroxy-group Deputy position 6 corresponds to the R-configuration.

Among the compounds of the present invention to the preferred class of compounds are the compounds of formula (I) and pharmaceutically acceptable salts and esters of these compounds, in which

R1represents a hydrogen atom or methyl group; R2represents a hydrogen atom or an unsubstituted alkyl group has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents AND1that will be defined below, alkenylphenol group having 3 or 4 carbon atoms, alkyl group having 3 or 4 carbon atoms, or, provided that Q does not contain a Quaternary nitrogen atom, a group of the formula-C(=NH)R0in which R0represents the atom vodorodny ion; and Q represents a group of formula (Q-I), (Q-II), (Q-III), (Q-IV), (Q-V), (Q-VI), (Q-VII), (Q-(VIII), (Q-IX), (Q-X), (Q-XI), (Q-XII) and (Q-XIII), the values of which are defined above, R4represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, or substituted alkyl having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B1whose values defined below;

R5and R6independently from each other selected from the group consisting of unsubstituted alkyl groups having 1-3 carbon atoms, and substituted alkyl groups with 1-3 carbon atoms, and substituted alkyl groups with 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B1whose values defined below; or R4and R5together represent a group of the formula -(CH2)m-, in which m is 2 or 3;

R7, R8and R9independently selected from the group consisting of alkyl groups unsubstituted, having 1-3 carbon atoms, and substituted alkyl groups with 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group of substituents B11whose values defined below; or R7and R10together represent a group of the formula -(CH2)p-(W)w-(CH2)qin which p is 0, 1, 2 or 3, q is 0, 1, 2 or 3, W represents an oxygen atom or sulfur and w is 0 or 1, provided that (p+q+w) is the multiplier, ranging 2-6 or R7and R10together represent a group of the formula -(CH2)p'-(W)w'-(CH2)q'in which p' is 0, 1, 2 or 3, q' 0, 1, 2 or 3, w represents an oxygen atom or sulfur, and w' is 0 or 1; n is 0 or 1; Z represents a group of the formula (Z-I) (Z-II), (Z-III), (Z-IV), (Z-V), (Z-VI), (Z-VII) or (Z-VIII), as defined above, in which R11and R12independently selected from the group consisting of unsubstituted alkyl groups having 1-3 carbon atoms, and substituted alkyl groups having 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B1defined below; and R13, R14and R15independently selected from the group consisting of carbamoyl g is 1 to 3 carbon atoms, and substituted alkyl groups which have from 1 to 3 carbon atoms, and substituted alkyl groups which have from 1 to 3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B1whose values defined below;

m' is 0 or 1, and n' is 0, 1 or 2, provided that (m'+n') is greater than 0; R16represents an unsubstituted alkyl group having from 1 to 3 carbon atoms, or a substituted alkyl group which has 1-3 carbon atoms, which is substituted by at least one Deputy, selected from the group of B1whose values defined below; R18represents an unsubstituted alkyl group having 1-3 carbon atoms, or a substituted alkyl group which has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B1whose values defined below; X represents a sulfur atom or a group of the formula in which R17represents unsubstituted alkyl having from 1 to 3 carbon atoms, or substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of carbamoyl groups the MOU carbon or substituted alkyl group, having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of carbamoyl groups and hydroxy groups; Y represents a group of formula R20, R21and R22independently selected from the group consisting of hydrogen atoms and unsubstituted alkyl groups having 1-3 carbon atoms; or R20and R21or R20and R22together represent a group of the formula -(CH2)s-(W)w'-(CH2)tin which s is 1 or 2, t is 1 or 2, W is oxygen atom or sulfur, and w' is 0 or 1, provided that (s+w'+t) is equal to 2, 3 or 4; R23and R24independently selected from the group consisting of hydrogen atoms, halogen atoms, unsubstituted alkyl groups have 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents C1, the values of which are defined below, hydroxy groups, carboxypropyl, carbamoyl groups, amino groups, cyano groups and carbamoyloximes; n3is 1, 2 or 3; R25represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, you who 4 carbon atoms, or alkylamino group having 3 or 4 carbon atoms; R26represents a hydrogen atom, a halogen atom, an unsubstituted alkyl group having 1-3 carbon atoms, a substituted alkyl group having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents C1, the values of which are defined below, hydroxy-group, carboxypropyl, carbamoyl group, amino group, ceanography, or carbamoyloximes; n4is 0, 1 or 2; p2is 0 or 1; R27represents a hydrogen atom or an unsubstituted alkyl having 1-3 carbon atoms; R28and R29independently selected from the group consisting of hydrogen atoms, unsubstituted alkyl having 1-3 carbon atoms, and substituted alkyl having 1-3 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of substituents C1whose values defined below; p3is 1 or 2; R30represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents D1the values which the and carbon, or a group of the formula-C(=NH)R33in which R33represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of halogen atoms and CNS groups having 1-3 carbon atoms, cycloalkyl group having from 3 to 6 carbon atoms in the ring or cycloalkenyl group, cycloalkyl part of which has 3 to 6 carbon atoms in the ring, and the alkyl part has 1 or 2 carbon atoms; R31represents a hydrogen atom, unsubstituted alkyl having from 1 to 3 carbon atoms, substituted alkyl having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents (F1whose values will be defined below, alkenylphenol group having 3 or 4 carbon atoms, or alkylamino group having 3 or 4 carbon atoms; R32represents a hydrogen atom, a halogen atom or an unsubstituted alkyl group having 1-3 carbon atoms; R34represents a hydrogen atom or an unsubstituted alkyl having 1-3 carbon atoms; substituted alkyl, who has 1-3 carbon atoms and which is substituted opredeleny below, alkenylphenol group having 3 or 4 carbon atoms, alkylamino group having 3 or 4 carbon atoms, or a group of the formula-C(=NH)R33in which R33has the values defined above; and U is imidazolidinyl group, triazolyl group or tetrazolyl group; the substituents AND1selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, cyano groups, halogen atoms and amino groups; the substituents IN the1selected from the group consisting of cyano groups, hydroxy groups, carboxylate, halogen atoms, alkoxygroup having 1-3 carbon atoms, alkylthio having 1-3 carbon atoms, alkylsulfonyl groups having 1-3 carbon atoms, alkylsulfonyl groups having 1-3 carbon atoms, alkanolamines having 1-5 carbon atoms, alkanoyloxy having 1-5 carbon atoms, alkanoyl groups having 1-5 carbon atoms, alkoxycarbonyl groups having 2-5 carbon atoms, urednik groups, carbamoyl groups, alkylcarboxylic groups having 2-5 carbon atoms, dialkylammonium groups, in which each alkyl portion has 1-3 carbon atoms, carbamoyloximes, alkylcarboxylic having 2-5 carbon atoms, diallylbarbituric carbon dialkylamino in which each alkyl portion has 1-4 carbon atoms, oxygen atoms for (education oxoprop) and cycloalkyl groups having 3-6 carbon atoms in the ring; Deputy C1selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, halogen atoms and amino groups; the substituents D1selected from the group consisting of hydroxy groups, cyano groups, urednik groups, alkoxygroup having 1-3 carbon atoms, alkoxycarbonyl groups having 1-3 carbon atoms, alkoxycarbonyl groups having 2-5 carbon atoms, alkanoyl groups having 1-5 carbon atoms, alkanolamines having 1-5 carbon atoms, alkanoyloxy having 1-5 carbon atoms, halogen atoms, amine groups, alkylamino having 1-3 carbon atoms, dialkylamino in which each alkyl portion has 1-3 carbon atoms, alkylcarboxylic groups having 2-5 carbon atoms, dialkylammonium groups, in which each alkyl portion has 1-3 carbon atoms, alkylcarboxylic having 2-5 carbon atoms and dialkylammonium in which each alkyl portion has 1-3 carbon atoms;

Deputy F1selected from the group consisting of GI amino groups; and

Deputy G1selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, carbamoyloximes, halogen atoms, alkoxygroup having 1-3 carbon atoms, and amino groups.

A more preferred class of compounds are those compounds of formula (I) and their pharmaceutically acceptable salts and esters of these compounds, in which

R1represents a hydrogen atom or methyl group; R2represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents (A2, the values of which are defined below, a group of the formula-C(=NH)R0in which R0represents a hydrogen atom or alkyl having 1-3 carbon atoms;

R3represents a hydrogen atom or a negatively charged ion; and Q represents a group of formula (Q-I), (Q-II), (Q-III), (Q-IV), (Q-V), (Q-VI), (Q-VII), (Q-(VIII), (Q-IX), (Q-X), (Q-XI), (Q-XII), (Q-XIII), the values of which are defined above, where R4represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms or substituted alkyl, who has 1-3 carbon atoms and which has at least one UP>5and R6independently selected from the group consisting of unsubstituted alkyl having 1-3 carbon atoms, and substituted Akilov that have 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B2whose values defined below; or R4and R5together represent a group of the formula -(CH2)m-, in which m is 2 or 3; R7, R8and R9independently selected from the group consisting of unsubstituted Akilov having 1-3 carbon atoms and substituted Akilov having 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of substituents B2whose values defined below; R10represents a hydrogen atom, karbamoilnuyu group, unsubstituted alkyl having 1-3 carbon atoms, or substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of hydroxy groups, amino groups and halogen atoms; R7and R8together represent a group of the formula -(CH2)p(W)w-(CH2)q- in which p is 1 or 2, q is 1, 2 or 3, W represents an oxygen atom or sulfur and w rawly -(CH2)p'-, in which p' is 1, 2 or 3; n is 0 or 1; Z represents a group of formula (Z-I) (Z-II), (Z-III), (Z-IV), (Z-V), (Z-VI), (Z-VII) or (Z-VIII), the values of which are defined above, in which R11and R12independently selected from the group consisting of unsubstituted alkyl having 1-3 carbon atoms, and substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B2whose values defined below; and R13, R14and R15independently selected from the group consisting of carbamoyl groups, unsubstituted Akilov having 1-3 carbon atoms, substituted Akilov having 1-3 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of substituents B2whose values defined below; m' is 0 or 1, n' is 0, 1 or 2, provided that (m'+n') is a multiplier whose values vary in the range of 1-3; R16represents unsubstituted alkyl having 1-3 carbon atoms, or substituted alkyl having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents B2whose values defined below; R18performance, which which is substituted by at least one Deputy, selected from the group consisting of substituents IN2whose values defined below; X represents a sulfur atom or a group of the formula NR17in which R17represents unsubstituted alkyl having 1-3 carbon atoms, or substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of carbamoyl groups and hydroxy groups; n2is 1 or 2; R19represents unsubstituted alkyl having 1-3 carbon atoms, or substituted alkyl having 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of carbamoyl groups and hydroxy groups; Y represents a group of formula R20, R21and R22independently selected from the group consisting of hydrogen atoms and unsubstituted Akilov having 1-3 carbon atoms; or R20and R21or R20and R22together represent a group of the formula -(CH2)s-(W)w'-(CH2)tin which s is 1 or 2, t is 1 or 2, W is oxygen atom or sulfur and w' is 0 or 1, provided that (s+w+t) is 2, 3 or 4; R23and R24independently selected from the group consisting of hydrogen atoms, halogen atoms, hydroxyprop groups, having 1-3 carbon atoms and which are substituted by at least one Deputy, selected from the group consisting of hydroxy groups, amino groups and carbamoyl groups; n3is 1, 2 or 3; R25represents a hydrogen atom or methyl group; R26represents a hydrogen atom; n4is 0, 1 or 2; p2is 0 or 1; R27represents a hydrogen atom or methyl group; R28and R29independently selected from the group consisting of hydrogen atoms and methyl groups; p3is 1 or 2; R30represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of substituents B2, the values of which are defined below, alkenylphenol group having 3 carbon atoms, alkenylphenol group having 3 carbon atoms, or a group of the formula-C(=NH)R33; in which R33represents a hydrogen atom, methyl, substituted alkyl that has 1 or 2 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of halogen atoms, methoxypropyl, cyclopropene group or cyclopropylmethyl group; R31to depict the R34represents a hydrogen atom or methyl; R35represents a hydrogen atom, unsubstituted alkyl having 1-3 carbon atoms, substituted alkyl, who has 1-3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of substituents G, the values of which are defined below, or a group of the formula-C(=NH)R33in which the value of R33defined above, and is imidazolidinyl group, triazolyl group, or tetrazolyl group;

Vice-A2selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, carbamoyloximes, halogen atoms and amino groups;

Deputy B2selected from the group consisting of cyano groups, hydroxy groups, carboxylate, halogen atoms, alkoxygroup having 1-3 carbon atoms, alkanolamines having 1-5 carbon atoms, alkanoyloxy having 1-5 carbon atoms, alkanoyl groups having 1-5 carbon atoms, alkoxycarbonyl groups having 2-5 carbon atoms, urednik groups, carbamoyl groups, alkylcarboxylic groups having 2-5 carbon atoms, dialkylammonium groups in which each alkyl portion has 1-3 carbon atoms, carbamoylated the ilen portion has 1-4 carbon atoms, amino group, alkylamino having 1-4 carbon atoms, dialkylamino in which each alkyl portion has 1-4 carbon atoms, and cycloalkyl groups having 3-6 carbon atoms in the ring;

Deputy D2selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyloximes, carbamoyl groups, halogen atoms, amine groups, alkylamino having 1-3 carbon atoms, and dialkylamino in which each alkyl portion has 1-3 carbon atoms;

Deputy G2selected from the group consisting of hydroxy groups, carboxypropyl, carbamoyl groups, carbamoyloximes, halogen atoms, methoxypropyl and amino groups.

Among these, more preferred are those compounds in which Q represents a group of formula (Q-I), (Q-II), (Q-III), (Q-VII), (Q-(VIII) and (Q-XI), but a more preferred group of formula (Q-II), (Q-III), (Q-(VII) and (Q-XI).

Among all these compounds are preferred those in which R1represents a methyl group.

Specific examples of the compounds of the present invention is represented by the following formulas (1-1) and (1-2). In these formulas, Q has the values listed in the table. 1-13; PL. 1-6 relate to the formula (1-1), and and R2can represent a hydrogen atom or methyl, i.e., each option 4 is possible, namely, (a) R1hydrogen, R2hydrogen; (b) R1= methyl, R2hydrogen; (C) R1hydrogen, R2methyl; (d) R1methyl, R2methyl.

Among the specific compounds of the present invention preferred are the following compounds:

6-(1-hydroxyethyl)-1-methyl-2-/2-(3-trimethylammoniumchloride-1 - ylcarbonyl)pyrrolidin-4-ylthio/-1 karbapin-2-em-3-carboxylate;

2-/2-(1,1-dimethyl-3-pyrrolidinylcarbonyl)pyrrolidin-4-yl-thio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-{2-/3-(carbamoyltransferase)pyrrolidin-1-ylcarbonyl/pyrrolidin-4-ylthio} -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-[2-{3-/(2-hydroxyethyl)dimethylammonio/pyrrolidin-1-ylcarbonyl}pyrrolidin-4-ylthio-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-/2-{ 3-/N-(2-toroidal)-N, N-dimethylammonio/-pyrrolidin-1-ylcarbonyl} pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/4-(3-methylimidazolium)piperidine-1 - ylcarbonyl/pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/3-(3-methylimidazolium)pyrrolidin-1 is in 4 ylthio/-6-(1 - hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(4-amidinophenoxy-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio/- 6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(4-amidinopropane-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(4-amidinopropane-1-ylcarbonyl)-1-methyl-pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/-(3-aminoamides-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-acetylethylenediamine-1-ylcarbonyl)-mirrodin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-formamidopyrimidine-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-aminoamides-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid:

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/3-(4-methyl-1-1,2,4-triazolo/-pyrrolidin-1-ylcarbonyl/-pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/3-(4-methyl-1-1,2,4-triazolo/-azetidin-1-ylcarbonyl/-pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-/2-(3-trimethylammonio)azetidin-1 - icarb lidin-1-ylcarbonyl/pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

2-/2-{ 3-/3-(2-toroidal)-1-imidazolyl azetidin-1-ylcarbonyl-pyrrolidin-4-ylthio}-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-/2-{ 3-/(2-toroidal)dimethylammonio/azetidin-1-ylcarbonyl}pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-/2-(3-acetylethylenediamine-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid; and

pharmaceutically acceptable salts based on these compounds.

The most preferred compounds include

6-(1-hydroxyethyl)-1-methyl-2-/2-(3-trimethylammonio)pyrrolidin-1 - ylcarbonyl/pyrrolidin-4-ylthio/-1 karbapin-2-em-3-carboxylate;

2-{2-/3-(carbamoyltransferase)pyrrolidin-1-ylcarbonyl/pyrrolidin-4-ylthio} -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-/2-{3-/(2-hydroxyethyl)dimethylammonio/pyrrolidin-1-ylcarbonyl}pyrrolidin-4-ylthio-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate;

2-/2-{ 3-/N-(2-toroidal)-N, N-dimethylammonio/pyrrolidin-1-ylcarbonyl} pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{2-/3-(3-methylimidazolium)pyrrolidin-1-ylcarbonyl/pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

2-/2-(4-amidinopropane deeperin-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio/- 6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(4-amidinopropane-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(4-amidinopropane-1-ylcarbonyl)-1-methyl-pyrrolidin-4-ylthio/- 6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-aminoamides-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-(1 - hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-acetylethylenediamine-1-ylcarbonyl)pyrrolidin-4-ylthio/-6-/1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-formamidopyrimidine-1-ylcarbonyl)-pyrrolidin-4-ylthio/-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

2-/2-(3-aminoamides-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio/-6-(hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/3-(4-methyl-1-1,2,4-triazolo)-pyrrolidin-1-ylcarbonyl/pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-/3-(4-methyl-1-1,2,4-triazolo)-azetidin-1-ylcarbonyl/pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-{ 2-(3-trimethylammonium-1 - ylcarbonyl)pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate;

6-(1-hydroxyethyl)-1-methyl-2-/2-/3-(3-methyl-1-imidazolyl)azetidin-1 elcaro the CLASS="ptx2">

Compounds of the present invention can be obtained in a variety of ways, well known in this area for producing compounds of this type. For example, as a rule, they can be obtained by the reaction of compounds carbapenem formula (II)

< / BR>
in which the value of R1defined above, RLis sulfonyloxy or phosphoryloxy or a group of formula-S(O)RL1where RL1represents an alkyl group, haloalkyl group, alkanolammonium group, alkanolammonium group, aryl or aromatic heterocyclic group, and R3Pis carboxyamide group (with arbitrary pyrrolidine formula (III)

< / BR>
in which R2Prepresents any of the groups or atoms represented by R2or any such group or atom, which is protected, and QPrepresents any of the groups or atoms represented by Q, or any such group or atom, which are protected, or any such group in which the Quaternary nitrogen atom is substituted by an appropriate tertiary nitrogen atom, and where, in the cases when QPrepresents a group containing a Quaternary nitrogen atom, the compound contains a balancing counterion(anion), and, if chetvertyy the nitrogen atom in the group of formula (Q-I), (Q-II), (Q-IV), (Q-V) or (Q-VI) or a group represented by the Deputy Z, and, if necessary, removing any protective groups and, possibly, in obtaining salt and/or the esterification product of interaction.

In more detail, included reactions may be like that illustrated in the following reaction schemes a and b (see end of text).

In the above schemes and formulas, R1, R2, R3, R2P, R3P, QPand Q have the meanings defined above;

RL1represents an alkyl group such as methyl, ethyl, propyl or isopropyl; haloalkyl group, such as vermeil, chloromethyl, foradil, chloroethyl, forproper, deformity, defloratin, dichloroethyl, trifluoromethyl, or triptorelin; 2-acetamidomethyl; 2-acetamidophenyl; possibly substituted aryl, such as phenyl or naphthyl which may be unsubstituted or may have 1-3 substituent which may be the same or different from each other, for example fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, propoxy, isopropoxy, methoxycarbonyl, etoxycarbonyl, tert.-butoxycarbonyl, nitro, carbarnoyl, mono - and disubstituted carbarnoyl (in which the alkyl group is, for example, makuu as pyridyl or pyrimidyl, which can be unsubstituted or can have 1-3 substituent which may be the same or different from each other, for example fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl;

RL2is alkanesulfonyl group, such as methanesulfonyl, trifloromethyl, econsultancy, propanesulfonyl, isopropylphenyl or butanesulfonyl; arylsulfonyl group, such as phenylsulfonyl, tamilselvan, for example p-tamilselvan, or 1 - or 2-naphthylmethyl; dialkylphosphorous group, such as dimethylphosphoric, diethylphosphate, dipropylacetic, diisopropoxyphosphoryl, dibutylester or dipentylester; or diarylphosphino group, such as diphenylphosphoryl or detailsfull;

Q+is any group represented by Q, which includes the Quaternary nitrogen atom;

X-represents an anion, such as chlorine, bromine, iodine, monomethylaniline group, sulfate group, methysulfonylmethane, triftormetilfullerenov or cryptanalytically.

If QPor R3Pcontains a protective group, it can be selected from a variety of such groups, which are well known to specialists in this field and Oba is Sana'a in many standard formulations, for example, T. W. Greene "Protective groups in organic synthesis", published by John Wiley Son, described here as a reference. Typical examples of such groups include n-nitrobenzisoxazole and paranitroaniline group.

As defined above, R3Prepresents a protective group for carboxypropyl, for example an alkyl group such as methyl, ethyl, or tert.-butyl; aracelio group, for example benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl; alkenylphenol group, such as allyl, 2-chloroallyl or 2-methylallyl; haloalkyl group, such as 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl; or 2-trimethylsilylmethyl.

In phase AI of the reaction scheme And the connection carbapenem formula (IV) is transformed into a compound carbapenem formula (IIA) in the interaction of active sulfonylurea or phosphoryl compounds containing group corresponding to the group R, for example the anhydride of alkanesulfonyl, anhydride of arylsulfonate, dialkylphosphinate or diarylheptanoid.

This reaction is usually, as a rule, is carried out in the presence of a base. On the nature of the used grounds there is no particular limitation, provided that it does not are examples of bases include organic bases, such as triethylamine, Diisopropylamine and 4-dimethylaminopyridine.

Examples of sulfonyl-, fosforilirovannyh, which can be used in this reaction include anhydrides of alkanesulfonyl, such as the anhydride of methansulfonate, the anhydride of triftoratsetata and the anhydride of econsultation; anhydrides of arylsulfonyl, such as the anhydride of benzosulfimide anhydride and para-toluenesulfonic acid; dialkylphosphorous halides, such as dimethylphosphoric chloride and diethylphosphoramidite; and diarylphosphino halides, such as diphenylphosphoryl and difenilfosfinilmetil. Among these reagents, we, in particular, the preferred anhydride para-toluenesulfonic acid and diphenylphosphoryl.

The reaction is normally and preferably carried out in the presence of a solvent. On the nature of the solvent there are no specific restrictions, provided that it does not adversely affect the course of the reaction and reagents, and provided that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; NITRILES, such geocom temperature range, and the exact value of the reaction temperature is not critical for the reaction of the present invention. As a rule, we find convenient to conduct the reaction at relatively low temperatures, for example in the temperature range from -20oC to +40oC, in order to suppress the occurrence of side reactions. The time of reaction may also vary widely, depending on many factors, such as the temperature at which the reaction is carried out and the nature of the reagents and solvent used. However, provided that the reaction is carried out in the preferred conditions set forth above, the duration from 10 minutes to 5 hours will normally suffice.

Thus obtained compound of formula (IIa) are usually not separated; instead of allocating the reaction mixture is run into the reaction with a mercaptan of the formula (IIIa) in the presence of a base to obtain the compounds of formula (V). The compound obtained can then, if necessary, to be launched in response to removing any protective groups represented by R3Por QPand obtaining in this way the target compounds of formula (I).

On the nature of the base, which can be used for the I to other parts of the molecule, in particular the b-lactam ring, and preferred examples of such bases include organic bases such as triethylamine and diisopropylethylamine; and inorganic bases such as potassium carbonate and sodium carbonate. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not a parameter that determines its flow. As a rule, we find it possible to carry out the reaction at a temperature of from -20oWith up to room temperature. The time required for the reaction may also vary widely, depending on many factors, specifically from the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under preferred conditions, which were discussed above, the duration from 30 minutes to 5 days is usually sufficient.

After completion of the reaction, the target compound of formula (V) may be collected from the reaction mixture in the traditional way. For example, in one of the appropriate procedures associated with its selection, from the reaction mixture the solvent is distilled off milking in order to obtain the target compound. Alternatively, in case of no-quaternionic compounds, rastvor washed with water and dried, then the solvent is removed by evaporation. Thus obtained compound can be subjected to further purification.

If necessary, use traditional cleaning methods, such as recrystallization, pereosazhdeniya or different ways of chromatographic methods such as column chromatography. If necessary, the connection can be cleaned in the processing of the reaction mixture by direct deposition. Alternatively, if desired, the compound of formula (V) may be subjected to consecutive reactions withdrawal carboxyamide group stage A5 without isolation from the reaction zone.

If necessary, in the stage A5 compound of formula (V) obtained in stage A2, can be converted into a carboxylic acid derivative of the formula (I) by removal of the protective group R3Pfrom carboxypropyl traditional ways. The nature of the reactions used for the elimination of the protective group, will of course depend on the nature of the protective group, which is well known to specialists in this field. For example, in those cases, when the protective group can be removed by restoring (as in the case haloalkyl groups, kalkilya groups and benzyloxyindole. For your preferred reducing agents which can be used in this reaction include zinc and acetic acid, in cases where carboxyamide group is, for example, haloalkyl group (such as 2,2-dibromoethyl or 2,2,2-trichloroethyl); or in those cases where the protecting group, for example, is kalkilya group (such as benzyl or 4-nitrobenzyl) or benzydamine group, it is possible to use as a reductant or a sulfide of an alkali metal (such as sodium sulfide or potassium sulfide, or hydrogen in the presence of a catalyst reaction recovery (such as palladium deposited on carbon). Response recovery usually and preferably carried out in the presence of a solvent. On the nature of the solvent there are no specific limitations, provided that the solvent does not have a deleterious effect on the reaction or on the reagents and that it can dissolve the reagents, at least to some extent. Suitable solvents include alcohols, such as methanol, ethanol; ethers type tetrahydrofuran or dioxane; fatty acids, such as acetic acid; and mixtures of any of the one or more solvents with water. Reacts the practical setting reaction conditions of the present invention. As a rule, we find it possible (easy) to carry out the reaction in the temperature range from about 0oC to about room temperature. 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 used. However, provided that the reaction is carried out in the preferred environment, which was discussed above, the duration, ranging from 5 min to 12 h, it is enough.

If QPand R2Pcontain a protective group for a hydroxy-group, aminogroup, amino or carboxypropyl (for example, para-nitrobenzisoxazole group or paranitroaniline group), such a protective group can be removed simultaneously with the removal of the above-mentioned carboxy-protective group (in the case when R3Pis paranitroaniline group).

After completion of the reaction, the target compound of the present invention may be collected from the reaction mixture by standard means. For example, one suitable procedures for selection includes removing an insoluble precipitate from the reaction mixture by filtration, followed the th treatment, if necessary, conventional procedures such as recrystallization, pereosazhdeniya or various chromatographic methods, in particular column chromatography.

Alternatively, when Q represents a group containing a Quaternary nitrogen, it can be derived from a mercaptan of the formula (IIIa), in which QPrepresents a tertiary nitrogen atom. In this case, in stage A2, the compound of formula (IIa) start the reaction with a mercaptan of the formula (IIIa) in order to obtain the compound of formula (V). Then this compound is converted into the corresponding compound of Quaternary ammonium in stage 3, if necessary, remove the protective group at the stage A4, in order to obtain the target compound of formula (I).

The quaternization in stage A3 can be made using methods known in this field, for example in the interaction of the compounds of formula (V) with the compound of the formula RX, in which R represents a possibly substituted alkyl, which may be the same as defined above in connection with any group attached to the Quaternary nitrogen atom in the group represented Q or z, and X represents a halogen atom (e.g. chlorine atom, atotonilco, toluensulfonate, trifluromethanesulfonate or persulfonic). The reaction of transformation of the nitrogen atom in Quaternary nitrogen compounds of formulas (V) and RX can react directly or in a solvent. On the nature of the solvent used in the reaction, there is no particular limitation, provided that it does not adversely affect the reaction or on the reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane or chloroform; NITRILES, such as acetonitrile; ethers such as tetrahydrofuran; esters such as ethyl acetate; amides, such as dimethylformamide or dimethylacetamide. The reaction can be carried out in a wide range of temperatures and the precise value of the reaction temperature is not critical in terms of the present invention. As a rule, we find convenient to conduct the reaction in the temperature range from -20oWith up to 100oC. After completion of the reaction, the target compound of formula (VI) may be collected from the reaction mixture by traditional methods. For example, the solvent may be just upar is mi ways, such as recrystallization, pereosazhdeniya, or the various chromatography techniques, notably column chromatography. Alternatively, the target compound can be purified by resultant deposition rates from the reaction mixture. If necessary, the compound of formula (VI) may be subjected to stage A4 subsequent stage of withdrawal carboxyamide group without isolation from the reaction mixture, which may be implemented as described above in connection with stage A5.

Carboxypropyl thus obtained compounds can be etherification, in particular, in such ester group, which easily undergoes hydrolysis under physiological conditions. In those cases where R3this essential group, which undergoes hydrolysis under physiological conditions (such as alkanolamine group, such as pivaloyloxymethyl, or acetoxymethyl group, alkoxycarbonylmethyl group, for example 1-(ethoxycarbonyl)ethyl or 1-(isopropoxycarbonyl)ethyl group, or phthalidyl, indanyl, methoxymethyl or 2-oxo-5-methyl-1,3-dioxolan-4-ylmethylene group), the compound of formula (I) do not need to deprive protective group and it can be introduced to the patient h is the conditions.

Alternatively, the compound (V) can be obtained as shown in reaction scheme, compound (IIB). This compound of formula (IIB) can be synthesized according to the method described in untested Japanese patent publication N SHO-62-30781 (Kokai). The reaction of the compound of formula (IIB) with a mercaptan of the formula (IIIA) in the presence of a base usually and preferably carried out in an inert solvent and leads to production of compound (V). On the nature of the solvent has no particular restrictions, provided that the solvent does not adversely affect the reaction or on the reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, water and a mixture of two or more solvents. There is also no particular restriction on the nature of the used grounds, provided that it does not touch other parts of the connection, in particular b-lactam ring. Examples of the base used in the reaction include organic bases such as diisopropylethylamine, triethylamine, N-methylpiperidine or 4-dimethylaminopyridine, and reorganizee temperature, values chiseled the reaction temperature is not critical in the present invention. As a rule, we find convenient to conduct the reaction at relatively low temperatures to suppress side reactions, it is usually the temperature range from -20oC to +40oC. the Time required for the reaction may vary within wide limits and depends on many factors, including the temperature of the reaction, the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred environment, which was discussed above, the period from 5 min to 5 days is sufficient.

After completion of the reaction, the target compound of formula (V) may be collected from the reaction mixture by conventional methods, which are described in connection with reaction scheme A. Then the connection start in stage B2 and B3 or stage B4, which correspond to the stages of A3, A4 or A5 reaction scheme A.

Any of the compounds obtained as described above, can be converted into a salt and/or etherification standard methods known in this field.

Compounds of the present invention are brilliant antibacterial (bactericidal) activity in the most tionalizing type compounds, responsive to the metabolic processes occurring in the body of a mammal. Derivative of the present invention, in addition, possess excellent stability against dehydropeptidase 1, which, as you know, also catalyzes the inactivation compounds tionalizing type. Derivative of the present invention showed strong antibacterial activity against a broad spectrum of pathogenic bacteria, including gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis. Gram-negative bacteria, such as Escherichia coli, Shigella species, Streptococcus pneumohiae, Proteus species, Serratia species, Ehterobacter spesies and Pseudomonas specics, and anaerobic bacteria such as Bacteroides fragilis.

Bactericidal activity was determined by the method of dilution agar plates and the minimum concentration of compounds of the present invention in relation to conventional pathogenic bacteria were identified and documented in the appropriate table. 14. In this table, the compounds of the present invention is characterized according to one of the following examples, which illustrate its receipt.

Used microorganisms are identified as follows:

A: Staphylococcus aureus 209P;

In: Escherichia coli NIHJ;

From: Pseudomonas Aegiali, which, as a rule, exceeds the activity of imipenem, in addition, they are unlike imipenem resistant to the action of dehydropeptidase 1 and b-lactamase.

Derived by carbapenem-3 carboxylic acid of the present invention are thus useful as therapeutic agents for the treatment and prevention of infections caused by the action of pathogenic bacteria. The compounds may be introduced in any convenient form, and used the exact composition depends on the disease that must be cured, the patient's age and the condition of the patient, and other factors that are well known to specialists in this field. For example, for oral administration, the compounds can be incorporated in tablets, capsules, granules, powders and syrups, for parenteral administration they may be included in the compositions for intravenous and intramuscular injection. Injected dose varies widely depending on age, body weight, symptoms and the condition of the patient, and the method of administration, time and rules of administration; however, for an adult daily dose (daily dose) ranges from about 100 mg to about 3000 mg, and this dose can be entered for a single dose or fractionally.

Policemilitary source is illustrated in the following preparative examples. All used here, the mesh sizes are given in accordance with standard sieves Tyler.

Example 1.

(1R, 5S,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-{(2S,4S)-2-/(3S)-3 - triaminopyrimidine-1-ylcarbonyl/-pyrrolidin-4-yl-thiol} -1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
1(1)(2S, S4)-2-/(3S)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidin

924 mg (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid was dissolved in 10 ml of dry tetrahydrofuran and the resulting solution was cooled to -20oC. To the resulting solution was added 209 mg of triethylamine followed by 250 mg pualeilani, after which the mixture was stirred at the same temperature for 5 minutes By the end of this time, to the mixture was added a mixture of 651 mg (3)-3-dimethylaminopyridine of triptoreline, 560 mg diisopropylethylamine and 7 ml of dry acetonitrile and the mixture is gradually heated and then stirred at 0oC for 1 h then the reaction mixture was filtered and the solvent was removed by evaporation under reduced pressure. The obtained residue was dissolved in ethyl acetate and the solution washed with an aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride, hydrated residue was purified chromatographically, having passed through a column Packed with silica gel, using a mixture of 3:1 in volume ratio of acetonitrile and methanol as eluent resulted 884 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1710, 1654, 1512, 1345, 1109, 857, 738

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) N. D. 1,49-of 3.31 (1H, multiplet); 3,35 is 3.57 (2H, multiplet); 3,71-4,00 (6N, multiplet); of 4.44-4,56 (1H, multiplet); 5,00-to 5.21 (2H, multiplet); to 6.88 (2H, doublet, J= 8,79 Hz); 7,27 (2H, doublet, J=8,31 Hz), 7,51-to 7.61 (2H, multiplet); 8,19 compared to 8.26 (2H, multiplet).

1(2) (2S, 4S)-3-/(3S)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-mercapto-1-(4-nitrobenzenesulfonyl)-pyrrolidin trifluromethanesulfonate

845 mg of (2S,4S)-2-/(3S)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine (obtained as described in stage (1) above, suspended in 1.7 ml of anisole and the resulting suspension is then added to 8.5 ml triperoxonane acid and 0.28 ml of triftoratsetata, the mixture was cooled with ice, after which the mixture was stirred at room temperature for hours Cycle including the removal of the solvent by evaporation under reduced pressure, washing the residue removal and the a and the grinding of the product, followed by decantation, repeated several times, the result was to 1.14 g of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1705, 1656, 1523, 1348, 857

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) M. D. 1,70-4,10 (N, multiplet); 4,47-of 4.66 (1H, multiplet); 5,04 at 5.27 (2H, multiplet); 7,51-the 7.65 (2H, multiplet).

1(3) 4-nitrobenzyl(1R, 5S,6S)-2-{/2S,4S)-2-/(3S)-3-dimethylamino-1 - pyrrolidinylcarbonyl/-6-(1R)-1-hydroxyethyl-1-methyl-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate

544 mg of 4-nitrobenzyl(1R,5R,6R)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 5.4 ml of dry acetonitrile and the resulting solution was dropwise added 204 mg diisopropylethylamine and 424 mg of diphenylphosphinylchloride under ice cooling, after which the mixture was stirred at the same temperature for hours Then dropwise added a solution of 582 mg of diisopropylethylamine and 1.10 g of (2S,4S)-2-/(3S)-3-dimethylamino-1 - pyrrolidinylcarbonyl-4-mercapto-1-(4-nitrobenzenesulfonyl)pyrrolidin triftoratsetata (obtained according to the description of stage 2 above) in 4 ml of dry acetonitrile under ice cooling. After that, the mixture was stirred at the same temperature for 6 hours after this is, amywali with water, aqueous sodium hydrogen carbonate solution, again with water and then saturated aqueous sodium chloride. The washing water (aqueous extract) was Proektirovanie with methylene chloride and the organic phase was combined with the extract in methylene chloride. The resulting mixture was dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the residue was purified by chromatographic method, having passed through a column of silica gel, using as eluent volume 14:1 mixture of methylene chloride and methanol. The result was 814 mg of the titled compound.

X (KBr) nmaxcm-1: 1773, 1711, 1650, 1607, 1522, 1346, 854, 738

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) memorial plaques to 1.15 (3H, doublet, J=3.42 Hz), of 1.18 (3H, doublet, J=3,90 Hz), is 2.09 (2H, doublet, J= 8,3 Hz); 2,17 (1H, singlet); 2,49 is 2.51 (1H, multiplet); 2,70-3,93 (N, multiplet); 3.95 to 4,08 (1H, multiplet); 4,11-4,20 (1H, multiplet); 4,23-the 4.29 (1H, multiplet); 4,55-of 4.66 (1H, multiplet); 5,06-5,75 (4H, multiplet); 7,53-7,74 (4H, multiplet), 8,21-of 8.25 (4H, multiplet).

1(4) (1R,5S,6S)-6-/(1R)-1-hydroxyethyl-1-methyl-2-{(2S,4S)-2-(3S)-3-trimethylammoniumchloride-4-ylcarbonyl/pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate hydrochloride

771 mg of 4-nitrobenzyl(1R,5S,6S)-2-{(2S,4S)-2-/(3S)-3-dimethylamino-12-em-3-carboxylate (obtained as described stage 3, above) was dissolved in 8 ml of dry acetonitrile and to the solution was added 182 mg methyltrichlorosilane under ice cooling, after which the mixture was stirred at the same temperature for hours Powdery product obtained after evaporation of the solvent under reduced pressure, dissolved in a mixture of 7 ml of tetrahydrofuran and 7 ml of water, after which the mixture was hydrogenosomal at room temperature for one hour in the presence of 10 wt./wt. palladium on carbon as catalyst. After this time the catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure; the aqueous phase was then washed with diethyl ether, after which it was concentrated under reduced pressure. The obtained residue was subjected to processing by the method of ion exchange chromatography (Dowex-1-X4, 50-100 mesh, C1 GORM, the production of DOW CHEMICAL, Dowex trademark), using water as eluent. The fractions containing the target compound were collected and dried freeze-drying, resulted in 460 mg of crude product in the form of a powder. The entire crude product is missed through the column (Cosmosil 75 ° C18- ven. Production Nacalai Cosmosil this trade mark) and Polyanovo water. The fractions containing the target compounds is of Oluchi in the 182 mg of the entitled compound as colorless powder.

X (KBr) nmaxcm-1: 1756, 1656, 1599, 1479, 1373

NMR spectrum (270 MHz, D2O, internal standard thetraditionally trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=6,83); OF 1.28 (3H, doublet, J= 6,35); 1,95-2,10 (1H, multiplet); 2.40 a-to 2.65 (2H, multiplet), 3,00 is 3.15 (1H, multiplet); 3,21 (6N, singlet); 3,23 (3H, singlet); 3,37 (1H, doublet of doublets, J=7,32 and 9.28 are Hz), 4,20-4,30 (2H, multiplet); 3,40-4,20 (N, multiplet); 4,65-of 4.75 (1H, multiplet).

Example 2.

(1R, 5S,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-{/2S,4S)-2-/(3R)-3 - trimethylammoniumchloride-1-ylcarbonyl/-pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
2(1) (2S, 4S)-2-/(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-/4 - methoxybenzylthio/-1-/4-nitrobenzenesulfonyl/pyrrolidin

2,60 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2 - pyrrolidinecarboxylic acid was dissolved in 20 ml of dry tetrahydrofuran and the resulting solution was cooled to -20oC. To this solution was added 590 mg of triethylamine and then 704 mg pualeilani, after which the resulting solution was stirred at the same temperature for 5 minutes to 2.00 g of (3R)-3-dimethylaminopyridine of triptoreline, 788 mg Diisopropylamine and 20 ml of dry acetonitrile was added to the solution in the order listed, then the mixture posttrial was removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride. Then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the obtained residue skipped through the chromatographic column filled with silica gel as the eluent used volume 3:1 mixture of acetonitrile and methanol, the result was of 2.56 g of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1710, 1655, 1512, 1344, 1110, 857, 738

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) M. D. 1,28-3,31 (15 NM, multiplet); 3.40 in-3,63 (2H, multiplet); 3.72 points-to 3.92 (6N, multiplet); 4,36-4,56 (1H, multiplet); 4,95 with 5.22 (2H, multiplet); 6,83 (2H, doublet, J=8,79 Hz); 7,27 (2H, doublet, J=8,31 Hz), 7,51-to 7.61 (2H, multiplet); 8,18 compared to 8.26 (2H, multiplet)< / BR>
2(2) (2S, 4S)-2-/(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-mercapto-1-(4-nitrobenzenesulfonyl)pyrrolidine triftorbyenzola

of 2.56 g of(2S, 4S)-2-/(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl/-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine (obtained according to the description of stage (1) above) suspended 5.1 ml of anisole, to the resulting suspension under ice cooling was added is mperature within 3 hours After this time the solvent was distilled under reduced pressure, to the residue was added 1,2-dichloroethane and removed the excess acid by azeotropic distillation. The remainder decantation, using hexane and then washed with diethyl ether, after which the mixture decantation and dried by evaporation under reduced pressure, the result was the 3.65 g of the titled compound in the form of a powdery product.

2(3) 4-nitrobenzyl(1R,5S,6S)-2-/(2S,4S)-2-/(3)-3-dimethylamino-1 - pyrrolidinylcarbonyl/-6-/(1R)-1-hydroxyethyl/-1-methyl-1-(4 - nitrobenzenesulfonyl pyrrolidin-4-ylthio/-1 karbapin-2-em-3-carboxylate

1,71 g of 4-nitrobenzyl(1R,5R,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 17 ml of dry acetonitrile and cooled with ice dropwise added to 1.34 mg diphenylphosphinylchloride and 646 mg diisopropylethylamine to the resulting solution, after which the mixture was stirred at the same temperature for hours after this time the mixture dropwise added a solution of 1.84 g of diisopropylethylamine and the 3.65 g of (2S, 4S)-2-/(3R)-3-dimethylamino-1-pyrrolidinylcarbonyl-4-mercapto-1-(4 - nitrobenzenesulfonyl)pyrrolidin/triftoratsetata obtained according to the description of stage (2), is given. what about after this time the solvent was distilled under reduced pressure, and the obtained residue was dissolved in methylene chloride. The resulting solution was washed with water, aqueous sodium hydrogen carbonate solution, again with water and then a saturated solution of sodium chloride. Aqueous extract was Proektirovanie with methylene chloride and the organic phase was combined with the extract was dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the resulting residue purified, having passed through a chromatographic column filled with silica gel, using as eluent volume 12:1 mixture of methylene chloride and methanol, in the received 2,60 g of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1773, 1712, 1652, 1608, 1523, 1346, 855, 738

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) memorial plaques to 1.15 (3H, doublet, J=3,91 Hz); of 1.18 (3H, doublet, J=4,39 Hz); 2,07 (2H, singlet); of 2.16 (2H, doublet, J= 4,88 Hz); 2.49 USD is 2.51 (1H, multiplet); 2.7 to 4.2V (1H, multiplet); 3,9-4,0 (1H, multiplet); from 4.2 to 4.3 (1H, multiplet); 4,4-4,6 (1H, multiplet); of 5.0-5.5 (4H, multiplet); 7,5-7,8 (4H, multiplet); for 8.2 and 8.3 (4H, multiplet).

2(4)(1R, 5S, 6S)-6-/(1R)-1-hydroxyethyl-1-methyl-2-{(2S,4S)-2-/(3R)- trimethylammoniumchloride-1-ylcarbonyl/pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxyl/-1-methyl-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio-1 karbapin-2-em-3-carboxylate (obtained in accord with the description of stage (3), this above), was dissolved in 13 ml of dry acetonitrile and the resulting solution was added 307 mg methyltrichlorosilane under ice cooling, after which the mixture was stirred at the same temperature for including Powder product formed after evaporation of the solvent under reduced pressure, dissolved in a mixture of 12 ml of tetrahydrofuran and 5 ml of water, after which the mixture was hydrogenosomal at room temperature in the presence of 3 g of 10 wt./wt. palladium on carbon as catalyst. After this time the catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure. The aqueous phase is then washed with diethyl ether and concentrated by evaporation under reduced pressure. Then the residue was subjected to ion-exchange chromatography (Dowex 1-H, 50-100 mesh, CI FOPM, manufacturing DOW CHEMICAL) as the eluent used water. The fractions containing the target compound were combined and dried by freezing in the received powdered crude product. This crude product pass through the column (Cosmosil 75 ° C18-prep, production Nacalai) and Polyanovo water. The fractions containing the target compound were combined; concentrated by evaporation under reduced pressure

X (KBr) nmaxcm-1: 1758, 1656, 1600, 1479, 1374.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=to 7.32 Hz); of 1.28 (3H, doublet, J=6,35 Hz); 1,95-2,10 (1H, multiplet); 2,45-2,60 (2H, multiplet); 3,05-of 3.25 (1H, multiplet); 3,20 (6N, singlet); is 3.21 (3H, singlet); 3,37 (1H, doublet of doublets, J=7,32 and 9,27 Hz); 3,45-3,55 (2H, multiplet); 3,60-4,20 (N, multiplet); 4,20 is 4.35 (2H, multiplet); 4.63 to-4,72 (1H, multiplet).

Example 3

(1R, 5S, 6S)-2-{(2S,4S)-2-/(3S)-1,1-dimethyl-3-pyrrolidinylcarbonyl/ pyrrolidin-4-ylthio}-6-/(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3 - carboxylate hydrochloride

< / BR>
3(1) (2S, 4S)-4-(4-methoxybenzylthio)-2-/(3S)-1-methyl-3 - pyrrolidinylcarbonyl/-1-(4-nitrobenzenesulfonyl)pyrrolidin

7,99 g of(2S, 4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2 - pyrrolidinecarboxylic acid was dissolved in 80 ml of dry acetonitrile and the resulting solution was added 3,05 g N,N'-carbodiimide, after which the mixture was stirred at room temperature for two hours after this time the mixture was cooled to 0oC, and then the solution is to 3.34 g of (3S)-3-amino-1-tert. butoxycarbonylamino in 30 ml of dry acetonitrile was added to the obtained solution. The mixture was then stirred at etoupe after this time the reaction mixture was concentrated by evaporation under reduced pressure, was diluted with 200 ml of ethyl acetate and then washed twice with water and twice with a saturated aqueous solution of sodium chloride. The organic phase is then dried over anhydrous magnesium sulfate and the solvent was distilled under reduced pressure. The residue was recrystallize from diethyl ether, having 9,11 g of powder, and 1.00 g of the thus obtained powder was mixed with 10 ml of ethyl acetate and dissolved by heating. 2.5 ml of 4 N solution of hydrogen chloride in ethyl acetate was then added to the solution, after which the mixture was heated under reflux for 30 minutes the Solvent was distilled under reduced pressure, and then to the residue was added ethyl acetate, the solvent was again distilled under reduced pressure, so it was deleted acid. The obtained residue was washed with diethyl ether, after which the mixture decantation. The solvent was distilled under reduced pressure, the result was 630 mg hygroscopic powder. The procedure was repeated to obtain additional quantities of powder.

2.5 g of the thus obtained powder was mixed with 25 ml of dioxane, and to the mixture at 10oC added 2.00 ml of 5 N aqueous sodium hydroxide solution, then to 0.47 ml dimethylsulfate, after which the mixture was stirred at the same temperature is removed under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride. The aqueous phase was Proektirovanie with ethyl acetate and the organic phase was combined and dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure and the obtained residue was subjected to purification, and passing it through a chromatographic column filled with silica gel, using a gradient elution method. As eluent was used volumetric mixture of from 1:1 to 1:5 ethyl acetate and methanol, the received 850 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1713, 1648, 1523, 1346, 1244, 1030, 850, 738.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,87-3,71 (1H, multiplet); with 3.79 (3H, singlet); 4,15-4,50 (2H, multiplet); 5,10-and 5.30 (2H, multiplet); 6,82-6,87 (2H, multiplet); 7,19-of 7.23 (2H, multiplet); 7,49 (2H, doublet, J=8,79 Hz); by 8.22 (2H, doublet, J=8.30 to Hz).

3(2) 4-nitrobenzyl(1R,5S,6S)-2-{(2S,4S)-2-/(3S)-1-methyl-3 - pyrrolidinylcarbonyl/-1-(4-nitrobenzenesulfonyl)pyrrolidin-4 - ylthio} -6-(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3-carboxylate

834 mg (2S,4S)-4-(4-methoxybenzylthio)-2-/(3S)-1-methyl-3 - pyrrolidinylcarbonyl-1(4-nitrobenzenesulfonyl)-pyrrolidine obtained with whom you and 0.28 ml of trifluromethanesulfonate added to the suspension under ice cooling, after which the mixture was stirred at room temperature for hours after this time the solvent was distilled under reduced pressure, to the residue was added 1,2-dichloroethane and then deleted the acid by azeotropic distillation. The obtained residue decantation with hexane and then washed with diethyl ether, after which the mixture decantation and dried by evaporation under reduced pressure, the obtained salt in the form of a powdery product.

572 mg 4-nitrobenzyl(1R,5R,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-oxo-1-karbapin-2-em-3-carboxylate was dissolved in 5.7 ml of dry acetonitrile and the resulting solution under ice cooling dropwise added 445 mg diphenylphosphinylchloride and 214 mg of diisopropylethylamine. The mixture was then stirred at the same temperature for hours after this time the mixture under ice cooling dropwise added a solution of 613 mg diisopropylethylamine and all the salt obtained in the above stage, 6.1 ml of dry acetonitrile. The mixture was stirred at the same temperature for 6 hours Then drove the solvent under reduced pressure, and the residue was dissolved in ethylacetate aqueous solution of sodium chloride. The aqueous extracts were combined and were Proektirovanie with ethyl acetate, and then the organic phase, including the extract was combined and dried over anhydrous magnesium sulfate. The solvent is then driven off under reduced pressure and the resulting residue purified, having passed through a chromatographic column filled with silica gel, using as eluent volume 6:1 mixture of methylene chloride and methanol. The result was 566 mg of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1775, 1722, 1670, 1606, 1522, 1346, 852, 737.

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) memorial plaques to 1.15 (3H, doublet, J=1,47 Hz); of 1.17 (3H, doublet); 1,39-3,35 (N, doublet, J= to 12.44 Hz), 3,29 (1H, doublet of doublets, J=2.44 and to 6.35 Hz); 3,54-3,66 (1H, multiplet); 3,79-4,32 (6N, multiplet); 5,09-5,48 (4H, multiplet); EUR 7.57-7,74 (4H, multiplet); 8,19 is 8.25 (4H, multiplet).

3(3) (1R,5S,6S)-2-{(2S,4S)-2-/(3S)-1,1-dimethyl-3 - pyrrolidinylcarbonyl/pyrrolidin-4-ylthio} -6-/(1R)-1-hydroxyethyl/-1 - methyl-1-karbapin-2-em-3-carboxylate hydrochloride

552 g of 4-nitrobenzyl(1R,5S,6S)-2-{(2S,4S)-2-/(3S)-1-methyl-3 - pyrrolidinylcarbonyl/-1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -6-/(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3-carboxylate, obtained in accordance with the description statuselement while cooling with ice. The mixture was then stirred at the same temperature for 30 minutes Powdery product obtained by evaporation of the solvent, was dissolved in a mixture of 14 ml of tetrahydrofuran and 7 ml of water, after which the mixture was hydrogenosomal at room temperature for one hour in an atmosphere of hydrogen and in the presence of a catalyst of 1.2 g of 10 wt./wt. palladium supported on carbon. After this time the catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure. The aqueous phase is then washed with diethyl ether, concentrated under reduced pressure by evaporation and was subjected to purification by ion-exchange chromatography (Dowex 1-X4, 50-100 mesh, CI FOPM, manufacturing Dow CHEMICAL), using as eluent water. The fractions containing the target compound were collected and dried by freezing, having a crude powdery product.

This crude product is missed through the column (Cosmosil 75 ° C18-prep, production Nacalai) and Polyanovo the contents of the column of water. The fractions containing the target compound were combined, concentrated and dried by freezing, resulting in 187 mg of the entitled compound as colorless powder.

X (KBr) nmaxsee the first trimethylsilylpropyne sodium) M. D. to 1.21 (3H, doublet, J=to 7.32 Hz); of 1.29 (3H, doublet, J=6,32 Hz); 2,10-of 2.20 (1H, multiplet); 2,25-2,40 (1H, multiplet); 2,70-to 2.85 (1H, multiplet); 2,85-of 3.00 (1H, multiplet); 3,24 (3H, singlet); or 3.28 (3H, singlet); at 3.35 (1H, doublet of doublets, J=7,33 and 9.28 are Hz); 3.40 in-4,10 (N, multiplet); 4,20-4,30 (2H, multiplet); 4,48 (1H, doublet of doublets, J=5,86 and 9.28 are Hz.

Example 4

(1R, 5S, 6S)2-{ (2S,4S)-2-/(3R)-1,1-dimethyl-3-pyrrolidinylcarbonyl/ pyrrolidin-4-ylthio}-6-/(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3 - carboxylate hydrochloride

< / BR>
4(1)(2S, 4S)-4-(4-methoxybenzylthio)-2-(3R)-1-methyl-3 - pyrrolidinylcarbonyl/-1-4-nitrobenzenesulfonyl/pyrrolidin

8.00 g (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid was dissolved in 80 ml of dry acetonitrile and the resulting solution was added 3,05 g N,N'-carbodiimide, after which the mixture was stirred at room temperature for two hours after this time the reaction mixture was cooled to 0oC and then was added to the mixture solution to 3.67 g (3)-3-amino-1-so-butoxycarbonylamino in 7 ml of dry acetonitrile, and then all was stirred at the same temperature for 10 min and then at room temperature for two hours after this time the reaction mixture is concentrated by evaporation p is 100 ml of water, and then once with 100 ml saturated aqueous solution of sodium chloride. The organic phase is dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure and the residue was purified on a chromatographic column filled with silica gel, using as eluent volume mixture of 3:1 ethyl acetate and cyclohexane. The result was 9,26 g of white powder.

4,80 g of this powder was dissolved in 45 ml of ethyl acetate and the resulting solution was added a 4 N solution of hydrogen chloride in ethyl acetate. The mixture then was heated under reflux for 30 min, after which the solvent was distilled under reduced pressure. Ethyl acetate was added to the residue and then to remove the acid, again drove the solvent. Thus obtained residue was washed with diethyl ether, after which the mixture decantation. The solvent is then driven off under reduced pressure, the result got 4.47 g of white powder.

1.98 g of this powder was mixed with 20 ml of dioxane and 1.58 ml of 5N aqueous sodium hydroxide solution and 0.41 ml of dimethylsulfate added at 10oC to the resulting mixture, after which the mixture was stirred at the same temperature for 30 minutes, after this time the solvent Udall phase was washed with a saturated aqueous solution of sodium chloride. Aqueous extract was Proektirovanie with ethyl acetate. The organic phase is combined with the obtained extract and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the obtained residue was subjected to purification, having passed through a chromatographic column filled with silica gel, using a volumetric 1: 5 mixture of ethyl acetate and methanol as eluent. The result was 550 mg of the titled compound in the form of a powder.

4(2) 4-nitrobenzyl(1R, 5S,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-{/ (2S, 4S-2-/(3R)-1-methyl-3-pyrrolidinylcarbonyl/-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate

550 mg of(2S,4S)-4-(4-methoxybenzylthio)-2-/(3R)-1-methyl-3 - pyrrolidinylcarbonyl-1-(4-nitrobenzenesulfonyl)pyrrolidine (obtained in accordance with the description of stage (1) above), suspended in 1.1 ml of anisole and cooled with ice to the resulting suspension was added 5.5 ml triperoxonane acid and 0.18 ml of triftoratsetata, after which the mixture was stirred at room temperature for hours after this time the solvent was distilled under reduced pressure, to the residue was added 1,2-dichloroethane and deleted acid by azeotropic distillation. The remainder of the Dean is pariani under reduced pressure. The result was salt in the form of a powdery product.

377 mg 4-nitrobenzyl(1R,5R,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 3.7 ml of dry acetonitrile and the resulting solution was dropwise added 293 mg diphenylphosphinylchloride and 141 mg of diisopropylethylamine under ice cooling, after which the mixture was stirred at the same temperature for hours after this time a solution of 403 mg diisopropylethylamine and all salts, obtained above, in 4 ml of dry acetonitrile was added dropwise to the obtained solution under cooling with ice. The resulting mixture was stirred at the same temperature for one hour and then left to stand in the refrigerator over night. After this time the mixture was stirred at room temperature for 1.5 h, and then at reduced pressure drove the solvent. The obtained residue was dissolved in 10 ml of methylene chloride, after which the mixture was washed with water, aqueous sodium hydrogen carbonate solution, then with water and finally saturated aqueous sodium chloride. Water extract was dried over anhydrous magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified pass through khromatograficheskoe is este eluent, the result obtained 230 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1775, 1712, 1670, 1617, 1522, 1345, 853, 738.

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) memorial plaques to 1.15 (3H, doublet, J=1,15 Hz); of 1.17 (3H, doublet, J=1,95 Hz); 1,47-of 1.56 (1H, multiplet); 1,72 is 1.75 (1H, multiplet); 1,98-3,39 (17H, multiplet); 3,54-3,62 (1H, multiplet); 3,84-4,34 (6N, multiplet); 5,08-5,49 (4H, multiplet); EUR 7.57-7,74 (4H, multiplet); 8,19 is 8.25 (4H, multiplet).

4(3)(1R, 5S, 6S)-2-{(2S,4S)-2-/(3R)-1,1-dimethyl-3 - pyrrolidinylcarbonyl/pyrrolidin-4-ylthio} -6-/(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

230 mg of 4-nitrobenzyl(1R,5S,6S)-6-/(1R)-1-hydroxyethyl)-1-methyl-2-(2S, 4S)-2-/(3R)-1-methyl-3-pyrrolidinylcarbonyl/-1-(4 - nitrobenzenesulfonyl)-pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate (obtained in accordance with the description of stage (2) above), dissolved in 2 ml dry acetonitrile and cooled with ice to a solution was added of 55.3 mg methyltrichlorosilane, after which the mixture was stirred at the same temperature for 30 minutes Powdery product obtained by evaporation of the solvent under reduced pressure was dissolved in 7 ml of tetrahydrofuran and 3 ml of water, after which the mixture was hydrogenosomal the aqueous carbon, as the catalyst. After this time the catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure. The aqueous residue was then washed with diethyl ether, concentrated by evaporation under reduced pressure and then subjected to purification by ion-exchange chromatography (Dowex 1-X4, 50-100 mesh. CI FOPM, manufacturing Dow CHEMICAL), using as eluent water. Those fractions which contained the desired product, were combined and dried by freezing, the result obtained crude product in powder form. This crude product is missed through the column (Cosmosil 75 ° C18- prep, production Nacalai) and Polyanovo water. Fractions containing the target compound were combined, concentrated by evaporation under reduced pressure and dried by freezing. The result was 42 mg of the titled product as a colorless powder.

X (KBr) nmaxcm-1: 1758, 1683, 1593, 1559, 1458, 1386.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) M. D. of 1.20 (3H, doublet, J=6,83); OF 1.28 (3H, doublet, J= 6,35); 2,11 TO 2.35 (2H, multiplet); 2.71 to to 3.02 (2H, multiplet); 3,20 (3H, singlet); with 3.27 (3H, singlet); to 3.34 (1H, doublet of doublets, J=7,33 and 9.28 are Hz); 3,45-4.09 to (N, Muller-4-trimethylammoniumchloride-1-ylcarbonyl/pyrrolidin-4-ylthio} -6-/(1R)-1-hydroxyethyl/-1-methyl-1-karbapin-2-em-3-carboxylate

< / BR>
866 mg of 4-nitrobenzyl(1R,5S,6S)-6-/(1R)-1-hydroxyethyl/-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 8 ml of dry acetonitrile and the resulting solution under ice cooling dropwise added 520 μl of diphenylphosphinylchloride and 437 μl of diisopropylethylamine. The mixture was then stirred at the same temperature for 45 minutes after this time to the mixture under ice cooling dropwise added a solution of 895 μl of diisopropylethylamine and of 1.62 g of (2S,4S)-2-/(2S,4S)-2-carbarnoyl-4-dimethylaminopyridine-1-ylcarbonyl - 4-mercapto-1-(4-nitrobenzenesulfonyl)pyrrolidine triftoratsetata in 7 ml of dry acetonitrile. The resulting mixture was then stirred at the same temperature for 30 min, after which it was left to stand overnight under cooling by ice. The mixture is then processed as described in example 1(2) and subjected to chromatographic purification on a column of silica gel. Fractions obtained by the method of gradient elution, using as eluent mixtures of ethyl acetate and methanol, in the range from 80:20 to 70:30 by volume, combined and concentrated by evaporation under reduced pressure. The result was 521 g of 4-nitrobenzyl(1R,5S,6S)- 2-{(2S, 4S)-2-/(2S, 4S)-2-carbarnoyl-4-dimethylaminopyridine-1-ylcarbonyl powder pale brown color. 505 mg of this compound was dissolved in 6 ml of dry acetonitrile and dropwise added 81 μl methylpredisolone under ice cooling, after which the mixture was stirred at the same temperature for hours after this time the solvent was distilled under reduced pressure and the resulting crude product was hydrogenosomal, processed and purified as described in example 1(4), the result was 161 mg of the entitled compound as colorless powder

X (KBr)maxcm-1: 1754, 1668, 1600, 1436, 1382, 1288, 1264, 1225.

UV absorption spectrum (H2O)maxnm: 298,0

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O) 270 MHz, M. D. was 1.04 (3H, doublet, J=6,84 Hz) and 1.15 (3H, doublet, J=6,35 Hz); 2,05-2,17 (1H, multiplet); 2,47-to 2.65 (3H, multiplet); 2,96-3,19 (2H, multiplet); 3,07 (N, singlet); 3,52-of 3.78 (4H, multiplet); 3,84-4,07 (3H, multiplet); 4,21-4,34 (1H, multiplet); 4,40-4,56 (2H, multiplet).

Example 6

(1R, 5S, 6S)-2-{ (2S,4S)-2-[(3S)-3-(carbamoylmethyl-dimethylammonio)- pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio} -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
to 1.00 g of 4-nitrobenzyl(1R, 5S, 6S)-2-{(2S,4S)-2-[(3S)-3-dimethylamino-1-pyrrolidinylcarbonyl] -6-[(1R)-1-hydroxyethyl] -1-methyl-(4-nitrobenzyl - oxycarbonyl/p is 1(3), dissolved in 10 ml of dry acetonitrile and 1,21 g 2-iodoacetamide added to the resulting solution, after which the mixture was stirred at 70oC for 1.5 hours after which time the solvent was distilled under reduced pressure and the residue was washed by decantation with diethyl ether and dried by evaporation under reduced pressure. The result was 1.28 g of powder. All the obtained compound was dissolved in a mixture of 12 ml of tetrahydrofuran and 12 ml of water and the resulting solution was added to 1.00 g of 10 wt./wt. palladium supported on carbon as catalyst. The mixture was hydrogenosomal at room temperature for 2 hours, after this time the reaction mixture was filtered, processed, purified and dried by freezing in the same way as described in example 1(4), the result was 155 mg of the entitled compound as colorless powder.

X (KBr)maxcm-1: 1758, 1695, 1656, 1600, 1469, 1375, 1286, 1226, 1182

UV absorption spectrum (H2O)maxnm: 296,9

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) memorial plaques to 1.14 (3H, doublet, J=6,84 Hz) and 1.15 (3H, doublet, J=6,34 Hz); 1,52-1,74 (1H, multiplet); 2,18-to 2.94 (4H, multiplet); 3,19 (1H, doublet of doublets, J=6,35 and of 2.44 Hz); of 3.25 (3H, singlet); 3,26 (3H, singlet); 3.25 to 4.25 in (15 NM, multitel)-dimethylammonio-pyrrolidin-1-ylcarbonyl] pyrrolidin 4 ylthio-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
1.68 g of 4-nitrobenzyl(1R, 5S, 6S)-2-{(2S,4S)-2-[(3S)-3-dimethylamino-1-pyrrolidinecarbonyl] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate, obtained as described in example 1(3), dissolved in 12 ml of dry acetonitrile and the resulting solution was added 1.68 g of 2-iodoethanol, the mixture was then stirred at 70-75oC for 6.5 h, the Solvent was distilled under reduced pressure and the residue was washed by decantation with diethyl ether and dried by evaporation under reduced pressure, the result was 1.66 g of powdery product. All the obtained compound was dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of water, to the solution was added 1.50 g of the catalyst 10 wt./wt. palladium supported on carbon. The mixture was then hydrogenosomal at room temperature for 2 hours, after this time the reaction mixture is treated, cleaned and dried in accordance with example 1(4), the received 250 mg of the entitled compound as colorless powder.

X (KBr)maxcm-1: 1758, 1656, 1599, 1469, 1374, 1286, 1258, 1227, 1148

UV absorption spectrum (H2O)maxnm: 296,2

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated the -2,64 (2H, multiplet); 2,94-and 3.16 (1H, multiplet); up 3.22 and 3.25 (together 6N, two singlets); 3.25 to 3,70 (6N, multiplet); 3.72 points-4,84 (11N, multiplet).

Example 8

(1R, 5S, 6S)-2-{(2S,4S)-2-[(3S)-3-[N-/N,N'-dimethylcarbamoyl)- dimethylaminopyridine-1-ylcarbonyl]pyrrolidin-4-ylthio}-6-[(1R)-1 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
500 mg of 4-nitrobenzyl(1R, 5S, 6S)-2-{ (2S,4S)-2-[(3S)-3-dimethylamino-1 - pyrrolidinecarbonyl] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate (obtained as described in example 1(3), dissolved in 5 ml of dry acetonitrile and the resulting solution was added 700 mg of 2-iodo-N,N-dimethylacetamide, after which the mixture was stirred at 80oC for 4 h after which time the solvent was distilled under reduced pressure, and the residue is washed with diethyl ether and dried by evaporation under reduced pressure, the result was 670 mg of a powdery product. All the obtained compound was dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran. To the resulting solution was added 2.0 g of the catalyst 10 wt. /Mac. palladium supported on carbon. The mixture was then hydrogenosomal at a temperature of 28-30oC for 2 h after which time reaklly 82 mg of the entitled compound as colorless powder.

X (KBr) maxcm-1: 1759, 1657, 1603, 1461, 1370, 1147.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=6,8 Hz) of 1.28 (3H, doublet, J= 6.4 Hz); 1,98-2,07 (1H, multiplet); 2,49-of 2.56 (2H, multiplet); of 2.97 (3H, singlet); 3,03 (3H, singlet); 2,95-3,13 (1H, multiplet); 3,37 (6N, singlet); 3,31-3,51 (3H, multiplet); 3,54-3,66 (1H, multiplet); 3.75 to the 3.89 (2H, multiplet), 3,92-of 3.97 (2H, multiplet); as 4.02-4,17 (1H, multiplet); 4,20-the 4.29 (2H, multiplet); 4,47 (2H, singlet); 4,69-to 4.81 (1H, multiplet); 4,86-to 4.98 (1H, multiplet).

Example 9

(1R, 5S, 6S)-2-[(2S, 4S)-2-{(3S)-3N-(2-foradil)-N,N-dimethylammonio-pyrrolidin-1-ylcarbonyl} -pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
501 mg 4-nitrobenzyl(1R, 5S, 6S)-2-{ (2S,4S)-2-[(3S)-3-dimethylamino-1 - pyrrolidinylcarbonyl] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate (obtained as described in example 1(3)), dissolved in 3 ml of dry acetonitrile and the resulting solution was added 419 mg of 1-bromo-2-foroutan, after which the mixture was heated under reflux for 13 hours after this time the reaction mixture was filtered, the solvent of the filtrate was distilled at pony is hydrofuran and 6 ml of water and the resulting solution was subjected to hydrogenation at room temperature for 1.5 h in the presence of 1.2 g of the catalyst 10 wt./wt. palladium supported on carbon. The reaction mixture is then processed, purified and dried by freezing as described in example 1(4), the result was to 36.0 mg of the entitled compound as colorless powder.

X (KBr)maxcm-1: 1758, 1656, 1599, 1470, 1375.

UV absorption spectrum (H2O)maxnm: 296,8

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,26 Hz); of 1.30 (3H, doublet, J=6,59 Hz); 1,97-2,10 (1H, multiplet); 2.40 a-to 2.65 (2H, multiplet); 3.00 and is 3.15 (1H, multiplet); 3,26 (4H, singlet); or 3.28 (2H, singlet); 3,30-5,20 (17H, multiplet).

Example 10

(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-4-(3 - methylimidazolium)piperidine-1-ylcarbonyl] pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
10(1) of(2S, 4S)-2-[4-(imidazol-1-yl)piperidine-1-ylcarbonyl] -4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidin

1520 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid was dissolved in 15 ml of dry acetonitrile and the resulting solution was added 660 mg of N,N'-carbonyldiimidazole, after which the mixture was stirred at room temperature for 30 minutes, after this time the solution was stirred at room temperature for 30 min, and then at 40oC for 7 h, the Reaction mixture is then concentrated by evaporation under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, water and aqueous saturated solution of sodium chloride, in that order. The mixture is then dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure, the residue was subjected to passing through the chromatographic column, using a column of silica gel and reverse phase (Cosmosil 75 ° C18Rev. 200 ml, the production of Nacalai Called), was Polyanovo with a mixture of acetonitrile and water in the range from 50: 50 to 55:45 by volume. Fractions containing the titled compound was collected and concentrated by evaporation under reduced pressure, the obtained 1450 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1709, 1655, 1609, 1512, 1345, 1246, 1110.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,70-of 1.95 (2H, multiplet); 2,05-of 2.23 (3H, multiplet); 2.40 a is 2.44 (1H, multiplet); 2,60-to 2.85 (1H, multiplet); 3,03-of 3.43 (3H, multiplet); to 3.73 (3H, singlet); of 3.77-of 4.25 (5H, multiplet); 4,59-4,84 (2H, multiplet); 5,02 to 5.35 (2H, multiplet); 6,85 (2H, doublet, J= 8,8 Hz), of 6.96 (1H, singlet); 7,07 and 7,09 (together 1H, two singlets); of 7.23 (2H, Dubinin-1-ylcarbonyl]-4 - mercaptopyrimidine

1.44 g of (2S,4S)-2-[4-(imidazol-1-yl)piperidine-1-ylcarbonyl]-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine, obtained as described in stage (1) above), was dissolved in a mixture of 1.5 ml of anisole and 7.5 ml triperoxonane acid and the resulting solution under ice cooling was added 350 l triftoratsetata. The resulting solution was then stirred at room temperature for hours, and then at the 35oC for 30 min, after which it was concentrated under reduced pressure. The obtained residue was washed with diethyl ether four times, the result was a colorless powder. All the obtained compound (powder) suspended in ethyl acetate and the suspension was parselocale, adding an aqueous solution of sodium bicarbonate. The ethyl acetate was separated and washed with an aqueous solution of sodium chloride, after which this phase dehydrational over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, the result was 1150 mg of the entitled compound as colorless powder.

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) d M. D. 1,55-of 1.85 (3H, multiplet); 2,00-2,11 (2H, multiplet); 2.63 in-2,89 (2H, multiplet); 3,05-3,30 (4H, multiplet); 3,92-to 4.15 (2H, multiplet); 4.25 in-4,59 (2H, multiplet, 1523, 1442, 1347, 1268, 1170, 1035.

10(3) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl-2-{ (2S,4S)-2-4- (imidazol-1-yl)piperidine-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio}-1-methyl-1-karbapin-2-em-3-carboxylate

910 mg of 4-nitrobenzyl(1R, 5S,6S)-6-(1R)-1-hydroxyethyl-1-methyl-2 - oxcarbazepine-3-carboxylate was dissolved in 10 ml of dry acetonitrile and cooled with ice to the resulting solution was dropwise added 560 μl of diphenylphosphinylchloride and 470 μl of diisopropylethylamine, after which the mixture was stirred at the same temperature for 30 minutes the Solution 1140 mg of (2S,4S)-2-[4-(imidazol-1-yl)piperidine-1-ylcarbonyl] -4-mercaptopyrimidine, obtained as described in stage (2) above in 10 ml of dry acetonitrile and 435 μl of diisopropylethylamine then dropwise added to the resulting mixture. The mixture was then stirred under ice cooling for 2 h, after which it was left to stand overnight at 4oC. after this time the reaction mixture was diluted with an equivalent amount of water and then there is added 800 mg of sodium bicarbonate. After that, the mixture was programatorului on a column of silica gel with reversible phase (Cosmosil 75 ° C18-prep, production Nacalai), poluyanova column then with a mixture of acetonitrile and water is the query result received of 1.40 g of the titled compound in the form of a powder.

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) M. D. 1,12-1,20 (6N, multiplet); 1,58-1,90 (3H, multiplet); 1,91 e 2.06 (2H, multiplet); 2,62-and 2.79 (1H, multiplet); 2,80-of 2.97 (1H, multiplet), 3,06-3,37 (4H, multiplet); 3,55-3,70 (1H, multiplet); 3,71-3,93 (1H, multiplet; 3,94-4,56 (5H, multiplet); 4,74 is equal to 4.97 (1H, multiplet); 5,04-5,49 (5H, multiplet); for 6.81-8,28 (11N, multiplet)

X (KBr) nmaxcm-1: 1773, 1710, 1656, 1522, 1346, 1208.

10(4) (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-{(2S,4S)-2-[4-(3- methylimidazolium/piperidine-1-ylcarbonyl] pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate hydrochloride

1000 mg 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-{(2S,4S)-2-[4-(imidazol-1-yl)piperidine-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio} -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in stage (3) above), dissolved in 10 ml of dry acetonitrile and the resulting solution under ice cooling dropwise added 150 ml methyltrichlorosilane, after which the mixture was stirred at the same temperature for 10 min and then at room temperature for 30 minutes the Reaction mixture was then concentrated under reduced pressure, and the obtained residue (1213 mg) was dissolved in a mixture of 20 ml of tetrahydrofuran and 15 ml of water. To the obtained solution of di-28oC for 1.7 h in hydrogen atmosphere. After this time the catalyst was filtered, the filtrate washed with diethyl ether (three times, 100 ml each time). The aqueous phase was concentrated under reduced pressure and missed then through a column of ion-exchange resin (Dowex 1-X4, model C1, 30 ml), poluyanova then the column with water. Fractions containing the titled compound was concentrated under reduced pressure by evaporation and missed then through a column of silica gel using a column of silica gel with reversible phase (Cosmosil 75 ° C18-ven, 50 ml), poluyanova then the contents of the column of water. Active fractions were collected and dried by freezing in the received 260 mg of the entitled compound as colorless powder.

X (KBr)maxcm-1: 1758, 1652, 1599, 1374, 1271, 1233, 1166.

UV absorption spectrum (H2O)maxnm: 297.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,3 Hz); of 1.29 (3H, doublet, J= 6.0 Hz); 1,88-of 2.09 (3H, multiplet); 2,28 is 2.43 (2H, multiplet); 2,96-and 3.16 (2H, multiplet); 3.33 and-3,55 (4H, multiplet); to 3.73-a-3.84 (1H, multiplet); 3,90 (3H, singlet); 3,91-4,12 (2H, multiplet); 4,20-or 4.31 (2H, multiplet); 4,55-to 4.73 (2H, THE 11

(1R, 5S, 6S)-6[(1R)-1-hydroxyethyl] -1-methyl-2-{ (2S, 4S)-2-[(3S)-3- (methylimidazole)pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
11(1) (2S, 4S)-2-[(3R)-3-(imidazol-1-yl)pyrrolidin-1-ylcarbonyl] -4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidin

Repeated the procedure described in example 10(1), with the exception of one time, used 2500 mg of (2S,4S)-4-(4-methoxybenzylthio)1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid and 805 mg (3R)-3-(imidazolyl-1-yl)pyrrolidine and got 2540 mg of the titled compound.

X (KBr)maxcm-1: 1708, 1656, 1609, 1512, 1438, 1404, 1345, 1246, 1173, 1110.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,88-2,05 (1H, multiplet); 2,15-2,31 (1H, multiplet); 2,36-to 2.57 (2H, multiplet); 3,02-3,18 (1H, multiplet); 3,31 is 3.40 (1H, multiplet); 3,49-3,63 (1H, multiplet); to 3.73 and 3.74 (together 2H, two singlets); 3,78 and 3,79 (together 3H, two singlets); 3,80-4,08 (3H, multiplet); 4.26 deaths-4,48 (2H, multiplet); 4,71-4,89 (1H, multiplet); 5,00-of 5.34 (2H, multiplet); 6,76-7,60 (N, multiplet); 8,15-of 8.27 (2H, multiplet).

11(2) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -2-{(2S,4S)-2-[(3R)- 3-(imidazolyl-1-yl)pyrrolidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio}-1-methyl-1-karbapin-2-em-3-carboxylate

2.5 g of (2S, 4S)-2-[(3R)-3-(IMO so as described in stage (1) above, launched in reaction and processed as described in example 10(2) and 10(3), the result was 2,31 g of the titled compound in the form of a powder.

NMR spectrum (270 MHz, CDCl3d M. D. 1,25-1,39 (6N, multiplet); 2,00 is 2.80 (4H, multiplet); 3.25 to 4,96 (13H, multiplet); of 5.05-of 5.53 (4H, multiplet); 6,82-8,29 (11N, multiplet);

11(3) (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3S)-3-(3-methylimidazolium)pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate hydrochloride

1.2 g of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-{(2S,4S)-2[(3R)- 3-(imidazolyl-1-yl)pyrrolidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio}-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in stage (2) above, launched in reaction and processed as described in example 10(4), the received 340 mg of the entitled compound as colorless powder.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) d M. D. between 1.19 to 1.31 (6N, multiplet); 1,82-2,07 (1H, multiplet); 2.40 a-2,58 (1H, multiplet); 2,60 is 2.80 (1H, multiplet); 2,92 (1H, multiplet); 3,32-3,51 (3H, multiplet); 3,71-or 4.31 (11N, multiplet); 3,60 of 3.75 (1H, multiplet); 5,17 at 5.27 (1H, multiplet); 7,50 and 7,54 (SUB>O), lmax/nm: 297.

Example 12

(1R, 5S, 6S)-2-[(2S, 4S)-2-(amidinopropane-1-ylcarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
12(1) 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl-1-methyl-2-[(2S,4S)- 2-[4-(4-nitrobenzenesulfonamide)piperazine-1-ylcarbonyl] -1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate

290 l of the acid chloride diphenylphosphinic acid and 244 l diisopropylethylamine dropwise added under ice cooling to a solution of 471 mg 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylate in 5 ml of dry acetonitrile and the resulting mixture was stirred at the same temperature for one hour. After this time the mixture under ice cooling dropwise added a solution of 910 mg of (2S,4S)-4-mercapto-2-[4-(4-nitrobenzenesulfonamide)-piperazine-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl)pyrrolidine triftoratsetata (obtained as described in obtaining 1), in 7 ml of dry acetonitrile, and 500 l of diisopropylethylamine; the resulting mixture was stirred and left to stand overnight at the same temperature. After the night the reaction mixture was concentrated by evaporation under reduced pressure, the residue is a thief of sodium chloride, an ethyl acetate layer was obezbedili over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The remainder pass through the chromatographic column (silica gel 60, Art. 9385, production Merck, 150 ml) was Polyanovo a mixture of ethyl acetate and acetonitrile in the ratio 8: 2, 7:3 and 6:4 in the listed sequence. The fractions containing the target compound were collected and concentrated by evaporation under reduced pressure, resulting in 691 mg of the titled compound in the form of amorphous powder.

X (KBr)maxcm-1: 1773, 1710, 1652, 1607, 1552, 1441, 1347.

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) M. D. 1,12-1,20 (6N, multiplet); 1,62-of 1.78 (1H, multiplet); 2.77-to of 2.93 (1H, multiplet); 3,11-4,30 (15 NM, multiplet); 4,79 and 4,78 (together 1H, two triplets, J= 7,8 Hz); 5,07-5,49 (6N, multiplet); 7,52-7,73 (6N, multiplet); 8,19-8,25 (6N, multiplet)

12(2) (1R, 5S,6S)-2-[(2S,4S)-2-(4-aminopiperidin-1-ylcarbonyl/-pyrrolidin - 4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

680 mg of 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S, 4S)-2-[4-(4-nitrobenzenesulfonamide/piperazine-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl)-pyrrolidin-4-ylthio] -1-karbapin-em-3-carboxylate (for the scientists to the solution was added 950 mg of the catalyst 10 wt./wt. palladium supported on carbon. The mixture was then hydrogenosomal in an atmosphere of hydrogen at 28oC for one hour. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure to 10 ml of the resulting solution was programatorului through a column of silica gel with reversible phase (Cosmosil 75 ° C18-ven. production Nacalai Tesque, 30 ml) was Polyanovo the contents of the column with mixtures of acetonitrile and water in the ratio 0:100, 2:98, 4:96 and 6:94, in the specified sequence. The fraction containing the target product was collected, concentrated under reduced pressure and dried by freezing, the result was 211 mg of the titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 299

X (KBr)maxcm-1: 1754, 1649, 1605, 1450, 1389, 1251.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,3 Hz); of 1.30 (3H, doublet, J=6.4 Hz); 1,64 (1H, double doublet of doublets, J=13,7, to 6.8 and 5.4 Hz); is 2.74 (1H, doublet of triplets, J=13.7 and an 8.8 Hz); of 3.07 (1H, doublet of doublets, 12,2 and 3.4 Hz); 3,17 (1H doublet of doublets, 12,2 and 5.4 Hz); 3,34-3,47 (2H, multiplet); 3,54-3,90 (M, multiplet); 4,13 (1H, tetramethylsilane was) d M. D. 16,0, 20,2, 35,5, 41,3, 42,6, 42,8, 43,5, 44,2, 44,7, 53,9, 56,0, 57,4, 58,4, 65,2, 132,0, 140,9, 156,6, 167,8, 172,5, 176,4.

Example 13

(1R,5S,6S)-2-[(2S,4S)-2-[4-amidinopropane-1-ylcarbonyl]-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
13(1) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-{(2S, 4S)-1-methyl-2-[4-(4-nitrobenzenesulfonamide)-piperazine-1-ylcarbonyl] pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate

1600 mg of 4-nitrobenzyl(1R, 5S,6S)-2-(diphenylphosphoryl)-6-[(1R)- hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, was dissolved in 16 ml of dry acetonitrile and the resulting solution under ice cooling was added dropwise a solution of 1120 mg of (2S,4S)-4-mercapto-1-methyl-2-[4-(4 - nitrobenzenesulfonamide)piperazine-1-ylcarbonyl] pyrrolidine (obtained as described in obtaining 2) in 11 ml of dry acetonitrile and 430 μl of diisopropylethylamine. The resulting mixture was stirred at the same temperature overnight, after which it was concentrated by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate and washed mixture with an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride in the specified posledovatelno the AI under reduced pressure. The obtained residue was programatorului through a column of silica gel with reversible phase (Cosmosil 75 ° C18-ven. production Nacalai Tesque, 300 ml) was Polyanovo volume 1: 1 mixture of acetonitrile and water. The fractions containing the target compound were collected and concentrated under reduced pressure, the received 1520 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1771, 1708, 1648, 1606, 1544, 1521, 1448, 1347.

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) M. D. 1,10-1,20 (6N, multiplet); 1,58 was 1.69 (1H, multiplet); of 2.24 (3H, singlet); 2,60 is 2.80 (2H, multiplet); 2,96-to 3.02 (1H, multiplet); 3,20-3,88 (N, multiplet); 3,90-of 4.05 (1H, multiplet); is 4.21 (1H, doublet of doublets), J=9.3 and 2.4 Hz); of 5.05 (1H, doublet, J=5.4 Hz); 5,13 (2H, singlet); from 5.29 (2H, doublet, J= 13,7 Hz); the 5.45 (2H, doublet, J=13,7 Hz), to 7.59 (2H, doublet, J=8,8 Hz); 7,73 (2H, doublet, J= 8,8 Hz); of 7.90-to 8.20 (2H, broadening); 8,21 (2H, doublet, J=8,8 Hz); 8,23 (2H, doublet, J=8,8 Hz).

13(2) (1R,5S,6S)-2-[(2S,4S)-2-(4-amidinophenoxy-1-ylcarbonyl)-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

1500 mg of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S, 4S)-1-methyl-2-[4-(4-nitrobenzenesulfonamide)-piperazine-1-ylcarbonyl] -pyrrolidin-4-ylthio} -1-karbapin-2-em-3-carboxylate), poluchenogo solution was added 2400 mg of catalyst 10 wt./wt. palladium supported on carbon. The mixture was then hydrogenosomal in an atmosphere of hydrogen at 28oC for one hour. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. Then the filtrate was concentrated to 20 ml by evaporation under reduced pressure. The resulting solution was programatorului through a column of silica gel with reversible phase (Cosmosil 75 ° C18prep, production Nacalai, Tesque 100 ml) was Polyanovo with a mixture of acetonitrile and water in the ratio 0:100, 2:98, 4:96, 6:94 and 8:92 in sequence. The fractions containing the target compound were collected and concentrated to 3 ml in the process of evaporation under reduced pressure, and then cooled, thus fell colorless needle crystals. The crystals were filtered and dried in the received 435 mg of the titled compound in the form of crystals with so pl. 218-220oC (decomposition).

UV absorption spectrum (H2O), lmaxnm: 298.

X (KBr)maxcm-1: 1755, 1652, 1606, 1449, 1386, 1246.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) M. D. of 1.20 (3H, doublet, J=6,8 Hz); of 1.30 (3H, doublet, J=6.3 Hz); of 1.66 (1H, double doublet of doublets, J=13,7, of 8.8, 5.4 Hz); of 2.28 (3H, singlet); 2,74-2,87 (2H, crown-rump length (13C, D2O, external standard: tetramethylsilane was) d M. D. 15,7, 19,9, 34,9, 39,1, 40,9, 42,4, 43,3, 43,9, 44,5, 55,7, 58,0, 62,2, 64,9, 65,0, 131,2, 141,6, 156,3, 167,5, 171,1, 175,9.

Example 14

(1R,5S,6S)-2-[(2S,4S)-2-(4-amidinopropane-1-ylcarbonyl)pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
Repeated the procedure similar to that described in example 13, but using 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained according to the description obtain 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2 4-(4-nitrobenzenesulfonamide) homopiperazin-1-ylcarbonyl/pyrrolidin received so as described in getting 3 as initial reagents in relative proportions similar to those used in the example, received the titled compound.

UV absorption spectrum (H2O)maxnm: 299.

X (KBr)maxcm-1: 1754, 1608, 1580, 1456, 1387, 1262.

NMR spectrum (1H, 270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=7,2 Hz); of 1.30 (3H, doublet, J= 6.3 Hz); 1,46-and 1.54 (1H, multiplet); 1,84-of 1.94 (2H, multiplet); 2.70 height is 2.80 (1H, multiplet); is 3.08 (1H, doublet of doublets, J=12,44,29 (2H, multiplet).

Example 15

(1R,5S,6S)-2-[(2S,4S)-2-(4-amidinopropane-1-ylcarbonyl)-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
Repeated the procedure similar to that described in example 13, but using 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32 and (2S,4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzenesulfonamide homopiperazin-1-ylcarbonyl] pyrrolidin received so as described in getting 4 as initial reagents in relative proportions similar to those used in the above example, the result was titled compound.

UV absorption spectrum (H2O)maxnm: 298.

X (KBr)maxcm-1: 1755, 1650, 1607, 1455, 1385, 1258.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) M. D. of 1.20 (3H, doublet, J=7,2 Hz); of 1.30 (3H, doublet, J=6.3 Hz); 1,60 (double doublet doublet, J=13,5, at 9.0 and 5.5 Hz); 1,80-of 1.95 (2H, multiplet); of 2.24 and 2.25 (together 3H, two singlets); 2,74-2,7 (2H, multiplet); to 3.09 (1H, doublet, J=9.0 Hz); 3.33 and-3,95 (N, multiplet); 4,19 (1H, doublet of doublets, J=9.0 and 2.4 Hz); 4,22-to 4.28 (1H, R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
Repeated the procedure similar to that described in example 13, but using 4-nitrobenzyl(1R, 5R, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[4-(4-nitrobenzenesulfonamide) piperidine-1-ylcarbonyl]pyrrolidine, obtained as described in the getting 5 as initial reagents, in relative proportions similar to those that were used in the above example, to obtain the titled compound.

UV absorption spectrum (H2O)maxnm: 299.

Example 17

(1R, 5S, 6S)-2-[(2S, 4S)-2-(4-guanidinopropionic-1-ylcarbonyl)-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure described in example 13, but as a source of reagents used 4-(nitrobenzyl)-(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32 and (2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzenesulfonamide) piperidine-1-ylcarbonyl]pyrrolidine, obtained as described in obtaining 6.

Raiden-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure described in example 13, but was used as initial reagents 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3S)-3-(4-nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl] pyrrolidine, obtained as described in obtaining 7.

UV absorption spectrum (H2O)maxnm: 299.

Example 19

(1R, 5S, 6S)-2-[(2S, 4S)-2-[(3S)-3-guanidinopropionic-1-ylcarbonyl)-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure of example 13, but was used as initial reagents 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(4-nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl] pyrrolidine, obtained as described in obtaining 8, in relative proportions, as mentioned in example 13.

UV absorption spectrum (H2O)<-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound was used the procedure described in example 13, but as a source of reagents used 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[3-(4- nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]pyrrolidine, obtained as described in 9, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 299.

Example 21

(1R,5S,6S)-2-[(2S,4S)-2-(3-guanidinoacetate-1-ylcarbonyl)-1-methyl - pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
To obtain the entitled compound was used the procedure described in example 13, but as a source of reagents used 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-4 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-methyl-2-[3-(4 - nitrobenzenesulfonamide) azetidin-1-ylcarbonyl] pyrrolidin, in relative proportions similar to those used/BR> (1R, 5S,6S)-2-[(2S,4S)-2-(2-guanidiniocarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure of example 13, but was used as initial reagents 4-nitrobenzyl (1R,5S,6S)-2 - diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[2-(4- nitrobenzenesulfonamide) ethylcarbamate]pyrrolidine, obtained as described in 11, in relative proportions similar to those used in the above example.

UV absorption spectrum (H2O)maxnm: 299.

Example 23

(1R, 5S,6S)-2-[(2S,4S)-2-(2-guanidiniocarbonyl)-1-methyl-pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound was used the procedure of example 13, but as a source of reagents used 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-methyl-2-[2-(4-nitrobenzenesulfonamide) ethylcarbamate mentioned in example 13.

UV absorption spectrum (H2O)maxnm: 298

Example 24

(1R,5S,6S)-6-[(1S)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-/4-(methylamino) piperazine-1-ylcarbonyl/pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure described in example 13, but was used as initial reagents 4-nitrobenzyl(1R, 5S, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S, 4S)-4-mercapto-2-[4-(methyl-4-nitrobenzenesulfonamide)piperazine-1-ylcarbonyl] -1-(4 - nitrobenzenesulfonyl)pyrrolidine, obtained as described in 13, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 299.

Example 25

(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-[(2S, 4S)-1-methyl-2-[4- (methylamino)piperazine-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure described in example 13, but was used as initial reagents 4-nitrobenzyl(1R, 5R, 6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl] -1-methyl-1-carlapetersonnude)piperazine-1-ylcarbonyl] pyrrolidin, obtained as described in obtaining 14, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 298

Example 26

(1R, 5S, 6S)-2-[(2S,4S)-2-[(3R)-3-guanidinopropionic-1-ylcarbonyl] pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure of example 13, but was used as initial reagents 4-nitrobenzyl(1R,5R,6S)-2- (diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3R)-3-(4-nitrobenzenesulfonamide/ pyrrolidin-1-ylcarbonyl]pyrrolidine, obtained as described in obtaining 15, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 299.

Example 27

(1R, 5S, 6S)-2-{(2S,4S)-[(3R)-3-guanidinopropionic-1-ylcarbonyl]-1 - methylpyrrolidine-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound was used the procedure of example 13, but in cachectin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-methyl-2-[(3R)-3-(4-nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl] pyrrolidine, obtained as described in obtaining 16, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)max/nm: 298.

Example 28

(1R, 5S,6S)-2-[(2S,4S)-2-[(3R)-4-amidino-3-methylpiperazin-1-ylcarbonyl]- pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure of example 13, but was used as initial reagents 4-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3R)-4-(4 - nitrobenzenesulfonamide)-3-methylpiperazin-1-ylcarbonyl] pyrrolidine, obtained as described in obtaining 17, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 299.

Example 29

(1R, 5S,6S)-2-[(2S,4S)-2-[(3R)-4-amidino-3-methylpiperazin-1-ylcarbonyl]- 1-methylpyrrolidine-4-Altadena repeated the procedure of example 13, but used 4-nitrobenzyl(1R,5R,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-methyl-2-[(3R)-4-(4-nitrobenzenesulfonamide)-3-methylpiperazin-1-ylcarbonyl]pyrrolidin received so as described in obtaining 18, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 298.

Example 30

(1R, 5S, 6S)-2-[(2S,4S)-2-[(3R)-1-amidinopropane-4-ylcarbonyl/ pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
To obtain the entitled compound was used the procedure described in example 13, but was used as initial reagents 4-nitrobenzyl(1R, 5R,6S)-2-(diphenylphosphoryl-6-[(1R)-1-hydroxyethyl]-1-methyl-1-Karabatan-1-em-3-carboxylate, obtained as described in obtaining 32, and (2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[1-(4- nitrobenzenesulfonamide)piperidine-4-ylcarbonyl] -pyrrolidine, obtained as described in obtaining 19, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O),
< / BR>
To obtain the entitled compound repeated the procedure of example but used as initial reagents 4-nitrobenzyl(1R, 5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-peroxyacyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3S)-1-(4-nitrobenzenesulfonamide) pyrrolidin-3-ylcarbonyl] pyrrolidine, obtained as described in obtaining 20, in relative proportions similar to those used in the above-mentioned example 13.

UV absorption spectrum (H2O)maxnm: 299.

Example 32

(1R,5S,6S)-2-{(2S,4S)-2-[1-imigination-3-ylcarbonyl]pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
To obtain the entitled compound repeated the procedure of example 13, but was used as initial reagents 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and (2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[1-(4- nitrobenzenesulfonamide)azetidin-3-ylcarbonyl] pyrrolidine, obtained as described in obtaining 21, in relative proportions, and the max nm: 299

Example 33

(1R,5S,6S)-2-[(2S,4S)-2-/(3-aminoamides-1-ylcarbonyl)pyrrolidin-4 - ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
33(1) 4-nitrobenzyl(1R, 5S, 6S)-2-{(2S,4S)-2-[3-(4- nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate

To a solution of 278 mg of 4-nitrobenzyl(1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-karbapin-2-em-3-carboxylate in 4 ml of dry acetonitrile at a time when ice cooling was bury 167 μl of the acid chloride diphenylphosphinic acid and 140 μl of diisopropylethylamine and the resulting mixture was stirred at the same temperature for one hour. After this time the mixture under ice cooling was added dropwise a solution of 430 mg of (2S,4S)-4-mercapto-2-[(3-(4-nitrobenzenesulfonamide)azetidin - ylcarbonyl]-1-(4-nitrobenzenesulfonyl)-pyrrolidine, obtained as described in obtaining 22, in 4 ml of dry acetonitrile, and simultaneously added dropwise 134 μl of diisopropylethylamine. The resulting mixture was then stirred at the same temperature for 2 h, then left it overnight while cooling with ice. Then the reaction mixture was diluted with ethyl acetate and washed and then concentrated, mpariwa under reduced pressure. The obtained residue was programatorului on a column of silica gel, using as eluent volume 98:2 mixture of ethyl acetate and methanol. Obtained after elution fractions were combined and concentrated, pariva under reduced pressure, the result was 224 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1772, 1713, 1659, 1608, 1522, 1453, 1403, 1347.

NMR spectrum (hexadeuterated dimethyl sulfoxide +D2O, 270 MHz) M. D. 1,06-1.27mm (6N, multiplet); 1.66 EN-1,89 (1H, multiplet); 2,64-to 2.85 (1H, multiplet); is 3.08-3,37 (2H, multiplet); 3,41-4,59 (11N, multiplet); 5,07-5,52 (6N, multiplet); 7,51-7,78 (6N, multiplet); 8,23 (6N, doublet, J=8,79 Hz).

33(2) (1R,5S,6S)-2-[(2S,4S)-2-(3-aminoamides-1-ylcarbonyl/pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid hydrochloride

216 mg of 4-nitrobenzyl(1R,5S,6S)-2-{(2S,4S)-2-[3-(4- nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio} -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained in accordance with the description of stage (1) above, dissolved in 10 ml volumetric 3:2 mixture of tetrahydrofuran and water. Then to the resulting solution was added 250 mg katal is Noah temperature for 1.5 h in an atmosphere of hydrogen. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. The aqueous phase is then concentrated, pariva under reduced pressure. The obtained residue was programatorului in column (Cosmosil 75 ° C18-prep, production Nacalai Tesque, 18 ml). The fractions containing after elution with water titled compound, concentrated, pariva under reduced pressure, and dried by freezing, the result was 46 mg of the titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 297.

X (KBr) max/cm-1: 1756, 1661, 1596, 1486, 1462, 1391, 1287, 1180

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=to 7.32 Hz); of 1.29 (3H, doublet, J= 6,35); 1,95-2,12 (1H, multiplet); 2,90 was 3.05 (1H, multiplet); 3,29-3,51 (3H, multiplet); 3.72 points-a 3.83 (1H, multiplet); 3,97-4,10 (1H, multiplet); 4,13-4,86 (8H, multiplet.)

Example 34

(1R,5S,6S)-2-[(2S,4S)-2-(3-acetamidomalonate-1-ylcarbonyl)- pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
34(1) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S-2-{ 3-[N-(4-nitrobenzenesulfonyl)-N-acetimidoyl] azetidin-1-ylcarbonyl} -1-(4-sforno acid and of 0.29 ml of diisopropylethylamine dropwise simultaneously added to a solution of 0.55 g of 4-nitrobenzyl-(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1 - carbapenam-3-carboxylate in 10 ml of dry acetonitrile, cooled by ice, and the resulting mixture was stirred at the same temperature for 50 minutes, after this time a solution of 0.82 g of (2S,4S)-4-mercapto-2-{3-[N-(4 - nitrobenzenesulfonyl)-2N-acetamidomalonate-1-ylcarbonyl}-1-(4-nitrobenzenesulfonyl)pyrrolidine, obtained as described in getting 23 in 10 ml of dry acetonitrile and 0.24 ml of diisopropylethylamine simultaneously was added dropwise to the mixture, cooled by ice. The resulting mixture was then stirred at the same temperature for 2 hours, and then an hour at room temperature. After this time the reaction mixture was concentrated, pariva her under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with water and an aqueous solution of sodium chloride, in that order. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure. The obtained residue was programatorului on a column of silica gel (Silica gel 60 9385, production Merck, 200 ml), the result was of 0.77 g of the entitled compound as amorphous powder of the fractions obtained by elution of sadism-1: 1773, 1709, 1607, 1549, 1522, 1448, 1346, 1225

NMR spectrum (270 MHz, CDCl3) memorial plaques of 1.27 and 1.28 (together 3H, two doublet, J= 7,33 Hz); of 1.36 (3H, doublet, J=6,35); 1,47 - OF 2.28 (3H, multiplet); 2,19 and 2,22 (together 3H, two singlets); 2,50-and 2.83 (1H, multiplet); 3,26-to 3.52 (3H, multiplet); 3,59-of 3.78 (1H, multiplet); 3,70-4,84 (N, multiplet); 5,06-5,51 (6N, multiplet); of 7.48-7,66 (6N, multiplet); 8,19-8,23 (6N, multiplet).

34(2) (1R,5S,6S)-2-[(2S,4S)-2-(3-acetylethylenediamine-1 - ylcarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

of 0.77 g of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2- [(2S, 4S)-2-{ 3-[N-(4-nitrobenzenesulfonyl)-N-acetaminophena] azetidin-1-ylcarbonyl} -1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1)was dissolved in 15 ml volumetric 2:1 mixture of tetrahydrofuran and water. To the resulting solution was added of 0.77 g of the catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for 2 hours under hydrogen atmosphere. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated, pariva under reduced pressure, and the obtained residue was programatorului at stake is the unity and obtained by elution with 4% by volume aqueous solution of acetonitrile, concentrated, pariva under reduced pressure and dried by freezing. The result was received with 0.13 g of the titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 300

X (KBr)maxcm-1: 1755, 1633, 1591, 1463, 1389, 1286, 1262.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=6,84 Hz); of 1.30 (3H, doublet, J=6,35 Hz); 1,64-1,74 (1H, multiplet); of 2.25 to 2.35 (3H, multiplet); 2,58-2,70 (1H, multiplet); 2,98 totaling 3.04 (1H, multiplet); 3,20 (1H, doublet of doublets, J= 12,21, 5,86 and of 2.44 Hz), 3,34 is-3.45 (1H, multiplet); 3,44 is-3.45 (1H, multiplet); 3,44 (1H, doublet of doublets, J=6,35 and of 2.44 Hz); of 3.73-3,88 (2H, multiplet); 4,03-4,10 (1H, multiplet); 4,19-4,37 (3H, multiplet); to 4.41-4,90 (3H, multiplet).

Example 35

(1R, 5S, 6S)-2-[(2S,4S)-2-(3-formamidopyrimidine-1-ylcarbonyl/ pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylic acid

< / BR>
Repeated the procedure described in example 34, but used as initial reagents 0.12 g of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1 - hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylate and 0.17 g of (2S,4S)-4-mercapto-2-[3-(N-4-nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)-pyrrolidine, CA

UV absorption spectrum (H2O)maxnm: 301

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,22 Hz); of 1.30 (3H, doublet, J=6,33 Hz); of 1.66 to 1.76 (1H, multiplet); 2,61 is 2.75 (1H, multiplet); 3,01-3,13 (1H, multiplet); 3,20-3,30 (1H, multiplet); 3,35-of 3.48 (2H, multiplet); 3,76-3,98 (2H, multiplet); 4,04 is 4.13 (1H, multiplet); 4,20-4,56 (4H, multiplet); br4.61-4,88 (2H, multiplet); 7,87 and 7,88 (1H, two singlets)

Example 36

(1R, 5S, 6S)-2-[(2S,4S)-2-(3-aminoamides-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
36(1) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S)-1-methyl-2-[3-(4-nitrobenzenesulfonyl/pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate

To a solution of 14 ml of dry acetonitrile 0,70 g of 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydrocity] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in obtaining 32, cooled by ice dropwise simultaneously added a solution of 0.42 g of (2S,4S)-4-mercapto-1-methyl-2-[3-(4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] pyrrolidine, obtained as described in obtaining 25, in 10 ml of dry acetonitrile, and 0.18 ml of diisopropylethylamine. The resulting mixture was left, pariva under reduced pressure and the residue was diluted with ethyl acetate and washed with water, and then aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated, pariva under reduced pressure. The obtained residue was programatorului on a column of silica gel (Silica gel 60 9385, production Merck, 100 ml), the received 0.25 g of the entitled compound as amorphous powder. Elution was performed with a mixture of acetonitrile and methanol were taken in a volume ratio of 95:5.

X (KBr)maxcm-1: 1771, 1723, 1641, 1608, 1522, 1455, 1347

NMR (spectrum (270 MHz, CDCl3+ D2O) M. D. of 1.27 and 1.28 (together 3H, two doublet, J=7,33 and 6,84); of 1.36 (3H, doublet, J=5,86); 1.85 TO 2,04 (1H, multiplet); of 2.33 and 2.37 (6N, two singlets); 2,67 is 2.80 (2H, multiplet); 2,67 is 2.80 (2H, multiplet); 3,03-3,39 (4H, multiplet); 3,65-to 3.73 (1H, multiplet); 3,90-of 3.95 (1H, multiplet); 4,10-a 4.83 (6N, multiplet); 5,09-5,52 (4H, multiplet); 7,47-to 7.67 (4H, multiplet); 8,15 compared to 8.26 (4H, multiplet).

36(2) (1R, 5S,6S)-2-[(2S,4S)-2-(3-aminoamides-1-ylcarbonyl)-1 - methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

5.5 ml of a mixture of tetrahydrofuran and water (volume ratio of 6:5) was dissolved 0.25 g of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-meth is carboxylate, obtained as described above in stage (1). To the resulting solution was added 0.25 g of catalyst 10 wt./wt. palladium supported on carbon. The mixture was then hydrogenosomal at room temperature for 90 min in an atmosphere of hydrogen. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated, pariva under reduced pressure. The obtained residue was programatorului on the column with the reversible phase (Cosmosil 75 ° C18-prep, production Nacalai Tesque 25 ml). Of the fractions obtained by elution of the column with 5% by volume aqueous solution of acetonitrile containing the target compound, it was concentrated by evaporation under reduced pressure and after freeze-drying was obtained 0.5 g of titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 301

X (KBr)maxcm-1: 1755, 1641, 1598, 1462, 1386, 1284, 1255

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=7,33 Hz); of 1.30 (3H, doublet, J=6,35 Hz); 1,75-of 1.85 (1H, multiplet); 2,46-2,47 (together 3H, two singlets); 2,79-2,89 (1H, multiplet); 2,97-of 3.07 (1H, multiplet); 3,22-of 3.53 (4H, multiplet); 3,90-4,06 (4H, multiplet); 4,13-the 4.29 (4H, multi is lidin-1-ylcarbonyl/- 1 methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
37(1) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S)- 1-methyl-2-{ 3-[N-(4-nitrobenzenesulfonyl)-N-acetylethylenediamine-1 - ylcarbonyl}pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate

Under ice cooling to a solution of 595 mg 4-nitrobenzyl(1R,5S,6S)-2- (diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, in 10 ml of dry acetonitrile were added simultaneously dropwise a solution of 435 mg (2S,4S)-4-mercapto-1-methyl-2-[3-[N-(4-nitrobenzenesulfonyl)-N - acetimidoyl]-azetidin-1-ylcarbonyl of pyrrolidine, obtained as described in obtaining 26, in 4 ml of dry acetonitrile and 174 μl of diisopropylethylamine. The resulting mixture is left to interact for about 20 minutes at the same temperature. Then left for three hours at room temperature and in the refrigerator over night. After this time the reaction mixture was diluted with ethyl acetate and washed with water, and then aqueous solution of sodium chloride. An ethyl acetate layer was then dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure. The obtained residue was programatorului on a column of silica gel and the fractions obtained by elution with a mixture of methylene chloride, ethylamine, the result was 464 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1771, 1690, 1607, 1549, 1521, 1455, 1378, 1346

NMR spectrum (270 MHz, DMSO-d6+ D2O) M. D. 1,16 (6N, doublet, J=6,83 Hz); 1,59-1,74 (1H, multiplet); 2,11 (3H, singlet); to 2.29 (3H, broadened singlet); 2,54-3,19 (3H, multiplet); with 3.27 (1H, doublet of doublets, J=6,35 and of 2.44 Hz); 3,32-4,27 (8H, multiplet); 4,42-4,60 (2H, multiplet); 5,11-5,49 (4H, multiplet); 7,60 and to 7.61 (together 2H, two doublet, J=8,79 Hz); 7,70 and 7,72 (together 2H, two doublet, J=8,79 Hz), 8,16-of 8.28 (4H, multiplet).

37(2) (1R,5S,6S)-2-[(2S,4S)-2-(3-acetylethylenediamine-1-ylcarbonyl)- 1-methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylic acid

453 mg of 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S, 4S)- 1-methyl-2-{ 3-[N-(4-nitrobenzenesulfonyl)-N-acetimidoyl azetidin-1 - ylcarbonyl]pyrrolidin-4-ylthio}-1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1), dissolved in 21 ml of a mixture of tetrahydrofuran and water collected in a volume ratio of 2:1. To the resulting solution was added 500 mg of catalyst 10 wt./wt. palladium supported on carbon. The mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen. Then the catalyst was filtered and the filtrate washed titilatingly on the column with the reversible phase (Cosmosil 75 ° C18-prep, production Nacalai Tesque 40 ml). Of the fractions obtained after elution of 8% by volume aqueous solution of acetonitrile, after concentration by evaporation under reduced pressure and freeze-drying has received 166 mg of the titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 301

X (KBr)maxcm-1: 1757, 1633, 1592, 1462, 1386, 1335, 1284, 1256.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=6,83 Hz); of 1.30 (3H, doublet, J= 6,35 Hz); 1,64-of 1.78 (1H, multiplet); and 2.27 (3H, singlet); to 2.29 (3H, singlet); 2.63 in-2,85 (2H, multiplet); 3,01-is 3.21 (2H, multiplet); 3.27 to of 3.46 (2H, multiplet); 3.75 to 3,88 (1H, multiplet); 4,00-4,10 (1H, multiplet); 4,15-4,96 (6N, multiplet)

Example 38

(1R, 5S, 6S)-2-[(2S, 4S)-2-(3-formamidopyrimidine-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
Repeated the procedure described in example 37, but used as initial reagents 0.35 g of 4-nitrobenzyl(1R,5S,6S)-2- (diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, and 0.22 g of (2S, 4S)-4-mercapto-1-methyl-2-{ 3-[N-(4-nitrobenzisoxazole received 17 mg of the titled compound in the form of a powder.

UV absorption spectrum (H2O)maxnm: 302

Example 39

(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S,4S)-2-[(3S)-3-(4-methyl-1-1,2,4-triazolo)pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1 - karbapin-2-em-3-carboxylate hydrochloride

< / BR>
39(1)4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-[(2S, 4S)-1-(4-nitrobenzenesulfonyl)-2-[(3S)-3-(1-1,2,4-triazolyl)-1 - pyrrolidinylcarbonyl]-pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate

486 mg 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 5 ml dry acetonitrile. To the resulting solution under ice cooling was added dropwise 379 mg diphenylphosphinylchloride and 182 mg of diisopropylethylamine. The mixture was then stirred at the same temperature for 1 h, after this time the mixture cooled with ice, was added dropwise a solution of 173 mg of diisopropylethylamine and 690 mg of (2S,4S)-4-mercapto-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl] -1-(4-nitrobenzyloxy-carbonyl)pyrrolidine, obtained as described in getting 28 in 4 ml of dry acetonitrile, and the mixture was left for 6 h at the same temperature. Then the solvent was distilled under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was then washed with water, water is Loy was Proektirovanie with methylene chloride and the combined aqueous layer with water extracts and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the residue was purified on a column of silica gel, using as eluent a mixture of ethyl acetate and methanol were taken in a volume ratio of 5:1. The result was 744 mg of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1772, 1709, 1655, 1607, 1522, 1346, 854, 738.

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide + D2O) M. D. 1,50-1,80 (1H, multiplet); 2,20-of 2.50 (2H, multiplet); 2,70-2,95 (2H, multiplet); 3,10-4,30 (N, multiplet); 4,45-of 4.75 (1H, multiplet); 5,00-5,50 (4H, multiplet); 7,45 for 7.78 (4H, multiplet); 7,80-of 8.00 (1H, multiplet); 8,15-of 8.28 (4H, multiplet); 8,50 at 8.60 (1H, multiplet).

39(2) (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-[(2S,4S)-2-[(3S)- 3-(4-methyl-1-1,2,4-Tripoli)pyrrolidin-1-yl-carbonyl pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate hydrochloride

528 mg 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S, 4S)-1-(4-nitrobenzenesulfonyl)-2-[(3S)-3-(1-1,2,4-triazolyl)-1 - pyrrolidinylcarbonyl] pyrrolidine-4-ylthio] -1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1), dissolved in 6 ml of dry acetonitrile. To the resulting solution was added 121 mg methyltrichlorosilane, cooling the solution with ice. Then the mixture was stirred at the same temrerature and 5 ml of water, after which the mixture was hydrogenosomal at room temperature in the presence of 1 g of the catalyst 10 wt./wt. palladium deposited on carbon. After this, the catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure. The aqueous layer was then washed with diethyl ether and concentrated, pariva under reduced pressure, then the residue skipped through the chromatographic column filled with ion exchange resin (Dowex 1-X4, 50-100 mesh, CI FOPM, manufacturing Dow CHEMICAL), using water as eluent. Fractions containing the titled compound was collected and concentrated under reduced pressure to a volume of 1.5 ml Concentrated aqueous solution pass through the column (Cosmosil 75 ° C18-prep, production Nacalai) and Polyanovo water. Fractions containing the titled compound were combined, concentrated, upriv under reduced pressure, and after freeze-drying has received 85 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O), lmaxnm: 296,7.

X (KBr)maxcm-1: 3394, 1758, 1655, 1586, 1460, 1373

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) M. D. 1,18-of 1.23 (3H, m), 1,27-1,30, multiplet); 3,70-of 3.85 (2H, multiplet); 3,85-of 4.05 (3H, multiplet); 4,05-to 4.15 (3H, multiplet); 4,15-4,30 (2H, multiplet); 4,70-is 4.85 (2H, multiplet); the 5.45 ceiling of 5.60 (1H, multiplet); 8,84 and 8,87 (together 1H, two singlets).

Example 40

(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[3-(4-methyl-1-1,2,4-triazolo-azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
40(1) 4-nitrobenzyl(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S)-2-[3-(1-1,2,4-triazolyl)-1-azetidinone] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate

886 mg 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1 - hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, was dissolved in 10 ml of dry acetonitrile. To the resulting solution was added under ice cooling is added dropwise 0,26 ml diisopropylethylamine and 873 mg of (2S,4S)-4-mercapto-2-[3-(1-1,2,4-triazolyl)-1-azetidinone] -1-(4-nitrobenzenesulfonyl) pyrrolidine, obtained as described in obtaining 29 dissolved in 5 ml of acetonitrile. The mixture was then stirred at the same temperature for 3 hours, after this time the solvent was distilled under reduced pressure and the residue was diluted with ethyl acetate, the mixture was washed with water, aqueous razvodnym magnesium sulfate and then concentrated, upriv the solvent under reduced pressure. The residue was purified through column chromatography with silica gel using a gradient elution method with mixtures of ethyl acetate and methanol ranging from volumetric composition of 6:1 to 4:1. The result was 661 mg of the titled compound in the form of a powder.

The IRS spectrum (KBr)maxcm-1: 3402, 1709, 1665, 1608, 854, 738

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) M. D. 1,10-1,30 (6N, multiplet); 1,75-1,90 (1H, multiplet); 2,70-to 2.85 (1H, multiplet); 3,55-the 3.65 (1H, multiplet); 3,20-5,10 (N, multiplet); 5,15-5,55 (5H, multiplet); 7,55-7,80 (4H, multiplet); 7,95-8,10 (1H, multiplet); 8,20-8,30 (4H, multiplet); 8,55 is 8.75 (1H, multiplet).

40(2) (1R, 5S, 6S)-6[(1R)-1-hydroxyethyl]-1-methyl-2-(2S,4S)-2-[3-(4-methyl-1-1,2,4-triazolo-azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate hydrochloride

660 mg of 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(2S, 4S)-2-[3-(1-1,2,4-triazolyl] -1-azetidinone] -1-/4 - nitrobenzenesulfonyl)-pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1), dissolved in 7 ml of dry acetonitrile. To the resulting solution under ice cooling was added 164 mg methyltrichlorosilane. The mixture was stirred at the same temperature and in a mixture of 14 ml of tetrahydrofuran and 14 ml of water. The resulting mixture was hydrogenosomal at room temperature for 1 h in the presence of a catalyst 10 wt./wt. palladium supported on carbon, and hydrogen atmospheres. The catalyst was filtered and the tetrahydrofuran was distilled under reduced pressure, after which the aqueous layer was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, and then pass through a chromatographic column Packed with ion-exchange resin (Dowex 1-X4, 50-100 mesh, CI FOPM, manufacturing Dow CHEMICAL), using as eluent water. Fractions containing the titled compound was collected and concentrated, upriv under reduced pressure. An aqueous solution pass through the column (Cosmosil 75 ° C18-prep, production Nacalai) and Polyanovo water. Fractions containing the titled compound were combined, concentrated, upriv under reduced pressure, the result was 139 mg of the titled compound after freeze-drying in the form of colorless powder.

X (KBr) nmaxcm-1: 3390, 1759, 1664, 1486, 1455, 1369.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=5,99 Hz); of 1.29 (3H, doublet, J= 6,29 Hz); 1,80-2,20, multiplet); 3,90-5,20 (8H, multiplet); the 5.45 the 5.65 (1H, multiplet); 5,70-5,80 (1H, multiplet); 8,96 and 8,97 (together 1H, two singlets).

Example 41

(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -1-methyl-2-[(2S, 4S)-2-(3-trimethyl - ammoniated-1-ylcarbonyl)-pyrrolidin-4-ylthio]-1-karbapin-2-em-3 - carboxylate hydrochloride

< / BR>
41(1) 4-nitrobenzyl(1R, 5S, 6S)-2-[(2S,4S)-2-(3-dimethylimidazolidin-1 - ylcarbonyl)-1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate

A solution of 0.98 g of (2S, 4S)-2-(3-dimethylimidazolidin-1-yl-carbonyl)-4 - mercapto-1-(4-nitrobenzenesulfonyl)pyrrolidine, obtained as described in obtaining 30, was dissolved in 20 ml of dry acetonitrile and 0,418 ml diisopropylethylamine added simultaneously and dropwise to a cooled with ice to a solution of 1.43 g of 4-nitrobenzyl(1R,5S,6S)-2- (diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-/-methyl-1-karbapin-2-em - 3-carboxylate, obtained as described in getting 32 in 25 ml dry acetonitrile. The mixture was stirred at the same temperature for 2 hours, then left it overnight in the refrigerator. Then the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The resulting mixture was washed with water and then with an aqueous solution of sodium chloride. Eiendom pressure. The residue was purified by the method of column chromatography on silica gel, and the fraction obtained after elution with a mixture of ethyl acetate and methanol were taken in a volume ratio of 75: 25, combined and concentrated, upriv under reduced pressure, the result was of 1.16 g of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1774, 1712, 1663, 1607, 1522, 1456, 1404, 1346.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. of 1.26 (3H, doublet, J=7,11 Hz); of 1.36 (3H, doublet, J=6,13 Hz); 2,00-to 2.18 (1H, multiplet); 2,10, 2,14, 2,25 and 2,28 (together 6N, four singlet); of 2.51-by 2.73 (1H, multiplet); 2,86-4,56 (13H, multiplet); 5.08 to 5,54 (4H, multiplet); 7,50 (2H, doublet, J=8,57); THE 7.65 (2H, doublet, J=8,57); 8,23 (4H, doublet, J=8,57 Hz).

41(2) (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(3 - trimethylammonium-1-ylcarbonyl)pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate hydrochloride

In 12 ml of dry acetonitrile was dissolved in 1.00 g of 4-nitrobenzyl(1R,5S,6S)-2-[(2S, 4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-1-(4 - nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl - 1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1). To the obtained solution under cooling with ice added 243 mg metiltiometilatsetata, after which the mixture was stirred at this jesica powdery product was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of water. Then the mixture was hydrogenosomal at room temperature for 2 h in the presence of a catalyst and 1 g of 10 wt./wt. palladium supported on carbon, and nitrogen atmosphere. Then the catalyst was filtered, the filtrate washed with diethyl ether. The resulting aqueous phase was concentrated, upriv her under reduced pressure. The remainder pass through the chromatographic column with ion-exchange resin (Dowex 1-X4, 50-100 mesh. Cl-the sample, the production of DOW CHEMICAL), using as eluent water. Fractions containing the titled compound, concentrated, upriv under reduced pressure, and then skipped through the chromatographic column with the reversible phase (Cosmosil 75 ° C18-prep, production Nacalai Tesque) and Polyanovo water. The desired fractions were concentrated, upriv under reduced pressure, and after freeze-drying has received 265 mg of the titled compound in the form of a powder.

UV absorption spectrum (H2O), lmaxnm: 296

X (KBr)maxcm-1: 1758, 1665, 1594, 1482, 1373, 1285, 1255, 1145

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=7,17 Hz); of 1.28 (3H, doublet, J= 6,29 Hz); 1,98-of 2.09 (1H, multiplet); 2.93 which was 3.05 (1H, multiplet); is 3.21 and 3.22 (instead of tiplet); 4,43-4,85 (6N, multiplet).

Example 42

(1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -2-(2S,4S)-2-[3-(1-imidazolyl) azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
42(1) 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3- (1-imidazolyl)azetidin] -1-ylcarbonyl/-1-(4-nitrobenzenesulfonyl)-pyrrolidin-4-ylthio]-1-methyl-1-karbapin-2-em-3-carboxylate

To a solution of 55 ml of dry acetonitrile 4,27 g of 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in obtaining 32, under ice cooling was added dropwise a solution of 3.10 g of (2S,4S)-2-[3-(1-imidazolyl)-azetidin-1 - ylcarbonyl)-4-mercapto-1-(4-nitrobenzenesulfonamide), obtained as described in getting 31 in 25 ml of dry acetonitrile and simultaneously 1.25 ml diisopropylethylamine. The resulting mixture was left to stand at the same temperature for one hour, and then left overnight in the refrigerator. Then the reaction mixture was concentrated under reduced pressure by evaporation, and the resulting residue was diluted with ethyl acetate. Thus obtained mixture was washed with water, then with an aqueous solution of sodium chloride. Formed an ethyl acetate solution is dried over basw and through a chromatographic column filled with silica gel, and the fraction obtained by elution with a mixture of methylene chloride, ethyl acetate and methanol were taken in a volume ratio of 7:7:6, consolidated and concentrated, upriv them in a vacuum, as a result got to 2.94 g of the titled compound in the form of a powder.

X (KBr)maxcm-1: 1772, 1708, 1667, 1607, 1522, 1449, 1403, 1346, 1209.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. of 1.27 (3H, doublet, J=7,19 Hz); of 1.36 (3H, doublet, J=6,14 Hz); 2,15-5,55 (N, multiplet); 7,10-8,28 (11N, multiplet).

42(2) (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl] -2-[(2S,4S)-2-[3-(1-imidazolyl)-azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylic acid

0.25 g of 4-nitrobenzyl(1R,5S,6S)-6-[(1R)-1-gidroksistil]-2-[(2S,4S)-2-[3-(1-imidazolyl)azetidin-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described above in stage (1), dissolved in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water. To the resulting solution was added 0.25 g of catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen. Then the catalyst was filtered, and the filtrate was washed with diethyl ether. The resulting aqueous layer was then concentrated, uparati (Cosmosil 75 ° C18-prep, production Nacalai Tesque). Of the fractions obtained by elution content columns 7% by volume aqueous solution of acetonitrile, after concentration and evaporation under reduced pressure, and freeze-drying, received 70 mg of the titled compound.

UV absorption spectrum (H2O), lmaxnm: 297.

X (KBr)maxcm-1: 1757, 1660, 1598, 1466, 1383, 1285, 1255, 1181, 1149.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,12 Hz); of 1.30 (3H, doublet, J= 6,27 Hz), 1,90-2,02 (1H, multiplet), 2,84-2,96 (1H, multiplet), 3,29-3,50 (3H, multiplet), 3,56-the 3.65 (1H, multiplet), 3,91-a 4.03 (1H, multiplet), 4,20-4,43 (4H, multiplet), 4,50-of 5.45 (4H, multiplet), 7,22 and 7.23 percent (together 1H, two singlets), 7,54 (1H, singlet), to 8.12 (1H, singlet).

Example 43

(1R, 5S, 6S)-6-[(1R)-hydroxyethyl] -1-methyl-2-[(2S, 4S)-2-[3-(3-methyl-1 - imidazolyl)azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
1,72 g of 4-nitrobenzyl(1R, 5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3-(1-imidazolyl/azetidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl) pyrrolidin-4-ylthio] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in example 42(1), dissolved in 18 ml dry the After that, the mixture was stirred one hour at the same temperature. After this time the solvent was distilled under reduced pressure, and the thus obtained powdery product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of water. The mixture was then hydrogenosomal at room temperature for 2 h in hydrogen atmosphere in the presence of 2.10 g of the catalyst 10 wt. /Mac. palladium supported on carbon. The reaction mixture is then processed, purified and dried by freezing as described in example 40(2), the received 383 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O)maxnm: 296

X (KBr)maxcm-1: 1759, 1664, 1597, 1561, 1466, 1373, 1284, 1184, 1147.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne) memorial plaques to 1.21 (3H, doublet, J=7,21 Hz); of 1.29 (3H, doublet, J= 6,38 Hz); 2,00-2,14 (1H, multiplet); 2.93 which was 3.05 (1H, multiplet); 3,30-3,51 (3H, multiplet); to 3.73-3,82 (1H, multiplet), to 3.92 (3H, singlet), 4,01-4,10 (1H, multiplet), 4,20-4,30 (2H, multiplet), to 4.38-4,47 (1H, multiplet); 4,55-4,96 (4H, multiplet); the 5.45 to 5.55 (1H, multiplet); at 7.55 (1H, singlet); 7,80 (1H, singlet); 9,00 and of 9.02 (1H, two singlets).

Example 44

(1R, 5S, 6S)-2-[(2S, 4S)-2-[3-[3-(2-toroidal/-1-imidazolyl] azetidin-1 - ylcarbonyl] pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-is ensil(1R,5S,6S)-6-[(1R)-1-hydroxyethyl] -2-[(2S, 4S)-2-[3-(1- imidazolyl)azetidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in example 42(1). To the resulting solution was added 0.63 ml of 1-bromo-2-foroutan, 0.84 g of sodium iodide and 80 ml of sodium carbonate, after which the mixture was heated under reflux for 14 hours after this time was filtered insoluble components of the mixture, and the filtrate was concentrated, pariva under reduced pressure. The obtained residue was washed repeatedly by decantation with methylene chloride and then diethyl ether. Then the residue was dried, pariva under reduced pressure, the obtained 0,494 g of powder. All the obtained compound was dissolved in a mixture of 12.5 ml of tetrahydrofuran and 12.5 ml of water. Then this mixture is added to 0.48 g of the catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for one hour. After this time the reaction mixture is treated, purified and dried by freezing as described in example 40(2), the result was 42 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O)maxnm: 297

X (KBr)maxcm-1

Example 45

(1R, 5S, 6S)-2-[(2S,4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl]-pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
In a mixture of 21 ml of tetrahydrofuran and 14 ml of water was dissolved 0.75 g of 4-nitrobenzyl(1R,5S,6S)-2-[(2S,4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in example 41(1). To the mixture was added 75 mg of catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen. After this time the catalyst was filtered, and the filtrate was washed with diethyl ether. The resulting aqueous solution was concentrated by evaporation under reduced pressure, after which the remainder pass through the chromatographic column with the reversible phase (Cosmosil 75 ° C18-prep, production Nacalai Tesque). Fraction, p is Toktom by evaporation under reduced pressure, and subsequent drying by freezing, received 171 g of the titled compound in the form of a powder.

UV absorption spectrum (H2O)maxnm: 299

X (KBr)maxcm-1: 1757, 1653, 1599, 1462, 1385, 1284, 1259, 1150

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,22 Hz); of 1.30 (3H, doublet, J= 6,40 Hz); 1,83-of 1.92 (1H, multiplet); to 2.41 (3H, singlet); of 2.45 (3H, singlet); 2,78-2,89 (1H, multiplet); 3,26 (1H, doublet of doublets, J= 12,14 and the 4.90 Hz); 3,34-to 3.73 (4H, multiplet); 3,89-4,06 (2H, multiplet); 4,19-4,33 (5H, multiplet); 4,43-of 4.54 (1H, multiplet);

Example 46

(1R, 5S, 6S)-2-[(2S, 4S)-2-2-{ 3-[N-(carbamoylmethyl)-N,N-dimethylammonio] azetidin-1-ylcarbonyl} pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl - 1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
In 8 ml of dry acetonitrile was dissolved 0,60 g of 4-nitrobenzyl(1R,5S,6S)-2-[(2S, 4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-1-(4-nitrobenzenesulfonyl)pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in example 41(1). To the resulting solution was added 0.74 g of iodoacetamide, after which the mixture was stirred at 70oC 2 hours after this time the solvent was distilled under reduced pressure, the residue letters evaporation under reduced pressure, receiving a result of 0.90 g of powder. All this compound was dissolved in a mixture of 24 ml of tetrahydrofuran and 16 ml of water. To the solution was added 0.95 g of the catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen.

The reaction mixture is then processed, purified and dried by freezing, in accordance with the procedures described in example 40(2), the result was 156 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O) maxnm: 297

NMR 270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=7.18 in Hz) of 1.29 (3H, doublet, J= 6,37 Hz), 1,98-2,10 (1H, multiplet); 1,98-2,93 totaling 3.04 (1H, multiplet); to 3.38 and 3.40 (together 6N, two singlets), 3,30-3,50 (HN, multiplet); 3,74-of 3.80 (1H, multiplet); 4,01-4,10 (1H, multiplet), 4,15-4,88 (5H, multiplet); 4,43-4,30 (4H, multiplet), 4,43-4,88 (5H, multiplet), 4,94-to 5.03 (1H, multiplet).

Example 47

(1R, 5S, 6S)-2-[(2S,4S)-2-[3-(2-toroidal/dimethylammonio]azetidin-1 - ylcarbonyl] pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
In 7 ml of dry acetonitrile was dissolved 715 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S, 4S)-2-(3-di karbapin-2-em-3-carboxylate, obtained as described in example 41(1). To the resulting solution was added 1.22 g of 1-bromo-2-foroutan, 721 g of sodium iodide and 67 mg of sodium carbonate, after which the mixture was heated under reflux for 23 hours Upon expiration of this time, insoluble components are filtered out, the filtrate was evaporated under reduced pressure. The obtained residue was washed repeatedly by decantation, first with methylene chloride, and then diethyl ether, and the mixture is dried by evaporation under reduced pressure, resulting in 400 mg of powder. All this compound was dissolved in a mixture of 8 ml of tetrahydrofuran and 8 ml of water. To the resulting solution was added 0.40 g of the catalyst 10 wt./wt. palladium supported on carbon, after which the mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen. Then the reaction mixture is treated, purified and dried by freezing as described in example 42(2), the result was 39 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O)maxnm: 296.

X (KBr)maxcm-1: 1759, 1668, 1598, 1476, 1374, 1285, 1226, 1180

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, the; ,33-3,51 (3H, multiplet); 3.75 to to 3.92 (3H, multiplet); as 4.02-4,11 (1H, multiplet); 4,20-to 4.28 (2H, multiplet), 4,43-4,85 (6N, multiplet), 4,90-of 5.06 (2H, multiplet).

Example 48

(1R, 5S, 6S)-2-[(2S, 4S)-2-[3-[2-hydroxyethyl/dimethylammonio]azetidin-1 - ylcarbonyl] pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate hydrochloride

< / BR>
In 7 ml of dry acetonitrile was dissolved 0.65 g of 4-nitrobenzyl (1R,5S,6S)-2-[(2S, 4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-1/4-nitrobenzenesulfonyl/pyrrolidin-4-ylthio] -6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylate, obtained as described in example 41(1). To the resulting solution was added to 1.05 g iodoethanol and then the mixture was heated under reflux 5 hours after this time the solvent was distilled under reduced pressure and the residue was washed by repeated decantation, first with methylene chloride, and then diethyl ether. The mixture is then dried, pariva her under reduced pressure, the obtained 0.84 g of powder. All the obtained compound was dissolved in a mixture of 21 ml of tetrahydrofuran and 14 ml of water. To the solution was added to 0.90 g of the catalyst 10 wt./wt. palladium supported on carbon. Then the mixture was hydrogenosomal at room temperature for 1.5 h in an atmosphere of hydrogen. The reaction iMER 40(2), the result obtained 55 mg of the titled compound.

UV absorption spectrum (H2O)maxnm: 297

X (KBr)maxcm-1: 1758, 1665, 1595, 1477, 1374, 1261, 1227, 1149

NMR (spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.21 (3H, doublet, J=7,20 Hz) of 1.28 (3H, doublet, J= 6,36 Hz), 1,98-2,10 (1H, multiplet), 2,93 totaling 3.04 (1H, multiplet) at 3.25 and 3.26 (together 6N, two singlets), 3,31-of 3.60 (5H, multiplet), of 3.77 (1H, doublet of doublets, J=12,23 and 6,63 Hz), 4,00-4,10 (3H, multiplet), 4,21-the 4.29 (2H, multiplet), 4,42-4,86 (6N, multiplet).

Example 49

(1R, 5S, 6S)-2-[(2S, 4S)-2-(3-aminoamides-1-ylcarbonyl)pyrrolidin-4 - ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
In 190 ml of a mixture of tetrahydrofuran and water (volume ratio 3:2) was dissolved 3630 mg 4-nitrobenzyl(1R,5S,6S)-2-{(2S,4S)-2-[3-(4- nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] -1-(4 - nitrobenzenesulfonyl)-pyrrolidin-4-ylthio} -6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate, obtained, as described in example 33(1). To the resulting solution was added 5500 mg of catalyst 10 wt./wt. palladium supported on carbon. The mixture was hydrogenosomal at room temperature (30oC) 1.5 h in an atmosphere of hydrogen. After was togetheranal by evaporation under reduced pressure to 10 ml The resulting solution pass through the chromatographic column with silica gel-reversible phase (Cosmosil 75 ° C18-ven, 250 ml, the production of Nacalai Tesque), then Polyanovo mixtures of acetonitrile and water collected in the following volume ratios 0:100, 2: 98, 4: 96, 6:94. Elution was performed in the specified order. The fractions containing the target compound were collected, concentrated by evaporation under reduced pressure and dried by freezing in the received 901 mg of the titled compound as a powder.

UV absorption spectrum (H2O)maxnm: 298,5

X (KBr)maxcm-1: 1755, 1642, 1594, 1464, 1387

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) memorial plaques to 1.22 (3H, doublet, J=7,2 Hz), of 1.29 (3H, doublet, J= 5.3 Hz), 1,75-of 1.85 (1H, multiplet), 2,70-and 2.83 (1H, multiplet), 3,14-is 3.21 (1H, multiplet), 3,35-3,47 (3H, multiplet), 3,82-to 3.92 (1H, multiplet), 3,96-a 4.03 (1H, multiplet), 4,05-4,18 (2H, multiplet), 4,19-to 4.28 (3H, multiplet), 4,34-4,43 (1H, multiplet), 4,56 with 4.65 (1H, multiplet).

Example 50

(1R,5S,6S)-2-[(2S,4S)-2-(3-acetylethylenediamine-1-ylcarbonyl) pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3 - carboxylic acid hydrochloride

< / BR>
In 20 ml of cold water were dissolved 0.40 g of (1R,5S,6 is-3-carboxylic acid, obtained as described in example 34. To the resulting solution was added to 0.88 ml of a 1M aqueous solution of hydrochloric acid. The mixture was dried by freezing and received 400 mg of the entitled compound as colorless powder.

UV absorption spectrum (H2O) maxnm: 296

X (KBr)maxcm-1: 1760, 1664, 1630, 1585, 1463, 1378, 1286, 1148

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) M. D. of 1.01 (3H, doublet, J=7,17 Hz); of 1.09 (3H, doublet, J= 6,37 Hz), 1,76 is 1.86 (1H, multiplet), 2,07 (3H, singlet), 2,70-2,82 (1H, multiplet), 3,10-3,30 (3H, multiplet), 3,55 (1H, doublet of doublets, J=12.9% and is 6.54 Hz), 3,78-of 3.96 (2H, multiplet), 4,00-4,17 (3H, multiplet), 4.26 deaths-of 4.67 (4H, multiplet).

Example 51

(1R, 5S, 6S)-2-[(2S,4S)-2-(azetidin-3-ylcarbonyl)-pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-karbapin-2-em-3-carboxylic acid

< / BR>
Following the procedure similar to that described in example 33(1), following this, using the methods described in example 49, but using as starting reagents of 0.80 g of 4-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3 - carboxylate, obtained as described in obtaining 32, and 0.95 g of (2S,4S)-4-mercapto-2-[1-(4-nitrobenzenesulfonyl)azetidin-3 - slow connections.

UV absorption spectrum (H2O)maxnm: 301

X (KBr)maxcm-1: 1754, 1590, 1450, 1389, 1287, 1264.

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium): memorial plaques to 1.22 (3H, doublet, J=7,25 Hz) of 1.30 (3H, doublet, J=6,36 Hz), 1,83-of 1.93 (1H, multiplet), 2,72-2,82 (1H, multiplet), is 2.88 (1H, doublet of doublets, J=11,64 and 5,19 Hz), 3,34-of 3.48 (3H, multiplet), 3,65-3,82 (4H, multiplet), Android 4.04 (1H, triplet, J=11,67 Hz), 4,19-the 4.29 (2H, multiplet), 4,34 (1H, doublet of doublets, J=9,02 and 5,98 Hz), 4,40-4,48 (1H, multiplet).

Getting 1

(2S, 4S)-4-mercapto-2-[4-(4-nitrobenzenesulfonamide)piperazine-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidine triftorbyenzola

1(a) 1-amidino-4-tert-butoxycarbonylamino hemisulfate

In 60 ml of a mixture of tetrahydrofuran and water collected in a volume ratio of 1: 1, was dissolved 2.50 g of 1-amidinopropane of hemisulfate. To the resulting solution was added a solution of 3.40 in g di-tert.-butyl dicarbonate in 10 ml of tetrahydrofuran, after which the mixture was stirred at room temperature for 2.5 hours after which time the tetrahydrofuran was distilled from the reaction mixture under reduced pressure, insoluble components were filtered, and the filtrate was dried to dryness under reduced davleniya for each extraction. The extract was evaporated to dryness and got 2,48 g of the titled compound in the form of crystals with so pl. 278oC (decomposition).

NMR spectrum (270 MHz, D2O, internal standard: tetradeuterated trimethylsilylpropyne sodium) d M. D. 1,47 (N, singlet), 3,49-of 3.64 (8H, multiplet).

X (KBr) nmaxcm-1: 1696, 1656, 1616, 1416, 1169, 1121

1(b) 4-so-butoxycarbonyl-1-4-nitrobenzenesulfonamide)piperazine

In 90 ml of a mixture of tetrahydrofuran and water (volume ratio 1:1), dissolved 2,22 g 1 amidino-4-tert.-butoxycarbonylmethyl of hemisulfate obtained above in stage (a). To the obtained solution under stirring and ice cooling was added a solution of 1.89 g of 4-nitrobenzotrifluoride in 16 ml of tetrahydrofuran and 16 ml of 1M aqueous sodium hydroxide solution at the same time. The resulting mixture was stirred for 30 min under these conditions, after which the organic solvent is removed from the reaction mixture under reduced pressure by distillation. The remaining aqueous solution was Proektirovanie with ethyl acetate, and an ethyl acetate layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The mixture is then concentrated by evaporation under reduced pressure. The obtained residue propose (volume ratio 4:1). The fractions containing the target compound were concentrated, upriv them under reduced pressure. The result has been 2,32 g of the entitled compound as amorphous powder.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,47 (N, singlet), 3,45-3,61 (8H, multiplet), to 5.21 (2H, singlet), 6,90-7,20 (2H, broadening), 7,56 (2H, doublet, J=8.6 Hz), to 8.20 (2H, doublet, J=8.6 Hz).

X (KBr) nmaxcm-1: 1698, 1652, 1601, 1547, 1523, 1279.

1(C) 1-(4-nitrobenzenesulfonamide)piperazine

In 10 ml triperoxonane acid dissolved 750 mg of 4-so-butoxycarbonyl-1-(4-nitrobenzenesulfonamide)piperazine obtained as described above in stage (b). The resulting solution was stirred at room temperature for 30 minutes and Then the reaction mixture was concentrated by evaporation under reduced pressure and the obtained residue was dissolved in a mixture of ethyl acetate and water, then parselocale system, adding thereto an aqueous solution of sodium bicarbonate. An ethyl acetate layer was separated and the aqueous layer was Proektirovanie with ethyl acetate three times. An ethyl acetate layer and all an ethyl acetate extracts were combined and concentrated, upriv them under reduced pressure, the result was 530 mg of the titled compound in the form of a powder.

NMR spectrum (270 which is 5.3 Hz), of 3.80 (4H, triplet, J= 5.3 Hz), a 5.25 (2H, singlet), to 7.61 (2H, doublet, J=8.6 Hz), of 8.27 (2H, doublet, J=8.6 Hz).

1(d) (2S, 4S)-4-(4-methoxybenzylthio)-2-[(-(4- nitrobenzenesulfonamide/piperazine-1-ylcarbonyl]-1-(4 - nitrobenzenesulfonyl/pyrrolidin

7.4 ml of dry acetonitrile was dissolved 740 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxy)pyrrolidin-2-carboxylic acid and the resulting solution was added 330 mg of N,N-carbonyldiimidazole, after which the mixture was stirred at room temperature for 30 minutes, after this time the resulting solution was added to the solution in 10 ml of acetonitrile 525 mg of 1-(4-nitrobenzenesulfonamide)piperazine obtained as described above in stage (C), and the mixture is left overnight in the same conditions. Then the reaction mixture was diluted with ethyl acetate, then washed with an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated, upriv under reduced pressure. The obtained residue was programatorului on a column of silica gel and was Polyanovo first ethyl acetate and then a mixture of ethyl acetate and acetonitrile (volume ratio 4:1). The fractions containing the target compound were concentrated, upriv when bonigen, 1652, 1608, 1520, 1439, 1346.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,72-1,89 (1H, multiplet), 2,39-2,52 (1H, multiplet), 3,03-3,18 (1H, multiplet), 3,30-4,10 (15 NM, multiplet), 4,51-to 4.62 (1H, multiplet), 4,98-5,32 (4H, multiplet), 6,85 (2H, doublet, J= 8,8 Hz), 7.23 percent (2H, doublet, J=8,8 Hz), 7,40-7,58 (4H, multiplet), 8,15-of 8.25 (4H, multiplet).

1(e)(2S,4S)-4-mercapto-2-[4-(4-nitrobenzenesulfonamide)piperazine-1-ylcarbonyl] -1-(4-nitrobenzenesulfonamide trifluromethanesulfonate

In a mixture of 4.4 ml triperoxonane acid and 0.88 ml of anisole was dissolved 880 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzenesulfonamide) piperazine-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidine obtained as described above in stage (d), then under stirring and ice cooling to this solution dropwise added 169 μl triftoratsetata. The resulting mixture was stirred at room temperature for 3 h, after which it was concentrated, upriv under reduced pressure. The obtained residue was washed three times with diethyl ether and the resulting powder was dried, receiving 918 mg of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1761, 1671, 1618, 1523, 1443, 1348, 1285, 1246, 1225, 1169.

NMR spectrum (270 MHz, exudate, ,94, of 4.05 (together 1H, two doublet of doublets, J=9,8 and 6.8), 4,74 and a 4.83 (together 1H, two triplets, J=7.8 Hz), of 5.05-5.25-inch (2H, multiplet), of 5.40 (2H, singlet), 7,53 and 7,63 (together 2H, two doublet, J=8.7 Hz), 8,21 and 8,23 (together 2H, two doublet, J=8,8 Hz), of 8.28 (2H, doublet, J=78 Hz.)

Getting 2

(2S,4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzenesulfonamide) piperazine-1-ylcarbonyl]pyrrolidin

2(a) 1-4-nitrobenzenesulfonamide)piperazine bis(triptorelin)

750 mg of 4-tert-butoxycarbonyl-1-(4-nitrobenzenesulfonamide/ piperazine obtained as described in obtaining 1(b), was dissolved in 12 ml triperoxonane acid and the resulting solution was stirred at room temperature for 30 minutes and Then the reaction mixture was concentrated, upriv under reduced pressure, and the obtained residue was added diethyl ether. The resulting powder was washed three times with diethyl ether and then dried, resulting in 1010 mg of the entitled compound as colorless powder.

X (KBr) nmaxcm-1: 1771, 1698, 1665, 1623, 1518, 1353, 1221, 1197

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) M. D. is 3.21 (4H, triplet, J=5.4 Hz), to 3.73 (4H, triplet), 5,31 (2H, singlet), to 7.68 (2H, doublet), compared to 8.26 (2H, doublet, J=8,8 Hz).

2(b)(2S, 4S)-4-(4-metago acetonitrile suspended 480 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-methylpyrrolidine-2-carboxylic acid and to this suspension was added 325 mg of N,N'-carbonyldiimidazole, then the mixture was stirred at 40oC for one hour. Then the reaction mixture was cooled with ice, and added to her 980 mg of 1-(4-nitrobenzenesulfonamide)piperazine-bis (triptoreline), obtained as described above in stage (a), and 320 l diisopropylethylamine, after which the mixture was stirred at room temperature overnight. After this time the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate, four times with water and then with an aqueous solution of sodium chloride. An ethyl acetate solution is dried over anhydrous sodium sulfate and then concentrated, pariva under reduced pressure. The resulting residue skipped through the chromatographic column filled with silica gel, was Polyanovo a mixture of ethyl acetate and methanol (volume ratio 4: 1). The fractions containing the target compound were concentrated under reduced pressure by evaporation, the result was 860 mg of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1648, 1609, 1542, 1513, 1440, 1346, 1303, 1273, 1239.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. of 1.78 (1H, double doublet of doublets, J= 13,7, to 9.3 and 5.4), of 2.33 (3H, singlet), 2,48-2,60 (3H, multiplet), 3,03-3,24 (3H, multiplet), 3,70 (2H, singlet), 3), to 8.20 (2H, doublet, J=8,8 Hz).

2(C) (2S,4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzenesulfonamide) piperazine-1-ylcarbonyl]pyrrolidin

In a mixture of 7.25 ml triperoxonane acid and a 1.45 ml of anisole was dissolved 1450 mg of (2S, 4S)-4-(4-methoxybenzylthio/-1-methyl-2-[4-(4 - nitrobenzenesulfonamide)piperazine-1-ylcarbonyl] pyrrolidine obtained as described above in stage (b). To the resulting solution, cooled with ice with stirring dropwise added 562 μl triftoratsetata. The reaction mixture was stirred under the same conditions for 60 min and then at room temperature for another 30 minutes After that, the mixture was concentrated by evaporation under reduced pressure. The obtained residue was washed three times with diethyl ether and the resulting powder was dried, resulted in 1940 mg bis/trifluromethanesulfonate) of the titled compound in the form of a powder.

NMR spectrum (hexadeuterated dimethyl sulfoxide + D2O, 270 MHz) d M. D. of 1.81 (1H, double doublet of doublets, J=13,2, to 9.3 and 8.8 Hz), 2,82 (3H, singlet), 2,98 (1H, doublet of triplets, J=13.2 and 7.8 Hz), 3,28-3,81 (11N, multiplet), 4,63 (1H, triplet), of 5.40 (2H, singlet), 7,72 (2H, doublet, J=8,8 Hz), of 8.28 (2H, doublet, J=8,8 Hz).

All the obtained salt was dissolved in ethyl acetate and water to Pastora. An ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. He got to 1.21 g of the entitled compound as amorphous powder.

X (KBr) nmaxcm-1: 1648, 1605, 1544, 1520, 1440, 1346, 1304, 1273, 1232.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,91 (double doublet of doublets, J= 13,7, 8,3 and 4.9 Hz), a 2.36 (3H, singlet), 2,65 is 2.80 (2H, multiplet), is 3.08 (1H, doublet of doublets, J= 10.2 and 2,9 Hz), 3,24 (1H, triplet, J=8,3 Hz), 3,32-3,44 (1H, multiplet), 3.46 in-4,00 (8H, multiplet), to 5.21 (2H, singlet), 7,56 (2H, doublet, J=8,8 Hz), 8,19 (2H, doublet, J=8,8 Hz).

Get 3-21

Connection receive 3 through 21 were synthesized by a method similar to that described in receive 1 and receive 2.

Getting 3

(2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl/-2-[4-(4- nitrobenzenesulfonamide) homopiperazin-1-ylcarbonyl]pyrrolidin

X (KBr) nmaxcm-1: 1708, 1651, 1605, 1551, 1520, 1441, 1346, 1284

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,75-of 1.97 (3H, multiplet), 2,00-of 2.20 (1H, multiplet), 2,66-2,82 (1H, multiplet), 3,13-of 3.96 (8H, multiplet), 4,06-to 4.15 (2H, multiplet), br4.61 (1H, triplet, J=8.0 Hz), 5,10-a 5.25 (4H, multiplet); 7,42-7,58 (2H, multiplet), 8,16-8,23 (4H, multiplet) the Il]pyrrolidin

X (KBr) nmaxcm-1: 1641, 1607, 1552, 1520, 1486, 1444, 1347, 1285

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,81 is 2.01 (3H, multiplet), 2,63 is 2.75 (1H, multiplet), 2,80-is 2.88 (1H, multiplet), of 3.07-3.15 in (1H, multiplet), 3,23-3,93 (10H, multiplet), to 5.21 (2H, singlet), 7,54-EUR 7.57 (2H, multiplet), 8,17 is 8.22 (2H, multiplet).

Getting 5

(2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[4-(4- nitrobenzenesulfonamide) piperidine-1-ylcarbonyl]pyrrolidin.

Getting 6

(2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzenesulfonamide)- piperidine-1-ylcarbonyl]pyrrolidin

Getting 7

(2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3S)-3-(4 - nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl]pyrrolidin

Getting 8

(2S, 4S)-4-mercapto-1-methyl-2-[(3S)-3-(4 - nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl]pyrrolidin

9

(2S,4S)-4-mercapto-(4-nitrobenzenesulfonyl)-2-[3-(4- nitrobenzenesulfonamide] azetidin-1-ylcarbonyl]pyrrolidin

Receive 10

(2S, 4S)-4-mercapto-1-methyl-2-[3-(4-nitrobenzenesulfonamide)- azetidin-1-ylcarbonyl]pyrrolidin

Receipt 11

(2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[2-(4- nitrobenzenesulfonamide) ethylcarbamate]pyrrolidin

13

(2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[4-(methyl-4 - nitrobenzenesulfonamide)piperazine-1-ylcarbonyl]pyrrolidin

Getting 14

(2S,4S)-4-mercapto-1-methyl-2-[4-(methyl-4-nitrobenzenesulfonamide) piperazine-1-ylcarbonyl]pyrrolidin

Receive 15

(2S,4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3R)-3-(4 - nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl]pyrrolidin

Getting 16

(2S, 4S)-4-mercapto-1-methyl-2-[(3R)-3-(4-nitrobenzenesulfonamide) pyrrolidin-1-ylcarbonyl]pyrrolidin

Getting 17

(2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3S)-4-(4 - nitrobenzenesulfonamide)3-methylpiperazin-1-ylcarbonyl]pyrrolidin

Getting 18

(2S, 4S)-4-mercapto-1-methyl-2-[(3R)-4-(4-nitrobenzenesulfonamide)-3-methylpiperazin-1-ylcarbonyl]pyrrolidin

Getting 19

(2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[1-(4- nitrobenzenesulfonamide)-piperidine-4-ylcarbonyl]pyrrolidin

Receive 20

(2S,4S)-4-mercapto-1-[1-(4-nitrobenzenesulfonyl)-2-[(3S)-1-(4 - nitrobenzenesulfonamide) pyrrolidin-3-ylcarbonyl]pyrrolidin

Getting 21

(2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[1-(4- nitrobenzyloxy is ebonyline)azetidin-1 - ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin

22(a) (2S, 4S)-2-(3-aminoamides-1-ylcarbonyl)-4-(4-methoxybenzylthio-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 20 ml of dry acetonitrile was dissolved 2,05 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidine carboxylic acid. To the resulting solution was added to 0.78 g of N,N'-carbonyldiimidazole, after which the mixture was stirred at 40oC for one hour. The resulting mixture then was added dropwise to a solution of 1.00 g of the dichloride 3-aminoacridine and 2,40 ml diisopropylethylamine in 10 ml of methanol under ice cooling. The resulting mixture was stirred at the same temperature for one hour. Then the reaction mixture was filtered and the filtrate was concentrated, pariva under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water and an aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure. The residue was programatorului through a column of silica gel (Silica gel 60 9385, production Merck, 100 g), the result was of 2.50 g of the entitled compound as amorphous powder. The selection was carried out on the fractions obtained by elution of the contents of the column with a mixture of ethyl acetate and methanol (volume ratio of 65:35),04 (1H, multiplet), 2,38-3,20 (4H, multiplet, 3,25-to 3.34 (1H, multiplet), 3,67-4,6 (6N, multiplet), and 3.72 (2H, singlet), 3,78, and 3,79 (together 3H, two singlets), 5,09 lower than the 5.37 (2H, multiplet), 6,84 (doublet, J= 8,78 Hz), 7,22 (2H, doublet, J=8,78), WAS 7.45 (2H, doublet, J=8,78), 8,21 (2H, doublet, J=8,78 Hz).

22(b) (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(4-nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 20 ml of methylene chloride was dissolved 0,81 g of (2S,4S)-2-(3-aminoamides-1 - ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine obtained above as described in stage (a). To the resulting solution under ice cooling was added 0.32 g of diisopropylethylamine and 0.40 g of para-nitrobenzenesulfonate. The resulting mixture was then stirred at the same temperature for 40 minutes, after this time the reaction mixture was diluted with ethyl acetate and washed with water and an aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure. The remainder pass through the chromatographic column with silica gel (Silica gel 60 9385, production Merck 40 g). The result was obtained 0.64 g connection, the name of which is given in the header. The compound obtained in the form of amorphous powder of f:1).

X (CHCl3nmaxcm-1: 1725, 1662, 1608, 1521, 1440, 1347, 1250

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,94-2,04 (1H, multiplet), 2,31-2,48 (1H, multiplet), 3.04 from-3,12 (1H, multiplet), 3,26-to 3.34 (1H, multiplet), and 3.72 (2H, singlet), with 3.79 (3H, singlet), 3,81-3,99 (1H, multiplet), 4,08-4,87 (6N, multiplet), 6,09-5,72 (5H, multiplet), PC 6.82-6.87 in (2H, multiplet), of 7.23 (2H, doublet, J=8,30 Hz)that was 7.45 and 7.50 (together 4H, two doublet, J= 8,79 Hz), by 8.22 and 8,23 (together 4H, two doublet, J=8,79).

22(C) (2S,4S)-4-mercapto-2-[3-(4-nitrobenzenesulfonamide)-azetidin - 1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 0,94 ml of anisole suspended 0,59 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[3-(4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] -1-(4 - nitrobenzenesulfonyl)pyrrolidine obtained as described above in stage (b). To the resulting suspension under ice cooling dropwise added 3,32 ml triperoxonane acid and 0.15 ml of triftoratsetata, after which the mixture was stirred at the same temperature for one hour. After this time the reaction mixture was added 1,2-dichloroethane and drove the solvent under reduced pressure. The residue was washed by repeated decantation, first with hexane, and then diethyl ether. The residue was diluted with ethyl acetate and parselocale, adding water which I then dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure, the result was of 0.44 g of the entitled compound as amorphous powder.

X (KBr) nmaxcm-1: 1709, 1665, 1521, 1440, 1405, 1347, 1257.

NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) M. D. 1,62-of 1.85 (1H, multiplet), 2,56-2,69 (1H, multiplet), 3,05-of 3.25 (2H, multiplet); 3,70-4,55 (8H, multiplet), 5,08 is 5.28 (4H, multiplet), 7,55-the 7.65 (4H, multiplet), 8,11-8,25 (5H, multiplet).

23

(2S, 4S)-4-mercapto-2-[3-(N-4-nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin

23(a) (2S,4S)-4-(4-methoxybenzylthio)-2-[3-(N-4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl/pyrrolidin

In 15 ml of ethyl acetate was dissolved 0,78 g of (2S,4S)-2-(3-aminoamides-1 - ylcarbonyl)-4-(4-methoxybenzylthio)-1-1(4-nitrobenzenesulfonyl)-pyrrolidine, obtained as described in obtaining 22(a). To the obtained solution under cooling with ice added to 0.78 ml of a 4M solution of hydrogen chloride in ethyl acetate, and then to the reaction mixture were added diethyl ether and the resulting powder was filtered and dried, resulting in the received 0,79 g (is.

0,78 g of this compound suspended in 20 ml of dry acetonitrile and the suspension was added 0.51 g of N-(4-nitrobenzenesulfonyl)acetamidine, after which the mixture was stirred at 50oC 80 minutes after this time the reaction mixture was concentrated, upriv her under reduced pressure and the residue was diluted with ethyl acetate, washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated, upriv under reduced pressure. The remainder pass through the chromatographic column Packed with silica gel (Silica gel 60 9385, production Merck, 150 ml), the received 0,99 g of the titled compound in the form of amorphous powder. The selection was carried out from the fractions obtained by elution of the contents of the column with a mixture of ethyl acetate and methanol (volume ratio of 95: 5).

X (KBr) nmaxcm-1: 1707, 1667, 1551, 1520, 1442, 1346, 1238.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,29-2,59 (7H, multiplet), 3,05-3,14 (1H, multiplet), 3,26-to 3.34 (1H, multiplet), 3,67-4,86 (6N, multiplet), to 3.73 (2H, singlet), with 3.79 (3H, singlet), 5,09-5,33 (4H, multiplet), 6,85 (2H, doublet, J=8,79 Hz), 7.23 percent (2H, doublet, J=8,79 Hz), 7,44-the 7.65 (4H, multiplet), 8,19 is 8.25 (4H, multiplet).

23(b) (2S, 4S)-4-mercapto-2-[3-(N-4 - nitrobenzyloxy is asterili 0,99 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[3-(N-4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] -1-(4-nitrobenzenesulfonyl)pyrrolidine, obtained as described in stage (a) above. To the resulting solution was pricipally 10 ml triperoxonane acid and 0.24 ml of triftoratsetata, the resulting mixture was stirred at the same temperature for 40 min and then at room temperature for another 50 minutes Then the reaction mixture was added 1,2-dichloroethane. The mixture was concentrated, pariva her under reduced pressure. The obtained residue was washed by repeated decantation first with hexane, and then diethyl ether. Then the mixture was again diluted with ethyl acetate and parselocale, adding an aqueous solution of sodium bicarbonate. An ethyl acetate layer was washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The result was of 0.82 g of the entitled compound as amorphous powder.

X (KBr) nmaxcm-1: 1706, 1664, 1607, 1551, 1521, 1442, 1346, 1228

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,73-to 2.65 (4H, multiplet), of 2.23 (3H, singlet), 3,23-of 3.54 (2H, multiplet), 3,78-4,94 (7H, multiplet), 5,11 lower than the 5.37 (4H, multiplet), of 7.48-to 7.59 (4H, multiplet), by 8.22 and 8,23 (together 4H, two doublet, J=8,79 Hz).

Getting 24

(2S, 4S)-4-mercapto-2-[3-(N-4-nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]-1-(4-NITR is the breaking of reagents (2S,4S)-2-(3-aminoamides-1-ylcarbonyl)-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl/pyrrolidine hydrochloride and N-(4-nitrobenzenesulfonyl)formamidine, in relative quantities, such as those that were used in the above receipt, was synthesized the titled compound.

Receive 25

(2S,4S)-4-mercapto-1-methyl-2-[3-(4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

25(1) (2S,4S)-2-(3-aminoamides-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine

In 20 ml of dry acetonitrile suspended of 1.62 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-pyrrolidine-carboxylic acid. To the resulting suspension were added to 1.02 g of N,N'-carbonyldiimidazole, after which the mixture was stirred at 40oC 45 minutes To the mixture dropwise added to 1.00 g of the dihydrochloride of 3-aminoacridine and 2,40 ml diisopropylethylamine in 10 ml of CH3OH while cooling with ice. The resulting mixture was stirred at the same temperature for 90 minutes, after this time the reaction mixture was concentrated by evaporation under reduced pressure. The remainder pass through the chromatographic column with the reversible phase (Cosmosil 75 ° C18-prep, production Nacalai Tesque 145g). Elution spent 30% by volume aqueous solution of acetonitrile. From these fractions allocated to 1.21 titled compound as a colorless oil.

X (CHCl3nmaxcm-1: 1618, 1510, 1465, 1288-2,95 (1H, multiplet), 3,00-and 3.16 (2H, multiplet), 3,70 (2H, multiplet is the Central value was reported), of 3.80 (3H, multiplet, the Central value was reported), the 3.65-4,06 (3H, multiplet), 4,23-to 4.33 (1H, multiplet), 4,50-and 4.68 (1H, multiplet), for 6.81-6.87 in (2H, multiplet), 7,18-7,24 (2H, multiplet).

25(b) (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

In 18 ml of methylene chloride was dissolved of 0.60 g of (2S,4S)-2-(3-aminoamides-1-ylcarbonyl] -4-(4-methoxybenzylthio)-1-methylpyrrolidine obtained as described above in stage (a). To the obtained solution under cooling with ice added to 0.38 ml of diisopropylethylamine and 0.46 g of paranitrophenylphosphate, after which the mixture was stirred at the same temperature for 30 minutes and Then the reaction mixture was diluted with ethyl acetate, washed with water and aqueous sodium chloride solution in this order. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated, pariva under reduced pressure. The obtained residue was programatorului through a column of silica gel (Silica gel 60 9385, production Merck, 40 g). Of the fractions obtained after elution of the contents of the column with a mixture of ethyl acetate and methanol (volume ratio of 95:5), had contributed to 0.85 g Sagl the DCl3) memorial plaques 1,77-of 1.95 (1H, multiplet), 2,32 and a 2.36 (together 3H, two singlets), 2,49-of 2.66 (2H, multiplet), 2,98-3,14 (3H, multiplet), of 3.69 (2H, singlet), of 3.80 (3H, singlet) of 3.73-of 3.94 (1H, multiplet), 4,11 of 4.83 (4H, multiplet), 5,20 (2H, multiplet, the Central value reported), 5.40 to-the 5.51 (1H, multiplet), for 6.81-6.87 in (2H, multiplet), 7,18-7,22 (2H, multiplet), 7,51 (2H, doublet, J=8,79), BY 8.22 (2H, doublet, J= 8,79 Hz).

25(C) (2S, 4S)-4-mercapto-1-methyl-2-[3-(4-nitrobenzenesulfonamide) azetidin-1-ylcarbonyl]pyrrolidin

In 1,53 ml of anisole was dissolved 0.73 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]-pyrrolidine obtained as described above in stage (b). To the obtained solution under cooling with ice dropwise added to 7.25 ml triperoxonane acid and 0.25 ml of triftoratsetata. The mixture was then stirred at room temperature for 90 min, after which the reaction mixture was added 1,2-dichloroethane and the solvent was distilled under reduced pressure. The obtained residue was washed by repeated decantation first with hexane, and then diethyl ether. The residue was diluted with ethyl acetate and parselocale, adding an aqueous solution of sodium bicarbonate. An ethyl acetate layer was washed with water and aqueous sodium chloride solution, dried over anhydrous frame connection in the form of an amorphous powder.

X (liquid film) nmaxcm-1: 1721, 1638, 1522, 1460, 1347, 1258

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,85-2,12 (2H, multiplet), to 2.35 and 2.37 together 3, two singlets), 2,63-2,82 (2H, multiplet), 3,00-3,10 (2H, multiplet), 3,30 (1H, broadened singlet), 3,86-of 3.96 (1H, multiplet), 4,08-4,79 (4H, multiplet), to 5.21 (2H, singlet), 5,40-5,62 (1H, multiplet), 7,51 (2H, doublet, J=8,9 Hz), by 8.22 (2H, doublet, J=8,79 Hz).

Getting 26

(2S, 4S)-4-mercapto-1-methyl-2-[3-(N-4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

26(a) (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

In 15 ml of ethyl acetate was dissolved 540 mg of (2S,4S)-2-(3-aminoamides-1 - ylcarbonyl]4-(4-methoxybenzylthio)-1-methylpyrrolidine, obtained as described in obtaining 25(a). To the resulting solution under ice cooling was added 5 ml of methylene chloride and 1.61 ml of a 4M solution of hydrogen chloride in ethyl acetate. The mixture was then stirred at the same temperature for 30 minutes, after which it was diluted with diethyl ether, the resulting powder was filtered and dried, obtaining 650 mg of the hydrochloride.

In 10 ml of dry acetonitrile is added 650 mg of the obtained hydrochloride and 277 μl of diisopropylethylamine, after which the mixture is ltrate concentrated, mpariwa under reduced pressure. The remainder pass through the chromatographic column with silica gel. Of the fractions obtained by elution of the contents of the column with a mixture of methylene chloride, ethyl acetate and methanol (volume ratio of 45:45:5), identified 622 mg of the titled compound.

X (KBr) nmaxcm-1: 1682, 1638, 1609, 1553, 1512, 1454, 1346, 1225, 1190, 1080.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,60-of 2.38 (7H, multiplet), 2,43 of 2.68 (2H, multiplet), 2,83-3,20 (3H, multiplet), of 3.69 (2H, singlet), with 3.79 (3H, singlet), 3,84-5,02 (5H, multiplet) 5,22 (2H, singlet), at 6.84 (2H, doublet, J= 8,79 Hz), 7,20 (2H, doublet, J=8,79 Hz), 7,51 to 7.62 (2H, multiplet), 8,15-of 8.28 (2H, multiplet).

26(b) (2S,4S)-4-mercapto-1-methyl-2-[3-(N-4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

In 1,19 ml of anisole was dissolved 610 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4-nitrobenzenesulfonamide)azetidin-1-ylcarbonyl] pyrrolidin obtained as described above in stage (a). To the resulting solution, cooled with ice, added to 4.23 ml triperoxonane acid and 193 μl triftoratsetata. The mixture was stirred under these conditions for one hour and then at room temperature for another one hour. The solvent is then removed Otley by evaporation under reduced pressure, turning the balance in triftorbyenzola in powder form. The entire mass of this compound was added ethyl acetate, and then an aqueous solution of sodium bicarbonate in a quantity sufficient to podselect environment. An ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and received 448 mg of the titled compound in the form of a powder.

X (liquid film) nmaxcm-1: 1642, 1608, 1522, 1465, 1457, 1237, 1193.

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 1,81-to 1.98 (1H, multiplet), 2,07-3,50 (11N, multiplet), 3,83-5,02 (5H, multiplet), 5,22 and 5,28 (together 2H, two singlets), 7,50 to 7.62 (2H, multiplet), 8,15-of 8.28 (2H, multiplet).

Getting 27

(2S, 4S)-4-mercapto-1-methyl-2-[3-(N-4 - nitrobenzenesulfonamide)azetidin-1-ylcarbonyl]pyrrolidin

He repeated the procedure in obtaining 26, but was used as initial reagents (2S,4S)-2-(3-imidazolidin-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-methylpyrrolidine] hydrochloride and N-(4-nitrobenzenesulfonyl)formamidine, in relative amounts, such as those that were used in the above-mentioned receiving 26.

Getting 28

(2S, 4S)-4-gametocytemia)-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinecarbonyl]-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 8 ml of dry tetrahydrofuran was dissolved 768 mg of (2S,4S)-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid and the resulting solution was cooled to 0oC. To the solution was added 191 mg of triethylamine, then 218 mg pualeilani, after which the mixture was stirred at the same temperature for 5 minutes Then after that time, to the mixture was added a mixture of 238 mg (3S)-3-(1-1,2,4-triazolyl)pyrrolidin of triptoreline, 440 mg diisopropylethylamine and 7 ml of dry acetonitrile. The mixture was gradually heated and then stirred at 0oC for 15 min and at room temperature for 2 hours the Solvent was then distilled under reduced pressure and the residue was diluted with ethyl acetate, and then the diluted solution was washed with an aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then driven off under reduced pressure, and the residue was purified through column chromatography with silica gel, using as eluent a mixture of ethyl acetate and methanol (volume ratio 7:1), resulted 803 mg of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1709, 1656, 1512, 1346, 857, 738

NMR spectrum (270 MHz, hexadeuterated), 4,35 with 4.65 (1H, multiplet), 5,00-and 5.30 (4H, multiplet), 6,80-to 6.95 (2H, multiplet), 7,20-to 7.35 (2H, multiplet), 7,40-of 7.70 (2H, multiplet), of 8.00 (1H, multiplet, the Central value reported), 8,13 compared to 8.26 (2H, multiplet), 8,49-8,61 (1H, multiplet).

28(b) (2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl]pyrrolidine

1.5 ml of anisole suspended 783 mg (2S,4S)-4-(4-methoxybenzylthio)-2- [(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl] -1-(4 - nitrobenzenesulfonyl)pyrrolidine obtained as described above in stage (a). To the resulting suspension, cooled by ice, was added 7.5 ml triperoxonane acid and 0.24 ml of triftoratsetata, after which the mixture was stirred at room temperature for 1.5 hours Cycle, consisting in the distillation of the solvent under reduced pressure, washing the residue of hexane to remove anisole, adding diethyl ether to the mixture to precipitate the product, and grinding the product, after which the mixture decantation was repeated several times to obtain a powder. All the resulting powder was mixed with 40 ml of ethyl acetate and aqueous sodium hydrogen carbonate solution, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated/P> X (KBr) nmaxcm-1: 1706, 1652, 1522, 1346, 867, 739

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) M. D. 1,15-1,25 (1H, multiplet), 1,50-1,80 (1H, multiplet), 2,20-2,60 (2H, multiplet), 2,60-2,90 (1H, multiplet), 3,10-4,10 (8H, multiplet), 4,40 with 4.65 (1H, multiplet), 5,00-and 5.30 (2H, multiplet), 7,45-of 7.70 (2H, multiplet), 8,00-8,02 (1H, multiplet); 8,10-8,30 (2H, multiplet), 8,50-to 8.62 (1H, multiplet).

Getting 29

(2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[3-(1-1,2,4-triazolyl)-1-azetidinone]pyrrolidin

29(a) (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(1-1,2,4-triazolyl)-1-azetidinone)-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 11 ml of dry tetrahydrofuran was dissolved 1.13 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2 - pyrrolidinecarboxylic acid and the resulting solution was cooled to 0oC. To the solution was added 280 mg of triethylamine, then 320 mg pivaloyloxy and the mixture was stirred at the same temperature for 5 minutes, after this time the mixture was added a mixture of 3-(1-1,2,4-triazolyl)-azetidine hydrochloride obtained according to the procedure described in obtaining 31(a) and (b), but using 1,2,4-triazole, 956 mg diisopropylethylamine and 6 ml of dry acetonitrile, after which the resulting mixture was stirred the spruce was distilled under reduced pressure. The obtained residue was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is then driven off under reduced pressure, and the residue was purified through column chromatography with silica gel, using as eluent a mixture of ethyl acetate and methanol (volume ratio 10:1), the result was 870 mg of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1708, 1656, 1512, 1346, 854, 738

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) M. D. 1,60-1,80 (1H, multiplet), 2,50-2,70 (1H, multiplet), 3,00 is 3.15 (1H, multiplet), 3,15-of 3.25 (1H, multiplet), 3,65-3,90 (6N, multiplet), 4,05-4,80 (4H, multiplet), 5,10-5,50 (4H, multiplet), to 6.88 (2H, doublet), J=8,50 Hz), 7,27 (2H, doublet, J= at 8.36 Hz), to 7.59 to 7.62 (2H, multiplet), of 7.90-8,10 (1H, multiplet), 8,21-of 8.28 (2H, multiplet), to 8.57-8,66 (1H, multiplet).

29(b) (2S, 4S)-4-mercapto-1-(4-nitrobenzenesulfonyl)-2-[3-(1-1,2,4- triazolyl)-1-azetidinone]pyrrolidin

1.7 ml of anisole suspended 858 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[3-(1-1,2,4-triazolyl)-1-azetidinone]-1-(4-nitrobenzenesulfonyl) pyrrolidine obtained as described above in stage (a). To the obtained suspenses was stirred at 0oC for 30 min and then at room temperature for another 30 minutes after which time the solvent was distilled under reduced pressure and the residue was washed with hexane to remove the anisole. The mixture then was mixed with diethyl ether for further washing. The compound obtained was combined with 100 ml of ethyl acetate and 30 ml of a saturated aqueous solution of sodium bicarbonate and separated the organic layer. The organic layer is then dried over anhydrous magnesium sulfate, and the residue was filtered and concentrated by evaporation under reduced pressure. The result was 873 mg of the entitled compound as a white powder.

X (KBr) nmaxcm-1: 1706, 1663, 1522, 1347, 854, 739

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide + D2O) M. D. 1,70-of 1.85 (1H, multiplet), 2,60-of 2.75 (1H, multiplet), 3,05-of 3.25 (1H, multiplet), 3,25 is 3.40 (1H, multiplet), 3,65-4,90 (7H, multiplet), 5,10-5,50 (4H, multiplet), 7,55-of 7.70 (2H, multiplet), 7,95-of 8.15 (1H, multiplet); 8,20-8,30 (2H, multiplet), 8,55-to 8.70 (1H, multiplet).

30

(2S, 4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-4-mercapto-1-(4 - nitrobenzenesulfonyl)pyrrolidin

30(a) (2S,4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-4-(4 - methoxybenzylthio)-1-(4-nitrobenzyloxy is of 1.75 g of (2S,4S)-2-(3-aminoamides-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine, obtained as described in obtaining 22(a), and the resulting mixture was stirred at 50oC for 5 h the Mixture was then diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride. Then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the obtained residue was programatorului on a column of silica gel. Of the fractions obtained by elution of the contents of the column with a mixture of methylene chloride, ethyl acetate and methanol (volume ratio of 45: 45: 10), had contributed to 1.45 g of the entitled compound as colorless powder.

X (KBr) nmaxcm-1: 1710, 1664, 1609, 1513, 1442, 1403, 1345, 1248, 1172.

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,86-2,05 (1H, multiplet); 2,11, 2,13 and of 2.27 (together 6N, three singlet), 2,34-2,52 (1H, multiplet); 2,83-to 3.36 (3H, multiplet), 3,3 (2H, singlet), 3,79 and 3,80 (together 3H, two singlets), 3,68-4,59 (6N, multiplet), of 5.05 and 5.36 (2H, multiplet), 6,85 (2H, doublet, J= charged 8.52 Hz), 7.23 percent (2H, doublet, J=charged 8.52 Hz), 7,46 and 7.50 (together 2H, two doublet, J=to 8.57 Hz), 8,23 (2H, doublet, J=8,57 Hz)

30(2) (2S, 4S)-2-(3-dimethylimidazolidin-1-ylcarbonyl)-4-mercapto-1-(4 - nitrobenzenesulfonyl)pyrrolidin

In 3,02 ml of anisole was dissolved 1.47 g of (2S,4S)-2-(3-dimethylimidazolidin-1 - stage (a). To the resulting solution was added 10,71 ml triperoxonane acid and 0,488 ml triftoratsetata, after which the mixture was stirred at the same temperature for one hour. The solvent is then driven off under reduced pressure, and the residue was washed by repeated decantation, first with hexane, and then diethyl ether. To the residue was added ethyl acetate, and the mixture was parselocale saturated aqueous solution of sodium bicarbonate. An ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, the obtained 1.01 g titled compound in the form of a powder.

X (KBr) nmax/cm-1: 1710, 1645, 1607, 1517, 1459, 1432, 1403, 1343, 1169

NMR spectrum (270 MHz, CDCl3) memorial plaques 1,87-of 2.05 (2H, multiplet), 2,11, to 2.13 and 2.25 (6N, three singlet), 2,58-by 2.73 (1H, multiplet), 2,82-of 3.46 (3H, multiplet), 3.75 to 4,54 (6N, multiplet), of 5.05 lower than the 5.37 (2H, multiplet), to 7.50 (2H, doublet, J=to 8.57 Hz), by 8.22 (2H, doublet, J=8,57 Hz).

Getting 31

(2S, 4S)-2-[3-(1-imidazolyl(azetidin-1-ylcarbonyl]-4-mercapto-1-(4 - nitrobenzenesulfonyl)pyrrolidin

31(a) 1-benzhydryl-3-(1-imidazolyl)azetidin

To a suspension of 2.10 g of sodium hydride (55 wt./wt. the dispersion in mineral oil) in 25 ml of dimethylformamide EXT is based temperature for one hour. To the mixture was added to 5.00 g of 1-benzhydryl-3-methanesulfonanilide in 50 ml of dimethylformamide, after which the mixture was stirred at 70oC for 17 hours, after this time the reaction mixture was diluted with ethyl acetate and washed with water and an aqueous solution of sodium chloride. An ethyl acetate layer was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The remainder pass through the chromatographic column with silica gel and the fractions obtained after elution of the contents of the column with a mixture of ethyl acetate and methanol (95:5), has allocated 2,88 g of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 1490, 1452, 1236, 1074, 905, 755, 707

NMR spectrum (270 MHz, CDCl3) memorial plaques 3,23-to 3.35 (2H, multiplet); 3,60 at 3.69 (2H, multiplet), 4,43 (1H, singlet), 4,67-rate 4.79 (1H, multiplet), 7,08-7,69 (13H, multiplet).

31(b) 3-(1-imidazolyl)-azetidine the dihydrochloride

In 30 ml of methanol was dissolved 3,20 g 1-benzhydryl-3-(1-imidazolyl)-azetidine, obtained as described in stage (a), and to the resulting solution was added 8,90 ml of 10% wt./about. solution of hydrogen chloride in methanol. To the mixture then added to 1.60 g of catalyst (20 wt./wt. of palladium hydroxide on carbon, after the mixture of hydrogeolo under reduced pressure. The obtained residue was washed with diethyl ether and dried under reduced pressure, the result was 2,03 mg of the titled compound as a powder.

X (KBr) nmaxcm-1: 1581, 1554, 1509, 1435, 1303, 1092, 839, 637, 623.

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) M. D. 4,27 is 4.35 (2H, multiplet), 4,39-to 4.46 (2H, multiplet), 5,40-of 5.50 (1H, multiplet), of 7.48 (1H, singlet), 8,03 (1H, singlet), cent to 8.85 (1H, singlet).

31(C) (2S,4S)-2-[3-(1-imidazolyl)azetidin-1-ylcarbonyl]-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidin

In 40 ml of dry acetonitrile was dissolved 3.80 g (2S,4S)-4-(4 - methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)-2-pyrrolidinecarboxylic acid. To the resulting solution was added 1.65 g of N,N'-carbonyldiimidazole, and the mixture was stirred at 40oC for one hour. At room temperature, to the mixture was added to 2.00 g of 3-(1-imidazolyl)-azetidine dihydrochloride (obtained as described above in stage (b)) and 2,90 g diisopropylethylamine dissolved in a mixture of 30 ml of dry acetonitrile and 5 ml of methanol. The resulting mixture was stirred at the same temperature for one hour. After this time the reaction mixture was concentrated, pariva her under reduced pressure and the residue was diluted with ethyl acetate, the Lily, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The obtained residue was programatorului through column chromatography with silica gel and the fractions obtained after elution with a mixture of ethyl acetate and methanol (volume ratio 85:15), singled out of 4.00 g of the titled compound.

X (KBr) nmaxcm-1: 1706, 1677, 1609, 1512, 1442, 1403, 1346, 1245.

NMR spectrum (270 MHz, CDCl3) memorial plaques 2,05-to 3.38 (4H, multiplet in), 3.75 (2H, singlet), with 3.79 (3H, singlet), 4,12-of 5.45 (N, 6,84-8,29 (11N, multiplet).

31(d) (2S, 4S)-2-[3-(1-imidazolyl/azetidin-1-ylcarbonyl]-4-mercapto-1-/4-nitrobenzenesulfonyl/pyrrolidin

In 7,88 ml of anisole was dissolved 4,00 g of (2S,4S)-2-[3-(1-imidazolyl/-azetidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzenesulfonyl)pyrrolidine obtained as described above in stage (C). To the resulting solution, cooled with ice, added to 27.9 ml triperoxonane acid and 1727 ml triftoratsetata, after which the mixture was stirred under the same conditions for one hour. After this time the solvent was distilled under reduced pressure and the residue was washed with hexane and diethyl ether and dried, pariva it under reduced pressure, the obtained t is eating saturated aqueous solution of sodium bicarbonate in the amount sufficient for reaction of the environment has become alkaline. An ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure received 3,10 g of the titled compound in the form of a powder.

X (KBr) nmaxcm-1: 2606, 1746, 1722, 1623, 1569, 1468, 1419, 1378, 1344, 1250

NMR spectrum (270 MHz, CDCl3+ D2O) M. D. 2,01-3,50 (4H, multiplet), 4,00 to 5.35 (M, multiplet), 7,10-8,30 (7H, multiplet).

Getting 32

4-nitrobenzyl(1R, 5R,6S)-2-(diphenylphosphoryl)-6-[(1R)-1-hydroxyethyl] -1-methyl-1-karbapin-2-em-3-carboxylate

3,63 g of 4-nitrobenzyl(1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate was dissolved in 72 ml of dry acetonitrile. To the resulting solution under ice cooling was added dropwise 2,28 ml of acid chloride diphenylphosphinic acid and 1.92 ml of diisopropylethylamine under stirring. The resulting mixture was stirred for another hour under the same conditions, and then concentrated by evaporation under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed twice with water, and then aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate and again concentrated at postolov. The mixture was diluted with 500 ml of diisopropyl ether and the resulting crystals were filtered and dried. The result was of 5.34 g of the entitled compound as colorless needle-type crystals, so pl. 123-125oC.

NMR spectrum (270 MHz, CDCl3d memorial plaques to 1.22 (3H, doublet, J=7,2 Hz), of 1.33 (3H, doublet, J=6.6 Hz), 3,32 (1H, doublet of doublets, J=6.6 and 2.6 Hz), 3,42 of 3.56 (1H, multiplet), 4,20-or 4.31 (2H, multiplet), with 5.22 (1H, doublet, J=13,8 Hz), to 5.35 (1H, doublet, J=13,8 Hz), 7,13-7,40 (10H, multiplet), 7,55 (1H, doublet, J=8.6 Hz), 8,13 (2H, doublet,8,6 Hz).

Receive 33

(2S, 4S)-4-mercapto-2-[(1-(4-nitrobenzenesulfonyl)-azetidin-3 - enaminocarbonyl]-1-(4-nitrobenzylidene)pyrrolidin

Following the procedure in obtaining 22, cooked titled compound.

X (KBr) nmaxcm-1: 1709, 1662, 1609, 1523, 1435, 1406, 1348, 1287

NMR spectrum (270 MHz, hexadeuterated dimethyl sulfoxide + D2O) M. D. 1,86-2,04 (1H, multiplet), 2,65 is 2.80 (1H, multiplet), 2,98-3,61 (5H, multiplet), a 3.87-a 4.53 (4H, multiplet), 5,08 at 5.27 (4H, multiplet), 7,51-to 7.67 (4H, multiplet), 8,14-826 (4H, multiplet).

1. Derivatives carbapenem General formula I

< / BR>
where R1hydrogen or methyl;

R2hydrogen or unsubstituted WITH1WITH6-alkyl;

R3COOH Il is R>< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R4hydrogen;

R5and R6the same or different, unsubstituted WITH1WITH6-alkali;

R7, R8and R9the same or different, unsubstituted or substituted C1WITH6-alkali;

R10carnemolla group;

n is 0 or 1;

The Z group of formula (Z-I) or (Z-II)

< / BR>
< / BR>
where R11and R12the same or different, unsubstituted or substituted C1WITH6-alkali;

m10 or 1 and n10, 1 or 2 provided that m1+ n1greater than 0;

R20, R21or R22the same or different, hydrogen or unsubstituted WITH1WITH6-alkali, or R20and R21or R20and R22together the group

< / BR>
where s is 0,1,2 or 3;

t 0, 1, 2 or 3;

W is an oxygen atom or sulfur;

w10 or 1;

R23and R24the same or different, hydrogen or unsubstituted WITH1WITH6-alkali;

n32 or 3;

R25and R26hydrogen;

n40, 1 or 2;

p20;

R27, R28, R29hydrogen;

p31WITH6-alkyl;

R32, R34and R35hydrogen;

U imidazolidine group,

or their pharmaceutically acceptable salts.

2. Connection on p. 1 of General formula I or their pharmaceutically acceptable salts which possess antibacterial activity.

3. Connection on p. 1, representing 6-(1-hydroxyethyl)-1-methyl-2-[2- (3-trimethylammoniumchloride-1-ylcarbonyl)pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate or its pharmaceutically acceptable salt.

4. Connection on p. 1 representing 2-[2-[3-(carbamoyltransferase)pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

5. Connection on p. 1, representing 2-[2-[3-(2-hydroxyethyl) dimethylammonio)pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-(1 - hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

6. Connection on p. 1 representing 2-[2-{3-[N-(2-foradil)-N, N'-dimethylammonio] pyrrolidin-1-ylcarbonyl}pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

7. Aerolin-4-ylthio}- 1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

8. Connection on p. 1 representing 2-[2-(4-amidinophenoxy-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2 - em-3-carboxylic acid and its pharmaceutically acceptable salts.

9. Connection on p. 1 representing 2-[2-(4-amidinophenoxy-1-ylcarbonyl)-1 methylpyrrolidine 4 ylthio]-6-(1-hydroxyethyl)-1 - methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

10. Connection on p. 1 representing 2-[2-(4-amidinopropane-1-ylcarbonyl)pyrrolidin-4-ylthio] -6-(1 - hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

11. Connection on p. 1 representing 2-[2-(4-amidinopropane-1-ylcarbonyl)-1-methylpyrrolidine-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

12. Connection on p. 1 representing 2-[2-(3-aminoamides-1-ylcarbonyl)pyrrolidin-4-ylthio] -6-(1-hydroxyethyl) -1-methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

13. Connection on p. 1 representing 2-[2-(3-acetylethylenediamine-1-ylcarbonyl)pyrrolidin-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-CI 2-[2-(3-formalisation-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

15. Connection on p. 1 representing 2-[2-(3-aminoamides-1-ylcarbonyl) -1-methylpyrrolidine-4-ylthio] -6-(1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid and its pharmaceutically acceptable salts.

16. Connection on p. 1, representing 6-(1-hydroxyethyl)-1-methyl-2-[2-[3-(4-methyl-1-1,2,4-triazolo)pyrrolidin-1-yl-carbonyl]pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

17. Connection on p. 1, representing 6-(1-hydroxyethyl)-1-methyl-2-[2-[3-(4-methyl-1-1,2,4-triazolo) azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

18. Connection on p. 1, representing 6-(1-hydroxyethyl) -1-methyl-2-[2-(3-trimethylammonium-1-ylcarbonyl)pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

19. Connection on p. 1, representing 6-(1-hydroxyethyl)-1-methyl-2-[2-[3-(3-methyl-1-imidazolyl) -azetidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylate and its pharmaceutically acceptable salts.

20. The method of obtaining the compounds of formula I on p. 1 or their pharmaceutically acceptable salts, characterized in that the derived carbapenemresistant or a group S(O)RL1where RL1alkyl, haloalkyl, alkanolamines or aryl;

R3Pcarboxyamide group,

subjected to interaction with derivative pyrrolidine General formula

< / BR>
where R2Punprotected or protected group, R2;

QPthe group Q or a group Q, in which the Quaternary nitrogen atom replaced by the corresponding tertiary atom,

with subsequent isolation of the target product or transformation, if necessary, compounds containing aquaterritory a nitrogen atom, a compound containing the corresponding Quaternary nitrogen atom in the group of formula (Q-I) and (Q-II), or, if necessary, removing the protective groups or translation product in a pharmaceutically acceptable salt.

Priority signs:

11.03.92 when R1, R2, R3and the Q group of formula (Q-I), (Q-II), and (Q-III), the values of which are specified in paragraph 1;

14.09.92 when the Q group of formulae (Q-(VII), (Q-(VIII), (Q-IX) and (Q-X);

16.09.92 when the Q group of formulae (Q-XI) and (Q-XII);

11.03.93 when Q is a group of the formula (Q-XIII).

 

Same patents:

The invention relates to 8-oxo-5-thia-1-azabicyclo(4.2.0) Oct-2-ene-5,5-dioxide-2-Carotinum acids, method of production thereof and containing pharmaceutical and veterinary preparations

The invention relates to new antibiotics that have carbapenemases skeleton

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The invention relates to heterocyclic derivatives having antibacterial activity, to processes for their preparation, to their containing compositions and to their use in medicine

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

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

The invention relates to new biologically active chemical compounds, derived diaminodiphenylsulfone General formula;

< / BR>
which is obtained by the interaction equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in water

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The invention relates to new compounds useful as herbicides, and to their use in weed control in the cultivation of fine-grained cereals

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

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

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 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: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

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