Antibacterial cephalosporins, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to new derivatives of cephalosporin of the General formula I, in which R1denotes hydrogen or ester group, R2denotes a group of formula (IIA, IIb, IIC), Y denotes hydrogen, alkyl, substituted alkyl or acyl, R4denotes hydrogen, phenyl, cycloalkyl or alkyl, R5denotes hydrogen, phenyl, cycloalkyl, lower alkyl, saturated or unsaturated 5-6 membered heterocyclyl, optionally substituted alkyl, triptorelin, oxo or amino group, benzothiazolyl or a group of formula (IId, IIe, IIf), R7denotes alkyl, R8denotes hydrogen, cycloalkyl or alkyl, R9denotes hydrogen or alkyl, R10denotes hydrogen, alkyl, substituted alkyl, where the Deputy is selected from triptoreline, pyridyl, hydroxy, alkoxy, halogen, amino or sulfonic acid residue; hydroxy, amino, phenyl, alkenyl, cycloalkyl or a group of the formula-N=CH-Phe, where Phe denotes phenyl, substituted hydroxy, or R9and R10together with the nitrogen atom represent a saturated, unsaturated or substituted 5-6-membered heterocyclyl containing one or two nitrogen atom or oxygen, and the Deputy chosen from groups etc., Ryrepresents NH, and Rzrepresents hydrogen, etc. Pharmaceutical composition intended for the treatment of diseases caused by bacteria, contains a compound of the formula I in the form of a pharmaceutically acceptable salt or in free form, in combination with at least one pharmaceutical carrier or diluent. A method of treating diseases caused by microbes, is administered to a subject in need of such treatment, an effective compounds of the formula I. the Technical result - obtaining new antibacterial cephalosporins. 4 C. and 9 C.p. f-crystals, 5 PL.

I

-O-Y IIa

< / BR>
-N=R6IIc

< / BR>
< / BR>
< / BR>

The invention relates to antibacterial compounds, which are 7-acylamino-3-(imino)methyl cephalosporins.

In particular, the present invention features a compound of formula

< / BR>
where R1denotes hydrogen or essential component,

R2denotes a group of the formula

< / BR>
< / BR>
or

< / BR>
where Y denotes hydrogen, alkyl, alkenyl, acyl, carbarnoyl, or aryl,

R4denotes hydrogen, alkyl, alkenyl, cycloalkyl, aryl, acyl or heterocyclyl,

R5oboznachaetsya R7denotes alkyl or aryl,

R8denotes hydrogen, cycloalkyl or alkyl,

R9denotes hydrogen or alkyl,

R10denotes hydrogen, alkyl, hydroxy, amino, phenyl, alkenyl, cycloalkyl, aryl, heterocyclyl or a group of the formula

-N=CH-Phe

where h denotes aryl,

R9and R10together with the nitrogen atom denotes heterocyclyl,

Z denotes oxygen, sulfur or N-R13where

R13denotes hydrogen, alkyl or cycloalkyl,

R11denotes hydrogen, alkyl, aryl, cycloalkyl or heterocyclyl, or

R4and R5together with the nitrogen atom represent heterocyclyl,

R6means heterocyclyl and

Speaker stands

(1) group

< / BR>
(2) a group of the formula

< / BR>
or

< / BR>
where In denotes N or CH,

Z1denotes aryl, cycloalkyl, 1,4-cyclohexadienyl or heterocyclyl,

Z2denotes hydrogen, alkyl or-CH2COOZ5,

where Z5denotes hydrogen, alkyl or cycloalkyl,

Z3denotes hydrogen or alkyl,

Z4denotes hydrogen or an organic radical,

D denotes an oxygen or CH2.

Subgroup according to the invention consists in they all essential component. Essential component includes alkyl, preferably1-6alkyl; arylalkyl, for example benzyl, alkoxybenzyl, such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, such as methoxymethyl; and (C1-6)alkanoyloxy(C1-6)alkyl, (C1-6)alkoxycarbonyl-hydroxy(C1-6)alkyl, pillarisetti, phenylglycidylether, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl and essential components that form with the COO-group of physiologically hydrolyzable and-acceptable ester, for example, known among hydrolyzable ester groups in the field of cephalosporins. The compound of the formula I can therefore be in the form physiologically hydrolyzable and physiologically acceptable ether complex. Under physiologically hydrolyzable and physiologically acceptable esters refers to an ester in which the group COO-etherification and which can be either hydrolyzed under physiological conditions to form acid, which is itself physiologically acceptable in the recommended doses. This term, therefore, should be understood as certain regular proletarienne form. Essential component may be preferably component, which is easily gidrol introduction can be shown, if ether per se is an active connection or if hydrolysis occurs in the blood.

Y may be preferably hydrogen, unsubstituted alkyl or alkyl substituted, e.g. by hydroxyl or preferably a residue of carboxylic acid. The remainder of the carboxylic acid includes the remainder of the carboxylic acid in free form or in salt form, the remainder of the ether carboxylic acids and carboxylic acid amide. Carboxylic acid is, for example, WITH1-7carboxylic acid, preferably C1-5aliphatic carboxylic acid, the alkyl part of which includes lower alkyl. Alkoxy group, ether carboxylic acids include C1-6preferably1-4alkoxy group. Alkyl represents preferably lower alkyl. The alkyl group is preferably unsubstituted or substituted by residues of carboxylic acids.

R4may be preferably hydrogen or alkyl, for example lower alkyl.

R5may be preferably hydrogen; unsubstituted alkyl; alkyl substituted, for example, oxo, alkyl or halogenated alkyl groups; amino; one or more than once substituted by heterocyclyl; or ƒ the measures 5 or 6 members in the ring and, for example, 1-3 heteroatoms such as N, O, S, preferably N or condensed heterocyclyl, such as benzothiazolyl.

R4and R5together with the nitrogen atom can be heterocyclyl, preferably having 5 or 6 members in the ring, and preferably having 1-3 heteroatoms such as a nitrogen atom; which may be unsubstituted heterocyclyl or one or more than once substituted by heterocyclyl, for example substituted by oxo, amino, alkyl groups.

R6can be saturated or unsaturated heterocyclyl, preferably having 5 or 6 members in the ring and having, for example, 1 or 2 nitrogen heteroatoms; for example unsubstituted heterocyclyl; or one or more than once substituted by heterocyclyl, for example amino, alkyl or thiono groups.

R7can be preferably alkyl.

R8can be preferably alkyl or cycloalkyl.

R9may be preferably hydrogen or lower alkyl.

R13can be preferably alkyl.

R10may be preferably hydrogen; aryl; alkenyl; cycloalkyl; unsubstituted alkyl; substituted the or N+(alkyl)3; or may be a group

-N=CH-Ar

where AG denotes heterocyclyl; unsubstituted aryl or substituted aryl, for instance hydroxy or alkoxy groups, preferably aryl, which may be preferably a phenyl.

R9and R10together with the nitrogen atom can be heterocyclyl, preferably having 5 or 6 members in the ring and 1-3 heteroatoms such as N, S, O, for example N, O; preferably saturated heterocyclyl. Heterocyclyl includes unsubstituted heterocyclyl or substituted heterocyclyl, such as acyl groups, formyl, alkyl, for example lower alkyl. Examples include pyrrolidine, morpholine, piperazine, preferably piperazine.

R11may be preferably hydrogen; unsubstituted alkyl; substituted alkyl, for example groups aminoalkyl, diaminoalkyl, diaminoalkyl; aryl, such as dihydroxyphenyl; cycloalkyl; or unsubstituted heterocyclyl; or substituted heterocyclyl, for example alkyl groups, cyanoethylation; heterocyclyl, preferably having 5 or 6 members in the ring and 1-3 heteroatoms, preferably N atom.

Unless otherwise noted, here, any carbon-containing group moeckel includes, for example, WITH1-4alkyl, preferably1-2alkyl. Alkenyl includes C2-20for example , WITH2-8alkenyl. Lower alkenyl includes, for example, WITH3-5alkenyl, preferably3alkyl. Cycloalkyl includes, for example, WITH3-6cycloalkyl, specifically WITH3C5or6cycloalkyl. Alkyl, alkenyl and cycloalkyl include unsubstituted alkyl, alkenyl or cycloalkyl and substituted alkyl, alkenyl or cycloalkyl, for example by halogen, sulfonic acid derivative, such as SO3N, CF3, hydroxy, alkoxy, acyl, alkylamino, pyridyl groups. Cycloalkyl preferably unsubstituted. Acyl includes C1-12for example , WITH1-6acyl, especially WITH1-4acyl. Acyl includes unsubstituted acyl and substituted acyl, for example hydroxy, alkoxy, amino groups. Aryl includes phenyl. Aryl can be unsubstituted aryl, or substituted aryl, for example alkyl, alkoxyl, acyl groups, halogen, hydroxy, unprotected or protected amino group. Alkoxyl includes alkoxyl, in which the alkyl part is the same as defined above.

Heterocyclyl includes heterocyclyl having 5 or 6 members in the ring and 1 to 3 heteroatoms of nitrogen, eroticly further includes unsubstituted heterocyclyl and substituted heterocyclyl, for example, oxo, alkoxy, hydroxy, tiono, mercapto, alkylthio, imino, alkylamino, alkylamino, amino, halogen, acyl, CF3, SNO, alkyl, cycloalkyl groups.

Carbarnoyl includes karbamoilnuyu group or carbamoyl with alkyl or aryl residues.

Z1denotes an unsubstituted cycloalkyl, 1,4-cyclohexadienyl, heterocyclyl or aryl, and one or more than once substituted cycloalkyl, 1,4-cyclohexadiene, heterocyclyl or aryl, for example carboxy, amino, nitro, cyano groups, lower alkyl, lower alkoxy, hydroxy groups, halogen, -CO-N(Z5Z6), -N(Z6)-COOZ7, Z6CO-, Z6OCO-, Z6COO-groups.

Z2denotes hydrogen; CH2COOZ5; unsubstituted lower alkyl; one or more than once substituted by lower alkyl, such as carboxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -COZ5Z6, -N(Z6)-COOZ7, Z6CO-, Z6OCO -, or Z6COO - groups.

Z3denotes hydrogen or lower alkyl.

Z4denotes hydrogen or an organic radical, preferably hydrogen; lower alkyl; cycloalkyl; aralkyl; acyl; carboxyethyl; Z6CO - C(ZPU 2-aminothiazol-yl or 2-aminothio-3,5-diazol-Il, Z4denotes a group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where Z9and Z10independently of one another denote hydrogen or a protected or unprotected carboxyl,

Z11denotes hydrogen or acetyl,

Z12means unprotected or protected carboxyl,

Z13denotes hydrogen or methyl,

Z14denotes hydrogen; chloro; unprotected or protected carboxyl; methyl; isopropyl; hydroxy; methoxy; acetoxy,

Z15and Z16denote independently from each other hydrogen, hydroxy, methoxy, ethoxy, 2-methoxyethoxyethoxy, acetoxy, chloroacetoxy, bugnology, methanesulfonate, p-toluensulfonate, amino, acetylamino, benzyloxycarbonylamino or methanesulfonyl group; or

Z15and Z16indicate together Ethylenedioxy or carbonyloxy group

Z17denotes hydrogen, hydroxy, acetoxy, methyl, methoxy, chloroacetoxy group, provided that not all Z14, Z15, Z16and Z17denote hydrogen,

Z18and Z19denote independently from each other hydrogen or methyl,

Z20, Z21, Z22, Z23and Z24denote independently from each other hydrogen,B>1-5
alkyl; nenamesceni phenyl or substituted phenyl,

Z27denotes unsubstituted lower alkyl or substituted lower alkyl,

Z28and Z29denote independently from each other hydrogen or hydroxyl group, and

n denotes 0 or 1,

Z5denotes hydrogen, alkyl, preferably lower alkyl,

Z6and Z7denote independently from each other hydrogen or alkyl, preferably lower alkyl,

Z6and Z7together with the carbon atom represent cycloalkyl and

Z5and Z6together denote cycloalkyl.

Z4can be selected from the following groups:

< / BR>
or

< / BR>
For example, Speakers can refer to a group of the formula

< / BR>
or

< / BR>
Preferably AC denotes the connection formulas

< / BR>
where W represents CH or N,

V represents CH or N-O and

R3denotes hydrogen, acyl, carboxyl or alkyl.

Configuration R3in the group-C=V-R3can be sin[(Z)] or anti - [(E)] and preferably sin[(Z)].

If R3denotes alkyl, R3includes unsubstituted alkyl, or substituted alkyl, for example halogen, carboxyla. Preferably W represents CH.


V represents CH or N-O,

R1denotes hydrogen or ester group,

R2denotes a group of the formula

< / BR>
< / BR>
or

< / BR>
where Y denotes hydrogen; unsubstituted lower alkyl or substituted lower alkyl residue of carboxylic acid, ester of carboxylic acid or carboxylic acid amide,

R4denotes hydrogen, phenyl, cycloalkyl or lower alkyl,

R5denotes hydrogen, lower alkyl, heterocyclyl or a group of the formula

< / BR>
< / BR>
or

< / BR>
where R7denotes lower alkyl,

R8denotes hydrogen, cycloalkyl or lower alkyl,

R9denotes hydrogen or lower alkyl,

R10denotes hydrogen, hydroxyl; amino; phenyl; alkenyl; cycloalkyl; heterocyclyl; unsubstituted alkyl; substituted alkyl CF3HE, alkoxy, carboxyla, halogen, amino, monoalkylamines, dialkylamines, trialkylamines group, pyridium or sulfonic acid residue; a group of the formula

< / BR>
where R12denotes hydrogen or lower alkyl,

Z denotes oxygen, sulfur or N-R13,

where R13denotes hydrogen or lower alkyl and

R11denotes hydrogen; dihydroxyphenyl; cycloalkyl; a heterocycle which ylamino groups;

R4and R5and/or R9and R10independently from each other together with the nitrogen represent heterocyclyl,

R6means heterocyclyl and

R3denotes hydrogen; acyl; carboxy; unsubstituted alkyl; substituted alkyl halogen or carboxyla.

In another aspect, the present invention features a compound of formula

< / BR>
where R1psame as R1in the formula I,

Speakers such as defined in formula I,

R2pdenotes a group of the formula

< / BR>
or

< / BR>
where Ypthe same as Y in the formula IA,

R4psame as R4in formula IA, and

R5pdenotes hydrogen, cycloalkyl, lower alkyl or a group of the formula

< / BR>
or

< / BR>
where R8psame as R8in the formula IA,

Zpthe same as Z in formula IA,

R9psame as R9in the formula IA,

R7pdenotes methyl,

R10pdenotes hydrogen, lower alkyl or hydroxy, and

R4pand R5pand/or R9pand R10pindependently from each other together with the nitrogen represent heterocyclyl and

compounds of formula IIb, IId and Er represent any tautomeric form in free form or, if such form sudesha aspect of the present invention features a compound of formula

< / BR>
where AC is the same as defined in formula I,

R1qsame as R1in formula IA, and

R2qdenotes a group of the formula

< / BR>
or

< / BR>
where Yqthe same as Y in the formula IA,

R4qsame as R4in formula IA, and

R5qdenotes hydrogen, cycloalkyl, lower alkyl or a group of the formula

< / BR>
or

< / BR>
where R7qsame as R7in the formula IA,

R8qsame as R8in the formula IA,

Zqthe same as Z in formula IA,

R9qsame as R9in the formula IA,

R10qdenotes hydrogen, lower alkyl or hydroxy, and

R4qand R5qand/or R9qand R10qindependently from each other together with the nitrogen represent heterocyclyl and

the compound of formula IIb, IId and Er represent any tautomeric form in free form or, if such a form exists in the form of salt accession acid, inner salt, Quaternary salt or hydrate.

In a further aspect the present invention features a compound of formula

< / BR>
where R1ssame as R1in the formula IA,

Vssame as V in formula IA,

Wssame as W in formula IA,

R3sR>R2sdenotes a group of the formula

< / BR>
< / BR>
or

< / BR>
where Ysdenotes hydrogen; unsubstituted lower alkyl or substituted alkyl with carboxyla,

R4sdenotes hydrogen or lower alkyl and

R5sdenotes hydrogen; a saturated or unsaturated unsubstituted heterocyclyl having 5 or 6 members in the ring and 1-3 nitrogen heteroatom; a saturated or unsaturated, one or more than once substituted heterocyclyl oxo group, a lower alkyl, an amino group or CF3having 5 or 6 members in the ring and 1-3 nitrogen heteroatoms; benzothiazolyl or a group of the formula

< / BR>
< / BR>
or

< / BR>
where Zsthe same as Z in formula I,

R7sdenotes lower alkyl,

R8sdenotes hydrogen, cycloalkyl or lower alkyl,

R9sdenotes hydrogen or lower alkyl,

R10srepresents hydrogen; phenyl; allyl; cycloalkyl; unsubstituted alkyl; substituted alkyl group CF3dialkylamino, dialkylamino, hydroxy, pyridium or SO3N, and

R11sdenotes hydrogen; pyridyl; cycloalkyl; unsubstituted lower alkyl; substituted lower alkyl by pyridium or trialkylamine; saturated or unsaturated heterocyclyl having 5 or ILOM and/or group tiono, having 5 or 6 members in the ring and 1-3 nitrogen heteroatom;

R4sand R5stogether with the nitrogen atom represent heterocyclyl selected from unsubstituted saturated heterocyclyl having 5 or 6 members in the ring and 1 or 2 nitrogen heteroatom; a saturated, one - or more than once substituted heterocyclyl oxopropoxy or lower alkyl having 5 or 6 members in the ring and 1 or 2 nitrogen heteroatom and/or

R9sand R10stogether with the nitrogen atom represent a saturated unsubstituted heterocyclyl having 5 or 6 members in the ring and 1 or 2 heteroatoms nitrogen and/or oxygen, unsaturated, one or more than once substituted heterocyclyl group Cho or a lower alkyl having 5 or 6 members in the ring and 1 or 2 heteroatoms nitrogen and/or oxygen.

In another aspect, the present invention features a compound of formula

< / BR>
where W represents CH or n

V represents CH or N-O,

R1denotes hydrogen or ester group, and

R2denotes a group of the formula

-N (R4R5) IIb

where R4as indicated in paragraph 1, and

R5denotes a group of the formula

< / BR>
where Z represents-N-R13where

R13such as the seat is sludge.

In another aspect, the present invention features a compound selected from

7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid (compound of Example 2).

7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]-amino]-3-[[(piperidinomethyl)hydrazono] methyl] -3-cefem-4-carboxylic acid (compound of example 96),

7-[[(5-amino-1,2,4-thiadiazole-3-yl)-(Z)-(formicoxenini)acetyl] amino] -3-[[(piperidinomethyl)hydrazono] methyl] -3-cefem-4-carboxylic acid (compound of example 139).

The compound of formula I, IA, IP, Iq, Is, IVi, IVa and VIa can exist in equilibrium with the tautomeric forms. The present invention includes a compound of formulas I, IA, Ip, Iq, Is, IVi, IVa and VIa any tautomeric form in which it can exist.

In another aspect, the present invention proposes a method for the production of compounds of formula I by the interaction of the compounds of formula

< / BR>
where Speakers are the same as defined in formula I and

a) either

Rbdenotes a hydroxy, a Rcand Rdtogether form a bond, or

Rddenotes hydrogen, a cation, atheromatous group or cellgroup, and Rband Rctogether on the 2< / BR>
where R2the same as defined in formula I, or

b) interaction of the compounds of formula

< / BR>
where R1and R2such as defined in formula I, with a compound of the formula

Ac-X'

where Speakers are the same as defined in formula I, a X' represents a leaving group.

Optionally, a reactive group may be protected by protective groups, which can be those hatshepsuts or in the conditions of the reaction or after the reaction described above. The compound of formula I, where R1denotes hydrogen, can be converted into a compound of formula I, where R1denotes a group of the ether carboxylic acid. The compound of the formula I can be isolated from the reaction mixture in the usual way.

The method may be carried out as follows.

The compound of formula III in a solvent which is inert under the reaction conditions, such as water, mixtures of water and lower alcohol and/or dioxane, or dipolar dehydrogenation solvent, for example dimethylformamide or dimethyl sulfoxide, possibly mixed with alcohol or water, is subjected to the interaction with the compound of the formula IV at a temperature of about-20-50oC. the Optimum pH can be achieved vs the way can be selected in the usual way, for example by adding antibacterial or chromatographic methods.

Method (b) can be carried out as follows.

The reaction is carried out as standard, for example the compound of formula I may be subject to interaction with the compound of the formula VII in a solvent, for example by dissolving or suspendirovanie in a mixture of acetone/water, for example at room temperature.

The reactive groups may be protected, preferably by technology silylamine groups. Suitable solvents include solvents which are inert under reaction conditions, such as chlorinated carbohydrates, NITRILES, such as acetonitrile, ethers such as tetrahydrofuran, or a mixture of such solvents. Further suitable solvents include dipolar dehydrogenation solvents such as N,N-dimethylformamide. Protective groups can be split-off in the traditional way.

The original connection of the formula II, for example, can be obtained

a) reaction of compounds of formula

< / BR>
where or

Rameans salt-NH2with an inorganic or organic acid, R'bdenotes hydroxy, and R'band R'ctogether represent oxo, agent sililirovanie and,

the compound obtained in stage a) of the formula

< / BR>
where Sil denotes silyl group, and either

) Rbmeans-Osil, and Rcand Rdtogether denote a bond, or

) Rdindicates Sil, and Rband Rctogether represent oxo,

acelerou or directly in the reaction mixture or after separation from the reaction mixture.

The acylation can be performed in a standard way.

The compound of the formula IIIc can be obtained

a) for the production of compounds of formula

< / BR>
in the form of salts of inorganic or organic acids, and where R"'bdenotes hydroxy, and R"'cand R"'dtogether denote a bond,

by reacting salts of organic or inorganic acid compounds of the formula

< / BR>
where R14and R15are the same or different and each denotes hydrogen or an organic residue in an organic solvent, sometimes in the presence of water with ozone;

b) for the production of compounds of formula

< / BR>
by treating the compounds of formula I, where R"'b, R"'eand R"'dsuch as defined above,

In another aspect, the present invention features a compound of formula

H2N-R2iIVi

where R2idenotes a group of the formula

-N (R4iR5i) IIbi

where R4isame as R4in formula I, and denotes hydrogen or alkyl and

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where R13isame as R13in formula I, and preferably denotes hydrogen or alkyl, or

R9iand R10itogether with the nitrogen atom represent heterocyclyl, which is piperazinil; or

R4isame as R4in formula I, and preferably denotes hydrogen and

R5idenotes a group of the formula

< / BR>
where R8idenotes alkyl, preferably at least2alkyl;

or cycloalkyl, preferably cyclopropyl and

R7idenotes alkyl, preferably methyl; or

R4isame as R4in formula I, and preferably denotes hydrogen or alkyl and

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where R13idenotes hydrogen, alkyl or cycloalkyl, prodocts(CH3)3HE or alkyl group having at least 2 carbon atoms, which is substituted by dialkylamino or dialkylammonium, hydroxy; or

R4isame as R4in formula I, and preferably denotes hydrogen;

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where alkyl, R13idenotes alkyl or cycloalkyl, preferably alkyl, and

R9iand R10itogether with the nitrogen atom represent heterocyclyl, which is morpholino or pyrrolidino; or

R4isame as R4in formula I, and preferably denotes hydrogen,

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where R13idenotes hydrogen, alkyl or cycloalkyl, preferably hydrogen,

R9idenotes hydrogen,

R10idenotes cycloalkyl, preferably cyclopropyl; or

R4isame as R4in formula I, and preferably denotes hydrogen;

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where R13isame as R13in formula I, and preferably denotes hydrogen,

R9ithe seat is oznachaet phenyl, preferably dihydroxyphenyl, or

R4isame as R4in formula I, and preferably denotes hydrogen,

R5idenotes a group of the formula

< / BR>
where Zidenotes N-R13i,

where R13idenotes hydrogen, alkyl or cycloalkyl, preferably hydrogen,

R11idenotes dihydroxyphenyl or pyrrolidyl, substituted alkyl; or

Zidenotes oxygen and

R11idenotes a group of the formula

< / BR>
In another aspect, the present invention features a compound of formula

< / BR>
where Rxrepresents a group of the formula

-NH-C(CH3)3< / BR>
or

-NH-CH2CF3< / BR>
or

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Ryrepresents NH and

Rzrepresents hydrogen; or

Rxrepresents a group of the formula

< / BR>
< / BR>
< / BR>
Ryrepresents NH and

Rzrepresents CH3; or

Rxrepresents-S3,

Ryrepresents a group of the formula

< / BR>
= N-C4H9< / BR>
and

Rzrepresents hydrogen; or

Rxis a group of forms is Rzrepresents hydrogen; or

Rxrepresents a group

< / BR>
Ryrepresents N-C2H5and

Rzrepresents hydrogen; or

Rxrepresents a group

< / BR>
Ryrepresents oxygen and

Rzrepresents hydrogen.

The compounds of formula VI are partly new, and can be obtained similarly to standard methods or as described in the examples.

In another aspect, the present invention features a compound of formula

< / BR>
where R1the same as defined in formula I, and

Rxxrefers to a group

< / BR>
where Rx, Ryand Rzsuch as defined above.

In this specification, unless otherwise indicated, the terms "compound of formula I, IA, Is, Ip, Iq, IVi, IVa and VIa" include connection in any form, for example in the form of a salt or free base form. The present invention therefore includes the compound in free or basic form or, where such a form exists in the form of a salt, for example in the form of salt accession acid, inner salt, a Quaternary salt and/or solvate form, for example in the form of a hydrate. Salt can be farmanimal, salts of sodium, potassium, calcium, barium, zinc, aluminum, preferably sodium or potassium. Amine salts include, for example, salts trialkylamine, novocaine, dibenzylamine and benzylamine. The free form of compounds of formulas I, IA, Is, Ip, Iq, IVi, IVa and VIa can be converted into a salt, and Vice versa.

In the following aspect the present invention provides compound of formula I, IA, Is, IP, Iq, IVi, IVa and VIa in free form or in salt form, for example in the form of salt accession acid or in the form of a metal salt; and a compound of formulas I, IA, Is, IP, Iq, IVi, IVa and VIa in the form of MES.

The compound of the formula I can also be obtained similarly to other methods, traditional chemistry-lactam.

The compounds of formula I, hereinafter designated as "active compound(I) according to the invention exhibit pharmacological activity and are therefore useful as pharmaceuticals. In particular, the active compounds according to the invention show antimicrobial, e.g. antibacterial activity against gram-negative and gram-positive bacteria, such as Pseudbmonas, such as Pseudomonas aeruginosa, Pseudomonas fluorescens; Enterobacter, such as Enterobacter cloacae; Enterococcus such as Enterococcus faecalis; rll, such as Moraxella catarrhalis; Haemophilus, e.g the faecium, Streptococcus pyogenes; Staphylococcus, such as Staphylococcus aureus, Staphylococcus pyogenes; Escherichia, such as Escherichia Li; and Proteus, for example Proteus mirabilis, in vitro Test cultivation of agar according to National Committee for Clinical Laboratory Standards (NCCLS) 1993, Document M7-A3, Vol.13, No. 25: "Methods for dillution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition; Approved standard and in vivo in models of septic mice. The active compounds according to the invention show activity in mice when injected in doses of from about 0.05 to 50 mg/kg body weight (dose value of the agent causing 50% effect, ED50Active compounds exhibit values OLS (µg/ml) in the Test cultivation of agar from about 0.005-about 50. The active compounds according to the invention exhibit a surprisingly comprehensive range of activity.

For example, it was determined that the OLS values (μg/ml) compound of Example 139 against, for example, Enterococcus faecalis, strains ATTC 29212 or ATSS 51299, approximately 0,08-0,25; against Staphylococcus aureus, strains ADS 29213 or ATSS 9144, approximately 0.2 to 0.4 and against Pseudomonas aeruginosa, strain 27853, about 0.8.

The active compounds according to the invention, therefore, useful for the treatment of microbial, e.g. bacterial diseases.

In another aspect, the present invention proposes a connection on p. 1 the CLASS="ptx2">

The following aspect in the present invention proposes a connection on p. 1 for use in the preparation of medicaments for the treatment of microbial diseases, for example diseases caused by bacteria, such as Pseudomonas, Enterobacter, Enterococcus, rll, Haemophilus, Klebsiella, Streptococcus, Staphylococcus, Escherichia, and Proteus.

The following aspect in the present invention proposes a method of treatment of microbial diseases in which a subject in need of such treatment, influence the effective amount of the compounds of formula I.

With this indication, appropriate dosage will vary depending on, for example, the compounds of formula I, the host, the mode of exposure and the nature and severity of batastini intended for treatment. However, in General, for satisfactory results for large mammals, such as humans, the prescribed daily dose in the range of about from 0.05 to 5 g, for example from 0.1 to about 2.5 g, the active compounds according to the invention that is administered as standard, for example, in divided doses up to four times per day.

The active compound according to the invention can be entered by any standard, for example, orally, for example in the form of tablets or cap is aksima.

The compound 7-[[(5-amino-1,2,4-thiadiazole-3-yl)-(Z)-(formicoxenini)-acetyl] amino] -3-[[(piperidinomethyl)hydrazono]-methyl]-3-cefem-4-carboxylic acid (compound of Example 139) is the preferred compound according to the invention for use as an antimicrobial agent.

It was, for example, it is determined that the value OLS (μg/ml) compound of Example 139 (tested in the form of trihydrochloride) against, for example, Streptococcus pneumoniae, strain ADS 49619, is about to 0.01, whereas, for example, Ceftriaxone shows the value OLS (μg/ml) is approximately 0.02. Therefore it is shown that for the treatment of microbial diseases, such as bacterial infections, preferred compounds according to the invention it is possible to introduce large mammals, for example humans, by similar ways in similar doses, what standard is used for Ceftriaxone.

The compounds of formula I can be introduced in the form of a pharmaceutically acceptable salt, for example in the form of salt accession acid or salts joining the Foundation, or the corresponding free forms, perhaps in the form of MES. Such salts show the same order of activity as the free form.

In the present invention that the problem of salt or in free form, in combination with at least one pharmaceutical carrier or diluent.

Such compounds can be produced in a standard way.

Form standard doses may contain, for example, from 10 mg to about 1 g, for example from 10 mg to about 700 mg.

In the following examples, temperatures are in degrees Celsius.

Example 1

The dihydrochloride of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]-amino-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid

(Method a)

1.24 g of bicarbonate aminoguanidine dissolved in 9,15 ml of 2n. HCl and added under stirring to a solution of 3.2 g of triptoreline amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino acetic acid in 125 ml of 4% aqueous acetonitrile. After 90 minutes the precipitated dihydrochloride of 7-[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[[(aminoiminomethyl)hydrazono] methyl] -3-cefem-4-carboxylic acid is filtered off, washed with acetonitrile and dried.

Example 2

The dihydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-(gtdoxycycline)-acetyl] -amino]-3-[[(ammoniacal)hydrazono]methyl]-3-cefem-4-carboxylic acid

(Method a)

a) 10 g of the hydrochloride of amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b the sludge and treated with 53 ml of water and 11 ml of 8h. HCl. The reaction mixture is stirred for 14 hours at room temperature. Get a clean solution in which acetoxysilane hydrolyzed with the formation of hydroxyisopropyl.

b) 3 g of hydrogen aminoguanidine dissolved in 11 ml of 1 N. Hcl and added dropwise to the solution obtained in stage a), which is cooled to 0oC. After 30 minutes the reaction mixture is heated to room temperature and stirred for another 2.5 hours the precipitated dihydrochloride of 7-[(2-amino-4-thiazolyl)-(Z)-(hydroxy-imino)acetyl] amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid is filtered off, washed with a mixture of acetonitrile and water, acetonitrile and ether and dried.

Example 3

Sodium salt of 7-[(2-amino-4-thiazolyl)(methoxyimino)-acetyl] amino-3-[(methoxyimino)methyl]-3-cefem-4-carboxylic acid

(Method b)

0.5 g of 7-amino-3-[(methoxyimino)methyl] -3-cefem-4-carboxylic acid and 0.75 g mercaptobenzthiazole ether (2-amino-4-thiazolyl)(methoxyimino)acetic acid are suspended in a mixture of 2.4 ml of water and 4.8 ml of acetone. 1.8 ml 2n. the sodium hydroxide solution is added dropwise in such a way as to achieve a pH of 8. The reaction mixture is stirred at 20owithin 1 h added dropwise to 2.4 is Hledat to 0oC. After 5 hours the precipitate is filtered and re-dissolved in 4 ml of water. Clean the solution is treated with 0.2 g of activated carbon and stirred for 15 minutes. Activated carbon is filtered off and add 100 ml of acetone over a period of 1 h at 0oC. Sodium salt of 7-[(2-amino-4-thiazolyl)(methoxyimino)acetyl] amino-3-[(methoxyimino)methyl]-3-cefem-4-carboxylic acid is obtained as colourless crystals, which are filtered off, washed with 5 ml of acetone and dried.

Compounds from table 1 of formula IA (V is =N-O - all of the Examples; and W represents CH in the Examples 4-68 and 70-138; and W represents N in the Examples 69-139 table 1) can be obtained in a similar way as described in Examples 1-3. See salt form. Configuration R3in the group-C=N-R3configuration is sin[(Z)].

Example 140

The dihydrochloride of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-pincemaille] -3-[[(aminoiminomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid

1 g of amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d] [1,3] -thiazin-6-yl)-2-[2-(tert. -butoxycarbonylamino)thiazol-4-yl)-(Z)-2-pentenol acid dissolved in a mixture of 30 ml of methanol and 30 ml of acetonitrile, and add 0.3 to the fair at room temperature. Within 30 minutes of light is formed precipitate, which is filtered off after 3 hours, washed with acetonitrile and ether and dried. The dihydrochloride of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-phenteramine] -3-{ [(aminoiminomethyl)hydrazono] methyl} -3-cefem-4-carboxylic acid is obtained in the form of light yellow powder.

Example 141

Triptorelin 7-[(2-amino-4-thiazolyl)-(Z)- (methoxyimino)acetyl] -amino-3-(hydrazinophenyl)-3-cefem-4-carboxylic acid

A suspension of 3 g of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)-acetyl]-amino-3-[[2-(1,1-dimethylmethoxy)-2-oksidoksi] hydrazinophenyl] -3-cefem-4-carboxylic acid in 75 ml of methylene chloride is treated at 0oWith 0.6 ml of anisole. With stirring, added dropwise 10 ml triperoxonane acid. The resulting solution was stirred for further 3 hours at 0oC. the Reaction mixture is poured into 600 ml of ether. Precipitation triptorelin 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl] amino-3-(hydrazinophenyl)-3-cefem-4-carboxylic acid is filtered off and dried.

Example 142

The hydrobromide 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]-amino-3-[(4-methylthiazole-2-yl)hydrazinophenyl]-3-cefem-4-carboxylic acid

1 g of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3-[(aminoethoxymethyl)hydrazinophenyl]-3-ceph is isolated for 20 minutes. Net solution is treated with 0.6 g of bromoacetone and stirred over night. Add 1 ml of water. The precipitate is filtered off and dried. The hydrobromide 7-[(2-amino-4-thiazolyl)-(Z)-(4-methoxyimino)acetyl] amino-3[(4-methylthiazole-2-yl)hydrazinophenyl] -3-cefem-4-carboxylic acid obtained as yellow solid.

Example 143

The hydrobromide 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]-amino-3-[(4-methylthiazole-2-yl)methylhydrazono]-3-cefem-4-carboneau acid

1 g of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3-[(aminoethoxymethyl)methylhydrazono] -3-cefem-4-carboxylic acid is treated in a similar way as described in Example 142, N,O-bistrimethylammomium and bromoacetone. The hydrobromide 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl] amino-3-[(4-methylthiazole-2-yl)methylhydrazono] -3-cefem-4-carboxylic acid obtained as yellow solid.

Example 144

Dehydrate 6R-TRANS (Z)-7-[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]-amino-3-[[(imino(methylamino)methyl)hydrazono] methyl]-3-cefem-4-carboneau acid

1.1 g of the dihydrochloride obtained according to Example 8, was dissolved in 25 ml of water, treated with 0.5 g of activated carbon and stirred for 5 minutes. what about the ammonia. The precipitate is filtered off and dried. Dehydrate 6R-TRANS (Z)-7-[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[[(imino(methylamino)-methyl)hydrazono]methyl] -3-cefem-4-carboxylic acid obtained as a yellowish powder.

Example 145

1-(Isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[[(imino(methylamino)-methyl)-hydrazono] methyl]-3-cefem-4-carboxylic acid

5.5 g of the dihydrate, obtained according to Example 144, dissolved in 55 ml of dimethylacetamide adding 1,43 ml tetramethylguanidine. This solution is cooled to 0oC, treated with a solution of 4.4 g of 1-iodocyclopentane in 30 ml of toluene and stirred for 90 minutes at 0oC. the Reaction mixture is poured into 1 l of diethyl ether. The precipitate is filtered off and stirred twice, each time adding 500 ml of acetonitrile. Acetonitrile phase unite, filtered and evaporated to a volume of 10 ml Oily residue is treated with 400 ml of water. The formed precipitate is filtered off and dried. The residue is stirred with 700 ml of ethyl acetate. After evaporation of ethyl acetate to obtain 1-(isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetyl] amino-3-[[(and the art in the ratio of 1:1.

Example 146

1-(Isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[((acetamino)-2-amino-4-thiazolyl)acetyl]amino-3-[[(aminoiminomethyl)hydrazono]methyl-3-cefem-4-carboxylic acid

0,72 g of bicarbonate aminoguanidine dissolved in 5.2 ml of 2n. HCl. This solution is added to a solution of 2 g of 1-(isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[((acetoacetamide)-2-amino-4-thiazolyl)acetyl]amino-3-formyl-3-cefem-4-carboxylic acid in 14 ml of acetonitrile containing 1.3 ml of water. The reaction mixture is stirred for 45 minutes at room temperature, and poured into 100 ml of acetonitrile. The formed precipitate is filtered off and dissolved in 100 ml of water. the pH of the resulting solution is brought to 7 by addition of 0.5 N. aqueous solution of sodium bicarbonate. The obtained yellow suspension is extracted twice with a mixture of 200 ml of ethyl acetate and 40 ml of acetonitrile. The combined organic phases, dried over Na2SO4and evaporated. 1-(Isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[((acetoacetamide)-2-amino-4-thiazolyl)acetyl] amino-3-[[(aminoiminomethyl)hydrazono] methyl] -3-cefem-4-carboxylic acid is obtained in the form of a yellow diastereomeric mixture in the ratio of 1:1.

Example 147

Ditosylate (isopropoxycarbonyl)ethyl-4-carboxylic acid.

A solution of 0.6 g of the compound obtained according to Example 146, in a mixture of 50 ml of acetonitrile and 20 ml of isopropanol is treated with 0.66 g of monohydrate toluene-4-sulfonic acid and stirred overnight at 25oC. the Reaction mixture is poured into 150 ml of tert.-butyl methyl ether. The precipitate is filtered off, washed with tert. -butylmethylamine ether and dried. Ditosylate (isopropoxycarbonyl)ethyl ester 6R-TRANS (Z)-7-[(2-amino-4-thiazolyl)(hydroxyimino)acetyl] amino-3-[[(aminoiminomethyl)hydrazono] methyl] -3-cefem-4-carboxylic acid obtained as light diastereomeric mixture in the ratio of 1:1.

Example 148

The dihydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[(carboxymethoxy)-imino]Actel] amino] -3-[[(aminoiminomethyl)-hydrazono]methyl]-3-cefem-4-carboxylic acid

(Compound of Example 5)

a) the Dihydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono] -methyl]-3-cefem-4-carboxylic acid

To 1.0 g of 7-amino-3-formyl-3-cefem-4-carboxylic acid in a mixture of 50 ml of acetonitrile and 5 ml of 2n. HCl is added dropwise 0.6 g of hydrogen aminoguanidine dissolved in 2.2 ml of 2n. HCl. The precipitate of the hydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono] -methyl] -3-cefem-4-carboxylic acid is filtered off, washed and the] acetyl] amino]-3-[[(aminoiminomethyl)-hydrazono]methyl]-3-cefem-4-carboxylic acid

4 g of the dihydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono]-methyl]-3-cefem-4-carboxylic acid are dissolved in 80 ml of methanol. The solution is cooled to 0oC and treated with a solution of 7 g of S-benzothiazolone ether (2-amino-4-thiazolyl)-(Z)-[2-(1,1-dimethylmethoxy)-2-oksidoksi] imino] teoksessa acid in 50 ml of methylene chloride. The reaction mixture was stirred for 2.5 h at 20oC. Approximately one-third of the solvent is evaporated and to the residue add 120 ml of ether. The precipitate of the hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(1,1-dimethylmethoxy)-2-oksidoksi] imino] -acetyl] -amino-3-[[(aminoiminomethyl)-hydrazono] methyl] -3-cefem-4-carboxylic acid is filtered off, washed with ether and dried.

c) the Dihydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[(carboxymethoxy)imino] Actel] amino] -3-[[(aminoiminomethyl)hydrazono] -methyl] -3-cefem-4-carboxylic acid

3.5 g of the hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(1,1-dimethylmethoxy)-2-oksidoksi] imino] acetyl]amino-3-[[(aminoiminomethyl)hydrazono]-methyl] -3-cefem-4-carboxylic acid was dissolved in 20 ml triperoxonane acid at 0oC. the Solution is stirred for 15 minutes at 0oC and for 1 h at 20oC. the Reaction mixture was treated with 40 ml of ether. The formed precipitate is filtered off, prayway precipitate the dihydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[(carboxymethoxy)-imino]Actel]amino] -3-[[(aminoiminomethyl)-hydrazono] methyl] -3-cefem-4-carboxylic acid, which is filtered off and dried.

Connection Examples 1-146 can be obtained as described in Example 147 and using the appropriate starting material.

The compounds used as starting material may be obtained as follows.

Example A)

Triptorelin amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-nitrogen[2,1-b] furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyethoxy acid

a) Hydrochloric 6-amino-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d] [1,3] thiazin (hydroxylation hydrohloride 7-aminopropyl-3-cefem-4-carboxylic acid)

13.8 g of the hydrochloride of 7-amino-3-[(Z/E)-prop-1-EN-1-yl]-3-cefem-4-carboxylic acid are dissolved in 200 ml of methanol. The solution is cooled to -50oWith and 8 l O2containing 2 % volume/objemy ozone is injected under stirring at this temperature. After 20 minutes 6-amino-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin is formed almost quantitatively, and ozonolysis finish, determining its completion method HPLC (liquid chromatography high pressure). Then through the reaction mixture miss 8 l N2within 2 minutes. The slightly turbid solution was poured into 1400 mlre.-butyl methyl ether and acetonitrile and dried. The hydrochloride of 6-amino-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-Aceto[2,1-b] furo[3,4-a][1,3]thiazine receive in the form of a white powder (HPLC content of more than 95%).

b) (6R-TRANS)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0] Oct-2-ene-2-carboxylic acid (7-amino-3-formyl-3-cefem-4-carboxylic acid)

2.64 g of the hydrochloride of 6-amino-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-Aceto[2,1-b]furo[3,4-d][1,3]thiazine dissolved in 50 ml of methanol. To this solution is added dropwise a solution to 0.78 g of pyridine in 10 ml of methanol under stirring and cooling on ice. The precipitate is filtered in a dry nitrogen atmosphere, washed with little methanol and dried. (6R-TRANS)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylic acid is obtained in the form of a light brown powder.

IR (KBR): 1799 cm-1(-lactam), 1672 cm-1(SNO), 1606 and 1542 cm-1(carboxylate)

UV Spectrum:maxin H2O = nm.

c) Amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b] furo[3,4-d] [1,3] -thiazin-6-yl)-2-(2-tritylimidazole-4-yl)-(Z)-2-methoxyethoxy acid

10 g of 7-amino-3-formyl-3-cefem-4-carboxylic acid in 200 ml of a mixture acetonitrile: methylene chloride (1:1) treated with 37.4 ml N,O-bis(trimethylsilyl)ndimethylacetamide and when added 21 g of the chloride of 2-(2-tritylimidazole-4-yl)-(Z)-2-methoxyethoxy acid. The temperature increases to -5oC. After 45 minutes the reaction mixture is treated with 4 ml of water. The temperature rises to 20oC. the Reaction mixture is stirred for 10 minutes and filtered. 15 g of activated charcoal is added to this filtrate and stirred for 10 minutes. After filtration the solvent from the resulting filtrate is evaporated. The residue from evaporation is treated with tert.-butylmethylamine ether. Get almost colorless crystalline precipitate, which is filtered off and dried. Crystalline amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-tritylimidazole-4-yl)-2-methoxyethoxy acid obtained as diastereomeric mixture in the ratio of 1:1.

d) Triptorelin amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyethoxy acid

5 g of amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-a] [1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyethoxy acid is introduced into 20 ml triperoxonane acid atoC. the Temperature is increased up to 10oC. the Reaction mixture is stirred for 30 minutes at 0oC and added dropwise to 200 dimensional mixture of triptoreline amide N-(a 1,4,5,6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d] [1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyethoxy acid get in the ratio of 1:1.

Example)

Triptorelin amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d][1,3]-thiazin-6-yl)-(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetic acid

obtained as a light yellow powder in the same way as described in example a) stage C) - d), but using on stage) chloride 2-(2-tritylimidazole-4-yl)-(Z)-2-hydroxylaminoxymes acid instead of the chloride of 2-(2-tritylimidazole-4-yl)-(Z)-2-methoxyethoxy acid.

Example)

Hydrochloride amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b] furo[3,4-d] [1,3] -thiazin-6-yl)-2-(5-amino-1,2,4-thiadiazole-3-yl)-(Z)-2-(formicoxenini)acetic acid

Suspension of 3.73 g of 7-amino-3-formyl-3-cefem-4-carboxylic acid in a mixture of 80 ml of methylene chloride and 30 ml of acetonitrile was stirred at 0oWith 16 ml of N, O-bis(trimethylsilyl)ndimethylacetamide. Over a period of 15 minutes to get a clean solution, which is added to 3.9 g of chloride (5-amino-1,2,4-thiadiazole-3-yl)-(Z)-2-formicoxenus acid, obtained for example as described in Example 1 of European patent EP 0590681. The reaction mixture was stirred for 1 h at 0o

Example D)

Hydrochloride amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b] furo[3,4-d] [1,3] -thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(acetoacetamide)acetic acid

40 g of 7-amino-3-formyl-3-cefem-4-carboxylic acid are suspended in 1500 ml of acetonitrile and cooled to 0oC. Over a period of 20 minutes, add 170 ml of N, O-bis(trimethylsilyl)ndimethylacetamide under stirring. Over a period of 15 minutes at 0oTo get a clean solution, which is cooled to -10oWith, and to which portions add 48 g of chloride (2-aminothiazol-4-yl)-(Z)-(acetoacetamide)acetic acid so that the temperature of the reaction mixture did not exceed -8oC. Stirring is continued for 60 minutes at -10oWith and add 168 ml of water. Stirring is continued for another 20 minutes at 0oC and 2 hours at room temperature. Formed crystallize is ahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d] [1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(acetoacetamide)acetic acid is obtained in the form diastereomeric mixture in the ratio of 1:1.

Example E)

Hydrochloride amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo - 3H,7H-azeto[2,1-b] furo[3,4-d] [1,3] -thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetic acid

10 g of the hydrochloride of amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d][1,3]-tiain-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(acetoacetamide)acetic acid are suspended in 160 ml of acetonitrile and treated with 53 ml of water and 11 ml of 8h. HCl. The reaction mixture is stirred for 14 h at room temperature. Get a clean solution, which is dissolved in anhydrous acetonitrile with 3-fold volume. The solvent is removed by evaporation to obtain a volume of 10 ml, which is treated with 200 ml of acetonitrile. The resulting residue is treated with ether, filtered and dried. Hydrochloride amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetic acid get in the form of a yellowish substance.

Example F)

Triptorelin amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] Fuego light brownish powder in the same way as described in example a) in stages a) to C), using on stage) chloride 2-(2-tritylimidazole-4-yl)-(Z)-2-[(1-carboxy-1-methylethoxy)imino] -acetic acid instead of the chloride of 2-(2-tritylimidazole-4-yl)-(Z)-2-methoxyethoxy acid.

Example (G)

Amide N-(1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto[2,1-b] furo-[3,4-d][1,3-thiazin-6-yl)-2-[2-(tert.-butoxycarbonylamino)-thiazol-4-yl] -(Z)-2-pentenol acid

receive in the form of a light brown powder in the same way as described in example a) at stages (C) - (d), using on stage) chloride 2-(2-tert. -butoxycarbonylamino)thiazol-4-yl)-(Z)-2-pentenol acid instead of the chloride of 2-(2-tritylimidazole-4-yl)-(Z)-2-methoxyethoxy acid.

Example N)

The dihydrochloride of 1-(hydrazinophenyl)piperazine

a) Hydroiodide 4-formyl-1-[imino(methylthio)methyl]piperazine

of 25.5 g of 4-formyl-1-piperazinecarboxamide suspended in 80 ml of methanol, treated with 22 g under the conditions and heated under reflux. Over a period of 10 minutes to get a clean solution. The mixture is cooled to room temperature. The solvent is evaporated. Get crystal hydroiodide 4-formyl-1-[imino(methylthio)methyl]piperazine.

(b) Hydrochloride of 4-poorat in 100 ml of water, expanded through a column filled with 800 ml of strong basic ion exchanger in the form of chloride and elute 850 ml of water. The solvent is evaporated to obtain a volume of 100 ml, which is treated of 7.35 g of hydrazine hydrate is added. The reaction mixture was stirred for 1 h at room temperature and the solvent is evaporated. Oily hydrochloride 4-formyl-1-(hydrazinophenyl)piperazine crystallizes upon drying.

(C) the Dihydrochloride of 1-(hydrazinophenyl)piperazine

11 g of the hydrochloride of 4-formyl-1-(hydrazinophenyl)-piperazine dissolved in 400 ml of methanol and treated with 50 ml Hclend. The reaction mixture is stirred for 14 h at room temperature. A white precipitate is formed, which is filtered off, washed with methanol and ether, dried and recrystallized from a mixture of water/ethanol. The dihydrochloride of 1-(hydrazinophenyl)piperazine get in colorless crystalline form.

The compounds of formula IV from table 2 can be obtained similarly to the method described in Example H).

Example P)

1-amino-3-(2-hydroxyethyl)-4-methylguanine

12.7 g of 2-methylamino-2-oxazoline dissolved in 50 ml of water, treated with 3 g of hydrazine hydrate is added and stirred for 17 h at manitoga residue, which crystallizes on cooling.

Example Q)

Hydrochloride 1,1-dimethyl-4-(hydrazinophenyl)piperazinediones

a) Hydroiodide 1,1-dimethyl-4-[imino(methylthio)methyl]-piperazinediones

3.2 g of 4-methyl-1-piperazinecarboxamide suspended in 100 ml of methanol. Add 6.2 g under the conditions and the mixture is heated under reflux for 2 hours and cooled to 20oC. the Precipitate of hydroiodide 1,1-dimethyl-4-[imino(methylthio)methyl]-piperazinediones filtered and dried.

(b) Hydrochloride, 1,1-dimethyl-4-(hydrazinophenyl)piperazinediones

to 6.57 g hydroiodide 1,1-dimethyl-4-[imino(methylthio)methyl]-piperazinediones dissolved in 70 ml of water, expanded through a column Packed with 150 ml of strong basic ion exchanger in the form of chloride, and elute with 250 ml of water. Water is evaporated from the eluate to a final volume of 50 ml, which is treated with 0.9 ml of hydrazine hydrate is added and stirred over night. The solvent is evaporated and the resulting residue is treated with n-hexane. Receive hydrochloride 1,1-dimethyl-4-(hydrazinophenyl)-piperazinediones.

Example R)

Trihydrochloride 1-[hydrazino(methylimino)methyl]piperazine

a) Hydrochloride of 3-methyl-2-methylsemicarbazide

R is 00 ml of strong basic ion exchanger in the form of chloride, and elute with water. The eluate lyophilizer and freeze-dried residue is treated with ether. The precipitate is filtered off and dried. Hydrochloride 3-methyl-2-methylsemicarbazide receive in the form of a white solid.

MP.116oC.

b) Hydrochloric 4-formyl-1-[hydrazino(methylimino)methyl]-piperazine

A mixture of 20 g of fresh formylpiperazine and 27.3 g of the hydrochloride of 3-methyl-2-methylsemicarbazide in 200 ml of ethanol is heated under reflux overnight and the solvent is evaporated. The oily residue is dissolved in 70 ml of hot isopropanol and the solution is slowly cooled to 20oC. a precipitate, and the mixture is left to stand for 2 h at 4oC. the Hydrochloride of 4-formyl-1-[hydrazino(methylimino)methyl]piperazine is filtered off and recrystallized from isopropanol.

c) Trihydrochloride 1-[hydrazino(methylimino)methyl]piperazine

10 g of the hydrochloride of 1-formyl-4-[hydrazino(methylamino)-methyl] piperazine dissolved in 250 ml of methanol. Add 50 ml Hclend, the resulting mixture is stirred overnight and the solvent is evaporated. Get a solid residue, which is dried over solid KOH. Trihydrochloride 1-[hydrazino(methylamino)-methyl]piperazine folklorica S-methylsemicarbazide, or hydrochloride of S-methyl-2-methylsemicarbazide, or the hydrochloride of S-methyl-4-methylsemicarbazide with the corresponding amines can be obtained the compounds of formula IV from table 3.

Example W)

Hydrochloride of 1-amino-3-(3,4-dihydroxybenzylamine)-guanidine

1 g of the hydrochloride diaminoguanidine dissolved in 10 ml of 4n. HCl and diluted with 20 ml of methanol. This solution is quickly treated with a solution of 1 g of 3,4-dihydroxybenzaldehyde in 40 ml of methanol. The reaction mixture is stirred for several minutes at room temperature and the solvent is evaporated. The residue is suspended in 50 ml of acetonitrile. The formed precipitate is filtered off and evaporated. Get the hydrochloride of 1-amino-3-(3,4-dihydroxybenzylamine)guanidine.

Example X)

Hydroiodide S-methyl-4-cyclopropanecarbonyl

295 mg of 4-cyclopropanecarbonyl dissolved in 5 ml of dry methanol and treated with 154 ml under the conditions. The mixture was stirred at 40oC in nitrogen atmosphere for 5 hours, cooled and treated with diethyl ether. The resulting colorless precipitate hydroiodide S-methyl-4-cyclopropanecarbonyl filtered off, washed with diethyl ether and dried.

Example Y)

abayat 149 mg under the conditions. The mixture is stirred under nitrogen atmosphere for 5 h, cooled and treated with diethyl ether. The resulting colorless precipitate hydroiodide S-methyl-4-n-butyldiethanolamine filtered off, washed with diethyl ether and dried.

Example Z)

Hydrazide 1-methyl-5-mercapto-1,2,4-triazole-3-carboxylic acid

of 0.48 g of methyl ester of 1-methyl-5-mercapto-1,2,4-triazole-3-carboxylic acid are dissolved in 10 ml of methanol, treated with 450 μl of hydrazine hydrate is added and stirred for 2 h at 20oC. the precipitate hydrazide 1-methyl-5-mercapto-1,2,4-triazole-3-carboxylic acid is filtered off, washed with methanol and dried.

IR (KBR): 1669 cm-1, 1608 cm-1, 1517 cm-1.

13C-NMR (300 MHz, DMSO-d6): 35,4 (NCH3); br143.3, 154,3 and 166,7.

Example AA)

Hydroiodide 1,5-dimethyl-2-(hydrazinophenyl)pyrrol

a) 1,5-dimethylpyrrole-2-carbothioamide

5 g of 2-cyano-1,5-dimethylpyrrole dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. Add 50 ml of an ethanol solution of H2S (3.8 g/100 ml) and the mixture is heated for 15 hours in an autoclave at 70oC. the Reaction mixture is cooled and the solvent is evaporated to obtain a quarter of its volume. 1,5-Dimethylpyrrole-2-carb is 5-dimethyl-2-[imino(methylthio)methyl]pyrrole

1 g of 1,5-dimethylpyrrole-2-thioamide group by forming dissolved in 20 ml of methanol and treated with 1.7 g under the conditions. The reaction mixture was stirred for 5 h at room temperature. The solvent is evaporated until then, until the start of crystallization. The residue is cooled to 0oC. Crystalline hydroiodide 1,5-dimethyl-2-[imino(methylthio)methyl] -pyrrol filtered off, washed with methanol and dried.

C) Hydroiodide 1,5-dimethyl-2-(hydrazinophenyl)pyrrol

1.3 g of hydroiodide 1,5-dimethyl-2-[imino(methylthio)methyl]-pyrrole dissolved in 20 ml of methanol. Added 0.28 g of hydrazine hydrate is added. The reaction mixture was stirred for 3 h, the solvent is evaporated and the residue is recrystallized from a mixture of acetonitrile/ether. Get hydroiodide 1,5-dimethyl-2-(hydrazinophenyl)pyrrole.

Example AB)

Hydroiodide 3,4-dihydroxy-2-(hydrazinophenyl)benzene

get similar to the method described in Example AA), but using 3,4-dihydroxycinnamic instead of 1,5-dimethylpyrrole-2-carbothioamide.

Example AU)

7-amino-3[[(carbomethoxy)imino]methyl]-3-cefem-4-carboxylic acid

A solution of 1.86 g of the hydrochloride aminooxyacetic acid in 20 ml of water is treated with stirring Pris stirred for 8 h at 0oC. 7-Amino-3-[[(carboxy-methoxy)imino] methyl] -3-cefem-4-carboxylic acid precipitates in the form of colourless crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.

Example AD)

7-Amino-3-[(methoxyimino)methyl]-3-cefem-4-carboxylic acid

A solution of 0.5 g of the hydrochloride of O-methylhydroxylamine in 10 ml of water is treated with stirring at 0o1.38 g of 7-amino-3-formyl-3-cefem-4-carboxylic acid and stirred for 8 h at 0oC. 7-amino-3-[(methoxyimino)methyl] -3-cefem-4-carboxylic acid precipitates in the form of almost white crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.

Example AE)

7-Amino-3-[(piroximone)methyl]-3-cefem-4-carbamid acid

a) a Solution of 1.26 g of hydroxylamine hydrochloride in 7.5 ml of water is treated with stirring at 0oFrom 4.74 g of the hydrochloride of 6-amino-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine and stirred for 8 h at 0oC in nitrogen atmosphere. the pH of the reaction mixture was adjusted to 3.5 using solid sodium bicarbonate. 7-Amino-3-[(hydroxyimino)methyl]-3-cefem-4-carboxylic acid precipitates in the form of colorless crystals, which hotfil the on-1,4,5 and 6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine in 10 ml of dichloromethane is treated with stirring at 4oWith 2.67 g of N,O-bis(trimethylsilyl)ndimethylacetamide. Net get solution over a period of 10 minutes. Added 0.21 g of hydroxylamine hydrochloride. The reaction mixture was stirred for 2 h in nitrogen atmosphere at 4oWith, and the solvent is evaporated. The residue is treated with 10 ml of isopropyl alcohol, pre-cooled to 1oC. 7-Amino-3-[(hydroxyimino)methyl]-3-cefem-4-carboxylic acid precipitates in the form of almost colorless crystals, which are filtered off, washed with 5 ml of acetone and dried.

In the same way as described in the Examples from speakers) to AE), can be obtained the compounds of formula (V) from table 4.

1H-NMR Spectra of compounds obtained according to Examples (cont'd), see the end of the description.

The results of the study in vivo antibacterial activity against systemic infections in mice for connections from example 139 compared with Cefotaxime.

Antibacterial activity in vivo was tested for septic infections (NMRI) in outbred mice. Mice were randomly divided into groups of 8 animals per dose and put in macrolone cells (type III). The control group was not exposed to the infection.

Strains of bacteria that are intended for the infection of 16 hours in medium Mueller-Hinton Broth and diluted with saline to inoculation concentration, which kills all mice after intrapreneuring infection (0.3 ml/mouse) in 24-48 hours after infection. The compounds were diluted with saline and injected subcutaneously in different dosages for each group.

In the case of E. coli infection treatment of the investigated compounds was performed simultaneously in 5 hours after infection, in the case of S. aureus infection after 1 and 4 hours after infection.

Dead mice were daily log up to 10 days after infection. The magnitude of the ED50calculated probit analysis, results and confidence limits are presented in table. 5.

Examples of pharmaceutical compositions

Tablets

120 mg of the compound obtained in example 139, mixed with 192 mg of dicalcium phosphate, 190 mg of lactose and 6 mg of corn starch. To the resulting mixture add 6 mg of corn starch, granularit and coarsely sieved. Then dried in high vacuum and again sieved through a sieve with openings of 1.00 mm Add 6 mg of corn starch and 292 mg of magnesium stearate and pressed into tablets weighing 800 mg and a diameter of about 1.27, see

Capsules

In having a hole vials containing 500 mg of soedinenii directly before administration to the patient. The dissolved product is mixed with 30 ml of physiological sodium chloride solution and the resulting solution was used for intravenous injection for 20-30 minutes.

1. Derivatives of the cephalosporin of the formula

< / BR>
where R1denotes hydrogen or ester group;

R2denotes a group of the formula

-O-Y - IIa

< / BR>
or

-N=R6IIc

where Y denotes hydrogen, alkyl, substituted alkyl, or acyl;

R4denotes hydrogen, phenyl, cycloalkyl or alkyl;

R5denotes hydrogen, phenyl, cycloalkyl, lower alkyl, unsaturated or saturated five - or six-membered heterocyclyl, optionally substituted alkyl, triptorelin, oxo or amino group, benzothiazolyl or a group of the formula

< / BR>
< / BR>
or

< / BR>
where R7denotes alkyl;

R8denotes hydrogen, cycloalkyl or alkyl;

R9denotes hydrogen or alkyl;

R10denotes hydrogen, alkyl, substituted alkyl, where the Deputy is selected from triptoreline, pyridyl, hydroxy, alkoxy, carboxy, halogen, amino or sulfonic acid residue; hydroxy, amino, phenyl, alkenyl, cycloalkyl or a group of the formula

-N=CH-Phe

where Phe appears sydeny or substituted five - or six-membered heterocyclyl, containing one or two nitrogen atom or oxygen, and the Deputy is selected from formyl or alkyl;

Z denotes oxygen, sulfur or N-R13where R13denotes hydrogen or alkyl;

R11denotes hydrogen, dihydroxyphenyl, alkyl, substituted alkyl, where the Deputy is chosen from amino or pyridyl; cycloalkyl, pyridyl, unsubstituted or substituted five - or six-membered heterocyclyl containing one to three nitrogen atoms, where the Deputy is chosen from alkyl, tiono, formyl or hydroxy,

or R4and R5together with the nitrogen atom represent a five - or six-membered heterocyclyl containing one or two nitrogen atom and optionally substituted by one or more substituents selected from alkyl or oxo;

R6represents a five-membered heterocyclyl having two or three nitrogen atom and substituted by one or more substituents selected from amino, alkyl or thiono;

AC denotes a group of the formula

< / BR>
< / BR>
where In denotes N or CH;

Z1represents a five-membered heterocyclyl containing one sulfur atom and one or two nitrogen atom and substituted amino;

Z2denotes hydrogen or alkyl;

Z3denotes hydrogen, hydroxy;

D denotes an oxygen or CH2< / BR>
in any possible tautomerism form, in free form, in salt form, MES or hydrate.

2. Connection on p. 1 formula

< / BR>
where W represents CH or N;

V represents CH or N-O;

R1denotes hydrogen or ester group;

R2denotes a group of the formula

-O-Y IIa

< / BR>
or

-N=R6IIc

where Y denotes hydrogen; unsubstituted lower alkyl; or lower alkyl substituted by a residue of carboxylic acid, ester of carboxylic acid or carboxylic acid amide;

R4denotes hydrogen, phenyl, cycloalkyl or lower alkyl;

R5denotes hydrogen, lower alkyl, unsaturated or saturated five - or six-membered heterocyclyl, optionally substituted alkyl, triptorelin, oxo or amino group, or a group of the formula

< / BR>
< / BR>
or

< / BR>
where R7denotes lower alkyl;

R8denotes hydrogen, cycloalkyl or lower alkyl;

R9denotes hydrogen or lower alkyl;

R10denotes hydrogen, hydroxy; amino; phenyl; alkenyl; cycloalkyl; heterocyclyl; unsubstituted alkyl; alkyl substituted groups, CF3HE, alkoxy, carboxy, GoLoG is s; a group of the formula

< / BR>
where R12denotes hydrogen or lower alkyl;

Z denotes oxygen, sulfur or N-R13where R13denotes hydrogen or lower alkyl;

R11denotes hydrogen; dihydroxyphenyl; cycloalkyl; unsubstituted or substituted five - or six-membered heterocyclyl containing one to three nitrogen atoms, where the Deputy is chosen from alkyl, tiono, formyl or hydroxy; unsubstituted lower alkyl; lower alkyl substituted by pyridium or groups of monoalkylamines, dialkylamines, trialkylamines;

R4and R5and/or R9and R10independently from each other together with the nitrogen represent heterocyclyl;

R6represents a five-membered heterocyclyl having two or three nitrogen atom and substituted by one or more substituents selected from amino, alkyl or thiono;

R3denotes hydrogen; acyl; carboxy; unsubstituted alkyl; substituted alkyl halogen or carboxy,

in any possible tautomerism form, in free form, in salt form, MES or hydrate.

3. Compounds according to any one of paragraphs.1 and 2 formula

< / BR>
where R1ssame as R1in formula IA;

Vssame as V in formula IA;

Ws replaced by carboxypropyl and/or fluorine;

R2sdenotes a group of the formula

OYsIIas

< / BR>
or

-N=R6sIIcs

where Ysdenotes hydrogen; unsubstituted lower alkyl; or alkyl substituted by carboxypropyl;

R4sdenotes hydrogen or lower alkyl;

R5sdenotes hydrogen; a saturated or unsaturated unsubstituted five - or six-membered heterocyclyl having 1-3 nitrogen atom; a saturated or unsaturated five - or six-membered heterocyclyl having 1-3 nitrogen atom, substituted by one or more groups such as oxo, lower alkyl, amino or CF3; benzothiazolyl; or a group of the formula

< / BR>
< / BR>
or

< / BR>
where Zsthe same as Z in formula I;

R7sdenotes lower alkyl;

R8sdenotes hydrogen, cycloalkyl or lower alkyl;

R9sdenotes hydrogen or lower alkyl;

R10srepresents hydrogen; phenyl; allyl; cycloalkyl; unsubstituted alkyl; alkyl substituted groups, CF3dialkylamino, dialkylamino, hydroxy, pyridyl or SO3H;

R11sdenotes hydrogen; pyridyl; cycloalkyl; unsubstituted lower alkyl; lower alkyl substituted by pyridium or group trialkylamine; saturated or unsaturated five - Il is nitrogen, substituted by one or more groups such as lower alkyl and/or thiono;

R4sand R5stogether with the nitrogen atom represent heterocyclyl selected from unsubstituted saturated five - or six-membered heterocyclyl having 1 or 2 nitrogen atom; a saturated five - or six-membered heterocyclyl having 1 or 2 nitrogen atom, substituted by one or more groups such as oxo or lower alkyl;

and/or R9sand R10stogether with the nitrogen atom represent a saturated unsubstituted five - or six-membered heterocyclyl having 1 or 2 heteroatoms nitrogen and/or oxygen; unsaturated five - or six-membered heterocyclyl having 1 or 2 heteroatoms nitrogen and/or oxygen, substituted by one or more groups, such as SNO or lower alkyl,

in any possible tautomerism form, in free form, in salt form, MES or hydrate.

4. The compound according to any one of paragraphs.1-3 formulas

< / BR>
where W represents CH or N;

V represents CH or N-O;

R1denotes hydrogen or ester group;

R2denotes a group of the formula

-N(R4R5) IIb

where R4the same as that defined in paragraph 1;

R5refers to a group formulate with the nitrogen atom represent heterocyclyl, which is piperazinil,

in any possible tautomerism form, in free form, in salt form, MES or hydrate.

5. Connection PP.1-4, representing

7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid;

7-[[(2-amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(piperidinomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid;

7-[[(5-amino-1,2,4-thiadiazole-3-yl)-(Z)-(formicoxenini)acetyl] amino] -3-[[(piperidinomethyl)hydrazono]methyl]-3-cefem-4-carboxylic acid;

in any possible tautomerism form, in free form, in salt form, MES or hydrate.

6. Connection on p. 1 or 2 formula

< / BR>
where R1psame as R1in formula I;

Speakers such as defined in formula I;

R2pdenotes a group of the formula

OYpIIap

or

< / BR>
where Ypthe same as Y in formula IA;

R4psame as R4in formula IA;

R5pdenotes hydrogen, cycloalkyl, lower alkyl or a group of the formula

< / BR>
or

< / BR>
where R8psame as R8in formula IA;

Zpthe same as Z in formula IA;

R9pTaco is silt or hydroxy;

R4pand R5pand/or R9pand R10pindependently from each other together with the nitrogen represent heterocyclyl,

and groups of formula IIbp, IIdp and Er represent any tautomeric form, in free form or, if such a form exists in the form of an acid additive salt, inner salt, Quaternary salt or MES or hydrate.

7. Connection on p. 1 or 2 formula

< / BR>
where Ac is the same as defined in formula I;

R1qsame as R1in formula IA;

R2qdenotes a group of the formula

OYqIIaq

or

< / BR>
where Yqthe same as Y in formula IA;

R4qsame as R4in formula IA;

R5qdenotes hydrogen, cycloalkyl, lower alkyl or a group of the formula

< / BR>
or

< / BR>
where R7qsame as R7in formula IA;

R8qsame as R8in formula IA;

Zqthe same as Z in formula IA;

R9qsame as R9in formula IA;

R10qdenotes hydrogen, lower alkyl or hydroxy;

R4qand R5qand/or R9qand R10qindependently from each other together with the nitrogen represent heterocyclyl,

and groups of formula IIbp, IIdp and Er represent any tautomeric form, in red salt or MES or hydrate.

8. The connection formulas

< / BR>
where (i)

Rxrepresents a group of the formula

-NH-C(CH3)3or

-NH-CH2CF3or

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Ryrepresents NH;

Rzrepresents hydrogen; or

(ii) Rxrepresents a group of formula-NH-(CH2)2-N(CH2)2;

Ryrepresents NH;

Rzrepresents CH3; or

(iii) Rxrepresents-SCH3;

Ryrepresents a group of the formula

< / BR>
=N-C4H9< / BR>
Rzrepresents hydrogen; or

(iv) Rxrepresents a group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
-NHOH or

-NH-CH2-CH2-OH

Ryrepresents N-CH3;

Rzrepresents hydrogen; or

(v) Rxrepresents a group

< / BR>
Ryrepresents N-C2H5;

Rzrepresents hydrogen; or

(vi) Rxrepresents a group

< / BR>
Ryrepresents oxygen;

Rzrepresents hydrogen;

in any of the possible tautomeric form, in free form or, ETA or hydrate.

9. The compound according to any one of paragraphs.1-8 in the form of an acid additive salt.

10. The compound according to any one of paragraphs.1-8 in the form of a metal salt.

11. Connection on p. 1 as pharmaceuticals.

12. The pharmaceutical composition intended for the treatment of diseases caused by bacteria containing compound under item 1 in the form of a pharmaceutically acceptable salt or in free form, in combination with at least one pharmaceutical carrier or diluent.

13. A method of treating diseases caused by microbes, which administered to a subject in need of such treatment, an effective amount of the compounds of formula I.

Priority points:

11.05.1995 on PP. 1-13;

12.06.1995 on PP. 1-13;

17.04.1996 on PP. 1-13;

23.04.1996 on PP. 1-13;

 

Same patents:

The invention relates to a method for producing derivatives of cafema General formula I(I) where R1is amino or protected amino group,

R2is lower alkyl or fluorinated methyl,

R3- COO-, carboxy or protected carboxy,

R4hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

R5is amino or protected amino group,

R6is hydrogen or methyl, or its salt additive triperoxonane acid, its additive salts of sulfuric acid, or its salts with trifurcation having antibacterial activity

The invention relates to medicine, specifically to antibacterial substance erythromycin

The invention relates to novel polycyclic phthalazine, in particular disubstituted moderatelysized (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen-[1,2-g] -phthalazine formula I, in which R1represents a residue of the formula -(CR4R5)n-SDA or-Ph(R6)(SDA), where R4and R5denote N, n denotes the number of 1-4, R6represents N and Y represents OR7where R7represents H or (C1-C10)alkyl, or alkali metal ion or ammonium ion; R2and R3denote hydrogen, and salts, esters and Amida compounds of the formula I
The invention relates to cosmetology, in particular to the agent for processing sensitive skin, to compositions containing an agent for treatment of sensitive skin, and also to a method for skin treatment

The invention relates to pharmaceutical industry

The invention relates to new derivatives carbapenem formula I, where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino; or pharmaceutically acceptable salts

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I)

The invention relates to new derivatives of cephalosporin of the General formula I and II where R1selected from the group consisting of-NНС(O)ZR3, -NR4R5; Z is selected from the group consisting of-CH2(X)m-, -C(NОR6)-; X is a sulfur atom; m = 0 - 1; R3- thiazolyl substituted by chlorine or amino group, and (CH2)T, where n = 1 to 6; T - guanidino; R4and R5each hydrogen; R6is hydrogen or may be a group which with the adjacent oxygen atom forms a protected hydroxyl group,2is hydrogen; each of G, H, L, and M - carbon; J is nitrogen; rings a, b, D and E are selected from the group consisting of thiazolyl and thiadiazolyl; R11is hydrogen; alk1- C1-6alkyl; alk2- C1-6alkyl, optionally substituted by a group selected from hydroxyl, amino, carboxamido; p is 0 to 1; R99selected from the group consisting of sulfur and SO2; q is 1; r = 1 - 3; R12- NR13R14group (a) or (b); R13-R17each is hydrogen, or its pharmaceutically acceptable salt

Cyclopeptide // 2171260
The invention relates to cyclopeptides and to their therapeutic use as inhibitors of the expression of adhesion molecules

The invention relates to new derivatives of cephalosporin of the General formula I and II where R1selected from the group consisting of-NНС(O)ZR3, -NR4R5; Z is selected from the group consisting of-CH2(X)m-, -C(NОR6)-; X is a sulfur atom; m = 0 - 1; R3- thiazolyl substituted by chlorine or amino group, and (CH2)T, where n = 1 to 6; T - guanidino; R4and R5each hydrogen; R6is hydrogen or may be a group which with the adjacent oxygen atom forms a protected hydroxyl group,2is hydrogen; each of G, H, L, and M - carbon; J is nitrogen; rings a, b, D and E are selected from the group consisting of thiazolyl and thiadiazolyl; R11is hydrogen; alk1- C1-6alkyl; alk2- C1-6alkyl, optionally substituted by a group selected from hydroxyl, amino, carboxamido; p is 0 to 1; R99selected from the group consisting of sulfur and SO2; q is 1; r = 1 - 3; R12- NR13R14group (a) or (b); R13-R17each is hydrogen, or its pharmaceutically acceptable salt
The invention relates to medicine, namely to rheumatology, and can be used for the treatment of ankylosing spondylitis
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