Compounds of the cephalosporin, their pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, isomers, having the s-configuration of the double bond in propenyloxy group, syn-isomers and optical isomers and method of production thereof


C07M9 -
C07M7 -
C07D501/24 - with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3

 

(57) Abstract:

The present invention relates to the connection of a cephalosporin represented by the following General formula (I)

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its pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable ether complex, hydrate or MES or its isomers,

where

Q represents CH or N;

R1represents hydrogen or a protective group for amino group;

R2and R3may be the same or different and independently of one another represent hydrogen or a protective group for a hydroxy-group; or

R2and R3together can form a protective group for cyclic diol group;

R4represents hydrogen or a protective group for carboxyl group;

R5, R6and R7independently of one another represent hydrogen, amino or substituted amino, hydroxy, alkoxy, C1-4-alkyl, carboxyl or alkoxycarbonyl, or R5and R6together with the carbon atoms to which they are attached, may form a C3-C7-cycle. 2 S. and 2 C.p. f-crystals, 2 tab.

The invention relates to new cephalosporin compound, which is suitable in quality is Lil-4 (or aminothiadiazole-4)-2-(-carboxy-3,4-substituted, benzylacetone)acetamidoxime in position 7 b and at the same time, 3-substituted propenyloxy group in position C-3, i.e. the connection of a cephalosporin represented by the following General formula (I) with 4-amino-triple-substituted pyrimidine of the substituent in position 3 propenyloxy group:

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where R1represents hydrogen or a protective group for amino group;

R2and R3may be the same or different and independently of one another represent hydrogen or a protective group or a hydroxy-group;

R2and R3together can form a protective group for cyclic diol group;

R4represents hydrogen or a protective group for carboxyl group;

R5, R6and R7independently of one another represent hydrogen, amino, or substituted amino-, hydroxy-, alkoxy-, C1-4-alkyl, carboxyl or alkoxycarbonyl;

R5and R6together with the carbon atoms to which they are attached, may form a C3-7-loop;

Q represents CH or N,

and its pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable ether complex, hydrate and MES and its isomers, which have potent antimicrobial activity and a broad antimicrobial spectrum of the second defined above, and medicinal product containing the compound of formula (I) as an active ingredient.

Cephalosporin antibiotics are widely used for treatment of diseases caused by pathogenic bacteria of humans and animals, and in particular they are suitable for treatment of diseases caused by bacteria that are resistant to other antibiotics, e.g. penicillin compounds, and for the treatment of patients with hypersensitivity to penicillin. For most bacterial infections, it is preferable to use antibiotics that are active against both gram-positive and gram-negative microorganisms. In addition, it is well known that antimicrobial activity such cephalosporin antibiotics is strongly influenced by the substituent in the 3 - or 7-position carambola kernel. Therefore, attempts have been made to develop antibiotic which exhibits a high antibacterial activity against a broad spectrum of gram-positive and gram-negative strains, and which is resistant-lactamases produced various gram-negative bacterial strains, and which is very stable in vivo.

the Fort worth 7 b-alluminare and in position 3 carambola kernel.

For example, U.S. Pat. UK N 1399086 widely and mostly describes the derivative of cephalosporin represented by the following General formula (A):

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where R11represents hydrogen or an organic group;

R12represents a monovalent esterified organic group which is chemically bound to the oxygen atom through a carbon atom;

B represents -- S -- or >S _ O

P represents an organic group.

After developing the above compounds continuously attempts were made to develop antibiotic with improved antibacterial activity, especially against gram-negative strains. As a result of such attempts, in U.S. Pat. UK N 15221 described cephalosporin antibiotic represented by the following General formula (I) where the connection represented in the form of SYN-isomer or a mixture of SYN - and anisomerous containing at least 90% of the SYN-isomer:

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where R13represents follow or thienyl group;

R14represents C1-4-alkyl, C3-4-cycloalkyl, furylmethyl or thienylmethyl group;

R15represents hydrogen, carbamoyl, carboxymethyl, sulfonanilide, having superior antibacterial activity against both gram-positive strains and gram-negative strains, and broad spectrum antibacterial action. In result, they have developed numerous connections of cyclosporine, it has a structure similar to the structure of the compounds of the above formula (B).

This development has caused a variety of changes, including the introduction of alluminare in the 7-position and specific groups at C-3 position Severnogo kernel formula (In).

For example, U.S. Pat. Belgium N 852427 discloses cephalosporin antibiotic, which is produced from the compounds of formula (A) by the substitution R11various other organic groups, for example, 2-amino-imazalil-4 group, and attach the oxygen atom of acetaminop to aliphatic hydrocarbon group, which in turn may be substituted by a carboxyl group. In this connection, the substituent in position 3 can be acyloxymethyl, hydroxymethyl, formyl, optionally substituted heterocyclic timeteam etc.

Compounds described in the aforementioned patents, are entirely different in structure from the compounds of the present invention.

activity against a broad spectrum of pathogenic microorganisms, including some gram-negative bacterial strains that produce-lactamases. One attempt consists in the introduction of specific groups, for example, various heterocyclic groups, aryl or alkylsulfonyl, aryl or Uralkalij group in position C-7, in particular, R12the compounds of formula (A), where R11is 2-aminothiazol-4 group. In the result, it was found that the compounds of cafema, in which R12is a-carboxy-3,4-substituted benzyl group, exhibit potent antibacterial activity against a broad spectrum of pathogenic microorganisms. Such connection cafema represented in many patents, for example, PCT/JP 86/00140, European application for Pat. N 87312525.2 etc.

In particular, in the application PCT/JP 86 presents the connection cafema having the following General formula (C):

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where R16represents hydrogen or a protective group for amino group;

R17and R18represent hydrogen, methyl, carboxyl protected carboxyl or an oxygen atom;

R19and R20represent hydrogen or oxygen atom;

R21represents hydrogen or a protective group for carboxyl group, a, b, and c capriolinae application PCT compounds are described in detail, when the substituent in position 7 may include (Z)-2-(2-aminothiazolyl-4)-2-( a-carboxy-3,4-substituted, benzylacetone)acetamidoxime, which is described in the present invention.

However, the structure of this compound differs from the structure of the compounds of the present invention, because in component-CH2V, is present at position C-3, heteroatom (S or N) Y is associated with position C-3 carambola kernel via a methylene bridge connection, whereas the connection of the present invention heteroatom in the corresponding component associated with cavemosum core through propenyloxy bridge.

In addition, although Y in the above-mentioned patent application may represent a substituted pyridine group, there is no mention or indication of substituted pyridine group, which is described in the present invention.

Moreover, in European application for Pat. N 87308525.2 described connection cafema represented by the following General formula (D):

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where R26represents hydrogen or a protective group for amino group;

R27and R28independently from each other represent hydroxy or substituted by a hydroxy-group; or R27and R28together can form a substituted cyclica the group;

R31represents hydrogen or C1-3is an alkyl group substituted by 1 to 3 atom (s) halogen (s);

Z is >S or S _ 0, and

the dotted line indicates the connection 2-cafema or 3-cafema.

However, the Deputy entered in the position 3 in the aforementioned European patent differs from the C-3 substituent in the compound of the present invention.

In addition, in European Pat. N 264091 disclosed connection cafema having the following General formula (E):

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where R32represents a lower alkyl group substituted by fluorine, or lower alkyl group substituted with cyano;

A represents A cyclic or acyclic AMERIGROUP.

In the above patent presents several cyclic AMERIGROUP in example A. However, it does not contain references or hints about pyrimidines group, which is described in the present invention. In addition, the structure of the Deputy 7 - in connection this patent also differs from the structure of the substituent in the compound of the present invention.

The present inventors based on the above-mentioned prior art in this area has been continuously engaged in the development of cephalosporin soegianto, including b-lactamase producing gram-negative bacterial strains, as well as having improved pharmacokinetic properties. In the result, it was found that a certain combination of cyclosporine with (Z)-2-(2-aminothiazolyl-4(or aminothiadiazole-4)-2-( a-carboxy-3,4-substituted, benzylacetone)acetamidoxime in position 7 - b and, at the same time, optionally substituted pyrimidinediamine group in position C-3 meets the above objectives.

So, now we can generalize the present invention.

Therefore, the aim of the present invention is the provision of a new cephalosporin compounds having General formula (I) as defined above, which has potent antimicrobial activity, broad spectrum antibacterial action and improved pharmacokinetic properties.

Another purpose of this invention is the provision of a method of obtaining a new cephalosporin compounds of formula (I).

In addition, another purpose of this invention is the provision of a medicinal product containing a new cephalosporin compound of the formula (I) as an active ingresa invention. These goals should be interpreted only to illustrate some of the features and applications that are relevant to the present invention.

Other many useful results can be obtained by applying the presented invention at different ways of modification within the scope of the description. Thus, different goals, and a more complete understanding of the invention may be obtained by reference to the description of the invention in addition to the scope of the invention defined by the claims.

In one aspect the present invention relates to new cephalosporin compound represented by the General formula (I):

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where R1represents hydrogen or a protective group for amino group;

R2and R3may be the same or different and independently of one another represent hydrogen or a protective group for a hydroxy-group;

R2and R3together can form a protective group for cyclic diol group,

R4represents hydrogen or a protective group for carboxyl group;

R5, R6and R7independently of one another represent hydrogen, amino, or substituted amino, hydroxy, alkoxyl they are attached, can form C3-7loop;

Q represents CH or N, and its pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable ether complex, hydrate and MES and its isomers.

The definition of R1R7in the above formula (I) will be more specifically described hereinafter. The most preferred example of R1R4is hydrogen; and R2and R3may be the same or different, and most preferably are hydrogen or acetyl. A preferred example of R5is hydrogen or amino; a preferred example of R6and R7independently of one another is hydrogen, amino or methyl; preferred example of a loop that can be formed R5and R6together with the carbon atoms to which they are attached, is a cyclopentane or cyclohexane.

As in the above formula (I), the carbon atom that is attached to 3,4-substituted phenyl group, is an asymmetric center, the compound of formula (I) can be represented in the form diastereomeric isomer. Accordingly, it should be understood that the present invention includes a separate diastereomeric isomer to coodinate tautomeric isomer, also included in the scope of the present invention. In addition, the present compound of the formula (I) can be represented in the form of CIS - or TRANS-geometrical isomers, depending on the geometric configuration of the double bonds propenyloxy group as part of the C-3 substituent. Accordingly, the present invention also includes such geometric isomers and their mixture.

The compounds of formula (I) in accordance with the present invention can be presented in the form of geometric isomers, including SYN-isomer or SYN - and anisomerous mixture containing 90% or more of the SYN-isomer. In the scope of the present invention also includes a hydrate and MES the compounds of formula (I). In addition, when the compound of formula (I), Q is CH, as aminothiazoline group can be represented by the tautomeric isomer with aminothiazole group, such tautomer may also be included in the scope of the present invention:

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2-aminothiazol-4-yl 2-aminothiazoline-4-yl

When Q means N, aminothiadiazole group can be represented by the tautomeric isomer with aminothiadiazole group. Such tautomeric isomers are also included in the scope of the present invention:

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5-is threaded depending on the geometric configuration of the double bonds propenyloxy group as part of the C-3 substituent, the compound of formula (I) can be represented as the following CIS - and TRANS-isomers:

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This individual geometrical isomers and mixture is also included in the scope of the present invention. However, from the point of view of their antibacterial activities of the TRANS-isomer is more preferable.

Pharmaceutically acceptable non-toxic salt of the compound of formula (I) include salts of inorganic acids, for example hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, etc. salts of organic carboxylic acids, for example acetic acid, triperoxonane acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, almond acid, ascorbic acid, malic acid, etc. or salts of sulfonic acids, for example methanesulfonic acid, paratoluenesulfonyl acid, etc., and similar salts of other acids, which is usually used in the field of penicillin and cephalosporin.

These acidic extension get salt in accordance with the usual method. In addition, the compound of formula (I) may also be formed with non-toxic base with droxide alkali metal, bicarbonates or carbonates (e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and so on), hydroxides or carbonates of alkaline earth metal (e.g. calcium hydroxide, calcium carbonate, etc. or organic bases, for example, amino acids.

Physiologically hydrolyzable esters of compounds of formula (I) includes, for example, indaily, Caligraphy, methoxymethyl, pivaloyloxymethyl, glycidoxypropyl, phenylglycinonitrile, 5-methyl-2-oxo-1,3-DIOXOLANYL-4-methyl ether and other physiologically hydrolyzable esters which are usually used in the field of penicillins and cephalosporins. Such esters can be obtained in accordance with the known method.

According to another aspect of the present invention provides a method for obtaining compounds of formula (I). In accordance with this invention the compound of formula (I):

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where R1R7and Q are defined as previously described, its pharmaceutically acceptable salts, its physiologically hydrolyzable esters, hydrates and the solvate can be obtained by a method, wherein the compound having a track>represents hydrogen or a protective group for carboxyl group;

X represents halogen;

m denotes 0 or 1,

interacts with the compound having the following formula (III)

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where R5, R6and R7defined as described earlier, in the presence of a solvent and, if necessary, before or after removal of the protective group for amino group or a protective group for carboxyl group, or before or after recovery, S-oxide [S _ (O)]

In the formula above, the protective group R1for amino group means a conventional protective group for the amino group, such as acyl, substituted or unsubstituted ar(lower)alkyl (e.g. benzyl, diphenylether, triphenylmethyl, 4-methoxybenzyl, and so on), halo(lower)alkyl (e.g., trichloromethyl, trichloroethyl and so on), tetrahydropyranyl, replaced phenylthio, substituted alkylidene, substituted aralkylated, substituted colloden etc. Suitable acyl group as a protective group for the amino group can be aliphatic and aromatic acyl group or an acyl group having a heterocyclic ring. An example of such acyl groups may include C1-C5lowest alkanoyl (for example, formyl, acetyl, etc (for example, methylsulphonyl, ethylsulfonyl and so on) or ar(lower)alkoxycarbonyl (for example, benzyloxycarbonyl and so on), etc.

The above-mentioned acyl groups can contain suitable substituents selected from 1-3 halogen, hydroxy, cyano-, nitro-, etc. in Addition, the reaction product of an amino group with a silane, borane or a phosphorus compound may also act as a protective group for amino group. As a protective group, R4and R8for a carboxyl group may be any suitable conventional groups, which can easily be fixed during the flow process under mild conditions. Its specific example involves a complex (lower) alkilany ester (e.g. methyl ester, tert-butyl methyl ether, and so on), complex (lower) alkenilovyh ester (e.g. vinyl ester, allyl ether, and so on ), complex (lower) alkoxy (lower) alkilany ether (for example, methoxymethyl ether and so on), complex (lower) alkylthio (lower) alkilany ether (for example, methylthiomethyl ether and so on), complex halo (lower) alkilany ether (for example, 2,2,2-trichlorethylene ether and so on), substituted or unsubstituted complex Uralkaliy ether (for example, benzyl ester, complex R-nitrobenzyloxy ether complex R-methoxybenzyloxy ether and the enable acyl group (for example, formyl or-CORathe group in which Rais C1-8-alkyl, such as acetyl), alkoxycarbonyl group [e.g., CO2Ra(where Rais C1-8by alkyl)] silyl group [for example, (C1-4alkyl)silyl, such as trimethylsilyl or tert-butyldimethylsilyl] or borate [B (ORb)] or phosphate [-P(O)(ORb)2] group (where Rbis C1-4by alkyl); and the protective group for cyclic diol groups, which may be formed R2and R3includes C1-7alcaligenaceae (for example, methylenedioxy, Ethylenedioxy or isopropylidenedioxy), alcaligenaceae containing one or more substituent (s), for example, methoxymethylethoxy, diphenylmethoxy or carbonyloxy), cyclic borate group (for example, -OB(OH)O-), a cyclic phosphate group (for example, -OP(O)(OH)O -, or-OP(O)(ORb)O-, where Rbdefined as described earlier), or di(C1-4alkyl)selectiongroup (for example, dimethylsilicone), etc.

The above-mentioned protective group for an amino group, a hydroxy-group, a cyclic diol groups and carboxypropyl can be easily eliminated by hydrolysis, recovery, etc. When applying the existing image selected depending on the chemical properties of the compounds of formula (I).

Tsepliaeva group, X represents halogen, e.g. chlorine, fluorine, iodine, etc.

The dashed line in formula (II) means that the compound of formula (II) may be present in the form of any of the compounds of formula (II-a) or the compounds of formula (II-b) or a mixture of compounds of formula (II-a) and the compounds of formula (II-b):

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where R1R4, R8, m, Q and X are defined as described earlier.

The original compound of formula (II) used in the present invention, can be obtained in accordance with the following reaction scheme. That is, the compound of formula (II) can be obtained by activating compounds having the following General formula (IV) or its salt allermuir agent, the interaction of the activated compound with the compound of the formula (V) to obtain the compounds of formula (VI) and then the introduction of 3-halogenated propenyloxy group in position C-3 compounds of formula (VI), given at the end of the description.

In the above reaction scheme, R1R4, R8, m, Q and X are defined as described earlier.

The dashed line in the structure of formulas (V) and (VI) and formula (VII) and (VIII), which are described in the following, means that the corresponding link is unity formula (VI) acylated derivative as activated forms of the compounds of formula (IV) includes a salt of hydrochloric acid, the acid anhydride, mixed acid anhydride (preferably, the acid anhydride formed by methylchloroform, methansulfonate, p toluensulfonate or Chlorophyta), activated ester (preferably, the ester formed from the reaction of N-hydroxybenzotriazole in the presence of a condensing reagent such as dicyclohexylcarbodiimide), etc. in Addition, the acylation reaction can be performed using the free acid of the formula (IV) in the presence of a condensing reagent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc. in General, the acylation reaction is conveniently carried out in the presence of organic bases, for example tertiary amines (preferably, triethylamine, dimethylaniline, pyridine, etc. or inorganic bases, for example sodium bicarbonate, sodium carbonate, etc.

In this reaction, suitable solvents that may be used include halogenated hydrocarbons such as methylene chloride, chloroform, etc., tetrahydrofuran, acetonitrile, dimethylformamide, etc., in Addition, this reaction can also be used a mixed solvent consisting of two or more selected from the above is but to carry out at temperatures from -50oC to 50oC (preferably from -30oC to 20oC).

Allerease agent of the formula (IV) can be used in an equivalent weight or slightly excess amount (from 1.05 to 1.2 equivalent weight) relative to the compound of formula (V).

The compound of formula (II) are obtained from the compounds of formula (VI), obtained above, in accordance with a customary method. Specifically, the compound of formula (II) can be obtained by exposure of the compounds of formula (VI) conventional method (for example, Wittig reaction) to obtain the intermediate compounds of ilide formula (VII), which then interacts with the halogenated acetaldehyde:

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where R1R4, m, Q, and R8defined as described earlier.

The alternate connection of the formula (II) can also be obtained by activating the compounds of formula (IV) or its salt allermuir agent, and then the immediate interaction of the activated compound with the compound of the formula (VIII).

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where m, X and R8defined as described earlier.

In this method, the activation and the acylation of the compounds of formula (IV) is carried out in accordance with the method, which was previously described.

Upon receipt of the compounds of formula (I), a protective group for an amino group or a protective group for the carboxyl group of the compounds of formula (II) can be eliminated in the usual way, which is widely known in the field of cephalosporin. More specifically, the protective group can be removed by hydrolysis or recovery. When the protective group include aminogroup, preferably eliminate by aminoguanidine or aminoethanethiol and subsequent hydrolysis. To resolve three-(di)-phenylmethylene or alkoxycarbonyl group suitable acid hydrolysis, which can be realized when using organic acids, such as formic acid, triperoxonane acid, p-toluensulfonate acid, etc. or an inorganic acid, e.g. hydrochloric, etc.

A method of obtaining compounds of formula (III), which is used in the method in accordance with the present invention, described in the following examples.

Meanwhile, upon receipt of the compounds of formula (I) by Eitel, which includes a lower alternately, for example acetonitrile, propionitrile etc., halogenated lower alkanes, for example, harmatan, dichloromethane, chloroform, etc., ethers, such as tetrahydrofuran, dioxane, ethyl ether, etc. amines, for example, dimethylformamide, etc. esters, e.g. ethyl acetate, etc., ketones, such as acetone etc., hydrocarbons such as benzene, etc., alcohols such as methanol, ethanol and so on sulfoxidov, for example, dimethylsulfoxide, etc. etc. or a mixture of two or more substances selected from them. The reaction is usually carried out at temperatures from -10oC to 80oC (preferably from 20oC to 40oC). The compound of formula (III) may be used in quantities of from 0.5 to 2 equivalent weights, preferably from 1.0 to 1.1 equivalent weight relative to the compound of formula (II).

The reaction product obtained above reaction, can be treated by various methods, for example, re-crystallization, infortm, column chromatography on silica gel, ion-exchange chromatography on resin, etc., for isolation and purification of the desired compounds of formula (I).

As described above, the compound of formula (I) exhibits a wide antibacterial is organizmov, including gram-positive and gram-negative strains. Similar antimicrobial activity may also be applicable to numerous gram-negative bacterial strains that produce-lactamases. Therefore, the compound of formula (I) can be effectively used for the prevention and treatment of bacterial infections of animals and humans.

The compound of formula (I) in accordance with the present invention can be prepared according to a known method and using known pharmaceutical carriers and excipients in the form of a single dose or for filling in the packaging of the drug for repeated administration. The composition may be in the form of a solution, suspension or emulsion in oil or aqueous medium and may contain dispersing agents, suspendresume agents or stabilizers. In addition, the composition can be obtained in the form of a dry powder that can be dissolved before use in sterilized pyrogen-free water. The compound of formula (I) can be prepared in the form of a suppository using conventional suppozitornyj bases, such as cocoa butter or other glycerides. If necessary, the compound of the present invention may be appointed in combination the imposition of the present invention prepared in Vira single dose, preferably, a single dose contains from about 50 to 1500 mg of the compounds of formula (I) as an active ingredient. Prescribed dose of the compounds of formula (I) is determined by a specialist, depending on various factors such as weight and age of each patient, the condition and the severity of the disease. However, the daily dose for an adult patient is usually from 500 to 5000 mg, depending on the receive frequency, and method of drug administration. When the compound of formula (I) assign intramuscularly or intravenously, for an adult patient enough total daily dose of from about 150 to 3000 mg However, in the case of infections caused by certain bacterial strains may be the preferred a higher daily dose.

The compound of formula I and its non-toxic salt (preferably a salt of an alkaline metal salt, alkaline earth metal, an inorganic acid incremental salt, organic acid incremental salt and the salt of the amino acids) in accordance with the present invention are very suitable for the prevention and treatment of diseases caused by bacterial infections of animals and humans, due to their potent antimicrobial activity protevi.

The following are typical examples of the compounds of formula (I) in accordance with the present invention.

Typical compounds

1-1: 7-[(Z)-2-(2-aminothiazolyl-4)-2-(alpha-carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3- (4,6-diaminopyrimidine-1-yl)-1-propenyl-1]-3-cefem-4-carboxylate.

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1-2: 7-[(Z)-2-(2-aminothiazolyl-4)-2-( -carboxy-3,4-dihydroanthracene)acetamido]-3-[(E)-3- (4-aminopyrimidine-1-yl)-1-propenyl-1]-3-cefem-4-carboxylate.

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1-3: 7-[(Z)-2-(2-aminothiazolyl-4)-2-( -carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3-(4-amino - 5,6-cyclopentenopyridine-1-yl)-1-PROPYNYL-1-]-3-cefem-4-carboxylate.

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1-4: 7-[(Z)-2-(2-aminothiazolyl-4)-2-( -carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3-(4,6 - diamino-5-methylpyrimidine-1-yl)-1-propenyl-1-]-3-cefem-4-carboxylate.

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1-5: 7-[(Z)-2-(2-aminothiazolyl-4)-2-( -karbasi-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3- (4,5,6-triaminopyrimidine-1-yl)-1-propenyl-1]-3-cefem-4-carboxylate.

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Hereinafter the present invention will be explained in more detail based on the subsequent preparation examples and working examples. However, it should be understood that the present invention is not limited to these premerger)acetic acid

A. Synthesis of 2-(3,4-dihydroxyphenyl)-2-hydroxy-1,1,1-trichloroethane.

To a solution of 440 g of 1,2-dihydroxybenzene dissolved in 1 l of methylenechloride added 1036 g of monohydrate trichloroacetaldehyde and then the reaction solution was cooled to 0oC. thereto dropwise slowly added 102 g of triethylamine. The reaction solution was heated to room temperature, was stirred for 20 min, heated to 50oC and then stirred for another three hours while maintaining the same temperature. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove methylenechloride.

The residue was dissolved in 4 l of ethyl acetate, sequentially washed 2400 ml of 0.5 N aqueous solution of hydrochloric acid and 2 l of saturated salt solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent and obtain 540 g of the named compound.

NMR ( acetone-d6): 5.2 (d, 1H), 6.0 (d, 1H), 6.8 (d, 1H) 7.0 (d, 1H), 7.2 (d, 1H), 7.9 (s, 1H) 8.0 (s, 1H)

B. Synthesis of a-trichloromethyl-3,4-0-isopropylthioxanthone alcohol.

515 g of 2-(3,4-dihydroxyphenyl)-2-hydroxy-1,1,1-trichloroethane, synthesized in preparation example 1(A), was dissolved in 2.5 liters of Bense under reflux. This reaction was performed in a reaction vessel equipped with a Soxhlet extraction apparatus, in which the extraction tube was filled with 600 g of calcium chloride to remove the side product of the reaction of methanol. After 2 h to the reaction mixture was added 77 ml of 2,2-dimethoxypropane and the mixture was heated under reflux for a further 3 hours After the reaction was completed, the reaction solution was cooled to room temperature, successively washed 1N aqueous solution of sodium bicarbonate (500 ml x 4) and saturated salt solution (500 ml 4), dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent.

The residue was purified column chromatography on silica gel to obtain 220 g called oily compounds.

NMR ( d CDCl3): 1.66 (s, 6N), 3.61 (d, 1H), 4.98 (d, 1H), 6.53-6.90 (m, 3H)

C. Synthesis of 2-(3,4-0-isopropylidenediphenol)-2-gidroksioksida acid.

119,4 g of the monohydrate of lithium hydroxide dissolved in 500 ml of water and then cooled to 0oC. To an educated solution was added 201 g a-trichloromethyl-3,4-0-isopropylthioxanthone alcohol obtained in preparatory example 1(B) and 413 ml of dioxane and the mixture was stirred at room temperature is 6N aqueous solution of hydrochloric acid there was added 120 g of ice. The mixture was stirred for 30 min to precipitate the solid product which was then filtered, washed with 1.8 l of water and 700 ml of chloroform and dried under nitrogen to obtain 60 g of the named compound.

NMR ( DMSO d-d6): to 1.61(s, 6N), 4.85(s, 1H), 6.60-6.83 (m, 3H), 8.2 (bs, 2H)

D. Synthesis diphenylmethylene ether 2-(3,4-0-isopropylidenediphenol)-2-hydroxyoctanoic acid.

50 g of 2-(3,4-0-isopropylidenediphenol)-2-hydroxyoctanoic acid obtained in preparation example 1(C), was dissolved in 400 ml of acetone and then there was added dropwise 1 M diphenyldiazomethane dissolved in diethyl ether until the termination of nitrogen excretion. After complete addition, the reaction mixture was stirred for another 20 min and then was distilled under reduced pressure to remove solvent. The residue was purified column chromatography on silica gel to obtain 70 g of the named compound.

NMR ( d CDCl3): 1.69(s,6N), 5.62(d,1H), 6.20(d,1H), 6.70(d,1H), 6.87(s, 1H), 6.89(d, 1H), 6.97 (d, 1H), 7.26 (b, 10H)

E. Synthesis diphenylmethylene ether, 2-bromo-2(3,4-0-isopropylidenediphenol)acetic acid.

108 g diphenylmethylene ether 2-(3,4-0-isopropylidenediphenol)-2-hydroxyoctanoic acid obtained in preparatory example is of 7.4 g tribromide phosphorus and then the temperature of the reaction solution was raised to -15oC.

The reaction mixture was stirred for 20 minutes After completion of the reaction, the reaction solution was distilled under reduced pressure to remove solvent. The residue was dissolved in 1 l of ethyl acetate, washed with saturated salt solution (1 l 4), dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent and obtain 115,96 g of the named compound.

NMR ( d CDCl3): 1.66(d, 6N), 5.41(s, 1H), 6.63(d, 1H), 6.84(s, 1H), 6.86(d, 1H), 6.97(s, 1H), 7.25(b, 10H).

Preparatory example 2: Synthesis of 2-{2-(triphenylmethyl)aminothiazol-4} -2(alpha diphenylmethylsilane-3,4-0-isopropylidenedicyclohexanol) acetic acid

A. Synthesis of allyl ester 2-{2-(triphenylmethyl)aminothiazol-4}-2-( a-diphenylethylenediamine-3,4-0-isopropylidenedicyclohexanol)acetic acid.

To a solution of 58,18 g allyl ether 2-(2-triphenylimidazole-4)-2-gidroksiiminobetulonovoi acid, dissolved in 140 ml of dimethylformamide, added 61 g of potassium carbonate and 29.4 g of potassium iodide. The reaction solution was cooled to 0oC and then to it is added dropwise within one hour was added to the solution 80,16 g diphenylmethylene ether, 2-bromo-2-(3,4-0-isopropylidenediphenol)expnsion the mixture was stirred for another 20 minutes After completion of the reaction, the reaction solution was distilled under reduced pressure to remove solvent. The residue was dissolved in 2 l of ethyl acetate, washed with saturated salt solution (400 ml x 6), dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent. The obtained solid product was purified column chromatography on silica gel to obtain 89 g of the named product.

NMR ( d CDCl3): 1.69(s, 6N), 4.81(d, 2H), 5.27(ABq, 2H), 5.79(s, 1H), 5.80-5.99(m, 1H), 6.53(s, 1H), 6.64(d, 1H), 6.78(d, 1H), 6.87(s, 1H), 7.13-7.36(m, N).

B. Synthesis of 2-{2-(triphenylmethyl)aminothiazol-4}-2-( a-diphenylethylenediamine-3,4-0-isopropylidenedioxy)-acetic acid.

60 g of allyl ester 2-{2-(triphenylmethyl)aminothiazol-4}-2-( a-diphenylethylenediamine-3,4-O-isopropylidenedioxy)acetic acid obtained in preparation example 2(A), was dissolved in 500 ml of methylenechloride.

To an educated solution was added 14.5 g of 2-ethylhexanoate potassium, 3.75 g of triphenylphosphine and 0.6 g of tetrakis(triphenylphosphine) palladium and the mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction solution was washed with a saturated solution of salt (500 m is Italia. The residue was purified column chromatography on silica gel to obtain 50 g of the named compound.

NMR ( d CDCl3): 1.70(s, 6N), 5.68(s, 1H), 6.55(s, 1H), 6.66(d, 1H), 6.80(d, 1H), 6.89(s, 1H), 7.04-7.27(m, N).

Preparatory example 3: Synthesis of parametersjpanel-3-chloromethyl-7-[(Z)-2( a-diphenylethylenediamine-3,4-0-isopropylidenedioxy)-2-{2-(triphenylmethyl)aminothiazol-4}acetamido]-3-cefem-4-carboxylate

36 g parametersjpanel-7-amino-3-chloromethyl-3-cefem-4-carboxylate suspended in 950 ml of methylenechloride and there added to 28.1 g of pyridine. The reaction solution was cooled to -20oC and to it was added 50,09 g of 2-{ 2(triphenylmethyl)aminothiazol-4} 2-( a-diphenylethylenediamine-3,4-0-isopropylidenedicyclohexanol)acetic acid obtained in preparation example 2(B). The reaction mixture was stirred for 5 min, it was added 13,62 g of phosphorus oxychloride and the mixture is then stirred for a further 30 minutes After completion of the reaction, the reaction solution was washed with saturated salt solution (400 ml x 3), dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent. The obtained solid was purified column chromatography on silica gel to receive the, H), 3.83(s, 3H), 4.51(q, 2H), 4.96(d, 1H), 6.27(s, 2H), 5.87(dd, 1H), 5.95(s, 1H), 6.6-7.45(m, N), 8.21(d, 1H).

Preparatory example 4: Synthesis of parametersjpanel-7-[(Z)-2-( a-diphenylethylenediamine-3,4-O-isopropylidenedioxy)-2 - 2-(triphenylmethyl)aminothiazol-4} acetamido] -3-[(Z)-3-chloro-1-propenyl-1] -3-cefem-4-carboxylate

A. Synthesis parametersjpanel-7-[(Z)-2-( a-diphenylethylenediamine-3,4-0-isopropylidenedioxy)-2-2-(triphenylmethyl)aminothiazol-4} acetamido] -3-triphenylphosphonium-3 - cefem-4-carboxylicacid.

28,41 g of the compound obtained in preparatory example 3, was dissolved in 150 ml of acetone and then there were sequentially added 7,52 g of triphenylphosphine and 3.76 g of sodium iodide. The reaction mixture was stirred at room temperature for 40 minutes After completion of the reaction, the reaction solution was distilled under reduced pressure to remove solvent. To the residue was added 300 ml of distilled water, and the mixture is thoroughly shaken to separate the layers. The separated organic layer was dried over 50 g of anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent. Formed solid product was washed with 400 ml of diethyl ether and then dried to receive the 3.85(s,3H), 3.88(q, 2H), 4.98(d, 1H), 5.30(s, 2H), 5.74-5.92(m, 2H), 5.96(s, 1H), 6.57(d, 1H), 6,63-7.42(m, N), 8.26(d, 1H).

B. Synthesis parametersjpanel 7-[(Z)-2-( a-diphenylethylenediamine-3,4-0-isopropylidenedioxy) -2-{2-(triphenylmethyl)aminothiazol-4} acetamido] -3-[( a )-3-chloro-1 - propenyl-1]-3-cefem-4-carboxylate.

and 32.3 g of the compound obtained in preparatory example 4(A), was dissolved in a mixed solvent consisting of 300 ml of chloroform and 100 ml of aqueous saturated solution of sodium chloride and then thereto was added 28 ml of 1 N aqueous sodium hydroxide solution. The reaction mixture was stirred for 20 min at 15oC. After completion of the reaction, the reaction solution advocated for the separation of layers. To separate the organic layer was added 10 g of potassium carbonate, and the mixture was stirred for 10 min and then filtered. To the filtrate was added 18,06 g 40% aqueous solution of chloroacetaldehyde and the mixture was stirred for 30 min at 28oC. After completion of the reaction, the reaction solution advocated for the separation of layers, the separated organic layers were dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent.

Formed solid product was column purified chromium is SUB>3): 1.60(d, 6N), 3.32(q, 2H), 3.82(s, 3H), 3.84(q, 2H), 4.96(d, 1H), 5.28(s, 2H), 5.76-5.84(m, 2H), 5.95(s, 1H), 6.53(d, 1H), 6.63-7.45(m, N), 8.21(d, 1H).

Preparatory example 5: Synthesis of parametersjpanel 7-[(Z)-2-( a-diphenylethylenediamine-3,4-0-isopropylidenedioxy)-2 - 2-(triphenylmethyl)aminothiazol-4} acetamido] -3-[(Z)-3-iodo-1-propenyl-1] -3-cefem-4-carboxylate

17,24 g of the compound obtained in preparatory example 4(B), was dissolved in 200 ml of acetone and then there was added 11,32 g of sodium iodide. The reaction mixture was stirred for 2 hours at a temperature of from 15oC to 20oC. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove solvent. The residue was extracted with 300 ml of ethyl acetate, washed 3 times with 300 ml of saturated salt solution, dried over anhydrous sodium sulfate, distilled under reduced pressure to remove solvent and then concentrated. The residue is added dropwise slowly added to 300 ml of diethyl ether for curing formed product, which is then filtered off, washed with 200 ml diethyl ether and was dried to obtain 15.3 g of the titled compound as a pale yellow solid product.

NMR ( d CDCl3): 1.60(d, 6N), 3.34(q, 2H), 3.81(s, 3H), 3.83(q, 26-diaminopirimidina

167,78 g 2-mercapto-4,6-diaminopirimidina dissolved in 1007 ml of 1.5 N aqueous solution of sodium hydroxide, and the reaction solution was cooled to 0-4oC. To this reaction solution was slowly dropwise added 267,55 g of 30% aqueous hydrogen peroxide solution. After completion of the reaction slowly dropwise added 170 ml of acetic acid to precipitate the solid product which was then filtered, successively washed with 200 ml of distilled water, 200 ml of methanol and 400 ml of diethyl ether and dried to obtain 185,56 g of solid product in the form of a white powder. The thus obtained solid product was slowly added to 1 liter of concentrated hydrochloric acid, which was cooled to 0-4oC. the Reaction solution was stirred for one hour at the same temperature, warmed to room temperature and then was stirred for another 8 hours Solid product obtained during the reaction, was filtered, then washed in 1 l of acetone and 1 l of diethyl ether and then dried to obtain 109,13 g of the above compound in the form of a hydrochloric salt. 109,13 g of the thus obtained solid product is suspended in 400 ml of distilled water and then there was added 200 ml of 15% aqueous sodium hydroxide solution. The mixture is washed with 400 ml of ethanol and then dried to obtain to 100.7 g of the named compound as a white powder.

NMR ( DMSO d-d6): 5.34(s, 1H), 6.01(s, 4H), 7.78(s, 1H).

Preparatory example 7: Synthesis of 4-aminopyrimidine

In accordance with the same procedure as described in preparatory example 6, except that instead of 167,78 g 2-mercapto-4,6-diaminopirimidina used in preparatory example 6, was used 150,07 g 2-mercapto-4-aminopyrimidine, got 91,24 g of the named compound as a white powder.

NMR ( DMSO d-d6): 6.42(d, 1H), 6.85(s, 2H), 8.04(d, 1H), 8.36(s, 1H).

Preparatory example 8: Synthesis of 5-methyl-4,6-diaminopirimidina

In accordance with the same procedure as described in preparatory example 6, except that instead of 2-mercapto-4,6-diaminopirimidina used in example 6 was used 184,30 g 2-mercapto-2-methyl-4,6-diaminopirimidina, got 109,47 g of the named compound as a white powder.

NMR ( DMSO d-d6): 1.83(s, 3H), 6.48(s, 4H), 7.84(s, 1H)

Preparation example 9: Synthesis of 4-amino-5,6-cyclopentenopyridine

In accordance with the same procedure as described in preparatory example 6, except that instead of 2-mercapto-4,6-diaminopirimidina used in preparatory example is I in the form of a white powder.

NMR ( DMSO d-d6): 1.96(m, 2H), 2.62(t, 2H), 2.68(t, 2H), 6.56(s, 2H), 8.13(s, 1H).

Preparatory example 10: Synthesis of 4,5,6-triaminopyrimidine

In accordance with the same procedure as described in preparatory example 6, except that instead of 2-mercapto-4,6-diaminopirimidina used in preparatory example 6, was used 200 g of 2-mercapto-4,5,6-triaminopyrimidine, received 89 g of the named compound as a white powder.

NMR ( DMSO d-d6): 3.82(s, 2H), 5.60(s, 4H), 7.42(s, 1H).

Further, each compound of examples 1-5 can be in the form of two diastereoisomers (R and S isomer) depending on the spatial configuration of the asymmetric carbon atom that is attached 7 b dihydroxybenzyl group. In addition, when the connection is subjected to liquid chromatography high pressure (HP a C) using steel columns m-Bondapak C18 and the elution of 25% aqueous solution of methanol containing 0.5% acetic acid, compounds having a short retention time and a long retention time, were distinguished from each other by adding respectively "a" and "b" to the number of separate connections.

Example 1: Synthesis of 7-[(Z)-2-(2-aminothiazolyl-4)-2-( a-carboxy-forma: 1-1a, R-form: 1-1b)

5.0 g of the compound obtained in preparatory example 5, was dissolved in 20 ml of dimethylformamide there was added 1.52 g of 4,6-diaminopirimidina obtained in preparatory example 6. The reaction mixture was stirred for 2 h at a temperature between 35o40oC. After completion of the reaction, the reaction solution was extracted with 200 ml of ethyl acetate. The extract was washed 3 times with 200 ml of saturated salt solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove solvent. Thus obtained concentrate is slowly dropwise added to 300 ml of diethyl ether to precipitate the solid product which was filtered, washed with 200 ml of diethyl ether and then dried to obtain 4.3 g of a solid product in the form of a white powder. 4.3 g of the obtained solid product was dissolved in 14 ml of anisole. The reaction solution was cooled to 0 to 4oC. After slowly adding dropwise 26 ml triperoxonane acid reaction solution was heated to room temperature and then stirred for another one hour at the same temperature. After completion of the reaction, the reaction solution was cooled to minus minus 15oC. To this reaction solution is Lee, sequentially washed with 100 ml of acetone and 100 ml of diethyl ether and dried to obtain 1.8 g of pale yellow solid. 1.8 g thus obtained solid substance was separated in the form of the corresponding diastereoisomer fractional liquid chromatography (steel column m-Bondapak C18, 19 mm x 30 mm), while elution with 5% aqueous solution of methanol to obtain respectively 320 mg and 280 mg of the above mentioned compounds 1 - 1A and 1 1B as a white solid.

M. S. (FAB; M+1): 684

NMR ( d, D2O + NaHCO3)

1 1a: 3.33(q, 2H), 4.71(q, 2H), 5.02(d, 1H), 5.37(s, 1H), 5.63(d, 1H), 5.77(s, 1H), 5.72-5.95(m, 1H), 6.55(d, 1H), 6.77-7.02(m, 4H), 8.16(s, 1H)

1 - 1b: 3.33(q, 2H), 4.78(q, 2H), 5.01(d, 1H), 5.38(s, 1H), 5.61(d, 1H), 5.79(s, 1H), 5.82-5.96(m, 1H), 6.58(d, 1H), 6.76-7.01(m, 4H), 8.17(s, 1H)

1R (KBr, cm-1): 1775 ( b-lactam), 1670, 1620, 1580

Example 2: Synthesis of 7 [(Z)-2-(2-aminothiazolyl-4)-2-( a-carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3- (4-aminopyrimidine-1-yl)-1-propenyl-1]-3-cefem-4-carboxylate (S-form: 1 - 2a, R-form: 1 2B)

5.0 g of the compound obtained in preparatory example 5, was dissolved in 20 ml of dimethylformamide and then the reaction solution was processed in accordance with the same procedure as in example 1, except that instead of 4,6-diaminopirimidina, which is respectively received 360 mg and 340 mg of the above mentioned compounds in the form of a white solid.

M. S. (FAB, M+1): 669

NMR ( d, D2O + NaHCO3)

1 2a: 3.37(q, 2H), 4.37(q, 2H), 5.02(d, 1H), 5.37(s, 1H), 5.66(d, 1H), 5.82-5.96(m, 1H), 6.70-7.01(m, 6N), 7.98(d, 1H), 8.53(s, 1H),

1 2B: 3.33(q, 2H), 4.78(q, 2H), 5.01(d, 1H), 5.38(s, 1H), 5.61(d, 1H), 5.82-5.96(m, 1H), 6.70-7.01(m, 6N), 7.98(d, 1H), 8.53(s, 1H)

1R (KBr, cm-1): 1775 ( b-lactam), 1680, 1630, 1590

Example 3: Synthesis of 7-[(Z)-2-(2-aminothiazolyl)-4]-2-( a-carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3- (4-amino-5,6-cyclopentenopyridine-1-yl)-1-propenyl-1]-3-cefem-4 - carboxylate (S-form: 1 3a, R-form: 1 3b)

5.0 g of the compound obtained in preparatory example 5, was dissolved in 20 ml of dimethylformamide and then the reaction solution was processed in accordance with the same procedure as described in example 1, except that instead of 4,6-diaminopirimidina used in example 1, to obtain respectively 290 mg 285 mg of the above mentioned compounds 1 3A and 1 3b as a white solid, used 1,90 g of 4-amino-5,6-cyclopentenopyridine obtained in preparation example 9.

M. S.(FAB, M+1) 697

NMR ( d, D2O + NaHCO4)

1 3a: 2.11-2.31(m, 2H), 2.79(t, 2H), 3.08(t, 2H), 3.35(q, 2H), 4.73(q, 2H), 5.03(d, 1H), 5.38(s, 1H), 5.66(d, 1H), 5.84-6.01(m, 1H), 6.56(d, 1H), 6.77-7.01(m, 4H), 8.44(s, 1H)

1 - 3b: 2.12-2.29(m, 2H), 2.79(t, 2H), 3.06(t, 2H), 3.34(q, 2H), 4.72(q, 2H), 5.02(d, 1H), 5.38(s, 1H), 5.64([(Z)-2-(2-aminothiazolyl-4)-2-( a-carboxy-3,4-dihydroxybenzylamine)acetamido]-3-[(E)-3- (4,6-diamino-5-methylpyrimidine-1-yl)-1-propenyl]-3-cefem-4-carboxylate (S-form: 1 4a, R-form: 1 4b)

5.0 g of the compound obtained in preparatory example 5, was dissolved in 20 ml of dimethylformamide and then the reaction solution was processed in accordance with the same procedure as described in example 1, except that instead of 4,6-diaminopirimidina used in example 1 was used to 1.67 g of 4,4-diamino-5-methylpyrimidine obtained in preparation example 8 were respectively received 300 mg 305 mg of the above mentioned compounds 1 4a 1 4b as a white solid.

M. S. (FAB, M+1): 698

NMR ( d, D2O + NaHCO3< / BR>
1 4a: 1.85(s, 3H), 3.34(q, 2H), 4.76(q, 2H), 5.00 (d, 1H), 5.38(s, 1H), 5.62(d, 1H), 5.68-5.92(m, 1H), 6.63(d, 1H), 6.80-7.01(m, 4H), 8.18(s, 1H)

1 4b: 1.84(s, 3H), 3.34(q, 2H), 4.73(q, 2H), 5.00(d, 1H), 5.38(s, 1H), 5.62(d, 1H), 5.68-5.92(m, 1H), 6.63(d, 1H), 6.80-7.01(m, 4H), 8.17(s, 1H)

1R (KBr, cm-1): 1770 ( b-lactam), 1680, 1620, 1570

Example 5: Synthesis of 7-[(Z)-2-(2-aminothiazolyl-4)-2-( a-carboxy-3,4-dihydroxybenzylamine)acetamido] -3-[(E)-3- (4,5,6-triaminopyrimidine-1-yl)-1-propenyl-1]-3-cefem-4-carboxylate (S-form: 1 5a, R-form: 1 5b)

5.0 g of the compound obtained in preparatory example 5, was dissolved in 20 ml of dimethylformamide and then the reaction solution was processed in accordance with the same procedure as described in example 1, except for the obtained in preparation example 10, this was accordingly 330 mg and 340 mg of the above mentioned compounds 1 5a 1 5b as a white solid.

M. S. (FAB, M+1): 699

NMR ( d, D2O + NaHCO3)

1 5a: 3.32(q, 2H), 4.70(q, 2H), 5.04(d, 1H), 5.32(s, 1H), 5.64(d, 1H), 5.70-5.91(m, 1H), 6.57(d, 1H), 6.71-7.05(m, 4H), 7.49(s, 1H),

1 5b: 3.32(q, 2H), 4.74(q, 2H), 5.03(d, 1H), 5.33(s, 1H), 5.61(d, 1H), 5.77-5.93(m, 1H), 6.58(d, 1H), 6.70-7.04(m, 4H), 7.50(s, 1H)

1R (KBr, cm-1): 1770 ( b-lactam), 1680, 1610, 1580.

Pharmacological utility connections in accordance with the present invention was evaluated in rats, based on the minimum dose of antibiotic, oppressive growth of the strains tested, including the standard strains, the strains isolated in the clinical field, strains resistant to antibiotics, and the strains that produce beta-lactamase, and pharmacokinetic properties compared with ceftazidime, used as control drugs. Minimum dose of antibiotic, generally hopeless growth of the tested strains was determined by double dilution of the tested compounds, their suspension in agar nutrient medium Miiller-Hinton, inoculation of 2 ml of the suspension containing the tested strains, with 107CFU (units forming the colony) to 1 ml in a nutrient medium and then culturing epicheskie properties of the compounds of the present invention was determined using SD rats (a ) weighing 23010, the Subjects of the sample were injected into the femoral vein in the amount of 20 mg/kg 4-5 test animals. Through 1, 2,5, 5, 10, 20, 40, 60, 120 and 180 min after injection of femoral vein took the blood, which is then subjected to biological analysis using the method in the agrarian gel for measuring the concentration of substances in the blood.

The results of pharmacokinetic properties, i.e., TI/2, and AUC is the area under the curve), calculated from the above-mentioned concentration of the substance in blood that is described in the following table.2.

Although this invention is described in its preferred form with a certain degree of detail, experienced specialists in this field will understand that the present description of its preferred form is made only as an example and that you can resort to numerous changes in the details of interpretation, combinations and cooking without deviating from the essence and scope.

1. The connection of a cephalosporin of the General formula I

< / BR>
their pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, isomers, having the S-configuration of the double bond in propenyloxy group, SYN-isomers and optical isomers, where R1represents hydrogen or aminosidine is a hydrogen or hydroxyamino group, or

R2and R3taken together, can education protective cyclic diol group;

R4represents hydrogen or carboxyamide group;

R5R7independently from each other represent hydrogen, an amino group and C1WITH4-alkyl, or R5and R6taken together with the carbon atoms to which they are attached, may form WITH3WITH7-cycloalkyl.

2. The compound of General formula I under item 1, in which R1and R4independently of one another represent hydrogen, R2and R3are the same or different and represent hydrogen or acetyl, R5represents hydrogen or amino, and R6and R7independently of one another represent hydrogen, amino or methyl, or R5and R6taken together with the carbon atoms to which they are attached, may form WITH5WITH6-cycloalkyl;

3. The compound of General formula I on p. 1, which is chosen from the group consisting of 7-/(Z)-2-(2-aminothiazolyl-4)-2-(alpha-carboxy-3,4 - dihydroxybenzylamine)acetamido/-3-/(E)-3-(4,6-diaminopyrimidine - 1-yl)-1-propen-1-yl/-3 cefem-4-carboxylate (R - and S-forms); 7-/Z)-2-(2-aminothiazol the FEM-4-carboxylate (R - and S-forms); 7-/(Z)-2-(2-aminothiazolyl-4)-2-(alpha-carboxy-3,4 - dihydroxybenzylamine)acetamido/-3-/(E)-3-(4-amino-5,6 - cyclopentenopyridine-1-yl)-1-propen-1-yl/-3-cefem-4-carboxylate (R - and S-forms); 7-/(Z)-2-(2-aminothiazol-4-yl)-2-(alpha-carboxy,4-dihydroxybenzylamine)acetamido/-3-/(E)-3-(4,6-diamino-5 - methylpyrimidine-1-yl)-1-propen-1-yl/-3-cefem-4-carboxylate (R - and S - forms); 7-/(Z)-2-(2-aminothiazol-4-yl)-2-(alpha-carboxy,4-dihydroxybenzylamine)acetamido/-3-/(E)-3-(4,5,6 - triaminopyrimidine-1-yl)-1-propen-1-yl/-3-cefem-4-carboxylate (R - and S - forms).

4. The method of obtaining compounds of General formula I on p. 1, and their pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, isomers, having the S-configuration of the double bond in propenyloxy group, SYN-isomers and optical isomers, characterized in that the compound of General formula II

< / BR>
where R1R4have the specified values;

R8represents hydrogen or carboxyamide group;

X is halogen,

subjected to interaction with the compound of General formula III

< / BR>
in which R5R7have the specified values,

in the presence of a solvent and, if necessary, carry out the removal of the amino - and carboxyamides g

 

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