PL128184B1 - Process for preparing novel beta-lactams - Google Patents

Description

The subject of the invention is a method for preparing new β-lactams of the general formula 1, in which Ri is a hydrogen atom or the acyl group or the Ri-NH- group is a protected amino group, R2 is a hydrogen atom or an alkoxy group of 1-4 carbon atoms, R3 and R4 are the same or different and represent hydrogen atoms, alkyl, cycloalkyl, phenyl or substituted phenyl radicals, or one of the substituents R3 and R4 is a hydrogen atom and the other is an alkoxycarbonyl group, an alken-1 radical -yl, alkyne-1-yl, 2-phenylethenyl or 2-phenylcetynyl and M+ denotes a hydrogen atom or a cation. The compounds prepared according to the invention, including compounds of formula 1 in the form of internal salts, have antibiotic properties, and Compounds of formula 1, in which Ri is an acyl group, have particularly valuable properties. - As used herein, the terms "alkyl radical" and "alkoxy radical" mean straight or branched chain radicals, preferably containing 1 to 10 carbon atoms. The terms "cycloalkyl radical" and "cycloalkenyl radical" refer to radicals having 3, 4, 5, 6 or 7 carbon atoms. The term "alkenyl radical" means straight or branched radicals, preferably with 2 to 10 carbon atoms. The term "halogen atom" means fluorine, chlorine, bromine and iodine atoms. The term 'secured; "carboxyl group" means a carboxyl group esterified in a known manner. Such groups are known, for example, from US Pat. No. 4,144,333. Preferred protected carboxyl groups are the benzyl, beruzhydiryl and tertium ester groups. butyl groups. The term "substituted phenyl radical" means a phenyl radical containing 1, 2 or 3 halogen atoms, hydroxyl groups, trifluoromethyl groups or lower alkyl or alkoxy groups. The term "acyl group" means all groups derived from organic acids (i.e. from carboxylic acids ), from which the hydroxyl group has been removed. In accordance with the invention, it is preferable to use certain acyl groups, and the invention is not limited to the use of such groups. Examples of such groups are known acyl groups used in known processes for the acyl names of antibiotics / α-lactams, including 6-aminopenicillanic acid and its derivatives and 7-aminocephalosporanic acid and its derivatives. Information on this subject can be found, for example, in the work Cephaloisporins and Penicillins, published by Flynn, Academic Press (1972), in the German patent description No. 2716C77, in the Belgian patent description No. 867994, in the United States patent descriptions. Am, Nos. 4,152,432, 3,971,778 and 4,172,199. The following are examples of acyl groups used in the present invention, but are not limiting. These exemplary acyl groups are as follows. 128 1843 128 184 4 "TC" a. Aliphatic groups of formula 4, wherein R5 is an alkryl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl group and an alkyl or alkenyl group containing one or more substituents such as atems Cyano, nitro, amino acid, methyl acid, amine oxide or cyanomethyl thio groups. and b. Carbocyclic {aromatic groups with the formulas nitro, amine, cyano, trifluoromethyl, alkyl with 1-4 carbon atoms or aminomethyl groups, n in the formula 5 means zero, 1, 2 or 3, and R9 in the formula 6 means an amino group, a hydroxyl group, a carboxylic acid salt group , a protected carboxyl group, a Formyloxy group, a sulfonic acid salt group, an azide group, a halogen atom, a hydrazine group, an alkyl-* hydirazime group, a phenylhydrirazino group or a [(alkyl-thioi-thioketomethyl]-thio group. Particularly preferred groups are used of the formula 5, in which n is the number 1, two of the substituents R6, R7 and R8 are hydrogen atoms, and the third is the hydroxyl group in the 4-position, groups of the formula 5 in which n is the number 1, two of the the substituents Re, R7 and Rs denote hydrogen atoms, and the third substituent represents the aminomethyl group in the 6-position, groups of formula 6, in which R9 denotes a carboxylic acid salt group or a sulfonic acid salt group and 2 of the substituents Re, R7 and Rs denote atoms hydrogen, and the third is a hydroxyl group in the 4-position, as well as groups of formula 6, in which R6, R7 and Rs are hydrogen atoms and R9 is a carboxylic acid salt group or a sulfonic acid salt group. c. Heteroaromatic acyl groups of the formulas 11, 12, 13, 14 and 15, in which Rio is a substituted or unsubstituted heterocyclic aromatic ring with 5, 6 or 6 members, containing 1, 2, 3 or 4, preferably 1 or 2 atoms of nitrogen, oxygen and sulfur, n in the formula 11 has the meaning given above and Rq in the formula 12 also has the meaning given above. Examples of heterocyclic Rio rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, morpholinyl, pdryrnidinyl and tetrazolyl rings. Examples of substituents in these rings are halogen atoms, hydroxyl groups, nitro amino, cyano, trifluoromethyl, alkyl with 1-4 carbon atoms and alkoxy with 1-4 carbon atoms. Particularly preferred are groups in which the Rio substituent is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidinyl-2, 5-amino-1,2,4 -thiadiazolyl-5 and 2-thienyl or 2-furanyl. d. {[i(4-substituted-2,3-diceto-1-pdperazinylj-carbonyl]-amino}-arylacetyl groups of formula 16, in which Rn is an aromatic group, including carbocyclic aromatic groups with formula 17, in which R6, R7 and Rs have the meanings given above, as well as the heteroaromatic groups described above in the discussion of the R10 substituent, and Rw is an alkyl group, an alkyl group containing one or more substituents such as halogen atoms, groups cyano, nitro, amino or mercapto, or RJ2 is an arylmethyleneamino group of the formula -N=CH-Rn, in which Rn has the above-mentioned meaning, or 1 arylcarbonylamino group of the formula -NH- -C(0)-Rn, wherein Rn has the meaning given above, or Ri2 represents an alkylcarbonylamino group. Preferred groups of formula 16 are especially those in which R12 represents an ethyl radical, a phenylmethyleneamine radical or a 2-furylmethyleneamino radical. e. Oxiiminoarylacetyl groups substituted in the oximine group, of the formula 18, in which Rn has the above-mentioned meaning, and R13 is a hydrogen atom, an alkyl, cycloalkyl, alkylaminocarbonyl group, an arylaminocarbonyl group of the formula -C(0)-NH-Rn, in wherein Rn has the above-described meaning, an alkyl group containing one or more substituents such as halogen atoms, cyano, amino, nitro, mercapto, alcolothio groups, aromatic groups Rn described above, carboxyl groups, carboxyl groups in the form of salts, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy-(phenylmethoxy)-phosphinyl, dialkoxyphosphinyl amide groups. Preferred groups of formula 18 are those in which Rn is a 2-amino-4-thiazolyl3a group and those in which R13 is a methyl, ethyl, carboxymethyl or 2-carboxyisopropyl radical. f. (Acylamino)arylacetyl groups of the formula 19, wherein Rn is as defined above and Ru is a group of formula 20, wherein R6, R7 and Rs3j are as defined above, or Ru is an amino, alkylamino, cyanoalkylamino- ava, amide, alkaliarnide, cyanoalkylamide or a group of formula 21, 22, 23, 24, 25 or 26. Preferred groups of formula 19 are those in which R14 is an amino or amide group, as well as those in which Rn means a phenyl or 2-thienyl radical. g. {[<3-substituted 2-keto-1-imidazolidinyl)-carbonyl]-amino}-arylacetyl groups of formula 27. tt in which Rn has the above-mentioned meaning and Rr is a hydrogen atom, an alkylsulfonyl group, an arylmethylene amino group of the formula -N=CH-Rii, in which Rn has the above-mentioned meaning, a Q group of the formula -C(0)-Ri6, in which Ri6 is a hydrogen atom, an alkyl radical or a haloalkyl radical, or R15 is an aromatic Rn group as described above, an alkyl radical or an alkyl radical containing one or more substituents such as halogen atoms, nitro, cyano, amino or mercapto groups. Preferred groups of formula 27 are those in which Rn is a phenyl or 2-thienyl radical, as well as those in which R15 is hydrogen, methylsulfonyl, phenylmethyleneamine or 2-furylmethyleneamine. As used in the description and claims, the term "cation" means any atom or group of atoms with a positive charge. The substituent of the formula -SO3-M+ on the nitrogen atom in the β-lactams produced in accordance with the invention means all acid salts sulfonic acids. Preferably, physiologically acceptable salts are prepared, but other salts can also be prepared and used in the purification of products or as intermediate products in the preparation of pharmacologically acceptable salts. The cationic part in the salts prepared according to the invention may come from organic or inorganic bases. Examples of such cationic parts are ammonium ions, substituted ammonium ions, such as alkylammonium ions, e.g. ' e.g. lithium, sodium and potassium, alkaline earth metal ions, e.g. calcium or magnesium, pyridimium, dicyclohexyl ammorrium, hridirabaminium, benzethinium and N-methyl-D-glufeathinium ions. As stated above, M+ can also attract lithium. Compounds of formula 1 have at least one carbon center, namely the carbon atom in the 3' position of the lanthane ring to which the amino compound or acylamine. The sphereoisomerism caused by this chiral center in the 3-position of the lactam ring corresponds to the stereoisomerism caused by the asymmetric carbon atom in the 6-position of penicillins of natural origin, e.g. in penicillin G and stereodomerism caused by the asymmetric carbon atom in the 7-position of cephamycin of natural origin, e.g. in cetamycin C. Taking into account the accepted rules of nomenclature, it is believed that compounds of formula 1, in which R2 is a hydrogen atom, have the configuration S, in which R2 is an alkoxy red group, have the R configuration. According to the invention, it is also possible to prepare racemic mixtures of the compounds of formula 1. ] The compounds of the formula I, in which all the symbols have the meanings given above, are prepared according to the invention in such a way that the compound b of the formula 2, in which Ri, R3 and R4 have the meanings given above, and V denotes the group cleavable, such as a methanesulfonyl, benzenesulfonyl or toluenesulfonyl group or a chlorinated bromine or iodine atom, is sulfonated and then no cyclization, or the compound of formula 2 is first cyclized and then the resulting intermediate product of formula 3 is sulfonated, in which Ri, R2, R* and R4 have the meanings given above. In the obtained product, the protective group of the amino group in the 3-position of the lactam ring is split off and/or the hydrogen atom in the sulfone group is converted into another cation, or the compound obtained in the form of a salt is converted into another salt using known methods. Sulfonation reactions is easily carried out by treating the compound of formula *2 with a sulfate trioxide complex or another sulfonating agent such as chlorosulphonate. The complex of pyridine, lutidium, dimethylformamide and picoline with sulfur trioxide is preferably used as the trioxide complex compound. This complex compound can also be prepared in situ, for example using chlarosulfonyl-trimethylsilyl ester and pyridine as reaction components. It can also be sulfonated by first silylating the nitrogen atom in the starting product and then subjecting the hydrolylated compound to a silyl group exchange reaction with trimethylsilyl chlorosulfonate or a similar compound. Examples of dilylating compounds used are monosilyltrifluoroacetamide, trimethylsilyl chloride/triethylamine or bis-trimethylsilyltrifluoroacetamide. The sulfonation reactions are preferably carried out in an organic solvent, e.g. pyridine, or in a mixture of organic solvents, preferably in a mixture of a polar solvent, such as dimethylformamide, with a halogenated hydrocarbon. 15 e.g. with dichloromethane. The process of sulfonation of a compound of formula 2 previously transformed into a compound with a closed lactam ring, i.e. into a compound of formula 3, is carried out similarly to the process of sulfonation of a compound of formula 2. If the compound to be sulfonated contains an amino group (Ri is a hydrogen atom), then It is advantageous to protect this group against sulfonation, e.g. using a benzyloxycarbonyl group. In the obtained product, these rots can be separated without pitting by known methods. Of course, other groups protecting the amino group can also be used, e.g. a tert-butyloxycarbonyl group, a conventional acyl group such as acetyl, benzoyl, phenylacetyl, triphenylmethyl, or the amino group can be converted into an azide group. The α-lactam ring can be prepared by cyclization after or before the sulfonation reaction. For example, the compound of formula 28 in which R3, R4 3| M+ and V have the meanings given above, are cyclized to obtain a compound of formula 1, in which R3, Ri and M+ have the meanings given above, acyl means an acyl group and R2 means a hydrogen atom. The acyl group also plays the role of a group here za- ^ without sealing, which can be split off with the release of the -NH2 group. Compounds of formula 2, which are the starting products in the process according to the invention, can be prepared from amino acids of formula 29, in which R3 and R4 have the meanings given above, but at least one of these substituents represents a hydrogen atom. First, the amino group is protected in a known manner, e.g. the tertiary-butoxycarbonyl group (these groups are further designated in the formulas by the abbreviation BOC), and then the carboxyl group of the protected amino acid is reacted with an amine salt of the formula Y-O-NH3+CI-, where Y is an alkyl or benzyl radical, carrying out these reactions in the presence of carbodiimide. This gives the compound of formula 30 in which BOC, Y, R3 and R4 have the meanings given above, but at least one of the symbols Rj and R4 represents a hydrogen atom. The hydroxyl group in this compound is then converted into a V group that can be easily split off using a known method, e.g. with methanesulfonyl chloride (the methanesulfonyl group is hereinafter abbreviated as Ms). Other V groups given above may also be used. The fully protected compound of formula 31, "in which BOC, Y, V, R3 and R" have the meanings given above, where at least one of the symbols R3 and R4 denotes a hydrogen atom, undergoes followed by cyclization by treatment with a base, e.g. with potassium carbonate. These reactions are preferably carried out in an organic solvent, such as acetone, at the boiling point of the mixture under reflux, obtaining a compound of formula 32, in which BOC, R3 and Ra have the meanings given above and at least one of the substituents R3 and R4 is hydrogen atom. The compound of formula 30 can also be cyclized before converting the hydroxyl group into the V group. For this purpose, the compound of formula 30 is treated with triphes, phosphine and diethyl azodicarboxylate, producing a compound of formula 32. formula 32 can be removed by reduction with sodium when Y is an alkyl radical, producing a compound of formula 33 in which BOC, R3 and R* have the meanings given above and at least one of the substituents R3 and R4 represents a hydrogen atom. When Ywe of formula 32 is a benzyl radical, then this radical is split off by catalytic hydrogenation, e.g. in the presence of palladium on charcoal, to obtain the appropriate N-hydroxyl compound, which, as a result of reaction with titanium trichloride, gives the compound of formula 33. Banded above the synthesis, associated with ring closing, causes a change in the spatial configuration of the substituents R3 and R4. As mentioned above, azetidinone of formula 33 may be sulfonated to produce a compound of formula 34 in which BOC, Rs, R4 and M+ are as defined above and at least one of R3 and Ra is hydrogen. Compounds of the formula 1, in which R2 is hydrogen and at least one of the substituents Ra and 114 is a hydrogen atom, can also be prepared using as the starting product an acid amide of the formula 35, in which at least one of the substituents R3 and R4 is hydrogen. The amino group in this compound is protected in a known manner, e.g. a benzyloxycarbonyl group or a tertiary butoxylcarboyl group, and then the hydroxyl group is transformed into a V group that can be split off, e.g. a methanesulfonyl group, to obtain the compound of formula 36, in which A is a benzyloxycarbonyl group, Ms is a methanesulfonyl group, and R3 and R4 have the meanings indicated above, wherein at least one of R3 and R4 is hydrogen. By sulfonation of the compound of formula 36, a compound of formula 37 is prepared, in which A, Ms, R8, R4 and M+ have the meanings indicated above, and at least one of the substituents Rj and R4 is hydrogen. The compound of formula 37 is cyclized with a base, e.g. potassium carbonate, preferably in a mixture of water with an organic solvent, e.g. a halogenated hydrocarbon such as 1,2-dichloroethane, at the reflux temperature of the mixture. The obtained sulfonated azetidinone of formula 38, in which A, R3, R4 and M+ have the meanings given above and at least one of the substituents Ri and R' is 65! 8 184 hydrogen atom, is subjected to the known reaction of cleavage of the protecting group A and optionally the above-described process of introducing the alkoxy group R2, obtaining a compound of formula 1, in which Ri and Ra denote hydrogen atoms, and R3, R4 and M+ have the meanings given above, wherein at least one of the substituents R3 and R4 represents a hydrogen atom. The compounds produced according to the invention are active against numerous Gram-negative and Gram-positive microorganisms. Particularly active are compounds of formula 1 in which R3 and/or P4 represent hydrogen atoms or alkyl radicals. especially methyl ones. Compounds of formula I can be used as agents for combating bacterial infections, including infections of the urinary tract and respiratory system in mammals, especially in humans and animals, e.g. domestic and farm animals. The daily dose of these compounds is 1.4-350 mg/kg, preferably 14-100 mg/kg. These compounds can be administered by all methods used to administer penicillins and caffeine aporins, and they can be administered orally, intravenously, intramuscularly or in the form of suppositories. a Example I. (S)-3-amino-2-ketoazetidinesulfonic acid-1. A. L-ni-butoxycarbonylserine amide methanesulfonate. A suspension of 16.2 g of L-111-butycarbonyl serine amide in 250 ml of methylene chloride is cooled to -10°C, 10.4 ml of triethylamine is added and 4.25 ml of methanesulfonyl chloride is added within 15 minutes. After the mixture was heated to 0°C, an additional 0.425 ml of methanesulfonyl chloride was added dropwise, stirred at 0°C for 0.5 hour, poured the mixture into 1 liter of ethyl acetate and added 250 ml of cold brine. The obtained organic layer is washed with 200 ml of 1N hydrochloric acid saturated with sodium chloride, then washed with 250 ml of saturated sodium bicarbonate solution and finally with 250 ml of brine. The obtained solution in ethyl acetate is dried over MgSO* and concentrated to a volume of 100 ml. The obtained suspension is diluted with 300 ml of diethyl ether and the precipitate is filtered off, obtaining 10.73 g of the desired addition salt. After concentrating the mother liquor, an additional 1.67 g of product is obtained. The melting point of the product is 105-107°C, [a]1 = +6.4° (c=2 in methanol). < B. L-III-cutaneous carbonylsulfonain tetra-n-butylammonium methanesulfonain. This compound is prepared in the same manner as in Example 2B, but using L-III-butoxycarbonylthreonine methanesulfonate amide methanesulfonate instead of L-III-butoxycarbonylthreonine methanesulfonate. C. (S)-3-t(tert.-butoxycarbonyl)-amino]-2-ketoazetidinesulfonic acid-1 tetramethylammonium salt. This compound is prepared as described in Example II C, using tetra-n-butylammonium amide methanesulfonate instead of tetra-n-butyl ammonium salt. 9 ^ 128 184 10 ' D/(S)-3-amino-2-ketoazetidinesulfonic acid-1 3.06 g tetra-ii-butylammonium salt of (S)-3- - [(Ill-raed.butoxycarboyl)-amino acid ] -2-ketoazetidine-oulfomic acid [dissolved in 18 ml of 97° formic acid, stirred for 4 hours, washed with methylene eliloric, filtered off the precipitate, washed with gq and dried, obtaining 0.52 g of the acid given in the title of this section . The product melts with symptoms of decomposition at a temperature of 208-210°C, "[a]'" = -39.9° (c= 2 in wc-ctzie). Example II. (3S-trans)-3-amino-4-methyl-2-ketoazetidyaxialHonic acid-1. A. L-111-butoxycarbonylthreonine amide methanesulfonate. This compound is prepared as described in Example 1A, but using L-primary-butoxycarbonylthreonine amide instead of the L-111-butoxycarbonylsarine amide. rins. The product melts at a temperature of 129-131°C, [a]^ = +18.9° (c = 10 in methanol). 17.8 mL of Z-TflT-ethyl-ttridiine in 90 ml of methyl chloride is cooled to -50°C and 5.97 ml of chlorosulfonic acid are added at such a rate that the temperature of the mixture is lower than 114-5°C. The obtained solution is imdeaseed for 15 minutes, then a solution of 8.9 g of L-III-butoxyicarbonylthreoinine methanesulfamide methanesulfonate in 30 ml of ethylene chloride is added and the obtained solution is refluxed for 16-16 minutes. 20 hours, then pour into 500 ml of 0.5 M sodium dihydrogen phosphate solution and dilute with 120 ml of methylene chloride. The organic layer is separated, washed with 100 ml of the above-mentioned phosphate solution and the combined aqueous solutions are treated with 10.2 g of hydrogen sulfate. tetra-n-butylainium acid, and then extracted with 300 ml and then with 2 portions of 150 ml of methylene chloride. The extracts are dried over Na2SO4 and evaporated, obtaining 17.2 g of the compound given in the title of this section. The product has a foam consistency.C. Tetra-n-butylammonium salt of (3S-trans)-3-[(n-butoxy-ketoazetidinesulfonic acid-1. 13.0 g of potassium bicarbonate is dissolved in 320 ml of water, 220 ml of 1,2-dichloromethane are added and bring the mixture to the boil under a reflux condenser. Then a solution of 20.0 g of methanesulfonate of the tetra-n-butylamine salt of L-III-tertiary bu1xoxyicarbonyltheoninosulfaimine acid in 100 ml of i,2-dichloroethane is added and the mixture is stirred vigorously. under reflux for 15 minutes. The obtained mixture is poured into a separatory funnel, the lower organic phase is separated and the aqueous phase is extracted with 200 ml of methylene chloride. The extract is combined with the previously separated organic phase, dried over Na2SO4 and evaporated to obtain 18 g of the product given in the title of this section. The product melts at 144---146°C, [aj o = -146° (C^.2 in methanol). D. . (3S-trans)-3-amino- acid 4-methyl-2-ketoazetidine sulfonic acid-1. 6.3 g of the salt obtained as described in section (C) are dissolved in 30 ml of 97% formic acid and stirred for 5 hours. The obtained mixture is diluted with 30 ml of methylene chloride, the precipitate is filtered off, washed with methylene chloride and dried, obtaining 1.53 g of the pure product given in the title of this section, [a]^ = -41.0 (c = l in water). Example III. (3S-trans)-3-amino-4-methyl-2-ketoazetidinesulfonic acid-1. A. Threonine methyl ester hydrochloride. and 500 ml of methanol are cooled in an ice-salt bath to -5°C and 130 ml (i.e. excess) of thiomyl chloride are added under nitrogen at such a rate as to maintain the mixture at a temperature of 0°C to 10°C. Then it is cooled to a temperature of -5°C, 59.5 g of 1-threonine are added, the mixture is allowed to warm up to room temperature and stirred for 16 hours, then it is concentrated and the residue is kept under a pressure of 0 13 Pa in 2 hours, obtaining a thick oil constituting the crude product given in the title of this paragraph.B. Threonine amide. The crude product obtained by the method described in section A is dissolved in 2.5 liters of methanol, cooled to -5°C and saturated with ammonia gas, then the cooling bath is removed, the vessel is closed tightly and left for 3 days. Then, the main mass of unreacted ammonia is removed, 100 g of NaHCO3 and 50 ml of water are added and evaporated to obtain threondine amide in the form of a viscous oil.C. Benzyloxycarbonylthionine amide. The crude product obtained by the method described in section B, already containing the necessary amount of NaHCO3, is diluted with water to a volume of 1 liter and, with vigorous stirring, 94 g (88 ml, 90% pure product) of benzyl chloride are added within 1 hour. - xicairbonyl dissolved in 80 ml of tetrahydrofuran. The mixture is then stirred for 16 hours, extracted with 500 ml and two 250 ml portions of ethyl acetate, the combined extracts are dried over MgSO4 and evaporated. The crystalline residue is dissolved in 250 ml of hot ethyl acetate, 300 ml of hex is added; san and heated under reflux until a clear solution is obtained, which is cooled, the crystalline precipitate is filtered off and dried to obtain 104 g of benzyloxycaiibonylthreonine amide. D. Benzyloxycarbonylthreonine amide O-methanesulfonate. 100 g of benzyloxycarbonylthreonine amide in an argon atmosphere are dissolved in 400 ml of anhydrous pyridine, cooled in a bath of ice and salt and, while stirring, 36.8 ml (54.5 g of methanesulfonyl chloride) are added within 15 minutes, and then stirred for 2 hours and adds an additional 0.3 equivalent of methanesulfonyl chloride. Then the mixture is stirred for 1 hour, poured into a mixture of 1.5 liters of ice with 2 liters of water, the suspension is stirred for 30 minutes and filtered off. The precipitate is dried at 60°C under reduced pressure for 16 hours, obtaining 109 g of the product given in the title of this paragraph. is brought to a temperature of -5°C and 5.97 ml of chlorosulfonic acid % are added at such a rate as to maintain the temperature of the mixture below 5°C. The resulting solution is introduced through a tube into a suspension of 7.56 g of the product prepared by the method described in section D in 120 ml of methylene chloride and the obtained non-uniform mixture is kept under reflux for 16 hours, then the resulting clear solution is poured into. 500 ml of 0.5 M phosphate solution with a pH of 4.5 and diluted with 120 ml of methylene chloride. The organic layer is washed with 100 ml of the same buffer phosphate solution and the combined aqueous solutions are treated with 10.2 g of tetra-butylammonium hydrogen sulfate and then extracted with 300 ml and 2 portions of 150 ml of methylene chloride. The combined extracts are dried over Na2SO4 and evaporated to give 12.7 g of the product given in the title of this paragraph. The product has the consistency of foam. F. (3Strans)-3-amino-4Hmethyl-2^ketoazety - dynosulfonic acid-1. A mixture of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane is heated to reflux and 15.5 mmol of the salt obtained as described in section E is added as a solution in 20 ml. 1,2-dichloroethane, rinsing the vessel with 20 ml of 1,2-dichloroethane. The mixture is refluxed for 30 minutes, then poured into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride and the layers separated. The organic layer is dried over Na2SC4 and evaporated to give crude (3S-trans)-3-benzyloxycarbonylamino-4-methyl-2-keto-1-azetidinesulfonic acid cisterobutyl ammonium salt. The product is stirred. with 250 ml of ethanol and 0.8 g of 5% palladium on charcoal and bubbled with hydrogen for 90 minutes, then filtered through celite and washed the precipitate with ethanol. 1.2 ml of formic acid is added to the filtrate, causing the amphoteric compound given in the title of the example to immediately precipitate. The mixture is stirred for 1 hour, the precipitate is filtered off and dried for 1 hour under a pressure of 0.13 Pa, obtaining 1.1 g of the product. The second batch is 1.3 g of the product; is obtained by concentrating the filtrate and adding formic acid again. The product melts with signs of decomposition at temperatures above 218°C, [a]D' = -41.1° (c= l, in water). NMR (D2O) 1.58 (3H, J =7), 4.80 (2H, M). Example IV. (3S-trans)-3-amino-4-methyl-2-ketoazetidinesulfomic acid-1. A. L-phenylacetyltreoniryl amide methanesulfonate. 16.9 g of L-phenylthionamide are dissolved in 500 ml of tetrahydrofuran at reflux temperature, then the mixture is cooled to -35°C, 15.0 ml of tri-ethylamine are added and then in 7.1 ml of methanesulfonyl chloride are added within 1 hour and stirred for 1 hour. The obtained mixture is diluted with 400 ml of water, the organic layer is separated and the aqueous layer is extracted with 3 300 ml portions of ethyl acetate. The combined organic solutions are washed with 0.1 N hydrochloric acid and brine, dried over magnesium sulfate, filtered and evaporated to a volume of about 200 ml, causing the product to precipitate. The obtained suspension is diluted with the same volume of hexane and filtered to obtain 19.2 g of product with a melting point of 132-133°C, [a];' = +19.25° (c=2 in methanol) B. L-phenylacetylthreoninesulfa-5 tetra-n-hutylammonium methanesulfonate This compound is prepared according to the method given in Example IX B, using L-III amide instead of methanesulfonate, buU)xycarboylthreoindium methanesulfonate of L-phenylacetylthreonine amide. C. Tetrabutylammonium salt of <3S-trans)-S-[(phenylacetyl)-amino]-4-methyl-2-ketoazetidine-sulfonic acid-1. This compound produces in a:o-, as described in Example II C, using instead of L-111-butoxycarbonyl methanesulfonate: trans)-3-aniine-4-methyl-2Hketoazetidinesulfonic acid-L 3.79 g of (3S-frans)-3-[(phenyla^^-4-methylic^2-ceioazetidl3mosulfone) acid ^ dissolved in 70 ml of methylene chloride, cooled to -15° C. and 2.3 ml of pyridine added. The cold mixture was treated with 5.8 ml of 12% (a mixture of phosgene in benzene, stirred for 90 minutes at -10°C, add 35 ml of methanol, stir for 30 minutes and add 1.62 ml of trifluoroacetic acid. The mixture is left at room temperature and stirred for 16 hours, the precipitate is filtered off, washed with methylene chloride and dried, obtaining 0.43 g of the acid given in the title of this section, [a] ^ = -41.0° ( c= l in water). Example V. (3S-cis)-3-amino-4-methyl-1o-2-ketoazetidinesulfonic acid-1. A. L-111-rt.ecLbutoxycarbonylallotreonine amide methanesulfonate. This compound is prepared in the manner given in Example I A, using L-III butoxycarbanylpserine amide instead of L-III butoxyicarbonylallothireonine amide. The product melts with symptoms of decomposition at 124°C, [a] D] = +16, 9° (c=2 in methanol) B. L-III tetra-al-butyl ammonium methanesulfonate. This compound is prepared as described in Example 2B, but using 1-111-butoxycarbonylthreonide instead of amide methanesulfonate. L-III-butoxycarbonyl-aUothreonine amide methanesulfonate.C. (3S-cis)-3-[(tert.butoxyicarbonyl)-amino]-4-methyl-2-ketoaethydinesulfonic acid-1 tetra-n-butyl ammonium salt. This compound was prepared as described in Example 2C, but using tetra-n-butylammonium L-II-butoxycarbonylthreoninesulfaimdate methanesulfonate instead of L-111-ed. -n-butylammonium.D. (3S-cis)-3-ammo-4-methylc-2-ketoazetydimosulfonic acid-1. This compound is prepared as described in Example 2D, but using 3S-trans)-3-[(tert-butoxycarbonyl)-amino]-4-methyl-2 acid instead of the tetrabutylammonium salt. -ketoa2ethidine sulfonic acid-1 tetrabutylammonium salt of (3S41)3-[(HI-rze4tbtitoxycarbonyl-13 128 184 14 l)-anilino]-4-methyl-2-ketoazetidine sulfonic acid-1. The product melts with symptoms of decomposition at a temperature of 200°C, [a}],1 = -61.8° (c = 5.1 in water). Example VI. (3S-trans)-3-a,mino-4-cyclohexyic-2 ketoazetidinesulfonic acid-1.A. α-(III-r2Yod.butoxycarbonylamino)-^-cyijohexyl-^-hydroxytreopropioic acid. 15 g of α-cyclohexyl-α-amino-^-hydroxythreopropionic acid are mixed with 150 ml of acetonitrile and 70 ml of water, and 17.8 g of trielylamine are added to the obtained suspension and, while stirring, the mixture is heated to a temperature of 60°C. , obtaining a clear solution. 21.0 g of di-tert-butyl pyrocarbonate are added to this solution and stirred at ℃ for 1.5 hours. Then the solvent is evaporated under reduced pressure, 50 ml are added water, extracting the aqueous layer with ethyl acetate and adjusting the pH to d ? to obtain 20.4 g of the acid given in the title of this section. The product melts at a temperature of 113-115°C. B. mp-(yl-butoxycarbonylaminc) - fi - cyclohexyl - fi' - hydroxytreopropionic acid amide. 20.2 g of a -ClII-butoxycarbonylamino)-^-cyclohexyl-^-hydixxytreopropionic acid and 5.4 g of ammonium chloride are mixed with 350 ml of water and 175 ml of tertiary butanol and the pH of the resulting mixture is adjusted with sodium carbonate. blue to 4. Then 16.4 g of 1-ethyl-3-(S-dimethylamiyl petroleum)kairboduvimide are added and the mixture is stirred for 1.5 hours, maintaining the pH value of 4, and then the solvent is evaporated under reduced pressure, the remaining aqueous solution is saturated with sodium chloride and extracted with 2 portions of 100 ml of ethyl acetate. The combined organic solutions are dried over Na2SO4 and evaporated to dryness to give the compound given in the title of this section.C. α-(tert.-butoxycarbonylamino)-^-cyclohexyl)-^-(metainesulfonyloxy)-threopropionic acid amide. 18.3 g of the acid amide obtained in the previous section are dissolved with stirring in 100 Nl of anhydrous pyridine, the solution is cooled to 0°C and 9.3 g of methanesulfonyl chloride are added dropwise. After 1 hour, still at 0°C, another 3.3 g of methanesulfonyl chloride are added and stirred for another hour. The obtained solution is poured into 300 ml of ice-cold water, 200 ml of ethyl acetate are added and sulfuric acid is adjusted to pH 3. The organic layer is separated, dried over Na2SQ and the solvent is evaporated under reduced pressure to give the compound given in the title of this section.D. Salt. . tetra-butylanion of α-(III-αbutoxycarboylamino)-^-cyclohexyl-^-methanesulfonyloxytreopropionylsyl acid. To a solution of 17.8 ml of 2-methylpyridine in 90 ml of methylene chloride, cooled to -50°C, 5.97 ml of chlorosulfonic acid are added at such a rate that the temperature of the mixture remains below 5°C. The obtained solution is stirred for 15 minutes and a solution of 10 15 20 25 35 55 60 65 12 g of α-(tert.butoxycarbonylami. in 30 ml of methylene chloride, then boiled under reflux for about 18 hours, then poured into 500 ml of 0.5 M potassium dihydrogen phosphate solution and diluted with 120 ml of methylene chloride. The organic layer was separated and washed with 100 ml of potassium dihydrogen phosphate solution and the combined aqueous solutions are treated with 10.2 g of tetra-n-butyl amine hydrogen sulfur, and then extracted with 300 ml and 2 portions of 150 ml of methylene chloride. The organic extracts are dried over Na2S04 and evaporated to obtain the compound given in the title of this section, having the consistency of foam.E. TetraHn-butylammonium salt of trans-3-[(tert.butoxide,ycarbonyl)-amino]-4-cyclohexyl-1-keazetidiniumUphonic acid. 13.0 g of potassium hydrogen carbonate are dissolved in 320 ml of water, 220 ml of 1,2-dichloroethamide are added and the mixture is brought to the boil under reflux, then a solution of 20 g of the tetra-n-butyl-ammonium salt of α is added -(12-butoxycarbonylamino)-/? - cyclohexyl-phi-methanesulfonyloxytreopropionylsulfamino acid in 100 ml of 1,2-dichloroethane and, stirring vigorously, keep it under reflux for 15 minutes. Then the mixture is poured into a separatory funnel*, the lower organic phase is separated and the aqueous layer is extracted with 200 ml of methylene chloride. The combined organic solutions are dried over sodium sulfate and evaporated to give the salt given in the title of this section. F. trans-3-amino-4-cyclohexyl-2-ketoazetidinesulfonic acid-1. 3.8 g of the crude salt obtained as described in the previous section is mixed with 20 ml of formic acid for 3 hours, then 20 ml of methylene chloride is added and the precipitate is filtered off. obtaining 1.0 g of the acid given in the title of the next section. The product melts at a temperature of 217-219°CL. Example VII. Trans-3-amino-4-ethyl-2-ketoazetidinesulfonic acid-1. This compound is prepared as described in Example 6A, using tert-ethyl-a-amino-i-hydroxytreopropionic acid instead of ?-cyclohexyl-?-amino-?-hydroxytreopropionic acid and proceeding \ the method given in Example VI B-VI F. The product obtained melts with symptoms of decomposition at a temperature of 185°C. Example VIII. trans-3-amino-4-phenyl-azetidine sulfonic acid-1. This compound is prepared as described in Example 6, using phy-phenyl-α-amino-β-hydroxytreopropionic acid instead of ?-cyclohexyl-?-amino-?-hydroxy-threopropionic acid. The product has the consistency of a solid and is brown in color. Patent claims 1. A method of preparing new β-lactams of the general formula 1, in which Ri is a hydrogen atom or an acyl group or the Ri-NH group is a protected amino group, R2 is a hydrogen atom or an alkoxy group with 1-4 carbon atoms, Rs and R4 are the same or different and denote hydrogen atoms, alkyl, cycloalkyl, phenyl or substituted phenyl radicals, or128 184 15 and« ~ *^r'*s 15 40 with the formula -NH(C/0)Ru or an alkyl group, an amino group, an alkyl group or an alkyl group carrying one or more substituents, such as halogen atoms, cyam, nitro, amino and mercapto groups, or R! means an acyl group constituting (e) a group of the formula 18, in which Rn has the above-mentioned meaning and R13 represents a hydrogen atom, an alkyl, cycloalkyl or ?lkylamiro^rbonyl radical, a group of the formula -C(0)-NH -Rn, in which Ru has the above-mentioned meaning, an alkyl radical containing one or more substituents such as halogen atoms, halogen, nitro, amine, mercapto, alkyl groups, r.r'ii? aromatic groups Rn above, carboxyl groups, carboxyl groups in the form of salts, amide groups, alkoxycarbotiyl, phenylmethoxycarbonyl, diphenylmethylethoxycarbonyl, hydroxyalkoisyphosphyriyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or di-alkoxycarbonyl groups finylawe, or R] means an acyl group constituting (f) a group of formula 19, wherein Rn is as defined above, and RJ4 is a group of formula 20, wherein R6, R7, P8 and m are as defined above, or "Rl4 is an amino group, alkyl - amine, cyanoalkylamino, amide, alkylamide, cyanoalkylamide or a group of the formula 21, 22, 23, 24, 25 or 26, or ^ means an acyl group constituting (g) a group of the formula 27 in which Ru has the above given meaning, and R15 represents a hydrogen atom, an alkylsulfonyl group, a group of the formula -N-CH-R11, in which Rn has the meaning given above, or a group of the formula -C(0)-Ri6, wherein Ris means a hydrogen atom, an alkyl or haloalkyl radical, or R15 means an aromatic group Rn with the above-mentioned meaning, an alkyl radical or an alkyl radical containing one or more substituents such as halogen atoms, nitro, cyano, amino or mercapto groups. 3. The method according to claim 1, characterized in that the sulfonation process is carried out using a complex sulfur trioxide compound. 4. The method according to claim 3, characterized in that the sulfonation process is carried out using a complex compound - sulfur trioxide and pyridine. 5. The method according to claim 3, characterized in that the sulfonation process is carried out using a complex compound of sulfur trioxide with a dimethylformimide. one of the substituents R3 and R4 is a hydrogen atom, and the other is an alkoxycarbonyl group, an alken-1-yl, alkin-1-yl, 2-phenylethenyl or 2-phenylethynyl radical and M+ is a hydrogen atom or a cation, characterized in that the compound of the formula 2^ in which Ri, R3 and R4 have the meanings given above and V denotes a cleavable group, such as a methanesailfonyl, benzenesulfonyl or toluenesulfonyl group or a chlorine, bromine or iodine atom, is sulfonated and then cyclized, or the compound of formula 2 is cyclized and then sulfonated, after which the protecting group of the amino group in the prepared product is optionally split off and/or the hydrogen atom in the sulfonate group is converted into another cation or the compound obtained in the form of a salt is converted into another salt using known methods. 2. The method according to claim 1, characterized in that the compound of formula 2 is subjected to the sulfonation and cyclization reaction or the cyclization and sulfonation reaction, in which Ri, R3, R4 and V have the meanings specified in claim 1. 1, and Ri is an acyl group constituting (a) an aliphatic group of formula 4, wherein R5 is an alkyl, cycloalkyl, alkenyl, cycloalkenyl or cyclohexadienyl radical or an alkyl or alkenyl radical containing one or more substituents such as halogen atoms, groups cyano, nitro, amino, mercapto, alkylothio or cyanomethylthio, or a pa acyl group being (b) a carbocyclic aromatic group of formula 5, 6, 7, 8, 9 or 10, wherein R6, R7 and Rb are the same or different and denote hydrogen atoms, halogen atoms, hydroxyl, nitro, amino and cyano groups. trifluoromethyl, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or aminomethyl groups, n in the formula 5 means zero, i, 2 or 3, and R9 in the formula 6 means an amino group, a hydroxyl group a carboxylic acid salt, a protected carboxyl group, a formyl-xyl group, a sulfonic acid salt group, a sulfoamine salt group, an azide group, a halogen atom, a hydrazine group, an alkylhydrazine group, a phenylhydrazine group or a [(alkylthio)thioketomethyl]thio group, or Ri is a group acyl constituting (c) a heteroaromatic group of the formula 11, 12, 13, 14 or 15, in which formulas Rio is a substituted or unsubstituted heterocyclic aromatic ring of 5, 6 or 7 members, containing 1, 2, 3 or 4 nitrogen, oxygen and sulfur atoms, n in the formula U and R9 in the formula 12 have the meanings given above, or with the acyl group being (d) a group of the formula 16, in which Rn is a group of the formula 17, in which R6, R7 and Rb have the meanings given above, or Rn is a substituted or unsubstituted heterocyclic ring with 5, 6 or 7 members, containing 1, 2, 3 or 4 atoms of nitrogen, oxygen and sulfur, g R12 is a group of the formula -N= OH-Rn or "6. Method According to claim 1, zftafttfenny t? m, that a compound of formula 2 is used, in which the group R1-NH- is the amino group zafo3fc$ifcxoraa -in the form of -azide. 7. Method according to instructions. 1, especially in that a compound of value 2 is used, in which the amino group in the 3-position is protected - a 4-enzyme group or -butototephric acid group. lt 15 20 25 30 35 40 46 50128 184 02 Hm Ri-NH-Cj^C-R^ ,2. 1 O" . C^N-SO^M Formula 1 + V I R.-NH-CH CC O s ¦NHS ^zo/' £ Ra R4 R-NH-C—4C-R3 0 / ,C^N-H formula 3 ¦R, R, O "^W R5-C- formula 4- Rfe-^/R8 1 R7 C-7-CH4-0-C— Formula 7 o 11 R7 R9 formula £ Re^t^* "C o Formula 5 0-ChVC — 0 S-CH^-C- R, R 6X /Ra O CHrf-C— z Formula 10 0 ii 0 n10 \CH2Jf} ^ Rio CH C J*/zor # o R9 Formula 12 0 II Rjo- O-CHz-C— R^S-CHi-C- tóór /3 Formula 44 000 9 II II II II r—\ R^Z-C- -C-CH-NH-C-N N-R12 Vzo/-/5 R^ 0 0 R7 R^R8 0 Formula 16 -C-C=N-0-Ri3 1 R11 Formula 18 R7 Formula 17 o g -C-CH-NH-C-R14 R Rn Formula 19 Formula 20 ^(CH2)n-0- r^ H -CHrNH-C-04 Formula 21 fflH2 0 -CH-CH2-C-NH-CH3 Formula 22 // V^Q^o2-N (CH2-CHr0H)2 =N OH Formula 23 HO Formula 24 OH W1- K OH L i j Formula 25 1 0 3"CH Formula 26 /128 184 O O -C-CH-NH-C-f ^-R« I CHrCH£ Rn Formula 27 v R< ocyl-NH-i—^Rj -n + 0 NH -SOaM Formula 28 CH-C C-OH Ra L\ Y nfeór ^ OH rR4 BOC-NH-CH-C\Ri A— NH-O-Y 0 w B0C-i,.-C V c R4 o ^ R3 NH-O-Y Formula 31 R, BOC-NH ^ C—N-O-Y 0'x V*e5r 52 BOC-NH- R< BOC-NH- O Formula 34 O — NH -R.I Ra Formula 33 ¦Ri J—N-S03"M + NH2- CH-C 0H n l. /R4 O f NH: ¦R< Formula 35 ANH-CH- I X- 0 OMs R, NH2 Formula 36 OMs / R4 ANH-CH— CCp nhso:m -l- o* ANH R < f— Ra J—N-SCKM4" Pattern *8 OZGraf. Z.P. Dz-wo, z.213 (83+15) 12.85 Cck» IN il PL PL PL

Claims (2)

1. Patent claims 1. A method of preparing new β-lactams of the general formula 1, in which Ri is a hydrogen atom or an acyl group, or the Ri-NH group is a protected amino group, R2 is a hydrogen atom or an alkoxy group with 1 —4 carbon atoms, Rs and R4 are the same or different and represent hydrogen atoms, alkyl, cycloalkyl, phenyl or substituted phenyl radicals, or (O)Ru or an alkyl group - an amino, alkyl or alkyl group carrying one or more substituents, such as halogen atoms, cyam, nitro, amino and mercapto groups, or R! means an acyl group constituting (e) a group of the formula 18, in which Rn has the above-mentioned meaning and R13 represents a hydrogen atom, an alkyl, cycloalkyl or ?lkylamiro^rbonyl radical, a group of the formula -C(0)-NH -Rn, in which Ru has the above-mentioned meaning, an alkyl radical containing one or more substituents such as halogen atoms, halogen groups, nitro groups, amine groups, mercapto groups, alkyl groups and aromatic groups Rn grouped above, carboxyl groups, carboxyl groups in the form of salts, amide groups, alkoxycarbotiyl, phenylmethoxycarbonyl, diphenylmetoxycarbonyl, hydroxyalkyloxyphosphyriyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or di-alkoxymethyloxycarbonyl groups, or R] is an acyl group that constituting (f) a group of formula 19 in which Rn has the above-described meaning and RJ4 denotes a group of formula 20 in which R6, R7, P8 and m have the above-described meaning, or "Rl4 denotes an amino, alkyl-amino, cyanoalkylamino, amide group , alkylamide, cyanoalkylamide or a group of the formula 21, 22, 23, 24, 25 or 26, or ^ represents an acyl group constituting (g) a group of the formula 27, in which Ru has the above-mentioned meaning and R15 is a hydrogen atom, an alkylsulfonyl group, a group of the formula -N-CH-R11, in which Rn has the meaning given above, or a group of the formula -C(0)-Ri6, in which 2. Ris is a hydrogen atom, an alkyl or haloalkyl radical, or R15 represents an aromatic group Rn with the meaning above, an alkyl radical or an alkyl radical containing one or more substituents such as halogen atoms, nitro, cyano, amino or mercapto groups. 3. The method according to claim 1, characterized in that the sulfonation process is carried out using a complex sulfur trioxide compound. 4. The method according to claim 3, characterized in that the sulfonation process is carried out using a complex compound - sulfur trioxide and pyridine. 5. The method according to claim 3, characterized in that the sulfonation process is carried out using a complex compound of sulfur trioxide with a dimethylformimide. one of the substituents R3 and R4 is a hydrogen atom, and the other is an alkoxycarbonyl group, an alken-1-yl, alkin-1-yl, 2-phenylethenyl or 2-phenylethynyl radical and M+ is a hydrogen atom or a cation, characterized in that the compound of the formula 2^ in which Ri, R3 and R4 have the meanings given above and V denotes a cleavable group, such as a methanesailfonyl, benzenesulfonyl or toluenesulfonyl group or a chlorine, bromine or iodine atom, is sulfonated and then cyclized, or the compound of formula 2 is cyclized and then sulfonated, after which the protecting group of the amino group in the prepared product is optionally split off and/or the hydrogen atom in the sulfonate group is converted into another cation or the compound obtained in the form of a salt is converted into another salt using known methods. 2. The method according to claim 1, characterized in that the compound of formula 2 is subjected to the sulfonation and cyclization reaction or the cyclization and sulfonation reaction, in which Ri, R3, R4 and V have the meanings specified in claim 1. 1, and Ri is an acyl group constituting (a) an aliphatic group of formula 4, wherein R5 is an alkyl, cycloalkyl, alkenyl, cycloalkenyl or cyclohexadienyl radical or an alkyl or alkenyl radical containing one or more substituents such as halogen atoms, groups cyano, nitro, amino, mercapto, alkylothio or cyanomethylthio, or a pa acyl group being (b) a carbocyclic aromatic group of formula 5, 6, 7, 8, 9 or 10, wherein R6, R7 and Rb are the same or different and denote hydrogen atoms, halogen atoms, hydroxyl, nitro, amino and cyano groups. trifluoromethyl, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or aminomethyl groups, n in the formula 5 means zero, i, 2 or 3, and R9 in the formula 6 means an amino group, a hydroxyl group a carboxylic acid salt, a protected carboxyl group, a formyl-xyl group, a sulfonic acid salt group, a sulfoamine salt group, an azide group, a halogen atom, a hydrazine group, an alkylhydrazine group, a phenylhydrazine group or a [(alkylthio)thioketomethyl]thio group, or Ri is a group acyl constituting (c) a heteroaromatic group of the formula 11, 12, 13, 14 or 15, in which formulas Rio is a substituted or unsubstituted heterocyclic aromatic ring of 5, 6 or 7 members, containing 1, 2, 3 or 4 nitrogen, oxygen and sulfur atoms, n in the formula U and R9 in the formula 12 have the meanings given above, or with the acyl group being (d) a group of the formula 16, in which Rn is a group of the formula 17, in which R6, R7 and Rb have the meanings given above, or Rn is a substituted or unsubstituted heterocyclic ring with 5, 6 or 7 members, containing 1, 2, 3 or 4 atoms of nitrogen, oxygen and sulfur, g R12 is a group of the formula -N= OH-Rn or 6. "6. Method According to claim 1 differs in that a compound of formula 2 is used, in which the group R1-NH- is an amino group in the form of an azide. 7. Method according to instructions. 1, especially in that a compound of value 2 is used, in which the amino group in the 3-position is protected - a 4-enzyme group or -butototephric acid group. lt 15 20 25 30 35 40 46 50128 184 02 Hm Ri-NH-Cj^C-R^ ,2. 1 O" .C^N-SO^M Formula 1 + V I R.-NH-CH CC O s ¦NHS ^zo/' £ Ra R4 R-NH-C—4C-R3 0 / ,C^N-H formula 3 ¦R, R, O "^W R5-C- formula 4- Rfe-^/R8 1 R7 C-7-CH4-0-C— Formula 7 o 11 R7 R9 formula £ Re^t^* "C o Formula 5 0-ChVC — 0 S-CH^-C- R, R 6X /Ra O CHrf-C— z Formula 10 0 ii 0 n10 \CH2Jf} ^ Rio CH C J*/zor # o R9 Formula 12 0 II Rjo- O-CHz-C— R^S-CHi-C- tóór /3 Formula 44 000 9 II II II II r—\ R^Z-C- -C-CH-NH-C-N N-R12 Vzo/-/5 R^ 0 0 R7 R^R8 0 Formula 16 -C-C=N-0-Ri3 1 R11 Formula 18 R7 Formula 17 o g -C-CH-NH-C-R14 R Rn Formula 19 Formula 20 ^(CH2)n-0- r^ H -CHrNH-C-04 Formula 21 fflH2 0 -CH-CH2-C-NH-CH3 Formula 22 // V^Q^o2-N (CH2-CHr0H)2 =N OH Formula 23 HO Formula 24 OH W1- K OH L i j Formula 25 1 0 3"CH Formula 26 /128 184 O O -C-CH-NH-C-f ^-R« I CHrCH£ Rn Formula 27 v R< ocyl-NH-i—^Rj -n + 0 NH -SOaM Formula 28 CH-C C-OH Ra L\ Y nfeór ^ OH rR4 BOC-NH-CH-C\Ri A— NH-O-Y 0 • w B0C-i,.-C V c R4 o ^ R3 NH-O-Y Formula 31 R, BOC-NH ^ C—N-O-Y 0'x V*e5r 52 BOC-NH- R< BOC-NH- O Formula 34 O — NH -R. I Ra Formula 33 ¦Ri J—N-S03"M + NH2-CH-C 0H n l. /R4 O f NH: ¦R< Formula 35 ANH-CH- I X- 0 • OMs •R, NH2 Formula 36 OMs / R4 ANH-CH— CCp nhso:m -l- o* ANH R< f— Ra J—N-SCKM4" Formula *8 OZGraph. Z.P. Dz-wo, z. 213 (83+15) 12.85 Cck» IN il PL PL PL