Derivatives of carbapenem, their using for preparing pharmaceutical composition, pharmaceutical composition based on thereof and method for treatment and/or prophylaxis of infectious diseases

FIELD: organic chemistry, antibiotics, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of carbapenem possessing high antibiotic activity with respect to methicillin-resistant microorganism Staphylococcus aureus, penicillin-resistant microorganism Streptococcus pneumoniae, influenza virus and microorganisms producing β-lactamase, and showing stability with respect to renal dehydropeptidase. Proposed derivatives of carbapenem represent compounds of the formulae (I) and (II) or their pharmaceutically acceptable salts wherein R1 represents hydrogen atom or methyl; each R2 and R3 represents independently hydrogen, halogen atom, carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylthio-group or formyl; n = 0-4; Hy represents 4-7-membered monocyclic or 9-10-bicyclic saturated or unsaturated heterocyclic group comprising 1-4 heteroatoms chosen from the group consisting of nitrogen and sulfur atoms wherein Hy group can be optionally substituted with halogen atom; substituted or unsubstituted lower alkyl, (lower alkyl)-thio-group, (lower alkyl)-sulfonyl, carboxyl, amino-group, aryl; or 6-membered monocyclic heterocyclic group comprising one or some nitrogen atoms. Also, invention describes the methods for treatment and/or prophylaxis of infectious diseases caused by gram-positive and gram-negative microorganisms that involve administration of indicated derivative of carbapenem in therapeutically and/or prophylactically effective doses to mammals including humans.

EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.

22 cl, 2 tbl, 73 ex

 

Background of the invention

The scope of the invention

The present invention relates to a derivative carbapenem having high antibiotic activity and a broad spectrum antibiotic. More specifically, the present invention relates to new derivatives carbapenem containing substituted imidazo[5,1-b]thiazole group at the 2nd position of the ring carbapenem, or their salts.

The technical field to which the invention relates.

Derivatives carbapenem have high antibiotic activity and a broad spectrum antibiotic and therefore has been studied intensively as a highly effective β-lactam means, and imipenem, panipenem and Meropenem have already been used clinically.

At present, however, and imipenem, and panipenem, applied in the form of a mixture due to their instability in relation to dehydropeptidase-1 kidney (hereinafter referred to as DHP-1) in the case of imipenem, and in order to reduce nephrotoxicity in case panipenem. On the other hand, Meropenem, due to the presence of the methyl group in 1β-position, has a high stability against DHP-1, and therefore can be applied independently. However, the stability of Meropenem against DHP-1 is still not satisfactory. In addition, antibiotic activity against methicillin-resistant the th Staphylococcus aureus (hereinafter referred to as MRSA), create a serious problem in the clinic, and penicillin-resistant Streptococcus pneumoneae (hereinafter referred to as PRSP), which is resistant Pseudomonas aeruqinosa, enterococci and influenza virus, also is not always satisfactory. Drugs effective against these microorganisms that cause infectious diseases are required in this field of technology.

For example, derivatives carbapenem, in which the carbon atom in imidazo[5,1-b]thiazole group attached to the 2-th position of the ring carbapenem are disclosed in publications of international applications WO 98/32760 and 00/06581.

The INVENTION

The authors of the present invention discovered that a certain group derived carbapenem containing imidazo[5,1-b]thiazole group, has a high antibiotic activity against a wide spectrum of gram-positive bacteria and gram-negative bacteria and, at the same time, has high antibiotic activity against MRSA, PRSP, influenza virus, and producing β-lactamase microorganisms, as well as highly resistant against DHP-1. The present invention is based on this observation.

Accordingly, the present invention relates to a derivative carbapenem, which have high antibiotic activity against MRSA, RSP, influenza and producing β-lactamase microorganisms and resistant against DHP-1. The present invention relates to a compound represented by the formula (I)or its pharmaceutically acceptable salt:

where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom;

halogen atom;

lower alkyl, optionally substituted by halogen atom, cyano, hydroxyl, carbamoyl, amino group, formylamino, (lower alkyl)carbylamines, aminocarbonylmethyl, (lower alkyl)diography, lower alkoxygroup, lower cycloalkyl, N,N-di(lower alkyl)amino group or N-carbarnoyl(lower alkyl)-N,N-di(lower alkyl)amniography;

lowest cycloalkyl;

(lower alkyl)carbonyl, where the alkyl part of the (lower alkyl)carbonyl optionally substituted by halogen atom, cyano, hydroxyl, carbamoyl, amino group, formylamino, (lower alkyl)carbylamines, aminocarbonylmethyl, (lower alkyl)diography, lower alkoxygroup, lower cycloalkyl, N,N-di(lower alkyl)amino group or N-carbarnoyl(lower alkyl)-N,N-di(lower alkyl)amniography;

carbarnoyl;

aryl, optionally substituted and what kinogruppoy, optionally substituted by one or two lower alkyl groups;

(lower alkyl)tighrope, where the alkyl part of the (lower alkyl)diography optionally substituted by amino, hydroxyl, azide, halogen atom, cyano, carbamoyl, formylamino, (lower alkyl)carbylamines, aminosulphonylphenyl or (lower alkyl)diography;

morpholinyl;

(lower alkyl)sulfonyl; or

formyl;

n is an integer from 0 to 4, and

Hy is a 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulphur,

saturated or unsaturated heterocyclic group, represented Hy, optionally substituted

a halogen atom;

the cyano;

lower alkyl, where one or more hydrogen atoms of the lower alkyl group optionally substituted by groups selected from the group consisting of a halogen atom; hydroxyl; carbamoyl; replaced by carboxylation of carbamoyl; amino; N,N-di(lower alkyl)amino; optionally substituted amino aryl; monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of atoms and the PTA, oxygen and sulfur, optionally substituted by aminosulfonyl or carboxyla, preferably 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, more preferably of pyridinyl, morpholinyl, pyrrolidinyl or piperidinyl; carboxyl; aminogroup; lower alkoxycarbonyl; (lower alkyl)carbonyl; aminosulfonyl; amino(lower alkyl)diography; (lower alkyl)sulfonyl; (N,N-di(lower alkyl)amino)sulfonylamino; N'-(N,N-di(lower alkyl)amino)sulfonyl-N'-(lower alkyl)amino group; halogenated (lower alkyl)carbonyl; N-aminomethylpyridine; and cyanopropyl;

(lower alkyl)diography, where one or more hydrogen atoms of the alkyl group optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, amino and aryl;

(lower alkyl)sulfonium, where one or more hydrogen atoms of the alkyl group optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, amino, 1-aminoethylamino and aryl; hydroxyl;

lowest alkoxygroup;

replaced by hydroxyquinolinium lower alkoxygroup;

halogen is trated lower alkoxygroup;

replaced by AMINOPHENYL lower alkoxygroup;

the formyl;

(lower alkyl)carbonyl;

arylcarbamoyl;

carboxyla;

lowest alkoxycarbonyl;

carbamoyl;

N-(lower alkyl)carbamoyl;

N,N-di(lower alkyl)aminocarbonyl;

amino group;

N-(lower alkyl)amino group;

N,N-di(lower alkyl)amino group;

formylamino;

(lower alkyl)carbylamines;

aminosulphonylphenyl;

(N-(lower alkyl)amino)sulfonylamino;

(N,N-di(lower alkyl)amino)sulfonylamino;

by aryl; or

monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, optionally substituted by aminosulfonyl or carboxyla, preferably optionally substituted 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulphur.

In addition, the present invention relates to a compound represented by the formula (II), or its pharmaceutically acceptable salt:

where R1, R2, R3n and Hy have the meanings given for formula (I).

With the unity of the present invention have a high antibiotic activity against a wide spectrum of gram-positive bacteria and gram-negative bacteria. In particular, the compounds of the present invention have a high antibiotic activity against MRSA, PRSP, influenza virus, and producing β-lactamase microorganisms. Accordingly, the compounds of the present invention are used as antibiotic drugs.

Moreover, the present invention relates to pharmaceutical compositions containing the compound of the present invention as an active ingredient. This pharmaceutical composition is used for treatment and/or prevention of infectious diseases.

In addition, the present invention relates to the use of compounds of the present invention for the manufacture of pharmaceutical compositions of the present invention.

In addition, the present invention relates to a method of treatment and/or prevention of infectious diseases, including the stage of introducing a therapeutically and/or prophylactically effective amount of the compounds of the present invention mammals, including humans.

DETAILED description of the INVENTION

The term "lower alkyl" and the term "lower alkoxygroup"is used here to denote a group or part of a group means alkyl and alkoxygroup with unbranched or branched chain containing 1-6, preferably 1-4, carbon atoms.

Examples of lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

Examples of the lower alkoxygroup include a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, sec-butoxypropyl and tert-butoxypropan.

The term "lower cycloalkyl" means a monocyclic alkyl containing 3 to 6 carbon atoms, preferably cyclopropyl.

The term "halogen atom" means a fluorine atom, chlorine, bromine or iodine.

The term "aryl"is used here to denote a group or part of a group, means a 5-7 membered monocyclic aromatic carbocyclic ring and 9-12-membered bicyclic aromatic carbocyclic ring, preferably phenyl or naphthyl, more preferably phenyl.

The term "monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atoms, oxygen or sulfur, preferably by means of a 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen or sulfur. In that case, if the heterocyclic group contains several heteroatoms, the heteroatoms may be the same what do different.

Preferred heterocyclic groups represented Hy, include heterocyclic group containing in the composition of the rings one or two nitrogen atom together with other carbon atoms, heterocyclic group containing in the composition of the one ring nitrogen atom and one sulfur atom along with other carbon atoms, and heterocyclic group containing in the composition of the ring, one atom of sulfur, along with other carbon atoms. More preferred are pyridinyl, (pyridine)Il, tetrahydropyridine, thiazolyl, pyrimidinyl, thienyl, chinoline, (hineline)Il, ethenolysis, dihydroisoquinoline, piperazinil, piperidinyl, indolyl, thiomorpholine, imidazole and pyrrolidinyl. Most preferred are pyridinyl, (pyridine)Il, tetrahydropyridine, thiazolyl, pyrimidinyl, thienyl, chinoline, (hineline)silt and pyrrolidinyl.

Deputy of the lower alkyl groups and lower alkylcarboxylic group, not necessarily represented by R2and R3preferably is hydroxyl, lower alkoxygroup, N,N-di(lower alkyl)amino group or N-carbarnoyl(lower alkyl)-N,N-di(lower alkyl)AMERIGROUP.

Deputy aryl group, optionally presents R2and R3preferably is N,N-dialkylamino.

Deputy (lower alkyl)diography, optional pre is provided R 2and R3preferably is amino, hydroxyl or azide.

Deputy heterocyclic group represented Hy, preferably is lower alkyl, optionally substituted substituted by carboxymethyl carbamoyl, carbamoyl, phenyl, AMINOPHENYL, N,N-di(lower alkyl)amino group, amino group, hydroxyl, morpholinium, pyrrolidinium, carboxyla, aminogroups, amino(lower alkyl)diography, lower alkoxycarbonyl, (lower alkyl)carbonyl, aminosulphonylphenyl, piperidino, (lower alkyl)sulfonyl, (N,N-di(lower alkyl)amino)sulfonylamino, N'-(N,N-di(lower alkyl)amino)sulfonyl-N'-(lower alkyl)amino group, halogenated (lower alkyl)carbonyl, N-aminosulphonylphenyl or cyano; carbarnoyl; pyridinyl; N-aminomethylpyrrolidine; 2-carboxypropyl; phenyl; hydroxyl; lower alkoxygroup; replaced by hydroxyquinolinium lowest alkoxygroup; substituted by a halogen atom lower alkoxygroup; replaced by AMINOPHENYL lowest alkoxygroup; amino group; carboxyl; optionally substituted amino (lower alkyl)tighrope; amino(lower alkyl)tighrope; amino(lower alkyl)sulfonyl; or 1 aminoethylamino(lower alkyl)sulfonyl. More preferred are lower alkyl, substituted by a group selected from the group is s, composed of carbamoyl, carboxyl and aminosulfonyl; and substituted amino (lower alkyl)tighrope.

Heterocyclic group, represented Hy, can be connected to the carbonyl, -CH(-OH)or C1-4-alkylene in any position of the heterocyclic ring. In that case, if Hy is a pyridinyl, it is preferable to join in the 3rd position. In that case, if Hy is pyrrolidinyl, it is preferable to attach the 2nd position.

In that case, if the heterocyclic group represented Hy, contains in its ring nitrogen atom, the nitrogen atom may be substituted with the formation of the Quaternary atom of ammonia.

Preferred used here substituents include carbamoylmethyl, carboxylmethyl and aminosulphonylphenyl.

R1preferably represents methyl.

R2and R3preferred are hydrogen atom, halogen atom, optionally substituted lower alkyl, lower cycloalkyl, (lower alkyl)carbonyl, carbamoyl, aryl, optionally substituted (lower alkyl)diography, morpholinium, formyl or (lower alkyl)sulfonium, more preferably a hydrogen atom.

n preferably is an integer from 0 (zero) to 2, more preferably 0. Hy preferably represents the FDS is th optionally substituted (pyridin-3-yl), (pyridine-3-yl), [1,4,5,6-tetrahydropyridine-3-yl] (pyridine-4-yl), (pyridine-4-yl, thiazol-5-yl), (pyrrolidin-2-yl), (pyrimidine-5-yl), (thiophene-2-yl), (quinoline-3-yl), (chinoline-3-yl), (isoquinoline-4-yl), (1,2-dihydroisoquinoline-4-yl), (piperidine-2-yl), (piperazine-1-yl), (piperazine-4-yl), (piperidine-4-yl), (indol-3-yl), (pyrrolidin-1-yl), (piperazine-1-yl), (pyrrolidine-1-yl, piperidine-3-yl), [1,2-dihydropyridines-3-yl], (imidazol-1-yl) or (thiomorpholine-4-yl).

More preferably, Hy is an optionally substituted (pyridin-3-yl), optionally substituted (pyridine-3-yl or optionally substituted ((2S)-pyrrolidin-2-yl).

A group of preferred compounds represented by formulas (I) and (II)are those where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom;

halogen atom;

lower alkyl, optionally substituted by halogen atom, cyano, hydroxyl, carbamoyl, amino group, formylamino, (lower alkyl)carbylamines, aminosulphonylphenyl or (lower alkyl)diography;

(lower alkyl)carbonyl, where the alkyl part of the (lower alkyl)carbonyl optionally substituted by halogen atom, cyano, hydroxyl, carbamoyl, amino group, formylamino, (Nissi is alkyl)carbylamines, aminosulphonylphenyl or (lower alkyl)diography;

carbarnoyl;

aryl; or

(lower alkyl)tighrope, where the alkyl part of the (lower alkyl)diography optionally substituted by halogen atom, cyano, hydroxyl, carbamoyl, amino group, formylamino, (lower alkyl)carbylamines, aminosulphonylphenyl or (lower alkyl)diography;

n is an integer from 0 (zero) to 4, and

Hy is a 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulphur,

saturated or unsaturated heterocyclic group, represented Hy, optionally substituted

a halogen atom;

the cyano;

lower alkyl, where one or more hydrogen atoms of the lower alkyl group optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, amino, aryl and monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, preferably 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group, steriade is 1-4 heteroatoms, selected from the group consisting of nitrogen atoms, oxygen and sulfur, more preferably of pyridinyl, morpholinyl, pyrrolidinyl or piperidinyl;

(lower alkyl)diography, where one or more hydrogen atoms of the alkyl group optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, amino and aryl;

(lower alkyl)sulfonium, where one or more hydrogen atoms of the alkyl group optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, amino and aryl;

by hydroxyl;

lowest alkoxygroup;

the formyl;

(lower alkyl)carbonyl;

arylcarbamoyl;

carboxyla;

lowest alkoxycarbonyl;

carbamoyl;

N-(lower alkyl)carbamoyl;

N,N-di(lower alkyl)aminocarbonyl;

amino group;

N-(lower alkyl)amino group;

N,N-di(lower alkyl)amino group;

formylamino;

(lower alkyl)carbylamines;

aminosulphonylphenyl; (N-(lower alkyl)amino)sulfonylamino;

(N,N-di(lower alkyl)amino)sulfonylamino;

by aryl; or

monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, being the equipment optionally substituted 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group, containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulphur.

Another group of preferred compounds represented by formulas (I) and (II)are those where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom,

halogen atom,

optionally substituted lower alkyl,

lowest cycloalkyl,

lowest alkylsulphonyl,

carbarnoyl,

optionally substituted aryl,

optionally substituted (lower alkyl)togroup,

morpholinyl,

(lower alkyl)sulfonyl, or

formyl, n is an integer from 0 (zero) to 2, and

Hy is a group selected from the group consisting of optionally substituted pyridinyl, optionally substituted (pyridine)yl, optionally substituted tetrahydropyridine, optionally substituted thiazolyl, optionally substituted pyrimidinyl, optionally substituted tanila, optionally substituted chinoline, optionally substituted (hineline)yl, optionally substituted izochinolina, optionally substituted dihydroisoquinolyl, optionally substituted piperazinil, optionally substituted piperidinyl, optionally substituted of indolyl, optional the nutrient substituted thiomorpholine, optionally substituted of imidazolyl and optionally substituted pyrrolidinyl.

An additional group of preferred compounds represented by formulas (I) and (II)are those where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom,

halogen atom,

optionally substituted lower alkyl,

optionally substituted lower alkylaryl,

carbarnoyl,

aryl, or

optionally substituted (lower alkyl)togroup,

n is an integer from 0 (zero) to 4, and Hy represents a group selected from the group consisting of optionally substituted pyridinyl, optionally substituted (pyridine)yl, optionally substituted tetrahydropyridine, optionally substituted thiazolyl, optionally substituted pyrimidinyl, optionally substituted tanila, optionally substituted chinoline, optionally substituted (hineline)silt and optionally substituted pyrrolidinyl.

A group of preferred compounds represented by formula (II)are those where

R1represents methyl,

R2and R3each represents a hydrogen atom,

n is 0, and

Hy is an optional Zam is placed 6-membered saturated heterocyclic group, containing 1-4 heteroatoms.

A group of preferred compounds represented by formulas (I) and (II)are those where

R1represents a hydrogen atom or methyl,

R2and R3represent a hydrogen atom,

n is 0, and

Hy represents (pyridine)silt containing carbamoylmethyl in its 1st position.

Another group of preferred compounds represented by formulas (I) and (II)are those where n is 0.

An additional group of preferred compounds represented by formulas (I) and (II)are those where R1represents methyl, and R2and R3represent a hydrogen atom.

Another group of more preferred compounds represented by formulas (I) and (II)are those where

R1represents methyl,

R2and R3represent a hydrogen atom,

n is 0, and

Hy represents (pyridine)yl, optionally containing in its 1st position carbarnoyl(lower alkyl), carboxy(lower alkyl) or aminosulfonyl(lower alkyl), and amino(lower alkyl)togroup in any position other than the 1st position.

Another group of more preferred compounds represented by formula (I)are those where R1represents methyl, R2and R3represent the Wallpaper hydrogen atom, n is 0, and Hy represents a pyridin-3-yl.

Particularly preferred compounds represented by formulas (I) and (II)include the

compounds where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carbamoylbiphenyl-3-yl,

compounds where R1, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carbamoylbiphenyl-3-yl,

compounds where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a 1-carbamoylmethyl-5-phenylpyridine-3-yl,

compounds where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a (2S)-pyrrolidin-2-yl,

compounds where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carboxymethylamino-3-yl,

and compounds, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a 1-(2-aminosulphonylphenyl)pyridine-3-yl.

Compounds of the present invention can form pharmaceutically acceptable salts. Examples of such salts include inorganic salts such as lithium salts, with whom Lee sodium, potassium salts, calcium salts or magnesium salts; ammonium salts; salts of organic bases, such as salts of triethylamine or salts diisopropylethylamine; inorganic salts, such as salts of hydrochloric acid, salts of sulfuric acid, salts of phosphoric acid or a salt of nitric acid; and salts of organic acids, such as salts of acetic acid, salts of carbonic acid, salts of citric acid, salts of malic acid, salts of oxalic acid or salt methanesulfonic acid. Preferred are intramolecular salt, sodium salt, potassium salt or salts of hydrochloric acid.

Specific examples of derivatives carbapenem represented by formulas (I) and (II) of the present invention, include compounds 1-175 described below in the working examples.

Compounds represented by formula (I) according to the present invention, it is preferable to receive in accordance with scheme 1. Scheme 1

In the above scheme, R1, R2, R3n and Hy have the meanings as defined above for formula (I); R4represents a hydrogen atom or a hydroxyl-protective group, for example, tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, 4-nitrobenzenesulfonyl, 4-methoxybenzeneboronic or relaxerror; R5is carboxyl-protective group, for example, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, tert-butyldimethylsilyl or allyl; R6represents lower alkyl, preferably n-butyl or methyl; R7and R8have the same meaning as R2and R3or represents a group formed in the protection contained in R2and R3functional groups such as hydroxyl, amino or carboxyl, conventional protecting group; and Hy' has the same meaning as Hy, or represents a group formed in the protection contained in Hy functional group such as hydroxyl, amino or carboxyl, conventional protecting group. Conventional protective group described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc.).

The compound of formula (III), specified in the first stage, represented in the diagram, can be synthesized using the conventional method, and the connection of the tin of formula (V), specified in the second stage, shown in the diagram, can be synthesized in accordance with the method described in published international application WO 98/32760.

In the first stage, the compound of formula (III) can be converted to the compound of formula (IV) in the following way. Specifically, the compound of formula (IV) can be obtained by carrying out in which aimogasta the compounds of formula (III) with one (1) equivalent, or excessive amounts, triftormetilfullerenov anhydride in the presence of an organic base, preferably of diisopropylethylamine, one (1) equivalent or in excess relative to triftormetilfullerenov anhydride quantity of inert solvent, such as acetonitrile, tetrahydrofuran, dichloromethane or toluene, or a mixed solvent composed of two or more of the above inert solvents, at temperatures from -50°C to +50°C in the time range from 10 minutes to 24 hours, then subjecting the reaction mixture to the generally accepted procedure of separation and purification.

In the second stage, the compound of formula (IV) can be converted to the compound of formula (VI) in the following way. Specifically, the compound of formula (VI) can be obtained by carrying out the interaction of the compounds of formula (IV) with one (1) equivalent or an excessive amount of compounds of formula (V) in the presence of from 0.001 to 1 equivalent of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)diplegia(0) or adduct of Tris(dibenzylideneacetone)diplegia(0) chloroform, from 0.01 to 1 equivalent of the phosphine ligand, such as triphenylphosphine, tri-2-furifosmin three-2-tanypodinae or Tris(2,4,6-trimethoxyphenyl)phosphine, and 1-10 equivalents of an additive, in the example, of zinc chloride, lithium chloride or fluoride, cesium, individually or in combination, in an inert solvent, e.g. tetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, acetone, ethanol, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone or hexamethylphosphoric triamide, or in a mixed solvent composed of two or more of the above inert solvents, at temperatures from 0°C to 100°C in the time range from 10 minutes to 7 days, and subjecting the reaction a mixture of conventional post-processing.

Finally, in the third stage, the compound of formula (I) according to the present invention can be obtained by removing the protection of the compounds of formula (VI) in the reaction unprotect numbering depending on the kinds of the protective groups one or several stages.

In this case, the reaction unprotect, which vary depending on the species used protective groups can be carried out in accordance with conventional methods, traditionally used in this area. In the case when some or all of the protective group can be removed under acidic conditions, for example, used an inorganic acid such as hydrochloric acid, an organic acid such as formic acid, acetic acid or citric who Isleta, or a Lewis acid such as aluminium chloride. In that case, when the protective group is removed in basic conditions, can be applied to catalytic reduction using a variety of catalysts or metal reducing agents such as zinc and iron. In the case when R4represents a protective group, silyl type, for example, tert-butyldimethylsilyloxy group, trimethylsilyloxy group or triethylsilyl group, the protective group can be easily removed with the use of containing fluorine ion reagent, for example, tetrabutylammonium. In the case when R4is allyloxycarbonyl, and R5represents the allyl protective group can be removed easily using a variety of palladium complexes, for example, tetrakis(triphenylphosphine)palladium(0).

Thus obtained compound of formula (I) can be easily isolated and purified, for example by crystallization or chromatography using nonionic macroporous resins, gel filtration through Sephadex, and the like, or column chromatography with reversed phase silica gel.

The compounds of formula (I), where Hy contains Quaternary atom, ammonium, can be obtained in accordance with scheme 2.

Scheme 2

In the above scheme, R1and n have the meanings as defined for formula (I); R4, R5, R7, R8and Hy' have the meanings as defined for scheme 1; R9represents an optionally substituted lower alkyl; and Y represents a suitable leaving group, for example, Cl, Br, I, -OSO2CF3, -OSO2CH3or-OSO2PhCH3.

Specifically, the compound of formula (VII) can be obtained by adding one (1) equivalent or an excessive amount of R9-Y, for example, methyliodide, carbamoylmethyl, methyltrichlorosilane, benzylbromide or 3-azithromycinformation, to the compound of formula (VI) in the absence or in the presence of an inert solvent, such as acetonitrile, acetone, tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, individually or in mixture of two or more inert solvents, and through interaction at a temperature of from -80°C to +60°C in the time range from 15 minutes to one week, and then subjecting the reaction mixture to conventional post-processing.

The compound of formula (VII) can be converted to the compound of formula (I) in a manner similar to that described for the compounds of formula (VI).

The compound of formula (II) according to the present invention can be is obtained in accordance with scheme 3.

Scheme 3

In the above scheme, R1, R2, R3n and Hy have the meanings as defined for formula (I); and R4, R5, R7, R8and Hy' have the meanings as defined in scheme 1.

Specifically, the compound of formula (II) according to the present invention can be obtained, depending on the type Hy, by removing the protection of the compounds of formula (VI) in the reaction unprotect numbering depending on the kinds of the protective groups one or several stages, similar to the way described above.

Thus obtained compound of the formula (II) can be isolated and purified, for example by crystallization or chromatography using nonionic macroporous resins, gel filtration through Sephadex, and the like, or column chromatography with reversed phase silica gel.

Compounds of the present invention have a high antibiotic activity against a wide spectrum of gram-positive bacteria and gram-negative bacteria and, at the same time, have high antibiotic activity against MRSA, PRSP, influenza virus, and producing β-lactamase microorganisms. In addition, they have low toxicity and are resistant to the action of the DHP-1. Therefore, the compounds of the present invention can note the change for the treatment of infectious diseases, caused by various pathogenic microorganisms, animals, including humans. Pharmaceutically acceptable compositions containing as active ingredient a compound of the present invention or its pharmaceutically acceptable salt may be administered orally or parenterally, for example, intravenous injection, intramuscular injection, or subcutaneous, rectal or percutaneous human and non-human animals.

Pharmaceutical composition containing as active ingredient a compound of the present invention, may be made in the form of suitable dosage forms, depending on ways of introduction. Specifically, the compounds of the present invention can be prepared in the form of, for example, injectables, such as drugs for intravenous injection and preparations for intramuscular injection, preparations for oral administration such as capsules, tablets, granules, powders, pills, fine powders and tablets; preparations for rectal administration; and oily suppositories.

These drugs can be obtained using conventional methods with the use of traditionally used to obtain drugs adjuvants, such as excipients, fillers, binders, humectants, disintegrants, surface-AK is active substances, oiling agents, dispersants, buffers, preservatives, thinning agents, antiseptics, flavoring agents, anesthetics and stabilizers.

Apply here nontoxic adjuvants include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, or their salts, gum Arabic, polyethylene glycol, syrup, vaseline, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite and sodium phosphate.

The dosage may be determined as appropriate, depending on various conditions, for example, the goals of treatment or prevention, age, sex and severity of condition of patients. Dosage for treatment of infectious diseases is usually from about 25 to 2000 mg, preferably from 50 to 1000 mg per day for an adult. This dosage can be applied once a day or may be divided into several stages.

EXAMPLES

The present invention is additionally illustrated by the following examples, synthesis examples and test examples, which are not intended as limitations of the invention.

[Synthesis example 1] 7-(Pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(Pyridine-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole

A solution of 2.50 g of 7-Jodi is idazo[5,1-b]thiazole in 50 ml of anhydrous THF was cooled on ice and in the atmosphere of argon to a cooled solution was added 11.3 ml of 0.93 M solution methylacrylamide in THF. The mixture was stirred at this temperature for 20 minutes. Then thereto was added pyridine-3-aldehyde (1,04 ml), the mixture was stirred at this temperature for 40 minutes and then at room temperature for 4 hours. To the reaction mixture was added water and was extracted five times a mixture of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the method of column chromatography on silica gel (eluent - dichloromethane:methanol=20:1) to obtain 1,925 g of 7-[(pyridine-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: 6,05 (1H, s), 6,72 (1H, d, J=4, 2 Hz), 7.3 to 7.4 (2H, m), 7,8-7,9 (1H, m), to 7.99 (1H, s), 8,55-8,65 (1H, m), 8,7-is 8.75 (1H, m)

b) 7-(Pyridin-3-yl)carbonlimited[5,1-b]thiazole

To a solution of 1.02 g of 7-[(pyridine-3-yl)hydroxymethyl]imidazo-[5,1-b]thiazole in 40 ml of dichloromethane was added manganese dioxide (1.0 g) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite (brownmillerite) and then washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain 1.10 g of 7-(pyridin-3-yl)carbonlimited[5,1-b]thiazole.

NMR (CDCl3) δ: 7,20 (1H, d, J=4, 2 Hz), between 7.4 to 7.5 (1H, m), 7,63 (1H, d, J=4, 2 Hz), 8,10 (1H, s), 8,75 cent to 8.85 (2H, m), a 9.7-of 9.75 (1H, m)

c) 7-(Pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

To a solution of 520 mg of 7-(pyridin-3-yl)is bonelight[5,1-b]thiazole in 25 ml of THF at -60° C in argon atmosphere was added tri-n-butylstannane (0,841 ml) and 2.95 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF, and the mixture was stirred for 20 minutes. The temperature of the mixture was raised to -50°C, was added a 1.0 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF and stirred the mixture for 30 minutes. The temperature of the mixture was raised to -40°C, was added thereto 0.5 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF and stirred the mixture for 30 minutes. To the reaction mixture were added an aqueous solution of ammonium chloride, was extracted with a mixture of ethyl acetate and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the residue was purified by the method of column chromatography on silica gel (eluent - hexane:ethyl acetate=2:1 → only ethyl acetate) to give 712 mg specified in the connection header.

NMR (CDCl3) δ: to 0.92 (9H, t, J=7.2 Hz), 1,2-1,3 (6H, m), from 1.3 to 1.45 (6H, m), 1,55-1,65 (6H, m), of 7.36 (1H, s), 7,4 was 7.45 (1H, m), 8,03 (1H, s), 8,75 cent to 8.85 (2H, m), 9,65 of 9.7 (1H, m)

[Synthesis example 2] 7-(Pyridin-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(Pyridine-4-yl)hydroxymethyl]imidazo[5,1-b]thiazole

7-[(Pyridine-4-yl)hydroxymethyl]imidazo[5,1-b]thiazole (1,32 g) was obtained by the method similar to that described in stage a) of example of synthesis 1, except that, as the original link is used 2.50 g 7 itemids[5,1-b]thiazole and 1.05 ml of pyridine-4-aldehyde.

NMR (DMSO-d6) δ: USD 5.76 (1H, d, J=4,8 Hz), to 6.19 (1H, d, J=4,8 Hz), 7,11 (1H, d, J=4.5 Hz), 7,35-7,45 (2H, m), 7,80 (1H, d, J=4.5 Hz), 8,11 (1H, s), 8,5-8,55 (2H, m)

b) 7-(Pyridin-4-yl)carbonlimited[5,1-b]thiazole

7-(Pyridin-4-yl)carbonlimited[5,1-b]thiazole (1,16 g) was obtained by the method similar to that described in stage b) of example of synthesis 1, except that as the starting compound used to 1.32 g of 7-[(pyridine-4-yl)hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: 7,21 (1H, d, J=4, 2 Hz), to 7.64 (1H, d, J=4, 2 Hz), 8,10 (1H, s), 8,3-8,35 (2H, m), 8,8 cent to 8.85 (2H, m)

c) 7-(Pyridin-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (1.78 g) was obtained by the method similar to that described in stage c) of example of synthesis 1, except that as the starting compound used of 1.03 g of 7-(pyridin-4-yl)carbonlimited[5,1-b]thiazole.

NMR (CDCl3) δ: to 0.92 (9H, t, J=7.5 Hz), 1,2-1,3 (6H, m), from 1.3 to 1.45 (6H, m), 1,55-1,65 (6H, m), 7,37 (1H, s), 8,03 (1H, s), 8,25 to 8.3 (2H, m), 8,8 cent to 8.85 (2H, m)

[Synthesis example 3] 7-(4-Methylthiazole-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(4-Methylthiazole-5-yl)carbonlimited[5,1-b]thiazole

A solution of 1.75 g of 7-itemids[5,1-b]thiazole in 35 ml of anhydrous THF was cooled on ice and in the atmosphere of argon to a cooled solution was added 8,56 ml of 0.9 M solution of methylmagnesium in THF. The mixture was stirred at this temperature for 20 minutes and then added to her 923 mg of 4-metelli the evil-5-aldehyde. The mixture was stirred at the same temperature for 20 minutes and then at room temperature for 1 hour. To the reaction mixture was added water and was extracted five times a mixture of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To prepare the solution, the residue was dissolved in 35 ml of dichloromethane. To the solution was added manganese dioxide (2.1 g) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite and then washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to obtain 1.50 g of 7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazole.

NMR (CDCl3) δ: is 2.88 (3H, s), to 7.09 (1H, d, J=4,1 Hz), 7,54 (1H, d, J=4,1 Hz), 8,00 (1H, s), 8,81 (1H, s)

b) 7-(4-Methylthiazole-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (254 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 502 mg of 7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazole, 0,598 ml of tri-n-butylstannane and 4.0 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.90 (9H, t, J=7,3 Hz)of 1.18 (6H, m), 1,24 (6H, m)of 1.34 (6H, m), with 2.93 (3H, s), 7,31 (1H, s), 7,98 (1H, s), 8,84(1H, C)

[Example of synthesis 4] 7-[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole

7-[[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole (of 2.21 g) was obtained by the method similar to that described in stage a) of example of synthesis 1, except that as the starting compounds used 2.50 g 7 itemids[5,1-b]thiazole and 2,32 g of (2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-aldehyde.

NMR (CDCl3) δ: about 1.7-2.3 (4H, m), 3,4-3,6 (2H, m), 4,15-of 4.25 (1H, m), to 4.87 (1H, d, J=8.7 Hz), and 5.30 (2H, s), PC 6.82 (1H, d, J=4.5 Hz), 7,37 (1H, d, J=4.5 Hz), 7,56 (2H, d, J=8.7 Hz), to 7.93 (1H, s), 8,24 (2H, d, J=8.7 Hz)

b) 7-[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole

7-[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole (1,79 g) was obtained by the method similar to that described in stage b) of example of synthesis 1, except that as the starting compound used of 2.21 g of 7-[[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: 1,9-2,5 (4H, m), 3,55-of 3.85 (2H, m), the 4.9 to 5.3 (2H, m), the 5.45 to 5.55 (1H, m), 7,05 and 7.6 (4H, m), 7,9-of 8.25 (3H, m)

c) 7-[(2S)-1-(4-Nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the header connection (1,82 g) received ways the Ohm, similar to that described in stage c) of example of synthesis 1, except that as the starting compound used 2.15 g of 7-[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.91 (9H, t, J=7.2 Hz), 1,2-1,3 (6H, m), 1,3-1,4 (6H, m), of 1.5-1.7 (6H, m), 1,9-2,5 (4H, m), 3,55-of 3.85 (2H, m), the 4.9 to 5.3 (2H, m), the 5.45 -5,55 (1H, m), 7,2-of 7.55 (3H, m), 7,9-of 8.25 (3H, m)

[Synthesis example 5] 7-(Pyrimidine-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(Pyrimidine-5-yl)hydroxymethyl]imidazo[5,1-b]thiazole

For preparation of a solution of 5-bromopyrimidine (1,11 g) was dissolved in a solution of 7 ml of tetrahydrofuran and 14 ml of diethyl ether. In the atmosphere of argon to the solution was added dropwise a 1.6 n solution of n-utility in n-hexane (4,56 ml) at -78°C and stirred the mixture for 30 minutes. Then in argon atmosphere at -78°C thereto was added dropwise 7 formelement[5,1-b]thiazole (608 mg) in tetrahydrofuran (16 ml). The mixture was stirred at this temperature for 30 minutes. Then the temperature was raised to room temperature and added to a mixture of 70 ml of ethyl acetate. The organic layer was twice washed polysystem salt solution and once with saturated saline solution. The washed organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation under reduced pressure and the residue was purified by column method XP is matography on silica gel (eluent - chloroform/methanol=40/1 → 25/1 → 10/1) to give 398 mg of 7-[(pyrimidine-5-yl)hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: 5,88 (1H, d, J=4.6 Hz), 6,33 (1H, d, J=4.6 Hz), to 7.15 (1H, d, J=4, 2 Hz), 7,81 (1H, d, J=4, 2 Hz), 8,11 (1H, s), 8,79 (2H, s), which is 9.09 (1H, s)

b) 7-(Pyrimidine-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The ketone compound (217 mg) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 398 mg of 7-[(pyrimidine-5-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 400 mg of manganese dioxide. 7-(Pyrimidine-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (68 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 46 mg of ketone compounds, 0,124 ml of tri-n-butylstannane and to 0.900 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: to 0.92 (9H, t, J=7,3 Hz), 1,25 -1,33 (6H, m), 1,36-1,49 (6H, m), 1,53-of 1.62 (6H, m), 7,38 (1H, t, J=7,1 Hz), of 8.04 (1H, s), 9,34 (1H, s), 9,78 (1H, s)

[Example of synthesis 6] 7-(Thiophene-2-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(Thiophene-2-yl)carbonlimited[5,1-b]thiazole

7-(Thiophene-2-yl)carbonlimited[5,1-b]thiazole (1,37 g) was obtained by the method similar to that described in stage a) of synthesis example 3, except that as starting compounds in anjali 1.50 g 7 itemids[5,1-b]thiazole and 0,561 ml thiophene-2-aldehyde.

NMR (CDCl3) δ: 6,98 (1H, d, J=4,1 Hz), 7,05 (1H, m), 7,44 (1H, d, J=4,1 Hz), 7,53 (1H, m), of 7.90 (1H, s), and 8.50 (1H, m)

b) 7-(Thiophene-2-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the header connection (923 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 550 mg of 7-(thiophene-2-yl)carbonlimited[5,1-b]thiazole, 0,701 ml of tri-n-butylstannane and 3.6 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.85 (9H, t, J=7,3 Hz), was 1.04 (6H, m), 1,11 (6H, m)of 1.42 (6H, m), 7,03 (1H, m), 7,18 (1H, c), of 7.48 (1H, m), 7,95 (1H, s), of 8.47 (1H, s)

[Synthesis example 7] 7-[5-(tert-Butyldimethylsilyloxy)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[[5-(tert-Butyldimethylsilyloxy)pyridine-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole

The solution 2,49 g of 5-bromo-3-(tert-butyldimethylsilyloxy)of pyridine in 25 ml of anhydrous diethyl ether was cooled to -85°C in argon atmosphere and cooled the solution for 10 minutes was added dropwise to 5.56 ml of 1.57 n solution of n-utility in hexane. The mixture was stirred at this temperature for 30 minutes, and then thereto was added a solution of 881 mg of 7-formylamino[5,1-b]thiazole in 20 ml of anhydrous THF and then stirred it at the same temperature for 30 minutes. To the reaction mixture were added water. The mixture three times the extras who were garofali chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the method of column chromatography on silica gel (eluent - ethyl acetate:methanol=10:1) to obtain 803 mg of 7-[[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.07 (6H, s)0,99 (9H, s), was 4.76 (2H, s), of 6.02 (1H, s)of 6.71 (1H, d, J=4,1 Hz), 7,32 (1H, d, J=4,1 Hz), to 7.77 (1H, s), 7,95 (1H, s), 8,55 (1H, m), 8,61 (1H, m)

b) 7-[5-(tert-Butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole

To a solution of 803 mg of 7-[[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole in 10 ml of dichloromethane was added manganese dioxide (1,43 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and then washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain 712 mg of 7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.10 (6H, s)to 0.94 (9H, s), is 4.85 (2H, s), 7,16 (1H, d, J=4.0 Hz), 7,58 (1H, d, J=4.0 Hz), 8,08 (1H, s), 8,72 (1H, m), 8,76 (1H, m), 9,60 (1H, m)

C) 7-[5-(tert-Butyldimethylsilyloxy)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the header connection (926 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, excluded the eat as source materials used 712 mg of 7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole, 0,572 ml of tri-n-butylstannane and 2.9 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF. NMR (CDCl3) 6: 0,10 (6H, s), and 0.98 (9H, t, J=7,2 Hz), and 1.00 (9H, s)of 1.18 (6H, m), 1,32 (6H, m), and 1.54 (6H, 20 m), is 4.85 (2H, s), 7,31 (1H, s), 7,98 (1H, s), 8,72 (2H, m), 9,58 (1H, m)

[Example of synthesis 8] 7-(6-Methylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(6-Methylpyridin-3-yl)carbonlimited[5,1-b]thiazole

7-(6-Methylpyridin-3-yl)carbonlimited[5,1-b]thiazole (885 mg) was obtained by the method similar to that described in stage a) of synthesis example 3, except that as the starting compounds used 1.10 g 7 itemids[5,1-b]thiazole and 532 mg, 2-methylpyridin-5-aldehyde.

NMR (CDCl3) δ: of 2.51 (3H, s), 7,02 (1H, d, J=4,1 Hz), 7,18 (1H, m)to 7.50 (1H, d, J=4,1 Hz), of 7.97 (1H, s), 8,61 (1H, m), 9,48 (1H, m)

b) 7-(6-Methylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (606 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 447 mg of 7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazole, 0,552 ml of tri-n-butylstannane and 3.2 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.85 (9H, t, J=7,3 Hz), 1,10 (6H, m)of 1.20 (6H, m), USD 1.43 (6H, m), the 2.46 (3H, s, 7,16 (1H, m), 7,20 (1H, s), a 7.85 (1H, s), to 8.57 (1H, m), 9,40 (1H, 10 m)

[Synthesis example 9] 7-(5-Methylthiopyridine-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(5-Methylthiopyridine-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole

7-[(5-Methylthiopyridine-3-yl)hydroxymethyl]imidazo-[5,1-b]thiazole (119 mg) was obtained in essentially the same manner as described in stage a) of synthesis example 5, except that the starting materials used 204 mg of 3-bromo-5-methylthiopyridine, 0,656 ml of a 1.6 n solution of n-utility in n-hexane and 102 mg of 7-formylamino[5,1-b]thiazole.

NMR (DMSO-d6) δ: 2,49 (3H, s), 5,78 (1H, d, J=4.6 Hz), 6,13 (1H, d, J=4.4 Hz), 7,11 (1H, d, J=4.4 Hz), to 7.67 (1H, s), 7,80 (1H, d, J=4, 2 Hz), 8,10 (1H, s), at 8.36 (2H, s)

b) 7-(5-Methylthiopyridine-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The ketone compound (408 mg) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 430 mg of 7-[(5-methylthiopyridine-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 320 mg of manganese dioxide. 7-(5-Methylthiopyridine-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (179 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 138 mg of ketone compounds, 0,300 ml of tri-n-butylstannane and 2.25 ml of 1.0 n solution of bis(Tr is methylsilyl)lithium amide in THF.

NMR (CDCl3) δ: of 0.93 (9H, t, J=7,3 Hz), 1,15-of 1.23 (6H, m), of 1.27 and 1.35 (6H, m), 1.56 to of 1.64 (6H, m), 7,35 (1H, t, J=7,3 Hz), 8,02 (1H, s)8,64 (2H, s), of 9.51 (1H, s)

[Synthesis example 10] 7-(Quinoline-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(Quinoline-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole

7-[(Quinoline-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole (203 mg) was obtained in essentially the same manner as described in stage a) of example of synthesis 1, except that the starting materials used 0.25 g 7 itemids[5,1-b]thiazole, 1,17 ml of 0.93 M solution methylacrylamide in tetrahydrofuran and 173 mg of 3-chinainternational.

NMR (DMSO-d6) δ: 6,01 (1H, d, J=4.4 Hz), of 6.26 (1H, d, J=4.4 Hz), to 7.09 (1H, d, J=4,1 Hz), 7,58 (1H, t, J=7.8 Hz), 7,71 (1H, t, J=7.9 Hz), 7,80 (1H, d, J=4,1 Hz), 8,00 (2H, d, J=8.0 Hz), 8,10 (1H, s), of 8.90 (1H with)

b) 7-(Quinoline-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The ketone compound (327 mg) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 577 mg of 7-[(quinoline-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 421 mg of manganese dioxide. 7-(Quinoline-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (73 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 64 mg of ketone compounds, 0,140 ml three-is-butylstannane and 1.50 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.93 (9H, t, J=7,3 Hz), 1,14-of 1.24 (6H, m), 1,33-of 1.42 (6H, m), 1,61 by 1.68 (6H, m), 7,38 (1H, t, J=7,3 Hz), to 7.61 (1H, t, J=8.0 Hz), 7,81 (1H, m), 8,03 (1H, d, J=8.0 Hz), 8,07 (1H, s), 8,16 (1H, d, J=8.6 Hz), to 9.57 (1H, s), 9,84 (1H, s)

[Synthesis example 11] 7-([3,3']Bipyridinyl-5-yl)carbonlimited-[5,1-b]thiazole

a) 7-[(5-Bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole

7-[(5-Bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole (2,77 g) was obtained in essentially the same manner as described in stage a) of example of synthesis 1, except that the starting materials used 2.50 g 7 itemids[5,1-b]thiazole, and 12.2 ml of 0.93 M solution methylacrylamide in tetrahydrofuran and was 2.05 g of 3-bromo-5-formylpyridine.

NMR (CDCl3) δ: a 4.86 (1H, s), 6,04 (1H, s), 6,74 (1H, d, J=4, 2 Hz), 7,35 (1H, d, J=4.4 Hz), of 7.97 (1H, c), of 8.04 (1H, s), to 8.62 (2H, s)

b) 7-([3,3']Bipyridinyl-5-yl)carbonlimited[5,1-b]thiazole

The ketone compound (a 1.96 g) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 2,77 g of 7-[(5-bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 2.00 g of manganese dioxide. For preparation of a solution of ketone compound (616 mg) was dissolved in 20 ml of N,N-dimethylformamide. To the solution at room temperature in an argon atmosphere was added diethyl(3-pyridyl)borane (588 mg), 232 mg of tetrakis(triphenylphosphine)palladium(0) and 552 mg of potassium carbonate. The mixture peremeshivaniya 90° C for 2.5 hours. To the reaction mixture were added ethyl acetate (200 ml) and washed four times the organic layer 80 ml of water and once with saturated saline solution. The washed organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation under reduced pressure and the residue was purified by chromatography on silica gel (eluent - chloroform/methanol= 20/1 → 10/1) to give 428 mg of 7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazole.

NMR (CDCl3) δ: 7,21 (1H, d, J=3,9 Hz), 7,45 (1H, m), the 7.65 (1H, d, J=4,1 Hz), 8,00 (1H, m), 8,11 (1H, s), 8,68 (1H, d, J=4.9 Hz), of 8.95 (1H, s), 9,05 (1H, s), the remaining 9.08 (1H, s), 9,76 (1H, s)

[Synthesis example 12] 7-(5-Vinylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(5-Vinylpyridin-3-yl)carbonlimited[5,1-b]thiazole

The ketone compound (a 1.96 g) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 2,77 g of 7-[(5-bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 2.00 g of manganese dioxide. 7-(5-Vinylpyridin-3-yl)carbonlimited[5,1-b]thiazole (285 mg) was obtained in essentially the same manner as described in stage b) of synthesis example 11, except that as the starting compounds used 308 mg of ketone compounds, 240 mg of phenylboronic acid, 116 mg of tetrakis(triphenylphosphine)palladium(0) and mg potassium carbonate.

NMR (CDCl3) δ: 7,20 (1H, d, J=4,1 Hz), 7,45-7,53 (3H, m), of 7.64 (1H, d, J=3,9 Hz), 7,65-of 7.70 (2H, m), 8,10 (1H, s), 9,01 (2H, c), 9,72 (1H, s)

b) 7-(5-Vinylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

7-(5-Vinylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (297 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 275 mg of 7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazole, 0,330 ml of tri-n-butylstannane and 1.80 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.93 (9H, t, J=7,3 Hz), 1,15-1,22 (6H, m), of 1.28 to 1.34 (6H, m), 1,59-of 1.64 (6H, m), 7,37 (1H, t, J=7,3 Hz), 7,41 was 7.45 (3H, m), to 7.67-of 7.70 (2H, m), 8,03 (1H, s), 8,99 (2H, m), RS 9.69 (1H, s)

[Example of synthesis 13] 7-(Thiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(Thiazol-5-yl)carbonlimited[5,1-b]thiazole

7-(Thiazol-5-yl)carbonlimited[5,1-b]thiazole (187 mg) was obtained by the method similar to that described in stage a) of synthesis example 3, except that as the starting compounds used 265 mg of 7-itemids[5,1-b]thiazole and 119 mg thiazole-5-aldehyde.

NMR (CDCl3) δ: 7,18 (1H, d, J=4,1 Hz), a 7.62 (1H, d, J=4,1 Hz), 8,10 (1H, s), 9,03 (1H, s), was 9.33 (1H, s)

b) 7-(Thiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (260 mg) was obtained in essentially the same manner as described in stage c) the application is and the synthesis of 1, except that the starting materials used 187 mg of 7-(thiazol-5-yl)carbonlimited[5,1-b]thiazole, 0,235 ml of tri-n-butylstannane and 1.2 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.90 (9H, t, J=7,3 Hz), 1,22 (6H, m)of 1.35 (6H, m), 1,58 (6H, m), 7,38 (1H, s), 8,02 (1H, s), of 9.02 (1H, s), 9.28 are (1H, s)

[Synthesis example 14] 7-[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole

7-[[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole (4,18 g) was obtained by the method similar to that described in stage a) of example of synthesis 1, except that as the starting compounds used 3,39 g 7 itemids[5,1-b]thiazole and 4.61 in (2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-aldehyde.

NMR (CDCl3) δ: of 0.01 (6H, s)of 0.82 (9H, c), about 1.7-2.3 (2H, m), 3,35-3,7 (2H, m), 4,1-4,2 (1H, m), a 4.3 and 4.4 (1H, m), 4,85-of 4.95 (1H, m), of 5.26 (1H, d, J=13.5 Hz), lower than the 5.37 (1H, d, J=13.5 Hz), the 5.45 is 5.5 (1H, m), 6,82 (1H, d, J=4, 2 Hz), 7,37 (1H, d, J=4, 2 Hz), 7,54 10 (2H, d, J=8.1 Hz), 7,92 (1H, s), 8,24 (2H, d, J=8.1 Hz)

b) 7-[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole

7-[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitro selecterror)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole (to 3.89 g) was obtained by way similar to that described in stage b) of example of synthesis 1, except that as the starting compound used 4,18 g of 7-[[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.08 (6H, s)to 0.89 (9H, s), 2,1-2,2 (1H, m), 2,3-2,5 (1H, m), 3,5-3,6 (1H, m), 3,8-3,9 (1H, m), 4,45-4,55 (1H, m), 4,85 to 5.35 (2H, m), 5,5-5,7 (1H, m), a 7.1 to 7.15 (1H, m), 7,2-of 7.55 (3H, m), a 7.85-8,2 (3H, m)

c) 7-[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (707 mg) was obtained by the method similar to that described in stage c) of example of synthesis 1, except that as the starting compound used 725 mg of 7-[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole. NMR (CDCl3) δ: of 0.07 (6H, s), of 0.8-1.0 (18H, m), 1.1 to 1.4 (12H, m), of 1.5-1.7 (6H, m), from 2.1 to 2.25 (1H, m), 2,35 at 2.45 (1H, m), 3.45 points and 3.6 (1H, m), 3,8-3,9 (1H, m), 4,5-4,6 (1H, m), the 4.9 to 5.3 (2H, m), 5,5-5,7 (1H, m), 7,2-of 7.55 (3H, m), 7,8-of 8.25 (3H, m)

[Synthesis example 15] 7-[[5-(Morpholine-4-yl)methylpyridin-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole

7-[[5-(Morpholine-4-yl)methylpyridin-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole (384 mg) was obtained in essentially the same manner as described in stage a) of synthesis example 5, except that the starting materials used to 1.05 g of 4-(5-bromopyridin-3-yl)metalmorph the ina, 2,70 ml of 1.59 n solution of n-utility in n-hexane and 426 mg of 7-formylamino[5,1-b]thiazole.

NMR (DMSO-d6) δ: of 2.46 (4H, t, J=4.6 Hz), of 3.54 (2H, s), of 3.69 (4H, t, J=4.6 Hz), equal to 6.05 (1H, s)of 6.71 (1H, d, J=4, 2 Hz), 7,34 (1H, d, J=4, 2 Hz), the 7.85 (1H, s), to 7.99 (1H, s), 8,54 (1H, s), 8,61 (1H, s)

[Synthesis example 16] 7-[5-(2-Azidoethyl)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[5-(2-Azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole

7-[5-(2-Azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole (667 mg) was obtained by the method similar to that described in stage a) of synthesis example 3, except that as the starting compounds used 650 g 7 itemids[5,1-b]thiazole and 570 mg of 3-(2-azidoethyl)pyridine-5-aldehyde.

NMR (CDCl3) δ: 3,19 (2H, t, J=7.2 Hz), of 3.56 (2H, t, J=7.2 Hz), 7,20 (1H, d, J=4,1 Hz), the 7.65 (1H, d, J=4,1 Hz), 8,10 (1H, s), 8,76 (1H, m), 8,91 (1H, m), of 9.56 (1H, m)

b) 7-[5-(2-Azidoethyl)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (857 mg) was obtained in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 667 mg of 7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole, 0,603 ml of tri-n-butylstannane and 3.7 ml of a 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: of 0.90 (9H, t, J=7,3 Hz), 1,24 (6H, m)to 1.38 (6H, m), 1,58 (6H, m), 3,18 (2H, t, J=7.2 Hz), of 3.57 (2H, t, J=7.2 Hz), 7,38 (1H, s), of 8.04 (1H, s, 8,76 (1H, m), 8,86 (1H, m), of 9.56 (1H, m)

[Synthesis example 17] 7-[(2S,4S)-4-Azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-[(2S,4R)-4-Hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole

7-[(2S,4R)-4-tert-Butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (1,15 g) was dissolved in 10 ml of a 1.6 n solution of hydrochloric acid in methanol to obtain a solution, which was stirred with cooling on ice for 30 minutes. To the reaction mixture were added an aqueous solution of potassium carbonate, the mixture was extracted with dichloromethane, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation to obtain 853 mg of 7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole.

NMR (CDCl3) δ: 1,90 (1H, m), 2,22 (1H, m), 2,52 (1H, m), 3,66-of 3.78 (1H, m), 3,88 (1H, m), 4,59 (1H, USS), 4,88-5,31 (2H, m), 5,66-5,72 (1H, m), 7,13 (1H, m), 7,22-EUR 7.57 (1H, m), to $ 7.91-8,23 (1H, m)

b) 7-[(2S,4R)-4-Methanesulfonate-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole

For preparation of a solution of 7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole (850 mg) was dissolved in 20 ml of dichloromethane and 7 ml of DMF under cooling in which IDU. To the solution was added triethylamine (0,425 ml) and to 0.19 ml methanesulfonanilide and stirred the mixture for 30 minutes. To the reaction mixture was added water, the mixture was extracted with dichloromethane, and then washed twice with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation to obtain 734 mg of the crude product 7-[(2S,4R)-4-methanesulfonate-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole.

c) 7-[(2S,4S)-4-Azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole

To a solution of 552 mg of 7-[(2S,4R)-4-methanesulfonate-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole in 5 ml of DMF was added sodium azide (87 mg) and the mixture was stirred at 100°C for 13 hours. To the reaction mixture was added water, was extracted with a mixture of ethyl acetate, and then washed three times with saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation to obtain 474 mg of the crude product 7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole.

d) 7-[(2S,4S)-4-Azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Specified in the title compound (321 mg) was obtained in essentially the same is the procedure, as described in stage c) of example of synthesis 1, except that the starting materials used 585 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazole, 0,396 ml of tri-n-butylstannane and 2.8 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF.

NMR (CDCl3) δ: to 0.92 (9H, t, J=7,3 Hz), 1,24 (6H, m)of 1.35 (6H, m), and 1.56 (6H, m), 2,31 (1H, m), 2,80 (1H, m), 3,66 (1H, m), 4,20 (1H, m), 4,95-5,31 (2H, m), 5,39-5,52 (1H, m), 7,29 (1H, m), 7,54 (1H, m), 7,88-7,98 (3H, m), 8,23 (1H, m)

[Example 1] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 1)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

To a solution of 474 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 13 ml of anhydrous acetonitrile in the atmosphere of argon at -30°C was added dropwise N,N-diisopropylethylamine (0,343 ml)and then was added dropwise 0,218 ml anhydrous triftormetilfullerenov acid. The mixture was stirred at this temperature for 30 minutes. Then thereto was added ethyl acetate (30 ml), then successively washed polysystem salt solution, a mixed solution (pH=1,1), composed of Polynesians salt solution and 1 n aqueous solution of hydrochloric acid, mixed the m solution (pH=8,9), composed of Polynesians salt solution and saturated aqueous sodium bicarbonate solution, and polysystem saline. The organic layer was then dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation under reduced pressure. To prepare the solution, the residue was dissolved in 6 ml of anhydrous N-methylpyrrolidinone. To the solution was added tri-2-furifosmin (37 mg), 343 mg of zinc chloride, 37 mg of Tris(dibenzylideneacetone)diplegia(0) and 712 mg of 7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole, and the mixture was stirred at 50°C in argon atmosphere for 2 hours. To the reaction solution were added ethyl acetate (30 ml) and 15 ml Polynesians aqueous solution of sodium carbonate, the mixture was stirred and removing insoluble substances by filtration. The organic layer was separated from the filtrate, washed three times with 20 ml Polynesians salt solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by the method of column chromatography on silica gel (eluent - dichloromethane:methanol=20:1 → 10:1) to give 388 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-the carboxylate.

NMR (DMSO-d6) δ: 1,19 (3H, d, J=6.0 Hz), 1,24 (3H, d, J=7.5 Hz), of 3.45 (1H,DD, J1=6.3 Hz, J2=3.0 Hz), 3,7-of 3.85 (1H, m), 4,0-4,1 (1H, m), and 4.68 (1H, DD, J1=9.9 Hz, J2=3.0 Hz), to 5.17 (1H, d, J=5.4 Hz), 5,41 (1H, d, J=13,8 Hz), of 5.55 (1H, d, J=13,7 Hz), 7,55-the 7.65 (1H, m), 7,74 (2H, d, J=9.0 Hz), by 8.22 (2H, d, J=9.0 Hz), of 8.47 (1H, s)8,64 (1H, s), 8,65 is 8.75 (1H, m), 8,75-8,8 (1H, m), of 9.55 and 9.6 (1H, m)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

For preparation of a solution of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (128,5 mg) was dissolved in 6.7 ml of THF and 6.7 ml of 1/15 M nutrifaster buffer solution (pH of 6.6) was added to a solution of 130 mg of 10% palladium-on-the carbon. In the reaction vessel was filling the air with hydrogen and stirred the contents of the reaction vessel at room temperature for 2 hours. The catalyst was removed by filtration through celite and then washed with water. The filtrate was washed with ethyl acetate and then concentrated under reduced pressure to a volume of approximately 2 ml of the Concentrate was purified by the method of column chromatography on Cosmosil 40C18-PREP (eluent of 5% aqueous solution of methanol) with the receipt of 40.9 mg specified in the connection header.

NMR (D2O) δ (HOD=4,80 ppm): to 1.15 (3H, d, J=7,2 Hz), of 1.33 (3H, d, J=6.3 Hz), 3,45-3,6 (2H, m), 4,2-of 4.35 (2H, m), 7,35-7,45 (1H, m), to $ 7.91 (1H, s), 8,07 (1H, s), 8,25 to 8.3 (1H, m), 8,5-8,55 (1H, m), cent to 8.85-8,9 (1H, m)

Connection№№ 33, 36, 37, 43, 45, 46, 47, 49, 50, 5, 57, 65, 66, 71, 73, 74, 88, 89, 96, 97, 98, 101, 107, 115, 118, 119, 124, 160, 165 and 172 was synthesized by a method similar to that described in example 1.

[Example 2] (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 2)

a) Iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxyla

For the preparation of suspensions 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (105,5 mg) suspended in 2 ml of acetonitrile. To the suspension was added 2-todatetime (340 mg), and stirred the mixture at 50°C for 6 hours. The reaction solution was concentrated under reduced pressure, the concentrate was added 5 ml of ethyl acetate and collected insoluble substances by filtration to obtain 157 mg of iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.20 (3H, d, J=6.3 Hz), 1,25 (3H, d, J=7,2 Hz), 3,47 (1H, DD, J1=6,0 Hz, J2=3.3 Hz), 3.75 to of 3.85 (1H, m), 4,0-4,1 (1H, m), to 4.38 (1H, DD, J1=10,2 Hz, J2=3.3 Hz), 5,42 (1H, d, J=13,8 Hz), 5,5-5,6 (3H, m), 7,7-7,8 (3H, m), 8,08 (1H, USS), by 8.22 (2H, d, J=8.7 Hz), 8,3 an 8.4 (1H, m), to 8.57 (1H, s), 8,69 (1H, s), 9,15-9,2 (1H, m), of 9.55 and 9.6 (1H, is), 9,76 (1H, s)

b) (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt)

Specified in the title compound (31.5 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 145 mg iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): to 1.16 (3H, d, J=7.5 Hz), of 1.33 (3H, d, J=6.0 Hz), 3,4-3,55 (2H, m), 4,15-of 4.35 (2H, m), the 5.65 (2H, s), 7,89 (1H, s), 8,03 (1H, s), of 8.1 to 8.2 (1H, m), cent to 8.85-8,95 (1H, m), 9,15-9,2 (1H, m), 9,58 (1H, s)

Connection№№ 38, 42, 44, 52, 75, 76, 77, 78, 84, 108, 116, 120, 122, 128, 138, 139, 140, 145, 153, 166, 167 and 168 synthesized by a method similar to that described in example 2.

[Example 3] (1S,5R,6S)-2-[7-(1-Benzylpiperidine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 3)

a) Bromide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-benzylpiperidine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

For the preparation of suspensions 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (78,1 mg) suspended in 1.5 ml of acetonitrile. To the suspension was added interbreed (to 0.032 ml) and the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain bromide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-benzylpiperidine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: 1,19 (3H, d, J=6.0 Hz), 1,24 (3H, d, J=6.9 Hz), 3,45-3,5 (1H, m), 3.75 to a 3.9 (1H, m), 4,0-4,1 (1H, m), 4.35, an increase of 4.4 (1H, m), 5,15-5,2 (1H, m), 5,41 (1H, d, J=13,8 Hz), 6,01 (2H, s), 7,25-the 7.65 (5H, m), 7,74 (2H, d, J=8.7 Hz), 8,21 (2H, d, J=8.7 Hz), 8,3 an 8.4 (1H, m), 8,54 (1H, s), 8,67 (1H, s), of 9.3 and 9.4 (1H, m), 9,45-of 9.55 (1H, m), 9,98 (1H, s)

b) (1S,5R,6S)-2-[7-(1-Benzylpiperidine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt)

Specified in the title compound (5.6 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the source of the whole connection was used bromide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-benzylpiperidine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate, received on described immediately above stage (a).

NMR (D2O) δ (HOD=4,80 ppm): from 1.0 to 1.15 (3H, m)of 1.30 (3H, d, J=6.0 Hz), 3,35-3,5 (2H, m), 4,1-4,3 (2H, m), 5,86 (2H, s), 7,4-7,6 (5H, m), a 7.85-8,1 (3H, m), 8,8-9,0 (2H, m), a 9.6 and 9.7 (1H, m)

[Example 4] (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (compound No. 4)

a) Triptorelin ulpanat 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

To prepare the solution, which was then cooled to -60°C in argon atmosphere in 3 ml of dichloromethane was dissolved 60 mg of 3-azido-1-propanol. To the cooled solution was added 2,6-lutidine (0,076 ml) and 0.015 ml triftormetilfullerenov anhydride and the mixture was stirred for 20 minutes. To the reaction mixture were added water and the mixture was extracted with dichloromethane, then washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and removing insoluble substances by filtration. To the filtrate was added 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (310 mg) and the mixture was stirred at room temperature for 3 hours. The reaction solution was added dropwise to 30 ml of diethyl ether and the precipitate was collected by filtration to obtain 452 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)pyridine-3-yl]carbonlimited-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (acetone-d6) δ: of 1.27 (3H, d, J=6.3 Hz), of 1.34 (3H, d, J=7,3 Hz), 2,52 (2H, m), 3,47 (1H, DD, J1=6,4 Hz, J2=3.0 Hz), to 3.67 (2H, t, J=7.0 Hz), 3,81 (1H, m), 4,18 (1H, m), 4,27 (1H, d, J=4.9 Hz), 4,47 (1H, DD, J1=10.0 Hz, J2=3.0 Hz), 5,11 (2H, t, J=7.0 Hz), lower than the 5.37 (1H, d, J=13,7 Hz), to 5.57 (1H, d, J=13,7 Hz), 7,78 (2H, d, J=9.0 Hz), 8,18 (2H, d, J=9.0 Hz), of 8.47 (1H, s), 8,59 (1H, s), 9,39 (1H, m), for 9.64(1H, m), 10,15 (1H, s)

b) (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride)

The reaction was carried out by a method similar to that described in stage b) of example 1, except that as the starting compound used 450 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate. The reaction product was subjected to column chromatography on Cosmosil 40C18-PREP (eluent of 10% aqueous solution of methanol). Faction loireau before, was collected and subjected ionoobmennoi column chromatography (eluent - water) on Amberlyst A-26) to obtain 38 mg specified in the connection header.

NMR (D2O) δ (HOD=4,65 ppm): 1,09 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6.4 Hz), 2,46 (2H, m), 3,14 (2H, m), 3,32-to 3.41 (2H, m)4,06 (1H, DD, J1=9,0 Hz, J2=2,6 Hz), 4,13 (1H, m), to $ 7.91 (1H, s), 8,08 (1H, s)to 8.14 (1H, m), 8,98 (1H, m), 9,12 (1H, m), 9,67 (1H, s)

Connection№№ 32, 62, 64, 70, 82, 86, 87, 90, 91, 99, 103, 121, 129, 130, 131, 135, 136, 137, 141, 142, 144, 146, 147, 149, 150, 151, 152, 154, 155, 156, 157, 158, 159, 161, 162, 163, 164, 170, 171, 174 and 175 synthesized by a method similar to that described in example 4.

[Example 5] (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)-1,4,5,6-tetrahydropyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (the compound is 5)

When performing column chromatography on Cosmosil 40C18-PREP (eluent of 10% aqueous solution of methanol) in stage b) of example 4, fraction, loireau later, collected by receiving 14 mg specified in the connection header.

NMR (D2O) δ (HOD=4,65 ppm): of 1.13 (3H, d, J=7,3 Hz)to 1.21 (3H, d, J=6.3 Hz), of 1.78 (2H, m), of 1.95 (2H, m), of 2.23 (2H, m), 2,95 (2H, m), 3,19 (2H, m)to 3.34 (2H, m), 3,38-3,50 (2H, m), 4,13-is 4.21 (2H, m), 7,82 (1H, (C), of 7.97 (1H, s), of 8.25 (1H, s)

[Example 6] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(1-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 6)

a) Triftorbyenzola 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

For the preparation of suspensions 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (240 mg) suspended in 10 ml of dichloromethane. To the suspension was added methyltrichlorosilane (0,047 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to get 333 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: 1,19 (3H, d, J=6.4 Hz), 1,25 (3H, d, J=7,1 Hz), 3,47 (1H, DD, J1=6,0 Hz, J2=3.0 Hz), with 3.79 (1H, m)4,06 (1H, m), to 4.38 (1H, DD, J1=10 Hz, J2=2,9 Hz), 4,47 (3H, s)to 5.17 (1H, d, J=5,1 Hz), 5,42 (1H, d, J=13,6 Hz), of 5.55 (1H, d, J=13,6 Hz), 7,76 (2H, d, J=9.1 Hz), by 8.22 (2H, d, J=9.1 Hz), 8,32 (1H, m), 8,56 (1H, s), 8,67 (1H, s), 9,16 (1H, m), for 9.47 (1H, m), 9,78 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(1-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt)

Specified in the title compound (36 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 333 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,08 (3H, d, J=7,1 Hz)of 1.20 (3H, d, J=6.3 Hz), 3.33 and-to 3.41 (2H, m), 4,08 (1H, DD, J1=9,3 Hz, J2=2.7 Hz), 4,14 (1H, m), and 4.40 (3H, s), 7,87 (1H, s), of 8.00 (1H, s), 8,03 (1H, s), 8,83 (1H, s), of 9.02 (1H, s), of 9.51 (1H, s)

Connection№№ 39, 41, 51, 59, 112 and 127 was synthesized by a method similar to that described in example 6.

[Example 7] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 7)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)is carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (1.23 g) was obtained by way similar to that described in stage a) of example 1, except that as the starting compounds used to 1.33 g of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 2.00 g of 7-(pyridin-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,2 Hz), of 1.41 (3H, d, J=6.3 Hz), to 3.41 (1H, DD, J1=6,6 Hz, J2=3.0 Hz), 3,5-3,6 (1H, m), a 4.3 and 4.4 (1H, m), and 4.40 (1H, DD, J1=9.6 Hz, J2=3.0 Hz), from 5.29 (1H, d, J=13.5 Hz), 5,54 (1H, d, J=13.5 Hz), 7,69 (2H, d, J=8.7 Hz), of 8.09 (1H, s), of 8.25 (2H, d, J=8.7 Hz), 8,3-8,35 (2H, m), to 8.57 (1H, s), 8,8 cent to 8.85 (2H, m)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (74,4 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 290 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): to 1.16 (3H, d, J=6.3 Hz), of 1.34 (3H, d, J=6.3 Hz), 3,4-3,6 (2H, m), 4,2 -4,35 (2H, m), 7,7-7,8 (2H, m), of 7.96 (1H, s), 8,11 (1H, s), is 8.5 and 8.6 (2H, m)

[Example 8] (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-4-yl)(hydroxy)methylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (mixture of diastereoisomers) (compound No. 8)

a) Iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoyl is terpyridine-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

Iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylbiphenyl-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (426 mg) was obtained by the method similar to that described in stage a) of example 2, except that as the starting compound used 327 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.20 (3H, d, J=6.3 Hz), 1,25 (3H, d, J=7.5 Hz), 3,4-3,5 (1H, m), of 3.7-3.9 (1H, m), 4,0-4,1 (1H, m), 4.35, an increase of 4.4 (1H, m), 5,42 (1H, d, J=13.5 Hz), of 5.50 (2H, s), of 5.55 (1H, d, J=13.5 Hz), 7,7-7,8 (3H, m), 8,08 (1H, s), by 8.22 (2H, d, J=9.0 Hz), 8,54 (1H, s), 8,68 (1H, s), 8,8-8,9 (2H, m), from 9.1 to 9.2 (2H, m)

b) (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-4-yl)(hydroxy)methylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (mixture of diastereoisomers)

The reaction was carried out by a method similar to that described in stage b) of example 1, except that as the starting compound used 426 mg of iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylbiphenyl-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate. The reaction product was subjected to column chromatography on Cosmosil 40C18-PREP (eluent of 5%-20% aqueous solution of methanol). Faction loireau before, was assembled with the receipt of 67.6 mg specified in the connection header.

2O) δ (HOD=4,80 ppm): 1,1-1,25 (3H, m)of 1.29 (3H, d, J=6.3 Hz), 3,4-3,6 (2H, m), 4,2-4,3 (2H, m), the 5.51 (2H, s), 6,28 (1H, s), 7,87 (1H, s), of 8.09 (1H, s), of 8.1 to 8.2 (2H, m), 8,75 cent to 8.85 (2H, m)

[Example 9] (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 9)

When performing column chromatography on Cosmosil 40C18-PREP (eluent of 5%-20% aqueous solution of methanol) in stage b) of example 8, fraction, loireau later, together with the receipt of 29.1 mg specified in the connection header.

NMR (DMSO-d6) δ: 1,1-1,25 (6H, m), 3,1-3,2 (1H, m), 3.45 points and 3.6 (1H, m), 3,9-4,0 (1H, m), 4,05-to 4.15 (1H, m), of 5.05 (1H, d, J=5.7 Hz), 5.5 to 5.7 (2H, m), of 7.75 (1H, s), with 8.33 (1H, s), scored 8.38 (1H, s), to 8.41 (1H, s), 8,98 (2H, d, J=6.6 Hz), 9,26 (2H, d, J=6,6 Hz)

[Example 10] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 10)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (92 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 112 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carbox elata and 165 mg of 7-(4-methylthiazole-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,3 Hz), 2,78 (3H, s), of 3.43 (1H, DD, J1=6,1 Hz, J2=2,8 Hz), 3,76 (1H, m), a 4.03 (1H, m), 4,35 (1H, DD, J1=10 Hz, J2=3.0 Hz), further 5.15 (1H, d, J=5,1 Hz), of 5.40 (1H, d, J=a 13.9 Hz), of 5.53 (1H, d, J=a 13.9 Hz), 7,73 (2H, d, J=8,8 Hz), 8,21 (2H, d, J=8,8 Hz), 8,43 (1H, s), at 8.60 (1H, s), which 9.22 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (21 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 57 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(4-methylthiazole-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): of 1.05 (3H, d, J=7,3 Hz)to 1.22 (3H, d, J=6.3 Hz), 2.49 USD (3H, s)to 3.36 (1H, m), 3,42 (1H, m), 4,13-4,22 (2H, m), to 7.77 (1H, s), 7,88 (1H, s)8,71 (1H, s)

[Example 11] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-((2S)-pyrrolidin-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 11)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]-carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (1.40 g) was obtained by method, the similarity is output as described in stage a) of example 1, except that as starting compounds used 926 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.85 g of 7-[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: 1,25-1,35 (3H, m), 1,35-1,45 (3H, m), 1.85 to-2,5 (4H, m), 3,35 of 3.8 (4H, m), 4,25 to 4.5 (2H, m), 4,8-5,6 (5H, m), of 7.2 to 8.3 (9H, m), and 8.50 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-((2S)-pyrrolidin-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (169 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 451 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(2S)-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): 1,24 (3H, d, J=6.9 Hz), of 1.35 (3H, d, J=6.3 Hz), 2,5-2,2 (3H, m), 2,6-of 2.75 (1H, m), 3,4-of 3.65 (4H, m), 4,2-4,4 (2H, m), of 5.05 was 5.2 (1H, m), with 8.05 (1H, s), 8,17 (1H, s)

[Example 12] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyrimidine-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 12)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrimidine-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrimidine-5-yl)CarbonLib is dazo[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (144 mg) was obtained in essentially the same way, as described in stage a) of example 1, except that as the starting compounds used 180 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 176 mg of 7-(pyrimidine-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6.3 Hz), to 3.41 (1H, DD, J1=6,4 Hz, J2=2,9 Hz), of 3.56 (1H, m), 4,34 (1H, m), 4,43 (1H, DD, J1,=9.8 Hz, J2=2,9 Hz), and 5.30 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,6 Hz), 7,69 (2H, d, J=9.0 Hz), 8,10 (1H, d), to 8.20 (2H, d, J=9.0 Hz), 8,58 (1H, s), 9,37 (1H, s), 9,81 (2H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyrimidine-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (6.9 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that as the starting compound used 57.4 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrimidine-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-the carboxylate.

NMR (DMSO-d6) δ: a 1.11 (3H, d, J=5,9 Hz), of 1.13 (3H, d, J=6.6 Hz), 3,24 (1H, m), of 3.56 (1H, m)to 3.92 (1H, m), is 4.15 (1H, DD, J1=9.8 Hz, J2=2,9 Hz), 5,02 (1H, USS), of 8.37 (1H, s), 8,44 (1H, s), 9,31 (1H, s), 9,56 (2H, s); MS (m/z 440 (M+H)+

[Example 13] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(thiophene-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 13)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydrox is ethyl)-1-methyl-2-[7-(thiophene-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiophene-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (815 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 640 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(thiophene-2-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,3 Hz), 3,43 (1H, DD, J1=6,1 Hz, J2=3 Hz in), 3.75 (1H, m), a 4.03 (1H, m), 4,35 (1H, DD, J1=10 Hz, J2=2,9 Hz), 5,13 (1H, d, J=5,1 Hz), of 5.40 (1H, d, J=a 13.9 Hz), of 5.53 (1H, d, J=a 13.9 Hz), 7,28 (1H, m), to 7.77 (2H, d, J=8,8 Hz), 8,00 (1H, m), 8,21 (2H, d, J=8,8 Hz), 8,44 (1H, s), at 8.60 (1H, m)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(thiophene-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (95 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 170 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiophene-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): a 1.01 (3H, d, J=7,3 Hz)to 1.21 (3H, d, J=6.3 Hz), 3.27 to to 3.36 (2H, m), 4,06-4,18 (2H, m), 6,93 (1H, m), 7,60 (1H, m), 7,68 (1H, s), 7,74 (1H, s), 7,87 (1H, m)

[Example 14] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[7-[5-(hydroxymethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazole-yl]-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 14)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (707 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 509 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 926 mg of 7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.01 (6H, s)0,81 (9H, s)to 1.19 (3H, d, J=7,3 Hz)of 1.27 (3H, d, J=6,1 Hz), 3,26 (1H, DD, J1=6,6 Hz, J2=2,9 Hz), 3,42 (1H, m), 4,19 (1H, m), the 4.29 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), to 4.73 (2H, s), of 5.15 (1H, d, J=13,6 Hz), of 5.39 (1H, d, J=13,6 Hz), 7,55 (2H, d, J=8,8 Hz), 7,94 (1H, s), 8,11 (2H, d, J=8,8 Hz), 8,43 (1H, s), 8,61 (1H, m), 8,66 (1H, m), 9,49 (1H, m)

b) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[5-(hydroxymethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate

To a solution of 563 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(tert-butyldimethylsilyloxy)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate in 8 ml of THF while cooling on ice was added 0,092 ml of acetic acid and 0.79 ml of 1 M solution of Tetra-n-butylammonium in THF, and the mixture was stirred for 6 hours. To the reaction mixture was added water and was extracted with a mixture of ethyl acetate, then washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The residue was purified by the method of column chromatography (eluent - dichloromethane:methanol=1:1) on Sephadex LH-20 to obtain 435 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[5-(hydroxymethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,1 Hz), of 3.45 (1H, m), of 3.77 (1H, m), a 4.03 (1H, m), 4,36 (1H, m), with 4.64 (2H, d, J=5,9 Hz), further 5.15 (1H, d, J=5,1 Hz), of 5.40 (1H, d, J=a 13.9 Hz), 5,46 (1H, t, J=5,9 Hz), 5,54 (1H, d, J=a 13.9 Hz), 7,73 (2H, d, J=8,8 Hz), 8,21 (2H, d, J=8,8 Hz), of 8.47 (1H, s), 8,63 (1H, s), 8,66 (1H, m), 8,71 (1H, m), for 9.47 (1H, m)

c) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[1-[5-(hydroxymethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (15 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 48 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[5-(hydroxymethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): of 1.06 (3H, d, J=7,0 Hz)of 1.20 (3H, d, J=6.3 Hz), to 3.38 (1H, m), 3,47 (1H, m), 4,13-is 4.21 (2H, m), 7,86 (1H, s), 8,03 (1H, s), 8,17 (1H, is), 8,42 (1H, s), 8,78 (1H, s)

[Example 15] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 15)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (499 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 398 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(6-methylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6,4 Hz)of 1.23 (3H, d, J=7,3 Hz), to 2.57 (3H, s), 3,44 (1H, DD, J1=6,0 Hz, J2=2,9 Hz), 3,76 (1H, m), a 4.03 (1H, m), 4,35 (1H, DD, J1=10 Hz, J2=2.7 Hz), further 5.15 (1H, d, J=5,2 Hz), of 5.40 (1H, d, J=13,7 Hz), of 5.53 (1H, d, J=13,7 Hz), 7,44 (1H, m), 7,73 (2H, d, J=8,8 Hz), to 8.20 (2H, d, J=8,8 Hz), to 8.45 (1H, s), 8,61 (1H, s), 8,63 (1H, m), 9,48 (1H, m)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (23 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used is 75 mg of 4-nor is roventil-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-the carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): was 1.04 (3H, d, J=7,1 Hz)to 1.21 (3H, d, J=6,1 Hz), is 2.37 (3H, s), 3,37 (1H, m), of 3.45 (1H, m), 4,14-is 4.21 (2H, m), 7,13 (1H, m), 7,82 (1H, s), of 8.00 (1H, s), 8,08 (1H, m), 8,68 (1H, )

[Example 16] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 16)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (100 mg) was obtained in essentially the same manner as described in stage a) of example 1, except that as the starting compounds used 169 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 179 mg of 7-(5-methylthiopyridine-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: to 1.15 (3H, d, J=7,3 Hz)to 1.22 (3H, d, J=7,1 Hz), 2,60 (3H, s), 3,44 (1H, m), 3,76 (1H, m)to 4.01 (1H, m), 4,35 (1H, DD, J1=6,9 Hz, J2=3.2 Hz), further 5.15 (1H, d, J=5,2 Hz), of 5.40 (1H, d, J=13,7 Hz), 5,52 (1H, d, J=13,7 Hz), 7,72 (2H, d, J=9.0 Hz), to 8.20 (2H, d, J=9.0 Hz), 8,30 (1H, s), of 8.47 (1H, s), to 8.57 (1H, s), 8,68 (1H, s), of 9.30 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (11.6 mg) was obtained on things is actually the same way as described in stage b) of example 1, except that as the starting compound used 93 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: to 1.15 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6.3 Hz), 2,60 (3H, s)and 3.15 (1H, m), 3,44 (1H, m), of 3.95 (1H, m), 4,07 (1H, DD, J1=6,7 Hz, J2=2.7 Hz), free 5.01 (1H, d, J=5.4 Hz), 8,29 (1H, s), 8,32 (1H, s), 8,56 (1H, s), 8,65 (1H, s), 9.28 are (1H, s); MS (m/z 507 (M+Na+H)+

[Example 17] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 17)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (86 mg) was obtained in essentially the same manner as described in stage a) of example 1, except that as the starting compounds used 180 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 185 mg of 7-(quinoline-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.12 (3H, d, J=6.3 Hz), 1,19 (3H, d, J=7,1 Hz)to 3.41 (1H, DD, J1=6,6 Hz, J2=2,9 Hz), to 3.58 (1H, m), 4,35 (1H, m), 4,43 (1H, DD, J1=9.6 Hz, J2=3.0 Hz), and 5.30 (1H, d, J=13,6 Hz) 5,54 (1H, d, J=13,6 Hz), 7,63 (1H, t, J=7,1 Hz), of 7.70 (2H, d, J=9.0 Hz), 7,83 (1H, t, J=7.2 Hz), of 8.04 (1H, d, J=7,3 Hz)to 8.14 (1H, s), 8,18 (1H, d, J=8,3 Hz), 8,24 (2H, d, J=8,9 Hz), 8,61 (1H, s), 9,63 (1H, s), 9,84 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (6.5 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that as the starting compound used 84 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-the carboxylate.

NMR (DMSO-d6) δ: of 1.09 (3H, d, J=7,3 Hz)of 1.11 (3H, d, J=6.4 Hz), 3,14 (1H, m), 3,47 (1H, m), of 3.95 (1H, m), 4.09 to (1H, DD, J1=9.8 Hz, J2=2,9 Hz), 5,02 (1H, USS), 7,71 (1H, t, J=6.8 Hz), of 7.90 (1H, t, J=8.5 Hz), 8,11 (1H, d, J=9.0 Hz), 8,21 (1H, d, J=7.8 Hz), 8,31 (1H, s)of 8.37 (1H, s), for 9.47 (1H, s), 9,73 (1H, s); MS (m/z 511 (M+Na+H)+

[Example 18] (1S,5R,6S)-2-[7-(1-Carbamoylmethyl-6-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 18)

a) Iodide 4-Nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylmethyl-6-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

The crude product (119 mg) iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylmethyl-6-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)--methyl-1-karbapin-2-em-3-carboxylate was obtained by way similar to that described in stage a) of example 2, except that as the starting compounds used 112 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 495 mg of 2-iodated.

b) (1S,5R,6S)-2-[7-(1-Carbamoylmethyl-6-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt)

Specified in the title compound (23 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 119 mg of the crude product iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1-carbamoylmethyl-6-methylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): was 1.04 (3H, d, J=7,1 Hz)to 1.21 (3H, d, J=6,1 Hz), 2,68 (3H, s), 3,23-to 3.35 (2H, m), a 4.03 (1H, m), 4,13 (1H, m), vs. 5.47 (2H, s), of 7.69 (1H, s), 7,80-to 7.84 (2H, m), 8,84 (1H, m), 9,34 (1H with)

[Example 19] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 19)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

7-([3,3']Bipyridinyl-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was synthesized on things is actually the same way as described in stage c) of example of synthesis 1, except that as the starting compounds used 263 mg of 7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazole, 0,316 ml of tri-n-butylstannane and 1,72 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF, and, due to the unstable nature of the compounds of tin, a cleaning method of column chromatography on silica gel did not. 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (80 mg) was obtained in essentially the same manner as described in stage a) of example 1, except that as the starting compounds used 270 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 7-([3,3']bipyridinyl-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.33 (3H, d, J=7,3 Hz)to 1.37 (3H, d, J=6.3 Hz), 3,37 (1H, m)to 3.64 (1H, m), 4,24 (1H, m)to 4.41 (1H, DD, J1=9.6 Hz, J2=3.0 Hz), 5,32 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,4 Hz), 7,52 (1H, m), 7,69 (2H, t, J=8.7 Hz), of 8.06 (1H, m), 8,15 (1H, s), 8,24 (2H, d, J=8.7 Hz), 8,67 (1H, m), of 8.92 (1H, s), 8,99 (1H, s), 9,07 (1H, ), 9,71 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-([3,3']bipyridinyl-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (16,7 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that, as source compounds used 47 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-([3,3']bipyridinyl-5-yl)carbonlimited-[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.18 (6H, d, J=7,3 Hz), 3,23 (1H, m), of 3.57 (1H, m), of 3.97 (1H, m), is 4.15 (1H, m), is 5.06 (1H, d, J=5.4 Hz), 7,46-EUR 7.57 (3H, m), 7,79 (1H, USS), 7,82 (1H, USS), 8,40 (1H, USS), of 8.95 (1H, USS), the remaining 9.08 (1H, USS), 9,49 (1H, OSS); MS (m/z 538 (M+Na+H)+

[Example 20] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 20)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (47 mg) was obtained in essentially the same manner as described in stage a) of example 1, except that as the starting compounds used 270 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 293 mg of 7-(5-vinylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.33 (3H, d, J=7,3 Hz)to 1.37 (3H, d, J=6,1 Hz)to 3.38 (1H, m), of 3.57 (1H, m)to 4.23 (1H, m)to 4.41 (1H, DD, J1=9.6 Hz, J2=2,9 Hz), of 5.34 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,4 Hz), 7,45-of 7.55 (3H, m), 7.68 per-7,73 (4H, m), 8,15 (1H, s), 8,24 (2H, d, J=9,2 Hz), 8,55 (1H, s), 8,97-of 9.02 (2H, m), 65 (1H, C)

b) (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (29,7 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that as the starting compound used 80 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.16 (3H, d, J=6,8 Hz)to 1.19 (3H, d, J=6.4 Hz), 3,14 (1H, DD, J1=6,8 Hz, J2=2,8 Hz), of 3.45 (1H, m), of 3.96 (1H, m), is 4.15 (1H, DD, J1=9.4 Hz, J2=2,4 Hz), 5,02 (1H, d, J=5,2 Hz), 7,46-7,58 (3H, m), 7,79-7,83 (2H, m), 8,31 (1H, s), a 8.34 (1H, s), to 8.94 (1H, USS), 9,07 (1H, d, J=2.0 Hz), 9,48 (1H, d, J=2.0 Hz); MS (m/z 537 (M+Na+H)+

[Example 21] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 21)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (244 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 179 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carb is enum-3-carboxylate and 260 mg of 7-(thiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,3 Hz), 3,43 (1H, DD, J1=6,0 Hz, J2=3.0 Hz), 3,76 (1H, m), a 4.03 (1H, m), 4,35 (1H, DD, J1=10 Hz, J2=2,9 Hz), further 5.15 (1H, d, J=5,1 Hz), of 5.39 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,6 Hz), 7,73 (2H, d, J=8,8 Hz), to 8.20 (2H, d, J=8,8 Hz), 8,48 (1H, s), to 8.62 (1H, s), 9,12 (1H, s), 9,40 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (47 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 114 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): of 1.06 (3H, d, J=7,3 Hz)to 1.22 (3H, d, J=6.3 Hz), 3,37 (1H, DD, J1=6,1 Hz, J2=2,9 Hz), 3,43 (1H, m), 4,14-4,22 (2H, m), to 7.77 (1H, s), of 7.90 (1H, s), to 8.45 (1H, c), 8,98 (1H, s)

[Example 22] (1S,5R,6S)-2-[7-(1,6-Dimethylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 22)

a) Triftorbyenzola 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1,6-dimethylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

For preparation of a solution of 92 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-carbap is n-2-em-3-carboxylate was dissolved under cooling on ice in 4 ml of dichloromethane and added to a solution 0,018 ml methyltrichlorosilane. The mixture was stirred at this temperature for 30 minutes. Then the reaction solution was concentrated under reduced pressure to obtain 110 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1,6-dimethylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.18 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,1 Hz), of 2.86 (3H, s), of 3.45 (1H, m), of 3.77 (1H, m), a 4.03 (1H, m), 4,34 (3H, s), to 4.38 (1H, m), of 5.15 (1H, d, J=5,1 Hz), of 5.40 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,6 Hz), 7,73 (2H, d, J=8,8 Hz), to 8.20 (2H, d, J=8,8 Hz), 8,54 (1H, s), 8,65 (1H, s), was 9.33 (1H, m), 9,76 (1H, m)

b) (1S,5R,6S)-2-[7-(1,6-Dimethylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt)

Specified in the title compound (16 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 110 mg triftoratsetata 4-nitrobenzyl-(1S,5R,6S)-2-[7-(1,6-dimethylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,08 (3H, d, J=7,3 Hz)of 1.20 (3H, d, J=6,1 Hz), 2,73 (3H, s), 3,30 is 3.40 (2H, m), 4,07-4,18 (2H, m), 4,22 (3H, s), 7,78 (1H, s), 7,80 (1H, s), 7,88 (1H, s), 8,77 (1H, m), 9,40 (1H m)

[Example 23] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-((2S,4R)-4-hydroxypyrrolidine-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate (compound No. 23)

p> a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (369 mg) was obtained by the method similar to that described in stage a) of example 1, except that as starting compounds used 312 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 707 mg of 7-[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 0.07, and 0.08 (total 6H, s, each), 0,88, 0,89 (total 9H, s each), 1,25-1,35 (3H, m), 1,35-1,45 (3H, m), 2,1-2,2 (1H, m), 2,35 at 2.45 (1H, m), 3,35-3,6 (3H, m), 3,8-3,9 (1H, m), 4,25-4,6 (3H, m), 4,8-5,6 (5H, m), of 7.2 to 8.3 (9H, m), 8,48, 8,50 (total 1H, s each)

b) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonlimited-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

To a solution of 369 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-tert-butyldimethylsilyloxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate at 0 ml of THF was added acetic acid (0,219 ml) and 1.27mm ml of 1 M solution of Tetra-n-butylammonium in THF, and the mixture was stirred at room temperature for 7 hours. To the reaction mixture were added a saturated salt solution. The mixture was brought to pH=8.2 adding saturated sodium hydrogen carbonate solution and then was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by the method of column chromatography on silica gel (eluent - dichloromethane:methanol=10:1) to give 239 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (CDCl3) δ: 1,25-1,35 (3H, m), 1,35-1,45 (3H, m), 2,15 was 2.25 (1H, m), 2,45 is 2.55 (1H, m), 3,35-3,9 (4H, m), a 4.3 with 4.65 (3H, m), 4,8-5,6 (5H, m), of 7.2 to 8.3 (9H, m), of 8.47, 8,50 (total 1H, s each)

c) (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-((2S,4R)-4-hydroxypyrrolidine-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate

Specified in the header connection (76,3 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 239 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbap is n-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): 1,24 (3H, d, J=6.9 Hz), 1,32 (3H, d, J=6.3 Hz), from 2.1 to 2.25 (1H, m), 2,65 is 2.75 (1H, m), 3,4-3,6 (4H, m), 4,2-of 4.35 (2H, m), 4,7-4,8 (1H, m), 5,2-5,3 (1H, m), of 8.00 (1H, s), 8,08 (1H, s)

[Example 24] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methylinosine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 24)

For preparation of a solution of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinoline-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (93 mg) was dissolved in a mixture of acetonitrile (2.25 ml) and chloroform (0.75 ml). To the solution at room temperature was added methyliodide (0,063 ml) and stirred the mixture at 40°C for 3 days. The reaction solution was poured into diethyl ether to obtain a powder, which was filtered to obtain N-quaternionic connection. Specified in the title compound (7.7 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that as the starting compound used this connection.

NMR (DMSO-d6) δ: of 1.16 (3H, d, J=8,3 Hz)of 1.18 (3H, d, J=6.4 Hz), 3,13 (1H, m), 3,49 (1H, m), of 3.94 (1H, m), 4.09 to (1H, DD, J1=9.6 Hz, J2=3.0 Hz), and 4.75 (3H, s), 5,02 (1H, d, J=5,2 Hz), 8,13 (1H, t, J=7,6 Hz), 8,31 (1H, s), 8,39 (1H, m), to 8.45 (1H, s), 8,58 (1H, d, J=9.0 Hz), 8,71 (1H, d, J=7,6 Hz), 10,15-10,28 (2H, m); MS (m/z 503 (M+H)+

[Example 25] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(morpholine-4-yl)methylpyridin-3-ylcarbonylglycine[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 25)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(morpholine-4-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

7-[5-(Morpholine-4-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazole (312 mg) was obtained in essentially the same manner as described in stage b) of example of synthesis 1, except that as the starting compounds used 384 mg of 7-(hydroxy)[5-(morpholine-4-yl)methylpyridin-3-yl]methylimidazo[5,1-b]thiazole and 200 mg of manganese dioxide. The corresponding connection tin synthesized in essentially the same manner as described in stage c) of example of synthesis 1, except that the starting materials used 407 mg of this compound, 0,450 ml of tri-n-butylstannane and 2.46 ml of 1.0 n solution of bis(trimethylsilyl)amide lithium in THF, and, due to the unstable nature of the compounds of tin, a cleaning method of column chromatography on silica gel did not. 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(morpholine-4-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (250 mg) was obtained in essentially the same manner as described in stage a) of example 1, except that in as starting compounds used 400 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and the compound of tin.

NMR (CDCl3)δ equivalent : 1.33 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6,1 Hz)of 2.50 (4H, USS), 3,40 (1H, DD, J=6,6 Hz, 2.9 Hz), of 3.56 (1H, m), 3,63 (2H, s), and 3.72 (4H, t, J=4.6 Hz), 4,33 (1H, m), 4,43 (1H, DD, J1=9.6 Hz, J2=3.0 Hz), from 5.29 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,4 Hz), 7,69 (2H, d, J=9.0 Hz), of 8.09 (1H, s), 8,24 (2H, d, J=8,8 Hz), 8,71 (1H, USS), 8,73 (1H, USS), 9,65 (1H, USS)

b) (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(morpholine-4-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (40,4 mg) was obtained in essentially the same manner as described in stage b) of example 1, except that as the starting compound used 101 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(morpholine-4-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: to 1.15 (3H, d, J=6,8 Hz)of 1.18 (3H, d, J=6.3 Hz), 2.40 a (4H, USS), 3,14 (1H, DD, J1=7,1 Hz, J2=2.7 Hz), 3,43 (1H, m), 3,52 (4H, t, J=4.6 Hz), of 3.54 (2H, s), of 3.94 (1H, m), 4,08 (1H, DD, J1=9,3 Hz, J2=2.7 Hz), 5,02 (1H, d, J=5,1 Hz), 8,30 (1H, s), with 8.33 (1H, s), 8,58 (1H, s), 8,67 (1H, s), 9,48 (1H, s); MS (m/z 560 (M+Na+H)+

[Example 26] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methyl-5-phenylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 26)

N-Quaternization compound (84 mg) was obtained in essentially the same way as described in example 24, except that as the source with the joining was used 97 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 0,063 ml methyliodide. Specified in the header connection (20,3 mg) was obtained in essentially the same manner as described in stage c) of example 1, except that as the starting compound used this connection.

NMR (DMSO-d6) δ: to 1.15 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6.3 Hz), 3,13 (1H, m), of 3.43 (1H, m), of 3.94 (1H, m), 4,07 (1H, m), 4,46 (3H, s), of 5.03 (1H, d, J=5,1 Hz), to 7.59-to 7.68 (3H, m), 7,94 (2H, d, J=8.0 Hz), 8,29 (1H, USS), 8,40 (1H, OSS), to 9.57 (1H, OSS), to 9.70 (2H, OSS); MS (m/z 529 (M+H)+

[Example 27] (1S,5R,6S)-2-[7-(1-Carbamoylmethyl-5-phenylpyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 27)

N-Quaternization compound (91 mg) was obtained in essentially the same way as described in example 24, except that as the starting compounds used 97 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-vinylpyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 185 mg of 2-iodated. Specified in the header connection (16,7 mg) was obtained in essentially the same manner as described in stage c) of example 1, except that as the starting compound used this connection.

NMR (DMSO-d6) δ: to 1.15 (3H, d, J=7,6 Hz)to 1.19 (3H, d, J=6.2 Hz), 3,14 (1H, DD, J1=7,2 Hz, J2=2,4 Hz), 3,37 (1H, m), of 3.94 (1H, m), 4.09 to (1H, DD, J1=8.6 Hz, J2=2.7 Hz), 5,02 (1H, d, J=5,2 Hz), to 5.58 (2H, s), 7,62-of 7.69 (3H, m), 7,2 (2H, d, J=7,6 Hz), 8,31 (1H, s), 8,40 (1H, s)to 9.57 (1H, USS), RS 9.69 (1H, USS), 9,82 (1H, OSS); MS (m/z 572 (M+H)+

[Example 28] (1S,5R,6S)-2-[7-[5-(2-aminoacetic)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 28)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (370 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 485 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 857 mg of 7-[5-(2-azidoethyl)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,3 Hz)of 1.42 (3H, d, J=6.4 Hz), 3,19 (2H, t, J=7,0 Hz)to 3.41 (1H, DD, J1=6,0 Hz, J2=3.0 Hz), 3,52-of 3.60 (3H, m)to 4.33 (1H, m), 4,43 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), and 5.30 (1H, d, J=13,6 Hz)5,54 (1H, d, J=13,6 Hz), 7,69 (2H, d, J=8,8 Hz), of 8.09 (1H, s), of 8.25 (2H, d, J=8,8 Hz), 8,56 (1H, s), 8,78 (1H, m), of 8.90 (1H, m), of 9.56 (1H, m)

b) (1S,5R,6S)-2-[7-[5-(2-aminoacetic)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (40 mg) was obtained in a manner similar to OPI the data in stage b) of example 1, except that as the starting compound used 128 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): a 1.01 (3H, d, J=7,0 Hz)to 1.19 (3H, d, J=6.4 Hz), 3,18 (4H, m), 3,30-3,37 (2H, m), 4,06-4,16 (2H, m), to 7.67 (1H, s), 7,80 (1H, s), of 8.04 (1H, s), 8,21 (1H, s), and 8.50 (1H, s)

[Example 29] (1S,5R,6S)-2-[7-((2S,4S)-4-Aminopyrrolidine-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (compound No. 29)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

The crude compound (261 mg), 4-nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate was obtained in a manner similar to those described in the example except as source compounds used 157 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 321 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

b) (1S,5R,6S)-2-[7-((2S,4S)-4-Aminopyrrolidine-2-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxyl the t

Specified in the title compound (23 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 130 mg of the crude compound 4-nitrobenzyl-(1S,5R,6S)-2-[7-[(2S,4S)-4-azido-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): to 1.11 (3H, d, J=7,1 Hz)to 1.21 (3H, d, J=6.4 Hz), 2,13 (1H, m), of 2.97 (1H, m), and 3.31 (1H, m), 3,40 (2H, m), of 3.60 (1H, m), 4,07 (1H, m), 4,17 (2H, m)to 4.92 (1H, m), 7,89 (1H, s), of 8.06 (1H, s)

[Example 30] (1S,5R,6S)-2-[7-[5-(2-aminoethanesulfonic)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 30)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

To 5 ml of a solution of 112 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate in dichloromethane while cooling on ice was added 123 mg of meta-chloroperbenzoic acid and the mixture was stirred for 4 hours. To the reaction mixture was added aqueous sodium thiosulfate solution and the mixture was extracted with dichloromethane, then washed with saturated saline solution. The organic layer was dried over anhydrous Sul is blockhead magnesium and solvent was removed by distillation. The residue was purified by the method of column chromatography (eluent - dichloromethane:methanol=1:1) on Sephadex LH-20 to obtain 70 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (CDCl3) δ: of 1.33 (3H, d, J=7,3 Hz)to 1.38 (3H, d, J=6.3 Hz), of 3.56 (2H, t, J=5,5 Hz)and 3.59 (1H, m), 3,81-to 3.89 (3H, m)to 4.23 (1H, m), 4,42 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), 5,32 (1H, d, J=13,6 Hz), of 5.53 (1H, d, J=13,6 Hz), 7,69 (2H, d, J=9,0), to 8.14 (1H, s), 8,24 (2H, d, J=9.0 Hz), charged 8.52 (1H, s), 9,27 (1H, m), 9,44 (1H, m), 9,92 (1H, m)

b) (1S,5R,6S)-2-[7-[5-(2-aminoethanesulfonic)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (10 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 69 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,10 (3H, d, J=7,3 Hz)to 1.21 (3H, d, J=6.3 Hz), 3,38-to 3.50 (4H, m), 3,83 (2H, t, J=7.0 Hz), 4,13-4,22 (2H, m), 7,88 (1H, s), 8,03 (1H, s), 8,83 (1H, m), 9,04 (1H, m), 9,26 (1H, m,)

[Example 31] (1S,5R,6S)-2-[7-[5-(2-Aminoacetic)-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (compound No. 31)

a) Iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

Iodide 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (140 mg) was obtained by the method similar to that described in stage a) of example 2, except that as the source compounds used 114 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and 312 mg of 2-iodated.

NMR (DMSO-d6) δ: 1,19 (3H, d, J=6,1 Hz)of 1.24 (3H, d, J=7,3 Hz), of 3.46 (1H, DD, J1=6,0 Hz, J2=2,9 Hz), 3,51 (2H, t, J=6.4 Hz), to 3.73 (2H, t, J=6.4 Hz), of 3.78 (1H, m), Android 4.04 (1H, m), 4,37 (1H, DD, J1=10.0 Hz, J2=2,9 Hz), 5,16 (1H, d, J=5,1 Hz), 5,41 (1H, d, J=13,6 Hz), of 5.48 (2H, s)5,54 (1H, d, J=13,6 Hz), 7,71-to 7.77 (3H, m), of 8.04 (1H, USS), 8,21 (2H, d, J=8,8 Hz), 8,55 (1H, s), 8,68 (1H, s), of 9.21 (1H, m), 9,46 (1H, m), of 9.51 (1H, m)

b) (1S,5R,6S)-2-[7-[5-(2-Aminoacetic)-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride)

Specified in the title compound (13 mg) was obtained by the method similar to that described in stage b) of example 4, except that as the starting compound used 140 mg nd the Dida 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,08 (3H, d, J=7,1 Hz)to 1.19 (3H, d, J=6,1 Hz), 3,29 (2H, d, J=6.5 Hz), 3.33 and-3,55 (4H, m), of 4.05 (1H, m), 4,13 (1H, m), 5,49 (2H, s), 7,86 (1H, s), of 7.97 (1H, s), 8,84 (1H, s), 9,11 (1H, s), of 9.30 (1H, s)

[Example 32] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[7-(isoquinoline-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 34)

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(isoquinoline-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate was synthesized in essentially the same way as described in example 1, except that as the starting compounds used 324 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 358 mg of 7-(isoquinoline-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole. Specified in the header of the connection (of 22.3 mg) was synthesized from 72,8 mg this connection.

NMR (DMSO-d6) δ: of 1.09 (3H, d, J=7,0 Hz)of 1.12 (3H, d, J=6,1 Hz), of 3.07 (1H, DD, J1=6,8 Hz, J2=2.7 Hz), to 3.36 (1H, m), a 3.87 (1H, m)to 4.01 (1H, DD, J1=9,3 Hz, J2=2,4 Hz), of 4.95 (1H, d, J=5,1 Hz), to 7.68 (1H, t, J=7.8 Hz), 7,76 (1H, m), 8,16-8,19 (3H, m), 8,21 (1H, s), 8,96 (1H, s), 9,39 (1H, s)

[Example 33] (1S,5R,6S)-2-[7-(1-carbamoylmethyl-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 35)

Specified in the title compound (19.9 mg) was synthesized in essentially the same way as described in the example 2, except that as the starting compound used 93,0 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(isoquinoline-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δwith 1.07 (3H, d, J=7,1 Hz)of 1.11 (3H, d, J=6,1 Hz), of 3.07 (1H, m), and 3.31 (1H, m), 3,86 (1H, m), was 4.02 (1H, m), 4,94 (1H, d, J=5.4 Hz), the 5.51 (2H, s), of 6.96 (1H, m), 6,98 (1H, m), 7,22 (1H, s), 7,56 (1H, s), 8,06-8,23 (3H, m), 8,51 (1H, d, J=8,3 Hz), 9,11 (1H, s)

[Example 34] (1S,5R,6S)-2-[7-(1-Carbamoylmethyl-5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 40)

Specified in the header connection (38,0 mg) was synthesized in essentially the same way as described in example 2, except that as the starting compound used 155 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-methylthiopyridine-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.09 (3H, d, J=7,0), is 1.11 (3H, d, J=6,1 Hz)to 2.67 (3H, s), is 3.08 (1H, m)to 3.35 (1H, m), a 3.87 (1H, m)to 4.01 (1H, DD, J1=9.5 Hz, J2=2.7 Hz), 4,96 (1H, d, J=5,1 Hz), 5,43 (2H, s), to 7.67 (1H, USS), 8,03 (1H, USS), 8,23 (1H, s), 8,31 (1H, s), 8,99 (1H, USS), of 9.30 (1H, USS), 9,41 (1H, USS)

[Example 35] (1S,5R,6S)-2-[7-[1-((2R)-3-Amino-2-hydroxypropyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (the connection is giving No. 48)

a) Triftorbyenzola 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-((2R)-3-azido-2-triethylsilanol)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

The crude compound (398 mg) triftorbyenzola 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-((2R)-3-azido-2-triethylsilanol)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate was obtained by the method similar to that described in stage a) of example 4, with the exception that as the starting compounds used 255 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and (2R)-3-azido-2-triethylchlorosilane.

b) (1S,5R,6S)-2-[7-[1-((2R)-3-Amino-2-hydroxypropyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride)

For preparation of a solution of the crude compound (398 mg) triftorbyenzola 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-((2R)-3-azido-2-triethylsilanol)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate was dissolved in 12 ml of THF and 12 ml of water. The solution was brought to pH=2.2 adding 1 n hydrochloric acid and was stirred for 24 hours. The solution was brought to pH=5 d is by the addition of 5% aqueous solution of sodium bicarbonate, and carried out the reaction in a manner similar to described in stage b) of example 4. Thus, the received 56 mg specified in the connection header.

NMR (D2O) δ (HOD=4,65 ppm): was 1.04 (3H, d, J=7,3 Hz)of 1.18 (3H, d, J=6.4 Hz), is 3.08 (1H, m), 3,23-3,39 (3H, m), was 4.02 (1H, DD, J1=9,0 Hz, J2=2,4 Hz), 4,13 (1H, m), 4,43 (1H, m), 4,55 (1H, m), 4,94 (1H, m), to 7.77 (1H, s), of 7.90 (1H, s), 8,08 (1H, m), 8,89 (1H, m), 9,18 (1H, m), 9,58 (1H, s)

[Example 36] (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(piperidine-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 53)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzylidene)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzylidene)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (1,16 g) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 938 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and at 1.91 g of 7-[1-(4-nitrobenzylidene)piperidine-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.30 (3H, d, J=7,2 Hz), of 1.40 (3H, d, J=6.3 Hz), a 1.7-2.1 (4H, m), to 3.0-3.2 (2H, m), 3,35-3,4 (1H, m), 3,4-3,6 (1H, m), up 3.6-3.7 (1H, m), 4,2-4,4 (3H, m)to 4.41 (1H, DD, J1=9.9 Hz, J2=2.7 Hz), of 5.24 (2H, s), 5,27 (1H, d, J=13.5 Hz), 5,52 (1H, d, J=13.5 Hz), 7,2 (2H, d, J=8.7 Hz), to 7.67 (2H, d, J=9.0 Hz), 8,01 (1H, s), and 8.2 and 8.3 (4H, m), 8,51 (1H, s)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(piperidine-4-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (142 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 344 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzylidene)piperidine-4-yl]carbonlimited-[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): to 1.21 (3H, d, J=6,9 Hz)of 1.33 (3H, d, J=6.3 Hz), of 1.8-2.0 (2H, m), 2.05 is-with 2.2 (2H, m), 3,1-of 3.25 (2H, m), 3,25-3,6 (5H, m), 4,2-of 4.35 (2H, m), 7,92 (1H, s), 8,02 (1H, s)

[Example 37] (1S,5R,6S)-2-[7-[5-(2-amino-ethyl)thio-1-carboxymethylamino-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 54)

Specified in the title compound (12 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that used in stage a) of example 4 3-azido-1-propanol and 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate was replaced by 63 mg of 4-nitrobenzisoxazole and 168 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dipyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-arbain-2-em-3-carboxylate, respectively.

NMR (D2O) δ (HOD=4,65 ppm)with 1.07 (3H, d, J=7,3 Hz)to 1.19 (3H, d, J=6.6 Hz), 3.25 to 3,37 (4H, m), of 3.45 (2H, m), Android 4.04 (1H, DD, J1=9.4 Hz, J2=2.3 Hz), 4,13 (1H, m), 5,18 (2H, m), 7,80 (1H, s), a 7.85 (1H, s), 8,76 15 (1H, s), 8,97 (1H, s), 9,19 (1H, s)

[Example 38] (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 58)

a) 4-Nitrobenzyl-(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (469 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 400 mg 4-nitrobenzyl-(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 700 mg of 7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.41 (3H, d, J=6.3 Hz), 3,34-of 3.46 (3H, m), 4,29-4,43 (2H, m), of 5.34 (1H, d, J=13,6 Hz), to 5.57 (1H, d, J=13,6 Hz), 7,45 (1H, m), 7,72 (2H, d, J=8,8 Hz), of 8.09 (1H, s), compared to 8.26 (2H, d, J=8,8 Hz), 8,51 (1H, s), 8,72 cent to 8.85 (2H, m), 8,75 cent to 8.85 (1H, m), 9,72 (1H, m)

b) (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)-carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (50 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used mg 4-nitrobenzyl-(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): to 1.16 (3H, d, J=6.3 Hz), 2,95 (2H, m), 3,24 (1H, m)to 4.01 (1H, m), 4.09 to (1H, m), 7,24 (1H, m), 7,54 (1H, s), to 7.84 (1H, s), 8,13 (1H, m), at 8.36 (1H, m), 8,77 (1H, m)

[Example 39] (5R,6S)-2-[7-(1-Carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 60)

Specified in the title compound (32 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that in stage a) of example 2 111 mg of 4-nitrobenzyl-(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate was used instead of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): to 1.15 (3H, d, J=6.4 Hz), 2,99 (2H, m), or 3.28 (1H, m), of 3.97 (1H, m), 4.09 to (1H, m), of 5.50 (2H, m), 7,58 (1H, s), to $ 7.91 (1H, s), 8,03 (1H, m), 8,78 (1H, m), 9,06 (1H, m), of 9.51 (1H, s)

[Example 40] (1S,5R,6S)-2-[7-(1-Carboxyethylidene-3-yl)-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 63)

Specified in the title compound (25 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 185 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-is roximate and 95 mg of 4-nitrobenzisoxazole.

NMR (D2O) δ (HOD=4,65 ppm): of 1.13 (3H, d, J=7,3 Hz)of 1.20 (3H, d, J=6.3 Hz), 3,40 (1H, m), 3,49 (1H, m), 4,12-4,22 (2H, m), of 5.24 (2H, s), of 8.00 (1H, s), of 8.09 (1H, m)to 8.14 (1H, s), 8,82 (1H, m), 9,10 (1H, m,), 9,52 (1H, s)

[Example 41] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetimidate[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 67)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-(7-chloroacetamido[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-(7-chloroacetamido[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (1.01 g) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 2.85 g of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.66 g of 7-chloroacetyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: 1,19 (3H, d, J=6.3 Hz), of 1.23 (3H, d, J=7,2 Hz), 3,4-of 3.45 (1H, m), of 3.7-3.8 (1H, m), 3.95 to a 4.1 (1H, m), a 4.3 and 4.4 (1H, m)to 4.92 (2H, s), of 5.39 (1H, d, J=13,8 Hz), 5,52 (1H, d, J=13,8 Hz), 7,74 (2H,, d, J=9.0 Hz), 8,21 (2H, d, J=9.0 Hz), scored 8.38 (1H, s), at 8.60 (1H, s)

b) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetimidate[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

For preparation of a solution of 4-nitrobenzyl-(1S,5R,6S)-2-(7-chloroacetamido[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (161 mg) was dissolved in 5 ml of acetone. To the solution was added to the Oded Hagai sodium (67 mg) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added a saturated saline solution and was extracted with a mixture of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation and to prepare the solution the residue was dissolved in 5 ml of N,N-dimethylformamide. The solvent was added pyrrolidine (0,03 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a saturated saline solution and was extracted with a mixture of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation and washed the residue with diethyl ether to obtain 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetimidate[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: 1,15-1,25 (6H, m), 1,7-1,8 (4H, m), 2,6-of 2.75 (4H, m), 3,4-of 3.45 (1H, m), of 3.7-3.8 (1H, m), 3,85 of 4.1 (2H, m), a 4.3 and 4.4 (1H, m), of 5.39 (1H, d, J=13,8 Hz), 5,52 (1H, d, J=13,8 Hz), 7,72 (2H, d, J=8,7 Hz), 8,21 (2H, d, J=8.7 Hz), 8,32 (1H, s), 8,54 (1H, s)

c) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetimidate[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (41.7 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 200 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetimidate[5,1-b]thiazol-2-yl]-1-karbapin-2-em-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): of 1.23 (3H, d, J=6.9 Hz), of 1.35 (3H, d, J=6.3 Hz), 2.1 to a 2.2 (4H, m), 3,4-3,7 (6H, m), 4,25-4,4 (2H, m), 4,7-4,8 (2H, m), to 7.93 (1H, s)to 8.14 (1H, s)

Connection№№ 55, 61, 72, 93, 95, 111 and 113 was synthesized by a method similar to that described in example 41.

[Example 42] (1S,5R,6S)-2-[7-[5-(2-amino-ethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 68)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (457 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 461 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 856 mg of [7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6.3 Hz), 2,62 (2H, t, J=6,7 Hz)to 3.41 (1H, DD, J1=6,6 Hz, J2=3.0 Hz), of 3.48 (2H, t, J=6,7 Hz), 3,57 (1H, m), 3,88 (2H, s), 4,34 (1H, m), 4,43 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), and 5.30 (1H, d, J=13,7 Hz)5,54 (1H, d, J=13,7 Hz), 7,69 (2H, d, J=9.0 Hz), 8,10 (1H, s), of 8.25 (2H, d, J=9.0 Hz), 8,58 (1H, s), a total of 8.74 (1H, m), 8,81 (1H, m), 9,63 (1H, m)

b) (1S,5R,6S)-2-[7-[5-(2-amino-ethyl)thiomethyl ridin-3-yl]-carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (19 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 96 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 0,99 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6,1 Hz)to 2.67 (2H, t, J=6,7 Hz), 3,10 (2H, t, J=6,7 Hz), 3,28-to 3.35 (2H, m), 3,62 (2H, s), 4,05-4,16 (2H, m), to 7.67 (1H, s), 7,81 (1H, s), 8,03 (1H, s), by 8.22 (1H, s), 8,49 (1H, s)

[Example 43] (1S,5R,6S)-2-[7-[5-(2-amino-ethyl)thiomethyl-1 carboxymethylamino-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 69)

Specified in the title compound (9 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 105 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and 45 mg of 4-nitrobenzisoxazole.

NMR (D2O) δ (HOD=4,65 ppm): 1,10 (3H, d, J=6,8 Hz)of 1.18 (3H, d, J=6.3 Hz), of 2.72 (2H, t, J=6.8 Hz), to 3.09 (2H, t, J=6.8 Hz), 3,36-to 3.49 (2H, m)to 3.99 (2H, s), 4,10-4,17 (2H, m), 5,19 (2H, s), 7,95 (1H, s), 8,08 (1H, s), 8,87 (1H, s), 9,11 (1H, s), 9,38 (1H, s)

[Example 44] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-[5-(piperazine-1-yl)methylpyridin-3-yl]carbon is imidazo[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 80)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-[4-(4-nitrobenzenesulfonyl)piperazine-1-yl]methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-[4-(4-nitrobenzenesulfonyl)piperazine-1-yl]methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (172 mg) was obtained by the method similar to that described in stage a) of example 1, except that as a source of compounds used 337 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 780 mg of 7-[5-[4-(4-nitrobenzenesulfonyl)piperazine-1-yl]methylpyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,1 Hz)of 1.41 (3H, d, J=6.3 Hz), a 2.45 (4H, m)to 3.41 (1H, DD, J1=6.3 Hz, 5 J2=2,9 Hz), 3,54 (5H, m), 3,66 (2H, s)to 4.33 (1H, m), of 4.44 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), 5,23 (2H, s), and 5.30 (1H, d, J=13.3 Hz), 5,54 (1H, d, J=13.3 Hz), to 7.50 (2H, d, J=8,8 Hz), 7,69 (2H, d, J=8,9 Hz), of 8.09 (1H, s), by 8.22 (2H, d, J=8,8 Hz), of 8.25 (2H, d, J=8,9 Hz), to 8.57 (1H, s), 8,69 (1H, DD, J1=2.1 Hz, J2=2.0 Hz), a total of 8.74 (1H, d, J=2.1 Hz), 9,67 (1H, d, J=2.0 Hz)

b) (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(piperazine-1-yl)methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (59 mg) was obtained by the method similar to that described in stage b) of example 1, except that ka is este starting compound used 172 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-[4-(4-nitrobenzenesulfonyl)piperazine-1-yl]methylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD =4,65 ppm): of 1.03 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6,1 Hz)to 2.66 (4H, m), 3,15 (4H, m), 3.33 and-of 3.43 (2H, m), of 3.56 (2H, s), 4.09 to to 4.16 (2H, m), to 7.77 (1H, s), 7,89 (1H, s)to 8.12 (1H, m), 8,30 (1H, m), 8,66 (1H, m)

[Example 45] (1S,5R,6S)-2-[7-[5-(2-amino-ethyl)thiomethyl-1 carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (compound No. 81)

Specified in the title compound (9 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that as the starting compound used 114 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(2-azidoethyl)dimethylpyridin-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,10 (3H, d, J=7,3 Hz)of 1.18 (3H, d, J=6.4 Hz), of 2.72 (2H, t, J=6.6 Hz), 3,11 (2H, t, J=6.6 Hz), 3,37 (1H, m), of 3.45 (1H, m)to 4.01 (2H, s), 4,10-to 4.15 (2H, m), the 5.51 (2H, s), 7,98 (1H, s), 8,11 (1H, s), 8,93 (1H, s), 9,19 (1H, s), 9,46 (1H, s)

[Example 46] (1S,5R,6S)-2-[7-[3-(4-Ethylpiperazin-1-yl)propionyl]imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 83)

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[3-(thiomorpholine-4-yl)propionyl]imidazo[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate was synthesized in essentially the same way as described in example 1, except that as the starting compounds used 2,52 g of 4-nitro nil-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 2.30 g of 7-[3-(thiomorpholine-4-yl)propionyl]-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole. This compound was treated with meta-chloroperbenzoic acid and then ethylpiperazine for the synthesis of 4-nitrobenzyl-(1S,5R,6S)-2-[7-[3-(4-ethylpiperazin-1-yl)propionyl]imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate. Specified in the header of the connection (of 33.4 mg) was synthesized from 164,9 mg this connection.

NMR (DMSO-d6) δ: 0,99 (3H, t, J=7.0 Hz), with 1.07 (3H, d, J=7,3 Hz), 1,10 (3H, d, J=6.3 Hz), 2,43-2,60 (8H, m), 2,68 (4H, USS), 2,96 (2H, m)of 3.00 (1H, m), 3,39 (1H, m), 3,85 (1H, m), was 4.02 (1H, m), equal to 4.97 (1H, d, J=5.4 Hz), 8,08 (1H, s), 8,15 (1H, s)

Compound No. 46 and 85 was synthesized by a method similar to that described in example 46.

[Example 47] (1S,5R,6S)-2-[7-[5-(3-Aminopropyl)thio-1-carbamoylbiphenyl-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (compound No. 92)

Specified in the title compound (10 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that as the starting compound used 141 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[5-(3-azithromy)dipyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 1,09 (3H, d, J=7,3 Hz)of 1.17 (3H, d, J=6.4 Hz), from 2.00 (2H, m), of 3.07 (2H, t, J=7,7 Hz), up 3.22 (2H, t, J=7.2 Hz), 3,35-3,47 (2H, m), 4,07-4,17 (2H, m), 5,46 (2H, s), 7,94 (1H, s), 8,07 (1H, s), is 8.75 (1H, s), 9,01 (1H, s), 9.28 are (1H, s)

[Example 48] (1S,5R,6S)-6-((1R)-1-Hydrox is ethyl)-1-methyl-2-[5-phenyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 94)

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-phenyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate was synthesized in essentially the same way as described in example 1, except that as the starting compounds used 480 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 417 mg of 5-phenyl-7-(pyridin-3-yl)-carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole. Specified in the header connection (48,0 mg) was synthesized from 97,0 mg this connection.

NMR (DMSO-d6) δwith 1.07 (3H, d, J=7,1 Hz)of 1.11 (3H, d, J=6,1 Hz)to 3.09 (1H, m), 3,63 (1H, m), 3,91 (1H, m), a 4.03 (1H, m), 4,96 (1H, d, J=5.6 Hz), 7,45 (1H, m), 7,52-of 7.55 (3H, m), of 7.96 (2H, d, J=8.6 Hz), 8,40 (1H, s), 8,72 (1H, s), 8,73 (1H, s), 9,59 (1H, s)

[Example 49] (1S,5R,6S)-2-[5-Chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 100)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (712 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 474 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-is carboxylate and 730 mg of 5-chloro-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.35 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6.3 Hz), 3,42 (1H, DD, J1=6,6 Hz, J2=3.0 Hz), 3,57 (1H, m), 4,34 (1H, m), 4,43 (1H, DD, J1=9.7 Hz, J2=2.7 Hz), 5,31 (1H, d, J=13,4 Hz)to 5.56 (1H, d, J=13,4 Hz), 7,46 (1H, m), of 7.69 (2H, d, J=8.7 Hz), of 8.25 (2H, d, J=8.7 Hz), a 8.34 (1H, s), 8,77-8,84 (2H, m)9,68 (1H, m)

b) (1S,5R,6S)-2-[5-Chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (49 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 91 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-the carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 0,97 (3H, d, J=7,1 Hz)to 1.19 (3H, d, J=6.4 Hz), 3,26-3,37 (2H, m), 4,07-4,17 (2H, m), 7,20 (1H, m), EUR 7.57 (1H, s), 8,08 (1H, m), of 8.37 (1H, m), 8,73 (1H, m)

[Example 50] (1S,5R,6S)-2-[5-Chloro-7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 102)

Specified in the title compound (76 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that as the starting compound used 185 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D O) δ (HOD=4,65 ppm): to 0.89 (3H, d, J=6.5 Hz), of 1.13 (3H, d, J=6,1 Hz), 3,05 is 3.23 (2H, m), 3,91 (1H, m), of 4.05 (1H, m), of 5.39 (2H, s), 7,42 (1H, s), 7,82 (1H, m), 8,66 (1H, m), 8,91 (1H, m), 9,14 (1H, )

[Example 51] (1S,5R,6S)-2-[7-(1-Carboxyethylidene-3-yl)carbonyl-5-phenylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 104)

Specified in the title compound (47.0 mg) was synthesized in essentially the same way as described in stages a) and b) of example 4, except that as the starting compounds used 130 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-phenyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 4-nitrobenzisoxazole.

NMR (DMSO-d6) δ: of 1.06 (3H, d, J=7,1 Hz)of 1.16 (3H, d, J=6.3 Hz), 3,11 (1H, DD, J1=6,6 Hz, J2=2,4 Hz), the 3.65 (1H, m), of 3.94 (1H, m)4,00 (1H, DD, J1=9.5 Hz, J2=2.7 Hz), 5,04 (1H, d, J=5.4 Hz), 5,64 (1H, d, J=15,8 Hz), of 5.81 (1H, d, J=15,8 Hz), 7,49-7,58 (3H, m), to 7.77 (1H, USS), 8,03 (2H, d, J=8.6 Hz), 8,30 (1H, s), 8,35 (1H, m), 8,44 (1H, USS), 9,14 (1H, d, J=6,1 Hz), 9,54 (1H, d, J=8,3 Hz), for 9.95 (1H, s)

[Example 52] (1S,5R,6S)-2-[5-(4-Dimethylaminophenyl)-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 105)

4-Nitrobenzyl-(1S,5R,6S)-2-[5-(4-dimethylaminophenyl)-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate was synthesized on), the Wu in the same way, as described in example 1, except that as the starting compounds used 486 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 348 mg of 5-(4-dimethylaminophenyl)-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole. Specified in the header connection (to 44.0 mg) was synthesized from 104 mg of this compound.

NMR (DMSO-d6) δwith 1.07 (3H, d, J=7,0 Hz)of 1.11 (3H, d, J=6.4 Hz), to 2.94 (6H, s)to 3.09 (1H, DD, J1=6,6 Hz, J2=2,4 Hz)and 3.59 (1H, m), 3,88 (1H, m)to 4.01 (1H, DD, J1=9.5 Hz, J2=2.7 Hz), 4,96 (1H, d, J=5.6 Hz), to 6.80 (2H, d, J=9.0 Hz), EUR 7.57 (1H, m), of 7.75 (2H, d, J=8,8 Hz), a 8.34 (1H, m), 8,70-8,72 (2H, m), 9,59 (1H, s)

[Example 53] (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-3-yl)carbonyl-5-(4-dimethylaminophenyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 106)

Specified in the header connection (35,0 mg) was synthesized in essentially the same way as described in example 2, except that as the starting compound used 138 mg 4-nitrobenzyl-(1S,5R,6S)-2-[5-(4-dimethylaminophenyl)-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.05 (3H, d, J=7,0 Hz)of 1.17 (3H, d, J=6.4 Hz), 3,01 (6H, s), 3,11 (1H, DD, J1=6,6 Hz, J2=2,7 Hz)and 3.59 (1H, m)to 3.92 (1H, m)to 3.99 (1H, m), 5,02 (1H, d, J=5.4 Hz), 5,63 (1H, d, J=15,4 Hz), 5,86 (1H, d, J=15,4 Hz), 6,82 (2, C), 7,78 (1H, USS), 7,81 (2H, d, J=8,8 Hz), 8,32 (1H, s), 8,53 (1H, USS), 9,13 (1H, d, J=6,1 Hz), 9,48 (1H, d, J=8,3 Hz), 9,98 (1H, s)

[Example 54] (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid (hydrochloride) (compound No. 109)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (862 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 658 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and of 1.16 g of 7-[1-(3-azithromy)piperidine-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.30 (3H, d, J=6.3 Hz), of 1.40 (3H, d, J=6.4 Hz), 1,78-2,02 (6H, m), and 2.14 (2H, m), of 2.45 (2H, t, J=7,1 Hz), 2,99 (2H, m)to 3.35 (2H, t, J=6.9 Hz), 3,37 of 3.56 (3H, m), 4,32 (1H, m)to 4.41 (1H, DD, J1=9.8 Hz, J2=2.7 Hz), 5,27 (1H, d, J=13,6 Hz), the 5.51 (1H, d, J=13,6 Hz), to 7.67 (2H, d, J=8.7 Hz), 8,00 (1H, s), 8,24 (2H, d, J=8.7 Hz), 8,51 (1H, s)

b) (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylic acid (hydrochloride)

Specified in the title compound (94 mg) was obtained FPIC is BOM, similar to that described in stage b) of example 1, except that as the starting compound used 862 mg 4-nitrobenzyl-(1S,5R,6S)-2-[7-[1-(3-azithromy)piperidine-4-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): to 1.11 (3H, d, J=7,0 Hz)to 1.19 (3H, d, J=6.3 Hz), to 1.79 (2H, m)to 2.06 (4H, m), 2.95 and-3,20 (6H, m), 3,36-the 3.65 (5H, m), is 4.15 (1H, m), 4,20 (1H, DD, J1=9,3 Hz, J2=2.7 Hz), 7,86 (1H, s), of 7.96 (1H, s)

[Example 55] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium (compound No. 110)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (1.78 g) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 1.10 g of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.88 g of 5-methylthio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6,1 Hz)of 2.75 (3H, s), 3,40 (1H, DD, J1,=6,5 Hz, J2=2,8 Hz), 3,57 (1H, m)to 4.33 (1H, m), 4,43 (1H, DD, J1=9.7 Hz, J2=2,8 Hz), and 5.30 (1H, d, J13,4 Hz), to 5.56 (1H, d, J=13,4 Hz), 7,46 (1H, m), of 7.69 (2H, d, J=8,8 Hz), of 8.25 (2H, d, J=8,8 Hz), with 8.33 (1H, s), 8,76-8,84 (2H, m), 9,83 (1H, m)

b) (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (37 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 108 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-the carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 0,99 (3H, d, J=7,0 Hz)to 1.21 (3H, d, J=6,1 Hz), 2,42 (3H, s), 3,28-3,39 (2H, m), 4,10-4,19 (2H, m), 7,25 (1H, m), 7,56 (1H, s)8,23 (1H, m), of 8.37 (1H, m), 8,87 (1H, m)

[Example 56] (1S,5R,6S)-2-[7-(1-Carbamoylbiphenyl-3-yl)carbonyl-5-methylthioribose[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 114)

Specified in the title compound (9 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that as the starting compound used 162 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: of 1.13 (3H, d, J=6,8 Hz)to 1.19 (3H, d, J=6,1 Hz)to 2.67 (3H, s)and 3.15 (1H, DD, J1=6,8 Hz, J2=2.7 Hz), 3,66 (1H, m), of 3.97 (1H, m), 4,10 (1H, DD, J1=9,3 Hz, J =2.7 Hz), 5,07 (1H, d, J=5,1 Hz), the ceiling of 5.60 (1H, d, J=15.7 Hz), of 5.83 (1H, d, J=15.7 Hz), 7,20 (1H, s), 7,74 (1H, s), a 8.34 (1H, m), to 8.45 (1H, s), 9,14 (1H, m), 9,50 (1H, m), 9,87 (1H, s)

[Example 57] (1S,5R,6S)-2-[5-Formyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 117)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[5-formyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[5-formyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (1.12 g) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 1.04 g of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.56 g of 5-formyl-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.37 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6.3 Hz), 3,42 (1H, DD, J1,=6,4 Hz, J2=3.0 Hz), of 3.69 (1H, m), 4,34 (1H, m), of 4.45 (1H, DD, J1=9.7 Hz, J2=2,9 Hz), 5,33 (1H, d, J=13,4 Hz), to 5.57 (1H, d, J=13,4 Hz), 7,51 (1H, m), of 7.69 (2H, d, J=8,8 Hz), of 8.25 (2H, d, J=8.7 Hz), 8,82-8,89 (2H, m), of 8.92 (1H, s), 9,83 (1H, m), 9,88 (1H, s)

b) (1S,5R,6S)-2-[5-Formyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (54 mg) was obtained by the method similar to that described in stage b) of example except that as the starting compound used 209 mg 4-nitrobenzyl-(1S,5R,6S)-2-[5-formyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): a 1.01 (3H, d, J=7,1 Hz)to 1.21 (3H, d, J=6.3 Hz), 3,30 is-3.45 (2H, m), 4,10-4,19 (2H, m), 7,34 (1H, m)to 8.12 (1H, s), 8,31 (1H, m), 8,48 (1H, m), 8,98 (1H, s), 9,40 (1H, s)

[Example 58] (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)-5-carboxybenzene-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride) (compound No. 123)

a) 4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzenesulfonyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzenesulfonyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (97,2 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 98 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 198 mg of 7-[5-(4-nitrobenzenesulfonyl)pyridine-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,2 Hz), of 1.41 (3H, d, J=6.3 Hz), to 3.41 (1H, DD, J1=6.3 Hz, J2=2.7 Hz), 3,5-of 3.65 (1H, m), 4.25 in and 4.4 (1H, m), of 4.44 (1H, DD, J1=9.6 Hz, J =2.7 Hz), from 5.29 (1H, d, J=13.5 Hz), 5,54 (1H, d, J=13.5 Hz), 5,54 (2H, s), and 7.6 to 7.75 (4H, m), 8,11 (1H, s), and 8.2 and 8.3 (4H, m), to 8.57 (1H, m), and 9.4 and 9.5 (2H, m), 9,9-9,95 (1H, m)

b) (1S,5R,6S)-2-[7-[1-(3-Aminopropyl)-5-carboxybenzene-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt, hydrochloride)

Specified in the title compound (11.5 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 97,2 mg 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzenesulfonyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 27.0 mg 3 azido-1-propanol.

NMR (D2O) δ (HOD=4,80 ppm)with 1.07 (3H, d, J=7.5 Hz), of 1.26 (3H, d, J=6.3 Hz), 2,5-2,7 (2H, m), the 3.2 and 3.4 (4H, m), 4,0-4,3 (2H, m), 4,8-5,0 (2H, m), 7,82 (1H, s), 7,98 (1H, s)to 9.15 (1H, s), which 9.22 (1H, s), RS 9.69 (1H, s)

[Example 59] (1S,5R,6S)-2-[5-Acetyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 125)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)-carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (112 mg) was obtained by the method similar to that described in stage a) of example 1, except that in kachestvuimportnym compounds were applied 269 mg 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 437 mg of 5-acetyl-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: 1,15-1,25 (6H, m), 2,68 (3H, s), 3,45-3,5 (1H, m), 3,8-of 3.95 (1H, m), 4,0-4,1 (1H, m), 4.35, an increase of 4.4 (1H, m), 5,38 (1H, d, J=13,8 Hz), the 5.51 (1H, d, J=13,8 Hz), and 7.6 to 7.75 (3H, m), 8,17 (2H, d, J=8,7 Hz), 8,75-8,9 (3H, m), 9,6-9,65 (1H, m)

b) (1S,5R,6S)-2-[5-Acetyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the header connection (18,8 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 112 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-the carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): a 1.01 (3H, d, J=6,9 Hz)of 1.34 (3H, d, J=6.3 Hz), of 2.33 (3H, s), 3,2-3,4 (2H, m), 4,1-4,3 (2H, m), 7,25-to 7.35 (1H, m), 7,88 (1H, s), 8,25 to 8.3 (1H, m), 8,45 to 8.5 (1H, m), 8,98 (1H, C)

[Example 60] (1S,5R,6S)-2-[5-Acetyl-7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 126)

Specified in the title compound (1.5 mg) was obtained in a manner similar to described in stages a) and b) of example 2, except that as the starting compound used to 52.1 mg 4-nitrobenzyl-(1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): 1,00 (3H, d, J=6.9 Hz), is 1.31 (3H, d, J=6.6 Hz), 247 (3H, C), 3,2-3,4 (2H, m), 4,0-4,3 (2H, m), to 5.66 (2H, s), 7,94 (1H, s), 8,15-of 8.25 (1H, m), 8,9-9,0 (1H, m), of 9.3 and 9.4 (1H, m)9,52 (1H, s)

[Example 61] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[5-methylthio-7-[1-(3-sulfamoylbenzoyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 132)

Specified in the title compound (41 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 222 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 166 mg of 3-(4-nitrobenzenesulfonyl)aminopropanol.

NMR (D2O) δ (HOD=4,65 ppm): 1,00 (3H, d, J=7,1 Hz)of 1.18 (3H, d, J=6.3 Hz), 2,14-of 2.27 (4H, m)to 3.09 (2H, t, J=6.3 Hz), 3,23-to 3.35 (2H, m), Android 4.04 (1H, m), 4,13 (1H, m)and 4.65 (2H, m), 7,49 (1H, s), of 7.96 (1H, m,), 8,83 (1H, m), 8,91 (1H, m), of 9.51 (1H, s)

[Example 62] (1S,5R,6S)-2-[5-Chloro-7-[1-(3-sulfamoylbenzoyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 133)

Specified in the title compound (64 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 218 mg 4-nitrobenzyl-(1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carb is pen-2-em-3-carboxylate and 160 mg of 3-(4-nitrobenzenesulfonyl)aminopropanol.

NMR (D2O) δ (HOD=4,65 ppm)with 1.07 (3H, d, J=7,1 Hz)to 1.19 (3H, d, J=6.3 Hz), 2,24 (2H, m)to 3.09 (2H, t, J=6.3 Hz), 3,29-to 3.41 (2H, m), 4,05-4,17 (2H, m), 4.72 in (2H, m), 7,71 (1H, s), to 7.99 (1H, m), 8,88 (1H, m,), of 9.00 (1H, m), 9,41 (1H, s)

[Example 63] (1S,5R,6S)-2-[7-(1-Carboxyethylidene-3-yl)carbonyl-5-phenylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 134)

Specified in the header connection (19,0 mg) was synthesized in essentially the same way as described in example 4, except that as the starting compounds used 115 mg nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-phenyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate and 4-nitrobenzimidazole.

NMR (DMSO-d6) δ: of 1.12 (3H, d, J=6,8 Hz)of 1.17 (3H, d, J=6,1 Hz), 3,14 (1H, DD, J1=6,6 Hz, J2=2,4 Hz), 3,71 (1H, m), of 3.94 (1H, m), 4,07 (1H, DD, J1=9,3 Hz, J2=2.7 Hz), free 5.01 (1H, d, J=5.4 Hz), of 5.05 (2H, s), 7,51-to 7.59 (3H, m), with 8.05 (2H, d, J=6.8 Hz), 8,23 (1H, m), 8,44 (1H, s), of 9.00 (1H, d, J=6,1 Hz), of 9.51 (1H, d, J=8,3 Hz), to 9.70 (1H, s)

[Example 64] (1S,5R,6S)-2-[5-Carbarnoyl-7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 143)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[5-carbarnoyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate 4-Nitrobenzyl-(1S,5R,6S)-2-[5-carbarnoyl--(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (239 mg) was obtained by way similar to that described in stage a) of example 1, except that as the starting compounds used 210 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 342 mg of 5-carbarnoyl-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: 1,15-1,25 (6H, m), 3,45-3,5 (1H, m), 3,8-3,9 (1H, m), 4,0-4,1 (1H, m), 4.35, an increase of 4.4 (1H, m), 5,16 (1H, d, J=4,8 Hz), of 5.40 (1H, d, J=13.5 Hz), of 5.53 (1H, d, J=13.5 Hz), 7,55-the 7.65 (1H, m), 7,72 (2H, d, J=9.0 Hz), 7,86 (1H, USS), 8,19 (2H, d, J=9.0 Hz), a 8.34 (1H, USS), 8,8 cent to 8.85 (1H, m), 8,95-9,0 (1H, m), 9,65 of 9.7 (1H, m)

b) (1S,5R,6S)-2-[5-Carbarnoyl-7-(1-carbamoylbiphenyl-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-C-carboxylate (intramolecular salt)

Specified in the title compound (8.6 mg) was obtained in a manner similar to described in stages a) and b) of example 1, except that as the starting compound used 95 mg 4-nitrobenzyl-(1S,5R,6S)-2-[5-carbarnoyl-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,80 ppm): 0,9-1,1 (3H, m), 1,25-1,35 (3H, m), 3,2-3,4 (2H, m), 4,0-4,3 (2H, m), 5,6-5,8 (2H, m), 7,7-7,8 (1H, m), 8,0-8,2 (1H, m), 8,8-9,0 (1H, m), 9,2-9,4 (2H, m), and 9.4 and 9.5 (1H, m)

[Example 65] (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-[7-[1-(2-sulfamoylbenzoyl)pyridine-3-yl]carbonyldiimidazole[5,1-b]thiazol-2-yl]-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 148)

At asanee the title compound (101 mg) was obtained by way similar to the one described in stages a) and b) of example 4, except that as the starting compound used 572 mg of 2-(4-nitrobenzenesulfonyl)aminoethanol instead of the 3-azido-1-propanol at a stage a) of example 4 and 585 mg of 4-nitrobenzyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonlimited[5,1-b]thiazole-2-yl]-1-karbapin-2-em-3-carboxylate.

NMR (DMSO-d6) δ: 1,14-to 1.21 (6H, m), and 3.16 (1H, DD, J1=6,0 Hz, J2=2,6 Hz), 3,42 is 3.57 (3H, m), of 3.95 (1H, m), 4.09 to (1H, DD, J1=9.5 Hz, J2=2.7 Hz), 4,84 (2H, m), 5,07 (1H, d, J=4, 2 Hz), to 6.80 (2H, s), 7,29 (1H, USS), of 8.27 (1H, s), 8,32 (1H, m), 8,35 (1H, s), 9,14 (1H, m)9,52 (1H, s), 9,78 (1H, s)

[Example 66] (1S,5R,6S)-2-[5-(2-amino-ethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound No. 173)

a) 4-Nitrobenzyl-(1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate

4-Nitrobenzyl-(1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (853 mg) was obtained by the method similar to that described in stage a) of example 1, except that as the starting compounds used 910 mg of 4-nitrobenzyl-(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.59 g of 5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylaniline[5,1-b]thiazole.

NMR (CDCl3) δ: of 1.34 (3H, d, J=7,3 Hz)of 1.41 (3H, d, J=6.4 Hz), the 3.35 (2H, t, J=6.5 Hz), to 3.41 (1H, DD, J1=6,6 Hz, J2=2.7 Hz), 3,57 (1H, m), 3,68 (2H, t, J=6.5 Hz), 4,33 (1H, m), 4,43 (1H, DD, J1=9.7 Hz, J2=2.7 Hz), 5,31 (1H, d, J=13,4 Hz)to 5.56 (1H, d, J=13,4 Hz), 7,47 (1H, m), of 7.69 (2H, d, J=8,8 Hz), of 8.25 (2H, d, J=8,8 Hz), scored 8.38 (1H, s), 8,76-8,88 (2H, m), 9,78 (1H, m)

b) (1S,5R,6S)-2-[5-(2-amino-ethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium

Specified in the title compound (42 mg) was obtained by the method similar to that described in stage b) of example 1, except that as the starting compound used 110 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate.

NMR (D2O) δ (HOD=4,65 ppm): 0,98 (3H, d, J=7,3 Hz)to 1.22 (3H, d, J=6,1 Hz), 3.33 and-3,44 (6H, m), 4,13-4,22 (2H, m), 7,25 (1H, m), of 7.70 (1H, s), 8,10 (1H, m), 8,19 (1H, m), 8,82 (1H, m)

[Example 67] (1S,5R,6S)-2-[5-(2-amino-ethyl)thio-7-(1-carboxyethylidene-3-yl)carbonlimited[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate (intramolecular salt) (compound No. 169)

Specified in the title compound (63 mg) was obtained in a manner similar to described in stages a) and b) of example 4, except that as the starting compounds used 220 mg of 4-nitrobenzyl-(1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonlimited[5,1-b]thiazol-2-the l]-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate and 85 mg of 4-nitrobenzisoxazole.

NMR (D2O) δ (HOD =4,65 ppm): of 1.06 (3H, d, J=7,3 Hz)to 1.19 (3H, d, J=6.4 Hz), 3,32-of 3.46 (6H, m), 4,10-4,19 (2H, m), of 5.24 (2H, s), 7,81 (1H, s), 8,00 (1H, m), 8,79 (1H, m), 8,98 (1H, m), for 9.64 (1H, s)

Connection No. 1 - 175 has the following chemical structure.

[Example 1 drug] Drug for injection

To obtain injectable compound of example 1 in aseptic conditions distributed by the bubbles in the amount of 1000 mg (titer) on the bubble.

[Example of preparation 2] a Soft capsule for rectal introduction

Olive oil160 parts (title)
Lauric simple ester of polyoxyethylene10 parts (title)
Hexadecanoate sodium5 parts (title)

To obtain soft capsules for rectal administration of the compound of example 1 in the amount of 250 parts (titer) was added to a homogeneous basis consisting of the above ingredients, mixed with her until smooth and filled in soft capsules in the amount of 250 mg (titer) on the capsule.

[Test example 1] Antibiotic activity

The minimum inhibiting concentration (MIC, μg/ml) of compounds characteristic among the new derivatives carbapenems of the present invention, various pathogenic microorganisms was measured in accordance with the method described in CHEMOTHERAPY, vol. 16, No. 1, 99, 1968. The results are presented in table 1. Culture medium for measurement was Sensitivity Disk agar-N + 5% horse blood, and the amount of inoculum was 106CFU/ml

Table 1
The tested microorganismsConnection example 1The compound of example 2The compound of example 39ConnectionConnectionConnection
S. aureus 209P

JC-1
<0,008<0,0080,0080,016<0,0060,008
S. aureus M*10,50,25 11,564
S. aureus M HR*42186,2564
S. pneumoniae PRC9**0,0310,0310,0310,0630,10,25
B. catarrhalis W-05000,0160,0160,0310,031<0,0250,063
H. influenzae PRC440,0310,0310,0630,0310,18
E. coli NIHJ JX-210,0310,0310,1253,130,125
K. pneumoniae PCI60210,0630,0310,253,130,25
*strain, hyperresonant to the action of methicillin

**strain, hyperresonant to the action of penicillin

Compound a: (1S,5R,6S)-2-(7-acetylimidazole[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound of example 134 in published international application WO 98/32760)

Compound B: (1S,5R,6S)-2-(7-benzoimidazol[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-karbapin-2-em-3-carboxylate sodium (compound of example 37 published in the international the Noi application WO 00/06581)

Connection C: Imipenem

Derivatives carbapenem, which are the compounds represented by formulas (I) and (II) of the present invention, have a high antibiotic activity against various pathogenic microorganisms, including MRSA, PRSP, influenza virus and producing β-lactamase organisms.

Derivatives carbapenem, which are the compounds represented by formulas (I) and (II) of the present invention, will undoubtedly surpass compound A and compound B, which are proposed in an earlier application derived carbapenem, particularly in relation to antibiotic activity against hyperresonance to the action of methicillin Staphylococcus aureus.

[Test example 2] therapeutic effect

therapeutic effect of the compounds characteristic among the new derivatives carbapenems of the present invention, in infected MRSA mice was evaluated according to the following method, and the results are presented in table 2. Specifically, mice (n=8) were injected intraperitoneally cyclophosphamide (200 mg/kg), and later, 4 days after the administration of cyclophosphamide mice infected by MRSA intraperitoneal introduction Staphylococcus aureus MF126 (MRSA). After two hours and four hours after infection the mice were injected subcutaneously cilastatin (1 mg/mouse) and the connection carbapenem in the specified Koli is este. ED50was calculated on the basis of survival on the seventh day after infection (see table 2).

Table 2
ED50,

mg/mouse
The number of seed: 2.5 x 106CFU/mouse

The compound of example 37
0,139
The amount of inoculum: 2.8 x 106CFU/mouse

The compound of example 2
0,07
The compound of example 110,25
Vancomycin0,50
The amount of inoculum: 2.9 x 106CFU/mouse

The compound of example 39
0,02
The amount of inoculum: 5,9 x 106CFU/mouse

The compound of example 65
0,32
Vancomycin0,71

Derivatives carbapenem, which are the compounds represented by formulas (I) and (II) of the present invention, had a significantly better therapeutic effect in vivo, compared with vancomycin, used as a common terapevticheskii means against MRSA.

[Test example 3] the Test for acute toxicity

The compound of example 1 was intravenously injected into mice (males line ICR, each group consisted of the PEX mice) in an amount of 2000 mg/kg As a result, all mice survived.

[Test example 4] the Test for acute toxicity

The compound of example 2 was intravenously injected into mice (males line ICR, each group consisted of three mice) in an amount of 1000 mg/kg as a result, all mice survived.

1. The compound represented by formula (I)or its pharmaceutically acceptable salt:

where R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom;

halogen atom;

carbarnoyl;

aryl, optionally substituted amino group, optionally substituted by one or two lower alkyl groups;

(lower alkyl)togroup, where the alkyl part of the (lower alkyl)diography optionally substituted amino group; or

formyl;

n is an integer from 0 to 4, and

Hy is a 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms and sulfur

moreover, saturated or unsaturated heterocyclic group, represented Hy, optionally substituted

a halogen atom;

lower alkyl, where the Dean or more hydrogen atoms of the lower alkyl group optionally substituted by the groups selected from the group consisting of hydroxyl; carbamoyl; amino; N,N-di(lower alkyl)amino; optionally substituted aryl amino group; a 6-membered monocyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atoms and oxygen; carboxyl; aminosulfonyl; amino(lower alkyl)diography;

(lower alkyl)diography, where one or more hydrogen atoms of the alkyl groups optionally substituted amino group;

(lower alkyl)sulfonium, where one or more hydrogen atoms of the alkyl groups optionally substituted amino group;

carboxyla;

amino group;

by aryl; or

6-membered monocyclic heterocyclic group containing one or more nitrogen atoms.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom;

halogen atom;

carbarnoyl;

aryl; or

(lower alkyl)togroup, where the alkyl part of the (lower alkyl)diography optionally substituted amino group;

n is an integer from 0 to 4, and

y represents a 4-7-membered monocyclic or 9-10-membered bicyclic saturated or unsaturated heterocyclic group, containing 1-4 heteroatoms selected from the group consisting of nitrogen atoms and sulfur

moreover, saturated or unsaturated heterocyclic group, represented Hy, optionally substituted

a halogen atom;

lower alkyl, where one or more hydrogen atoms of the lower alkyl group optionally substituted by groups selected from the group consisting of hydroxyl, carbamoyl, amino, aryl, and monocyclic heterocyclic groups containing one or more heteroatoms selected from the group consisting of nitrogen atoms and oxygen;

(lower alkyl)diography, where one or more hydrogen atoms of the alkyl groups optionally substituted amino group;

(lower alkyl)sulfonium, where one or more hydrogen atoms of the alkyl groups optionally substituted amino group;

by aryl; or

6-membered monocyclic heterocyclic group containing one or more nitrogen atoms.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a hydrogen atom,

halogen atom,

carbarnoyl,

optionally substituted aryl,

optionally substituted (lower alkyl)togroup, or

formyl,

n is an integer from 0 to 2, and

Hy is a group selected from the group consisting of optionally substituted pyridinyl, optionally substituted (pyridine)yl, optionally substituted tetrahydropyridine, optionally substituted thiazolyl, optionally substituted pyrimidinyl, optionally substituted tanila, optionally substituted chinoline, optionally substituted (hineline)yl, optionally substituted izochinolina, optionally substituted dihydroisoquinolyl, optionally substituted piperazinil, optionally substituted piperidinyl, optionally substituted of indolyl, optionally substituted thiomorpholine, optionally substituted of imidazolyl and optionally substituted pyrrolidinyl.

4. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, where

R1represents a hydrogen atom or methyl,

R2and R3that may be the same or different, each represents a

a hydrogen atom,

halogen atom,

carbarnoyl,

aryl, or

optionally substituted (lower alkyl)togroup,

n is an integer from 0 to 4, and

Hy made the focus of a group, selected from the group consisting of optionally substituted pyridinyl, optionally substituted (pyridine)yl, optionally substituted tetrahydropyridine, optionally substituted thiazolyl, optionally substituted pyrimidinyl, optionally substituted tanila, optionally substituted chinoline, optionally substituted (hineline)silt and optionally substituted pyrrolidinyl.

5. The compound represented by formula (II), or its pharmaceutically acceptable salt:

where R1represents methyl,

R2and R3each represents a hydrogen atom;

n is 0,

Hy is a 4-7-membered monocyclic unsaturated heterocyclic group containing nitrogen atom, and the heterocyclic group represented Hy, optionally substituted lower alkyl, where one or more hydrogen atoms of the lower alkyl group optionally substituted by carbamoyl.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where

Deputy aryl group, optionally presents R2and R3is N,N-di(lower alkyl)amino group, and Deputy saturated or unsaturated heterocyclic ring represented Hy is lower alkyl, the optional is tion substituted carbamoyl, the phenyl, AMINOPHENYL, N,N-di(lower alkyl)amino group, amino group, hydroxyl, morpholinium, carboxyla, amino(lower alkyl)diography, aminosulphonylphenyl, piperidinium; pyridinyl; amino group; carboxyl; optionally substituted amino (lower alkyl)tighrope; amino(lower alkyl)tighrope; amino(lower alkyl)sulfonyl.

7. The compound according to claim 1 or 5, where

R1represents a hydrogen atom or methyl,

R2and R3represent a hydrogen atom,

n is 0, and

Hy represents (pyridine)silt containing carbamoylmethyl in its 1st position.

8. The compound according to claim 1, where n is equal to 0.

9. The compound according to claim 1, where R1represents methyl, and R2and R3represent a hydrogen atom.

10. The compound according to claim 1, where

R1represents methyl,

R2and R3represent a hydrogen atom,

n is 0, and

Hy represents (pyridine)yl, optionally containing in its 1st position carbarnoyl(lower alkyl), carboxy(lower alkyl) or aminosulfonyl(lower alkyl), and amino(lower alkyl)togroup in any position other than the 1st position.

11. The compound according to claim 1 or 5, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, the Hy represents a pyridin-3-yl.

12. The compound according to claim 1 or 5, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carbamoylbiphenyl-3-yl.

13. The compound according to claim 1 or 5, where R1, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carbamoylbiphenyl-3-yl.

14. The compound according to claim 1, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a 1-carbamoylmethyl-5-phenylpyridine-3-yl.

15. The compound according to claim 1 or 5, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a (2S)-pyrrolidin-2-yl.

16. The compound according to claim 1, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents 1 carboxymethylamino-3-yl.

17. The compound according to claim 1, where R1represents methyl, R2and R3represent a hydrogen atom, n is 0, and Hy represents a 1-(2-aminosulphonylphenyl)pyridine-3-yl.

18. Pharmaceutical composition having antibiotic activity containing a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according p, which additionally contains additives for whom the courthouse square.

20. The pharmaceutical composition according p or 19 for use as antibiotic drugs.

21. The use of compounds according to any one of claims 1 to 17 or its pharmaceutically acceptable salt for the manufacture of a pharmaceutical composition according to any one of p-20.

22. The method of treatment and/or prevention of infectious diseases caused by gram-positive and gram-negative bacteria, including the stage of introduction of mammals, including humans, a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry of natural compounds, pharmacy.

SUBSTANCE: invention relates to derivatives of mutilins of the formula (I): wherein R means hydrogen atom or alkyl; R1 means group of the formula: wherein X means sulfur or oxygen atom, -NR10 or -N+(R'10)2; R9 means amino-group, alkyl, aryl, heterocyclyl or mercapto-group, and if X means oxygen atom then hydrogen atom represents the additional value for R9; R2 means phenylene; R4 means hydrogen atom or alkyl; R5 means hydrogen atom or alkyl; each among R3, R'3, R7 and R8 means independently of one another hydrogen or deuterium atom; or R and R2 in common with nitrogen atom to which they are bound form 5- or 6-membered ring; R1 means group of the formula: . Also, invention describes pharmaceutical composition based on compounds of the formula (I), method for treatment of diseases caused by microorganisms, and using these compounds as antibacterial agents in medicine and veterinary science.

EFFECT: valuable medicinal and veterinary properties of compounds and pharmaceutical composition.

12 cl, 2 tbl, 52 ex

FIELD: medicine, pediatric gastroenterology.

SUBSTANCE: the present innovation deals with selecting children with functional dyspepsia at helicobacteriosis for the purpose to carry out anti-helicobacter therapy. So, one should detect the following signs in a child: hypertrophic gastropathy in gastric antral department, relapses of dyspepsia symptoms during 1 yr and more, despite treatment by applying antacids and anti-secretory preparations, inheritance on ulcerous disease, previously observed erosions in gastroduodenal area; and in case of any of the above-mentioned signs in a child it is necessary to fulfill anti-helicobacter therapy, and in case of the absence of the above-mentioned signs this therapy should not be carried out. This innovation provides differentiated approach to therapy, it, also, enables to avoid groundless medicinal loading upon a child and decrease financial expenses for the treatment.

EFFECT: higher efficiency of individualization.

4 ex

FIELD: biotechnology, microbiology.

SUBSTANCE: invention proposes a nutrient medium containing components chosen in the following ratio, g/1 l: casaminic acids, 10-12; yeast extract, 3-5; potassium hydrogen phosphate, 7-8; magnesium sulfate, 0.1-0.2; sodium citrate dihydrate, 0.5-0.6; ammonium sulfate, 2-2.5, and glucose, 1-2. Using a liquid nutrient medium provides the intensive growth of staphylococci since first hours of cultivation and allows attainment of maximal yield of antibacterial compound after 8 h growth of culture. Invention is designated for culturing staphylococci in aim for preparing antibacterial peptide compounds.

EFFECT: improved and valuable properties of nutrient medium.

1 dwg, 2 tbl, 3 ex

FIELD: veterinary medicine.

SUBSTANCE: method involves per os administering 10% Enrofloxacin solution in 50 ml/100 ml water dilution once a day during 5 days and Immunobac is introduced twice a day during 5 days in three courses depending on hen age in the amount of 0.5 times dose at the age of 6-10 days, 1 dose at the age of 30-34 days and 2 doses at the age of 70-74 days per one hen.

EFFECT: enhanced effectiveness in suppressing mycoplasmosis pathogens; normalized intestinal microbiocenosis.

7 tbl

FIELD: medicine.

SUBSTANCE: method involves administering fluoroquinolone-series antibiotic like Ciproflaxin at a dose of 100-250 mg twice a day during 3-5 days and non-steroid anti-inflammatory preparation of Diclophenac at a dose of 75-150 mg/day during 3-7 days are sequentially introduced in preparing patient to diagnostic examination.

EFFECT: enhanced effectiveness in increasing method sensitivity.

2 tbl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: invention involves the combined use of antibacterial preparations and immunomodulator. Method involves complex of single and double RNA sodium salts from killer yeast Saccharomyces cerevisiae as an immunomodulator and synthetic polymer-carrier taken in the dose 0.3-0.4 mg/kg. Immunomodulator is administrated in animals in a single dose before onset of critical period, i. e. in 15-20 days of piglets growing. Method provides stimulation of factors of cellular and humoral immunity of animals without adverse reactions and complication due to selection of optimal dose of immunomodulator and its prolonged effect.

EFFECT: improved method for treatment and prophylaxis.

3 cl, 4 tbl, 3 ex

FIELD: veterinary science.

SUBSTANCE: invention proposes a preparation for treatment and prophylaxis of mastitis in cows at onset of the lactation period and in dry cows that comprises the following components, wt.-%: furacrylin, 0.4-0.6; dioxydin, 0.8-1.2; bee wax, 4-6, and sunflower oil, the balance. The preparation is heated to 38-40°C and administrated in cow mammary gland being in damaged and healthy lobules of udder through a nipple duct by using a syringe in the dose 5 ml. Using the preparation provides enhancing therapeutic and prophylactic effectiveness, decreasing labor intensity in treatment and prophylaxis of mastitis in cows at the lactation period and in dry cows.

EFFECT: enhanced and valuable properties of preparation.

3 tbl, 3 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention relates to 9a-N-[N'-(phenylsulfonyl)carbamoyl]-derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A that are new semisynthetic macrolide antibiotics relating to class of azalides showing antibacterial effect and describing by the general formula (1):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl or halogen atom; R means H or cladinosyl radical, and to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof.

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

16 cl, 2 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: method involves covering lesion focus with cell containing dialysis solution composed of Dimexid, antibiotic, 0.1% potassium furagin and 25% glucose solution taken in 1:4:3:2 proportion. The cell is fixed on teeth with ligature. Cell wall adjacent to gingiva is covered with semipermeable Cuprofan membrane and the opposite wall with latex rubber. Dialysis is carried out 20 min long twice a day.

EFFECT: enhanced effectiveness of treatment; retained natural protection factors; reduced edema and inflammation manifestations.

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing an antibacterial agent. Method involves mixing active components - ampicillin trihydrate and oxacillin sodium salt, and starch as a vehicle and filling gelatin capsules with the prepared mixture. Method involves separate mixing each active component with half of potato starch and following their combination, addition of lactose and powdering with aerosil. Then the prepared dry mixture is added into gelatin capsules that are covered preliminary by gelatinized potato starch layer from the interior of capsule and dried with inert gas at the rate of gas feeding 3-5 m/s. Method provides simplifying preparing capsulated preparations due to facility filling capsules and to enhance stability of the preparation in storing.

EFFECT: improved preparing method, improved properties of preparation.

1 tbl

The invention relates to medicine, namely concerns a method for obtaining tablets oxacillin sodium salt

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing an antibacterial agent. Method involves mixing active components - ampicillin trihydrate and oxacillin sodium salt, and starch as a vehicle and filling gelatin capsules with the prepared mixture. Method involves separate mixing each active component with half of potato starch and following their combination, addition of lactose and powdering with aerosil. Then the prepared dry mixture is added into gelatin capsules that are covered preliminary by gelatinized potato starch layer from the interior of capsule and dried with inert gas at the rate of gas feeding 3-5 m/s. Method provides simplifying preparing capsulated preparations due to facility filling capsules and to enhance stability of the preparation in storing.

EFFECT: improved preparing method, improved properties of preparation.

1 tbl

FIELD: organic chemistry, antibiotics, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of carbapenem possessing high antibiotic activity with respect to methicillin-resistant microorganism Staphylococcus aureus, penicillin-resistant microorganism Streptococcus pneumoniae, influenza virus and microorganisms producing β-lactamase, and showing stability with respect to renal dehydropeptidase. Proposed derivatives of carbapenem represent compounds of the formulae (I) and (II) or their pharmaceutically acceptable salts wherein R1 represents hydrogen atom or methyl; each R2 and R3 represents independently hydrogen, halogen atom, carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylthio-group or formyl; n = 0-4; Hy represents 4-7-membered monocyclic or 9-10-bicyclic saturated or unsaturated heterocyclic group comprising 1-4 heteroatoms chosen from the group consisting of nitrogen and sulfur atoms wherein Hy group can be optionally substituted with halogen atom; substituted or unsubstituted lower alkyl, (lower alkyl)-thio-group, (lower alkyl)-sulfonyl, carboxyl, amino-group, aryl; or 6-membered monocyclic heterocyclic group comprising one or some nitrogen atoms. Also, invention describes the methods for treatment and/or prophylaxis of infectious diseases caused by gram-positive and gram-negative microorganisms that involve administration of indicated derivative of carbapenem in therapeutically and/or prophylactically effective doses to mammals including humans.

EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.

22 cl, 2 tbl, 73 ex

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: into tympano-cartilagenous part of auditory canal one should insert a Ziegle's funnel with a pre-applied obturating cuff and an optic headpiece and a manometer and a rubber balloon fixed to optic cuff. Under visual control it is necessary to alternate negative and positive pressure at fluctuation pace ranged -75 mm mercury column up to +75 mm due to making mobile liquid and gaseous content in the cavity of auris media. The content should be evacuated into auditory canal to be removed. The procedure should be repeated till maximally possible removal of pathological content out of deep cavities of auris media. Moreover, one should sample deep fraction of pathological content of air-bearing cells of auris media to carry out its microbiological analysis and, due to providing negative pressure within 75 mm mercury column it is necessary to introduce medicinal preparation that corresponds to pre-fulfilled antibioticogram. The innovation widens the quantity of preparations for treating diseases of auris media.

EFFECT: higher efficiency of therapy.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: offered medicinal agents are applied to prevent post acute stroke infections. As such mezlocylline, moxifloxacine, cy-lastatine, imipenem and sulbactam, or gamma-interferon is offered. At that preventive therapy starts in 12-72 hours after stroke. Immunomodulating properties of propranolol are discovered for application to prevent infectious starting before 12 hours after stroke, specifically after stroke.

EFFECT: invention enables to prevent serious bacterial infectious and increase post-stroke survival rate.

8 cl, 4 ex, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: medicine; otorhinolaryngology.

SUBSTANCE: in early postoperative period, after finishing antibiotic system and local therapy course, into patient's ear his own saliva is instilled. The saliva is taken fasting in the morning, after oral cavity cleaning, by spitting into boil treated glass. 3 drops of saliva 3 times a day during 20 to 45 days is instilled.

EFFECT: disease recurrence reducing due to mastoidal cavity populating with normal microflora.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: therapy of exudative otitis media is ensured by introduction of antibacterial, mucolytic, vasoconstrictive and proteolytic agents. It is combined with transtympanic introduction of 1.5% sodium deoxyribonucleate solution (Derinate) dosed 0.5 ml every second day into tympanic cavity. The therapeutic course is 4 injections of Derinate.

EFFECT: higher clinical effectiveness, reduced time of auditory perception threshold restoration.

3 tbl, 2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely pulmonology, and can be used for treating community-acquired pneumonia in the patients with mid-severe and severe clinical course involving immunogram abnormalities. That is ensured by antibacterial therapy. In addition, for 3-4 day of treatment, the treatment regimen is supplemented with Polyoxidonium in a dose 6 mg daily intramuscularly within 5 days.

EFFECT: early positive dynamics of the main clinical symptoms of disease and normalisation of immunological indicators which allow reducing treatment time and preventing complications.

1 tbl, 1 ex, 1 dwg

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