Connection cafema and their pharmaceutically acceptable salts

 

(57) Abstract:

In the present invention proposed new derivatives of cafema formula 1 in which R1is amino or a protected amino group, R2represents lower alkyl which may be substituted by 1 to 3 halogen atoms, R3is COO, carboxy or protected carboxy, R4is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R5is amino or a protected amino group, R6represents hydrogen or lower alkyl, Xis triptorelin, n is 0 when R3is COOprovided that n is 1 when R3is carboxy or protected carboxy and its pharmaceutically acceptable salt, exhibiting antibacterial activity. 6 C.p. f-crystals, 3 tables.

The present invention relates to a new compound cafema and its pharmaceutically acceptable salts.

More specifically, it relates to a new compound cafema and its pharmaceutically acceptable salts, which possess antimicrobial activity.

In line with this objective of the present invention consists in the join clause C is organizmov.

Another objective of the present invention is the provision of a method of obtaining Severnogo substance or its salt.

Target connection cafema is new and can be represented by the following General formula (I)

< / BR>
in which R1represents amino or a protected amino group,

R2lower alkyl which may have one or more suitable substituents,

R3this COOcarboxy - or protected carboxypropyl,

R4this is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

R5amino or protected amino group,

R6a hydrogen atom or lower alkyl,

Xrepresents an anion, and

n is 0 or 1,

provided that:

1) When R3this COOthen n is 0, and

2) when R3is carboxy or protected carboxypropyl, then n is 1.

With regard to the target substance (1), it is necessary to note the following points.

That is, the target substance (1) includes SYN-isomer, antisolar and mixtures thereof. SYN-isomer means the geometrical isomer having the partial structure represented by the following formula:

< / BR>
(in which R1in store partial structure, represented by the following formula:

< / BR>
(in which R1and R2each is such as described above), and all such geometric isomers and mixtures thereof are included in the scope of this invention.

In the present description and claims partial structure of these geometrical isomers and their mixtures, for convenience represented by the following formula:

< / BR>
(in which R1and R2each is such as described above).

The next point that should be noted is that pyrazolo-group substances (1) may also exist in tautomeric forms, such tautomeric equilibrium can be represented by the following scheme:

< / BR>
(in which R4, R5and R6each is such as described above).

Both of the above tautomeric isomers are included in the scope of the present invention, however, in the present description and claims the target substance (1) is presented for the convenience of a single expression pyrazolo group of formula (A).

Severnoe substance (I) of the present invention can be obtained using methods that are illustrated by the following reaction schemes.

< / BR>
< / BR>
< / BR>
< / BR>
R5ol is new, and it can be prepared by the following reaction schemes.

< / BR>
< / BR>
< / BR>
n each, as indicated above,

R7is a protected amino group and

z tsepliaeva group.

Some of the starting compounds (Y) or their salts are new, and they can be prepared in accordance with the methods disclosed in the following preparative examples, or similar methods.

Suitable pharmaceutically acceptable salts of the target substance (1) are conventional non-toxic mono - or double salts and include a metal salt such as a salt of an alkali metal (e.g. sodium salt, potassium salt, etc. and salts of alkaline-earth metal (e.g. calcium salt, magnesium salt, and others), ammonium salt, salt with organic base (e.g., salt of trimethylamine, salt, triethylamine salt of pyridine, picoline salt, salt dicyclohexylamine, salt N,N-dibenziletilendiaminom and others), additive salt of organic acid (e.g., formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate and others) and additive salt of inorganic acid (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and others), salt with the amino acid is evidena and subsequent description of the application examples of different definitions explained in detail as follows.

The term "lower" means from 1 to 6 carbon atoms, unless otherwise specified amount.

A suitable protecting group in the protected amino group" may include ar(lower) alkyl such as mono - or di-, or triphenyl(lower)alkyl (e.g. benzyl, phenethyl, 1-phenyl ethyl, benzhydryl, trityl and others), acyl, as explained below, and the like.

Suitable acyl residues may be aliphatic acyl, aromatic acyl, arylaliphatic the acyl and heterocyclic-aliphatic acyl derived carboxylic acid, of carbonic acid, carbamino acid, sulfonic acid, etc.

A suitable example is explained thus acyl group may be lower alkanoyl (for example, formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.) mono- (or di-or tri-)-halogen(lower)alkanoyl (e.g., chloroacetyl, TRIFLUOROACETYL, and others), lower alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxybenzoyl, hexyl-oxycarbonyl and others ), mono-(or di-, or three)halogen(lower)alkoxycarbonyl (for example, chlorocarbons, dichlorocarbene, trichlorocyanuric and others ), aroyl (for example, benzoyl, toluoyl, xyloyl, naphtol and others), ar(n is l (for example, phenoxycarbonyl, naphthalocyanines and others), aryloxy-(lower)-alkanoyl, such as phenoxy(lower)alkanoyl (for example, phenoxyacetyl, phenoxypropionyl and others), acilglycerol (for example, phenylglyoxal, afterpotential and others), ar(lower)alkoxycarbonyl, which may have suitable substituents(s) such as phenyl(lower)alkoxycarbonyl, which may have nitro or lower alkoxygroup (for example, benzyloxycarbonyl, ventilatsioonil, paranitroaniline, para-methoxybenzeneboronic and others), titilate, imidazolylalkyl, ferilizer, tetrazolate, triazolylmethyl, thiadiazolyl, tanypodinae, thiadiazolidine, lower alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl), isopropylphenyl, peterculter, butylsulfonyl and other arylsulfonyl (for example, penetrameter, trisulfonic, cellsurface, naphthylmethyl and others), ar(lower)alkylsulfonyl, such as phenyl(lower)alkylsulfonyl (for example, bansilalpet, phenylsulfonyl, Benzylalcohol and others), etc.

A preferred specific example thus "protected amino" may be ar(lower)alkylamino and lower alkanolamine group, more than what can be telelatino-, formamide and acetaminophe.

Suitable "protected carboxy" may be esterified with carboxypropyl or the like, and specific examples of essential functions specified in the esterified carboxylate can be such as a complicated lower alkilany ester (e.g. methyl ester, complex ethyl ester, complex propyl ether complex isopropyl ether complex butyl ether, complex isobutyl ether complex tert-butyl ether, complex pentalogy ether complex hexyl ester, complex 1-cyclopropyl-ethyl ester, and others), which may have suitable substituents(l), for example, lower alkanoyloxy(lower)alkilany ester (for example, a complex acetoxymethyl ether complex propionylacetate ether complex butyrylacetate ether complex veterinarinary ether complex pivaloyloxymethyl ether complex 1-acetoxymethyl ether, 1-propionylacetate ester, complex pivaloyloxymethyl ether, 2-propionylacetate ester, complex hexaniacinate ether and others), lower alkanesulfonyl (lower)-alkilany ester (for example, a complex 2-mutilative ether and others) or mono- (or di-, or three) halogen(lower)alkilany the th ester (for example, complex vinyl ether, allyl complex ether, and others); the lower alkinilovymi ester (for example, a complex atinlay ether complex propenyloxy ether and other); ar(lower)-alkilany ester which may have suitable substituent(s) (e.g. compound a benzyl ester, a complex 4-methoxybenzyloxy ether complex 4-nitrobenzyloxy ether complex finitely ether complex trailovic ether complex benzhydrylamine ether, complex, bis(methoxyphenyl)methyl ester, complex 3,4-dimethoxybenzyl ether, complex 4-hydroxy-3,5-di-tertbutylbenzene ether and other); complex arrowy ester which may have suitable substituent(s) (for example, a complex phenyl ether complex 4-hlorfenilovy ether complex trilogy ether complex 4-tertbutylphenyl ether complex Kilroy ether complex mesityloxy ether complex comenjoy ether and others); or the like, in which preferable may be mono - or di - or tri-phenyl(CL-C4)alkilany ester and the most preferred may be difficult benzhydrylamine ether.

Suitable "lower alkyl" may be alkyl with an unbranched or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, 2-ethylpropyl, hexyl or t is Teal.

Examples of "suitable substituent(s)" in the "lower alkyl which may have one or more suitable substituents(l)" may include halogen (e.g. fluorine, chlorine, bromine, iodine), etc.

Suitable examples of the mentioned lower alkyl having one or more suitable substituents(l) may include lower alkyl having one or more halogen atoms, such as vermeil, deformity, trifluoromethyl, 2-foretel, 2-chloro-2-foretel, 3-bromo-2-forproper, 1-chloromethyl-2-iodine-1-bromacil, 2-direcror, 1-dichloromethyl-1-methylethyl, 2-fluoro-4-chloro-5 - bromopentyl, 1-debtor-2-ethylpropyl, 2-fluoro-3-iohexol or etc., which may be preferred (CL-C4)alkyl having 1 to 3 halogen atoms, more preferred may be diploid(CL-C4)alkyl and the most preferred may be deformity.

Suitable "hydroxy(lower)alkyl" may include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1-(hydroxymethyl)ethyl, 1-hydrosylate, 1-hydroxymethyl-1-methylethyl, 3-hydroxyphenyl, 3-hydroxy-2-ethylpropyl, 6-hydroxyhexyl and the like, in which preferable may be hydroxy(CL-C4)alkyl and the most preferable one may be 2-hydroxyethyl.

Appropriate anion can be formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate, chloride, bromide, iodide, sulfate, phosphate, etc.

Suitable "tsepliaeva group" can be an atom is XI, tosyloxy, mesilate and others), the lowest alkanoyloxy (for example, atomic charges, propionyloxy and others), etc.

Methods of obtaining a target substance of the present invention are explained in detail below.

Method 1.

The target substance (1) or its salt can be obtained by reacting the compound (II) or its reactive derivative at the amino group or its salt with the compound (III) or its reactive derivative at the carboxy group or its salt.

Suitable reactive derivative at the amino group of compound (II) may include Schiff base imine type or its tautomeric isomer unaminoage type formed by reaction of compound (II) with a carbonyl compound such as aldehyde, ketone, etc., silyl derivative formed by the interaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)ndimethylacetamide, mono(trimethylsilyl)acetamide", she bis(trimethylsilyl)urea or similar derivative formed by the interaction of the compound (II) with phosphorus trichloride or phosgene, etc.

Suitable salts of the compound (II) and its reactive derivative can be referred to as uke compound (III) may include an acid halide, the acid anhydride, activated amide, an activated ester, etc., Suitable examples of the reactive derivatives may be an acid chloride acid; acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, and others), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g., methanesulfonate acid and others), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, somalina acid, trimethylhexane acid, pentane acid, isopentane acid, 2-ethylmalonate acid, tigaraksa acid, etc. or an aromatic carboxylic acid (e.g. benzoic acid and others), a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (for example, cinematology ester, methoxymethyl ester, complex dimethylaminomethylene [(CH3)2N=CH-]new ether, complex trichloranisole ether complex pentachlorphenol ether complex methylphenylene ether complex phenylazophenyl ether complex penaltiesfor, complex para-nitrophenyl-tiefer, complex para-cresyl-tiefer, complex carboxymethyl-tiefer, complex pyranyloxy ether complex pyridyloxy ether complex piperidinyl ether complex 8-chinolin-thioether and others), or an ester with N-hydroxidealuminum (for example, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole etc. etc. These reactive derivatives may not necessarily be selected from those corresponding to the type of compound (III).

Suitable salts of the compound (III) and its reactive derivative may be, as shown, for example, for the substance (I).

Usually the interaction is carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol and others), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which has no adverse effect on the reaction. These Trad is e (III) is used in the form of the free acid or in the form of its salts, preferably, the interaction is carried out in the presence of a conventional condensing agent such as N,N-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinobutyrophenone; N-cyclohexyl-N'-(4-di-acylaminoalkyl)carbodiimide, N, N'-diethylcarbamoyl, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-(2-Mei); pentamethylene-N-cyclohexylamine; diphenylethan-N-cyclohexylamine; ethoxyacetylene; 1-alkoxy-1-chlorethylene; trialkylphosphine; etiloleat; phosphorus oxychloride (chlorine phosphoryl), phosphorus trichloride; chloride thionyl; oxacillin; lower alkylsulfonic (for example, ethylchloride, isopropylcarbamate and others); triphenylphosphine; 2-ethyl-7-hydroxybenzotriazole salt; intramolecular salt of 2-ethyl-5-(metasulfite)isoxazoline hydroxide; 1-(para-chlorobenzenesulfonate)-6-chloro-1H-benzothiazole; the so-called reagent, Vilsmeier prepared by the interaction of N,N-dimethylformamide with chloride tiomila, phosgene, trichlorethylene ether Harborview acid, phosphorus oxychloride, chloride methanesulfonyl etc. or etc.

This reaction can also be carried out in the presence of inorganic or organization is in, pyridine, N-(lower)alkalifying, N,N-di(lower)alkylbenzenes or etc.

The reaction temperature is not critical, and generally the reaction is carried out or under cooling or under heating.

Method 2.

The target substance (1b) or its salt can be obtained by the inclusion of a substance (1A) or its salt to elimination reaction aminoamide group in R1a.

This reaction is carried out in accordance with a conventional method such as hydrolysis, repair, or etc.

Preferably the hydrolysis is carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and organic base, such as alkali metal (e.g. sodium, potassium, and others), alkaline earth metal (e.g. magnesium, calcium, and others ), hydroxide, or carbonate, or bicarbonate of these metals, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo-/4,3,0/non-5-ene, 1,4-diazabicyclo/2,2,2/octane 1,8-diazabicyclo/5,4,0/-unded-7-ene, or etc.

Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trithorax the GTC, sulfuric acid, hydrogen chloride, hydrogen bromide, and others).

The reaction of elimination using a Lewis acid such as troglodytella acid (e.g., trichloroacetic acid, triperoxonane acid and others ) or similar, preferably conducted in the presence of agents that monitor cation (e.g. anisole, phenol, and others).

Usually the reaction is carried out in a solvent such as water, alcohol (e.g. methanol, ethanol and others), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which has no adverse effect on the reaction. The solvent can also be applied liquid base or acid. The reaction temperature is not critical, and generally the reaction is carried out under conditions of from cooling to heating.

Communication method used for the reaction of eliminowania may include chemical reduction and catalytic reduction.

Suitable reducing agents which can be used in chemical reduction are a combination of metal (e.g. tin, zinc, iron and others) or compounds of the metal (e.g. chromium chloride, chromium acetate, etc. and organic the red acid, para-toluenesulfonic acid, hydrochloric acid, Hydrobromic acid, and others).

Suitable catalysts that can be used in the catalytic reduction, this traditional catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, and others), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide on charcoal, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, and others), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, Raney Nickel, etc.), cobalt catalysts (e.g., the recovered cobalt, the Raney cobalt and others ), iron catalysts (e.g. reduced iron, Raney iron, and others), copper catalysts (for example, the recovered copper, Raney copper, Ullman copper, and others), etc.

Usually the recovery is carried out in a conventional solvent which does not exert any harmful effects on the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide or mixtures thereof.

In addition, when the above-mentioned acid used in the reaction, n is ritel, which is used in the catalytic reduction, can represent the above-mentioned solvent, other traditional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The temperature of the reaction mixture when the recovery is not critical, and generally the reaction is carried out under conditions of from cooling to heating.

The present invention includes in the scope of protection of a case when a protected amino group, R5converted into the amino group, the case when a secure carboxypropyl in R3turns into carboxypropyl, and the case when protected hydroxy(lower)alkyl in R4turns into a hydroxy(lower)alkyl.

Method 3:

The target substance (I) or its salt can be obtained by reacting compound (IV) or its salt with the compound (V) or its salt.

Suitable salts of the compounds (IV) may be salts of organic acids (e.g., formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate and others ), salts of inorganic acids (for example, hydrochloride, hydrobromide, sulfate, phosphate and others), etc.

This interaction can be Providence, chloride ethylene, formamide, N, N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethylsulfoxide or any other organic solvent which has no adverse effect on the reaction, preferably in solvents having a strong polarity. Among the solvents, hydrophilic solvents may be used in mixture with water. When the compound (V) is liquid, it can also be used as solvent. Preferably the reaction is carried out in the presence of a base, for example, inorganic bases such as hydroxide of alkali metal carbonate, alkali metal bicarbonate, alkali metal organic bases, such as trialkylamine, etc., the reaction Temperature is not critical, and usually the interaction is carried out at room temperature, during heating or cooling. Preferably this interaction is carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, and others), thiocyanate of an alkali metal (e.g. sodium thiocyanate, potassium thiocyanate, etc. or etc.

The anion Xcan be one of the derived tsepliaeva group and Y may be other and its salt can be obtained by involving substances (1C) or its salt to elimination reaction carboxy-protecting group, R3b.

This reaction can be conducted in a similar manner as mentioned in method 2, and therefore on the type of reaction and reaction conditions (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction, we shall refer to those, which are explained in method 2.

The present invention includes in the scope of protection cases where a protected amino group, R1and/or R5and/or protected hydroxy(lower)alkyl in R4converted into the amino group and/or hydroxy(lower) alkyl, respectively, in the course of this reaction.

Method 5.

The target substance (1f) or its salt can be obtained through the involvement of the compound (1E) or its salt to elimination reaction of the hydroxy-protecting group, R4a..

This reaction can be carried out in a manner analogous to the above in method 2, and therefore on the type of reaction and reaction conditions (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction, we shall refer to those, which are explained in method 2.

The present invention includes within the scope of protection cases where a protected amino group, R1and/or R5and who respectively.

Method 6.

The target substance (1h) or its salt can be obtained through the involvement of the compound (1g) or its salt to elimination reaction of the amino-protecting group, R5a< / BR>
This reaction can be conducted in a similar manner as mentioned above in method 2, and therefore on the type of reaction and reaction conditions (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction, we shall refer to those, which are explained in method 2.

The present invention includes in the scope of protection of a case when a protected amino group, R1and/or protected carboxypropyl in R3and/or protected hydroxy(lower)alkyl in R4morph into amino - and/or carboxylate and/or hydroxy(lower)alkyl, respectively, in the course of this reaction.

Reactions in methods a through C for the preparation of starting compounds (II) or their salts can be carried out in accordance with methods similar to those described in methods 2 6 to obtain the substance (I) or its salt.

Now, in order to demonstrate the usefulness of the target substance (I), the following test data on the MIC (minimum inhibitory concentration) characteristic wisecat method of double dilution agar plate, as is described below.

One loop overnight culture of each test strain in trypticase-soy broth (108viable cells per 1 ml) is applied stripes on agar heart extract (H1 agar) containing calibrated concentration of a particular test substance, and the minimum inhibitory concentration (MIC) expressed in units of μg/ml after incubation at 37oC for 20 hours.

The test substance.

(1) beta-[2-(2-Aminothiazol-4-yl)-2-methoxykynuramine]-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate(SYN-isomer)-the substance of example 4.

The test result is shown in table. 1.

The results of the comparative tests.

1) test Method 2.

In vitro antibacterial activity was determined using two-fold dilution plates with agar medium as described below.

One full loop of the culture grown over night, each test line in trypticase-soy broth (108viable cells per ml volume) was applied to the extract agar heart (H1-agar) containing calibrated concentration of a particular test compound, and the minimum and the.

2) Test the connection.

Test connection(1): 7-[2-(2-Aminothiazol-4-yl)-2-(deformatsionno)-acetamido] -3-[3-amino-2-(2-oxyethyl)-1-pyrazole] -methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example 3).

Test connection(2): 7-[2-(2- Aminothiazol-4-yl)-2-methoxykynuramine]-3-[4-methyl-3-amino-2-(2-oxyethyl)-1-pyrazolyl]-methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example 17).

Test the connection (And): 7-[2-(2- Aminothiazol-4-yl)-2-(deformatsionno)-acetamido] -3-(3-amino-2-methyl-1-pyrazole)-methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example 67 from Europe patent N0223246).

The tested compound (B): 7-[2-(2-Aminothiazol-4-yl)-2-methoxykynuramine] -3-(4-methyl-3-amino-2-methyl-1-pyrazolyl)-methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example 89 from Europe patent N0223246).

3) the Results are given in table. 2.

Test method 3.

In vitro antibacterial activity was determined using the method of two-fold dilution plates with agar medium.

One full loop of the culture grown over night, each test line in trypticase-soy broth (108viable cells per ml volume) was Nan the connection, and minimum inhibitory concentration (MIC) was expressed in units of μl/ml after incubation at 37oC for 20 hours.

Test compound: 7-[2-(2-aminothiazol-4-yl)-2-/(deformatsionno)-acetamido] -3-[3-formamido-2-(2-oxyethyl)-1-pyrazolo] methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example 8).

The test result is shown in table. 3.

For therapeutic target substance (I) and its pharmaceutically acceptable salt of the present invention are used in the form of conventional pharmaceutical preparation which contains the specified substance as an active ingredient in a mixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid medium for a drug that is suitable for oral, parenteral and external purposes. These pharmaceutical preparations can be in solid form such as tablets, granules, powder, capsules, or in liquid form such as solution, suspension, syrup, emulsion, lemonade, etc.

If necessary, the above drugs can be included ancillary compound, a stabilizing alenty, moisturizing agents and other commonly note the th earth sucrose, corn starch, talc, gelatin, agar, pectin, oil of groundnuts, olive oil, cacao butter, ethylene glycol, etc.

The dosage of the substance (I) may vary and also depend on the age, condition of the patient, the nature of the disease, the type of substance (I) that applies, and other General patient per day you can assign a dose of between 1 mg and about 4000 mg, or even more. For the treatment of diseases caused by pathogenic microorganisms, can be applied average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the target substance (I) of the present invention.

The following data for testing the claimed compounds of cafema toxicity with intravenous clearly show that they are practically non-toxic.

The method of analysis.

The test compound (dose: 320 mg/kg / day) injected SD rats (one group: 5 rats) for 4 weeks and watching them. During this period of time no animal died.

Test compound: 7-[2-(2-aminothiazol-4-yl)-2-methoxykynuramine] -3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolo] methyl-3-cefem-4-carboxylate(SYN-isomer) (compound of example II).

Preparative example 1.

A mixture of acetic anhydride (11, 13 ml) and formic acid (5,93 ml) was stirred at room temperature for 30 minutes. To this solution was added 5 g of 5-amino-1-(2-hydroxyethyl) pyrazole with ice cooling, and the mixture was stirred at 30 to 40oC for 1 hour. The reaction mixture was poured into a mixture of water, tetrahydrofuran and ethyl acetate, and set its value pH 6 aqueous solution of sodium bicarbonate. The organic layer is separated and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate three times. The organic layers are combined, dried over magnesium sulfate and evaporated in vacuum, obtaining 5,18 g 6 formamido-1-(2-formyloxyethyl)pyrazole.

IR-spectrum (in nujol): 3180, 1705, 1660 cm-1.

NMR-spectrum (in perdeuteromethoxy), d:4,21 br4.61 (4H, multiplet), 6,11 and 6,34 (1H, each doublet, J 3 Hz), 7,47 (1H, doublet, J 3 Hz), 8,00 (1H, singlet), with 8.33 (1H, singlet).

Preparative example 2.

To the mixture benzhydryl ether 7-beta-tert-butoxycarbonylamino-3-chloromethyl-3-cefem-4 - carboxylic acid (20 g) and iodine sodium (of 5.82 g) in 20 ml of N, N-dimethylformamide add 21,34 g 5-formamido-1-(2-formyloxyethyl)pyrazole at room temperature. After stirring for taaut and washed with water, aqueous solution of sodium chloride, and dried over magnesium sulfate. The solution is evaporated in vacuum, obtaining benzhydrylamine ether 7-beta-tert-butoxycarbonylamino-3-(3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)methyl-3-cefem-4 - carboxylic acid iodide (29,6 g).

IR-spectrum (in nujol): 17,80, 1720 cm-1.

NMR-spectrum (perdeuteromethoxy), s: for 1.49 (9H, singlet), of 3.43 (2H, broad singlet), 4,14 of 4.38 (2H, multiplet), to 4.52 to 4.73 (2H, multiplet), of 5.15 (1H, doublet, J=5 Hz), of 5.40 (2H, broad singlet), 5,67 (1H, doublets, J=5 Hz and 8 Hz), to 6.88 (1H, singlet), 7,02 (1H, doublet, J=3 Hz), 7.18 in - 7,52 (10H, multiplet), 7,94 (1H, doublet, J=8 Hz), to 7.99 (1H, singlet), of 8.27 (1H, doublet, J=3 Hz), 8,51 (1H, broad singlet).

Preparative example 3.

To a solution of benzhydryl ether 7-beta-tert-butoxycarbonylamino-3-(3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylic acid, iodide (29.5 g) and 30 ml of anisole in 90 ml of methylene chloride are added dropwise 60 ml triperoxonane acid under ice cooling. After stirring for 1 hour at room temperature the mixture was poured in a mixture of diisopropyl ether (600 ml) and ethyl acetate (600 ml). The resulting precipitate is collected by filtration, getting salt of bis (triperoxonane acid) 7-beta-amino-3-(3-fo is 60 cm-1.

NMR-spectrum (perdeuteromethoxy): s of 3.53 (2H, broad singlet), 4,28 4,56 (2H, multiplet), 4,78 4,99 (2H, multiplet), from 5.29 (2H, broad singlet), of 5.53 (2H, broad singlet), 7,14 (1H, doublet, J=3 Hz), by 8.22 (1H, singlet), 8,46 (1H, doublet, J=3 Hz), 8,63 (1H, singlet).

Preparative example 4.

Concentrated hydrochloric acid (5,67 ml) is added to a mixture of salts of bis (triperoxonane acid) 7-beta-amino-3-(3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate (10 g) in 50 ml of methanol at room temperature. After stirring at this temperature for 3 hours this mixture is added dropwise into 500 ml of ethyl acetate. The resulting precipitate is collected by filtration, getting trihydrochloride 7 betanine-3-(3-amino-2- (2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (6,1 g).

IR-spectrum (nujol): 3250, 1770, 1700, 1625 cm-1.

NMR-spectrum (perdeuteromethoxy), s: of 3.43 (2H, broad singlet), 3,52 3,88 (2H, multiplet), 4,18 4,48 (2H, multiplet), 5,28 (2H, broad singlet), lower than the 5.37 (2H, broad singlet), 5,97 (1H, doublet, J=3 Hz), 8,18 (1H, doublet, J=3 Hz).

Example 1.

A mixture of N,N-dimethylformamide (0,41 ml) and 0.49 ml of chloride phosphoryla in 2 ml of ethyl acetate is stirred under cooling with ice in them is 2-(2-formalization-4-yl)-2 - methoxyethoxy acid and the mixture is stirred at the same temperature for 30 minutes, to obtain the activated acid solution. This activated acid solution is added to a solution of 7-beta-amino-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate, trihydrochloride (2 g) and 5.85 g of N-(trimethylsilyl) ndimethylacetamide in 40 ml of tetrahydrofuran under ice cooling and the mixture is then stirred at 10 to 15oC for 1 hour. The resulting mixture is then poured into 500 ml of diethyl ether, and the precipitate collected by filtration to obtain 7-beta-(2-(2-formalization-4-yl)-2 - methoxykynuramine)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate, hydrochloride (SYN-isomer, 2.55 g).

IR-spectrum (nujol): 1770, 1660 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 3,30 (2H, multiplet), 3,68 (2H, multiplet), to 3.92 (3H, singlet), or 4.31 (2H, multiplet), from 5.29 (1H, doublet, J=5 Hz), 5,32 (2H, multiplet), 5,88 (1H, doublets, J=5 Hz and 8 Hz), of 5.99 (1H, doublet, J= 3 Hz), of 7.48 (1H, singlet), to 8.12 (1H, doublet, J=3 Hz), 8,59 (1H, singlet), 9,81 (1H, doublet, J=8 Hz).

The following substances (examples 2 and 3) were obtained by the method similar to that in example 1.

Example 2.

7-beta-(2-(2-Aminothiazol-4-yl)-2-methoxykynuramine)-3-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate(SYN is evil-4-yl)-2- (deformatsionno)-acetamido)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1760, 1660 cm-1.

Example 4.

To a solution of the dichloride beta-(2-(2 - formalization-4-yl)-2-methoxykynuramine)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer, 2.5 g) in methanol (12.5 ml) is added to 0.88 ml of concentrated hydrochloric acid (0,88 ml) at room temperature. After stirring at the same temperature for 2 hours the mixture was poured into ethyl acetate (500 ml) and the resulting precipitate collected by filtration. The precipitate is dissolved in water (100 ml) and alkalinized to pH 2 aqueous solution (5% ) of sodium bicarbonate. This solution is subjected to chromatographicaliy on a column of macroporous non-ionic adsorption resin "Dijon h-PI-20" (trademark, produced by Mitsubishi chemical industries). The target substance is eluated with 10% isopropyl alcohol and liabilitiesa, giving 0,43 g (7-beta-(2-(2-aminothiazol)-4-yl)-2-methoxykynuramine)-3-(3-amino-2-(2 - hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate (SYN-isomer) of 0.43 g).

IR-spectrum (nujol): 3300, 1770, 1640 cm-1.

NMR-spectrum (perdeuteromethoxy), s: of 3.00 and 3.30 (2H, AB-Quartet, J 18 Hz), 3,60 (2H, multiplet), 3,83 (3H, singlet), 4,37 (2H, multiplet), is 5.06 (1H, take the years), 7,38 (2H, broad singlet), 8,03 (1H, doublet, J 3 Hz), 9,52 (1H, doublet, J 8 Hz).

The following substance (example 5) was obtained by the method similar to that in example 4.

Example 5.

7-beta-(2-(2-Aminothiazol-4-yl)-2- (deformatsionno)-acetamido)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1760, 1660 cm-1.

Example 6.

In the suspension benzhydryl ether 7-beta-(2-deformatsionno)-2-(2-tritylimidazole)-4-yl)acetamido)-3-chloromethyl-3-cefem-4-carboxylic acid (SYN-isomer, 5 g) and 0,856 g iodine sodium in 5 ml of N,N-dimethylformamide add 4,18 g 5-formamido-1-(2-formyloxyethyl)pyrazole at room temperature. After stirring for 24 hours the mixture was poured into a mixture of ethyl acetate and water. Selected organic layer is washed with water and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. The residue is dissolved in tetrahydrofuran and subjected to chromatographicaliy on a column of ion exchange resin Amberlite AI-Ar-Hey 400 (type trifenatate) (trademark, produced by room and Haas Co.). The target substance to elute the tetrahydrofuran and evaporated in vacuum, obtaining Sol Tr is)-3-(3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylic acid (SYN-isomer) 4,80 kg).

IR-spectrum (nujol): 1780, 1720, 1675 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 3,50 (2H, multiplet), the 3.65 (2H, multiplet), 4,35 (2H, multiplet), a 5.25 (1H, doublet, J 5 Hz), 5,50 (2H, broad singlet), 5,88 (1H, doublets, J 5 Hz and 8 Hz), 6,91 (1H, singlet), 7,03 (1H, singlet),? 7.04 baby mortality of 7.70 (27H, multiplet), 8,08 (1H, singlet), with 8.33 (1H, doublet, J 3 Hz), 8,67 (1H, singlet), 9,05 (1H, singlet), of 10.05 (1H, doublet, J 5 Hz).

The following substance (example 7) was obtained by the method similar to that in example 6.

Example 7.

7-beta-(2-(2-Aminothiazol-4-yl)-2 - methoxykynuramine)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo) methyl-3-cefem-4-carboxylate (SYN-isomer).

To a suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxykynuramine] -3-acetoxymethyl-3-cefem-4 - carboxylic acid (SYN-isomer) 152); edotreotide (6.6 g in N,N-diisopropylethylamine (6.4 g) in methylene chloride (20 ml) is added a mixture of 5-amino-(2-hydroxyethyl)-pyrazole (4,20 g), chloromethylstyrene (7.2 g) and N,N-diisopropylethylamine (7.5 g) in methylene chloride (10 ml) at room temperature. After stirring for 20 hours the mixture was poured into a mixture of 1N hydrochloric acid and methylene chloride while cooling with ice and the pH adjusted with sodium bicarbonate solution. The aqueous layer was separated and chromatogra the isopropyl alcohol and lyophilized, receiving 0.4 g named in the connection header.

IR-spectrum (nujol): 3300, 1770, 1640 cm-1.

Example 8.

The salt solution triperoxonane acid benzhydryl ether beta-(2-(deformatsionno)-2-(2-tritylimidazole-4 - yl)acetamido)-3-(3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylic acid (SYN-isomer, 4.7 g) in 15 ml of methylene chloride and 5 ml of anisole add 10 ml triperoxonane acid under ice cooling. After stirring for 1.5 hours the mixture was poured into diisopropyl ether and the resulting precipitate collected by filtration. The residue is dissolved in water, alkalinized solution to pH 12 with an aqueous solution of sodium hydroxide under ice cooling. The mixture was stirred at the same temperature for 10 minutes and acidified to pH 2 with hydrochloric acid (1 normal). This solution is subjected to chromatographicaliy on a column of macroporous non-ionic adsorption resin "Dijon h-PI-20". The target substance elute 10% isopropyl alcohol and lyophilized getting 0,80 g beta-(2-(2 - aminothiazol-4-yl)-2- (deformatsionno)acetamido)-3-(3-formamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

Example 9.

In the suspension beta-(2-(2-aminothiazol-4-yl)-2- (deformatsionno)acetamido)-3-(3-formamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylic acid (SYN-isomer, 0.7 g) in methanol (3.5 ml) is added at 0.42 ml of concentrated hydrochloric acid at room temperature. After stirring at the same temperature for 2 hours the mixture was poured into ethyl acetate. The precipitate is dissolved in water and alkalinized it to pH 2 with 5% aqueous sodium bicarbonate solution. This solution is subjected to chromatographicaliy on a column of macroporous non-ionic adsorption resin "Dijon h-PI-20". The target substance elute 10% isopropyl alcohol and lyophilizers getting 0,41 g 7 beta(2-(2-aminothiazol-4-yl)-2- (deformatsionno)acetamido)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1760, 1660 cm-1.

NMR-spectrum (in heavy water), s: 3,02 and the 3.35 (2H, AB Quartet, J 18 Hz), of 3.78 (2H, m is, ,83 (1H, doublet, J 3 Hz).

The following substance (example 10) was obtained by the method similar to that in example 9.

Example 10.

7-beta-(2-(2-Aminothiazol-4-yl)-2-methoxykynuramine)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1770, 1640 cm-1.

Example 11.

In a solution of 6.5 g beta-(2-(2-aminothiazol-4-yl)-2-methoxy, aminoacetyl)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer) in 6.5 ml of water is added to 6.5 ml dvuhseriynoy sulfuric acid at room temperature. The mixture is stirred at this temperature that fell crystalline precipitate. These crystals are collected by filtration and washed them in cold water and then with acetone, getting salt of sulfuric acid 7-beta-(2-(2-aminothiazol-4-yl)-2-methoxykynuramine)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer) of 5.92 g).

NMR-spectrum (perdeuteromethoxy), s: 3,13 a 3.83 (2H, multiplet), 3,40 a 3.83 (4H, multiplet), of 5.15 (1H, doublet, J 5 Hz), of 5.05 and and 5.30 (2H, AB Quartet, J 13 Hz), 5,79 (1H, doublets, J 5 Hz and 8 Hz), 5,88 (1H, doublet, J 3 Hz), of 6.71 (1H, singlet), 7,28 (2H, broad singlet), 7,95 (1H, doublet, J 3 Hz), to 9.57 (1H, doublet, J 8 Hz).

The preparation is hydrochlorid (66 g) was dissolved in 264 ml of water. The aqueous solution is subjected to chromatographicaliy on a column with "Diiana h-PI-20", using as eluent water. The fractions containing the target substance, unite, and this combined solution is added dropwise to 1.15 l of isopropyl alcohol under ice cooling. This mixture is stirred for 1.5 hours while cooling with ice, fell to precipitate crystals. These crystals are collected by filtration and washed with a mixture of isopropyl alcohol and water (10: 1) under cooling with ice and dried over phosphorus pentoxide, getting 29,95 g 7 beta-amino-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate, hydrochloride dihydrate.

IR-spectrum (nujol): 3270, 1790, 1560 1635 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 3,43 of 3.77 (2H, multiplet), 4,47 5,07 (1H, doublet, J 5 Hz), 5,12 and 5.38 (2H, AB Quartet, J 16 Hz), of 5.92 (1H, doublet, J 3 Hz), 7,56 (2H, broad singlet), 8,11 (1H, doublet, J 3 Hz).

Analysis (% ): calculated for C13H17N5O4S. HCl. 2H2O C-37,90, H is 5.38, N-17,00, Cl 8,60

found: C-37,82, H-5.56mm, N-16,73, Cl 8,60.

Preparative example 6.

A mixture of acetic anhydride (44,5 ml) and formic acid (22,3 ml) was stirred at room temperature for 1 hour. To this mixture is added 30 g of 5-amine is followed by a session poured into water, ice, alkalinized her to pH 10.5 solution of potassium carbonate (40%) and stirred under ice cooling for 30 minutes. The mixture is extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer is dried over magnesium sulfate and evaporated in vacuum, obtaining 30,8 g 5-formamido-1-(2-hydroxyethyl)-pyrazole. So melting 109 112oC.

IR-spectrum (nujol): 3230, 1695, 1570, 1540 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 3,62 of 3.95 (2H, multiplet), 3,98 4,32 (2H, multiplet), 6,22 and 6,36 (1H, each doublet, J=3 Hz), 7,42 (1H, doublet, J=3 Hz), 8,32, and to 3.36 (1H, each singlet).

Preparative example 7.

To a suspension of 5-formamido-1-(2-hydroxyethyl)pyrazolo (1 G) in 50 ml of acetonitrile was added dropwise 0,77 ml chlorosulfonylisocyanate at a temperature of from -15oC to -20oC.

This mixture is stirred for 3 hours under ice cooling. To the reaction mixture was added 1 ml of water and leave it to Mature over night. The solution is alkalinized to pH=7,5 using 5-normal sodium hydroxide solution and then adjusted to pH 8.5 odnomomentnym solution of sodium hydroxide. The organic layer is separated, and the aqueous layer was extracted with tetrahydrofuran. The extract and the organic layer objed g of 5-amino-1-(2-carbamoylethyl)pyrazole.

NMR-spectrum (perdeuteromethoxy), s: 3,83 of 4.35 (4H, multiplet), 4,80 is 5.18 (2H, broad singlet), 5,32 (1H, doublet, J=3 Hz), 6,38 6,87 (2H, broad singlet), was 7.08 (1H, doublet, J=3 Hz).

Preparative example 8.

5-Formamido-1-(2-carbamoylethyl)pyrazole (of 3.69 g) was obtained from 5-amino-1-(2-carbamoylaspartate (3.3 grams) according to the method similar to that used in preparative example 6.

NMR-spectrum (perdeuteromethoxy), s: 4,22 (4H, singlet), 6,17 - 6,40 (1H, multiplet), 6,40 6,63 (2H, multiplet), 7,30 7,53 (1H, multiplet), 8,13 of 8.47 (1H, multiplet).

Example 12.

To a solution of benzhydryl beta-(2-2-formalization-4-yl)-2-methoxykynuramine)-3-chloromethyl-3-cefem-4-carboxylate (SYN-isomer, 1.52 g) in N,N-dimethylformamide (3 ml) is added modesty sodium (0.36 g) in a nitrogen atmosphere. This mixture was stirred at room temperature for 30 minutes.

Then it added 1.42 g of 5-formamido-1- (2-carbamoylethyl)pyrazole and the mixture is stirred at the same temperature for 24 hours. This reaction mixture was added a mixture of ethyl acetate (50 ml) and ice water (30 ml). Selected organic layer was washed with water and sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated in vacuum and poluchka triptorelin benzhydryl ether beta-(2-(2-formalization-4-yl)-2-methoxykynuramine)-3-(3-formamido-2-(2-carbamoylethyl)-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer) 1,60 g).

Example 13.

Beta-(2-(2-Formalization-4-yl)-2 - methoxykynuramine)-3-(3-formamido-2-(2-carbamoylethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer, 1.10 g) was obtained from trifenatate benzhydryl ether beta-(2-(2-formalization-4-yl)-2-methoxykynuramine)-3-(3-formamido-2-(2-carbamoylethyl)-1 - pyrazolo)methyl-3-cefem-4-carboxylic acid (SYN-isomer, 1.6 g) using the procedure similar to the described in example 8.

Example 14.

Beta-(2-(2-Aminothiazol-4-yl)-2-methoxyamphetamine-3-(3-amino-2-(2-carbamoylethyl)-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer, 0.10 g) was obtained from beta-(2-(2-formalization-4-yl)-2-methoxykynuramine)-3-(3-formamido-2-(2-carbamoylethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer) according to the method similar to that described in example 9.

IR-spectrum (nujol): 3200 3300, 1760, 1710, 1650 cm-1.

NMR (perdeuteromethoxy), s: 3,0 3,90 (2H, multiplet), 3,90 4,27 (4H, multiplet), 3,82 (3H, singlet), 4,40 5,47 (5H, multiplet), 5,47 5,77 (1H, multiplet), of 5.81 (1H, doublet, J=3 Hz), of 6.71 (1H, singlet), 6,90 EUR 7.57 (4H, multiplet), of 7.97 (1H, doublet, J=3 Hz), of 9.51 (1H, doublet, J=8 Hz).

Preparative example 9.

5-Formamido-4-methyl-1-(2 formyloxyethyl)Piras is 715, 1660 cm-1.

NMR-spectrum (in perdeuteromethoxy), s: 1,81 and 1.86 (3H, each singlet), 4,01 4,48 (4H, multiplet), 7.25 and yield of 7.40 (1H, each singlet), of 8.06 (1H, singlet), by 8.22 and 9,13 (1H, each singlet).

Preparative example 10.

5-Amino-1-(2-hydroxyethyl)pyrazole (5 g) are added to 14.7 ml of acetic anhydride with stirring and ice cooling. There also add 6.3 ml of pyridine. This mixture is stirred for 2 hours at 25oC.

The reaction mixture was added to a mixture of ethyl acetate (50 ml) and aqueous sodium chloride solution (50 ml). Then there is added an aqueous solution of sodium bicarbonate to bring the pH of the solution to 7.0. The aqueous layer was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is dried over magnesium sulfate. The magnesium sulfate is filtered off and the filtrate is evaporated under reduced pressure, getting 5,98 g of 5-acetamido-1-(2-acetoxyethyl)pyrazole. So melting 83 - 84oC.

IR-spectrum (nujol): 3270, 1750, 1670, 1565 cm-1.

NMR-spectrum (in perdeuteromethoxy), s: of 1.93 (3H, singlet), 2,03 (3H, singlet), 4,22 (4H, broad singlet), 6,13 (1H, doublet, J 2 Hz), 7,82 (1H, doublet, J 2 Hz), 9,76 (1H, singlet).

The following substances (preparative examples 11 to 13) were prepared according to the method, first aired beta-tert-butoxycarbonylamino-3-(4-methyl-3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylic acid, iodide.

IR-spectrum (nujol): 3250, 1780, 1710, 1680 cm-1.

NMR-spectrum (penetrationsexy), s: of 1.53 (9H, singlet), of 1.97 (3H, singlet), 3,51 (2H, broad singlet), 4,04 was 4.42 (2H, multiplet), to 4.52 4,78 (2H, multiplet), to 5.08 (1H, doublet, J 5 Hz), of 5.39 (2H, broad singlet), 5,61 (1H, doublets, J 5 Hz and 8 Hz), 6,86 (1H, singlet), 7,08 7,52 (10H, multiplet), to 7.93 (1H, singlet), 8,18 (1H, singlet), to 8.34 (1H, singlet), 9,12 (1H, singlet).

Preparative example 12.

Benzhydrol ether beta-tert - butoxycarbonylamino-3-(3-acetamido-2-(2-acetoxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylic acid iodide.

IR-spectrum (nujol): 1780, 1720, 1230 cm-1.

NMR-spectrum (perdeuteromethoxy), s: of 1.41 (9H, singlet), to 1.86 (3H, singlet), of 2.25 (3H, singlet), 3,40 (2H, broad singlet), of 4.0 to 4.4 (4H, multiplet), 5,12 (1H, doublet, J 5 Hz), lower than the 5.37 (2H, singlet), the ceiling of 5.60 (1H, doublet, J 8 Hz and 5 Hz), 6,85 (1H, singlet), from 7.24 (1H, doublet, J 3 Hz), of 7.1 to 7.6 (10H, multiplet), of 7.90 (1H, doublet, J 8 Hz), 8,21 (1H, doublet, J 3 Hz), 11,17 (1H, singlet).

Preparative example 13.

Benzhydrylamine ether beta-tert-butoxycarbonylamino-3-(3-formamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylic acid iodide.

IR-spectrum (nujol): 3300, 1780, 1710, 1560, 1150 cm-1.

NMR-spectrum (predeterminable, J 8 Hz and 5 Hz), make 6.90 (1H, singlet), 7,01 (1H, doublet, J 3 Hz), and 7.1 to 7.5 (10H, multiplet), of 7.97 (1H, doublet, J 8 Hz), of 8.28 (1H, doublet, J 3 Hz) and 8.50 (1H, singlet).

The following substances (preparative examples 14 to 16) were obtained by the procedure similar to that described in preparative example 3.

Preparative example 14.

Bis(salt triperoxonane acid) beta - amino-3-(4-methyl-3-formamido-2-(2-formyloxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate.

IR-spectrum (nujol): 1780, 1710, 1670 cm-1.

NMR-spectrum (perdeuteromethoxy), s to 1.98 (3H, singlet), 3,49 (2H, broad singlet), 4,22 4,48 (2H, multiplet), br4.61 to 4.87 (2H, multiplet), is 5.18 (2H, broad singlet), 5,46 (2H, broad singlet), with 8.05 (1H, singlet), 8,23 (1H, singlet), 8,35 (1H, singlet).

Preparative example 15.

Bis(salt triperoxonane acid) beta-amino-3-(3-acetamido-2-(2-acetoxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate.

IR-spectrum (nujol): 1780, 1660, 1990 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 1,95 (3H, singlet), of 2.23 (3H, singlet), of 3.46 (2H, broad singlet), of 4.2 to 4.4 (4H, multiplet), 5,20 (2H, multiplet), 5,46 (2H, singlet), 7,01 (1H, doublet, J 3 Hz), of 8.27 (1H, doublet, J 3 Hz), 11,17 (1H, singlet).

Preparative example 16.

Bis(salt triflorus the range (nujol): 3 400, 1 780, 1 680, 1 580, 1200, 1 140 cm-1.

NMR-spectrum (perdeuteromethoxy), s: 3,70 (2H, broad singlet), 4,2 4,7 (4H, multiplet), 5,23 (2H, multiplet), of 5.50 (2H, singlet), 7,07 (1H, doublet, J 3 Hz), 8,35 (1H, doublet, J 3 Hz), 8,53 (1H, singlet).

The following substances (preparative examples 17 and 18) were obtained by the procedure similar to that described in preparative example 4.

Preparative example 17.

Beta-Amino-3-(4-methyl-3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate, trihydrochloride.

NMR-spectrum (perdeuteromethoxy), s: of 1.94 (3H, singlet), 3,39 (2H, broad singlet), 3,47 of 3.78 (2H, multiplet), 4,06 was 4.42 (2H, multiplet), to 5.21 (4H, broad singlet), 7,87 (1H, singlet).

Preparative example 18.

Beta-Amino-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate, trihydrochloride.

IR-spectrum (nujol): 3300, 3150, 1780, 1710, 1640, 1580 cm-1.

NMR-spectrum (perdeuteromethoxy), s: of 3.60 (2H, broad singlet), 4,1 4,5 (4H, multiplet), 5,23 (2H, multiplet), and 5.30 (2H, singlet), of 5.92 (1H, doublet, J=3 Hz), 8,07 (1H, doublet, J=3 Hz).

The following substances (examples 15 to 18) were obtained by the procedure similar to that described in example 1.

Example 15.

Beta-2(2-formaliteiten).

NMR-spectrum (perdeuteromethoxy), s: of 1.94 (3H, singlet), 3,32 (2H, broad singlet), 3,52 3,68 (2H, multiplet), 3,88 (3H, singlet), 4,12 4,39 (2H, multiplet), 5,14 (2H, broad singlet), 5,19 (1H, doublet, J=5 Hz), of 5.82 (2H, doublets, J=5 Hz and 8 Hz), was 7.36 (1H, singlet), 7,83 (1H, singlet), of 8.47 (1H, singlet), 9,63 (1H, doublet, J=8 Hz).

Example 16.

Beta-(2-(2-formalization-4-yl)-2-methoxyethylamine)-3-(3-acetamido-2-(acetoxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 1780, 1660, 1550 cm-1.

NMR-spectrum (perdeuteromethoxy), s: a 1.96 (3H, singlet), and 2.27 (3H, singlet), 3,2 3,6 (2H, multiplet), a 3.87 (3H, singlet), 4,1 4,5 (4H, multiplet), with 5.22 (1H, doublet, J=5 Hz), 5,43 (2H, singlet), 5,90 (1H, doublets, J=8 Hz and 5 Hz), 7,00 (1H, doublet, J=3 Hz), 7,33 (1H, singlet), 8,29 (1H, doublet, J=3 Hz), 8,43 (1H, singlet), 9,62 (1H, doublet, J=8 Hz).

Example 17.

Beta-(2-(2-Aminothiazol-4-yl)-2-methoxykynuramine) -3-(4-methyl-3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1765, 1660, 1605 cm-1.

Example 18.

Beta-(2-2-Aminothiazol-4-yl)-2-methoxykynuramine) -3-(3-acetamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carbox - Silat (SYN-isomer).

IR-spectrum (nujol): 3200, 1770-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4 - carboxylate (SYN-isomer) was obtained according to the method similar to that described in example 4.

IR-spectrum (nujol): 3300, 1765, 1660, 1605 cm-1.

NMR-spectrum (in heavy water), s: of 1.97 (3H, singlet) 3,06 and 3,37 (2H, AB Quartet, J= 18 Hz), to 3.73 3.93 (2H, multiplet), 3,98 (3H, singlet), 4,19 - 4,43 (2H, singlet), 5,09 (2H, broad singlet), 5,19 (1H, doublet, J=5 Hz), of 5.89 (1H, doublet, J=5 Hz), of 6.96 (1H, singlet), 7,71 (1H, the singlet).

Example 20.

In the suspension beta-(2-(2-formalization-4-yl (2-methoxykynuramine)-3-(3-acetamido-2-(2-acetoxyethyl)-1 - pyrazolo)-methyl-3-cefem-4-carboxylate (SYN-isomer) (1,46 g) in 7.3 ml of methanol added 0.51 ml of concentrated hydrochloric acid at room temperature. This mixture is stirred for 5 hours at room temperature.

The reaction mixture was added to ethyl acetate with stirring and ice cooling. The resulting amorphous solid is dried in vacuum and dissolved in 40 ml of water. The aqueous solution is brought to pH=13 with 1-normal aqueous sodium hydroxide solution under stirring at a temperature of from -3o0oC and stirred for 2 hours at the same temperature. The pH of the aqueous solution was adjusted to 2 using 1-normal hydrochloric acid and subjected to solution chromatographicaliy to unite and concentrate, to remove isopropyl alcohol. When lyophilization obtain 159 mg beta-(2-(2-aminothiazol-4-yl) -2-methoxykynuramine)-3-(3-acetamido-2-(2-hydroxyethyl)-1 - pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer). T. melting 160oC (decomposition). IR-spectrum (nujol): 3200, 1770, 1600 cm-1.

NMR-spectrum (in heavy water), s: of 2.26 (3H, singlet), 3,10 (1H, doublet, J 18 Hz), 3,47 (1H, doublet, J 18 Hz), 3,8 4,1 (4H, multiplet), of 3.95 (3H, singlet), 5,20 (1H, doublet, J 5 Hz), 5,32 (2H, singlet), 5,77 (1H, doublet, J5 Hz), 6,93 (1H, doublet, J 3 Hz), 6,94 (1H, singlet)that is 8.16 (1H, doublet, J 3 Hz).

The following substances (examples 21 and 22 were obtained by the procedure similar to that described in example 7).

Example 21.

Beta-(2-(2-Aminothiazol)-4-yl (2-methoxykynuramine) -3-(4-methyl-3-amino-2-(2-hydroxyethyl)-1-pyrazolo)- methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1765, 1660, 1605 cm-1.

Example 22.

7 beta-(2-2-Aminothiazol)-4-yl)-2-methoxykynuramine) -3-(3-acetamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carbox - Silat (SYN-isomer).

IR-spectrum (nujol): 3200, 1770, 1600 cm-1.

The following substances (examples 23 to 27) were obtained by the procedure similar to that described in example 8.

Example 23.

boxill (SYN-isomer).

IR-spectrum (nujol): 3300, 1770, 1640 cm-1.

Example 24.

Beta-(2-(2-Aminothiazol-4-yl)-2-(deformatsionno-acetamido)-3-(3-amino-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3 - cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3300, 1760, 1660 cm-1.

Example 25.

Beta-(2-(2-Aminothiazol-4-yl)-2-methoxykynuramine)-3-(3-amino-2-(2-carbamoylethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3200 3300, 1760, 1710, 1650 cm-1.

Example 26.

Beta-(2-(-Aminothiazol-4-yl)-2-methoxykynuramine)-3-(4 - methyl-3-amino-2-(2-hydroxyethyl)-1-pyrazolo)-methyl-3-cefem-4-carbox - ilat (SYN-isomer).

IR-spectrum (nujol): 3300, 1765, 1660, 1605 cm-1.

Example 27.

Beta-(2-Aminothiazol-4-yl)-2-methoxykynuramine)-3-(3-acetamido-2-(2-hydroxyethyl)-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR-spectrum (nujol): 3200, 1770, 1600 cm-1.

1. Connection cafema General formula I

< / BR>
where R1amino or protected amino group;

R2lower alkyl which may be substituted by 1 to 3 halogen atoms;

R3carboxytherapy, carboxy - or protected carboxypropyl;

R4hydro is>R6a hydrogen atom or lower alkyl;

triptorelin;

n 0 provided that R3carboxytherapy, and n 1, provided that R3carboxy - or protected carboxypropyl,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1amino group, triphenyl(lower) alkylamino or (lower)alkanolamine; R2alkyl which may be substituted by 1 to 3 halogen atoms; R3carboxytherapy, carboxypropyl or mono-, di - or tri-(phenyl)- or mono, di -, or three(substituted phenyl) (lower)alkoxycarbonyl group; R4hydroxy(lower) alkyl, lower alkanoyloxy(lower)alkyl or carbamoylated(lower)alkyl; R5the amino or(lower)alkanolamines.

3. Connection on p. 2, in which R1amino group; R3- carboxytherapy or carboxypropyl.

4. Connection on p. 3 in which R2lower alkyl or dihalogen(lower)alkyl.

5. Connection on p. 4, in which R2methyl or deformity; R42-hydroxyethyl, 2-formyloxyethyl, 2-acetoxyethyl or 2-carbamoyloximes; R5amino group, formamido or acetaminophe; R6a hydrogen atom or methyl.

6. Connection on p. 5, Prel-3-cefem-4-carboxylate (SYN-isomer) or its salt of sulfuric acid.

7. Connection on p. 1 or their pharmaceutically acceptable salts as antimicrobial agent.

Priority signs:

14.09.87 R1, R2, R3, R4, R5such as they are defined in the claims; R6a hydrogen atom;

13.09.88 R6lower alkyl.

 

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 a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate

The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

-d - galactopyranosides -2) - 4,5-dihydrothiazolo-4 - carboxylic acid" target="_blank">

The invention relates to carbohydrates and heterocyclic compounds and in particular to a new method of obtaining-D-galactoside D-luciferin formula I

used as a substrate for the enzyme activity determination-galactosidase, which can find application in genetic engineering, enzyme analysis and DNA probes

The invention relates to the derivatives of pyrazole, specifically to N-phenylpyrazole, which can find application in agriculture

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl
Up!