PL89964B1 - - Google Patents

Description

The invention is a method for producing cephalosporins of general formula I, which exhibit a broad spectrum of antibacterial activity against numerous species of Gram-positive and Gram-negative bacteria. For this reason, these compounds are useful as therapeutic agents, and to a lesser extent also as prophylactic agents, for humans and animals, including poultry. A number of commercially available semi-synthetic cephalosporins with a broad spectrum of activity are known, but to date no cephalosporin has been known to exhibit a clinically useful level of antibacterial activity against all pathogenic organisms important in clinical practice. Broad-spectrum cephalosporins are sought, characterized by either enhanced antibacterial activity or an even broader spectrum of activity than that of currently available cephalosporins. The invention is is a method for preparing cephalosporins of the general formula I or their pharmacologically acceptable salts or esters, wherein Y is an oxygen or sulfur atom, R1 is an organic radical of not more than 20 carbon atoms, R2 is an alkyl group of 1-3 carbon atoms or an enzyme, or R1 and R2 together with the carbon and nitrogen atoms to which they are attached form a 5-, 6- or 7-membered ring, R3 is a phenyl group, a phenyl group substituted with one or more functional groups such as a hydroxyl group, a halogen atom, a nitro group, an alkoxy group of 1-3 carbon atoms and an amino group, a 2- or 3-thianyl group, a cycloalkyl group of 3-7 carbon atoms or an alkyl group of 1-4 carbon atoms, and R4 is an acetoxy group or a nucleophile carbon, nitrogen or sulfur. Preferably Y is an oxygen atom. The group R1 may be, among others, an alkyl group with 1-10 carbon atoms, an alkenyl group with 1-10 carbon atoms, an alkyl or aralkenyl group, in which the alkyl and alkenyl radicals contain 1-10 carbon atoms, and the aryl radicals are phenyl, thienyl, furyl, pyridyl or substituted phenyl groups, in which the substituents are groups such as alkyl with 1-13 carbon atoms, alkoxy with 1-3 carbon atoms, halogen atom, nitro and ammonium groups, alkoxy with 1-10 carbon atoms, cycloalkoxy with 5-7 carbon atoms, alkylamino with 1-10 carbon atoms, phenyl, furyl, oxyl, pyridyl, substituted phenyl, in which the substituents are groups such as alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, halogen atom, nitro and amino group, substituted alkyl group with 1-10 carbon atoms, in which the functional substituents are groups such as alkylthio group with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or phenoxy group. In particular, the group with the symbol R1 may be a methyl, ethyl, n- or isopropyl, n-secondary or tertiary butyl, n-pentyl, n-hexyl, n-eptyl, ω-methylheptyl, n-octyl, ω-dimethyloctyl, 2-propenyl, 3-methylpropenyl, 1-methylpropenyl, 2-butenyl, 2-octenyl, 2-phenylethyl, 2-phenylvinyl, 2-( ... butoxy, n-pentoxy, n-hexyloxy, cyclohexyl, methylamino, dimethylamino, phenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-ethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-nitrophenyl, 2-methylphenyl, 4-methylphenyl, methoxyethyl, ethoxymethyl, ethoxymethyl, methylthiomethyl, phenoxymethyl. The group with the symbol R2 may be, among others, a methyl, ethyl or benzyl group, preferably R2 is a methyl group. y Groups with the symbols R2 and R3 together with the carbon and nitrogen atoms to which they are attached can form a ring with the formula 7, 81, 9 or 10, in which n means a total numerical value of 3-5, and m means a total numerical value of 2-4. I Ra means a hydrogen atom, an alkyl group with 1-3 carbon atoms, and an acyl group with 1-3 atoms. carbon or alkylsulfonyl with 1-3 carbon atoms. Preferably the ring is imidoazolidine-2-onyl-1, 3-acetylimidazolidine-2-anil-1,3 methylsulfonylimidazolidine-2-onyl-1 or hexahydroazepine-2-onyl ring. The group with the symbol R3 may be, among others, a phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-nitrophenyl, 2-thienyl, 3-thienyl, cyclopropyl, cyclohexyl, cyclohexadienyl-1,4, propyl or methyl group. Preferably R3 is a phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl or 3-thienyl group. The group R4 may be, among others, a strong carbon, nitrogen or sulfur nucleophile. Such nucleophiles displace the acetoxy group from the 7-aminocephalosporanic acid ring and such a displacement has been observed in the action of various pyridine derivatives (Hale et al., Biochem. J. 79, 403 (1961) and Spencer et al., J. Org. Chem., (USA), 32, 500 (1967); other heterocyclic aromatic compounds (Hale et al., loc. cit); Kariyone et al., J. Antibiotics, 23, 131 (1970), and Spencer et al., J. Antibiotics, 23, 131 (1970). co.loc. cit (xanthates - — dithioaramates) Van Heynjngen et al.J. Chem Soc (London), 5015 (1965), and aniline derivatives (Bradshaw et al., J.ChemSoc, (London), 80 Jan (1968). In particular, the group with the symbol R4 may be a radical of the formula 11,12,13,14,15,16,17,18,19,20 or 21. Preferably, R4 means 2-methyl-1,3,4-thiadiazolylthiol-5, 1-methyl-(1H)-1,2,3-tetrazolylthiol-5,2-methyl-1,3,5-oxadiazolylthiol-5 or (1HH,2,4,-triazolylthiol-5. Preferably atom The carbon to which the R3 group is attached has the D configuration. Suitable pharmacologically acceptable salts are sodium, potassium, calcium, magnesium, aluminium, ammonium or substituted ammonium salts, i.e. salts with trialkylamines such as triethylamine, procaine, dibenzylamine and triethanolamine. In the case of compounds of formula 1 containing a basic nitrogen binding site in the side chain, inorganic acid addition salts such as sulfate, nitrate, phosphate, borate and hydrohalides such as hydrochloride, hydrobromide and hydroiodide, and organic salts such as acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate and methanesulfonate can also be formed. Suitable pharmacologically acceptable salts include: Esters are primarily those that readily decompose in the human body, releasing the parent acid, such as acyloxyalkyl esters, such as acetoxymethyl, trimethylacetyloxymethyl, α-acetoxymethyl, α-acetoxybenzyl and α-trimethylacetyloxymethyl, and alkoxycarbonylalkyl esters, such as methoxycarbonyloxymethyl or α-methoxycarbonyloxyethyl. Other readily hydrolyzable esters are lactone, thiolactone and dithiolactone, i.e. compounds of formula 1, in which the 4-carboxyl group is esterified to a group of formula 6, in which X1 and Y1 represent an oxygen or sulfur atom and Z1 represents a divalent radical, and especially phthalidic and substituted phthalidic esters, such as esters 5,6-dimethoxyphthalidodecanoic acid.89964 3 Compounds of general formula 1 are divided into two classes depending on their structure. One class includes compounds in which the group designated by the symbol R1 is connected to the carbonyl group by a C-C bond, and the other class includes those compounds in which the group designated by the symbol R1 is connected to the carbonyl group by an N-C bond. According to the invention, the method for preparing compounds of formula 1 consists in reacting a compound of formula 2 or a salt or ester or silyl derivative thereof, in which formula 2 the dotted lines denote a bond in positions 2 or 3, n is 0 or 1 and R4 has the meaning given above, with an N-acylating derivative of an acid of formula 3, in which Y, R1, R2 and R3 have the meaning given above and in which the groups The reactive groups, such as the amino and hydroxyl groups, can be blocked, and then the A* isomer is optionally converted into the desired A9 isomer, the silyl groups are removed by alcoholization or hydrolysis, the sulfoxide is reduced to the desired sulfide, and the blocking groups in the acyl side chain R are removed and the ester is converted into the free acid or its salt. The term "silyl derivative" of the compound of formula 2 denotes the reaction product of the compound of formula 2 with a silylating agent such as a halodialkylsilane, a halotrialkylsilane, a halodialkoxysilane and a halotrialkoxysilane or the corresponding aryl- or aralkylsilane, and such compounds as hexamethyldisolanone. Silyl derivatives of the compound of formula 2 are extremely sensitive to the influence of moisture and hydroxyl compounds and after reaction with them The N-acylating derivative of the acid of formula II can be desilylated from the acylated intermediate by hydrolysis or alcoholysis. In the process according to the invention, a reactive N-acylating derivative of the acid of formula II is used. The choice of the reactive derivative depends on the chemical nature of the substituents on the acid. If the acid contains only stable acidic groups, a suitable N-acylating derivative is an acid halide, preferably an acid chloride. Such reagents are avoided when a labile acid group is present in the acid of formula III. In such cases, a suitable N-acylating derivative is a mixed anhydride. For this purpose, mixed anhydrides are particularly preferred. Alkoxyformic anhydrides are other alternative N-acylating derivatives of the acid of formula III are active esters. Esters such as, for example, the ester formed by reaction with 1-hydroxybenzotriazole or N-hydroxysuccinimide is prepared in situ by reacting the acid with the appropriate hydroxy compound in the presence of a carbodiimide, preferably dicyclohexylcarbodiimide. Other reactive N-acylating derivatives of the acid of formula II include reactive intermediates formed by in situ reaction with carbodiimide or carbonyl diimidazole, but the literature on the preparation of semisynthetic penicillins provides examples of still other reactive N-acylating derivatives of acids suitable for coupling with 6-APA. When it is necessary to prepare the free acid of formula I or a salt thereof, it is also convenient to carry out the acylation using an ester of the compound of formula II, followed by removal of the ester group. Conversely, when it is necessary to obtain an ester, it is convenient to carry out the acylation using 7-ACA or its salt. salt followed by esterification of the free acid. In the process according to the invention, when it is necessary to block a reactive substituent in the acid of formula III, conventional blocking groups can be used. Free amino groups can be blocked by converting them to tertiary butyloxycarbonyl or benzyloxycarbonylamino groups. Alternatively, the amino group can be blocked as a nitro group and then converted to an amino group. In the case where the compound formed by N-acylation contains a sulfoxide group in position 1 of the cephem ring, it can be reduced by one of the known methods, for example that described in British Patent Specification No. 1,280,693. One such method consists in the action of triphenylphosphine with acetyl chloride. When the compound obtained is A2-cephem, the desired A3-cephem can be obtained by treatment of the A2 compound with a base such as potassium hydroxide or a tertiary amine such as pyridine and triethylamine, or by oxidation to A2 -cephem sulfoxide, followed by reduction to A3 -cephem. The choice of method for converting the ester to the free acid or base depends on the nature of the ester in question. Acid, basic, or enzymatic hydrolysis can be used. However, aqueous solvents should be avoided to reduce isomerization and side reactions. Lewis acids are preferred de-esterifying agents. Another method for preparing a compound of formula 1 consists in reacting a compound of formula 4 or a salt, ester, or silyl derivative thereof, in which formula 4 the dotted line denotes a bond in the 2- or 3-position, R3 | R4 having the meanings given above for the compound of formula 1, with a compound of formula 5, wherein Y, R1, R2, and R3 have the meanings given above, followed by optional conversion of the A2-isomer to the desired A3-isomer, removal of the silyl groups by alcoholization or hydrolysis, reduction of the sulfoxide to the desired sulfide, and removal of the blocking groups in the acyl side chain R, and conversion of the ester to the free acid or its salt. The compounds prepared by the method of the invention are broad-spectrum cephalosporins, i.e., cephalosporins that are active not only against Gram-positive bacteria but also against numerous clinically important Gram-negative bacteria. Distinctive compounds prepared by the method of the invention are active against such important organisms as Pseudomonas spp., against which commercially available cephalosporins are usually inactive. Furthermore, these compounds are active against numerous Gram-negative cephalosporinase-producing organisms, such as Enterobaoter spp., Serratia spp., and indole-positive Proteus. The following examples illustrate the process of the invention without limiting its scope. Example 1. Preparation of Dnx-(N-imidazolidinone-2-ylcarbonylamino)-benzyl-cephalosporin sodium salt. 2.2 g of D-α-aminobenzylcephalosporin dihydrate was dissolved in 30 ml of water, 5 ml of acetone, and 0.7 ml of triethylamine. A solution of 0.75 g of imidazolidinone-2-ylcarbonyl chloride in 20 ml of dry acetone was slowly added to the solution, along with a further 0.7 ml of triethylamine, maintaining this rate. The addition was carried out so as not to exceed the pH of the reaction mixture between 7.5-8.0. The addition time was approximately 5 minutes, after which the mixture was stirred for 1 hour with slight changes in the pH value. The acetone was removed under reduced pressure, the aqueous concentrate was covered with a layer of 35 ml of ethyl acetate, and both layers were cooled to 0°C. With vigorous stirring, the pH of the mixture was carefully adjusted to 1.5 with dilute HCl. The layers were separated, and the aqueous phase was immediately re-extracted with 15 ml of fresh ethyl acetate. The combined organic layers were washed with 20 ml of water and then twice with 50 ml of saturated aqueous sodium chloride solution. The organic phase was filtered through siliconized paper to remove the last traces of saturated aqueous sodium chloride solution. and then, with stirring, 5 ml of 1.0 normal sodium 2-ethylhexanoate in isopropanol were added. The yellowish precipitate was filtered off, thoroughly washed with dry diethyl ether and dried under reduced pressure, obtaining 1.2 g of the desired cephalosporin. IR i: *max/nuJ°D 1768 cm"1) /Hactam CO). Iodometric assay: 54%. Paper chromatography: - Rp ¦ 0.23 (butanol-ethanol-water). The starting compound, cephaloglycin, showed R p = 0.19). Example. Preparation of D-α-1N-3-cinnamoyl-3-methylreido)benzylcephalosporin sodium salt. To a solution of 2.2 g of D-α-aminobenzylcephalosporin in A solution of 1.12 g of N-chloroformyl-N-methyl-cinnamic acid amide in 25 ml of dry acetone was added to 30 ml of water, 5 ml of acetone and 0.7 ml of triethylamine, simultaneously with a further portion of 0.7 ml of triethylamine, at such a rate as to maintain the pH of the reaction mixture at 7.5-8.0. The addition time was about 5-8 minutes, after which the mixture was stirred for 1 hour and then the acetone was removed by extraction with two 100 ml portions of diethyl ether. The yellowish aqueous phase was covered with 40 ml of ethyl acetate, cooled to 0°C and, with constant, vigorous stirring, carefully adjusted to pH 1.5 with dilute hydrochloric acid. The layers were separated, the aqueous phase was back-extraction with 20 ml of fresh ethyl acetate. The combined organic layers were washed with 20 ml of water and then twice with 50 ml of an aqueous saturated sodium chloride solution, the last traces of which were removed by filtration through silicone paper. Then 5 ml of 1.0 N sodium 2-ethylhexanoate in isopropanol were added with stirring. The thick, white precipitate was filtered off, carefully washed with dry diethyl ether and dried under reduced pressure, yielding 2.8 g of the desired compound.IR :*max(nuJ°0 17? 0 cm"1 (/Maktam CO). Iodometric assay: 58%. Paper chromatography: Rp = 0.51 (butanol — ethanol — water). Example III. Preparation of D-α-(3-ethoxycarbonyl)-3-methylureabenzylcephalosporin sodium salt. 2.2 g of D-α-aminobenzylcephalosporin dihydrate and 1.5 ml of triethylamine in 30 ml of anhydrous dichloromethane were stirred for 2 hours with 2.0 g of 4A molecular sieves. The mixture was filtered, cooled in an ice bath and treated with a solution of 0.84 g of ethyl N-chloroformyl-N-methylcarbonate in 15 ml of dichloromethane. The solution was stirred for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water, washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate, acidified with N hydrochloric acid to pH 1.5, and filtered to remove insoluble materials. The ethyl acetate layer was separated, and the aqueous layer was back-extracted with N water (twice with 50 ml) and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, diluted with 100 ml of anhydrous ether, and treated with 2 N sodium 2-ethylhexanoate in methyl isobutyl ketone until no further precipitation occurred. The cephalosporin sodium salt was collected on a filter, washed with anhydrous ether and dried under vacuum over phosphorus pentoxide. Yield was 1.25 g, 43.1%. NMR : [(CD3)2SO + D2O]8 - 7.55) 5 H, $, aromatic protons 5.9-5.6 (2 H, m# protons a I C7 ,3-4.7 (3 H, m, C$ protons iCH2OCOCH3), 4.38 [2 H, q4J = 7Hz), NCO2CH2 CH3], 2.13 (3H, S, -OCOCH3), 1.41 (3H, t(J = 7 H2) - C02CH2CH3). Paper chromatography: single zone with a value of Rp = 0.49 (butanol-ethanol-water).89964 5 Example IV. Preparation of D-α(3-cyclohexylcarbonyl-3-methylureido)-benzylcephalosporin sodium salt. 2.2 g of D-a-aminobenzylcephalosporin dihydrate was reacted as described in Example 3 above with 1.1 g of cyclohexyl-N-chloroformyl-N-methylcarbonate to obtain 1.01 g of cephalosporin sodium salt in a yield of 32%. NMR: [(CD3)2SO + D20], 8 - 7.40/5 H, s, aromatic protons), 5.8-5.4/2 H, m, C7 protons and a (5.3-4.5) 4 H,m, C6 proton, -CH2OCOCH3 and cyclohexylmethine),3.5-3.0 (2 H,m, C2 protons),3.10/ 3H, s, ,N-CH3, 2.01) 3H, s, -OCOCH3), 3.1-1.2) 10 H, m, cyclohexylmethylene protons). Paper chromatography: single spot with Rp value = 0.60 (butanol-ethanol-water). Example 5. Preparation of D-α-(2,4-dimethylallophanamido)benzylcephalosporin sodium salt. 0.005 mol of anhydrous triethylammonium D-α-aminobenzylcephalosporinate, prepared from D-α-aminobenzylcephalosporin dihydrate as described in Example 3 above, in 30 ml of dichloromethane was cooled in an ice bath, and then a solution of 0.75 g of 2,4-dimethylallophanamido)benzylcephalosporin in 15 ml of dichloromethane was added. The solution was stirred for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water, washed twice with 50 ml of ethyl acetate, covered with 50 ml of fresh ethyl acetate, and acidified with 1 N hydrochloric acid to a pH of 1.5. The mixture was filtered to remove insoluble materials, the ethyl acetate layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined ethyl acetate solutions were washed twice with 50 ml of water, with 50 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the acetate solution was concentrated to a volume of approximately 25 ml under reduced pressure, and 1.5 ml of a 2 N solution of sodium 2-ethylhexanoate in methylisobutylketone was added. The precipitated sodium salt was collected on a filter, washed with anhydrous ether, and dried in vacuo over phosphorus pentoxide. The yield was 1.29 9.492%. NMR : [(CD3)2SO+D2O], δ = 7.38 (5H, s, aromatic protons 5.9-5.3) 2H, m, protons and C7 1a(5.2-4.6) 4 H, m, C6 proton and -CH2OCOCH3), 3.5-2.9/2H, m, C2 methylene protons, 3.13/3H, t, N-CH3/, 2.73/ 3H, s, -NHCH3/, 2.01/ 3H, s, -OCOCH3/ UV : Xmax26t ,5 nm (e = 7 276), (95% ethanol). Paper chromatography: single zone with Rp value = 0.41 (n-butanol -ethanol -water). Example VI. Preparation of D-α-(hexahydroazepinon-2-yl-1-carbonylamino)-benzyl cephalosporin sodium salt. The compound was prepared from 1-chlorocarbonylhexahydroazepine-2 and Dtx-aminobenzyl cephalosporin dihydrate in the manner described above in Example V, with a yield of 40.3%. NMR : [(CD3)2SO + D2O], δ = 7.44 (5 H, s, aromatic protons), 5.7-5.5 (2 H, m, proton a and proton C7), 5.2-4.6 (4 H, m, proton C6 and ^CH2OCOCH3), 4.1-3.8 (2 H, m, methylene C3 of hexahydroazepinone), 3.5-2.1 (2 H, m, methylene C2), 3.0-2.6 (2 H, m, methylene C7 of hexahydroazepinone), 2,D1 (3 H, s, -OCOCH3), 1.9-1.4 (6 H, m, methylene protons C4, Cs and C6 of hexahydroazepinone). UV : Xmax263.5 nm (e = 650μ), (95% ethanol). Paper chromatography: single zone with Rp value of 0.58. Example VII. Preparation of D-α-(3-cinnamoyl-3-methylureldo)benzylcephalosporinate sodium salt. The compound was prepared from N-chlorocarbonyl-N-methylcinnamic acid amide and D-α-aminobenzylcephalosporin dihydrate in the manner described above in Example V with a yield of 37.5%. NMR : [(CD3)2SO + D2O], δ = 8.0-7.1 (12 H, m, aromatic and olefinic protons), 5.8-5.5 ftµm, C7 and a protons), 5.3-4.6 (3H, m, C6 protons and -CH2OCO- (, 3.35 (5 H, singlet overlapping with the multiplet, C2 methylene and N-CH3), 2.04 (H, s, -O-COCH3). UV : Xmax 279 nm (e = 18326), 95% ethanol). Paper chromatography: single zone with Rp value = 0.52. Example VIII. Preparation of D-α-(3-crotonoyl-3-methylureido)-benzylcephaloporin sodium salt. The compound was obtained from Crotonic acid N-chlorocarbonyl-N-methylamide and D-α-aminobenzylcephalosporin dihydrate as described above in Example V, with a yield of 24%. NMR: [(CD3)2SO + D20], 6 = 1.89 (3 H, s, =CHCH3), 2.02 (3 H, s, -OCO-CH3), 3.23 (3 H, singlet overlapping multiplet, ^N-CH3 and methylene protons (^ (4.85-4.95) 3H, m, C6 and -CH2OCOCH3), 5.5-5.7/2 H, m,protonsC7 and a(6.7-7.5)2 H,m,protons oWnowef? fldjb H,s, aromatic protons UV Xmax265 nm (e = 8.684), 95% ethanol). Paper chromatography: single zone with Rp = 0.48. Example IX. Preparation of D-a (3-methyl-3-phenylpropionoloureldo)benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methylphenylpropionic acid amide and D-a-amlnobenzylcephalosporin dihydrate as described above in Example V, with a yield of 55.5%.6 89 964 NMR: [ (CD3)2SO + D20],8 - 1.03 (3 H, s, -OCOCH3), 23-3.5 (9 H, m,N-CH3, -OCH2CH2 and methylene protons C2), 4.8-5.0 (3 H, m, proton C6 and -CH2OCO- (, 5.5-5.7) 2 H, m, protons C7 and a, 7.30 (5 H, $, aromatic protons, 7.40 5 H, s, aromatic protons. UV: Rp = 0.63. Example efficiency 34.3%. NMR: [(CD3)2SO + D2O], δ = 2.03 (3 H, s, -OCOCH3), 3.36 (3 H, s, -OCH3), 3.75 (5 H, slanglet overlapping with the multiplet, ; N-CH3 and C2 methylene 4.85-5.05 (3 H, m, C6 proton and -CH2OCO-), ,60-5.80 (2 Hjr., m, C7 protons and a/7.0-8.2/11 H, m, olefinic and aromatic protons). UV : Xmax 229 (e=17 856), (95% ethanol), 277 (e = 17 767), (95% ethanol) and 331 nm (e=11249), (95% ethanol). Paper chromatography: single zone with Rp value = 0.38. Example XI. Preparation of D-3-methyl-3-(2'-thienyl)acryloylureidobenzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-(2-thienyl)acrylic acid amide and D-α-aminobenzylcephalosporin dihydrate in the manner described above in Example V, with a yield of 26.3%. NMR :[(CD3)2SO+ D2O], δ = 2.03 (3 H, s, -OCOCH3), 3.32 (5 H, m, ^ N-CH3 3 and methylene protons δ^4.7-5.1 (2 H, m, C6 proton and -CH2OCO-), 5.5-5.8 (2 H, m, C7 protons and α (6.8-8.1 (10 H, olefinic and aromatic protons). UV: Xmax267 (e=12843) and 322.5 nm (e=15,205), (95% ethanol). Paper chromatography: zone with Rp = 0.63. Example XII. Preparation of D-a-[3-methyl-3-(p-nitrocinnamoyl)ureido]benzylcephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl-p-cinnamic acid nitroamide and D-a-aminobenzylcephalosporin dihydrate as described above in Example V, with a yield of 13%. NMR : [(CD3)2SO + D20], S = 1.97 (3 H, s, OCOCH3, 2.74 (5 H, m,^N-CH3 and protons methylene (4.7-5.2 (3 H, m, -CH2OCO- and C6 proton (5.5-6jD (2H,m, C7 protons and a (7.0-8.3) 11 H, m, aromatic and olefinic protons). UV: Xmax266 nm (e = 13,797), (95% ethanol). Paper chromatography: - zone with Rp value = 0.57. Example XIII. Preparation of D-a-[3-methyl-3-(a-methylcinnamoyl)ureido]benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-a-methylamide of cinnamic acid and D-a-aminobenzylcephalosporin dihydrate as described in the example above. V, with an efficiency of 33 J5%,' NMR: [(CD3)2SO + D2O], δ = 2.03 (3 H, s, OCOCH3), 2.10 (3 H, d, CH3-CH=), 3.25 (3 H, s, N-CH3), 3.2-3.5 (2 H, m, methylene C2 4.8-5.0 (3 H, m, -CH2OCO- and proton C6\5.5-5.7 (2 H, m, protons C7 and a 6.80 (1 H, m,)Nc=CH- 7.3-8.1 (10 H, m, aromatic protons). UV: Xmax266 nm) = 13797). Paper chromatography: zone with Rp value = 0.67. Example XIV. Preparation of sodium salt D-a-(3-benzyl-3-cinnamoylureido)benzylcephalosporins. The compound was prepared from N-chlorocarbonyl-N-benzylamide of cinnamic acid and D-a-amino-benzylcephalosporin dihydrate as described in Example V above, with a yield of 49.5%. NMR :[(CD3)2SO + D20], 5 = 2.03 (3 H, s, CH3OCO), 3.33 (2 H, m, C2 methylene protons), 4.95 (3 Htr, m -CH2OCO- and C6 proton), 5.28 (2 H, m, PhCH2-),5.67 (1 H,d, C7 proton), 5.72 (1 H,s,protoha), 7.40 (17 H, m, aromatic and olefinic protons). UV : Xmax 289 nm) (e = 14100), (95% ethanol). Paper chromatography: zone with Rp value = 0.64. Example XV. Preparation of D^-[3-(3',4'^'-trimethoxybenzoyl)-3-methylureido]benzylcephalosporin sodium salt. The compound was prepared from benzoic acid N-chlorocarbonyl-N-methyl-3,4,5-trimethoxyamide and D-α-aminobenzylcephalosporin dihydrate in the manner described above in Example V, in a yield of 27%. NMR : [(CD3)2SO + D2O], δ = 2.03 (3 H, s, CH3OCO-), 3.17 (5 H, mN-CH3 and methylene C2), 3.83 (9 H, m, 3XCH30-), 4.96 ( 3 H, m,-CH2OCO- and C6 proton), 5.63 (1 H,d, C7 proton) # 5.68 (1 H,s, a proton), 6.88 (2 H, s, trisubstituted phenyl protons), 7.40 (5 H, s, Ph-), UV : Xmax265 nm (e = 11,832). Paper chromatography: zone with Rp value = 0.42. Example XVI. Preparation of D-a-[3-(j3j3-dimethylacrylyl)-3-methylureido]benzylcephalosporin sodium salt. The compound was obtained from N-chlorocarbonyl-N-methyl-j3/3-dimethylamide of acrylic acid and dihydrate D-α-aminobenzyl cephalosporin as described above in form V, with a yield of 24.7%.89 964 7 NMR: [ (CD3)2SO + D2O],5 = 1.9-2.1 (9H,m, /CH3 and -OCOCH3), 3.20 (2 H, O N-CH3), 3.2-3.4 =c --¦ \CH3 (2 H, m, methylene C2 (4.8-5.0) 3 H, m, -CH2DCO- and proton C6 (5.6-5.8) 2 H, m, protons C7 and a (6.20) 1 H, m, -CH=CC(7.42) 5 H, s, aromatic protons). UV: Xmax 227 nm (e = 18 460), (95% ethanol). «' Paper chromatography : zone with Rp value = 0.62. Example XVII. Preparation of D-α-methyl-3-(3',4',5'-trimethoxycinnamoyl)uraidobenzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-3,4,5-trimethoxycinnamoyl and D-α-aminobenzylcephalosporin dihydrate in the manner described above in Example V, in a yield of 33.5%. NMR : [(CD3)2SO + D2O], δ = 2.03 (3 H, s, -OCOCH3), 3.2-3.5 (2 H, m, methylene C2), 3.36 (3 H, s, N-CH3), 3.77 (3 H, s, -OCH3), 3.87 (3 H, s, -OCH3), 3.96 (3 H, s, -(CH3), 4.8-5.0 ( 3 H, m, C6 and -CH2OCO-), 5.5-5.7 (2 H, m, a and C7 protons), 7.1-7.7 (9 H, m, aromatic and olefinic protons). UV : Xmax235/5 nm) te = 21 396) and 320 nm (e = 17 935), (95% ethane<). Paper chromatography: zone with Rp value = 0.63. Example XVIII. Preparation of DtH2-imidazolidonecarbonylamino)benzylcephalosporin sodium salt. A solution of 1.32 g, 0.005 mol of D-α*(2-imidazolidonecarbonylamino)phenylacetic acid in 20 ml of anhydrous tetrahydrofuran was cooled to <=-10°C and treated with 1 drop of N-methylmorpholine, 0.71 ml of triethylamine and 0.48 ml of ethyl chloroformate. The suspension was stirred for 15 minutes at <=-10°C, after which an ice-cold solution of 1.36 g, 0.005 mole, 7-aminocephalosporanic acid and 0.71 ml of triethylamine in 30 ml of 50% aqueous tetrahydrofuran was added. The solution was stirred for 3 hours at room temperature, then the tetrahydrofuran was removed under reduced pressure and the residue was dissolved in 100 ml of water. The aqueous solution was washed with 2 x 50 ml of ethyl acetate and acidified with 1 N hydrochloric acid to pH 1. 1.5. The precipitate was collected and dried in vacuo to give 0.87 g of product, which was suspended in 10 ml of water and 0.95 equivalent of 1 N sodium bicarbonate solution was added. The solution was filtered and the filtrate was evaporated in vacuo to dryness. Yield: 0.70 g, 26%. NMR: [(CD3)2SO + D2O]* 5 = 9.17)[1 H, d) J = 8 Hz), NH-], 7.41 (5 H, s, aromatic protons), .9-5.4 (2 H, m, C7 and a protons), 5.3-4.6 (3 H, m, C6 protons and -CH2OCO-), 4.1-3.1 (6 H, m, C2 methylene and methylenes imiazolidone), 2.01 (3 H, s, -(COCH3). UV : Amax 264 nm (e = 6 527), (95% ethanol). Paper chromatography : single zone with Rp value = 0.32 (n-butanol - ethanol - water). Example XIX. Preparation of D-(3-cinnamoyl-3-methylureido)benzylcephalosporin sodium salt. A solution of 1.69 g, 0.005 mol, D-ar(3-methylureido)phenylacetic acid in 15 ml of anhydrous acetone was cooled to <—10°C, then 1 drop of N-methylmorpholine, 0.71 ml of triethylamine and 0.48 ml of ethyl chloroformate were added. The suspension was stirred for 15 minutes at <—5°C, Then a cooled to 0°C solution of 1.36 g, 0.005 mol, heptanoic acid and 0.71 ml of triethylamine in 30 ml of 50% aqueous acetone was added. The solution was stirred for 3 hours at room temperature, then the acetone was removed under reduced pressure, and the residue was diluted with approximately 50 ml of water. The aqueous solution was washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate, and acidified with 1 N hydrochloric acid to pH 1.5. The layers were separated, and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic layers were washed twice with 50 ml of water and with 50 ml of aqueous sodium chloride solution, and dried with anhydrous sodium sulfate. magnesium solution, concentrated under reduced pressure and treated with 1.5 ml of a 2-N solution of sodium 2-ethylcaproate in methyl isobutyl ketone. The precipitate was collected on a filter paper, washed with anhydrous ether and dried under reduced pressure. The yield was 0.70 g, 223%. NMR : [(CD3)2SO + D20], 8 = 8.0-7.1 (12 H, m, aromatic iolefin protons), 5.8-5.4 (2H, m, C7 and a protons) 5.2-4.7 (3 H, m, C6 protons and -CH2OCO-), 3.34 (5 H, singlet overlapping multiplet, ^ N-CH3 and methylene C2), 2.05 (3 H,s,-OCOCH3). UV : Xmax 275 nm (e - 17119), (95% ethanol. Paper chromatography: single zone with Rp value = 0.52. Example XX. Preparation of DtH3-furylacrylyl-3-methylureido)benzylcephalosporin sodium salt. The compound was prepared from DtH3-(3-furylacrylyl-3-methylureido)phenylacetic acid and 7-aminocephalosporanic acid in the manner described in Example XIX, with a yield of 14%. NMR: [(CD3)2SO + D2O], δ - 2.03 (3 H, δ, -OCOCH3 3.32 (5 H, singlet overlapping with t multiplet, δN-CH3 and methylene protons C2), 4.8-5.1 (3 H, m, -CH2OCO- and proton CJ, bjó 5.8 (2 H, m,8 89964 protons C7 and a) 6.6-7.9 (10 H, m, furyl, olefinic and aromatic protons). Paper chromatography: zone with Rp value - 0.58. Example XXI. Preparation of D-α(3'-cinnamoyl-3'-methylureido)-4-hydroxybenzylcephalosporin sodium salt. The compound was obtained from D-α(3'-cinnamoyl-3'-methylureido)-4-hydroxyphenylacetic acid and 7-aminocephalosporanic acid in the manner described in Example XIX, with a yield of 35.9%. NMR : [(CD3)2SO + D2O], δ - 8.0-6.6 (11 H, m, aromatic and olefinic protons), 53-5/* (2 H, m, C7 and a protons), 5.1-4.7 (3 H, m, C6 and -CH2OCO-), 3.35 (5 H, s, N-CH3 and methylene (^, 205 (3 H, s, -OCOCH3). UV : max225 ( 24 468 (and 282 nm (-19 152), (95% ethanol). Paper chromatography : - single zone with Rp value = 0.65. Example XXII. Preparation of 7-[D-α-(3'-cinnamoyl-3'-methylureido)phenylacetamido]-3-(2"-methyl- 4-Sodium 7-amino-3-(2-carboxylate)-(3-cinnamoyl-3-methylureido)phenylacetic acid (0.5 g, 0.0025 mol) in 10 ml of benzoic acetone was cooled to <-10°C and 1 drop of N-methylmorpholine, 0.35 ml of triethylamine and 0.24 ml of ethyl chloroformate was added. The suspension was stirred for 15 minutes at <-10°C and then a cooled to 0°C solution of 0.86 g, 0.0025 mol) 7-amino-3-(2-carboxylate)-(3 ... methyl-[1,3#,4#-thiadiazoyl-5'-thio]-methylcephem-3-carboxylic acid 10.35 ml of triethylamine in 15 ml of 50% aqueous acetone. The solution was stirred for 2 hours at room temperature, then the acetone was removed under reduced pressure, and the residue was diluted with approximately 50 ml of water and washed twice with 50 ml of ethyl acetate. The aqueous phase was covered with 50 ml of ethyl acetate and acidified with 1 N hydrochloric acid to pH 1.5. The acetate layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined acetate solutions were washed twice with 50 ml of water, 50 ml of aqueous sodium chloride, and sodium hydroxide, dried with anhydrous magnesium sulfate and treated with 0.7 ml of a 2 N solution of sodium 2-ethylhexanoate in methylisobutylketone. The precipitated sodium salt was collected on a filter, washed with anhydrous ether and dried in vacuo. The yield was 0.53 g, 30.9%. NMR : [(CD3)2SO + D2O], δ - 8.0-7.0 (12 H, m, aromatic and olefinic protons), 53-5.4 (2 H, m, C7 protons and a (5.1 -4.8 (1 H, m, C6 proton and 4.8-4.0 (2 H, m, -CH2-S- (3.34 (5 H, slang overlapping with the multiplet, N-CH3 and C2 methylene), 2.67 (3 H, s, thiadiazole methyl protons). UV: Xmax219 nm (e = 24010) and 282 nm (e = 27901), 95% ethanol). Paper chromatography: single zone with RF'=0.63. EXAMPLE XXIII. Preparation of 7-[D-a-(3'-cinnamoyl-3'-methylureldo)phenylacetamido]-3-(1"-methyl-r' H-tetrazoyl-5"-thio)methylcephem-3-caboxylate4 sodium. To a solution of 0.85 g, 0.0025 mol, acid D-a-(3-cinnamoyl-3-methylureido)phenylacetic acid in 20 ml of anhydrous acetone added at <-10° 1 drop N-methylmorpholine, 0.35 ml of triethylamine and 0.24 ml of ethyl chloroformate were added and stirred at the same temperature for 15 minutes. A solution, cooled to 0°C, of 0.82 g, 0.0025 mol, of 7-amino-3-(1'-methyl-1'H-tetrazoyl-5'-thio)methylcephe-3-carboxylic acid and 0.35 ml of triethylamine in 30 ml of 50% aqueous acetone was added and the solution was stirred for 2 hours at room temperature. The acetone was removed under reduced pressure and the residue was diluted with 100 ml of water, washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate and acidified. 1 N m hydrochloric acid to pH 1.5. The layers were separated and the aqueous solution was extracted with 50 ml of ethyl acetate. The combined layers were washed twice with 50 ml of water, dried with anhydrous magnesium sulfate and treated with 0.8 ml of a 2 N solution of sodium 2-ethylhexanoate in methylisobutylketone. The precipitated salt was collected on a filter, washed with anhydrous ether (dried in vacuo). The yield was 0.64 g, 38.2%. NMR : [(CD3)2SO + D2O,],3 - 8.0-7.1 (12 H, m, aromatic and olefinic protons /, 5.8-5.5/ 2 H, m, C7 1a protons), 5.1-4.8 (1 H, m, C6 proton (4.6-4.1 (2 H, m, -CH2S-), 3.95 ( 3 H, s, tetrazole methyl protons), 3.33 (5 H, singlet overlapping with the multiplet, y N-CH3 and methylene protons C2). UV: Xmax 282 nm (e85 25 277), (95% ethanol). Paper chromatography: single zone with Rp value of -0.66. Example XXIV. Preparation of DtH3-benzoyl-3-methylureido)-benzylcephalosporin sodium salt. A solution of 0.005 mol of anhydrous D-α-aminobenzylcephalosporin triethylammonium salt in 30 ml of dichloromethane, prepared from 2.2 g of D-α-aminobenzylcephalosporin dihydrate in the manner described above. in Example III, was cooled in an ice bath, and then a solution of 0.98 g, 0.005 mole of benzoic acid N-chlorocarbonyl-N-methylamide in 15 ml of dichloromethane was added. The solution was stirred for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water, washed twice with 50 ml of ethyl acetate and, in the presence of 50 ml of ethyl acetate, acidified with 1 N hydrochloric acid to pH 1.5. The organic layer was separated, the aqueous phase was extracted with 50 ml of ethyl acetate, and the combined ethyl acetate extracts were washed twice with 100 ml of water and 50 ml of ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was treated with 1.5 ml of 2N sodium 2-ethylhexanoate in methyl isobutyl ketone, diluted with 200 ml of anhydrous ether, the precipitated sodium salt was collected and dried under vacuum. Yield was 1.68 g, 57.2%. NMR: [(CD3)2SO + D2O], 6 - 7.7-7.2 (10 H, m, aromatic protons), 5.8-5.4) 2H, m, C7 and α protons, 5.2-4.6 (3 H, m, C6 proton and -CH2OCO-), 3.6-23 (2 H, m, C2 methylene protons), 3.08 (3 H, s, NCH3), 2.00 (3H, s, -OCPCH3). UV: Xmax263 nm (e = 8,710), (95% ethanol). Paper chromatography: - single zone with Rp value = 0.52 (n-butanol-ethanol-water). Example XXV. Preparation of D-cr(3-methyl|o-3-acetylureido)benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-acetic acid amide and Dtfc-aminobenzylcephalosporin dihydrate as described above in Example XXIV, with a yield of 27%. NMR :[(CD3)2SO + D20],6 = 7.43 (5H,s,aromatic protons),6.8-6.5(2H,m,C7 protons and a (6.2-4.6 (3H, m, proton C* and -CHaOCO-), 3.7-2.7 (2H, m, methylene protons C*), 3.20 (3 H, i, NCH3, 2.33 (3 H, i, -C0CH3), 2.03 (3 H, s, -OC0CH3). UV : Xmax266 nm) (e * 7920), (95% ethanol). Paper chromatography: single zone with Rp value: 0.42. Example XXVI. Preparation of D-a-[3-(2-methylcrotonoyl)-3-methylurea]benzylcephalosporin sodium salt. j of D-α-aminobenzylcephalosporin dihydrate as described above in Example XXIV, with a yield of 37.4%. NMR: [(CD3)2SO + D2O], δ = 1.5-2.2 (6 H, m, =CHCH3 and -OCOCH3), 3.12 (3 H, s, N-CH3), 3.2-3.4 (2 H, m, C2 methylene protons) 4.9 (3 H, m, C6 proton and -CH2OCO-) 5.6 (2 H, m, C7 protons and a) 7.4 (aromatic protons, 5H, m, UV : Xmax 257 nm (e-7 930), (95% ethanol). Paper chromatography: - single zone with a value of Rp = 0.62. Example XXVII. Preparation of D-α(3-phenylacetyl-3-methylurea)benzylcephalose sodium salt gutters). The compound was prepared from N-chlorocarbonyl-N-methylphenylamide acetic acid and DtK-aminobenzylcephalosporin dihydrate as described above in Example XXIV, in a yield of 10.5%. NMR: [(CD3)2SO +' Q20],5 = 2.03 (3 H, s,-OCOCH3),3.29 (5 H,singlet overlapping the multiplet ^ NCH3 and methylene protons C2),4.04 (2 H,s,-COCH2Ph),4.92 (3 H,m,OCOCH2- and proton C6 5.7 (2 H, m, C7 and a protons), 7.32-7.40 (10 H, d, aromatic protons). UV: Xmax 264 nm (e = 5,720, (95%) ethanol). Paper chromatography: zone with Rp value = 0.51. Example XXVIII. Preparation of D-[3-(4-phenylbenzylbenzylcephalosporin] sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-4-phenylamide of butyric acid and D-α-aminobenzylcephalosporin dihydrate in the same manner as described in Example XXIV above, in a yield of 49.2%. NMR : [(CD3)2SO + D2O], δ = 2.02 (7 H, singlet overlapping the multiplet, -OCOCH3 and -CH2CH2Ph), 2.7 ( 2H, m, -COCH2-), 3.18 (5 H, singlet overlapping the multiplet. NCH3 and methylene protons C2), 4.92 (3 H, m, -CH2OCO- and C6 proton), 5.65 (2 H, m, C7 and a protons), 7.26 (5 H, s, aromatic protons), 7.40 (5 H, s, aromatic protons). UV: X max 261 nm (e = 7 785), (95% ethanol). Paper chromatography: zone with Rp value = 0.62. Example XXIX. Preparation of D-α-(3-octen-2'-ollo-3-methylureido)-benzylcephaloporin sodium salt. The compound was obtained from 2-dehydrocaprylic acid N-chlorocarbonyl-N-methylamide and D-α-aminobenzylcephalosporin dihydrate in the manner described above in Example XXIV in 25% yield. NMR : [(CD3)2SO + D2O], 6 = 0.8-1.5 (9 H, m, -(CH2)3CH3), 2.02 (5 H, singlet overlapping the multiplet, -OCOCH3 and -CH2CH = ), 3.25 (5 H, singlet overlapping the multiplet; NCH3 and C2 methylene protons), 4.8-5.0 (3 H, m, C6 proton and -CH2OCO-), 5.5-5.7 (2 H, m, C7 and a protons), 6.5-7.5 (2 H, m, olefinic protons), 7.42 (5 H, s, aromatic protons). Paper chromatography: zone with Rp value = 0.58. Example XXX. Preparation of the sodium salt D-a-(3-furoyl-3-methylureido)benzylcephalosporin. The compound was prepared from N-chlorocarbonyl-N-methyl-2-furamide and D-a-aminobenzylcephalosporin dihydrate as described in Example XXIV above, in a yield of 55.0%. NMR : [(CD3)2SO + D20], 8 = 2.04 (3 H, s, -OCOCH3), 3.37 (5 H, singlet overlapping multiplet, ^NCH3 and methylene protons C2), 4.8-5.0 (3H,m, -COCH2- and proton C6), 5.5-5.8 (2 H,m,protons , C7 and^6.6-8.0 (8 H, m, aromatic and furyl protons. UV:Xmax268nm (e = 19,990), (95% ethanol). Paper chromatography: zone with Rp value = 0.39. Example XXXI. Preparation of DtH3-cinnamoyl-3-ethylureido)-benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-ethylamide of cinnamic acid and Dt**amino-10,89,964 benzylcephalosporin dihydrate in the manner described above in Example XXIV, in 27.4% yield. NMR : [(CD3)2SO + D2O], S - 1.2-1.4 (3 H, m, CH3CH2-), 2.04 (3 H, s, -OCOCH3), 3.2-3.5 (2 H, m, C2 methylene protons), 3.7-4.2) 2 H, m, ^N-CH2-, 4.9-5.05 (3 H, m, -(COCH2- and C6 proton), .6-5.8 (2 H, m, C7 protons and a (7.3-8.0 (12 H, m, aromatic lolefin protons), UV:Xmax285 nm (e-19370), (95% ethanol). Paper chromatography: zone with Rp value = 0.57. Example XXXII. Preparation of DtH3-acetyl|mldazolidin-2Hlo-1*arbonylamino)-benzylcephalosporin sodium salt. The compound was prepared from 3-acetyl-1-chlorocarbonyl-imidazolidinone-2 and D-craminobenzylcephalosporin dihydrate as described. above in Example XXIV, with yield 61 £%. NMR : [(CD3)2SO + D2O], δ = 7.42 (5 H, s, aromatic protons) 5.8-5.3 (2 H, m, C7 and a protons), ,2-4.6 (3 H, m, C6 proton and -CH2OCO-), 3.73 (4 H, s, methylene protons of imidazolidinone), 3.6-2.9 (2 H, m, C2 methylene protons) 2.42 (3 H, s, / NCOCH3), 1.99 (3 H, s, -(COCH3). UV X max 260 nm (e = 8 180), (95% ethanol). Paper chromatography: single zone with a value of Rp = 0.30. Example XXXIII. Preparation of the sodium salt D-a-(3-methylsulfonylimidazolidinone-2-llo-1-carbonylamino)-benzylcephalosporin. The compound was prepared from 11-chlorocarbonyl-3-methylsulfonylimidazolidinone-2 and DtK-amino-benzylcephalosporin dihydrate as described above in Example XXIV, with efficiency 38.1%. NMR :[(CD3)2SO+ D20]5 = 7.48 ( 5 H,s, aromatic protons),5.7-5.4, (2 H, m, C7 and a protons), (4 H, s, aromatic protons), 57-5.4, (2 H, m, C7 and a protons) 5.2-4.5/3 H, m, C6 proton and -CH2OCO-/ , 3.89 (4 H, s, methylene protons of imidazolidinone) 3.7-2.8 (2 H, m, methylene protons of C2) 3.38 (3 H, s#-SO2CH3) 2.03 (3 H, s,-OCOCH3). UV: Xmax 262 nm (e = 7825), (95% ethanol). Paper chromatography: single zone with Rp value = 0.27. Example XXXIV. Preparation of DtH2,4,4-trimethylamino(phenamido)benzylcephalosporin sodium salt. The compound was prepared from 1-chlorocarbonyl-1,4-trimethylurea and DtK-aminobenzylcephalosporin dihydrate as described in Example XXIV above, with yield 33.2%. NMR : [(CD3)2SO + D2O], 6 = 2.02 (3H, s, -OCOCH3), 2.88 [6H, s, -N(CH3)2], 3.0 (3 H, s, NCH3), 3.33 (2 H, m, C2 methylene protons), 4.93 (3 H, m, C6 protons and -CH2OCO-), 5.58 (2 H, m, C7 protons and a) 7.40 (5 H, m, aromatic protons). UV : Xmax 266 nm (e = 6 890), (95% ethanol). Paper chromatography: zone with Rp value = 0.30. Example XXXV. Preparation of DtH3-phenoxyacetyl-3-methylureldot)benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methylphenoxyacetamide and Dtraminobenzylcephalosporin dihydrate as described above in Example XXIV, with a yield of 62.1%. NMR: [(CD3)2SO + D20], 6 = 2.01 (3 H, s, -OCOCH3), 3.23, (5 H, m, NCH3 and methylene protons C2), 4.92 (3 H, m, -CH2OCO- and proton C6), 5.10 (2 H, s, PhOCH2-), 5.61 (2 H,m, protons C7 pfte a), 6.9-7.5 (10 H, m, aromatic protons). UV: Xmax 266 nm (e = 9000), (95% ethanol). Paper chromatography: zone with values Rp = 0.50. EXAMPLE XXXVI. Preparation of D-a[3-(2-chlorobenzoyl)-3-methylureido]benzylcephalosporin sodium salt. The compound was prepared from N-chlorocarbonyl-N-methyl-2-chloroamide benzoic acid and D-a-aminobenzylcephalosporin dihydrate as described above in Example XXIV, with a yield of 28.5%. NMR: l/(CD3)2SO +D20], 8 = 2.03 (3 H, s,-OCOCH3), 3.01 (3 H, s, ^N-CH3), 3.2-3.5 (2 H, m, methylene protons CJ, 4.8-5.1 (3 H, m, -CH2OCO and C6 protons) 5.6-5.8 (2 H, m, C7 and a protons), 7.3-7.7 (9 H, m, aromatic protons). UV: Xmax 266 nm (e = 7920), (95% ethanol). Chromatography - paper: zone with Rp value = 0.58. Example XXXVII. Preparation of D-α-[3-(2-methylbenzoyl)-3-methylureld]-benzylcephalosporin, sodium salt. The compound was prepared from benzoic acid N-chlorocarbonyl-N-methyl-2-methylamide and D-α-aminobenzylcephalosporin dihydrate in the manner described in Example XXIV above, in a yield of 51%. NMR: [(CD3)2SO + D2O], 6 = 2.01 (3H, s, -OCOCH3), 2.28 (3 H, s, benzoyl-CH3), 2.96 (3 H, s, N-CH3), 3.2-3.4 (2 H, m, C2 methylene protons), 4.9-5.1 (3 H, m, -CH2OCO- and C6 proton), ,6-5.8 (2 H, m, C7 protons and a) 7.3-7.5 (9 H, m, aromatic protons). UV: Xmax260 nm (e - 8 310), (95% ethanol). Paper chromatography: zone with Rp value - 0.50. Example XXXVIII. Preparation of 7{D-a-(3-cinnamoyl-3-methylurea|do)phenylacetamido]-3-(2-methyl- Sodium 1,3,4-thiadiazolyl-5-thio)-methylcephem-3-carboxylate.89 964 11 A solution of 1.77 g (0.003 mol) of 7-(D-aminophenyl-1,3,4-thiadiazolyl-5-thio)-methylcephem-3-carboxylate, t.f.a. (trifluoroacetic acid) salt and 1.35 ml of triethylamine in 30 ml of dichloromethane was cooled in an ice bath and treated with a solution of 0.78 g (0.0035 mol) of cinnamic acid N-chlorocarbonyl-1-methylamide in 10 ml of dichloromethane. The solution was stirred for 3 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of water (washed twice with 50 ml of ethyl acetate). The aqueous solution was covered with 50 ml of ethyl acetate, acidified with 1 N hydrochloric acid to pH 1.5, filtered, the ethyl acetate layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined extracts were washed twice with 50 ml of water and 25 ml of a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and treated with 1.0 ml of a 2 N solution of sodium 2-ethylhexanoate in methylisobutyl ketone. Then 200 ml of anhydrous ether was added, and the precipitated sodium salt was collected and dried in vacuo. The yield was 0.96 g, 46.6%. NMR : [(CD3)2SO + D2O], δ = 8.0-7.0 (12 H, m, aromatic and olefinic protons), 5.8-5.5 (2 H, m, C7 and <* protons), 4.93 [1 H d,)] = 5 Hz), C6 proton, 4.7-4.1) 2H, m, -CH2S-), 3.8-2.9 (2 H, m, C2 methylene protons), 3.25 (3 H, $, ^ NCH3), 2.67) 3 H, s, thiadiazole-CH3). UV : Xmax 282 nm (e = 30630), (95% ethanol). Paper chromatography; single zone with Rp value = 0.65. Example XXXIX. Preparation of sodium 7-D-(3-cinnamoyl-3-methylureido)phenylacetamido-3-(1-methyl-1H-tetrazoyl-5-thio)methylcepheme-3-carboxylate. The compound was prepared from the t.f.a. salt of 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazoyl-5-thio)methylcepheme-3-carboxylic acid-4- and N-chlorocarbonyl-N-methylcinnamide in the manner described in Example XXXVI 11, in a yield of 50.7%. NMR : r(CD3)2SO + D2O], δ = 7.9-7.1 (12 Hm, aromatic and olefinic protons), 5.8-5.5 (2 H, m, C7 protons and a(5.1-4.8 (1 Hm m, C6 proton) 4.7-4.0 (2H, m, -CH2S-) 3.93 (3H, s, tetrazole -CH3), 3.8- 3.1 (2H, m, C2 methylene protons), 3.33 (3 H, s, NCH3). UV : Xmax282 nm) (e = 24490), (95% ethanol). Paper chromatography: single zone with Rp value = 0.51. __ _ _ „ Example xL. Preparation 7-[D-cr(3-cinnamoyl-3HTiethylureido)phen7lacetamido]-3-(1H-1,2,4-tri* azolyl-3-thio)methylcephamo-3-carboxylate-4 sodium. The compound was obtained from the t.f.a. salt. 7-(D-a-aminophenylacetamido)-3-(1H-1,2,4-triazolyl-3-thio)-methyl-cephem-3-carboxylic acid-4 and N-chlorocarbonyl-N-methyl cinnamic acid as described in Example XXXVII I, with a yield of 55.7%. NMR: (CD3)2SO + D20, = 8.0-7.0 (13 H, aromatic, olefin and triazole protons), 5.7-5A (2 H, m, C7 protons and a), 5.0-4.3 (3 H, m, C6 proton and -CH2S), 3.8-3.0 (2 H, m, C2 methylene protons), 3.33 (3 H, s, ^N-CH3). UV: Xmax287 nm (e = 21980), (95% ethanol). Paper chromatography: zone with Rp = 0.58. Example XLI. Preparation of sodium 7-[Dtx*(2,4 tladiazolyl-5-thio)methylcephem-4-carboxylate. The compound was obtained from the t.f.a. salt. 7-(D-a-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazolyl-5-thio) acid -methylcephem-3-carboxylic acid4 and 2,4-dimethylallophanoyl chloride as described above in Example XXXVIII, with a yield of 58.7%. NMR : [(CD3)2SO = D20], 5 = 7.7-7.1 (5 H, m, aromatic protons 5.7-5.5 (2 H,m, C7 and a protons),5.0-4.8(1 H,m, C6 proton), 4.7-4.1 ( 2H,m,-CH2S-3.1-(3 H,s, N-CH3),2.70 (6 H,s,-NHCH3 and thiadiazo|-CH3). UV: Xmax274 nm (e = 13,010), 95% ethanol). Paper chromatography: single zone with Rp = 0.41. Example 7-(D-a-aminophenylacetamido)-3-(1-methyl-1H-tetrazolyl-5-thio)-methylcephem-3-carboxylic acid 2,4-dimethylallophanoyl chloride as described in Example XXXVIII in 53.0% NMR yield: [(CD3)2SO + D20], 5 = 7.42 (5H, s, aromatic protons), 5.7-55 (2H, m, C7 and a protons), 4.88 [1 H, d, (J = 5 HZ), C6 proton], 4.6-4.0 (2 H, m, -CH2S-),3.93 (3 H, s, tetrazole-CH3),3.8-3.1 (2 H, m, C2 methylene protons), 3.10 (3 H, s N-CH3), 2.70 (3 H, s, -NHCH3), UV : Xmax 268 nm (e = 8 020), (95% ethanol). Paper chromatography : single zone with Rp value = 0.47. Example XLIII. Preparation of 7-[D-a-(3-acetyl-3-methylureldo)-phenylacetamido]-3-(2-methyl-1,3,4- sodium thiadiazolyl-5-thio)methylcephem-3-carboxylate-4.12 89 964 The compound was obtained from the t.f.a salt of 7-(Stk-aminophenylacetamido)-3-(2-methyl-1^34-thiadiazolyl-5-thio)-methylcephem-3-carboxylic acid and N-chlorocarbonyl-N-methylacetamide as described above in Example XXXVIII, with a yield of 76.9%. NMR: [(CD3)2SO + D20], 8 = 7.47 ( 5H, s, aromatic protons) 5.8-5.4 (2 H, m, C7 and a protons), 4.93 [1 H, d, (J - 5 HZ), C6 proton], 4.7-4.0 (2 H, m, -CH2S-), 3.8-3.0 (2 H, m, methylene protons C2), 3.21 (5 H, s, ^N-CH3), 2.72 (3 H, s, tladiazole-CH3), $33 (3 H, s, -COCH3. UV :Xniax 275 nm), (c - 12 410), (95% ethanol). Paper chromatography: single zone with Rp = 0.31. Example XLIV. Preparation of 7-[D-a-(3-acetyl-3-methylureido)phenylacetamido]-3-(1«methyl-m-tetrazoyl-5-tJo-methylcephem-3-carboxylate-4 sodium. The compound was obtained from the t.f.a. acid salt 7-(D-α-aminophenyl acetamido)-3-(1-methyl-IH4-etrazolyl-B110)-methylcemethyl-3-carboxyl-4 and N-chlorocarbonyl-N-methylacetamide as described above in Example XXXVIII, with a yield of 24.8%. NMR : [(CD3)2SO + D20], 8 = 7.40) 5 H, singlet, aromatic protons), 5.7-5.4 (2 H, m, C7 and a protons), 4.89 [1 H, d, (J = 5 Hz), C6 proton], 4.6-4.0 (2 H, m, -CH2S-), 3.94 (3 H, s, tetrazol-CH3), 3.8-3.1 (2 H, m, methylene protons C2), 3.18 (3H, s, ^N-CH3), 2.30 (3H, s, -COCH3). UV Xmax265 nm) (e = 8,040). Paper chromatography: single zone with Rp = 0.33. Example acid 7-(D-a-amnophenylacetamido)-3-(2-methyl-1#3,4-thiadiazolyl-5-thio)- methylcephem-3-(3-carboxylic-4 and N-chlorocarbonyl-N-methyl4-phenylamide butyric acid as described above in Example XXXVIII, with a yield of 46.8%. NMR: (CD3)2SO+D20, $ = 1.8-2.2 (2 H, m, PhCH2CH2-), 2.5-2.9) 7 H, m, tladiazole CH3, -COCH2CH2CH2Ph), 3.17 (3 H, s, N-CH3), 3.3-3.5 (2 H, m, methylene protons C2), 4.2-4.7 (2 H, m, -CH2S-), 4.8-5.0 (1 H, m, proton C6), 4.5-43) 2 H, m, C7 protons and <*), 7.27 (5 H, s, aromatic protons), 7.41 (5 H, s, aromatic protons). UV'Xmax275 nm (e = 12,770), (95% ethanol). Paper chromatography: zone with Rp = 0.62. EXAMPLE XLVI. Preparation of 7-[D-a-[3-(4-phenylbutyryl)'3-methylure|do]phenylacetamido]-3-(1 - methyl-1H-tetrazolyl-5-thio)methylcephemor-3-carboxylate-4-sodium. The compound was obtained from the t.f.a. acid salt 7-(D-a-aminophenylacetamldo)-3-(1HfDethyl-1H-tetrazolyl-5-thio)met- ylcefemo-3-carboxylic acid-4 in the manner described above in Example XXXVIII, with a yield of 17.5%. NMR:[(CD3)2SO + D20]* 8 = 1.7-2.2 (2 H, m, PhCH2CH2CH2-), 2.5-2.7 (4 H, m, PhCH2CH2CH2CO), 3.16 (3 H, s, N-CH3), 3.4-3.6 (2 H, m, methylene protons C2), 3.94 (3 H, x,s, tetrazole-CH3), 4.3-4.5 (2 H, m, -CH2-S), 4.8-5.0, (1 H, m, C6 proton), 5.5-5.8 (2 H, m, C7 and a protons), 7.25 (5 H, s, aromatic protons), 7.37 (5 H, s, aromatic protons). UV : Xmax 270 nm (e = 8,410), (95% ethanol). Paper chromatography : zone with Rp value = 0.47. Example XLVII. Preparation of sodium 7-[D«α-[3-(2-methylcrotonoyl)-3-methylureido]phenylacetamido]-3-(1-methyl-1H-tetrazolyl-5-thio)methylcephem-3"-4-carboxylate. The compound was obtained from the t.f.a. salt 7-(D-a-aminophenylacetamido)3-(1imethyl-1H-tetrazolyl-5-thio-methylcephem-3-carboxylic acid4-j and N-chlorocarbonyl-N-methyl-2-methylamide crotonic acid as described above in Example XXXVIII, with a yield of 17.1% NMR:[ (CD3/2SO = D20],5 = 1.6-1.9 (6 H, m, 2Xcrotonoyl<;H3), 3.11 (3 H,s, y N-CH3), 3.4-3.6 (2 H, m, methylene protons C2), 4.96 (3Hf s, tetrazol-CH3), 4.2-4.4 (2 H, m, -CH2S-),4.7-5.1 (1H, m, proton C6), 5.5-6.0 (3H, m, -CH=C, C7 and a protons), 7.40 (5H, s, aromatic protons). UV: Xmax270 nm) (e = 9,260), (95% ethanol). Paper chromatography: zone with Rp = 0/43. Example XLVIII. Preparation of 7-[D-a-[3-(2-methylcrotono||o)-3Hphnethylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiaddiazolyl-5-thio)methyl cefemo-3-carboxylate4- The compound was obtained from the salt t.f.a. 7-(D-a-aminophenylacetamido)-3-(2-methyl-1^,4-tladiazolyl-5-thio)c)triethylcephem-3-carboxylic acid and N-chlorocarbonyl N-methyl*2-f-methylamide crotonic acid as described above in Example XXXVI 11, with a yield of 35.6% NMR :[(CD3)2SO + D20], 6 = 1.6-1.9 (6 H, m, 2 m, -CH2S-, 4.9-51 (1 H, m, C6 proton), 5.5-6.0 (3 H, m, -CH=C <. C7 and a protons), 7/*1 (5 H, s, aromatic protons). UV : Xmax275 nm) (e - 13470), (95% ethanol). Paper chromatography: zone with Rp value = 0.52. Example XLIX. Preparation of sodium 7-[D-α-[3-(3-phenylpropionyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazolyl-5-tholmethylcepham-3-carboxylate-4-(89 964 13) The compound was prepared from the t.f.a. salt of 7-(D-α-aminophenylacetamido)-3-(2-methyl-1/3/4-thiadiazolyl-5-thol)methylcepham-3-carboxylic acid-4-N-chlorocarbonyl-N-methyl-3-phenylamide in the manner described above in Example XXXVIII, in a yield of 34.9%. NMR : [(CD3)2SO + D2O], δ = 2.68 (3 H, s, thiadiazole-CH3-, 2.94 ( 4H, s, -CH2CH2Ph) 3.19 (3 H, s, ^N-CH3), 3.3-3.5/2 H, m, C2 methylene protons, 4.2-4.5 (2 H, m, -CH2S- 4.8-5.0 (1 H, 'm, C6 proton) 5.4-5.7 (2 H, m, C7 protons and a) 7.28 (5 H, s, aromatic protons) 7.37 (5 H, s, aromatic protons). UV: Xmax 275 nm (e = 13500), (95% ethanol). Paper chromatography: zone with RF value = 0.61. Example L. Preparation of sodium 7-D-α-3-(3-phenylpropionyl)-3-methylureidophenylacetamido-3-(1-methyl-1H-tetrazolyl-5-thio)methylcepheme-3-carboxylate-4. The compound was obtained from the t.f.a. salt of (7-D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazolyl-5-thio)methylcepheme-3-carboxylic acid-4 and propionic acid N-chlorocarbonyl-N-methyl-3-phenylamide in the manner described above in Example XXXVIII, in 26.8% yield. NMR : [(CD3)2SO + D2O], δ = 2.94 (4 H, s, -CH2CH2Ph), 3.19 (3 H, s, , N-CH3),3.0-3.8 (2 H, m, C2 methylene protons), 3.95 (3 H, s, tetrazole-CH3), 4.2-4.5 (2 H, -CH2S- 4.8-5.0 (1 H, m, C6 proton ,5-5.8 (2 H, m, C7 protons and a 7.2-7.5 (10 H, d, aromatic protons). UV : Xmax 260 nm (e = 9120), (95% ethanol). Paper chromatography : zone with Rp value = 0.54. Example LI. Preparation of 7-[Dxx-[3-(3-methylcrotonoyl)-3-methylureldo]phenylacetamido]-3-(2-methyl-1 ,3,4-thiadiazolyl-5-thio)methylcephem-3-carboxylate-4-sodium. The compound was obtained from the t.f.a. salt. 7-(D-a-arninophenylacetamido)-3-(2-methyl-1/3<4-thiadiazolyl-5-t-thio)methylcephem-3-carboxylic acid-4 and N-chlorocarbonyl-N-methyl-3-methylamide crotonic acid as described above in Example XXXVIII, with a yield of 24.6%. NMR: [(CD3)2SO + D20], 5 = 1.9-2.1 (6 H, m, -CH=C (CH3]2, 2.70 thiadiazole-CH3), 3.18 (3 H,s, N-CH3), 3.3-3.6 (2 H, m, C2 methylene protons) 4.3-4.5 (2 H, m, -CH2S-) 4.8-5.0 (1 H, m, C6 proton), 5.5-5.7 (2 H, m, C7 and a protons), 6.1-6.3 (1 H, m -CH=C<;) 7/11 (5 H, s, aromatic protons). UV: Xmax270 nm) 6 = 11870), (95% ethanol). Paper chromatography: zone value Rp = 0.56. Example LII. Preparation of 7-[D-a [3-(3-methylcrotonoyl)-3-methylureldo]phenylacetamido]-3-(1-methyl-1H'tetrazolyl-5-thiomethylcephem-3-carboxylate-4 sodium. The compound was obtained from the t.fa. salt. 7 (D-a-aminophenylacetamido)-3-(1-methyl-1H-tetrazolyl-5-thio)methylcephemo-3-carboxylic acid-4 and N-chlorocarbonyl-N-methyl-3-methyl-crotonic acid amide as described above in Example XXXVIII, with a yield of 56.7%. NMR:[(CD3)SO + D20], =1.9-2.1 (6 H, m, =CH=C (CH3)2), 3.18 (3 H, s, N-CH3) 3.4-3.6(2 H, m methylene protons C2), 3.96 (3 H, s, tetrazol-CH3 4.3-4.5 (2 H, m, -CH2S- 4.9-5/) (1 H, m, C6 proton) 5.5-5.8 (2 H, m, C7 and a protons), 6.1-6.3 (1 H, m, -CH=C^ ), 7.40 (5 H, s, aromatic protons UV: Xmax274 nm (e = 10,130), (95% ethanol), Paper chromatography: RF zone = 0.40 Example LIII Preparation of sodium 7{D-a(3-furoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3-4-t1a)methylcephem-4-carboxylate 7-(D-α-aminophenylacetamido)-3-(2-methyl-1/3/1-thiadiazolyl-5-thi4-,-methylcephamine-3-carboxylic acid) and N-chlorocarbonyl-N-methylfuramide by the method described in Example XXXVIII above, in a yield of 32.6%. NMR: [(CD3)2SO + D2Oj, δ = 2.69 (3 H, s, thiadiazole-CH3), 3.35 (5 H, singlet overlapping the multiplet, δ:N-CH3 and C2 methylene protons), 4.2-4.5 (2 H, m, -CH2S-) 4.9-5.1 (1 H, m, C6 proton), 5.5-5.8 (2 H, m, C7 protons and a) 6.6-8.0 (8 H, m, aromatic andfuryl protons). UV: Xmax 272 nm (e = 25690), (95% ethanol). Paper chromatography: zone with Rp = 0.50. Example LIV. Preparation of 7-[D^-(3-crotonoyl-3Hnetylureido)phenylacetamido]-3-(2-methyl-1^,4-thiadiazolyl-5-thio-methylcephem-3-carboxylate-4 sodium. The compound was obtained from the t.f.a. acid salt 7-(D-a-amlnophenylacetamido)-3-(2-methyl-1^(4-thiadiazolyl-5-thio)-methylcephem-3-carboxylic acid4 and crotonic acid N-chlorocarbonyl-N-methylamide in the manner as described above in Example XXXVIII, with a yield of 38.8%. NMR : [(CD3)2SO + D2O], δ 1.8-2.1 (3 H, m, crotonyl-CH3), 2.70 (3 H, s, diazole-CH3) 3.25 (3 H, s, N-CH3), 3.5-3.7 (2 H, m, C2 methylene protons), 4.3-4.5 (2 H, m, -CH2S-), 4.9-5.1 (1 H, m, C* proton), 5.5-5.8 (2 H, m, C7 and a protons), 6.6-7.1 (2 H, m, olefinic protons), 740 (5 H, s, aromatic protons). UV : Xmax273 nm) = 14510), (95% ethanol). Paper chromatography: RF value zone - 0.65.14 89 964 Example LV. Preparation of 7-{D-a-(3-crotonoyl-3-methylureldo)phenylacetamido]-3-(1-methyl-1H-te\trazolyl-5-thio)methylcephem-3-carboxylate-4 sodium. The compound was obtained from the t.f.a. salt. 7-(D-amlnophenylacetamido)-3*(1-methyl-1H-tetrazolyl-5-thio)methylephemo-3-carboxylic acid4 and crotonic acid N-chlorocarbonyl-N-methylamide as described in Example XXXVIII, with a yield of 30.6%. NMR: [(CD3)2SO + D20], 6 = 1.9—2.1 (3 H, m, crotonyl-CH3), 3.23 (3 H, s, N-CH3), 3/*-3.7 (2 H, m, C2 methylene protons), 3.94 (3 H, s, tetrazole-CH3 (4.2-4.4 (2 H, m, -CH2S), 4.9-5.1 (1 H, m, C6 proton (5.5-5.8 (2 H, m C7 protons and a 6.6-7.1 (2 H, m, olefinic protons), 7.39 (5 H, s, aromatic protons). UV : Xmax270nm) (e = 10 010), (95% ethanol). Paper chromatography: zone with Rp value = -0.45. P'z y k M d LVI. Preparation 7-D-a-3-(2-chlorobenzo)-3-methylourdo-phenylacetamydo-3-(2-methyl-1,3,4-thiadiazolyl-5-thio-methylcephem-3-carboxylate-4 sodium. The compound was obtained from the t.i. acid salt 7-(D'a-aminoaminophenylacetamido)-3-(2-methyl-1/3,4-thyadiazol-yl-5-thio)methylcecephem-3-carboxylic acid4 and N-chlorocarbonyl-N-methyl-2-chloroamide benzoic acid as described above in Example XXXVI 11, with a yield of 31 JB%, NMR:[(CD3)2SO + D20],8 = 2.68 (3H, s, thiadiazole-CH3), 2.98 (3H,s, - N-CH3-, 3.3-3.6 (2 H, m methylene protons C2 (4.3-4.6 (2 H, m, -CH2S- (4.8-5.0 (1 H, m, proton C6;(5.5-5.8 (2 H, m, protons C7 and a) 7.3-7.7 (9 H, d, aromatic protons). UV: Xmax276 nm = 11910, (95% ethanol). Paper chromatography: zone with Rp value = 0^4. Example LVII. Preparation of 7{D^J3-(2'ethylbenzoyl)-3'methylurea|do]-phenylalkylKJetam|do]-3-(2-. sodium methyl-1,3,4-thiadiazolyl-5-thio)methylcephem-3-carboxylate4. The compound was obtained from the t.f.a. salt. 7-(d-a-aminophenylacetamido)-3-(2-methyl-1^,4-thiadiazolylO'5-ti4-i;methylcephem-3-carboxylic acid4 and N-chlorocarbonylb-N-methyl and 2-methylamide benzoic acid as described above in Example XXXVI 11, with a yield of 32.7%. NMR : [(CD3)2SO + D20], 5 - 2.27 (3 H, s, benzoyl-CH3), 2.68 (3 H, s, thiadiazole-CH3 2.97 (3 H, s, N-CH3 (3.3-3.6 (2 H, m, methylene protons C2) 4.4-4.6 (2 H, m, -CH2-5, 5.3-5.5 (1 H, m, proton CJ 5.6-5.8 (2 H, m, protons C7 and ot), 7.3-7.6 (9 H, m, aromatic protons UV:Xmax274 nm) = 12,190). ( 95% ethanol).Paper chromatography: zone with Rp = 0.62. Example LVIII. to]-3-(2-methyl-1,3,4-tladiazo|yl-5-thio)-methylcephem-3-carboxylate-4 sodium. The compound was obtained from the ti.a salt of 7-(Dtx-aminophenylacetamido)-3-(2-methyl-1^(1-thiadiazolyl-5-thio)methylcephem-3-carboxylic acid4 and 3-acetyl-1-chlorocarbonylimidazolidinone-2 as described above in Example XXXVIII, with a yield of 74.3%. NMR : [(CD3)2SO + D20], 5 = 7.43 (5 H, s, aromatic protons), 5.7-5/4 (2 H, m, C7 and a protons) 5.1-4.8 (1 H, m, C6 proton 4.7-4.1 (2 H, m, -CH2S-), 3.70 (4 H, s, methylene protons Imidazolidinone), 3.8-3.0 (2 H, m, methylene protons C2), 2.70 (3 H, s, thiadiazole-CH3), 2.45 (3 H, s, # ICOCH3). UV: ^¦max 274.5 nm (e — 10 270), (95% ethanol). Paper chromatography: single zone with Rp value = 0.43. Example LIX. Preparation of 7-[D-a-)3-acetylimidazolidinone-2-llo-Hcarbonylamino)phenylacetate to sodium-3-(1-methyl-1H-totrazolyl-5-thio)methylcephem-3-carboxylate4. The compound was obtained from the t.fa. salt. 7-(D-a-aminophenylacetamido)-3-(1-methyl-1H-tetrazolyl-5-thio)-methylcephem-3-carboxylic acid4 and 3^acetyl-1-chlorocarbonyl imidozolidinone-2, as described in Example XXXVIII, with a yield of 43.5%. NMR : [(CD3)2SO + D2O], 6 = 7.47 (5 H, s, aromatic protons), 5.8-5.4 (2 H, m, C7 and a protons), 5.0-4.8 (1 H, m, C6 proton), 4.7-4.0 (2 H, m, -CH2S-), 3.96 (3 H, s, tetrazole-CH3, 3.70 (4 H, s, methylene protons of Imidazolidinone), 3.8-3.1 (2 H, m, methylene protons (^J, 2/15 (3 H, s, ^NCOCH3). UV: Xmax 265 nm (e = 8 400), (95 % ethanol). Paper chromatography: single zone with Rp value - 0.38. Example LX. Preparation of salts D-α-(imidazolidinone-2-yl-1-carbonylamino)benzylcephalosporin sodium. A solution of the anhydrous triethylammonium salt of D-α-aminobenzylcephalosporin, prepared from 2.2 g (0.005 mol) of the dihydrate as described in Example III above, in 30 ml of dichloromethane was cooled in an ice bath, and a solution of 0.75 g (0.005 mol) of 1-chlorocarbonylimidazolidinone-2 and 10 ml of dichloromethane was added. The solution was stirred for 3 hours at room temperature, evaporated to dryness under reduced pressure, and the residue was dissolved in 100 ml of water. The aqueous solution was washed twice with 50 ml of ethyl acetate. ethyl acetate, covered with 50 ml of ethyl acetate and acidified with 1 N hydrochloric acid to pH 1.5. The precipitated cephalosporin as the aqueous acid was collected on a filter, washed with 100 ml of water and dried in vacuo. The free acid was suspended in 25 ml of water, the pH was adjusted to 6.5 with 1 N sodium hydroxide solution, the solution was filtered and lyophilized to give the sodium salt. The yield was 1.77 g at 68.4%. NMR: [(CD3)2SO+D2O], δ = 7.43 (5 H, s, aromatic protons (5.8-5.4 (2 H, m, C7 and tx protons), 5.2-4.6 (3 H, m, C6 proton and -CH2OCO-), 4.0-3.0 (6 H, m, C^ and methylene protons of Imidazolidinone) 2.00 (3 H* s, -OCOCH3). UV:Xmax264nm (e = 6,950), (95% ethanol). Paper chromatography: single zone with Rp = 0.27. Example LXI. Preparation of 7-(D-a-(imidazolidinone-2-yl-1carbónylamino)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazolyl-5-thio)methylcephem-3-carboxylate-4-sodium. The compound was obtained from 7-(D-t*-aminopheny|oacetamido)-3- acid (2-methyl-1,3,4-thiadiazolyl- 5-thio)methylcephem-3-carboxylic acid-4 and 1-chlorocarbonyl imidazolidinone-2 as described above in Example LX, with a yield of 63.5%. NMR : [(CD3)2SO + D20], 8 = 7.43 (5 H, s, aromatic protons), 5.8-5.4 (2 H, m, C7 and a protons), 4.88 [1 H, d, (J = 5 Hz), C6 proton], 4.8-4.1 (2 H, m, -CH2S-), 4.0-3.0 (6 H, m, C2 and methylene protons of imidazolidinone), 2.69 (3 H, s, thiadiazole-CH3). UV: Amax275 nm) (e = 12,210, (95% ethanol). Paper chromatography: single zone Rp = 0.38. Example 62. Preparation of sodium 7-[Dt]imidazolidinone-2-11-yl-1-carbonylamino]-3-(1-methyltetrazolyl-5-thiomethylcephem-3-carboxylate]. 1.72 g, 0.003 mol, of 7-(S-α-aminophenylacetamido)-3-(1-methyltetrazolyl-5-thio)methylcephem-3-carboxylic acid was acylated with 1-chlorocarbonylimidazolidinone-2-one as described in Example 63 above to give the free acid as a gummy solid. This was dissolved in 30 ml of acetone, dried over anhydrous sodium sulfate, and dried. magnesium and treated with a 2N solution of sodium 2-ethylcaroate in methyl isobutyl ketone. The precipitated sodium salt was collected in a filter, washed with anhydrous ether and dried under reduced pressure. The yield was 1.16 g, 65%. NMR: [(CD3)2SO + D20], d = 7.43 (5 H, s, aromatic protons), 53-5.4 (2 H, m, C7/,and oc protons), 4.88 [1H,d,) J=5Hz), C6 proton], .7-4.0 (2 H, m, -CH2S-), 3.95 (3 H, s, tetrazol-CH3), 4.0-3.0 (6 H, m, methylene C2 and imidazolidinone protons). UV : Xmax 271 nm (e = 8600), (95% ethanol). Paper chromatography: single zone with Rp value -0.24. Example LXIII. Preparation of D,L-α-(3-cinnamoyl-3-methylureido)-thienyl-2-methylcephalosporin sodium salt. A solution of 1.72 g, 0.005 mol, D,L-α-(3-cinnamoyl-3-methylureido)-thienyl-2-acetic acid, 1 drop of N-methylmorpholine and 0.71 ml, 0.005 mol, triethylamine in 15 ml of anhydrous acetone was cooled to -10°C and treated with 0.48 ml, 0.005 mol, ethyl chloroformate. The solution was stirred for 20 minutes at at -5°C-10°C, then a solution, cooled to 0°C, of 1.36 g, 0.305 mole, of 7-aminocephalosporanic acid and 0.71 ml of triethylamine in 30 ml of aqueous acetone was added. The mixture was stirred for 2 hours at room temperature, then the acetone was removed under reduced pressure, 50 ml of ethyl acetate was added and washed twice with 50 ml of ethyl acetate. The aqueous solution was acidified with 1 N hydrochloric acid to pH 1.5 in the presence of 50 ml of ethyl acetate and extracted with 50 ml of ethyl acetate, which had also been added. The extracts were washed twice with 100 ml of water and with 50 ml of aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, quenched with 1.8 ml of a 2N solution of sodium 2-ethylhexanoate in methyl isobutyl ketone and diluted with 200 ml of anhydrous ether. The precipitated sodium salt was collected on a filter, washed with ether and dried. Yield: 1.12 g, 36.1%. NMR: [(CD3)2SO + D2O], 6 = 8.0-6.7) 10 H, m, aromatic, olefinic and thienyl protons) 6.0-53 (1 H, m, a-proton), 5.7-5.3 (1 H, m, C7 proton), 5.2-4.5 (3 H, m, C6 proton and -CH2OCO-), 3.8-3.0 (2 H, m, C2 methylene protons), 3.33 (3 H, s, ^N-CH3), 2.01 (3 H, m, -OCOCH3). UV : Xmax286 nm) e(e = 21 650), (95% ethanol). Paper chromatography: single zone with Rp value - 0.53. Example LXIV. Preparation of sodium 7-(D,L-a-(3-cinnamoyl-3~methylureido)thienyl-2-acetamido]-3-(2-methyl-1H-tetrazolyl-5-thio)methylcephem-3-carboxylate-4. The compound was obtained from 7-amino-3-(1-methyl-1) H-tetrazolyl-5-tio)-methylcephem-3-carboxylic acid 4 I DL-«-(3-cinnamoyl-3-methylure[do)thienyl-2-acetic acid as described above in Example LXIX, in 34% yield NMR:[(CD3)2SO + D2O], 5 = 8.0-6.8 (10, H, m aromatic, olefinic and thienyl protons), 6.0-5.7 (1 H, m, proton a), 5.7-5.3 (1 H, m, proton C7), 5.1-4.8 (1 H, m, proton C6), 4.6-4.0 (2 H, m, -CH2S-), 2.93 (3 H, s, tetrazole-CH3, 3.8-3.1 (2 H, m, methylene protons C2), 3.34 (3 H, s, .,£ N-CH3).16 89064 UV: \mtx285 (e - 25 190 (95% ethanol). Paper chromatography: single zone with Rp value « 0.52. Example LXL. Preparation of sodium salt D-a-(3*c/mimollo-3-motylourekio)-b©nzylcaphaloporin. Solution 1.09 g 0.005 mol, D-a-(3-cinnamoic acid-3-methylureido)phenylacetic acid 10.77 g, 0.005 mol, hydroxybenzotriazole dihydrate in 10 ml t.h.f. (tetrahydrofuran) was cooled in an ice bath and then 130.006 mole of dicyclohexylcarbodivulmide were added. The mixture was left for 16 hours at 5°C, then 4 drops of acetic acid were added, stirred at room temperature for 15 minutes, then the dicyclohexylurea was filtered off and washed with ml of tetrahydrofuran. The filtrate was added to a solution of 1.36 g, 0.005 mol, 7-(minocepha)sporanic acid in 30 ml of 50% aqueous t.f.h., the pH of which had been adjusted to 6.5 with N-methylmorpholine. The solution was stirred for 3 hours, maintaining the pH between 6.5 and 7.0, then the t.f. was removed under reduced pressure and the residue diluted with 50 ml of water. The sodium salt was isolated from this solution as described in Example 11. Yield: 1.21 g, 19.4%. NMR: [(CD3iSO+P2O), 6-8.0-7.0 ( 12 H, m, aromatic and olefinic protons (5.8-5.5 (2 H, m, C7 and a protons), 5.2-4.6 (3 H, m, C« proton and -CHaOCCM, 3.8-2.9 (2 H, m, C* methylene protons). 3.33 (3 H, s, N-CH3), 2.02 (3 H, s, -OCOCH3). UV : Xmax286 nm (95% ethanol). Paper chromatography : single zone with Rp value = 0.54.PL PL PL PL PL

Claims (1)

1.