PL151546B1 - 2-oxo-1-(substituted sulfonyl)amino-carbonylazetidines - Google Patents

Abstract

Antibacterial activity is exhibited by 2-azetidinones having a 3-acylamino substituent and having an activating group in the 1-position of the formula <IMAGE> wherein <IMAGE> wherein A1 to A6 are selected from various defined divalent groups (including single bonds).

Description

THE REPUBLIC PATENT DESCRIPTION 151 546 POLAND

Additional patent to patent no.- Applied: 86 09 26

Int. Cl. ⁵ C07D 401/14 (P. 261575) ^{A61K 31/44}

Priority: 85 09 26 United States of America

OFFICE

PATENT

RP

Application announced: 88 07 21

Patent description published: 1991 02 28

Inventors: Hermann Breuer, Uwe D. Treuner, William H. Koster, Robert Zahler

Patent holder: E. R. Squibb and Sons, Inc.,

Princeton (United States of America)

Method for the preparation of new 1-sulfonylaminocarbonyl-2-ketoazetidine derivatives

The present invention relates to a process for the preparation of the new 1-sulfonylaminocarbonyl-2-ketoazetidine derivatives of the general formula I, in which R1 is a C1-C8-alkyl group optionally substituted with a carboxylic acid group, N-hydroxyamide group or a halogen atom, R2 and R3 are identical or different and represent a hydrogen atom or a methyl group, and L is the group NH-CH ₂ -, -NH-NH-CO-, -NH-NH-CO-CH = CH-, -NH-NH-CO-NH-CO-, NHCH2CH2-NH-CO- or -NH-NH-CO - NH-NH-CO- or a group of the formula 2,3,4,5,6,7 or 8, as well as the pharmacologically acceptable salts of these compounds. These compounds have an antibacterial effect.

The compounds of formula I form basic salts with various inorganic and organic bases. A method of producing such salts falls within the scope of the invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts, salts with organic bases, e.g., dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine and the like. Pharmacologically acceptable salts are preferred, although other salts are also useful. , for example, in isolating or purifying a product.

Certain compounds of formula I can be crystallized or recrystallized from water-containing solvents. The products may therefore contain water of crystallization. The invention relates to a process for the preparation of hydrates with a stoichiometric water content and compounds with a different water content, which can be obtained, for example, by lyophilization.

The [beta] -lactams of formula I contain at least one chiral center due to the presence of the asymmetric carbon atom at the 3-position of the [beta] -lactam ring attached to the -CO-NH- terminated acylamino substituent. The method of the invention produces β-lactams having the 3-position configuration of the ring / J-lactam such as the 6-position configuration of natural penicillins (e.g. penicillin G) and the 7-position configuration of natural cefamycins (e.g. cepamycin C) and racemic mixtures containing such / J -lactams.

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The inventive process for the preparation of the new 1-sulfonylaminocarbonyl-2-ketoazetidine derivatives of general formula I and their pharmacologically acceptable salts consists in that a compound of general formula 9, in which R2, R3 and L are as defined above, is acylated with a carboxylic acid of the general formula 10, in which R 1 is as defined above or its halide or anhydrous, and then optionally converting the resulting compound into its pharmacologically acceptable salt.

The reaction with the carboxylic acid occurs most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole. In case the acyl group contains reactive functional groups (such as an amino or carboxyl group), it may be necessary to protect these protecting groups from the product after performing the acylation reaction.

The starting compounds of formula 9 are new. May be prepared from the 3-protected 2-aminoazetidinone of Formula 11 in which, as throughout the description, R4 is an amino protecting group. Such protecting groups are well known in the art of β-lactam chemistry, and the nature of the group selected is not critical. Exemplary protecting groups are benzyloxycarbonyl, trityl and tert-butoxycarbonyl. Reaction of a 5-lactam of formula 11 with an isocyanate of formula O = C = N-SO2-Y, in which Y is a leaving group such as chlorine, provides a compound of formula 12. The reaction is preferably carried out in an inert solvent. organic, such as, for example, ethyl acetate, tetrahydrofuran, dimethoxyethane, dichloromethane, acetonitrile or a mixture of these solvents. The leaving group Y may be replaced by the desired group of formula 13 by treatment with a suitable nucleophilic compound of formula 14, optionally in the presence of a base (e.g. triethylamine) to provide a compound of formula 15. The leaving group can also be removed by reacting a compound of formula 12 with with a protected compound of formula 14. After this reaction, the protecting groups can be removed in a known manner to obtain a compound of formula 15.

Protected compounds of formula 14 and all other 3-hydroxypyridone-4-containing reagents described herein include hydroxy protected compounds, hydroxy protected compounds protected with ring nitrogen, and compounds with two oxygen protected pyridone atoms. Examples of protecting groups are silica (e.g. trimethylsilyl), benzyl and acyl (e.g. acetyl). The silyl group can be cleaved by hydrolysis or by using fluoride. The benzyl group can be cleaved by hydrogenelysis and the acyl group by hydrolysis.

After cleavage of the protecting groups from the compound of formula 9 or its salt. Depending on the nature of the protecting group R4, suitable cleavage reactions are carried out. For example, when R4 is a tert-butoxycarbonyl protecting group, it can be cleaved by treating the compound of Formula 15 with an acid (e.g., formic acid or trifluoroacetic acid). When R4 is a benzyloxycarbonyl protecting group, it can be cleaved by catalytic hydrogenation of a compound of formula 15. The R4 protecting group can also be removed uniformly with other protecting groups in the pyridone moiety immediately after displacement of the Y group.

The 5-lactams of the formula I and their pharmacologically acceptable salts show activity against gram-positive and gram-negative microorganisms. These compounds can be used as agents to combat bacterial infections (including urinary tract infections and respiratory tract infections) in mammals, such as pets (e.g., dogs, cats, cows, horses, etc.), and in humans.

To combat bacterial infections, the compounds of formula I and their salts can be administered to patients in an amount of about 1.4-350 mg / kg / day, preferably in an amount of about 14-100 mg / kg / day. These compounds can be administered as penicillins or cephalosporins to the site of infection, i.e. orally, intravenously, intramuscularly or in the form of suppositories.

The invention is illustrated by the following Examples in which the abbreviation 1.1. means melting point.

Example 1: [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- {3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] ] -2-ketoimidazolidinyl-l} sulfonylaminocarbonyl / -2-ketoazetidinyl-3] amino} -2-ketoazetidinyl-aminoxy] -2-methylpropionic.

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A) 2-Hydroxymethyl-5-phenylmethoxy-4H-pyranone-4

69 g (3 mmol) of sodium are dissolved in 5 liters of methanol. 425.3 g (3 mmol) of 5-hydroxy-2-hydroxymethyl-4H-pyranone-4 are added to the solution and the mixture is stirred at 30 ° C until a clear solution is obtained. After adding 595 g (3.5 mmol) of benzyl bromide, the solution is stirred for 1 hour at reflux temperature. The warm, very dark solution was poured into 15 liters of ice-water, the product immediately crystallizing out. The crystals are separated and washed with 8 liters of water and then twice with 2.5 liters of ether, allowed to stand overnight and then dried at 50 ° C for 16 hours to yield 646 g (92.6%) of product.

B) 4-keto-5-phenylmethoxy-4H-pyranecarboxylic acid-2

232 g (1 mol) of 2-hydroxymethyl-5-phenylmethoxy-4H-4H-pyranone-4 are charged to a 10 L flask containing 6.6 liters of acetone and 400 ml of water. The clear solution is cooled to + 5 ° C with an ice bath and, keeping the temperature at + 5 to 10 ° C, 640 ml of Jones' reagent (202 g OrCh, 600 ml of water, 174 ml of H2SO4) are added dropwise to it for 1 hour. continued stirring for 2 hours without cooling. The reaction mixture is filtered through a sintered glass filter and the dark-green residue is washed with 500 ml of acetone. The filtrate was evaporated until complete removal of acetone. 1.2 L of methanol is added to the water-containing, partially crystalline product and the mixture is heated to reflux temperature. The resulting clear dark green solution is placed in an ice bath and the product is allowed to crystallize out. The crystals are filtered off and washed with 500 ml of a cold mixture of 250 ml of methanol and 250 ml of water and then dried to give 195 g (79%) of the product. A further 5% of product can be isolated from the mother liquor.

C) 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid

300 g (1.22 mol) of 4-keto-5-phenylmethoxy-4H-pyranecarboxylic acid-2 are placed in the flask and 5 liters of 33% NH4OH are carefully added while stirring, and the reaction mixture is stirred under reflux. After 3 hours, an additional 1 liter of 33% NH4OH is added and stirring is continued for 2 hours at reflux temperature. The reaction solution was evaporated until the product crystallized. The product is transferred back to the reaction flask and water is added to it until a clear solution is obtained (approx. 5 liters, pH = 6.38). The solution is stirred vigorously and concentrated hydrochloric acid is added dropwise thereto until pH = 3. The precipitated white substance is filtered off, washed thoroughly with water and dried to obtain 273 g (1.12 mol, 91.8%) of the product.

D) 1,4-Dihydro-4-keto-N- (2-ketoimidazolidinyl-1) -phenyl- (5-phenylmethoxy) -pyridinecarbonamide-2

12.26 g (0.05 mol) of 1,4-dihydro-4-oxo-5 (phenylmethoxy) -pyridinecarboxylic acid-2 in 12.26 g (0.05 mol) of 2-aminoimidazolidinone are dispersed in 120 ml of dimethylformamide. 0.3 g of dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole are added to the suspension, and the mixture is stirred for 30 minutes at room temperature. After dropwise addition of a solution of 11.35 g (0.055 mol) of dicyclohexylcarbodiimide in 50 ml of dimethylformamide, the mixture was stirred overnight at room temperature. The precipitated solid (dicyclohexylurea) was filtered off and the filtrate was evaporated in vacuo. The resulting syrup is mixed with an aqueous solution of sodium bicarbonate, causing crystallization. 11.7 g of the title compound o 1.1 are obtained. 158-160 ° C. An additional 0.8 g of product with 1.1 is obtained from the aqueous filtrate by crystallization. 162-164 ° C.

E) 1,4-Dihydro-5-hydroxy-4-keto-NH- (2-ketoimidazolidinyl-1) -pyridinecarbonamide-2

To a suspension of 12 g (0.0365 mol) 1,4-dihydro-4-keto-N- (2-ketoimidazolidinyl-1) - (5-phenylmethoxy) -pyridinecarbonamide-2 in 150 ml acetonitrile, 36.1 ml (0.146 moles) of bis (trimethylsilylacetamide, giving a slightly cloudy solution. After filtration and addition of 6 g of 10% palladium on carbon, hydrogen is passed through the reaction mixture with stirring. Hydrogenation is carried out for 60 minutes, then the catalyst is filtered off, and the mixture is treated with 15 ml. methanol and 2 ml acetic acid and stirring was continued overnight, while the product crystallized to give 6.6 g of the title compound, 1.1 270-275 ° C.

F) (3S) - [1 - ({3 - [(1,4-Dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl-1-sulfonylaminocarbonyl / -2-catoazetidinyl-3] carbamate

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5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate are added to a suspension of 13.8 g of (S) -3-phenylmethoxycarbonylamino / azetidinone-2 in 500 ml of ethyl acetate. The mixture was stirred for 1 hour at room temperature to form a solution of (S) -1-chlorosulfonylaminocarbonyl 3- (phenylmethoxycarbonylamino) -2-azetidinone. The solution is cooled to 0 ° C and at this temperature is slowly added to silylated 1,4-dihydro-5-hydroxy-4-keto-N- (2-ketoimidazolidinyl-1) -pyridinecarbonamide-2, prepared from a suspension of 14.9 g ( 0.0626 mol) 1,4-dihydro-5-hydroxy-4-keto-N- (2-oxoimidazolidinyl-1) -pyridinecarbonamide-2 in 500 ml of ethyl acetate by adding 46.4 ml (0.25 mol) N-methyl -N- (trimethylsilyl) trifluoroacetamide and stirring for 30 minutes. After adding 150 ml of dichloroethane, the reaction mixture was stirred at room temperature overnight. To the clear solution are added 26.2 ml (0.188 mol) of triethylamine and then 300 g of ice and 200 ml of water. The solution with pH = 6.5 is stirred for 1.5 hours, then the 2 phases are separated and the aqueous phase is washed with ethyl acetate (3 x 200 ml). After evaporation of the remaining ethyl acetate in vacuo, the pH of the aqueous phase is adjusted to 2 by slowly adding 47 ml of 2N hydrochloric acid and with cooling. The crystals are filtered off, dispersed in 200 ml of ethyl acetate and stirred for 1 hour, then filtered, washed with 2 × 30 ml of ethyl acetate and 2 × 50 ml of petroleum ether and dried in vacuo. 28.6 g of the title compound are obtained, mp 190-200 DEG C. (decomposition).

G) Trifluoroacetate (2: 1) (3S) -3-amino-N - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl-1} sulfonyl) - 2- ketoazetidinecarbonamide

To a mixture of 15 ml of trifluoroacetic acid and 3.5 ml of thioanisole at 10 ° C are added 4 g (0.00713 mol) of (3S) - [1 - ({3 - [(1,4-dihydro-5-hydroxy- Phenylmethyl 4-ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl-1} sulfonyl) -2-ketoazetidinyl-3] carbamate and the clear solution was stirred overnight and then evaporated in vacuo at room temperature. The remaining syrup was treated with ether to afford the title compound in an almost quantitative yield as a yellowish solid. ·

H) [3S (Z)] - 2- {1- (2-aminothiazolyl-4) -2- [1 - / {3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino Diphenylmethyl -2-ketoimidazolidinyl-1) sulfonylaminocarbonyl / -2-ketoazetidinyl-3] -2-ketoethylideneaminoxy} -2-methylpropionate

To a solution of 3.08 g (0.007 mol) of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimino) thiazole-4-acetic acid in 70 ml of dimethylformamide, 2.9 ml of ( 0.021 mol) of triethylamine and, after cooling to -30 ° C under nitrogen, 1.55 ml (0.007 mol) of diphenyl chlorophosphate are added. The mixture was stirred for 1 hour at -30 ° C. 1.95 ml (0.014 mol) of triethylamine and 0.007 mol of trifluoroacetate (2: 1) (3S) -3-amino-N - ({3 - [(1,4-dihydro-5-hydroxy-4- ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl-1} sulfonyl) -2-catoazetidinecarbonamide-3. The reaction mixture is stirred at -10 ° C for 2 hours and at 0 ° C for 1 hour, then the solvent is evaporated off in vacuo. The residue is mixed with water and ethyl acetate, and the resulting insoluble product is treated with ether to obtain 8.0 g of crude product as a solid.

I) [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- / {3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl) acid disodium salt -2) carbonylamino] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl / 2-ketoazetidine-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

8 g of crude [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[l - ({3 - [(1,4-dihydro-5-hydroxy-4)] are dispersed in 15 ml of anisole. diphenylmethyl-ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl-l} sulfonylaminocarbonyl (-2-ketoazetidinyl-3] amino-2-ketoazylideneaminoxy} -2-propionate is added dropwise to -10 ° C. of trifluoroacetic acid and the mixture is stirred at -10 DEG C. for 1 hour. The mixture is treated with ether at 0 DEG C. to precipitate the free acid trifluoroacetate (4.1 g of crude product). This product is dissolved in water and the solution is pH adjusted. to pH = 5.5 by adding sodium bicarbonate solution, then the solution is lyophilized The crude sodium salt is purified by chromatography on HP-20 (macrorecrosslinked styrene-divinylbenzene copolymer resin. Mitsubishi Chemical Industres Ltd) using water as eluent to give 0, 52 g of the product.

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NMR spectrum (DMSOd 6): < 5 = 1.35 (s, 3H), 1.40 (s, 3H), 3.37 (dd, 1H), 3.47 (t, 2H), 3.81 (t , 2H + dd, 1H), 5.05 (m, 1H), 6.75 (s, 1H), 7.27 (s, 1H), 7.72 (s, 1H), 11.52 (broad s , 1H).

Example II. [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl) acid sodium salt ] -hydrazine-l} sulfonylaminocarbonyl / -2-ketoazetidinyl-3] amino} -2-ketoelideneaminoxy] -2-methylpropionic

A) 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid 2- (1,1-dimethylethoxycarbonyl) hydrazide

61.3 g (0.25 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -pyridine-2-carboxylic acid are dispersed in 500 ml of dimethylformamide at room temperature. 39.65 g (0.3 mol) of N-tert-butoxycarbonyl hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxybenzotriazole are added to the suspension and the mixture is stirred for 30 minutes at room temperature. While stirring, a solution of 57.7 g (0.28 mol) of dicyclohexylcarbodiimide in 100 ml of dimethylformamide was added dropwise to the mixture within 30 minutes, and the mixture was stirred at room temperature overnight. The precipitated solid (dicyclohexylurea) was filtered off and the filtrate was evaporated in vacuo. The remaining syrup is mixed with dilute sodium bicarbonate solution to crystallize the product. The dried crude product is recrystallized from 2 liters of ethyl acetate to give 69.5 g of the title compound of 1.1. 173-175 ° C. After evaporation of the mother liquor, an additional 3.2 g of product by 1.1 is obtained. 160-165 ° C.

B) 1,4-dihydro-5-hydroxy-4-ketopyridine-2-carboxylic acid hydrazide

69 g (0.191 mol) of 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid are added to 370 ml of trifluoroacetic acid at 0 ° C. The mixture was stirred for 1 hour at room temperature and then evaporated. The remaining syrup was treated with ether to obtain 68.2 g of crude 1,4-dihydro-4-keto-5 (phenylmethoxy) -pyridine-2-carboxylic acid trifluoroacetate (2: 1) hydrazide as a solid. The crude product was dissolved in 250 ml of acetonitrile and the solution was stirred with cooling for 1 hour. The crystals are filtered off and dispersed in 600 ml of acetonitrile. 135 ml of bis (trimethylsilyl) acetamide and 28 g of 10% palladium-carbon are added to the suspension, and the stirred solution is purged with hydrogen. Hydrogenation is carried out for 90 minutes, then the catalyst is filtered off, the mixture is mixed with 70 ml of methanol and 2 ml of acetic acid and the mixture is stirred overnight. Precipitated crystals were filtered off to obtain 19.4 g of the title compound of 1.1. 290-340 ° C (decomp.).

C) Phenylmethyl (3S) -1 - {1,4-Dihydro-4-keto-5- (phenylmethoxy) pyridinyl-2] carbonylhydrazine sulfonylaminocarbonyl] -2-ketoazetidinyl-3) carbamate

To a suspension of 5.19 g (0.0236 mol) of S / -3- (phenylmethoxycarbonylamino) azetidinine-2 in 160 ml of ethyl acetate, 2.05 g (0.0236 mol) of chlorosulfonyl isocyanate were added with stirring at room temperature. The mixture was stirred for 1 hour at room temperature to give a solution of (S) -1-chlorosulfonylaminocarbonyl-3- (phenylmethoxycarbonylamino)-2-azetidinone. The solution is cooled to 0 ° C and 20 ml of dichloromethane and a solution of 1,4-dihydro-5-hydroxy-4-ketopyridine carboxylic acid silylated hydrazide2 obtained from a suspension of 3.99 g (0.0236 mol) of 1,4-acid hydrazide are added to it. -dihydro-5-hydroxy-4-ketopyridine-2-carboxylic acid, in 50 ml of ethyl acetate and 8.75 ml (0.0472 mol) of N-methyl-N (trimethylsilyl) trifluoroacetamide. The mixture was stirred at room temperature overnight, then mixed with ice water and stirred for 30 minutes. The aqueous layer was covered with ethyl acetate, acidified to pH = 2.5, and stirred for 1 hour. The crystallized product is separated to obtain 6.6 g of the title compound. After evaporation of the organic phase and treatment with petroleum ether, an additional 1.4 g of the title compound is obtained.

D) Trifluoroacetate (2: 1) N - [{3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2-carbonyl] hydrazine} su! Phonyl) -2-ketoazetidinecarbonamide-1

To a mixture of 22 ml of trifluoroacetic acid and 5.3 ml of thioanisole, 6.6 g (0.0133 mol) of (3S) -1 - {[1,4-dibydro-4-keto-5- (phenylmethoxy) pyridinyl-2] carbonylhydrazine sulfonylaminocarbonyl} -2-ketoazetidinyl-3) phenylmethyl carbamate, and the mixture was stirred overnight at room temperature. The trifluoroacetic acid is removed in vacuo and the remaining syrup is mixed with ether to afford the title compound in quantitative yield.

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Ε) [3S (Ζ)] - 2- [1 - (2-aminothiazolyl-4) - {2- [1 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl- 2-carbonyl] -hydrazine sulfonylamino) carbonyl-2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methyl diphenylmethylpropionate

To a solution of 5.84 g (0.0133 mol) of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimimino) -thiazole-4-acetic acid in 135 ml of dimethylformamide is added 5 , 6 ml of triethylamine and, after cooling to -30 ° C, 3.78 g (0.0133 mol) of diphenyl chloroform. The mixture is stirred for 1 hour at -30 ° C, then 3.72 ml of triethylamine and 0.0133 mol of trifluoroacetate (2: 1) (3S) -3-amino-N - ({2- [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazine} sulfonyl) -2-ketoazetidinecarbonamide-1. The mixture was stirred at -10 ° C for 2 hours and at 0 ° C for 1 hour. The solvent is removed in vacuo and the remaining syrup is mixed with 150 ml of ethyl acetate and 70 ml of ice water, acidified to pH = 1.5-2 with 2N hydrochloric acid. The insoluble matter was separated and mixed with ether to obtain 5.3 g of crude product.

F) [3S (Z)] - 2- [1 - (2-aminothiazolyl-4) 2 - {[1 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2)) acid salt carbonyl] hydrazine} sulfonylaminocarbonyl-2-ketoazetidinyl-3]} - 2-ketoethylideneaminoxy] -2-methylpropionic

5.3 g (0.0069 mol) of [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[l ({2 - [(1, Diphenylmethyl 4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazino Jsulfonylaminocarbonyl (2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionate is cooled to -10 ° C with stirring. 53 ml of trifluoroacetic acid are added, the mixture is stirred at -10 ° C for 1 hour and then 200 ml of ether are added at -10 ° C to precipitate the trifluoroacetate salt of the title compound as the free acid. Crude product (7.3 g) is dissolved in a mixture of 100 ml of water and 50 ml of acetone. After adjusting the solution to pH 5-5.5, acetone is removed in vacuo. The remaining aqueous solution is freeze-dried to give 8.1 g of crude product. After chromatographic purification on HP- 1.05 g of product are obtained with water as the eluent.

NMR spectrum (DMSOd 6): δ = 1.40 (s, 1H), 1.42 (s, 3H), 3.25 (dd, 1H), 3.70 (dd, 1H), 5.10 (m, 1H), 5.10 (m, 1H), 6.75 (s, 1H), 7.40 (s, 1H), 7.80 (s, 1H), 11.32 (broad s, 1H).

Example III. [3S (Z)] - 2- {l- (2-aminothiazolyl-4) -2 - [(l - {[2 -) {2 - [(l, 4-dihydro-5-hydroxy-4) acid disodium salt -ketopyridinyl-2) carbonyl] hydrazine} carbonyl) hydrazino] sulfonylaminocarbonyl} -2-ketoazetidinyl-3) amino] -2-ketoethylideneaminoxy} -2-methylpropionic ^g °

A) 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid 2- (4-methoxyphenylmethoxycarbonyl) hydrazide

To a stirred suspension of 4.90 g (0.020 mol) of 1,4-dihydro-4-oxo-5 (phenylmethoxy) -pyridine-2-carboxylic acid, 4.50 g (0.022 mol) of 4-methoxybenzyl carbazate, 0.12 g (1 .0 ml) 4- (dimethylamino) pyridine and 0.155 g (1.0 mol) of 1-hydroxybenzotriazole hydrate in 25 ml of anhydrous dimethylformamide are added at room temperature, a solution of 4.54 g (0.022 mol) of dicyclohexylcarbodiimide in 25 ml of anhydrous dimethylformamide is added at room temperature. continues overnight. The precipitated solid was filtered off and the filtrate was evaporated in vacuo. After mixing with ether and aqueous sodium bicarbonate solution, the residue solidifies. The solid is separated, washed with water and dried in vacuo. The crude product (8.14 g) is extracted based on a Soxhlet with 800 mL of CHCl3 (7 hours). 5.70 g (67%) of pure 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2o-carboxylic acid 2- (4-methoxyphenylmethoxycarbonyl) hydrazide directly crystallizes from the cold extract, mp 174.5-178 ° C . An additional 1.5 g (18%) of impure title compound can be obtained by evaporating the chloroform solution in vacuo.

B) 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid trifluoroacetate (2: 1)

To an ice-cold suspension of 3.71 g (8.76 mmol) of 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridinecarboxylic acid 2- (4-methoxyphenylmethoxycarbonyl) hydrazide in 15 ml of anhydrous dichloromethane is added, cooled to temperature -10 ° C 3.81 ml (35.04 mmol) solution of anisole in 38 ml trifluoroacetic acid, then the mixture is stirred for 20 minutes

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Ί temperature 0 ° C. The solution was evaporated in vacuo and the residual material was mixed with a few ml of anhydrous ether, filtered off with suction and dried in vacuo, yielding 3.25 g (99%) of the title compound, mp 173-175 ° C (decomposition).

C) 1,4-Dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid hydrazide

To a suspension of 3.19 g (8.55 mmol) of 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid trifluoroacetate (2: 1) in 35 ml of anhydrous acetonitrile is added 3.84 ml (19 , 64 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and stirring is continued for 30 minutes at room temperature, then the mixture is evaporated in vacuo. The residue is taken up in ether and 1 ml of methanol is added dropwise to the mixture. The precipitate is filtered off with suction, washed with ether and petroleum ether and dried in vacuo to give 2.05 g (92%) of the title compound by 1.1. 204-208 ° C (decomp.).

D) 1,4-dihydro-4-keto-5- (phenylmethoxy) -pyridine-2-carboxylic acid 2 - {[2- (phenylmethocarbonyl) hydrazino] carbonyl} -hydrazide

While cooling, to a suspension of 5.19 g (0.020 mol) of 1,4-dihydro-4-keto-5 (phenylmethoxy) -pyridinyl-2-carboxylic acid hydrazide in 20 ml of anhydrous acetonitrile was added 11.69 ml (0.060 mol) of N- methyl-N- (trimethylsilyl) trifluoroacetamide and stirring is continued for 30 minutes at room temperature. The clear solution is evaporated in vacuo and the residue is dissolved in 30 ml of anhydrous dichloromethane. This solution is added dropwise to a solution of PhCHaOCONHNHCOCl (J. Gante, Chem. Ber., 97, 2551, 1964) in 60 ml of dichloromethane, while stirring at 0-5 ° C, and stirring is continued for 2.5 hours at the same temperature. . The solution was evaporated in vacuo and the foam solid was dissolved in 20 ml of methanol. Evaporation in vacuo gave a foam solid which crystallized on mixing with anhydrous ether. 8.79 g (98%) of the title compound by 1.1 is obtained. > 120 ° C (decomposition).

E) 1,4-dihydro-5-hydroxy-4-keto-pyridine-2-carboxylic acid 2- (hydrazcarbonyl) hydrazide dihydrochloride

A solution of 4.02 g (8.9 mmol) of 1,4-dihydro-4-keto-5- (phenylmethoxy) pyridinecarbonyl-2 - {[2- (phenylmethocarbonyl) hydrazino] carbonyl} -hydrazide in 50ml of methanol containing 2 94 ml (35.6 mmol) of concentrated hydrochloric acid were hydrogenated for 10 minutes in the presence of 0.4 g of 10% palladium on carbon. The catalyst was filtered off and the solvent was distilled off in vacuo. The residual solid (2.58 g) is mixed with a few ml of anhydrous ether, filtered off with suction and dried in vacuo to give 2.47 g (92%) of the title compound by 1.1. 235-236 ° C (decomp.).

F) (3S) - (1 {-2 - [(2 - {[1,4-Dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazine} carbonyl) hydrazine] sulfonylaminocarbonyl} -2-ketoazetidinyl -3 phenylmethyl carbamate

To a suspension of 1.5 g (5.0 mmol) of 1,4-dihydro-5-hydroxy-4-ketopyridine-2-carboxylic acid 2- (hydrazinecarbonyl) hydrazide dihydrochloride in 20 ml of anhydrous acetonitrile is added 4.86 ml (25.0 mmol) ) N-methyl-N-trimethylsilyltrifluoroacetamide and the mixture is stirred for 45 minutes at room temperature. The clear solution is evaporated in vacuo and the residue is dissolved in 20 ml of anhydrous ethyl acetate (solution A).

To a suspension of 1.10 g (5.0 mmol) of (S) -3- (phenylmethoxycarbonylamino) azetidinone-2 in 40 ml of anhydrous ethyl acetate, 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate was added with stirring, and the mixture was stirred for a while 1 hour at room temperature, then cooled to 0 ° C. After addition of 10 ml of anhydrous dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, solution A was added dropwise to the mixture while stirring at 0 ° C and the mixture was stirred overnight at 0 ° C. The reaction mixture is poured into ice water and the organic layer is separated. The aqueous phase is acidified to pH = 2 by adding 1M hydrochloric acid. The precipitated sticky solid was filtered off with suction, washed with water and dried in vacuo to give 1.7 g (64% of the title compound).

G) (2: 1) (3S) -3-amino-N- {2 - [(2 - {[1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazine} carbonyl (hydrazine) trifluoroacetate ) sulfonyl} -2-ketoazetidinecarbonamide-1

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To a mixture of 5.13 ml of trifluoroacetic acid and 1.21 ml of thionisole are added at 0 ° C 1.73 g (3.1 mmol) (3S) - (1 - {[(2 - {[(1,4-dihydro Phenylmethyl -5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazino} carbonyl) hydrazino] sulfonylaminocarbonyl} -2-ketoazetidinyl-3-) carbamate and the mixture was stirred overnight at room temperature. The solution was evaporated in vacuo and the residue. mixed with anhydrous dichloromethane, the precipitate was filtered off with suction, washed with dichloromethane and dried in vacuo to give 1.78 g (88%) of the title compound.

H) [3S (Z)] - 2- {1 - (2-Aminothiazolyl-4) -2 - [(1 - {[2 -) {2 - [(1,4-dihydro-5-hydroxy-4- ketopyridinyl 2) carbonyl] hydrazine} carbonyl) hydrazino] sulfonylaminocarbonyl} -2-ketoazetidinyl-3) amino] -2-ketoethylideneaminoxy} -2-methylpropionate.

At -30 ° C to a solution of 1.10 g (2.5 mmol) of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimimo) thiazole-4-acetic acid in 22 ml of anhydrous dimethylformamide are successively added to 1.05 ml (7.5 mmol) of triethylamine and 0.53 ml (2.5 mmol) of diphenyl chloroformate. The mixture is stirred for 1 hour at -30 ° C, 1.05 ml (7.5 mmol) of triethylamine are added dropwise to it, and then 1.62 g (2.5 mmol) of trifluoroacetate (2: 1) (3S) -3 are added. -amino-N - {[2 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazine} carbonyl) hydrazino] sulfonyl} -2-ketoazetidinecarbonamide-1. The mixture is stirred for 2 hours at -10 ° C and for 1 hour at 0 ° C. The solvent is evaporated off in vacuo and the residue is taken up in a few ml of ethyl acetate and ice water. The mixture is acidified to pH = 2 by adding dilute hydrochloric acid. The insoluble matter is filtered off with suction and mixed with a few ml of ethyl acetate until a crystalline product is obtained. After dissolution in vacuo, 1.72 g (82%) of the title compound are obtained.

I) [3S (Z)] - 2- {1- (2-aminothiazolyl-4) -2 - [(1 - {[2 - ({2 - [(1,4-dihydro-5-hydroxy -4-ketopyridinyl-2) carbonyl] hydrazine} carbonyl) hydrazino] sulfonylaminocarbonyl} -2-ketoazetidinyl-3) amino] -2-ketoethylideneaminoxy} -2-methylpropionic

1.68 g (2.0 mol) of crude [3S (Z)] - 2- {1- (2-aminothiazolyl-4) -2 - [(l - {[2 -) {2 - [(l Diphenylmethyl 4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonyl] hydrazino} carbonyl) hydrazine] sulfonylaminocarbonyl} -2-ketoazetidinyl-3) amino] -2-ketoethylideneaminoxy} -2-methylpropionate in 3 ml of anhydrous dichloromethane is added 2.0 ml of anisole and 20 ml of trifluoroacetic acid successively at -10 ° C and the mixture is stirred for 10 minutes at 0 ° C. The solvent is removed in vacuo at 0-5 ° C. The residue is taken up in ice water and ether and brought to pH = 6.0 by adding dilute 1% sodium hydroxide solution. The organic phase and the insoluble matter (0.38 g) are separated and the aqueous phase is lyophilized (2.60 g). The freeze-dried residue is purified over XAD-2 resin (macrocrosslinked copolymer of styrene and divinylbenzene, Rohm and Haas Company) using water as eluent. After lyophilization, 0.25 g (17%) of the title compound is obtained as a colorless powder with 1.1. > 213 ° C (decomposition).

Example IV. [3S (Z)] -1 - [(2-aminothiazolyl-4) -2 - {[1 -) {3 - [(1,4-dihydro -5-hydroxy-4-ketopyridinyl-2) carbonylamino] - disodium salt of 2-ketoimidazolidinyl-1-sulfonylaminocarbonyl) -2-ketoazetidinyl-3) amino} -2-ketoethylideneaminoxy] cyclopentanecarboxylic A) [3S (Z)] - 1 - [(2-aminothiazolyl-4) -2- [1-) {3- [ diphenylmethyl (1,4-dihydro -5-hydroxy-4-ketopyridinyl2) carbonylamino] -2-ketoimidazolidinyl-1-sulfonylaminocarbonyl) -2-ketoazetidinyl-3) amino} -2-ketopyridinyl-3] cyclopentanecarboxylate

To a suspension of 3.9 g (8.3 mmol) of (Z) -2-aminocr- [1- (diphenylmethoxycarbonyl) cyclopentyloxyimino] thiazole-4-acetic acid in 100 ml of anhydrous acetonitrile, 3.5 ml (25 mmol) of triethylamine are added. . The resulting clear solution is cooled to -30 ° C, 1.8 ml (8.3 mmol) of diphenyl chlorophosphate are added and the mixture is stirred for 1 hour at -30 ° C (solution A).

Simultaneously, 4.3 g (8.3 mmol) of trifluoroacetate (2: 1) (3S) -3-amino-N- ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] -2 - ketoimidazolidinyl-1-sulfonyl) -2-ketoazetidinecarbonamide-1 is dispersed in 100 ml of anhydrous ethyl acetate. The suspension is mixed at room temperature with 7.2 ml of bis (trimethylsilyl) acetamide, resulting in a clear solution after 5 minutes. This solution is stirred for 1 hour and then cooled to 0 ° C (solution B). .

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Solution B is added dropwise to solution A with stirring at -30 ° C for 10 minutes. The mixture is stirred for 1 hour at -10 ° C and for 1.5 hours at 0 ° C. The aqueous substances are evaporated and the residue is triturated with water, the residue solidifying. The solids were separated, dispersed in water maintaining approximately pH = 2, and the suspension was stirred for 30 minutes. The solid was separated and dried to give 12.0 g of a raw title compound.

B) [3S (Z)] - 1- [1- (2-aminothiazolyl-4) -2 - {[1-) {3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl) acid disodium salt -2) carbonylamino] -2-ketoimidazoIidinyl-1-sulfonylaminocarbonyl) 2-ketoazetidinyl-3) amino} -2-ketoethylideneaminoxy] cyclopentanecarboxylic acid

12 g of crude [3S (Z)] - 1- [1- (2-aminothiazolyl-4) -2 - {[1-) {3 - [(1,4-dihydro-5-hydroxy-4) are dispersed in 20 ml of anisole. diphenylmethyl -ketopyridinyl-2) carbonylamino] -2-ketoimidazolidinyl} sulfonylaminocarbonyl) -2-ketoazetidinyl-3) amino} -2-ketoethylideneaminoxy] cyclopentanecarboxylate and, after cooling to -10 ° C, trifluoroacetic acid is added to the suspension. The mixture is stirred for 1 hour at -10 ° C and 300 ml of ether are added at this temperature to form a precipitate, then stirred for 1 hour and the precipitate (5.7 g) is filtered off. The precipitate is dissolved in a mixture of 30 ml of water and 60 ml of acetone and, while stirring at 0 ° C, the solution is basified to pH = 5.5 by adding 0.1 N NaOH. The acetone was evaporated in vacuo and the aqueous phase was freeze-dried to give 5.7 g of a solid residue. This product was chromatographed on HP-20 using water as eluent to give 1.69 g (27%) of pure title compound.

¹ H NMR spectrum (DMSOd ₆ + CF ₃ COOH): <5 = 1.67 (s, 4H), 2.07 (2.4H), 3.65 (t, 2H), 3.75 (dd, 1H ), 3.97 (dd, 1H), 4.07 (t, 2H), 5.07 (dd, 1H), 7.00 (s, 1H), 7.67 (s, 1H), 8.07 (s, 1H), ppm.

Example 5: [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2- {[1- ({3- [(1,4-dihydro-5- hydroxy-4-ketopyridinyl-) 2) methyl o] -2-ketoimidazolidinyl -1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-keto-ethylideneaminoxy] -2-methylpropionic acid

A) 2-Azidomethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4

3.9 g (60 mmol) of sodium azide and 0.1 g of 1.4 are added to a suspension of 2.0 g (6 mmol) of 2-chloromethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 in 20 ml of acetonitrile. 7,10,13,16 of cexaoxacyclooctadene, and the mixture is heated to reflux for 2 hours. The salts are filtered off in vacuo and the filtrate is evaporated in vacuo. The residue was purified by chromatography on a silica gel column using a mixture of ethyl acetate and methanol (8: 2) as eluent to give 1.86 g of the title compound. 120 ° C.

B) 2-Aminomethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4

1.0 g (2.89 mmol) of 2-azidomethyl-5-phenylmethoxy-lphenylmethyl-1H-pyridinone-4 is dissolved in 50 ml of methanol and 0.10 g of platinum oxide is added to the solution. Hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off in vacuo using Hyflo filter aid. The filtrate was evaporated in vacuo and the oily residue was triturated with ether. 0.89 g of the crystalline title compound of 1.1 is obtained. 207 ° C.

C) 2- (2-chloroethylaminocarbonylaminomethyl) -5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4

12.8 ml (0.15 mol) of 2-isocyanate are added to a suspension of 48.0 g (0.15 mol) 2-aminomethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 in 1.5 liters of ethyl acetate. chloroethyl and the mixture was stirred overnight at room temperature. The product is filtered off with suction, washed with ethyl acetate and dried in vacuo to give 59.6 g of the title compound of 1.1. 130 ° C.

D) 2 - [(2-oxoimidazolidinyl-1) methyl] -5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4

To a mixture of 60.8 g (0.13 mol) of 2- (2-chloroethylaminocarbonylaminomethyl) -5-phenylmethoxy-2-phenylmethyl-1H-pyridinone-4 and 1.3 liters of ethanol, a solution of 7.29 g (0.13 mole) of potassium hydroxide in 500 ml of ethanol. The reaction mixture is heated to reflux for 3 hours. The solvent is evaporated off in vacuo and the residue is purified by chromatography on a silica gel column using a mixture of ethyl acetate and methanol (7: 3) as eluent. The obtained product was purified by recrystallization from acetonitrile to give 17.0 g of the title compound, mp 190 ° C (decomposition).

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E) 5-hydroxy-2 - [(2-ketoimidazolidinyl-1) methyl] -1H-pyridinone-4 p-toluenesulfonate

To a solution of 4.89 g (12.8 mmol) of 2 - [(2-oxoimidazolidinyl-1) methyl] -5-phenylmethoxy-l-phenylmethyl-1H-pyridinone-4 in 90 ml of dimethylformamide are added 4.86 g (25.6 mmol) ) p-toluenesulfonic acid monohydrate II, 0 g palladium on carbon, then hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off in vacuo, the filtrate is evaporated in vacuo and the residue is triturated with dichloromethane and ether. The product was filtered off with suction to give 4.12 g of the title compound of 1.1. 195 ° C.

F) 5-hydroxy-2 - [(2-oxoimidazolidinyl-1) methyl] -1H-pyridinone-4 _:

4.0 g (10.5 mmol) of 5-hydroxy-2 - [(2-oxoimidazolidinyl) methyl] -1H-pyridinone-4 are dissolved in 50 ml of water and the solution is basified to pH = 6.5 by adding 2N hydroxide soda. The precipitate is filtered off with suction, washed with water and dried in vacuo, yielding 1.5 g of the title compound of 1.1. 280 ° C (decomp.).

G) Phenylmethyl (S) - [1 - ({3 - [(1,4-Dihydro-5-hydroxy-4-ketopyridinyl-2) methyl] -2-ketoimidazolidinyl} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] carbamate

1.10 g (5 mmol) of (S) -3- (phenylmethoxycarbonylamino) 2-azetidinone are dispersed in 20 ml of anhydrous ethyl acetate and 0.44 ml (5 mmol) of chlorosulfonyl isocyanate are added to the suspension. The mixture is stirred for 1 hour at room temperature (solution A).

To a suspension of 1.04 g (5 mmol) of 5-hydroxy-2 - [(2-oxoimidazolidinyl-1) methyl] -1H-pyridinone-4 in 10 ml of anhydrous ethyl acetate are added 3.70 ml (20 mmol) of N- methyl-N (trimethylsilyl) trifluoroacetamide and the mixture heated to 60 ° C. The resulting clear solution is evaporated in vacuo and the residue is dissolved in 10 ml of anhydrous ethyl acetate (solution B).

Solution B is added to solution A and the reaction mixture is stirred overnight at room temperature. The solvent is removed in vacuo and the residue is triturated with ether to give 2.91 g of the title compound by 1.1. 180 ° C (decomposition).

H) (S) -3-amino-N - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methyl] -2-ketoimidazolidinyl-3-sulfonyl) -2-ketoazetidinecarbonamide-1 trifluoroacetate

To a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid is added 0.50-g (0.93 mmol) of (S) - [1- ({3 - [(1,4-dihydro-5-hydroxy-4- phenylmethyl ketopyridinyl-2) methyl] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] carbamate. The solution was stirred overnight at room temperature and evaporated in vacuo and the residue was triturated with ether. The product is filtered off with suction and dried in vacuo to give 0.49 g of the title compound, 1.1. 155 ° C.

I) [3S (Z)] - 2- [1- (2-Aminothiazolyl-4) -2 - {[1- ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl -2) methyl] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-keto-ethylideneaminoxy] -2-methyl-diphenylmethylpropionate

To a suspension of 0.41 g (0.93 mmol) of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimimo) -thiazole-4-acetic acid in 20 ml of anhydrous acetonitrile is added 0.39 ml (2.8 mmol) of triethylamine was obtained. The mixture is cooled to -30 ° C and 0.19 ml (0.93 mmol) of diphenyl chloroform is added dropwise thereto. The reaction mixture is stirred for 1 hour at -30 ° C (solution A).

0.48 g (0.93 mmol) of (S) -3amino-N - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methyl] trifluoroacetate is dispersed in 20 ml of anhydrous acetonitrile. -2-ketoimidazolidinyl-1} sulfonyl) -2-ketoazetidinecarbonamide-1, and 0.78 ml (3.2 mmol) of bis-trimethylsilylacetamide are added to the suspension. The suspension is stirred for 30 minutes at room temperature and then added to solution A.

The reaction mixture is stirred for 1 hour at -10 ° C and for 1.5 hours at 0 ° C. The resulting clear solution is evaporated in vacuo, and the oily residue is taken up in 50 ml of water. The mixture is acidified to pH = 2 with 2N hydrochloric acid and crystallization gives [3S (Z)] - 2- [1- (2-aminothiazolyl) -4) - 2 - {[1 - ({3- [(1,4-dihydro-5-hydroxy-4-ketopyridinyl -2) methyl] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2 diphenylmethyl-ketoethylideneaminoxy] -2-methylpropionate. The product is filtered off with suction, washed with water and dried in vacuo to yield 0.7 g of the title compound.

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J) [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[l - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl) acid disodium salt -2) methyl] -2-ketoimidazolidinyl-l} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

In 1.4 ml of anisole 0.7 g (0.85 mmol) [3S (Z) j -2- [1- (2-aminothiazolyl-4) -2 - {[l ({[(l, 4- dihvdro -5-hydroxy-4-ketopyridinyl -2) methyl] -2-ketoimidazolidinyl-l} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionate. The suspension is cooled to -10 ° C and treated with trifluoroacetic acid. The solution is stirred for 1 hour at -10 ° C and mixed with 100 ml of ether. The precipitated solid is suction filtered, washed with ether and dried in vacuo.

The trifluoroacetate is dissolved in a mixture of methanol and water and the solution is basified to pH = 6.5 by adding 2N NaOH. The methanol was removed in vacuo and the aqueous solution was lyophilized to give 0.5 g of product. After chromatographic purification, the title compound is obtained, mp 250 ° C (decomposition).

Example VI. [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- ({4 - [(1,4 dihydro-5-hydroxy-4-ketopyridinyl-2)) acid disodium salt methyl] -2,3-dimetopiperazinyl -1 J-sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

A) 2-Chloromethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 hydrochloride

0.5 g (9.3 mmol) of 2-chloromethyl-5-phenylmethoxy-1-phenylmethyl-1H-4-pyridinone-4 hydrochloride are dissolved in a mixture of water and ethyl acetate and the layers are separated. The organic phase is washed twice with water, dried over magnesium sulphate and evaporated in vacuo. The residue is triturated with petroleum ether. The solid is filtered off with suction to give 2.27 g of the title compound of 1.1. 115-120 ° C (decomposition).

C) N-Triphenylmethyl / piperazinedione-2,3

A mixture of 1.4 g (100 mmol) of 2,3-piperazinedione, 55.7 g (270 mmol) of bis-trimethylsilylacetamide and 150 ml of acetonitrile is refluxed for 1 hour. 22.2 g (80 mmol) of triphenylmethyl chloride are added dropwise to the mixture over 30 minutes, kept under reflux for 2 hours and then stirred overnight at room temperature. The clear solution is mixed with 21.6 ml of water, the precipitate formed is filtered off and the filtrate is concentrated in vacuo. The residue was triturated with water and dried to give 25.5 g of crude product. After recrystallization from ethanol, 12.19 g of the title compound are obtained with 1.1. 230-235 ° C.

D) 1- {1,4-Dihydro-4-keto-5-phenylmethoxy- [1- (phenylmethyl) pyridinyl-2] methyl -} - 4- (triphenylmethyl) piperazidione-2,3

0.35 g (11.77 mmol) of sodium hydride (80% oil) is added to a solution of 4.19 g (11.77 mmol) of 2.5-N- (triphenylmethyl) piperazinedione in 95 ml of anhydrous dimethylformamide. After the evolution of hydrogen has ceased, a solution of 4.0 g (11.77 mmol) of 2-chloromethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 is added to the thick suspension and the resulting clear solution is stirred for 0.5 hours at room temperature, whereupon a precipitate began to form. After 2 hours, the crystals are filtered off, washed and dried in vacuo to give 5.13 g of the title compound of 1.1. 165-168 ° C.

E) 1 - {[1,4-Dihydro-4-keto-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl -} - piperazidione-2,3

To a solution of 8.77 g (13.23 mmol) of 1 - {[1,4-dihydro-4-keto-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl-} - 4- (triphenylmethyl) piperazinedione 2.3 in 65 ml of dichloromethane are added dropwise at room temperature to 65 ml of formic acid, and the mixture is stirred for 3 days. Volatiles were distilled off in vacuo and the residue was triturated twice with ether to give 2.54 g of 1 - {[1,4-dihydro-4-keto-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl} -piperazinodione-2,3 by 1.1. 260-265 ° C.

F) (S) - {1 - [(4- [1,4-Dihydro-4-keto-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl} -2,3-dimetopiperazinyl-1) sulfonylaminocarbonyl] Phenylmethyl -2-ketoazetidinyl-3} carbamate

To a solution of 0.44 g (2.0 mmol) of (S) -3- (phenylmethoxycarbonylamino) azetidinone-2 in 25 ml of anhydrous ethyl acetate, 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate was added and the solution was stirred for a while 30 minutes at room temperature. 12 ml of dichloromethane, 0.61 g (6 mmol) of triethylamine are added to the solution and a mixture of 0.83 g (2.0 mmol) of 1 - {[1.412

151 546 dihydro-4-keto-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl} piperazinedione-2,3 and 1.59 g (8.0 mmol) N-methyl-N- (trimethylsilyl) trifluoroacetamide in 25 ml of anhydrous ethyl acetate, subjected to prior stirring for 3 hours. The mixture was stirred for 3 days at room temperature, mixed with ice-water and acidified to pH = 1 with hydrochloric acid. The insoluble residue is filtered off and dried in vacuo to give 1.15 g of the title compound with a purity of 72U.

G) (S) -3-amino N - ({4 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl2) methyl)] -2,3-dimetopiperazinyl-1} sulfonyl 4-methylbenzenesulfonate) -2 -ketoazetidinecarbonamide-1

To a solution of 0.89 g (1.32 mmol) of (S) - {1 - [(4 - {[1,4-dihydro-4-oxo-5-phenylmethoxy-1- (phenylmethyl) pyridinyl-2] methyl} Phenylmethyl -2,3-dice-piperazinyl-1) sulfonylaminocarbonyl] -2-ketoazetidinyl -3} carbamate in 20 ml of dimethylformamide is added 0.5 g (2.64 mmol) of p-toluenesulfonic acid and 0.5 g of 10% palladium on carbon then hydrogen is bubbled through the mixture for 1 hour. The catalyst is filtered off, the solvent is distilled off in vacuo and the residue is triturated with dichloromethane. After drying, 0.82 g of the title compound of 1.1 is obtained. 160-185 ° C (decomposition).

H) [3S (Z)] - 2- [l- (2-aminothiazolyl-4) -2 - {[l - ({4 - [(l, 4-dihydro-5-hydroxy-4-ketopyridinyl-2) methyl] -2,3-dimetopiperazinyl-1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionate

To a solution of 0.57 g (1.3 mmol) of (Z) -2-amino-ff- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimimo) -thiazole-4-acetic acid in 30 ml of dimethylformamide is added at - 30 ° C 0.39 g (3.9 mmol) of triethylamine and 0.31 g (1.3 mmol) of triphenyl chlorophosphate, and the mixture was stirred for 1 hour. 0.39 g (3.9 mmol) of triethylamine and 0.98 g (1.3 mmol) of (S) -3-amino-N - 4-methylbenzenesulfonate ({4 - [(1,4-dihydro -5-hydroxy-4-ketopyridinyl-2) methyl] -2,3-dice-piperazinyl-1} sulfonyl) -2-ketoazetidinecarbonamide-1, and it is stirred for 2 hours at -10 ° C and 1.5 hours at at 0 ° C. After adding water and ethyl acetate, the mixture is acidified to pH = 1 with 3N hydrochloric acid. The precipitated solid was filtered off, washed with ethyl acetate and dried in vacuo to give 0.86 g of the title compound of 1.1. 130-190 ° C (decomp.).

I) [3S (Z)] - 2- [l- (2-aminothiazolyl-4) -2 - {[l - ({4 - [(l, 4-dihydro-5-hydroxy-4-ketopyridinyl) acid, disodium salt -2) methyl] -2,3-dice-piperazinyl} sulfonylaminocarbons! O) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

For a suspension of 0.89 g (0.94 mmol) [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- ({4 - [(1,4-Dihydro- Diphenylmethyl 5-hydroxy-4-ketopyridinyl-2) methyl] -2,3-dice-piperazinyl-1} sulfonylaminocarbonyl) 2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionate in 1.4 ml of anisole is added at - 10 DEG C. 7 ml of trifluoroacetic acid are stirred for 1 hour, then it is mixed with 30 ml of ether. The precipitate formed is filtered off and dried in vacuo. The resulting trifluoroacetate is dispersed in water and the suspension is basified to pH = 6.5 with 2N sodium hydroxide. After lyophilization of the solution, 0.66 g of crude product is obtained. This product, along with a second sample obtained in the same way (1.55 g in total), was chromatographed on a macrocrosslinked copolymer of styrene and divinylbenzene under MPLC conditions to give 0.34 g of the title compound. After purification by chromatography on a column packed with a macroscrosslinked copolymer of styrene and divinylbenzene, 0.18 g of the title compound is obtained, 1.1. 242-270 ° C.

Example VII. [3S (Z)] - 2- [l- (2-aminothiazolyl-4) -2 - {[l - ({4 - [(l, 4-dihydro-5-hydroxy-4-ketopyridinyl-2) acid disodium salt ) carbonylamino] -2,3-dice-piperazinyl-} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

A) 4,5-bis (phenylmethoxy) pyridine-2 carboxylic acid

16 ml of water and 35 ml of 1 N potassium hydroxide are added to a solution of 11.8 g (28 mmol) of 2-phenylmethyl 4,5-bis (phenylmethoxy) pyridinecarboxylate in 115 ml of tetrahydrofuran and the mixture is stirred overnight at room temperature. The mixture is mixed with 115 ml of water and acidified to pH = 2.5 with 1N hydrochloric acid. The solid is filtered off, washed with water and dried in vacuo to give 8.6 g of the title compound of 1.1. 203.6 ° C.

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B) N- (2,3-Duketopiperazinyl-1) -4,5-bis (phenylmethoxy) -pyridinecarbonamide-2

For a suspension of 7.1 g (21.17 mmol) of 2, 4,5-bis (phenylmethoxy) pyridinecarboxylic acid, 0.29 g (2.12 mmol) of hydroxybenzothiazole and 2.73 g (21.17 mmol) of 2-N-aminopiperazinedione 3 in 140 ml of anhydrous dimethylformamide which is stirred for 15 minutes, 4.80 g (23.3 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred for 21 hours at room temperature. Dicyclohexylurea is filtered off (4.0 g) and the solvent is evaporated off in vacuo. The solid residue is triturated with 2401 tetrahydrofuran for 40 minutes, filtered, washed with tetrahydrofuran and dried in vacuo, to give 7.76 g of the title compound, i.e. 231.1 ° C. '

C) Phenylmethyl (S) - {1 - [(4 - {[(4,5-bis (phenylmethoxy) pyridinyl-2] carbonylamino} -2,3-dimetopiperazinyl-1) sulfonylaminocarbonyl] -2-ketoazetidinyl-3} carbamate

1.43 g (10 mmol) of chlorosulfonyl isocyanate are added to a suspension of 2.02 g (9.18 mmol) of (S) -3-phenylmethoxycarbonylamino / azetidinone-2 in 130 ml of ethyl acetate and the mixture is stirred for 1 hour and then thereto is added at 0 ° C 2.79 g (27.54 mmol) of triethylamine. To this mixture is added a solution of 4.10 g (9.18 mmol) of N- (2,3-dimethopiperazinyl-1) 4,5-bis (phenylmethoxy) pyridinecarbonamide-2 and 5.4 g (27.4 mmol) of N- methyl-N- (trimethylsilyl) trifluoroacetamide in 150 ml of ethyl acetate, subjected to prior stirring for 1.5 hours. The mixture is stirred overnight at room temperature, mixed with 220 ml of ice water and acidified from pH = 10.3 to pH = 2 with 3N hydrochloric acid. The organic phase was separated and treated with brine. The resulting precipitate was filtered off, washed with water and dried in vacuo, yielding 5.35 g of product. After triturating 2.5 g of this product for 1 hour with a mixture of 25 ml of water and 37.5 ml of acetone at pH = 3, 2.12 g of the title compound are obtained.

D) (S) -N- {4 - [(3-Amino-2-ketoazetidinyl-1) carbonylamino-sulfonyl] -2,3-dice-piperazinyl-1} -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-2

For a solution of 1.54 g (2 mmol) of (S) - {1 - [(4 - {[(4,5-bis (phenylmethoxy) pyridinyl-2] carbonylamino} -2,3-dice-diethopiperazinyl-1) sulfonylaminocarbonyl] -2 Phenylmethyl-ketoazetidinyl-3} carbamate in 30 ml of dimethylformamide is added 0.77 g of palladium on carbon and the mixture is hydrogenolyzed for 45 minutes, the catalyst is filtered off using Hyflo and the solution obtained is used in the next step without isolating the title compound.

E) [3S (Z)] - 2- [1 - (2-aminothiazolyl-4) -2 - {[1 - ({4 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl2) carbonylamino] Diphenylmethyl -2,3-dimetopiperazinyl-1} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionate

To a solution of 0.88 g (2 mmol) of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimimo) -thiazole-4-acetic acid in 20 ml of dimethylformamide, 0.60 g of ( 6.0 mmol) of triethylamine and then, at -30 ° C and under nitrogen atmosphere, 0.54 g (2.0 mmol) of triphenyl chlorophosphate. The mixture is stirred for 1 hour at -30 ° C, and 0.20 g (2 mmol) of triethylamine and a solution of (S) -N- {4 - [(3-amino-2-ketoazetidinyl-1) are added dropwise thereto. carbonylamino-sulfonyl] -2,3-dice-piperazinyl-1} -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-1 in dimethylformamide. The mixture is stirred for 2 hours at -10 ° C and for 17 hours at 0 ° C. The solvent is distilled off in vacuo and the residue is partitioned between 40 ml of ethyl acetate and 20 ml of ice water. The mixture is acidified to pH = 1.5 with dilute hydrochloric acid and the separated oil is freed from the solvent and dried in vacuo to give 1.35 g of the title compound.

F) [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- ({4 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl) -2) carbonylamino] -2,3-dice-piperazinyl-1} sulfonylaminocarbonyl) 2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic

1.3 g (1.48 mmol) of [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2] are added to the mixture of 2.6 ml of anisole and 13 ml of trifluoroacetic acid at -10 ° C. - {[l - ({4 - [(l, 4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] -2,3-dimetopiperazinyl-l} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2- diphenylmethyl ketoethylideneaminoxy] -2-methylpropionate and the mixture is stirred for 2 hours at 0 ° C. The volatiles were evaporated in vacuo and the residue was triturated with ether to give 1.06 g of trifluoroacetate after drying. This material is dispersed in 20 ml of water and the suspension is basified to pH = 6.5 with 1N sodium hydroxide. After lyophilization of the solution, 1.10 g of crude product are obtained. After cleaning

By chromatography on a macrocross-linked copolymer of styrene and divinylbenzene under MPLC conditions with water as the eluent, 0.48 g of product is obtained. This product is chromatographed twice more with the other samples prepared in the same way, first on the macroscrosslinked copolymer of styrene and divinylbenzene and then on the Organogen preparation, both using water as eluent. 0.10 g of the title compound o 1.1 is obtained. > 300 ° C.

Example VIII. [3S (Z)] - 3 - {(2-aminothiazolyl-4) {[2-fluoroethoxy) iminoacetylamino]} N- / [3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-) salt 2) carbonylamino] -2-ketoimidazolinyl-1} su 1-phonyl) -2-ketoazetidinecarbonamide-1 and ethyldiisopropylamine

0.19 (1.4 mmol) N-hydroxybenzotriazole is added to a solution of 0.33 g (1.4 mmol) of (Z) -2-amino-α- (2-fluoroethoxyimimimo) thiazole-4-acetic acid in 5 ml of anhydrous dimethylformamide. and 0.18 g (1.4 mmol) of N-ethyldiisopropylamine. After adding 0.29 g (1.4 mmol) of dicyclohexylcarbodiimide at 0 ° C, the mixture was stirred for 1 hour. A solution of 0.87 g (1.6 mmol) of trifluoroacetate (2: 1) (3S) -3-amino-N-) {3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) is added to the mixture. ) carbonylamino] -2-ketoimidazolidinyl-1} sulfonyl (-2-ketoazetidinecarbonamide-1 (from Example IG) and 0.41 g (3.2 mmol) of N-ethyldiisopropylamine in 3 ml of anhydrous dimethylformamide, and the mixture is stirred for 16 hours at temperature Dicyclohexylurea is filtered off and the solvent is distilled off in vacuo The residual oil is triturated with water until crystallization is complete, the solid (0.82 g) is filtered off and the filtrate is lyophilized after adjusting to pH 6.1. The solid is dispersed in 40 ml of water and the suspension is basified to pH = 6.0 with 0.25N sodium hydroxide. The undissolved material is filtered off and the filtrate is lyophilized. Both portions of the lyophilization product are combined (about 0.6 g) and chromatographed on a a copolymer of styrene and divinylbenzene using water and a mixture of water and acetonitrile (95: 5) as eluent. After freeze drying the appropriate fractions, 0.22 g of the title compound is obtained with 1.1. 163-165 ° C.

Example IX. [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1 - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) acetylamino) acid disodium salt ] -2-ketoimidazolidinyl-1] sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-keto-ethylideneaminoxy] -2-methylpropionic acid

A) 2-Cyanomethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4

3.9 g (60 mmol) of potassium cyanide and 0.1 g of 1 are added to a suspension of 2.0 g (6 mmol) of 2-chloromethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 in 20 ml of acetonitrile. 4,7,10,13,16 hexaoxazacyclooctadecane, and the mixture was heated to reflux for 2.5 hours. The salts are filtered off in vacuo and the filtrate is evaporated in vacuo. The residue is purified by chromatography on a silica gel column using a mixture of ethyl acetate and methanol (8: 2) as eluent to give 0.55 g of the title compound o 1.1. 175-180 ° C.

B) 1,4-dihydro-5-hydroxy-4-keto-1- (phenylmethyl) -pyridine-2-acetic acid

A mixture of 2.45 g (7.16 mmol) of 2-cyanomethyl-5-phenylmethoxy-1-phenylmethyl-1H-pyridinone-4 and 40 ml of concentrated hydrochloric acid (37%) is stirred for 4 hours at 70 ° C. then evaporated in vacuo. The residue is dispersed in 15 ml of ice water and the pH of the suspension is adjusted to 2 by adding 5N NaOH. The precipitate is filtered off, washed with ice water and ether and dried in vacuo to give 1.71 g of crude product. This product is dissolved in 20 ml of 0.5 N NaOH, the solution is acidified with 2 N HCl to pH = 1.8, and the precipitate is suction filtered and washed with ice water to give 1.52 g of the title compound of 1.1. 231-235 ° C.

C) 1,4-Dihydro-5-hydroxy-4-keto-N- (2-ketoimidazolidinyl-1) -1- (phenylmethyl) pyridine-2-acetamide

For a suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy-4-keto-1- (phenylmethyl) pyridine-2-acetic acid, 0.28 g (1.79 mmol) of N-hydroxybenzotriazole 0.22 g (1.79 mmol) of N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.41 mmol) of dicyclohexylcarbodiimide in 115 ml of anhydrous dimethylformamide are added 4.99 ml ( 35.83 mmol) of triethylamine and the mixture is stirred overnight at room temperature. The precipitated dicyclohexylurea is filtered off, washed with dimethylformamide, and the filtrate is evaporated in vacuo to give a residue which crystallizes upon mixing with 110 ml of dichloromethane. The precipitate is filtered off with suction and dried in vacuo. For the suspension of this raw

14.0 ml (71.6 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide are added to the product in 65 ml of acetonitrile and the mixture is stirred for 30 minutes at room temperature. Undissolved dicyclohexylurea is filtered off and the filtrate is evaporated in vacuo. The oily residue and 70 ml of methanol are boiled for 15 minutes and then cooled. The precipitate formed is filtered off, washed successively with methanol, a mixture of methanol and ether (1: 1) and ether, and dried in vacuo, yielding 8.7 g of the title compound, mp 260-265 ° C (decomposition) and sintering point 242 ° C.

D) (S) - (1 - {[3- {[1,4-dihydro-4-keto-1 - (phenylmethyl) pyridinyl-2] acetylamino} -2-ketoimidazolidinyl-1] sulfonylaminocarbonyl} -2- monosodium salt phenylmethyl ketoazetidinyl-3] carbamate

To a suspension of 3.42 g (10.0 mmol) 1,4-dihydro-5-hydroxy-4-keto-N- (2-ketoimidazolidinyl) -1- (phenylmethyl) pyridine-2-acetamide in 50 ml of anhydrous ethyl acetate is added 5.86 ml (30.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide were added and the mixture was stirred for 1 hour at room temperature (solution A).

To a stirred solution of 2.20 g (10.0 mmol) of (S) -3- (phenylmethoxycarbonylamino) azetidinone-2 in 50 ml of anhydrous ethyl acetate, 0.90 ml (10.0 mmol) of chlorosulfonyl isocyanate is added with stirring, the mixture is stirred with for 1 hour at room temperature and then cooled to 0 ° C. While stirring at this temperature, solution A is added dropwise to the mixture, and the mixture is stirred overnight at room temperature. The mixture is evaporated in vacuo and the residue is taken up in a few ml of methanol and water. After adjusting the pH to 5.5 with dilute NaOH solution, the solution is filtered and lyophilized. The product is purified by MPLC on a macrocrosslinked copolymer of styrene in divinylbenzene using a mixture of water and acetone (8: 1) as eluent. After lyophilization of the corresponding pure fractions, 0.40 g of the title compound is obtained. Impure fractions are purified by MPLC as above to afford 0.60g of the title compound.

E) (S) -N- {3 - [(3-Amino-2-ketoazetidinyl-1) carbonylamino-sulfonyl] -2-ketoimidazolidinyl-1} -1,4-dihydro-5-hydroxy-4-ketopyridine-2- trifluoroacetate acetamide

A solution of 0.90 g (1.3 mmol) of the monosodium salt of (S) - {1 - [(3 - {[1,4-dihydro-5-hydroxy-4-ketol) phenylmethyl (pyridinyl-2] acetylamino} -2- ketoimidazolidinyl-l) sulfonylaminocarbonyl] ketoazetidinyl-3} phenylmethyl carbamate in 13 ml of anhydrous dimethylformamide containing 0.50 ml (6.5 mmol) of trifluoroacetic acid is hydrogenated for 20 minutes in the presence of 0.15 g of 10% palladium on carbon. The catalyst is filtered off and washed with a few ml of dimethylformamide. The filtrate is evaporated in vacuo to give an oily residue which crystallizes on mixing with a few ml of ethyl acetate. 0.675 g of crude product of 1.1 is obtained. 150 ° C (decomposition). The product was stirred with anhydrous ethyl acetate for 1 hour, filtered, washed with ethyl acetate and dried in vacuo to improve the purity of the product. The title compound by 1.1 is obtained in 80% yield. > 165 ° C (decomposition).

F) [3S (Z)] - 2- [1- (2-Aminothiazolyl-4) -2 - {[l - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) acetylamino] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl-2-ketoazetidinyl-3] amino} 2-ketoethylideneaminoxy] -2-methylpropionate

To a suspension of 0.75 g (1.35 mmol) of (S) -N- {3 - [(3-amino-2-ketoazetidinyl) carbonylaminosulfonyl] -2-ketoimidazolidinyl-1} -1,4-dihydro-5- trifluoroacetate was suspended. 1.1 ml (4.45 mmol) of bis-trimethylsilylacetamide are added to the hydroxy-4-ketopyridine-2-acetamide in 12 ml of anhydrous ethyl acetate and the mixture is stirred for 1 hour at room temperature. The clear solution is evaporated in vacuo and the oily residue is dissolved in 12 ml of anhydrous ethyl acetate (solution A).

To a suspension of (Z) -2-amino-α- (2-diphenylmethoxy, 1-dimethyl-2-ketoethoxyimino) thiazole-4-acetic acid in 12 ml of anhydrous acetonitrile, 0.57 ml (5 ml) was added dropwise to a suspension cooled to -30 ° C. , 4 mmol) triethylamine and then 0.29 ml (1.35 mmol) diphenylchlorophosphate and the mixture is stirred for 1 hour at -30 ° C and for 1 hour at 0 ° C. The solvent is removed in vacuo and the residue is crystallized by stirring with a few ml of water at 0 ° C. The precipitate is suction filtered, washed with cold water, dispersed in water at pH = 2 (with the addition of a few drops of dilute HCl), filtered, washed successively with water, methanol and ether, then dried in vacuo to give 1.07 g.

151 546 of the title compound with 1.1. > 180 ° C (decomposition). The crude product is used in the next step without further purification.

G) [3S (Z)] - 2- [l- (2-aminothiazolyl-4) -2 - {[l - ({3 - [(l, 4-dihydro-5-hydroxy-4-ketopyridinyl) acid, disodium salt -2) acetylamino] -2-ketoimidazolidinyl-1} sulfonylaminocarbonyl-2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

To a solution of 2.0 ml of anisole in 10 ml of trifluoroacetic acid, cooled to -10 ° C, 1.01 g (1.17 mmol) of crude [3S (Z)] - 2- [1- (2-aminothiazolyl-4) are added. ) -2 - {[l - ({3 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) acetylamino] -2-ketoimidazolidinyl-l} sulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino] 2- diphenylmethyl ketoethylideneaminoxy] -2-methylpropionate and the mixture is stirred for 20 minutes at -10 ° C. The solvent is removed in vacuo at + 10 ° C, and the residue is mixed with a few ml of dichloromethane, suction filtered, washed with hexane and dried in vacuo. The crude product (1.06 g) was suspended in a few ml of a mixture of water and acetonitrile and dissolved by adding 1N NaOH until pH = 6.0. After concentration in vacuo, the aq. Solution is chromatographed (MPLC) on a macroscrosslinked copolymer of styrene and divalent benzene, eluting with water. The appropriate fractions were combined and lyophilized, yielding 0.10 g of the title compound as 1.1. > 255 ° C.

Example X. Disodium salt of [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1- ({2 - [(1,4-dihydro-5-hydroxy-4- ketopyridinyl-2) carbonylamino] ethyl} aminosulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic acid

A) N- (4-methoxybenzyl) -O-benzylcomenamic acid

A mixture of 10 g of O-benzylcomenamic acid and 10 ml of 4-methoxybenzylamine in 60 ml of water is refluxed for 4 hours. The reaction mixture is acidified at room temperature with 2 N HCl to pH = 2, yielding 15 g of crystals. After recrystallization from dioxane, 12.3 g of the title compound are obtained with 1.1. 175 ° C.

Β) 1,4-Dihydro-1- (4-methoxyphenylmethyl) -4-keto-5-phenylmethoxy-N- [2- (phenylmethylamino) ethyl] pyridinecarbonamide-2

A mixture of 3.69 g of N- (4-methoxyphenylmethyl) -O-benzylcomenamic acid, 1.50 g of N-hydroxybenzotriazole and 2.05 g of dicyclohexylcarbodiimide in 50 ml of dioxane is stirred for 1 hour at room temperature. A solution of 1.35 g of Nbenzylethylenediamine in 5 ml of dioxane is added dropwise to this mixture and it is stirred overnight. The dicyclohexylurea formed is suction filtered and the dioxane is evaporated from the filtrate. The resulting oil was dissolved in 50 mL of dichloromethane and the solution was extracted with 10% sodium bicarbonate (2X50 mL) and washed with water. The dichloromethane solution is dried over sodium sulfate and evaporated, and the resulting solid is recrystallized from ethanol to give 4.2 g of the title compound as crystals of 1.1. 112 ° C.

C) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-2 p-toluenesulfonate

To a mixture of 9.95 g 1,4-dihydro-1- (4-methoxyphenylmethyl) -4-keto-5- (phenylmethoxy) -N [2- (phenylmethylamino) ethyl] pyridinecarbonamide-2 and 7.7 g p-toluenesulfonic acid 3 g of 10% palladium-carbon is added and, at 45-50 ° C, hydrogen is bubbled into the reaction mixture for 6 hours, then argon is bubbled through the reaction mixture for 10 minutes. The mixture was filtered and the filtrate was evaporated. The resulting beige crystals are washed successively with 20 ml of cold methanol and 50 ml of ether. 10.5 g of the title compound o 1.1 are obtained. 271 ° C.

D) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-2-chlorohydride

5.42 g of N- (2-aminoethyl) 1,4-dihydro-5-hydroxy-4-ketopyridine-2-carbonamide p-toluenesulfonate are dissolved in 50 ml of formic acid and the solution is treated with 7.5 ml of hydrochloride solution (2.2 HCl equivalent) in formic acid and then 150 mL of ether to give white crystals. After isolation by filtration and washing with 200 ml of ether, 2.60 g of the title compound are obtained, 1.1. 287 ° C.

E) Phenylmethyl (3S) - [l - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] ethyl} aminosulfonylaminocarbonyl-2-ketoazetidinyl-3] carbamate

151 546

To a suspension of 4.38 g of (S) -3- (phenylmethoxycarbonylamino) azetidinone-2 in 50 ml of ethyl acetate was added 2.83 g of chlorosulfonyl isocyanate at room temperature and stirred for 30 minutes to give a clear solution (solution A).

5.40 g of two N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-2 dihydrochloride in 50 ml of acetonitrile are mixed with 24 g (6 eq.) Of N-methyl-N (trimethylsilyl) .il1) trifluoroacetamide for 1 hour at 50 ° C. Volatiles are evaporated off in vacuo and the oily residue is added to 50 ml of ethyl acetate (solution B).

Solutions A and B were cooled to 0 ° C and while stirring solution B was added to solution A and the mixture was stirred overnight. Then the mixture is mixed with 200 ml of isopropanol and stirred at 0 ° C. After isolation, 8.77 g of the title compound are obtained in the form of beige crystals of 1.1. 145 ° C.

F) (3S) -N - [(3-Amino-2-oxetidinyl-1) -carbonylamino-sulfonylamino-ethyl] -1,4-dihydro-5-hydroxy-4-ketopyridinecarbonamide-2 trifluoroacetate

A mixture of 2g of phenylmethyl (3S) - [({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] ethyl} aminosulfonylaminocarbonyl) -2-ketoazetidinyl-3] carbamate in a mixture of 20 ml of thioanisole and 40 ml of trifluoroacetic acid are stirred for 12 hours at 0 ° C. After the mixture is treated with 100 ml of ether, white, fine crystals are isolated by filtration. After washing with 50 ml of isopropanol and 100 ml of ether, 2.12 g of the title compound are obtained as 1.1. 136 ° C (decomposition).

G) [3S (Z)] - 2- [1- (2-Aminothiazolyl-4) -2 - {[l - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] ethyl} aminosulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylphenylmethylpropionate

4.40 g of (Z) -2-amino-α- (2-diphenylmethoxy-1,1-dimethyl-2-ketoethoxyimino) thiazole-4-acetic acid and 3 g of triethylamine are dissolved in 150 ml of acetonitrile. 2.8 g of diphenyl chlorophosphate are added dropwise to the solution at -30 ° C, and the mixture is stirred for 1 hour.

A mixture of 6.13 g of (3S) -N - [(3-amino-2-ketoazetidinyl-1) carbonylamino-sulfonylaminoethyl] -1,4-dihydro-5-hydroxy-4-ketopyridine-2-trifluoroacetate and 17 g of N-methyl-N ( trimethylsilyl) trifluoroacetamide in 100 ml of ethyl acetate is stirred for 2 hours. The solvent is evaporated from the solution in vacuo and the residual oil is evaporated for 2 hours at 30 ° C under a vacuum of less than 1.33 Pa (made with an oil pump). The residue is dissolved in 100 ml of ethyl acetate and the activated acid is added dropwise to the solution at -30 ° C over 30 minutes. The mixture is stirred for 1 hour at -10 ° C and for 1 hour at 0 ° C. The solvent is evaporated off and the oily residue is mixed with ice water, maintaining the pH = 3 with 2N phosphoric acid, and the water is discarded. The residue is washed with ice water and dried to give 7.8 g of beige crystals.

H) [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl) acid disodium salt -2) carbonylamino] ethyl} aminosulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylpropionic

A mixture of 3g [3S (Z)] - 2- [1- (2-aminothiazolyl-4) -2 - {[1 - ({2 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) carbonylamino] ethyl} aminosulfonylaminocarbonyl) -2-ketoazetidinyl-3] amino} -2-ketoethylideneaminoxy] -2-methylphenylmethylpropionate in 30 ml of a mixture of trifluoroacetic acid and anisole is stirred for 30 minutes. After treatment with ether, the free acid trifluoroacetate was isolated. This material (7.9 g) was suspended in 20 ml of water, the suspension was quenched with sodium bicarbonate until pH = 6.0, stirred for 0.5 h and filtered. The solution was chromatographed on a macroscopic copolymer of styrene and divinylbenzene with water as the eluent to give 0.24 g of product. This product was chromatographed on a Lobar C column (Merck) to give 0.078 g of the title compound of 1.1. 275 ° C (decomp.).

Example 11 (3S) -2- [1- (2-Aminothiazolyl-4) -2- {1 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl] -2-ketoazetidinyl -3} amino) -2-ketoethylideneaminoxy] -2-methylpropionic

A) 2-Hydroxymethyl-5-phenylmethoxy-4H-pyranone-4

A suspension of 58.6 g (0.4 mol) of 5-hydroxy-2-hydroxymethyl-4H-pyranone-4 in 400 ml of methanol is mixed with 16 g (0.4 mol) of sodium hydroxide in 200 ml of warm methanol and then 50 6 g

Benzyl chloride 151 546 (46 mL, 0.4 mol). The mixture was heated to reflux for 3.5 hours, cooled and poured into 1 liter of water. The resulting solid is filtered off, washed with about 1.5 liters of water, 200 ml of ethanol and 400 ml of hexane. After drying under high vacuum, 53.7 g of product are obtained.

Β) 1,4-Dihydro-2-hydroxymethyl-5- (phenylmethoxy) -pyridinone-4

A mixture of 9.64 g (41.59 mmol) of 2-hydroxymethyl-5-phenylmethoxy-4H-pyranone-4, 95 ml of concentrated ammonium hydroxide solution and 20 ml of ethanol was heated to reflux overnight. After the addition of 75 ml of ammonium hydroxide solution, the mixture is refluxed for 2 hours and cooled. The resulting brown solid is filtered off and washed with water until the washing solution is neutral. The crude product is dispersed in ethanol, filtered, washed with ethanol and dried in vacuo to yield 7.61 g of the title compound.

C) 1-Chloromethyl-1,4-dihydro-5- (phenylmethoxy) -pyridinone-4 hydrochloride

A suspension of 3 g (12.99 mmol) of 1,4-dihydro-2-hydroxymethyl-5- (phenylmethoxy) -pyridinone-4 in 15 ml of chloroform is cooled to 0 ° C under argon and 6.1 ml (83 62 mmol) of thionyl chloride to give a homogeneous solution within a few minutes, which is stirred for another 5 minutes, precipitating a cream solid. After removal of the cooling bath, the mixture was refluxed for 45 minutes and then cooled to 0 ° C. The white material is filtered off, washed with chloroform and hexane and dried in vacuo to give 3.65 g of the title compound.

D) 2-Azidomethyl-1,4-dihydro-5- (phenoxymethyl) -pyridinone-4

A mixture of 3.59 g (12.54 mmol) of 1-chloromethyl-1,4-dihydro-5- (phenylmethoxy) -pyridinone-4.4.08 g (62.7 mmol) of sodium azide hydrochloride and 2.19 ml (12 54 mmol) of diisopropylethylamine in 70 ml of dimethylformamide is stirred for 3 days at room temperature under argon. After the addition of 4.08 g of sodium azide, the mixture was heated to 45-50 ° C for 2 hours. After cooling, the reaction mixture is poured into 500 ml of water, precipitating a white solid. The solution above the solid is acidified with dilute hydrochloric acid from pH = 8.5 to pH = 7.5, and the solid is filtered off. After washing with water, acetone and hexane and drying in vacuo, 2.81 g of the title compound are obtained.

E) α-Aminomethyl-4-keto-5- (phenylmethoxy) pyridine

A suspension of 2.030 g (7.93 mmol) of 2-azidomethyl-1,4-dihydro-5- (phenoxymethyl) pyridinone-4 and 200 mg of platinum oxide in 100 ml of dimethylformamide is stirred for 6 hours at room temperature under a hydrogen atmosphere under pressure. 0.1 MPa. The catalyst was filtered off and the solution concentrated in vacuo to give 1.5 g of the title compound as a gray powder.

F) (3S) -1 [(1,4-Dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl] -2-keto-3 (phenylmethoxycarbonylamino) azetidin

To a suspension of 2.330 g (10.13 mmol) of 2-aminomethyl-4-keto-5- (phenylmethoxy) pyridine in 60 ml of ethyl acetate, 3.76 ml (20.26 mmol) of N-methyl-N- (trimethylsilyl) are added with stirring. ) trifluoroacetamide. The resulting solution is stirred for 30 minutes at room temperature, then cooled to 0 ° C. Simultaneously, 882 microliters (10.13 mmol) of chlorosulfonyl isocyanate are added to a suspension of 2.228 g (10.13 mmol) of (S) -3 (phenylmethoxycarbonylamino) azetidinone-2 in 60 ml of ethyl acetate. The resulting solution is stirred for 30 minutes at room temperature, then cooled to 0 ° C and mixed successively with 4.23 ml (30.39 mmol) of triethylamine and a solution of silylated 2-aminomethyl-4-keto-5- (phenylmethoxy). of pyridine prepared as above, and the mixture is stirred for 2 days at room temperature. The mixture was concentrated in vacuo, the residue was dissolved in a mixture of acetonitrile and water (40:60) and the solution was acidified to pH = 2.9, giving off a thick oil which solidified upon cooling to 5 ° C. The solid is filtered off, washed four times with water and dried in vacuo to give 3.4 g of crude product. This product is dissolved in the minimum amount of dimethylformamide and applied to a column filled with a macroscrosslinked copolymer of styrene and divinylbenzene (1 liter), and a gradient is eluted with acetone and water in appropriate proportions. The desired product is eluted with about 65% acetone solution. The appropriate fractions were combined and lyophilized to give 2.64 g of the title compound.

151 546

G) (3S) -2- [l - {2-aminothiazolyl-4) -2 - ({l - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl] -2-ketoazetidinyl- 3} amino) -2-ketoethylideneaminoxy] -2-methylpropionate diphenylmethyl

A mixture of 912 mg (1.64 mmol) (3S) -1 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl] -2-keto-3- (phenylmethoxycarbonylamino) azetidine, 625 mg (3.28 mmoles) of p-toluenesulfonic acid monohydrate and 190 mg of 10% palladium on carbon are stirred under an atmosphere of hydrogen at 0.1 MPa pressure until 3.28 mmoles (73 ml) of hydrogen have been absorbed (within about 3 hours) .

To a solution of 846 mg (1.804 mmol) of (Z) -2-amino-α- (2-diphenylmethoxy) -1,1-dimethyl-2-ketoethoxyimino / thiazole-4-acetic acid in 16 ml of dimethylformamide, stirring at -20 ° C C, 374 microliters (1.804 mmol) of diphenylchlorophosphate and 450 microliters (3.28 mmol) of triethylamine are successively added. The solution is stirred for 1 hour at -20 ° C, then the hydrogenolysis reaction mixture prepared as described above is added and then 921 microliters (6.6 mmol) of triethylamine. The mixture was stirred for 1 hour at -20 ° C and overnight at 5 ° C. The catalyst is filtered off, the volatiles are removed in vacuo, the remaining oil is dissolved in a minimum amount of a mixture of acetone and water (70:25, pH = 512) and the solution is added dropwise to a suspension of 20 ml of Dowex 50X2-400 (K ⁺ ) in the mixture acetone and water (35:55) with agitation. After 40 minutes, the mixture was filtered and the filtrate was lyophilized to give 2.1 g of a solid. This material is dissolved in a minimum amount of acetonitrile and water (40:60, pH = 5.6) and applied to a column filled with a macrocrosslinked copolymer of styrene and divinylbenzene (800 ml) by gradient elution with acetonitrile and water in the appropriate proportions. The desired product is eluted with about 30% acetonitrile. The appropriate fractions are combined and lyophilized to afford the title compound.

H) (3S) -2- [1- (2-Aminothiazolyl-4) -2 - ({1 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl] -2-ketoazetidinyl -3} amino) -2-ketoethylideneaminoxy] -2-methylpropionic

For the stirred suspension 131 mg (0.113 mmol) (3S) -2- [1- (2-aminothiazolyl-4) -2 ({1 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) Diphenylmethyl methylaminosulfonylaminocarbonyl] -2-ketoazetidinyl-3} amino) -2-ketoethylideneaminoxy] -2-methylpropionate in 3 ml of dichloromethane and 0.3 ml of anisole are added dropwise at 0 ° C to 4.7 ml of trifluoroacetic acid and the mixture is stirred for a while 45 minutes at 5 ° C. After the addition of 2 ml of toluene, the volatiles are removed in vacuo. The residual oil was washed with hexane (3 x 4 mL) and triturated with 10 mL of ether to give a solid. The material is washed with 10 ml of ether and dried in vacuo. The above reaction and work-up was repeated using 0.166 mmol of (3S) -2- [1- (2-aminothiazolyl- 4) -2 - ({1 - [(1,4-dihydro-5-hydroxy-4-ketopyridinyl-2) methylaminosulfonylaminocarbonyl Diphenylmethyl] -2-ketoazetidinyl-3} amino) -2-ketoethylideneaminoxy] -2-methylpropionate. The crude products are combined, dissolved in 2 ml of a mixture of acetonitrile and water (40:60, pH = 2.5) and chromatographed on a column packed with a macrocrosslinked copolymer of styrene and divinylbenzene with a gradient elution. The desired product is eluted with a mixture of acetonitrile and water (20:80). The appropriate fractions were combined and lyophilized to give 103 mg of the title compound as a white solid, 1.1. 180 ° C (decomposition).

Claims (5)

Patent claim The method of producing new 4-sulfonylaminocarbonyl- derivatives 2-ketoazetidines of the general formula in which R 1 is a C 1 -C 8 -alkyl group optionally substituted with a carboxylic acid group, an N-hydroxy amide group or a halogen atom, R 2 and R 3 are the same or different and represent a hydrogen atom or a methyl group, and L is the -NH-CH2- group, 151 546 -NH-NH-CO-, -NH-NH-CO-CH = CH-, -NH-NH-CO-NH-CO-, NH-CH ₂ CH ₂ -NH-CO- or NH-NH-CO- NH-NH-CO-, or the group of formula 2.3, 4,5,6,7 or 8, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula 9 wherein R _2, R 3 and L are as defined above, is acylated with a carboxylic acid of formula 10, wherein R 1 is as defined above, or a halide or anhydride thereof, optionally then converting the resulting compound of the formula I into its pharmacologically acceptable salt. Formula 1 Formula 2 II Formula 5 -n ^ n-nh-ch ₂ NH-NH-N N-NH-COO Formula 3 Formula 6 -N N-NH -N N-CH Pattern A Formula 7 -rf N-NH-CO Formula θ NH ₂ ^ 2 CH — r R, r> oH N-C-NH-SO ^ Ó H. Pattern 9? π, R4NH HzN- ^ N ^ ę ^_C00H \ u _a_ fc N-OR, Formula 10 CH —-R, cNH Formula 11 R, NH ^ 2 5 ^H- e- * 3, CN- C-NH-SO ₂ -Y Formula 12 Η H. Pattern 13 Pattern 14 Formula 15