SU1396969A3 - Method of producing derivatives of 6-substituted methylene-1,1-dioxopenicillic acid or its salts with alkali metals or its esters - Google Patents

Abstract

The invention relates to substituted penicillanic acid, in particular derivatives of 6-substituted methylene-1,1-β-dioxopenicillanic acid (PCC) or its alkaline salts, or pivaloyl-oxymethyl or allyl esters, in which in the 6-position there may be one of the following groups: thiazole1-2} 4-methylthiazolyl-2 J benzothiazolyl-2; 6-methoxybenzothiazolyl-2} isothiazolyl-3 l 2-methyl-1,2,4-t {) azolyl-3, 2-phenyl-1,2,3-triazolyl-5} 1,2,3-tya - diazol1-4 5-methyl-1,2,4-oxadiazolyl-3; furyl-2; thienyl-2, 1-acetylpyrrol or 2 j pyridyl-2 (or -3, or -4); Pyradazinyl-3; pyrimidinyl-4; pyrazinyl-2 or vinyl, which can be used in medicine in combination with pinicillan and cephalosporin antibiotics. The goal is to create new antimicrobial activity enhancing substances of these antibiotics. Synthesis of PCR is carried out from the corresponding cephalosporic acid containing in position 6 the specified group attached to the CHR group, where R is H or C (0) CHj, or its ally-g, of the terminal ester, which is treated with 1,5-diazabicyclo 4,3 , 0 non-5-ene in methylene chloride or alkaline i salt of an inorganic acid in an aqueous medium, or trifluoromethylsulfonyl-chloride at room temperature. The desired product is isolated in the form of the free acid, its salt or ester. The activity of new substances in combination with these antibiotics is manifested in relation to one or several microorganisms, i.e. they are β-lactamase inhibitors. 4 tab. i CO so CP O) co 05; O

Description

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The invention relates to a process for the preparation of new derivatives of .6-3-substituted methylene-1,1-dioxopenicillic acid or its salts with alkali metals or its esters, which have the property of inhibitors of p-lactamase and can be used in medicine in combination with penicillin and cephalosporin series antibiotics.

The purpose of the invention is to obtain new compounds that enhance the antimicrobial efficacy of antibiotics.

The method is carried out as follows.

Nuclear magnetic resonance, proton and C spectra were measured at 60, 90, 250 or. 300 MHz for solution in deuterochloroform (CDC1j) of deuterium oxide (D70), perdeuterated acetone (CDjCOCDj) or perdeuterated dimethyl sulfoxide (DISO-d), with peak positions expressed in ppm (ppm) in the direction of reducing poly from tetramethylsilane. The following abbreviations are used: S or c is a singlet, d or d is a doublet, dd or dd is a pair of doublets, t or t is a triplet, q or q is a quartet, m or m is a multiplet, bs or shir is a wide singlet.

Example 1. Benzyl 6- (2-pyridyl) oxymetag penicillanate.

A. Benzyl-bromo-6- (2-pyridyl) oxymethylpenylshans.

A solution of 9.0 g (0.02 mol) of benzyl 6,6-dibromopenicillanate in 200 ml of freshly distilled toluene is cooled to -78 ° C and 9 ml is added dropwise.

To a solution of 0.40 g of benzyl 6- (2-pyridyl) oxymethyl penicillanate in 5 ml of methylene chloride was added 0.20 g of methacid-chloroperbenzoic acid and the mixture was stirred at room temperature for 1 hour. Analysis by thin-layer chromatography 35, shows that the mixture contains an amount of sulfoxide. In addition, 0.2 g of meta-chloroperbenzoic acid is added and the mixture is stirred overnight. Mixture of times

2.2 M solution of tert-butyl lithium in foam-40 is added with methylene chloride, then the mixture is stirred for 30 minutes, 2.14 g (0.02 mol) of 2-pyridinecarboxaldehyde is added and stirring is continued for another 40 minutes. The reaction is quenched by adding 45 drops of a solution of acetic acid in toluene. After stirring for 1 hour, the cooling bath is removed, the mixture is heated to, diluted with 200 ml

washed with saturated sodium thiosulfate solution, water, saturated with sodium bicarbona solution. with sodium, and the organic layer was concentrated under vacuum. Ethyl acetate was added to the residue, washed with sodium bicarbonate solution, water, brine, and dried over anhydrous sodium sulfate. 330 m is obtained by evaporation of the solvent.

The solution is washed with a saturated sodium thiosulfate solution, water, and a saturated solution of sodium bicarbonate, and sodium and the organic layer is concentrated under vacuum. Ethyl acetate is added to the residue, washed with sodium bicarbonate solution, water, and brine, and dried over anhydrous sodium sulfate. 330 mg is obtained by evaporation of the solvent.

toluene, washed 5 times with water and dry with 50% benzyl ester in a boil over anhydrous sodium sulfate. The toluene solution was loaded onto a Florisil column (1 kg) and zleuyut with a mixture of toluene - ethyl acetate (2: 1). The product fractions were combined, evaporated with iodine in vacuo and 4.2 g of a brown syrup-like compound were obtained, which was used in the next step.

a brown oil, which is purified by chromatography on a silica gel column, eluting with ethyl acetate-hexane 11: 9 to obtain 60 mg of yellow oil.

1 H-NMR (CDC11), ppm (delta): 1.25 (singlet, GN); 1.52 (singlet, ZN); 4.1 (double doublet, 1H) i 4.5 (syn0

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B. The brown syrupy compound (4.2 g) obtained in Section A is dissolved in 50 ml of benzene and tributyl halide added to 2.65 g. The mixture was heated under reflux for 2 hours, an additional amount (1.65 g) of tributyl hydride was added and reflux was continued overnight. The solvent is evaporated under vacuum, the residue is washed with hexane, loaded onto a column containing 500 g of silica gel, eluted with a mixture of toluene-ethyl acetate 2: 1, and 425 g of the title compound are obtained.

1H-NMR (COClS), ppm (delta): 1.33 (singlet, GN)} 1.7 (singlet, GH); 4.0 (double doublet, 1H) j 4j5 (singlet; 1H); 5.1 (singlet, 2H); 5.2 (doublet, 1H); 5.4 (doublet, 1H); 7.0-7.8 (multiplet, 3H) j 8.5 (multiplet, 1H).

Example 2. 6- (2-5-pyridyl) oxymethylpenicillanic acid 1,1-dioxide.

A. Benzyl 6- (2-pyridyl) oxymeglyl -1,1-dioxopenicshans.

To a solution of 0.40 g of benzyl 6- (2-pyridyl) oxymethyl penicillanate in 5 ml of methylene chloride was added 0.20 g of methane chloroperbenzoic acid and the mixture was stirred at room temperature for 1 hour. Analysis carried out using a thin layer chromatography shows that the mixture contains some sulfoxide. Additionally, 0.2 g of meta-chloroperbenzoic acid is added and the ne ' mixture is stirred overnight. Mix

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0 is charged with methylene chloride, successively washed with a saturated sodium thiosulfate solution, water, and a saturated bicarbona solution of sodium, and the organic layer is concentrated under vacuum. Ethyl acetate is added to the residue, washed with sodium bicarbonate solution, water, and brine, and dried over anhydrous sodium sulfate. 330 mg is obtained by evaporation of the solvent.

target benzyl ester in

target benzyl ester in

a brown oil, which is purified by chromatography on a silica gel column, eluting with ethyl acetate-hexane 11: 9 to obtain 60 mg of yellow oil.

1 H-NMR (CDC11), ppm (delta): 1.25 (singlet, GN); 1.52 (singlet, ZN); 4.1 (double doublet, 1H) i 4.5 (singlet, 1H); 4.72 (doublet, 1H); 5.5 (doublet, 2H) i 5.8 (doublet, 1H); 7.1-8.0 (multiplet, 3N); 8.5 (multiplet, 1H).

B. A suspension of 118 mg of catalyst 10% Pd / C in 10 ml of tetrahydrofuran (THF) and 4 ml of water are pre-hydrogenated for 20 minutes under a hydrogen pressure of 3 atm. 130 mg of the benzyl ester obtained in Step A are added to this suspension.

4 ml of the same mixture of THF is water, the mixture is hydrogenated with 3.5 kg / cm for 30 minutes. Additionally, 129 mg of 10% Pd / C is added and hydrogenation at 3.5 kg / cm is continued for 2 hours. The catalyst is removed by filtration, the solvent is evaporated under vacuum and the residue is taken up with a mixture of water and ethyl acetate. The aqueous layer is dried and dried. 85 mg of the target acid is obtained,

1 H-NMR (CDClj), ppm (delta): 1.3 (singlet, 3N); 1.5 (singlet, SN); 4, (singlet, 1H); 5.0-5.35 (multiplet, 2H); 5.9 (doublet, 1H)

IR spectrum (KBG) cm 1620, 1731, 3407.

C. Reproduce the above procedure, but use stage A meta-chloroperbenzoic acid in an amount that is generally 175 mg (equimolar amount), and isolate the product, which is a mixture of the corresponding alpha and beta sulfoxides.

Example 3, Agshil 6- (2-thiazolyl) acetoxime tetyl-1,1-dioxopenicillanate.

A. Acylation of 0.5 g (1.29 mol) allyl 6- (2-thiazolyl) oxymethyl-1,1- α-dioxopenicillanate with the help of 0.396 (3.88 mmol) acetic anhydride and 0.307 g (3.88 g) pyridine in 5 ml of tetrahydrofuran is carried out with stirring at room temperature for 4 hours. The mixture is then diluted with methylene chloride, washed with water until neutral (pH 6.0-6.5), the organic phase is dried over anhydrous sodium sulfate, the solvent is evaporated and 0.688 g of the desired acetate.

1H-NMR (ATPR), ppm (delta): 1.52 (singlet, GN) 1.70 (singlet, GN), 2.35 (singlet, GN); 4.4 - 4.6 (multiplet, 2H), 4.6-5.0 (multiplet, 3N), 5.2-6.4 (multiplet, 3N);

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6.65 (doublet, 1H); 7.4 (doublet, 1H); 7.8 (doublet, 1H).

Example 4. Allyl 6- (2-thiazolyl) methylene-1,1-dioxopenicillanate and its hydrolysis into a potassium salt.

A. The acetoxy ester obtained in Example 3 (0.688 g, 1.29 mmol) is mixed with 0.16 g (1.29 mmol) of 1,5-diazabicyclo (4.3.0) non-5-ene ( DBN) and 5 ml of methylene chloride and stirred for 1 h at room temperature. The mixture is diluted with methylene chloride, washed with water (2 x X 50 ml), dried over anhydrous sodium sulfate, the solvent is evaporated

and get a butter. This oil is chromatographed on a column of silica gel, eluting with ethyl acetate: hexane 1: 1, and 0.189 g (39%) of a light yellow oil is obtained.

1 H-NMR (CDCl1), ppm (delta): 1.53 (singlet, 3N); 1.65 (singlet, SN); 4.33 (singlet, W), 4.55 (doublet, 2H); 5.0-5.4 (multistet, 2H); 5.45 (singlet, 1H); 5.4-6.0 (multiplet, 1H); 7.1 (multiplet, 1H); 7.75 (multiplet, 1H); 7.65 (doublet, 1H).

B. Hydrolysis of the allyl ester obtained in stage A using potassium 2-ethylhexanoate gives 6- (2-thiazole) methyne-1, 1-dioxopenicillanate potassium with a yield at this stage equal to 84.7% as an iron . that solid compound.

1H-NMR, 250 MHz SDMSO-dp, ppm (delta): 1.40 (singlet, GH), 1.45 (singlet, GH), 3.80 (singlet, 1H), 5.83 (singlet, 1H), 7.66 (singlet, 1H); 8.04 (multiplet, 2H).

C.6 (E) - (L-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate sodium.

A solution of 46 mg of allyl 6 (E) - (N-Methylpyrrol-2-yl) metshlen-1,1-dioxopenitates, 5 mg of tetrakis (triphenylphosphine) palladium (O), 4 mg of triphensh-phosphine and 1 ml of methylene chloride is stirred under nitrogen for 5 minutes, the mixture is diluted with 1 ml of ethyl acetate, and 0.25 ml of a solution of sodium 2-ethylhexanoate in ethyl acetate is added. After stirring at room temperature for 1 h, the mixture is filtered, the precipitate is washed with ethyl acetate, diethyl ether and -30 mg of a yellow solid is obtained.

1 H-NMR (), ppm (delta): 1.50 (singlet, GN); 1.60 (singlet, 3H) i 3.65 (singlet, GN), 4.10 (singlet, 1H); 5.4 (singlet, 1H)} 6.1 - 6.5 (multiplet, 1H) j 7.0 (broad singlet, 2H); 7.2-7.4 (m, 1H).

IR (CVB) cm: 1568, 1616 1660, 1745, 3465.

Similarly, target pro- ducts are obtained, the yields and physicochemical characteristics of which are listed in Table. one.

PR and measure 5. A mixture of (E) - and (Z) - isomers of 6- (benzothiazol-2-yl) methylene-1,1-dioxopenicillanic acid

To a solution of 400 mg (0.91 mmol) of 6- (benzothiazol-2-yl) acetoxynethyl -1 -1, T-dioxophenylillanoic acid in 5 ml of water is added a solution of 0.15 g (1.82 mmol) of sodium bicarbonate in 2 ml water and the resulting mixture is stirred for 2 hours. The reaction mixture (pH 7.55) is freeze dried. The lyophlate is then taken up in 8 ml of water, the pH is adjusted to 3.5 with dilute hydrochloric acid, extracted with ethyl acetate, the organic layers are dried (MgSO4) and the solvent is evaporated in vacuo.

The NMR spectrum of the obtained product showed that it is a mixture of (E) - and (Z) -isomers in a ratio of 60:40.

1 H-NMR (CDCl1), ppm (delta): 1.55 (singlet, 1.2 N)) 1.6 (singlet, 1.8 N) -, 1.65 (singlet, 1.2 N) ; 1.67 (singlet, 1.8 N)} 4.55 (singlet, 0.6 N); 4.58 (singlet, 0.4 N); 5.38 (singlet, 0.4 N); 5.74 (singlet, 0.6 N); 7.44 (singlet, 0.4 H) j 7.48 (singlet, 0.6H) j 7.5 (multiplet,. 4H); 7.89 (doublet, 1H) i 8.07 (doublet, 0.4 N); 8.15 (doublet, 0.6 N).

Example 6. A mixture of (E) - and (Z) - isomers of 6- (3-methyl-1,3,4-triazol--2-yl) methylene-1,1-dioxopenicillanic acid in relation to (E) : (Z) 60: 4 was prepared as in Example 5, the outcome

from the corresponding acetoxymethyl derivative, with a yield of 84%.

1H-NUR (), ppm (delta): 1.54 (singlet, 3N) j 1.62 (singlet, 3N); 4.04 (singlet, ZN); 4.35 (singlet, 1H); 5.7 (singlet, 0.6 N); 5.9 (singlet, 0.4 H) i 7.26 (singlet, 0.6 H) i 7.55 (singlet, 0.4 I); 8.09 (singlet, 2H).

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Example 7. Getting pivalo iloxymethyl ether.

A. To a solution of 470 ml (1.28 mmol) of potassium 6- (isothiazol-3-yl) -methylene-1,1-α-pyoxopenicillanate in 2 ml of diamethylformamide, 0.18 ml (1.28 mmol) of chloromethyl pivalate is added at room temperature. The mixture was poured into water, extracted with ethyl ether (3 X 20 ml). The extracts were dried, the solvent was evaporated, yielding 500 mg (88%) of a dark orange oil.

Chromatography on a column of silica gel, eluting with chloroform: ethyl acetate 9: 1, yields 315 mg of pivaloyl Simethyl 6- (isothiazol-3-yl) methylene-1,1-dioxopenicillanate (55%) as a light oil.

1 H-NMR (COCl 3), ppm (delta): 1.22 (m, 9H); 1.5 (C, 3N); 1.6 (s, 3N); 4.44 (s, 1H); 5.64 (p. 1H); 5.84 (AB quartet, 2H); 7.36 (s, 1H); 7.38 (d, W), 8.72 (d, 1H).

Example 8. Allyl 6- (furan--2-yl) methylene-1,1-dioxopenicillanate (E) - and (d) -isomers.

To a solution of 310 mg (0.84 mmol) of allyl 6-alpha (furan-2-yl) oxymethyl -1 -1-dioxopenicillanate in 5 ml of methylene chloride was added 0.14 ml (1 mmol) of triethylamine and 0.1 ml (0.924 mmol) of trifluoromethylsulfonyl chloride and the mixture is stirred under nitrogen at room temperature for 2 hours. The reaction is quenched with water, extraction is carried out with methylene chloride, the extracts are dried over anhydrous magnesium sulfate, the solvent is evaporated under vacuum to obtain 330 mg of crude product. After purification by column chromatography on silica gel using chloroform as eluent, 130 mg of product are obtained, which, according to an analysis using high-pressure liquid chromatography, is a mixture of 4: 1 (E) and (g) isomers. 1 H-NMR (CDCl1), ppm (delta): 1.47 (singlet, 3N); 1.61 (singlet, SN); 4.47 (singlet, 1H); 4.75 (doublet, 2H); 5.1-6.2 (multiplet, 4H); 5.52 (double doublet, 1H); 6.8 (multiplet, 1H); 7.15 (doublet, 1H); 7.6 (doublet, 1H).

Example 9. Allyl 6 (E) - (N-acetylpyrrol-2-yl) methyl-1,1-dioxopenicillanate ./

A. Lillyl 6- (L-acetylpyrrol-2-yl) acetoxymethyl-1,1-dioxogeniciclanate.

Allyl 6- (K-acetylpyrrol-2-yl) hydroxymethyl-1,1-dioxypenicillanate (210 mg, 0.51 mmol) is dissolved in 3 ml of tetrahydrofuran, 0.15 ml of acetic anhydride and ml of pyridine are added. and the mixture is stirred at room temperature for 24 hours. The reaction is quenched with water, extraction is carried out with methylene chloride, the extracts are dried, concentrated and 171 mg (75%) of yellow crystals are obtained.

1H-CR (CBC1), h / min (delta): 1.4 (singlet, ZN), 1.6 (singlet, ZN) j 2.15 (singlet, ZN) 32.55 (singlet, 3H) i 4 , 15-4.3 (double doublet, 1H); 4.4 (singlet, 1H); 4.6-4.8 (multiplet, 3H) i 5.1-6.0 m (multiplet, 3N); 6.1-6.6 (multiplet, 2H) 6.6 - 7.4 (multiplet, 2H).

B.Y., the 0-diacetate product (170 mg, 0.38 mmol) obtained in Step A is dissolved in methylene chloride and 47 mg (0.38 mmol) of 1,5-diacabicyclo (4.3, 0) non-5-ene (DBN). The mixture is stirred at room temperature for 1 hour. Water is added and the mixture is extracted with methylene chloride. The extracts are dried, concentrated and 158 mg of oil are obtained, which is purified by chromatography

on silica gel using 2% ethyl acetate in chloroform as eluant, and 108 mg of product is obtained as a pale yellow oil. 1 H-NMR (COCl 3) h.mln (delta): 1.5 (singlet, 3H) j 1.6 (singlet, GN); 2.55 (singlet, SN); 4.4 (singlet, 1H), 4.65 (doublet, 2H) i 5.0-6.0 (multiplet, 4H); 6.3 (triplet, 1H); 6.8 (double doublet, 1H)} 7.2 (multiplet, 1H); 8.2 (doublet, 1H). Similarly get the target products in the form of allyl ethers, the outputs and physico-chemical characteristics of which are given in Table. 2

Example 10. Starting from the allyl esters of 6-K, 51-methylene-1,1-dioxopenitric acid, obtained above, sodium salts or potassium salts of 6-K; 1-methylene-1,1-dioxopenicillanic acid are obtained, the outputs and physico-chemical characteristics of which are given in table. 3

Example 11. 6- (E) - (1-methyl-imidazol-2-yl) -methylene-1,1-dioxopenicillanate potassium.

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A. Allyl 6- (l-methylimidazol-2-yl) oxymethyl-1,1-dioxopenicillate.

6- (1-Methylimidazol-2-yl) oxime-T11L-1,1-dioxopenicillanate (472 mg, 1.23 mmol) is acylated according to the procedure described in Step A of Example 9, and 392 mg (75%) of the acetoxy compound in the form of a mixture of two isomers. 1H-III-1R (CBCI3), ppm (delta):

1.4 (singlet, 1.5H), 1.5 (sinGlet,

1.5I) -, 1.6 (singlet, 1.5 N); 1.7 (singlet-1H); 2.2 (singlet, 3H) j 3.7 (singlet, 1.5 I); 3.75 (singlet,

1.5 H) i 4.0-6.0 (multiplet, 8H); 6.3-6.5 (multiplet, 1H); 6.8 (multiplet, 1H) J 7.0 (multiplet, 1H).

B. Allyl 6- (E) - (1-methylimidazol--2-yl) methylene 1,1-dioxopinicillate.

The product obtained in Stage A (392 mg, 0.920 mmol), 5 ml of methylene chloride and 0.115 ml of 1,5-diazabicyclo (4.3.0) non-5-ene (DBN) are converted to the desired ester with yield 53 % according to the method of stage C of example 9.1H-NMR (CDClj), ppm, (delta): 1.5 (singlet, 3N); 1.6 (singlet, GN) -, 3.7 (singlet, GN); 4.35 (singlet, 1H), - 4.7 (multiplet, 2H); 5.0-6.1 (multiplet, 3N); 5.7 (doublet, 1H); 6.9 (multiplet, 1H); 7.1 (doublet, 1H); 7.2 (multiplet, 1H).

C. Allyl ester ester, obtained at stage B (163 mg, 0.45 mmol), is converted to the target potassium salt. The resulting product is 143 mg (87%) of the individual (E) -isomer.

1 H-NMR (DMSO), ppm (delta): 1.38 (singlet, GN); 1.45 (singlet, SN); 3.8 (singlet, 4H); 5.68 (singlet, 1H); 7.15 (singlet, 1H); 7.35 (multiplet, 2H); 13C-NMR (DMSO), ppm (delta): 18.5, 20.2, 32.5, 64.4, 66.2, 70.55, 115.2, 124.6, 129.9, 130.6, 141.2, 167.9, 169.0.

IR spectrum (KBG) cm: 1614, 1762, 3428.

Tests in vitro β-lactamase activity.

The β-lactamase inhibitory activity was determined by comparing the results of in vitro MIC tests for the test compound in combination with the well-known beta-lactam antibiotic ampicillin. Lactamase inhibition was determined by the degree

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combination synergism versus ampicillin directly. Minimal inhibitory concentrations (MICs) were determined in micrograms / ml using a cerebrospinal fluid (BH1) in agar and a replication apparatus located in the corner of the eye.

The contents of the tubes, grown overnight, were 100-fold. Diluted to use as standard graft material (20,000-10000 cells in approximately 0.002 ml and have an agar surface: 20 ml BH1 agar / plate).

Twelve 2-fold dilutions of the test compound were made, bringing the concentration of the test drug to 200 micrograms / ml. Simple colonies were discarded on counting plates after 18 hours at 37 ° C.

The sensitivity (MIC) of the experimental microorganisms appeared at very low concentrations of the test compound or combinations of compounds capable of completely inhibiting growth, as judged by the naked eye.

Test results are summarized; in the table below. 4, from which it can be seen that each of the compounds according to the invention has a high degree of p-lactamase activity against HPA or several microorganisms, i.e. are highly effective (5-lactamase inhibitors.

When testing compounds for beta-lactamase activity, they did not cause serious signs of toxicity at the tested doses and should be classified as compounds with a low to moderate toxicity.

Claims (1)

Invention Formula The method of obtaining derivatives of 6-for | methylen-1,1-dioxopenicil 9  ABOUT lanoic acid or its lactic metals, or esters of the formula oh oh V  . CH 3 / h -N- h, COOR five 0 five where RI is hydrogen or alkali metal, pivaloyloxymethyl or allyl; Rj - thiazolyl-2, 4-methylthiazolyl-2, benzothiazol-1-2, 6-methoxybenzothiazol-1-2, isothiazolyl-3, 2-methyl-1,2,4-triazolyl-3, 2-phenyl-1 , 2,3-triazolyl-5, 1,2,3-thiadiazolch1-4,5-metsh1-1,2,4 oxadiazolsh1-3, fursh1-2, thiene-2, 1-acetylpyrrolyl -2, pyridyl-2, pyridyl-3, pyridyl-4, pyridazinyl-3, pyrimidinyl-4, pyrazinyl-2 or VINIL; characterized in that the compound of the general formula OKz Cg-CH. ABOUT O / SNZ KG-1 3,   COORi where Rj is hydrogen or acetyl R7 has the indicated meanings) R. - hydrogen or allyl; 1,5-diazabicyclo t4,3,0 non-5-ene in methylene chloride or an alkaline salt of an inorganic acid in an aqueous medium, or trifluoromethylsulfonyl chloride at room temperature followed by isolation of the desired product in the form of the free acid, its salt with an alkali metal or its corresponding ester complex. five 2 36 3 iri 1A  18 3 a N (d. 1H); 5.1-6.2 (M, 3H) i 7.3-7.5, (M, 2H) D 7.7-8.0 (M, 1H) 8.53-8.83 (M, 2H) (d) isomer: 1.48 (s, 3N); 1.6 (s, 3H) i 4.5 (s, 1H) i 4.7 (d, 2H); 5.25 (s, 1H); 5.1-6.2 (m, 3N); 6.88 (s, 1H); 7.2-7.5 (m, 1H); 8.43-9.0 (m, ЗН) Ethylacea- A mixture of isomers: 1.45 (s, 3N); 1p62 (SrZN); tat: hexane 4.5 (s, 1H); 4.7 (d, 2H); 5.2-6.2 (m, E); 6.75 (s, 0.3 N), 7.2-7.5 (m, 1.7 N) 7.6- 7.85 (m, 1H) -, 8.5-8.83 (m , 2H). (1: 1) CHClj 1.45 (s, 3N)} 1.6 (s, 3H) v 4.4 (s, 3N); 4.7 (d, 2H); 5.0-6.2 (m, 3N); 5.25 (d, 1H); 7.0-7.65 (m, 4H) CHClj = 1.45 (s, 3N); 1.65 (s, ZN); 3.7-4.2 (m, 1H); 4.45 (s, 0.6H); 4.5 (s, 0.4 N); 4.75 (d, 2H), 5.1-6.4 (m, 7H) Ethyl acetate — 1.48 (s, 3N); 1.63. (s, ZN); 4.45 (s, 1H); tat: hexane 4.73 (d, 2H)) 5.1-6.2 (m, ZN)} 5.77 (d, (1: 3) 1H) -, 7.27 (d, 1H); 7.1-8.1 (m, 3N)} 8.6 (m, 1H) About about 2-SN Si l.CH, , Table 4 R,  or to 23 1396969 24 Continued table. four 27 1396969 28 Continuation of table. four Note: In .table. 4, the following abbreviations have been used: AMF - ampicillin, PS - newly expressed synergism; S - synergism; A - additional effect; N - no effect; AT - antagonism; N1 - no interpretation.