JPS5852996B2 - Beta-lactams and antibacterial agents - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel β-lactams.

Certain α-(imidazolidin-2-oxol-yl-
It has already been disclosed that carbonylamino)-benzylpenicillin exhibits antibacterial activity (see Belgian Patents No. 767.647 and No. 767.648;
Dutch Patent No. 7,114,254 and Japanese Patent Publication No. 2,152,968).

The novel β-lactam resistance agent according to the present invention is chemically different from previously known compounds in that, in particular, N3 of the imidazolidinone group is bonded to the N atom of the imino group.

The present invention relates to formula (I) where R1 represents hydrogen, and R2 is optionally halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyano, alkylsulfonyl having 1 to 4 carbon atoms, or A phenyl group or β-phenylethynyl group optionally substituted with methoxycarbonyl; or optionally substituted with halogen, alkyl having 1 to 4 carbon atoms, nitro, or alkoxy having alkoxycarbonyl having 1 to 4 carbon atoms or acetoxymethyl; May be 5
or 6-membered heterocyclic group, B represents an optionally substituted phenyl, cyclohexenyl or cyclohexagenyl group, X represents S, SO or SO2, and represents, with the proviso that carboxyl The carbon atom bearing the group is bonded to the nitrogen atom of the β-lactam ring, and T is hydrogen, alkyl-CO-O
-, pyridinium, aminopyridinium, carbamoyloxy, azide, cyanide, hydroxyl, optionally substituted -S-phenyl group or -S-Het group,
Note that Het represents a 5- or 6-membered heterocycle which may be substituted] to provide a β-lactam antibiotic.

However, the compound of formula I may exist in any of the two possible R- and S-configurations with respect to its asymmetric center C and in the form of mixtures of diastereomers resulting therefrom; The compounds may exist in the syn or anti form with respect to >C=N-, and the compounds of formula I may exist in the form of various hydrates and salts.

The compounds of the invention, ie the compounds of formula I and their salts, exhibit strong antibacterial activity and have properties that improve growth and nutrient absorption in animals.

Therefore, among the salts of the compounds of the invention, those that are pharmacologically acceptable are important and preferred.

The compound of the present invention is prepared by adding a compound of the formula (2) or a salt thereof in the presence of a solvent and optionally an acid binder, R1 and R2 are as defined above and W represents a halogen, azide or other removable nucleophilic group] at about -20 to about +50°C and the resulting β-lactam antibiotic The free acid can be obtained by converting it into its salt as needed, or by producing the free acid from the salt obtained if desired.

Surprisingly, the compounds of the invention exhibit a substantially stronger and particularly broad-spectrum antibacterial action, ie, a greater action against bacteria of the Durum-negative species than, for example, the hitherto known β-lactam antibiotics.

The compounds according to the invention thus represent an advance as a pharmaceutical.

For example, when D-α-aminobenzylpenicillin and 1-chlorocarbonyl-3-benzylideneimino-imidazolidin-2-one are used as starting materials, the reaction process is represented by the following equation: In the above general formula, R1 is Represents hydrogen.

R2 is an optionally substituted phenyl group, β-phenylethynyl group, or a 5- or 6-membered heterocyclic group.

Optionally substituted heterocycles are heteroparaffinic, heteroaromatic or heteroolefinic 5- to 7-membered, preferably having 1 to 3, especially 1 or 2, identical or different heteroatoms. It is a 5- or 6-membered ring.

Heteroatoms are oxygen, sulfur or nitrogen.

optionally substituted chenyl, furyl, oxasilyl, inxazolyl, thiazolyl, isothiazolyl, pyrrolyl,
Imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morphorinyl, pyronyl-2 and pyronyl-4 may be mentioned by way of example. .

Phenyl and β-phenylethynyl groups R2 can have one or more, preferably 1 to 3, especially 1 or 2, identical or different groups R3.

It is very particularly preferred that the radical R2 is unsubstituted or carries one substituent.

Hetero FjA R2 is one or more, preferably one
It can have up to 3, especially 1 or 2, identical or different radicals R4.

It is very particularly preferred that the heterocycle R2 is unsubstituted or carries one substituent R4.

R3 is halogen, preferably fluorine, chlorine, bromine and iodine;
Especially fluorine, chlorine and bromine: straight-chain or branched alkyl having 1 to 4 carbon atoms, especially methyl, ethyl, propyl, isopropyl, n-butyl, 5ee-butyl or tert-butyl, preferably methyl; Alkoxy, preferably methoxy or ethoxy, methoxy; nitro; cyano; alkylsulfonyl having 1 to 4 carbon atoms, preferably methylsulfonyl or ethylsulfonyl; or methoxycarbonyl.

If R4 is present on one or more carbon atoms of the heterocyclic group R2, R4 is halogen, preferably fluorine, chlorine or bromine; alkyl having 1 to 4 carbon atoms, preferably methyl, ethyl, isopropyl, especially methyl:nitro ; Alkoxycarbonyl having 1 to 4 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl; or acetoxymethyl.

When R4 is present on one or more nitrogen atoms of the heterocyclic group R2, R4 is preferably alkyl of 1 to 4 carbon atoms, preferably methyl, ethyl, propyl or isopropyl, especially methyl or ethyl; or an alkoxy carbon Alkoxycarbonyl having a number of 1 to 4 is preferably methoxycarbonyl, ethoxycarbonyl, impropoxycarbonyl or tert-butoxycarbonyl.

Phenyl B may contain one or more, preferably 1 to 3, especially 1 or 2, identical or different substituents.

This substituent is present in the o-, m- and/or p-positions.

Preferably one substituent is present in the p- or m-position.

Examples of substituents that may be mentioned are halogens, such as fluorine, chlorine and bromine; carbon atoms 1 to 6, preferably 1 to 4;
or 2 alkyl; cyano and methylsulfonyl.

Substituted phenyl groups B which may be mentioned in particular are hydroxyphenyl groups (preferably p-hydroxyphenyl), methylphenyl groups (preferably p-methylphenyl), cyanophenyl groups (m- and p-cyanophenyl groups), methyl They are a sulfonyl group (preferably p-methylsulfonylphenyl) and a fluorophenyl group (preferably 0-fluorophenyl and m-fluorophenyl).

In the definition of T, alkyl in alkyl-CO-O- preferably represents an alkyl having 1 to 4 carbon atoms, especially 1 or 2 carbon atoms.

Examples that may be mentioned are methyl and ethyl, methyl being particularly preferred.

The heterocycle Het of -S -net (definition of T) is
It consists of a 5- or 6-membered ring and contains 1 to 4, preferably 1 to 3, identical or different heteroatoms.

Heteroatoms here are oxygen, sulfur and nitrogen.

Preferably the heterocycle is unsaturated, particularly preferably 2
Contains double bonds.

This heterocycle has one or more, preferably one or two
, especially one substituent.

Examples of substituents that may be mentioned are halogens, such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, amines, lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (of the cycloalkyl moiety). carbon number 3-7, preferably 5 or 6), trifluoromethyl,
Phenyl, benzyl and preferably acylamino having 2 to 5 carbon atoms, especially 2 or 3 carbon atoms.

The following may be mentioned as particularly suitable -5-Het.

The -S-phenyl group in the definition of T may have one or more, preferably 1 to 3, especially (1 or 2) the same or different substituents.

Suitable substituents are those mentioned above as possible substituents for the group -8-Het.

Compounds according to the invention G in which C'' is in the D--R- configuration are very particularly preferred.

All crystalline and hydrated forms of the compounds of general formula (1) and their salts according to the invention likewise exhibit antibiotic activity.

Halogen W is fluorine, chlorine and bromine, preferably bromine or chlorine, especially chlorine.

Nucleophilic removable groups in the definition of W include all nucleophilic groups commonly used in organic chemistry and among others Angew.
, Chem-, 81, 543 (196, 9).

Non-toxic, pharmacologically acceptable salts of compounds of formula I are
Salts of the compounds with inorganic and organic bases at the acid carboxyl group or at the acid carboxyl and sulfonic acid groups.

Bases that can be used for this purpose are all bases commonly used in pharmaceutical chemistry, especially in antibiotic chemistry.

Examples of inorganic bases that may be mentioned are alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, and heavy alkali metal carbonates, such as hydroxides).
aluminum hydroxide and potassium hydroxide, calcium hydroxide and magnesium hydroxide, sodium carbonate and potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; aluminum hydroxide and ammonium hydroxide.

As the organic amine, primary, secondary, and tertiary aliphatic amines and heterocyclic amines can be used.

Examples which may be mentioned are di- and tri-lower alkylamines, such as diethylamine, triethylamine, tri-β-hydroxyethylamine, procain
, dibenzylamine, N, N'~dibenzylethylenecyamine, N-benzyl-β-phenylethylamine, N
-methylmorpholine and N-ethylmorpholine, 1
-Efenamine, dehydroabiethylamine, N, N'
-bis-dehydroabiethylethylenediamine and N-
It is a lower alkylpiperidine.

So-called basic amino acids, such as risine or arginine, can also advantageously be used as bases.

Particularly preferred salts are the sodium salts.

Very particularly preferred compounds of formula (1) are those in which the radicals are defined as follows: R2 is halogen (in particular fluorine, chlorine and bromine), has 1 carbon number
~4 alkyl (especially methyl), C1-4 alkoxy (especially methoxy), nitro, cyano, C1-4
alkylsulfonyl (especially (this methylsulfonyl)) or phenyl optionally substituted with CH300C-;
or 4 or 5 position is optionally a halogen (especially chlorine or bromine),
NO2, alkoxycarbonyl having 1 to 4 alkoxy carbon atoms, or CHs furyl or chenyl optionally substituted with COOCH2- and preferably bonded at the 2 and 3 positions; or pyridyl (preferably pyridyl-3); and B represent phenyl, hydroxyphenyl (preferably p-hydroxyphenyl) or cyclohexagenyl (preferably cyclohex-1,4-dien-1-yl); and T is hydrogen, -0-CO-CH3 , represents thiadiazolylthio or tetrazolylthio optionally substituted with hydroxyl or alkyl having 1 to 4 carbon atoms or CF3; and *C is present in the D--R- form.

Further very particularly preferred compounds include the sodium salts of the compounds as defined above.

The compound of general formula (1) used as a starting material is already known or can be produced according to known methods.

All crystalline forms, hydrate forms and salts of the compounds of general formula H are suitable for use as starting materials for the process according to the invention.

Examples that may be mentioned are α-aminobenzyl-penicillin, α
-amino-p-hydroxybenzylpenicillin, α-amino-p-methylbenzylpenicillin, α-amino-p
-Chlorbenzylpenicillin, 6-[2-amino-2-
(1,4-cyclohexadien-1-yl)-acetamidotupenicillanic acid, 7-(α-amino-phenylacetamido)-3-methyl-cef-3-em-4-carboxylic acid and 7-(α -amino-phenylacetamide)
-3-acetoxy-methyl-cef-3-em-4-carboxylic acid.

As the salt of the compound of formula (1), it is preferable to use a salt with the above-mentioned bases suitable for producing the salt of the compound of formula (I).

Sodium salts are particularly preferred.

The compound of general formula (1) used as a starting material can be produced according to a known method, for example, as follows (Sansai, J,
A-C,S, 78.5349 (1956)): The following are examples of compounds of general formula (1) according to the invention =1-chlorocarbonyl-2-oxo-3-benzaliminoimidazolidine, 1- Azidocarbonyl-2-oxo-3-
Benzalimino-imidapridine, 1-chlorocarbonyl-2-oxo-3-(4-chlor)-benzaliminoimidapridine, 1-chlorocarbonyl-2-oxo-
3-(4-methoxy)-benzalimino-imidapridine, 1-chlorocarbonyl-2-oxo-3-(4-nitro)-benzaliminoimidazolidine, 1-chlorocarbonyl-2-oxo-3-(4- cyan)-benzalimino-imidapridine, ■-chlorocarbonyl-2-
Oxo-3-(4-methylsulfonyl)-benzalimino-imidazolidine, 1-chlorocarbonyl-2-oxo-3-(thiophene-2-aldimino)-imidapridine, 1-azidocarbonyl-2-oxo-3-(thiophene -2-Aldoimino)-imidapridine, 1-
Chlorocarbonyl-2-oxo-3-(furan-2-aldoimino)-imidapridine and 1-azidocarbonyl-2-oxo-3-(furan-2-aldoimino)-imidapridine.

Compounds of general formula (1) in which W is azide can be prepared according to conventional methods, for example from the corresponding compound (2) in which W is halogen, for example by reaction with an alkali metal azide.

Diluents that can be used in the process according to the invention are those which are miscible with water and all inert organic solvents, preferably water.

These include, among others, lower dialkyl ketones, such as acetone and methyl ethyl ketone, and cyclic ethers, such as tetrahydrofuran and dioxane; nitriles, such as acetonitrile; lower dialkyl formamides, such as dimethylformamide; lower alkyl alcohols, such as ethanol and impropatol, and dimethyl sulfoxide. .

These solvents can be used both as mixtures with each other and, optionally, with water and one or more of these solvents.

Thus, the process according to the invention can be carried out in the presence of (a) water alone, (b) one or more organic solvents alone, or (c) water and one or more organic solvents. .

If the pH during the reaction can be determined due to the presence of water, the pH of the reaction mixture is preferably adjusted to 6 by adding a base or by using a buffer mixture.
．． Maintain between 5 and 7.5.

However, the method according to the invention allows, at different pH ranges,
For example, 4.5 to 9.0 or 20 to 4.5 can be carried out very easily.

Furthermore, in a water-immiscible solvent such as a halogenated hydrocarbon such as chloroform or methylene chloride, an organic base, preferably a lower alkylamine such as triethylamine or diethylamine, or a cyclic base such as N
- The reaction can be carried out in the presence of ethylpiperidine.

The reaction is carried out in water and water-immiscible solvents such as lower alkyl ethers such as diethyl ether; halogenated hydrocarbons such as chloroform and methylene chloride; carbon disulfide; isobutyl methyl ketone; esters such as ethyl acetate; and aromatic hydrocarbons, For example, it may be carried out in a mixture of benzene.

In this case, the mixture is stirred vigorously and the pH is brought to 4.5 by adding base or by using customary buffer solutions, such as phosphate, acetate or citrate buffers.
It is advisable to keep it at ~9.0 or e.g. 2.0-4.5.

However, the reaction can also be carried out in water alone in the absence of organic solvents, in the presence of organic or inorganic bases, or with the addition of customary buffers.

As acid binders all acid binders commonly used in antibiotic chemistry can be used.

These include, for example, inorganic bases and organic bases that are difficult to acylate as a result of steric hindrance.

Hydroxide) IJium and potassium hydroxide can be exemplified as inorganic bases.

Organic bases that can be used are virtually all open chain or cyclic amines, unacylated or acylated.

Examples of bases that may be mentioned are tertiary amines, preferably lower alkyl amines, such as triethylamine, and/or cyclic bases, such as pyridine, and acylated secondary amines, such as dicyclohexylamine.

The addition of a base in the process of the invention is only necessary if an acid compound is formed during the reaction, for example W is a halogen or an azide.

The reaction temperature can be varied within a substantial range.

Generally the reaction is carried out at about -20°C to about +50°C, preferably between 0 and 2°C.
Performed at 0°C.

However, as with many chemical reactions, higher or lower temperatures than those mentioned above may also be essential.

The reaction can be carried out under normal pressure, but can also be carried out under reduced pressure or increased pressure.

Normal pressure is generally used. When carrying out the process according to the invention, the proportions of the reactants of formulas (1) and (2) can be varied within a wide range without adversely affecting the results.

For example, the starting materials can be reacted with each other in equimolar amounts.

However, it is advantageous to use an excess of one of the two reactants to facilitate purification or to produce the desired penicillin in pure form and to increase yield.

For example, the reactant of general formula (1) is used in an excess of 0.1 to 0.3 molar equivalents, thereby reducing the decomposition of the reactant of general formula (1) in the aqueous solvent mixture.

Excess reactant of general formula (1) can be easily removed during work-up of the reaction mixture since it is easily dissolved in the aqueous mineral acid.

However, for example, 0.1 to 1
．． It may also be advantageous to use an excess of 0 molar equivalents.

As a result, the compound of the general formula (1) can be favorably used, and the decomposition of the reactant of the general formula (1) that occurs as a side reaction in an aqueous medium is offset.

Since the compound of general formula (2) added in excess is easily added to the neutral nitrogen-containing heterocyclic compound which can be easily removed in water, the purity of the antibiotic is hardly affected.

The amount of base that can be used is determined, for example, with regard to maintaining the desired pH value.

Measuring and adjusting pH is not possible or possible or meaningless unless water is present in sufficient quantities in the diluent;
Two molar equivalents of base are preferably added.

The treatment of the reaction batches for preparing the compounds according to the invention and their salts is carried out essentially according to methods generally known for producing these compounds.

The separation and purification of the compounds according to the invention and the liberation of the free acids from the salts or the conversion of the free acids into salts can also be carried out according to general organic chemistry methods known to those skilled in the art.

Compounds of the general formula (2) in the free acid form have the same kind of antibiotic activity, whether they are crystalline or amorphous and whether they are anhydrous or in various aqueous forms.

Similarly, the compound of the general formula (■) is in the form of a salt, for example)
In the form of their salts, they have the same kind of antibiotic activity, whether they are crystalline or amorphous and whether they are in anhydrous or hydrous form.

The compounds in the table below are examples of novel compounds: The active compounds of the invention combine low toxicity with potent and broad-spectrum antimicrobial activity.

As a result of these properties, they are used as chemotherapeutically active compounds in drugs and in inorganic and organic materials, especially all kinds of organic materials, such as polymers, lubricants, paints, textiles, leather, paper and wood, foods and Used as a compound to preserve water.

The active compounds according to the invention are active against a wide range of microorganisms.

They can be used to combat Gram-negative and Gram-positive bacteria and bacteria-like microorganisms and to prevent, ameliorate, and/or treat diseases caused by these pathogens.

The active compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms.

They are therefore particularly suitable in human medicine and for the prophylaxis and chemical treatment of local and systemic infections caused by these pathogens.

For example, local and/or systemic diseases caused by the following pathogens or by a plurality of the following pathogens can be treated and/or prevented: Micrococcus species such as Staphylococci, e.g. Staph, aureus. ), 5taph
, epidermidls , 5t
aph, aerogenes and affkya tetragena ()
na); Streptococci
) such as Lactobacterium
r 1aceae ), such as Streptococcus pyrogenes (Sir.

pyrogenes), α- or β-hemolytes (h
a-emolytic) Streptococcus, Str, faecalis (Enterobacter = En
terococci), Str, agaracce (ag
alact 1ae), Str, lactis (fact
is), Str, equi (equ i), Str.

Anerobis and Diplococcus pn
Pneumoco
cci); Neisseriaceae such as Neisseriae, e.g. Neisseria gonorrhoeae (Neisser 1a);
(-N,) gonorrhoeae) (Gonokotsushi G
onococci), N. meningitidis (men
ingi tidis) (Meningokotsushi = Men
ingococci), N. Catal Harris (c
atarrhalis) and N, flava
; Corynebacteria such as Corynebacteria, e.g.
Shifter: T-(C, diphther 1ae), C
, Pyrogenes, C. diphtheroides
oides), C, acnes, C, parvum, C, bovis, C
, renale, C. ovis and C. murisepticum
, Listeriabacterium
er ia), such as Listeria monocytogenes (
monocytogenes), Erysipelothrix bac
mycobacterioses;
) Pathogen-like Mycobacterium
1a-ceae), such as Mycobacterium tuberculosis, M. bovis, M. avium and Ru.
so-called atypical mycobacteria and M lepral of groups 1, II, I and ■;
hiae) Enterobacteriaceae like bacteria;
Escherichia bacterium
Bacteria, such as E, Aeromonas and E, cloacae, Klebs 1e.
lla = ni, ) bacteria, e.g. ni, pneumoniae,
K, ozaenae, Erwi
niae), such as Erwinia sp.
Serratia, e.g.
marcescens, Proteae bacteria of the Proteus group: Proteus =Pr,
, for example Prj vulgalis, Pr,
morgan ii, Pr, rettgeri and Pr, mi
labilis), Pyrovidencia (Providen)
eia), e.g. Providencia sp., Salmonellae (S.
salmonellae): Salmonella (S a 1
monella (=8.) bacteria, such as S, paratyphi A and B, S, typhi, S.

Enteritidis, S. cholerae 5uis and S. typhi murium, and Shige 11a=sh, bacteria,
For example, Sh, dysenteriae
), sh, ambigua, Sh, flexneri, Sh.

boydii, sh, son
nei); Pseudomonas
=Ps,) Bacteria-like Pseudomonadaceae (P
pseudomonadaceae), such as Ps, aeruginosa and Ps, 7' pseudomallei, and Aeromonas (A,) bacteria, such as Ps.
) and hydr-ophila; Vibrio (Vibrio = V,) Bacteria-like Spiracee, such as ■
, Korere, ■.

Prochus and ■, fetus, and Spirillum bacteria, such as Spirillum minus (fnlnus); Pasteurella (Pasteurella)
Bacteria-like Parvobacteriaceae
acter 1aceae) or pulcellaceae (Bru
cellaceae), such as Pa5t, Multocida (
mu 1tocida), Pa5t, Pestis (pes
tis) (Yersinia), Pa5t.

pseudotuberculosis
c-ulosis) and Pa5t, tularensis (tu
rarensis), pulsella (Burcella=B
r,) Bacteria, such as Br, abo
rtus), Br, meletens
is) and Br, suis, Haemophilus (
Haemophilus = H,) bacteria, such as H, influenzae, H
, ducreyi, H. suis, H. canis and H. aegyp.
itcus), Bordetella=B
, ) bacteria, such as B. pertus
sis) and Bj ronchiseptica (Bronchise
pt 1ca), and Moraxella (Moraxe l
la) Bacteria, such as Moraxella lacunata (1a
cutana) ; Bacteroides (B,) like Bacteria;
daceae), such as B, fragilis
is) and B, serpens, Fus i form bacteria, such as Fusobacterium fus i form, and Sphaerop
horus=Sph,) bacteria, e.g. Sph,
Necrophorus, Sph
, necrot 1cus and Sph
, pyrogenes; aerobic spore-forming organisms such as Bacillus, such as Bacillus (=B,) anthra
cis) (B, subtilis)
and B. cereus) and anaerobic spore-forming Lostrizoia (C1ost-ridia), such as Clostridium perfringens (Clostr.
idium (=C1,) perfringens),
C1, septicium, C1, oedemat 1en, C1, histolyticum, C1, tetani and CI, botul
inum); Borrelia (Borelia=B,)
Bacteria-like Spirochaetaceae (Sp~1rocha)
etaceae), such as B.
rrrent ia) and B, vince
nt i i), Trepone? (Trepone-m
a=Tr, ) bacteria, such as Tr, pallidum (pa
l l idum), Tr, per t
1nne) and Tr, carateum
), and Leptospira (Leptospira =
L,) Bacteria - Leptospira interrogans (i
interrogans), for example, Icterohaemorrha-giae L
, can ico la, L, gr 1ppotyphosa, L, Homo f
(pom-osa), L. mitis, and bovis.

The pathogens mentioned above are merely illustrative and do not limit the invention.

The following may be mentioned as examples of diseases that can be prevented, ameliorated and/or treated by the active compounds of the invention:
Respiratory and throat diseases; otitis; pharyngitis; pneumonia; peritonitis;
Nephritis; cystitis; endocarditis; systemic disease; bronchitis; local disease.

The present invention comprises the compound of the present invention mixed as an active ingredient with a solid or liquefied gas diluent, or with a liquid diluent other than a solvent having a molecular weight of 200 or less (preferably 350 or less) in the presence of a surfactant. Provided is a pharmaceutical composition comprising:

The invention further provides disinfectants or sprays (including aerosols), syrups containing the compounds of the invention as active ingredients.

A pharmaceutical composition is provided, characterized in that it contains the active ingredient in the form of an isotonic aqueous solution in an aqueous or non-aqueous diluent.

The invention furthermore provides a medicament in dosage unit form, characterized in that it contains a compound of the invention, alone or in admixture with a diluent.

Furthermore, the present invention provides pharmaceuticals in the form of tablets (including sweetener tablets and granules), sugar-coated tablets, capsules, pills, ampoules or herbal medicines, which are characterized in that they contain the compound of the present invention alone or in admixture with a diluent. give.

By "drug" herein is meant a physically distinct mass suitable for the administration of a drug.

``Drug in dosage unit form'' means the daily dose of a compound according to the invention or its divisions (up to 4 doses) or sub-divisions (40
means a physically distinct mass suitable for the administration of a drug containing doses of 1 or less).

Whether the drug contains the daily dose or, for example, □, % or It will depend on.

The pharmaceutical compositions according to the invention may take the form of e.g. soft creams, pastes, creams, suspensions, solutions and milk syrups, granules or powders, tablets, dragees, capsules and pills. Diluents that may be used in pharmaceutical compositions suitable for molding (e.g. granules) include: (a) fillers and extenders such as starches, sugars, mannitol, and silicic acids; (b) Binders, such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; (c) Wetting agents, such as glycerol; (d) Disintegrants, such as agar-agar, calcium carbonate and sodium bicarbonate. (e) dissolution retardants, such as paraffin; (f) resorption enhancers, such as quaternary ammonium compounds; (g) surfactants, such as cetyl alcohol, glycerol monostearate; (h
) Adsorption rods such as kaolin and bentonite); (i)
Lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.

Tablets, dragees, capsules, and pills formed from the pharmaceutical compositions of the present invention may have conventional coatings, wrappers, and protectors that may contain opacifying agents.

They can be shaped so as to release the active ingredient, preferably in a particular part of the gastrointestinal tract, preferably over a period of time.

Coatings, wrappers and protectors may be made of polymeric materials or waxes, for example.

The ingredients may be in the form of microcapsules together with one or more of the diluents mentioned above.

Diluents that can be used in pharmaceutical compositions suitable for formulation into herbal medicines include, for example, common water-soluble or water-insoluble diluents such as polyethylene glycols and fats such as cocoa oil and C14 alcohols and C16 fatty acids. higher esters) or mixtures of these diluents.

Pharmaceutical compositions which are pastes, creams and gels can be prepared, for example, by using the usual diluents such as animal and vegetable fats, waxes, paraffin, starches, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites,
It may contain silicic acid, talc and zinc oxide or mixtures of these substances.

Pharmaceutical compositions which are powders and propellants can be prepared, for example, by using common diluents such as lactose, talc, silicic acid, aluminum hydroxide,
It may contain calcium silicate, and polyamide powder or mixtures of these materials.

Aerosol propellants may, for example, contain common propellants, such as chlorofluorohydrocarbons.

Pharmaceutical compositions that are solutions and emulsions may contain, for example, the usual diluents (excluding, of course, the presence of surfactants and solvents with a molecular weight below 200 as mentioned above), e.g. solvents that dissolve the drug and emulsifiers. .

Particular examples of such dilutions are water, ethyl alcohol,
Fatty acids of isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. ground nut oil), glycols, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol. ester or a mixture thereof.

For parenteral administration, solutions and emulsions should be sterile and suitably isotonic with blood.

Pharmaceutical compositions that are suspensions can be prepared using conventional diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline diluents, etc. It may contain cellulose, aluminum metahydroxide, bentonite, agar and tragacanth and mixtures thereof.

All pharmaceutical compositions according to the invention may also contain colorants and preservatives, as well as perfumes and flavoring agents (eg pepper oil and eucalyptus oil) and sweetening agents (eg saccharin).

The pharmaceutical composition according to the invention comprises about 0.1 to 99% of the total composition.
．． 5, preferably about 0.5 to 95% by weight of active ingredient.

In addition to the present compounds, pharmaceutical compositions and medicaments according to the invention include:
It may also contain other pharmacologically active compounds.

They may contain more than one compound of the invention.

The diluent in the medicament of the invention may be any of those described above with respect to the pharmaceutical composition of the invention.

Such agents may contain a solvent having a molecular weight of less than 200 as the sole diluent.

The distinct bulk portions (either in dosage unit form or otherwise) constituting the medicament of the invention may be, for example, any of the following:

Tablets (including sweetened tablets and granules), pills, dragees, capsules, herbal medicines and ampoules.

Some of these forms are designed to retard the release of the active ingredient.

Something like a capsule contains a protective envelope that physically separates the parts of the drug and holds it together.

The suitable daily dose for administering this drug is 50 ~
It is 25.9.

The manufacture of the above-mentioned pharmaceutical compositions and medicaments may be carried out according to methods known in the art, for example by mixing the active ingredient with a diluent to produce a pharmaceutical composition (e.g. granules) and then converting the composition into a medicament (e.g. tablet). This is done by molding it into

Furthermore, the invention excludes the modulation of carbohydrate metabolism in humans and non-human animals, characterized in that the compounds of the invention are administered to the animals alone or in admixture with diluents or in the form of a medicament according to the invention. Provide methods (including prevention, cure and treatment).

It will be understood that the active compound may be administered orally, parenterally (for example intramuscularly, intraperitoneally or intravenously) or rectally, preferably orally.

Suitable pharmaceutical compositions and medicaments are therefore those suitable for oral administration such as tablets, pills, powders, suspensions and capsules.

Administration in this method is preferably oral and parenteral.

The present invention includes a medicated bait containing a compound according to the invention and a nutrient for use in medicament.

Examples of suitable nutrients include oil cake, grains (eg barley), fish meat, soybean meat, spent sugar beet chips, fresh grass, hay and skimmed milk.

Generally, to achieve the desired results in human and veterinary medicine, the active compound according to the invention is administered in a total amount of about 5 to about 1000, preferably 20 to 300, every 24 hours.
It has been found to be advantageous to administer the dosage in divided doses at my/kg body weight.

In the latter case each administration preferably contains from about 1 to about 50, in particular from 10 to 100 m9/k19 body weight of the active compound according to the invention.

However, deviations from the dosages mentioned above and in particular as a function of the nature and weight of the subject to be treated, the nature and severity of the disease, the nature and method of administration of the drug preparation, and the time and interval at which the administration is carried out are not permitted. is necessary.

Thus, in some cases it may be sufficient to work with less than the above-mentioned amounts of active compound, whereas in other cases the above-mentioned amounts of active compound must be exceeded.

The particularly required optimum dose and dosage of the active compounds can be readily determined by those skilled in the art based on their specialized knowledge.

When used as additives to foods, the novel compounds can be administered in common concentrations and formulations with feed or feed preparations, or with drinking water.

Infections with Gram-negative or Gram-positive bacteria can thereby be prevented, ameliorated and/or treated, and growth promotion and improved nutrient absorption can equally be achieved.

Novel penicillins and cephalosporins (cepha)
losporins) is characterized by a strong antibacterial effect as shown by in vivo and in vitro experiments and by oral absorption.

The penicillins and cephalosporins according to the invention can be combined with other antimicrobial active compounds, such as penicillins, which are especially resistant to penicillinase, in order to widen the range of action and increase the action, especially in the case of β-lactamase-forming bacteria. can.

An example of such a combination is oxacillin (oxac i
l l in) or dicloxacillin (diclo-x
acillin).

The penicillins and cephalosporins according to the invention may be combined with aminoglycoside antibiotics, such as gentamicin, sisomicin, kanamicin, amikacin or togeramicin, in order to widen the spectrum of action and increase the action.

The activity of the β-lactam antibiotics according to the invention can be illustrated by the following in vivo and in vitro experiments: 1. In vitro experiments Example 1.3., which can be considered as a typical representative of the compounds according to the invention. , 2.3. and 2.4. Muller Hinton nutritional soup supplemented with o, i% glucose at 100 μg/ml! diluted to a content of

In each case, the nutrient solution kills the bacteria
It contained ~2XIO'' pieces/ml.

Each tube containing this mixture was incubated for 24 hours and the turbidity was determined.

No cloudiness indicates the compound is active.

At a dose of 100 μg Al, there was no turbidity in the case of cultures of the following bacteria (sp, = species): Klebsiella pneumoniae; E, KoIJBE; Salmonella Sp, t
Shigella Sp,; Proteus, indole negative and indole positive; Pasteurella pseudotuberculosis; Pulsella Sp-; Haemophilus influenzae; Podetella prontiseptica; Staphylococcus aurius 133; Neisseria catarrhalis sp,; Diplococcus Pneumoniae Sp-; Streptococcus pyogenes W; Enterococcus 5l)-; Lactobacillus Sp-; Corynebacterium diphtheriae gravis; Corynebacterium pyogenes M; Clostridium tetani; Bushidomonas aeruginosa Sl
); Bacteroides fragilis sp.

2. In Vivo Test The following Table 1 shows the action of the compound according to the invention against one bacteria in an animal test using white mice.

In each case white mice of the CF1 generation were infected intraperitoneally with the bacteria described.

Treatment: 2 doses administered 30 and 90 minutes after infection.

EDloo is the dose at which 100% of infected animals still survive after 24 hours.

The following manufacturing examples illustrate the method according to the invention.

The α-aminobenzyl-penicillin used in the following preparation examples contained approximately 14% water, but anhydrous α-aminobenzyl-penicillin [see U.S. Pat. No. 3,144,445] can be used as well. .

The α-amino-p-hydroxybenzylpenicillin used in the production examples contained approximately 13% water, but anhydrous α-amino-p-hydroxybenzylpenicillin contained approximately 13% water.
p-Hydroxybenzylpenicillin can be used as well.

The 6-[2-amino-2-(1°4-cyclohexadien-1-yl)icedamide penicillanic acid used in the production example was substantially anhydrous.

The 7-(α-amino-phenylacetamide)-3-methyl-cef-3-em-4-carboxylic acid used in the production example contained about 5% water, but anhydrous 7-(α-amino-phenylacetamide) -3-methyl-cef-3-m-4-
Carboxylic acids can be used as well.

7-(α-amino-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylic acid used in the production example contained 8% water, but anhydrous 7-(α-amino-phenylacetamide) 3-acetoxymethyl-cef-3-em-4 carboxylic acid can be used as well.

The water content of the starting compounds is not critical for carrying out the process according to the invention.

“Ampicillin” refers to a special α-aminobenzylpenicillin with the D=R-form in the side chain;
n)'" indicates a special α-amino-p-hydroxy-benzylpenicillin having the D=R-form in the side chain, and"
"Epicillin" has D=R- in the side chain.
A special α-amino-α-(1°4-,y'7
0hexadien-1-yl)-methylpenicillin.

“Cephalexin” has D in the side chain.
7-(α-amino-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid with the =R-form and “cephaloglycine”
"loglyc 1ne)" is a special 7-(α-amino-phenylacetamide)-3 with a D=R-form in the side chain.
-acetoxymethyl-cef-3-em-4-carboxylic acid.

NMR spectra of compounds according to the invention were recorded in CD20D solution unless otherwise stated.

The symbols in parentheses have the following meanings: s = singlet q = quartet d = doublet m = multiplet t = triplet AB = AB system IR spectra of compounds according to the invention unless otherwise specified Recorded in paraffin oil suspension.

Explanation of abbreviations used in manufacturing examples: THF=tetrahydrofuran DMF-dimethylformamide Room temperature - approx. 20℃ The yield in % is the yield in % of theory.

Production example 1 2-oxo-imidazolidine (31°5 parts by weight) was added to 2N
Dissolve in sulfuric acid (1000 parts by volume) and stir this solution at 3-6°C.
C., a solution of sodium nitrite (25.25 parts by weight) in water (50 parts by volume) was added dropwise over 13 minutes with stirring and cooling, and the mixture was then further heated in a water bath for 1.5 minutes. After stirring for 5 hours, purified zinc powder (55 parts by weight) was introduced over a period of 1 hour.

The mixture was stirred for an additional 0.5 h while cooling on ice and for 1 h at room temperature.
Stir for hours.

The unconverted zinc was then filtered off, washed with a small amount of water, benzaldehyde (35 parts by weight) was added to the combined solution, and the mixture was stirred vigorously for 0.5 hour.

Then, the precipitated 1-benzalimino-2-oxo-imidapridine was taken from house to house and dried (49.2 parts by weight; melting point = 1
94-200°C) and then recrystallized from ethanol.

Yield 41.4 parts by weight, melting point -202℃0 IR spectrum: l 720 cm' (c=o).

Calculated value: C63,5H5,9N22.2 Analysis value: C64,L H5,7N22.71-Benzalimino-2-oxo-imidazolidine (11.7 parts by weight) (Reference 1.1), benzene (120 parts by volume) and triethylamine (13.8 parts by volume) was heated to boiling, and then a solution of trimethylchlorosilane (10 parts by weight) in benzene (50 parts by volume) was heated to boiling point.
Added dropwise over time.

The mixture was then kept at boiling point for a further 5.5 hours, and the separated triethylammonium chloride salt was hot-furnaced and washed with hot benzene.

A solution of phosgene (6.2 parts by weight) in benzene (30 parts by volume) was added to the cooled and combined benzene solutions.

The mixture was then left well-sealed at room temperature overnight.

Excess phosgene present was then removed with a stream of dry air.

The l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine was filtered off and dried.

Yield 8.9 parts by weight, melting point -250-252°C (decomposed).

■R spectrum/l/: 1800'cm' (-C
o-C1) Calculated value: C52,5H4,0C114,I
N16.7 analysis value: C51,8H5,6CZ14.6
N16.81.3 Empiedrine (14 parts by weight) was suspended in 80% aqueous tetrahydrofuran (140 parts by volume) and dissolved using the minimum amount of triethylamine (pH = 8.0).
): l-chlorocarbonyl-2oxo-3-pengelimino-imidapridine (7.8 parts by weight) (reference, 1
2. ) was gradually introduced with stirring, and at the same time triethylamine was appropriately added to maintain the pH at 7.0-7.5.

The mixture was then stirred further (approximately 1-2 hours) as long as triethylamine still had to be added to further maintain the above mentioned pH range.

The mixture was then diluted with water (200 parts by volume) and the pH was adjusted to 6.
．． 5, most of the tetrahydrofuran was distilled off under vacuum, and the remaining aqueous solution was washed once with water in a separating funnel, then covered with ethyl acetate and acidified with dilute HCl to pH 2 with stirring.

The organic phase was then separated, washed with saturated NaCl solution and M
diluted with an equal volume of ether and then treated with methanol-containing ether solution approximately IM2-sodium ethylhexanoate until precipitation ceased.

6-(D-α-[(2-oxo-3-benzalimino-
Sodium imidazolidin-l-yl) carbonylaminoco-phenylacetamido) penicillanate is separated by furnace,
ether, then ether and methanol (5-1O
%) and isopropanol and dried.

Yield: 6.2 parts by weight, β-lactam content: 91%.

According to the NMR spectrum, the substrate contains 202.5 moles of N20,
It still contained 0.61 moles of Improper Tool and 0.04 moles of sodium 2-ethylhexanoate.

This was taken into account in the analysis.

Calculated value: C51,5N5.3 N13. OS5.0 analysis value: C50.9N5.2 N12.9 S5. I
NMR signal, r (in CDaOD) = 2.12.8
(l IH); 4.8-4.65 (3H); 5
．． 8 (IH); 6.1-6.35 (4H) and 8.3
-8.6p West (6H) IR spectrum (in paraffin oil) (carbonyl range): 1.4 This penicillin was compared to 1.3. Produced from amoxicillin trihydrate (6.0 parts by weight) and 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine (3.6 parts by weight) according to the method described in 1.2. did.

When the aqueous reaction solution was acidified with dilute hydrochloric acid (approximately 20% by weight) to pH 1.5, some of the liberated penicillic acid was not captured by ethyl acetate.

This portion was separated, washed with water, and dried (yield: 52 parts by weight).

It was then still possible to precipitate some of the sodium salt of penicillin from ethyl acetate by using sodium 2-ethyl-hexanoate (yield=1.4 parts by weight).

6-(D-α-[(2-oxo-3-benzalimino-
imidazolidin-1-yl)-carbonyl-aminoco-
Yield of 4-hydroxyphenylacetamino)-penicillanic acid = 5.2 parts by weight.

β-lactum content (determined by iodometry) = 81% (N
From the MR spectrum): 89% According to the NMR spectrum, the substrate contains H2O per mole of
It contained 3.4 moles and 0.5 moles of ether.

This was taken into account in the analysis.

Calculated value: C51,2N5.9 N12.4 84.7
Analysis value: C50.7N5.5 N12.8 84.8
NMR signal, r (in CDa OD) = 2.2
-3.3 (l OH); 4.3-4.65 (3H);
5.7 (LH); 6.15-6.4 (4H) and 8.3
5-8.6pIXn(6H).

IR spectrum (in paraffin oil) (carbonyl range)
: 1,780, 1,740 (Shoulder) 1,725.1.
645 and 1,520CrfL-1゜6-(D-α-[
(2-oxo-3-benzalamino-imidapridine-
1-yl)-carbonylaminoco-4-hydroxyphenylacetamido)-sodium penicillanate Yield: 1.4 parts by weight.

β-lactam content (determined by iodometry): 96% (N
According to the NMR spectrum, the substrate has a molar equivalent of H
202,5 mol and sodium 2-ethylhexanoate 0
．． 25 mol (further used amoxil (Amox i
Contained unknown impurities and unknown amounts derived from 1).

The analysis took into account the identified mixture: Calculated value: C50
,6H5,2N12.2 84.6 Analysis value: C51,2
H6, ON11.7 S4.5HMR signal, r
(in CD20D) = 2.1-3.3 (IOH); 4.4
-4.7 (3H); 5.8 (LH); 6.1-6.4 (
4H) and 8.3-8.6ppm (6H).

IR spectrum (in paraffin oil) (carbonyl range)
: 1,770.1,735.1,67011.60
0 and 1,560-1,520 crn'.

1.5 This penicillin, 13. It was prepared from epicillin (1.5 parts by weight) and l-chlorocarbonyl-2-oxo-benzalimino-imidazolidine (1.1 parts by weight) according to the method described in .

Yield: β-lactam content (determined by iodometry) 90%
6 -CD-α-[(2-oxo-3-penzaliminoimitasol-1-yl)-carbonylaminoco-cyclohex-1,4-genyl(1)-acetamido)-penicillanic acid 1.7 Weight part.

(β-lactam content determined from NMR spectrum; 9
1%).

According to the NMR spectrum, the substrate contained 2.5 moles of H20 and 0.07** moles of sodium 2-ethylhexanoate.

This was taken into account in the analysis. Calculated value: C51,2H5,4
N13.0 84.9 Analysis value: C50,9H5,7N1
3.6 S4.6HMR signal, r (CD20D
Medium) = 2.0-2.65 (5H); 4.0 (IH)
; 4.25 (2H); 4.45 (2H); 4.95
(LH); 5.75 (tH); 6.0-6.3 (4
H); 7.1-7.4 (4H) and 8.25-s
, 5ppm (6H).

IR spectrum (in paraffin oil) (carbonyl range)
:1,765.1,73011,660,1,600 and 1,530 cIrL-1°1.6 2.25 parts by weight of cephaloglycine dihydrate were suspended in 50 TL of 80% aqueous THF, and l-chloro Carbonyl-2-oxo-3-benzalimino-imidazolidine 1
2.6 parts by weight and processed as in Preparation Example 13.

When acidified with dilute hydrochloric acid (e.g. 2N HCl), 7-(D
-α-[(2oxo-3-benzalimino-imidazolidin-1-yl]-carbonylamino]-phenylacetamide)-3-acetoxymethyl-cef-3<em>-4-
Carboxylic acid precipitated (1.9 parts by weight, corresponding to 61.4%).

This material was dissolved in 5 parts by volume of dimethylacetamide and L
3 parts by volume of M methanolic sodium 2-ethylhexanoate were added and this mixture was then added to 80 parts by volume of a 10:1 mixture of ether and methanol with stirring.

At this time, 7-(D-α-[
(2-oxo-3-benzalimino-imidazolidine-
1.7 parts by weight of sodium 1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylate were precipitated.

The ethyl acetate phase was prepared in Example 1.3. By treating as in step 1, an additional 0.9 part by volume of sodium salt (28.0%
) was obtained.

C2oH2□N6NaO8S, H20 Calculated value: C52,72H4,42N12.71 84.
85 analysis value: 52.5 4,9 12.2
4.6IR (KBr): 1,76011,725
．． 1,670.1.605 and 1,520crfL-1
°NMR (CD30D/D20): 7.75 and 7,
40 (m, IIH), 5.75 (d, IH), 5.57
(s, LH), 5.00 (d, LH), 4.87
(The signals of protons that can be exchanged overlap), 3
．． 82 (m, 4H) and 2.08 (s, 3H) δ
.

The CD30D solvent peak overlapped with the tail of the C-2 proton.

β-lactam content was 80-85%.

Production Example 2 15.8 parts by weight of 2-oxo-imidazolidine, 12.6 parts by weight of sodium nitrite and 27.5 parts by weight of zinc powder were added to Production Example 1.1. and stirred overnight with 232 parts by weight of 4-chlorobenzaldehyde.

20.5 parts by weight of 1-(4-chloro)benzalimino-2-oxo-imidazolidine, melting point 233-235°C.

C1oH1oC1N30 Total, calculated value: C53,70H451N18.79 C1
15,85 analysis value: 53.9 4.5 187
16.0IR(KBr): 3,250,3,13
011,735.1.705 and 1,595c1rL'
.

NMR (d,-DMSO): 7.66 and 7.45
(AB.

4H), 7.60 ('s, IH), 7.15 (s
, broad.

LH), m, 3.6 (4H) δ center.

2.2 21.4 parts by weight of l-(4-chloro)-benzalimino-2-oxo-imidazolidine and 31 parts by weight of triethylamine
．． To a boiling solution of 0 parts by weight of anhydrous dioxane in 2.40 parts by volume of anhydrous dioxane, a solution of 31.0 parts by weight of trimethylchlorosilane in 100 parts by volume of anhydrous dioxane was added dropwise with stirring over a period of 1 hour.

The mixture was then heated under reflux overnight, and the triethylammonium hydrochloride that had separated out was filtered off hot, washed with hot dioxane and, after cooling, a solution of 9.9 parts by weight of phosgene in 60 parts by volume of anhydrous dioxane was added.

After standing for 12 hours at room temperature, excess phosgene was driven off with dry air.

Then, the precipitate was separated, the P solution was condensed, and the residue was recrystallized from anhydrous acetonitrile.

1-chlorocarbonyl- with a decomposition temperature of 188-192°C
8.9 parts by weight of 2-74-so-3-(4-chlor)benzalimino-imidazolidine.

IR (paraffin oil): i, soo and l, 7Q□cf
rL-1°2.3 80% by volume 7.9 parts by weight of ampicillin trihydrate in 80 parts by volume of aqueous THF was added to Examples 1 and 3. The mixture was reacted with 2.8 parts by weight of l-chlorocarbonyl-2-oxo-3-(4-chloro)-benzalimino-imidazolidine as in .

As a result, the decomposition temperature was 210-5℃ and the β-lactam content was 8.
7% of 6-(D-α[(2-oxo-3-(4-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-penicyl*
*1.4 parts by weight of sodium lanate was obtained.

I R (KBr): 1,76011,725.1,
665 and 1,595 cfrL-1O NMR (CDaOD) Near, 6 7.2 (m, 10H
), 5.60 (s, LH), 5.45 (q, 2H
), 4.15 (s, LH), 3.80 (wide width s, 4H)
, 1.57 (s.

3H), and 1.48 (s, 3H)δ.

2.4 Production example 1.5. 80% by volume aqueous THF40 as in
2.0 parts by volume of sodium epicillin were reacted with 3.5 parts by weight of 1-chlorocarbonyl-2-oxo-3-(4-chloro)-benzalimino-imidazolidine.

As a result, 6-(D-α-[(
2-Oxo-3-(4-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-cyclohex-1,4-genyl(1)-acetamido)-
0.4 part by weight of sodium penicillanate was obtained.

**IR(KBr): 1,770.1,7
30.1,670 and 1,605 crrL-1°NMR (CD30D) near, 78 (s, IH), 7.7
6 and 7.36 (AB, 4H), 5.95 (m
, LH), 5.72 (s, 2H), 5.50
(s, 2H), 5.00 (s, LH), 4.20
(s, IH), 3.95 (s.

droad, 4H), 2.75 (s, wide width, 4H), 1
．． 65 (s, 3H) and 1.58 (s, 3H) δ
.

2.5 Production Example 1.6. 2.25 parts by weight of cephalopridine dihydrate in 40 parts by volume of 80% THF was added to 1-
It was reacted with 3.5 parts by weight of chlorocarbonyl-2-oxo-3-(4chloro)-benzalimino-imidazolidine.

As a result, 7-(D-α) with a β-lactam content of 80-85%
-[(2-oxo-3-(4-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylic acid sodium 0 .6 parts by weight were obtained.

IR (KBr): 1,760. 1,720.1
, 660 and 1,595 crrL-1° NMR (CD30D): 7.7 and 7.4 (m, l0
H), 5.65 (d, LH), 5.60 (s
, IH), 5.0-4.8m (overlapping with the exchangeable proton signal) 3.88 and 3.70 (overlapping multiplet), 2,036゛・3H)"・101, C29H26ClN6Na03S, 1-H20, 7methylacetamide Calculated value: C50,25H4,22N11.72 84.
48 analysis value: 50.1 4,5 11.1
5.42.6 Production Example 1.4. 80% by volume aqueous THF80 as in
6.3 parts by volume of amoxicillin trihydrate were reacted with 2.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-(4chlor)-benzalimino-imidapridine.

As a result, 6-(D-α-[(2
-oxo-3-(4-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-4-hydroxyphenyl-acetamido)-penicillanic acid
-4.6 parts by weight of IJum was obtained.

IR(KBr): 1,775.1,73011.
670 and 1,615 crIL-1° NMR (CD30D): 6.7-8.0 (9H), 5.
45.6 (3H), 4.95 (3 exchangeable H),
4.15 (IH), 3.80 (4H), 1.58 (3
H), 1.52(3H)δ.

C27H25ClN6 Nap7S, 2H20 calculated value: C48,18H4,49N12.49 84.77
Analysis value: C48,7H5,IN12.6 84.5
Production Example 3 15.8 parts by weight of 2-oxo-imidazolidine, 12.6 parts by weight of sodium nitrite and 27.5 parts by weight of zinc powder were added to Production Example 2.1. and stirred with 22.4 parts by weight of 4-methoxybenzaldehyde overnight**.

15.8 parts by weight of 1-(4-methoxy)benzalimino-2-oxo-imidazolidine having a melting point of 233 DEG -235 DEG C.

IR (KBr): 3,250.3,13011,72
5.1.700 and 1,605crIL-1°NMR (
d6-DMSO) near, 56 and 6.92 (AB.

4H), 7.52 (s, LH), 7.04 (s
, IH), 3.72 (s, 3H), m,
3.52 (4H) δ center.

C11H13N302 Calculated value: C60,27H5,97N19.17 Analysis value:
60.3 5.9 To a boiling solution of 13.6 parts by weight of l-(4-methoxy)-benzalimino-2oxo-imidazolidine and 27.6 parts by weight of triethylamine in 120 parts by volume of anhydrous dioxane is added trimethylchlorosilane. A solution of 20.0 parts by weight in 50 parts by volume of anhydrous dioxane is added dropwise with stirring and the mixture is prepared according to Preparation Example 1.2. Reacted and processed as in.

8.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-(4-methoxy)-benzaliminoimidazolidine having a melting point of 204 DEG -208 DEG C.

IR (paraffin oil): 1,800cIrL-1080
Ampicillin trihydrate 6% by volume in aqueous THF 80 parts by volume
．． 9 parts by weight were added to Production Examples 1 and 3. The mixture was reacted with 2.4 parts by weight of l-chlorocarbonyl-2-oxo-3-(4-methoxy)-benzaliminoimidazolidine as in .

As a result, 6(D-α-[(2-oxo-3-(4-methoxy)benzalimino-imidazolidin-1-yl) with a decomposition temperature of 213-223°C and a β-lactam content of 87%
4.5 parts by weight of sodium penicillanate (carbonylaminotwophenylacetamide) was obtained.

I R (KBr): 1,770.1,730,1.
675** and 1,605 crrL-1° NMR (CD30D) near, 60 and 6.85 (AB.

4H), 7.4 (m, 5+IH), 5.60 (s,
IH), 5.45 (q, 2H), 4.15 (s,
IH), 3.72 (s, 3H), 3-68 (wide width s,
4H), 1,55 (s, 3H), 1.50 (s,
3H) δ.

3.4 Production example 1.5. <80% by volume aqueous THF40
2.0 parts by weight of sodium epicillin was reacted with 2.1 parts by weight of 1-chlorocarbonyl-2-oxo-3-(4-methoxy)-benzalimino-imidazolidine.

As a result, 6-(D-α-[(
2-oxo-3-(4-methoxy)-benzalimino-
imidazolidin-1-yl)-carbonylaminoco-cyclohex-1,4-genyl<1)-acetamide)
3.5 parts by weight of sodium penicillanate were obtained.

** IR (KBr): 1,760.1,720.
1,655 and 1600 crfL-1O NMR (CD30D) near, 60 and 6.85 (AB.

4H), 7.50 (s, overlapping on AB system, IH), 5
-90 (wide width s, IH), 5.67 (s, 2H)
, 5.50 (s, 2H), 5.00 (s,
LH), 4.20 (s, IH), 3.77 (wide width s, 4
H), 2.72 (wide width s, 4H), 1.65 (s,
3H), 1.57(s, 3H)δ.

Production example 1.6. <80% by volume 2.25 parts by weight of cephalopridine dihydrate in 40 parts by volume of THF at 1-1
It was treated by reacting with 1.41 parts by weight of carbonyl-2-oxo-1-(4methoxy-benzalimino-imidazolidine).

When acidified, 7-(D-α-[(2-oxo3-(4
-methoxy)-benzalimino-imidazolidine-1-
yl)-carbonylaminocophenylacetamide-3
-acetoxymethyl-cef-3-em-4-carboxylic acid (1.2 parts by weight) was precipitated.

This was prepared in Production Examples 1 and 4. 7-(D-
α-[(2-oxo-3(4-methoxy)-benzalimino-imidapridin-1-yl)-carbonylamino]-phenylacetamide)-3-acetoxymethyl-
Sodium Cef-3-M-4-carboxylate (0.7 parts by weight) was obtained.

The ethyl acetate phase was prepared in Example 1.3. Further, the decomposition temperature was 220-230°C and the β-lactam content was 80°C.
% sodium salt was obtained.

I R (KBr): 1,770, 'r, 730.
1,660 and 1,610α-1°NMR (CD30D/D20): 7.55 and 668
5 (AB, 4H), 7.40 (s, L overlapping the AB system
H), 5.67 (d, IH), 5.47 (s, I
H), 5.15-4.85 (m, signals of easily exchangeable protons overlap), 3.76 (wide width s, 4
H), 2.05(s, 3H)δ.

C30H2g H6Na0g S, H20690,6
Calculated value: C52, 18H4, 52N12.17 84.
65 analysis value: 51.9 4.4 11.8
5.1 Production Example 4 15.8 parts by weight of 2-oxo-imidazolidine, 2.6 parts by weight of sodium nitrite, 27.5 parts by weight of zinc powder, and 24.9 parts by weight of 4-nitrobenzaldehyde were prepared in Production Example 2. , 1.

The impurities were removed by boiling the obtained 1-(4-nitro)-benzalimino-2-oxo-imidazolidine with ethanol: mp 265-267°C, 3
7.6 parts by weight.

I R (KBr): 3,430.3,260.1,
720.1.595 and 1,570C77L'.

NMR (d6-DMSO): 8.20 and 7.88 (A
B, **4H), 7.68 (s, LH), 7.87 (
Width 5IH), m, 3.65 (4H) δ center.

Calculated value: C51,28H4,31N23.92 Analysis value:
51.2 4,3 23.9 l-(4-nitro)-benzalimino-2-oxo-imidazolidine 8.8 parts by weight, triethylamine 12.1 parts by weight, trimethylchlorosilane 12. "0 parts by weight and phosgene 3.
9 parts by weight of Production Example 2.2. The reaction was carried out as shown in .

l-Chlorocarbonyl-2-oxo-3-(4-nitro)-benzaliminoimidapridine was recrystallized from anhydrous acetonitrile with a bi-decomposition temperature of 188-192°C, 2,
6 parts by weight.

IR (paraffin oil): 1,800.1,760 and 1
,700crIL'.

Preparation Example 1.3: 6.8 parts by weight of ampicillin trihydrate in 70 parts by volume of 80% by volume aqueous THF. The mixture was reacted with 2.5 parts by weight of 1-chlorocarbonyl-2-oxo-3-(4-nitro)-benzalimino-imidazolidine as in .

As a result, the decomposition temperature was 220-5℃ and the β-lactam content was 9.
3.0 parts by weight of 8% sodium 6-(D-α[(2-oxo-3-(4-nitro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-penicillanate. Obtained.

IR (KBr): L765.1,730.1,670
and 1,600 crr L-1O NMR (CD30D): 8.30 and 7.96 (AB
system, 4H), 7.81 (s, IH), m, 7.4
5 (5H) center, 5.64 (s, IH), 5.5
7 (q, 2H), 4.20 (s, IH), 3.8
8 (wide width s, 4H), 1°58 (s, 3H), 1.50
(s, 3H)δ.

C27H26N7 Na Og S, 2.5 H20
Word Shin f direct: C47, 93H4, 62N14.5O
S4.74 analysis value: 47.7 4.3 14.
4 4.8 Production example 3.5. As in <80 volume%T
6.5 parts by weight of cephaloglycine dihydrate in 40 parts by volume of HF was mixed with 1-chlorocarbonyl-2-,oxo-3-(4
nitro)-benzalimino-imidazolidine (4.4 parts by weight).

As a result, 7-(D-α-[(2
-oxo-3-(4nitro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cephem-4
-9.3 parts by weight of carboxylic acid I-IJ were obtained.

I R (KBr): 1,76011,730, i,
660 and 1,605 (X, 1°CHN Na01oS, 2H20 20267 Calculated value: C48, 13H4, 19N13.56 84.
42 analysis value: 48.0 4.1 13.4
4.4 Preparation Example 5 12.6 parts by weight of 2-oxo-imidazolidine, 10.1 parts by weight of sodium nitrite and 21.8 parts by weight of zinc powder were treated as in Preparation Example 2.1 to obtain 4-cyanobenzaldehyde 17 , 3 parts by weight.

(2) 26.2 parts by weight of -(4-cyano)-benzalimino-2-oxo-imidapridine was obtained, which was successively washed with water, ethanol and ether** to remove impurities.

Melting point 265-267°C.

I R (KBr): 3,210.3,120.2,
22011.720 and 1,590 crIl'.

NMR (d6-DMSO) near, 88 (s, 4H
), 7.66 (s, LH), 7.30 (wide width s, IH)
), m13.7(4H)δ・center.

Calculated value: C61,68H4,71N26.15 Analysis value:
59.8 4,6 25.9 1-(4-cyano)-benzalimino- in 60 parts by volume of anhydrous dioxane
7.5 parts by weight of 2-oxo-imidazolidine and 12.1 parts by weight of triethylamine, 12.0 parts by weight of trimethylchlorosilane in 25 parts by volume of anhydrous dioxane and 3 parts by weight of phosgene.
．． 9 parts by weight of Production Example 2.2. The reaction was carried out as shown in .

l-Chlorocarbonyl-2-oxo-3-(4-cyano)-benzalimino-imidazolidine was recrystallized from anhydrous acetonitrile: mp 260-264°C 4
．． 7 parts by weight were obtained.

IR (paraffin oil): 1,800 cTL'.

Calculated value: C52,09H3,28N20.25 Cl
12.82 Analysis value: 52.0 3.3 20.
3 12.5° 80% by volume 7.9 parts by weight of ampicillin trihydrate in 80 parts by volume of aqueous THF was prepared in Production Example 1.3. l-chlorocarbonyl-2-ox7-3- as in
(4cyano)-benzalimino-imidazolidine 2.7
Reacted with parts by weight.

As a result, 6-(D-α-[(2-oxo-3-(4
-cyan)-benzalimino-imidazolidin-l-yl)-carbonylaminoco-phenylacetamide)-
2.3 parts by weight of sodium penicillanate were obtained.

IR (KBr): 2,220.1,77011,73
0°1.665 and 1,600crfL-1°NMR (
CD30D) Near, 95-7.20 (l0H), 5.5
6 (s, LH), 5.42 (q, 2H),
4.12 (s, IH), 3.87 (wide width s, 4H),
1.57 (s, 3H), 1.48 (s, 3H) δ
・C28H26N7Na06S, 2.5H20 calculated value:
C51,2L H4,76N14.93 analysis value:
51.6 4.9 14.4 Preparation Example 6 The above substrate was used except that the reaction was carried out from 15.8 parts by weight of imidabritone and 31.0 parts by weight of 4-methylsulfonylbenzaldehyde in a 1=1 (by volume) mixture of water and dichloromethane. Production example 1.1. Manufactured by the method described in.

The crude product was recrystallized from nitromethane.

Yield: 9.2 parts by weight of t-(4-methylsulfonyl)-benzalimino-2-oxo-imidapridine, melting point -2
64°C.

NMR signal, r = 2.0 (4H), 2.2
(IH).

5.9-6.65 (4H) and 6.7p (3H).

Calculated value: C49,4H4,9N15.7018. OS1
2. O** Analysis value: C48,6 H5,0 N15.7 018.3 812.1 This substrate was prepared in Production Example 1.2. It was prepared from 9.2 parts by weight of (1-(4-methylsulfonyl)-benzalimino-2-oxo-imidazolidine).

The crude product was recrystallized from nitromethane and acetonitrile.

Yield: l-chlorocarbonyl-2-oxo3-(4-methylsulfonyl)-benzalimino-imidazolidine 5
．． 4 parts by weight.

Melting point = 208-213°G Calculated value: C43,7H3,6C110,8N12.8
89.7 Analysis value: 43.8 4,9 10.2
12.5 9.5 This penicillin was produced in Example 1.3. Empicillin trihydrate (2.0 parts by weight) and 1
-chlorocarbonyl-2-oxo-3-(4-methylsulfonyl)benzalimino-imidazolidine (1.6 parts by weight).

The penicillin-acid separated out as a crystalline precipitate (1.6 parts by weight), insoluble in water and ethyl acetate.

The sodium salt of penicillin is precipitated by dissolving this penicillin-acid in a small amount of dimethylformamide, adding a calculated amount of sodium 2-ethylhexanoate (in methanol-containing ether), and pouring the mixture into a large amount of ether. I let it happen.

Yield: 0.85 parts by weight of the sodium salt of D-α-([2-oxo-3-(4-methylsulfonyl)-benzalimino-imidazolidin-1-ylyocarbonylamino)-benzylpenicillin.

β-lactam content: 90% According to the NMR spectrum, this penicillin contains about 1.
5 moles, 0.2 moles of ethyl acetate, 0.25 moles of dimethylformamide and 0.2 moles of sodium 2-ethylhexanoate.
It contained 15 moles.

This was taken into account in the analysis.

Calculated value: C49, I H5, I N11.6 88
．． 5 analysis value: 48.5 4.8 11.8
8.4NMR signal r = 2.05 (4H), 2.
2 (IH), 2.2-2.8 (5H), 4.3-4.6
5 (3H), 5.8 (IH), 5.9-6.4 (4
H), 6.85 (3H) and 8.2-8.7ppHl (
6H).

This penicillin was prepared in Production Example 1.3. and 6,3. was prepared from amoxicillin (1.5 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(4-methylsulfonyl)-benzalimino-imidazolidine (1.18 parts by weight) as described in .

Obtained first as crystalline penicillin-acid (1.8 parts by weight) and then as its sodium salt.

Yield: 2.0 parts by weight of the sodium salt of D-α-([2-oxo-3-(4-methylsulfonyl)-benzalimino-imidazolidin-1-yl)]-carbonylamino)-p-hydroxyphenylpenicillin.

β-Lactam content: 85% * * According to the NMR spectrum, this penicillin contains 2.0 mol of rodent, 0.25 mol of ethyl acetate, 0.7 mol of dimethylformamide and 0.08 mol of sodium 2-ethylhexanoate. Contained.

This was taken into account in the analysis.

Calculated value: C47, 4H5, I N11.7 88.0
Analysis value: 47.2 5.0 11.1 7.
9HMR signal, r = 2.1 (4H), 2.2
(IH), 2.5-3.3 (4H), 4.35-4.6
5 (3H), 5.8 (IH), 5.9-6.4 (4
H), 6.85 (3H) and 8.2-8.7pINIl
(6H).

This penicillin was prepared in Production Examples 1 and 3. and 6.3. epicillin (1.0 parts by weight) and l-chlorocarbonyl-2-oxo-3-(4-methylsulfonyl)-
Prepared from benzalimino-imidapridine (0.94 parts by weight).

Obtained first as crystalline penicillin-acid (1.8 parts by weight) and then as its sodium salt.

Yield: D-α-([2-oxo-3-(4-methylsulfonyl)-benzalimino-imidazolidin-1-yl)]-carbonylamino)-α(1,4-cyclohexadien-l-yl)- 1.6 parts by weight of sodium salt of methylpenicillin.

β-lactam content: 81% **
According to the NMR spectrum, this penicillin is 3.
0 mol, 0.3 mol of ethyl acetate, 0.4 mol of dimethylformamide and 0.0 mol of sodium 2-ethylhexanoate.
It contained 12 moles.

This was taken into account in the analysis.

Calculated value: C47,3H5,5N11.3 88.1 Analysis value: 46.9 5.5 11.3 8. IN
MR signal, r=2.0 (4H), 2.15 (IH)
, 4.0 (LH), 4.25 (2H), 4.45 (2H
), 5.0 (IH), 5.8 (IH), 5.8-6.3
(4H), 6.8 (3H), 7.0-7.4 (4H)
and 8.2-8.7 pI) III (6H).

This cephalosporin was prepared in Production Example 1.3. and 6.3. Cephaloglycin (1.5 parts by weight) and 1
-10 Carbonyl-3-oxo-2-(4methylsulfonyl)-benzalimino-imidazolidine (1.0 parts by weight).

first as a partly crystalline acid (the part insoluble in ethyl acetate and water) (1,0 parts by weight) and then partly as a sodium salt (the part that can be dissolved in ethyl acetate and precipitated from it as the sodium salt) (0,0 parts by weight). 75 parts by weight).

The sodium salt was then further prepared in Preparation Example 6.3. It was prepared from penicillin-acid as described in .

Total yield = 7-D-α-/([2-oxo-3(4-methylsulfonyl)-benzalimino-imidazolidine-1
-ylocarbonylamino)-phenylacetamide/-3-acetoxymethyl-ceph-3-em-4-carboxylic acid) 185 parts by weight.

β-lactum content: According to the 84-coupled NMR spectrum, this penicillin is 1.
7 mol, ethyl acetate 0.4 mol, dimethylformamide 04 mol and sodium 2-ethylhexanoate 0.16
contained moles.

This was taken into account in the analysis.

Calculated value: C47,4H4,6N10.5 87.5 Analysis value: 47.3 4,2 10.8 8.1NM
R signal, r=2.1 (4H), 2.25 (IH),
2.5-2.9 (5H), 4.3-4.6 (,2H
), 5.05-5.3 (3H), 6.0-6.3 (
4H), 6.7 (2H), 6.9 (3H) and 8. Op
IMI1(3H).

Production Example 7 15.8 parts by weight of 2-oxo-imidazolidine, 12.6 parts by weight of sodium nitrite, and 27.5 parts by weight of zinc powder.
and 18.5 parts by weight of thiophene-2-aldehyde were reacted as described in Preparation Example 1.1.

The obtained 1-(thiophene-2-aldoimino)**-
2-Oxo-imidapridine was boiled with ethanol to remove impurities or recrystallized from dimethylformamide.

22.4 parts by weight of one with a melting point of 263-265°C.

IR (KBr): 3,240 and 1,705 (wide) CrfL-1°NMR (d, DMSO) near, 88 (s, LH)
, 7.370 (heteroaromatic proton and NH,4
H1m, 3.6 (4H) center.

Calculated value: C49,22H4,65N21.52S
16.42 Analysis value: 49.4 4.6 21.
4 16.11-(thiophene-2-aldoimino)
-2oxo-imidazolidine 9.8 parts by weight, triethylamine 16.2 parts by weight, trimethylchlorosilane 16.
1 part by weight and 5.1 parts by weight of phosgene were reacted as in Preparation Example 1.2.

1-Chlorocarbonyl-2-oxo-3-(thiophene-2-aldimino)-imidapridine was recrystallized from anhydrous acetonitrile: mp 184-188°C, 7.
7 parts by weight.

IR (paraffin oil): 1,880 and 1,720 cr
The fL-1° chlorocarbonyl compound still contained starting material that could not be removed.

This did not become an interfering substance in the subsequent reaction.

Production Example 1 2.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-(thiophene-2-aldimino)-imidapridine and 4.1 parts by weight of empicillin trihydrate were added in 40 parts by volume of water-related THF. .3 (It reacted as if it were cold.

Decomposition temperature 210-220°C and β-lactam content 89
0.4 part by weight of sodium 6-(D-α-[(2-oxo-3-(thiophene-2-aldimino)-imidapridin-1yl)-carbonylaminoco-phenylacetamide)-penicillanate of φ was obtained. .

IR (KBr): L760.1,720.1,660
and 1,600 cx-”.

NWfR (CD t OD) Near, 90 (s, I
H), 7.5-6.8 (aromatic and heteroaromatic protons, 8H), 5.51 (s, overlaps with m around 5.4,
Total 3H), 4.12 (s, IH), 3.79 (wide width s1, 4H), 1.57 (s, 3H), 1.48
< s, 3H) δ.

**C25H25N6Na06S2-2.5H2Q, 0.
25x-tel; 656.1 Calculated value: C47,60H5,00N12.81 89
．． 79 analysis value 47.6 5.5 12.4 1
1 chlorocarbonyl-2-oxo-3-(thiophene-2-
2.6 parts by weight of aldoimino-imidazolidine and 2.0 parts by weight of Ebicillina) IJum were reacted as in Preparation Example 1.5.

Decomposition temperature 205-215°C and β-lactam content 89
ol) Noro(D-α-[(2-oxo-3-(thiophene2-aldimino)-imidapridin-1-yl)carbonylaminoco-cyclohex-1,4dienyl(1
)-acetamido)-0.8 parts by weight of sodium penicillanate was obtained.

IR (KBr): 1,770.1,730.1,66
5** and 1,605crfL-1°NMR (CD30D): 8.00 (s, 1H
), 7.5-7.0 (heteroaromatic proton, 3H)
, 5.95 (wide width s, 1f(), 5.70 (8>2
H), 5.50(s, 2 f(), 5.00-(S
51 H), 4.20 (S>LH), 3.86 (wide width s
, 4H), 2.73 (wide width S.

4H), 1.64 (s, 3H), 1.57 (S
, 3H) δ0C25H27N6Na06 S2-2
H20,530,6 calculated value: C47,61H4,95
N13.32 S10.16 analysis value: 47.6
5.1 13.0 10.2Q=H or Na 80% by volume 1.50 parts by weight of 1-chlorocarbonyl-2-oxo-3-(thiophene-2-aldoimino)-imidapridine and cephaloglycine 2 in 40 parts by volume of THF 2.25 parts by weight of the hydrate was reacted as in Production Example 1.60.

When acidified, 7-(D-α-[(2-oxo3-(thiophene-2-aldoimino)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide-3-acetoxymethyl-ceph -3-M-4-carboxylic acid (0.6 parts by weight) was precipitated.

This was reacted with 3 parts by volume of sodium IM-2-ethylhexanoate as in Production Example 1.4.
[(2-oxo-3-(thiophene-2-aldoimino)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide) 3-acetoxymethyl-cef-3-em-4-carboxylic acid sodium Obtained.

β-lactam content was 75-80%.

IR (KBr): 1,755.1,720.1,66
0 and 1,600CrrL-1O NMR (CD30D)' 7.95 (s, I
H), 7.56.8 (aromatic and heteroaromatic protons, 8H), 5.75-5.00 (m, 3f()
, 48 (overlaps with the exchangeable proton signal), 3
．． 82 (wide width S.

4H), 2,00(s, 3H)δ.

15.8 parts by weight of 2-oxo-imidazolidine, 12.6 parts by weight of nitrite, 27.5 parts by weight of zinc powder, and 15.8 parts by weight of furan-2-aldehyde were prepared in Production Example 1.1 tl. As I described (I made this reaction.

17.5 parts by weight of 1-furiritinamino-2oxoimidazolidine having a melting point of 218-220°C was obtained.

IR (KBr): 3,200.3,110.1,71
5 and 1,585CrrL-1°NMR (d6-DMsO): 7.7o (arc,
LH), 7.50 (s, LH), 7.15 (wide width s
, L H), 6.50-6.75 (m, 2H), m
, 3.55 (4f()δ center.

** Calculated value: C53,63 Analytical value 53.7 H5,06 5.0 N23.45 23.2 1-furiritinamino-2-oxo-imidapridine 1
1.5 parts by weight, 10.0 parts by weight of triethylamine, 13.2 parts by weight of trimethylchlorosilane, and 6.2 parts by weight of phosgene.
Parts by weight were reacted as in Preparation Example 1.2.

1-chlorocarbonyl-2-oxo-3-furylideneaminoimidazolidine was obtained.

Decomposition temperature 188-192°C, 3.8 parts by weight.

IR (paraffin oil): 1,800 and 1,700CI
rL-18 6.1 parts by weight of 1-chlorocarbonyl-2-oxo-3-(furan-2-aldimino)-imidapridine and 20.4 parts by weight of empicillin trihydrate in 200 parts by volume of 80 volumes of hydrophilic THF. The reaction was carried out as in Preparation Example 1.3.

Decomposition temperature 200-207°C and β-lactam content 81
% of 6(D-α-[(2-oxo-3-(furan-2-
aldoimino)-imidapridin-1-yl)-carbonylaminoco-cyclohex-1,4-genyl (1)
-Acetamide)-2.3 parts by weight of sodium penicillanate was obtained.

**IR(KBr): 1
, 760.1, 715.1, 660 and 1,600cI
rL-”.

NMR (CDs OD)' 7.60 (s, L
H), 7.50-6.35 (aromatic and heteroaromatic protons, 8H), 5.55 (stlH), 5.40 (C
1,2H), 4.12(s, IH), m, 3.75
(4H) center, 1.55 (s, 3H), 1.48
(s, 3H)δ.

C24H25N6NaO7S, 1.5H20,0,25
1-chill calculated value: C49,22H5,04N13.7
685.26 Analysis value: 49.5 4,8 13
．． 5 5.2Q=H or Na 10.0 parts by weight of cephaloglycine dihydrate and 1-chlorocarbonyl in 100 parts by volume of 80 volumes polyhydric THF
2-oxo-3-furylideneaminoimidabridine 6
1 part by weight was reacted and processed as in Preparation Example 1.6.

When the mixture was slowly acidified with 0.1N HCl at 5 to 10[deg.] C., 13.1 parts by weight of crystalline acid (Q-H) precipitated.

The acid was dissolved in 500 parts by volume of acetone, a small amount of insoluble material was separated, and the P solution was concentrated.

The residue was suspended in 120 parts by volume of water and 1.5N sodium hydroxide solution was added until the material was dissolved and the pH was maintained at 7.5-8.0.

The solution was then filtered once and 940 parts by volume of acetone were added, followed by 190 parts by volume of ethyl acetate, followed by 380 parts by volume of ether.
Volume portions were added dropwise to precipitate the sodium salt.

Crystals 7-(D-α-[(2oxo-3-furylideneamino-imidapridin-1-yl)-carbonylaminoco-phenylacetamide)- with a decomposition temperature of 215-220°C and a β-lactam content of 95 μl. 3-acetoxymethyl-
7.8 parts by weight of sodium cef-3-M-4-carboxylate were obtained.

* * I R (KBr): 1,765.1,730,■,
6701.615.1, 530.1, 480.1, 39
0.1.265.1, 230.1, 020.740 and 695crfL-1°NMR (D20/CD30D): 7.50 (S,
2H).

7.30 (S, 5H), 6.65 (if(), 6
．． 45 (IH), 5.56 (d, IH), 5.38 (
s, LH), 4.91 (pseudo-d, overlaps with the exchangeable proton signal), 3.76 (6H), 2.
03(s.

3H) δ.

C2C27H25N6NaO-H20 Calculated value: C49,84H418N12.91 84.9
2 analysis value: 49.4 4,6 12.9 4
．． 9 Production Example 1.41 80 volume aqueous THF
9.4 parts by weight of amoxicillin trihydrate in 100 parts by volume was added to 1-chlorocarbonyl-2-oxo-3(furan-2-
The mixture was reacted with 5.5 parts by weight of (aldoimino)-imidapridine.

6-(D-α-[(2-oxo-3-furylideneaminopenzaliminoimidapridin-1-yl)-carbonylaminoco-4-hydroxyphenyl-acetamide)-sodium penicillanate 0.1 weight I got the department.

IR (KBr): 1,775.1,730.1,67
0 and 1.615 cx-t.

NMR (CD30D): 7.7-6.6 (8H),
5.5 (3H), 4.18 (s, IH), 3.90
(S, 4H), 1.58 (s, 3H), 1.50
(s t 3H) δ.

Production Example 9 18.9 parts by weight of 2-oxo-imidazolidine, 15.2 parts by weight of sodium nitrite and 33.2 parts by weight of zinc powder were treated as in Example 2.11 to obtain 2-chlorothiophene-5- It was reacted with 29.1 parts by weight of aldehyde.

1-(2-chlorothiophene-5aldimino)-2-
36.0 parts by weight of oxo-imidazolidine was obtained, which was successively washed with water, ethanol and ether to remove impurities.

Melting point 194-197°C0IR (KBr): 3,26
0.1,700 (wide width), 1.580 crrL-'.

NMR (d6-DMSO): 7.92 and 7.78 (
stIH, 5yn- and anti-forms), 7.16 and 7.10 (overlaps AB, NH).

3H), m, 3.6 (4H) δ center.

Calculated value: C41,84H3,51N18.28 S13
．． 96 analysis value: 41.9 3.8 18.0
14.3 8.6 parts by weight of 1-(2-chlorothiophene-5-aldimino)-2-oxo-imidapridine and 121 parts by weight of triethylamine in 60 parts by volume of anhydrous dioxane and 12.6 parts by weight of trimethylchlorosilane in 25 parts by volume of anhydrous dioxane. 0 parts by weight and 3.9 parts by weight of phosgene were reacted as in Preparation Example 2.2.

The precipitate that separates after removing excess phosgene is separated door to door,
Dry.

5.1 parts by weight of 1-chlorocarbonyl-2-oxo-3-(2-chlorothiophene-2-aldimino)-imidapridine having a decomposition temperature of 215 to 220°C** was obtained.

IR (paraffin oil): 1800cx-'.

13.9 parts by weight of ampicillin trihydrate in 140 parts by volume of polyhydric Tf (F) 1 as in Preparation Example 1.3.
-chlorocarbonyl-2-oxo-3-(2-chloro-
Thiophene-5-aldoimino)imidazolidine 5.0
Reacted with parts by weight.

As a result, 6-(D-α-[(2-oxo-3-
7.5 parts by weight of sodium (2-chlorothiophene-5-aldoimino)-imidapridin-1-yl)-carbonylaminocophenylacetamide)-penicillanate was obtained.

**IR (KBr):
C765, 1,730, 1,670 and 1.605cI
rL'.

NMR (CD s OD )' 7.77 (s t
IH), 椛, 7.32 (5H) center, 7.06 and 6.83 (AB, 2H), 5.55 (s, 1H), 5.
42 ((1,2H)4.13 (s,'H),3.
77C wide width s t 4H), 1.56 (s, 3H), 1
．． 48(s,3H)δ.

C25N24 CI N6 NaOa S 2 , I
N204 ether calculation value: C47,10I (4,33
N12.68 S 9.68 C15,35 analysis value:
47.0 4.2 12.5 9.5 4.9 As in Production Example 1.6, 2.5 parts by weight of cephaloglycine dihydrate in 50 parts by volume of THF per 80 volumes was added to 1-chlorocarbonyl-2-oxo- 3-(2-chlorothiophene-
The mixture was reacted with 1.7 parts by weight of 5-aldoimino)-imidapridine.

This result 7 (D-α-[(2-oxo-3-(2-chlorothiophene-5-aldoimino)-imidapridine-
2.5 parts by weight of sodium 1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylate was obtained.

IR (KBr): 1,760.1,730.1,67
0 and 1,600CrfL.

NMR (CD30D/D20): 7.87 (S, I
H), 7.50 (s, 5H), 7.1 s (c
i, IH), 6.93 (a, IH), 5.65 (d,
IH), 5.53 (atif(), 5.05 (overlaps with the exchangeable proton signal), 3.83 (6H)
, 2.10 (s, 3H)δ.

C2□H24CIH60s S 2 , N20 calculated value:
C46,26f (3,74N11.9989.14
CI 15.07 Analysis value: 46.3 3,9 11
．． 9 9.5 5.0 Production Example 10 10.1 15.8 parts by weight of 2-oxo-imidazolidine, 12.6 parts by weight of sodium nitrite and 27.5 parts by weight of zinc powder were poured into Production Example 2.1G. and reacted with 31.5 parts by weight of 3-bromothiophene-5-aldehyde.

1-(3-bromothiophene-5-aldoimino)-2
41.2 parts of -oxo-imidazolidine were obtained.

This material was washed successively with water, ethanol and ether and recrystallized from DMF.

Melting point 253-255°C IR (KBr): 3,230 and 1.710 crt
t-1°NMR (d5-DMSO): 7.77 (s
, LH), 7.60 (S, LH), 7.2 s (s
, 1H), 7.24 (stlH), m, 3.6 (4H)
center.

Calculated value: C35.04N2.93 N15.33S
11.70 B r 29.15 Analysis value: 34.
7 2.9 15.5 11.8 29.180 volume φ Ampicillin trihydrate in 70 volume parts of aqueous THF 6.5
Parts by weight were reacted with 2.7 parts by weight of 1-chlorocarbonyl-2-oxo-3-(3-bromothiophene-5-aldimino)-imidapridine as in Preparation Example 1.3.

As a result, the decomposition temperature was 210-220°C and the β-lactam content was 85%.
-bromothiophene-5-aldoimino)-imidapridin-1-yl)-carbonylamino]-ph** 1-(3-butylated muchhiophene-5-aldimino)-2-oxoimidazolidine 12 in 120 parts by volume of anhydrous dioxane
．． 2 parts by weight and 14.1 parts by weight of triethylamine, and 1 part by volume of trimethylchlorosilane in 50 parts by volume of anhydrous dioxane.
Production Example 2.2: 4.0 parts by weight and 4.6 parts by weight of phosgene
The reaction was carried out as shown in .

Separate the precipitate that separates after removing excess phosgene,
The r solution was concentrated, and the residue was masticated with anhydrous ether, P was removed, and dried.

7.5 parts by weight of 1-chlorocarbonyl-2-oxo-3-(3-fromthiophene-2-aldimino)-imidazolidine having a melting point of 165 to 170°C was obtained.

The product still contained some of the starting material.

IR (paraffin oil): 1,780 and 1,6901 cI'rL0 *enylacetamide)-sodium penicillanate2.
2 parts by weight were obtained.

IR (KBr): 1,765.1,730.1,675
and 1,610crfL-1O NMR (CD30D): 7.83-7.20 (
8H), 5.53 (s, LH), 5.42 (qj
2H), 412(stlf(), 3.78(wide width s
, 4 H), 1.55 (s, 3 H), 1.48 (
S, 3K) δ010.4 As in Preparation Example 1.6, 6.5 parts by weight of cephaloglycine dihydrate in 80 parts by volume of THF was added to 1-chlorocarbonyl-2-oxo-3-(3-bromothiophene- The mixture was reacted with 5.0 parts by weight of 5-aldoimino)-imidapridine.

As a result, 7-(D-α-[(
2-oxo-3-(3-bromothiophene-5-aldoimino)-imidazolidin-1-yl)-carbonylaminoco-phenylacetamido)-3-acetoxymethyl-cef-3-em-4-carboxylic acid ) 4.2 parts by weight of IJum was obtained.

IR (KBr): 1,760.1,725.1,67
0 and 1605cfrL-1°C27H24BrN6Na03S2-H20 calculated value: C
43,50H3,52N11.28 S8.59
**Analytical value: 43.8 3.8 08 8.1 10.5 Production example 1.4G Kokeru-like 80 volume hydrophilic THF10
7.5 parts by weight of amoxicillin trihydrate in 0 parts by volume
Chlorocarbonyl-2-oxo-3 (reacted with 6.0 parts by weight of 3-bromothiophene-5-aldimino-imidapridine).

As a result, sodium 6-(D-α-[(2-oxo-3-(3-bromothiophene-5-aldimino)-imidapridin-1-yl)-carbonylaminoco-4-hydroxyphenyl-acetamide)-penicillanate 4.
3 parts by weight were obtained.

IR (KBr): C760, 1,720, 1,670
and 1,605CrfL-1°NMR (CD30D): 7.80 (s, LH), 6
．． 67.4 (6H), 5.5 (m, 3H), 4.12
(stIH) 3.78 (s, wide, 4.H), 1.54
(s.

3H), 1.48 (873H)δ.

C25H24BrN6Na07S2-f (2Q calculated value:
C41,50H3,91S8.84 Analysis value: C41,7
H4,3S8.3 Preparation Example 11 1-Amino-2-oxoimidazocillin hydrochloride (21 parts by weight) in 1N sodium hydroxide solution (150 parts by volume)
Cinnamaldehyde (18.5 parts by weight) was added with stirring at 20° C., and the mixture was then stirred for a further 90 minutes at the same temperature and then left in H for 16 hours.

Separate the separated precipitate, wash thoroughly with water, and desiccate.
Middle P20. It was dried.

Yield: 29.9 parts by weight.

Melting point -209-210°C (Kofler bench).

This substrate still contained 0.28 molar equivalents of water.

This was taken into account in the analysis.

Calculated value: C65,4H6,I N19.1 Analysis value: C
65,5H6,IN 15
Stir phosgene (4.3 parts by volume) in ice/
It was added dropwise after cooling with water.

The mixture was then stirred for an additional 4.5 hours while continuing to cool.

The formed precipitate was boiled, stirred in about 30 parts by volume of methylene chloride at 20°C for 2 hours, separated again, and placed in a desiccator.
Dry in medium P2O5.

Yield = 8.2 parts by weight.

Melting point = 227-230°C (Kofler bench).

This substrate still contained triethylamine hydrochloride, but
This did not prevent further reactions.

IR spectrum (-CO-C1): 1,800ct
rt-1 (in paraffin oil).

11.3 This Penicillin Production Example 1.3 (as described herein empicillin trihydrate (2.0 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(cinnamylideneamino)-imidapurine (2.0 parts by weight) , 06 parts by weight; used in excess due to triethylamine present in the substrate).

Yield: 2.1 parts by weight of the sodium salt of D-α-[(2-oxo-3-cinnaminodenaminoimidapridin-1-yl)-carbonylaminoco-benzylpenicillin.

β-lactam content - 82% NMR spectrum (according to which the substrate contains approximately 2.6 molar equivalents of H20 and 2-ethylhexanoate)
It contained 0.56 molar equivalent.

This was taken into account in the analysis.

Calculated value: C53,6N5.6 N11.2 84.3
Analysis value: C53,6N5.6 N10.8 S4.
3HMR signal, r=2.3-3.2 (13f()
, 4.45 (LH), 4.45-4.75 (AB,
2H), 5.9(If(), 6.1-6.4 (4H
), 8.5(3H)i and 8.55ppm (3H)
.

IR spectrum (in paraffin oil) (carbonyl range)
:1,770. 1,730.1,670.1.610
and L525Cr/l-'.

This penicillin was mixed with amoxicillin trihydrate (1.5 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(cinnamylidene-amino)- as described in Preparation Example 1.3.
Manufactured from imidazolidine (1,49 parts by weight).

Yield: 1.3 parts by weight of the sodium salt of D-α-[(2-oxo-3-cinnamyl)-carbonylaminoco-p-hydroxy-benzylpenicillin.

β-lactam content: According to the NMR spectrum, the substrate contained approximately 1.5 molar equivalents of H20 and 0.36 molar equivalents of sodium 2-ethylhexanoate.

This was taken into account in the analysis.

Calculated value: C53,6f (5,2N11.8 84.5 Analysis value: C53,6N5.7 N11.7 84.6I
R spectrum (in paraffin) (carbonyl range): 1
, 770.1, 740.1, 670.1, 615 and 1
555-1,520crrLt0 11.5 This penicillin was prepared as described in Preparation Example 13 (epicillin (1.5 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(cinnamylideneamino)imidapurine (1,
77 parts by weight; MM from the substrate (used in excess due to triethylamine present).

Yield: D-α-[(2-oxo-3-cinnaminoimidazolidin-1-yl)-carbonylamino]-α-(1,4-cyclohexadien-1-yl)-
Sodium Salt of Methylpenicillin 1.6 weight pounds β-lactam content: 82 pounds According to the NMR spectrum, the substrate contained approximately 2 mole equivalents of H20 and 0.36 mole equivalents of sodium 2-ethylhexanoate.

This was taken into account in the analysis. Calculated value: C54, ON5.6
N11.8 S4.5 analysis value: C54, ON5.
7 N11.7 84.5 IR spectrum (in paraffin oil) (carbonyl range): C772,1,730,
1,670, 1,610 and 1,530cx-'.

NMR signal, r==2.25-3.15 (8H)
, 4.05 (LH), 4.3 (2H), 4.5 (2f (
), s, otIH), 5.8 (LH), 6.05-
6.4 (4f(), 7.15-7.45 < 4H)
, 8.4 (3,E() and 8.46 ppm (3H).

Similar to the description for penicillin in Preparation Examples 1.3 and 1.6 of this cephalosporin, cephaloglycin dihydrate (1.5 parts by weight) and -amino)-imidapridine (1.08 parts by weight; used in excess since the substrate still contained triethylamine hydrochloride).

After removing THF at pH 7.0, water and ethyl acetate (
This insoluble precipitate was separated and stirred with a mixture of ethyl acetate and water at pH 2.0.

After filtration, the product was stirred with 10 parts by volume of dimethylformamide to remove insoluble materials, and the r solution was diluted with 150 parts by volume of ether to precipitate the thorium salt.

Yield nia-(D-α-[(2-oxo-3-cinnamylideneamino-imidazolidin-1-yl)carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4carboxylic acid 0.5 parts by weight of sodium.

β-lactam content: According to the 80 NMR spectrum, the substrate contained approximately 3 molar equivalents of H, O and 0.65 molar equivalents of sodium 2-ethylhexanoate.

This was taken into account in the analysis. Calculated value: C52,3N5.4
N10. I S3.9 analysis value: C52,4N5.
6 N10.3 83.8 IR spectrum (in paraffin oil) (carbonyl range): 1,770.1,780
．． 1,668.1.612 and 1.540 cm-'.

NMR signal (in deuterated DMF), r-2,1-2
, 9 (13H), 3.9-4.3 (2H), 4.75
-5.1 (3,H), 4.0 (4H), 6.6 (2H
) and 7. c+ppm (3H).

Production Example 12 1 in a mixture of methanol and water (50 parts by volume each)
Pyridine-3-aldehyde (10.7 parts by weight) was added to a solution of -amino-2-oxo-imidazolidine (10.1 parts by weight) and the mixture was then stirred at 20'C for about 20 hours.

The formed precipitate was separated, washed with water and a small amount of methanol, and dried over P2O5 at 60°C under vacuum.

Yield: 16.5 parts by weight.

Melting point -195°C (Kofler bench).

Calculated value: C56,9N5.3 N29.5 08.4
Analysis value: C56,9N5.2 N30.0 08.0
1-(3-pyridyl-methylideneamino)-2-oxo-imidazolidine (3,
A solution of phosgene (1.35 parts by volume) in THF (10** parts by volume) was added to a suspension of 1.0 parts by volume) while cooling with ice water.

After 20 minutes the mixture was strained at 20°C and stirred at this temperature overnight.

The precipitate present was filtered out, washed with ether and then with dichloromethane and dried.

Yield = 4.2 parts by weight.

IR spectrum (C0-Cl): 1,800 cI
rL-' (in paraffin oil).

Melting point -252°C (Kofler bench).

This penicillin was prepared as described in Preparation Example 1.3, empicillin trihydrate (1,0 wt. Manufactured from ).

When the THF was removed and the reaction solution covered with ethyl acetate was made acidic, some of the benidinone was obtained as a free acid insoluble in ethyl acetate (0.20 parts by weight: IR spectrum (
(in paraffin oil) (carbonyl range): 1,775.1
, 725.1.670 and 1,520 cm-') o sodium salt was obtained from the organic phase by precipitation with 2-ethylhexanoic acid.

Yield: 0.70 parts by weight of the sodium salt of D-α-([(2-oxo-3-(3-pyridyl-methylideneamino)-imidapridin 1-yl)-carbonylaminoco-benzylpenicillin.

β-lactam content = 90 coefficient According to the NMR spectrum, the substrate contained approximately 3.3 molar equivalents of H20 and 0.13 molar equivalents of I-IJ 2-ethylhexanoate.
It contained molar equivalents.

This was taken into account in the analysis.

Calculated value: C48,6N5.3 N14.7 84.8
Analysis value 2C48.5N5.8 N14.5 84.8
IR spectrum (in paraffin oil) (carbonyl range)
:1,768.1,722.1,667.1625.1
．． 600. 1,550 and 1,525 cfrL'.

NMR signal, r=1, O-1,2(LH), 1.3
5-1.55 (IH), 1.6-1.85 (IH)
, 2.15 (II (), 2.3-2.8 (6H),
4.3 (LH), 4.3-4.6 (AB; 2H
), 5.8 (IH), 5.96.2 (4H), 8.4 (
3f() and 8.45ppI11(3H).

Production example 13 3-methylbenzaldehyde was converted into 1-amino-2oxo-
Imidazolidine hydrochloride (14.0 parts by weight) and IN hydroxide solution (100 parts by volume) were added to the mixture and the mixture was then stirred for a further 5 hours at 20°C.

The generated precipitate was boiled, washed with water, and dried.

Yield: 20.3 parts by weight.

Melting point -205-207°C (Kofler bench).

1-(3-methylbenzylidene-amino)-2-oxo-imidazolidine (12.1 parts by weight), benzene (15
0 parts by volume) and triethylamine (13.4 parts by weight) in a gently boiling mixture of
A solution of 9.65 parts by weight) in benzene (50 parts by volume) was added dropwise over 1 hour.

The mixture was then boiled under reflux for 20 hours, the triethylamine hydrochloride was removed hot and rinsed with hot benzene.

A solution of phosgene (4.7 parts by volume) in benzene (30 parts by volume) was added to the solution cooled to 10°C, and the mixture was then left at 20°C for 48 hours.

The resulting precipitate was separated from P, washed with benzene, masticated with methylene chloride (40 parts by volume), and dried.

Yield: 3.2 parts by weight.

Melting point -209-210°C** (Kofler Bench).

Calculated value: C54,3H4,5C113,4N15.8 Analysis value: C54,5H4,6 (j13.5 N15.4I
R spectrum (co, cl): 1810 cm-'' (in paraffin oil).

Empicillin trihydrate (20 parts by weight) and 1-chlorocarbonyl-
2-oxo-3-(3-methylbenzylideneamino)-
Manufactured from imidapurine (1.6 parts by weight).

Yield: D-α-[(2-oxo-3-(3-methylbenzylideneamino)-imidapridin-1-yl)-carbonylaminoco-benzylpenicillin sodium 2.5
5 parts by weight.

β-lactam content: 90% According to the NMR spectrum, the substrate contains about 3 equivalents of H2020 and about **0.06 sodium 2-ethylhexanoate.
It contained molar equivalents.

This was taken into account in the analysis.

Calculated value: C52, I H5, 4N12.6 84.8
Analysis value: C51,9H6,3N12.4 34.9IR
Spectrum (in paraffin oil) (carbonyl range): 1
, 770.1, 730.1, 675.1.612 and 1
,530cm'.

NMR signal (CD30DLr=2.25-2.9(
IOH), 4.35 (LH), 4.35-4.65 (A
B, 2H), 5.85 (IH), 6.1-6.4 <
4) T), 7.7 (3H), 8.4 (3H) and 8.
5p door (3H).

This penicillin was mixed with amoxicillin trihydrate (1.0 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(3-methylbenzylideneamino)-imidapridine (0.73 parts by weight) as described in Preparation Example 1.3. Manufactured from ).

Yield: Crystal D-α-([(2-oxo-3-(3-methylbenzylideneamino)-imidapridin-1-yl)
1.1 parts by weight of the sodium salt of -carbonylaminoco-p-hydroxy-benzylpenicillin.

β-lactum content: 90φ NMR spectrum (according to which the substrate contained approximately 2.9 molar equivalents of H20 and 0.16 molar equivalents of sodium 2-ethylhexanoate).

This was taken into account in the analysis.

Calculated value: C50, 5H5, 3N12. I S4.6 analysis value: C50,5f (5,4N11.9 84.6IR
Spectrum (in paraffin oil) (carbonyl range): 1
,790.1,765.1,720°1.690.1,
660.1, 612.1, 590.1.550 and 1.
51QcrrL-'.

NMR signal (in CD30D), r=2.2-3.3
(9H), 4.4-4.65 (3H), 5.85 (I
H), 6.0-6.3 (4H), 7.65 (3H)
, 8.4 (3H) and 8.5p (3H).

This penicillin was prepared by mixing epicillin (1.0 parts by weight) with 1-chlorocarbonyl-2-oxo-3-(3-methylbenzylidene-amino)-imidazolidine (0.91 parts by weight) as described in Preparation Example 1.3. ) was produced by reacting with

0.8 parts by weight of amorphous penicillin salt were initially obtained by precipitating the sodium salt.

Further precipitation from the mother liquor then yields 0.9 parts by weight of crystallized α([2-oxo-3-(3-methylbenzylideneamino)-imidapridin-1-yltucarbonylamino)-α-(1, 4-cyclohexadiene-
The sodium salt of 1-yl)-methylpenicillin was obtained.

* * IR spectrum of amorphous salt (in paraffin oil) (carbonyl range): 1,770.1,730.1.670
．． 1,610 and 1.525 crrL-1°I of crystalline salt
R spectrum (in paraffin oil) (carbonyl range):
1,790, (1,775), 1.740.1,712
．． 1,66011,600.1.575 and 1,520
crrL-1° NMR signal (in CD30D), r=
2.1-2.8 (5H), 4.05 (IH), 4.3 (
2H), 4.5 (2H), 5.0 (IH), 5.8 (
IH), 6.1 (4H), 7.25 (4H), 7.
65 (3H), 8.35 (3H) and 8.45p Ashi (3
H).

This cephalosboron was prepared using cephaloglycin dihydrate (1.0 parts by weight) according to the methods of Production Examples 1.3 and 1.6.
was prepared by reacting with 1-chlorocarbonyl-2-oxo-3-(3-methylbenzylideneamino)-imidazolidine (0.69 parts by weight).

n) l) Rum salt was separated as a gel-like precipitate that could not be separated.

For this reason, all volatiles were removed and the residue was treated with dry ether.

As a result, cephalosboron was obtained as a fluffy white powder.

Yield near-(D-α-[(2-oxo-3-rrL-methylbenzylideneamino-imidapridin-1-yl)
-carbonylaminoco-phenylacetamide)-3-
1.2 parts by weight of sodium acetoxymethyl-cef-3-em-4-carboxylate.

β-Rakukum content: 90 steamed rice.

The cephalosporin salt contained 2.9 molar equivalents.

This was taken into account in the analysis. Calculated value: C51,2H4,9
N11.9. 84.6 Analysis value: C51,4H5,5N
11.7 84.7IR spectrum (in paraffin oil)
(Carbonyl range): 1,765 (shoulder), 1,740.
1,6601.610 and 1,535crfL-1°N
MR signal (in d7-DMF), r=1.85-2.
8 (10f(), 3.9-4.3 (2H), 4.7-
5.0 (3H), 5.8-6.1 (4H), 6.4-
6.7 (2H), 7.5 (3H) and 7.8p west (3
H).

Production Example 14 Amino-2-oxo-imidazolidine hydrochloride (14,0
parts by weight) and 4-fluorobenzaldehyde (12,8
parts by weight).

Yield: 20.4 parts by weight.

Melting point -229-230°C (Kofler bench).

1-(4-fluorobenzylideneamine)-2-oxo-imidazolidine (6.0 parts by weight), benzonitrile (
50 parts by volume) and triethylamine (8 parts by volume), phosgene (4.2 parts by volume)** of benzoni) I
The J.L. (10 parts by volume) solution was added dropwise while cooling with ice/water and stirring.

The mixture was then stirred for a further 3 hours at 20'C.

The precipitate was separated, suspended in methylene chloride (240 parts by volume), separated again, and dried.

Yield = 0.9 parts by weight (mother liquor also contains some of this substrate).

This substrate was not able to completely remove triethylamine hydrochloride, but this did not interfere with further reactions.

IR spectrum (Co, C1): L820/1,81
0cIrL-1 (in paraffin oil).

Melting point = 240-247°C, decomposition (Kofler bench).

This penicillin was mixed with empicillin trihydrate (1°0 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(4-fluorobenzylideneamino)-imidapurine (0,8 parts by weight) as described in Preparation Example 1.3. parts by weight).

Yield = D-α-[(2-oxo-3-(4-fluorobenzylideneamino)-imidapridin 1-yl)-carbonylaminoco-benzylpenicillin sodium salt 1
．． 2 parts by weight.

β-lactum content: 93% According to the NMR spectrum, the substrate is H20 approx. 1.7**
It contained molar equivalents.

This was taken into account in the analysis. Calculated value: C51,1f(4,
6N13.2 85.0 Analysis value: C51, L H5,
4N13.2 S5. IIR spectrum (in paraffin oil) (carbonyl range): 1790 (1,767)
, 1,730° 1.702.1,670 (shoulder), 1,6
60 and 1,602 crrL-18 NMR signals (in CD30D), r = 2.13.
1 (IOH), 4.4 (LH), 4.4-4.65 (A
B, 2f(), 5.85(IH), 6.0-6.3(4
H), 8.45 (8H) and 8.55pp[ll (3H
).

This cephalosboron was prepared using cephaloglycin dihydrate (1.0 parts by weight) according to the methods of Production Examples 1.3 and 1.6.
was prepared by reacting with 1-chlorocarbonyl-2-oxo-3-(3-fluorobenzylideneamino)-imidapridine (0.7 parts by weight).

The sodium salt separated out as a distinct gel-like precipitate.

Since it is therefore difficult to filter in this form, all volatiles were removed and the residue was treated with dry ether.

As a result, cephalosboron was obtained as a fluffy white powder.

Yield near-(D-α-[(2-oxo-3-p-fluorobenzylideneamino-imidapridine-1-(ru)-
0.5 parts by weight of sodium carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylate.

β-Lactam content: 91 cephalosporin salt contained 2.9 molar equivalents of Hondori and about 0.13 molar equivalents of sodium 2-ethylhexanoate.

This was taken into account in the analysis: Calculated value: C50,7f(4,
4N11.8 S4.5 analysis value: C50.7f (4,
4N11.8 84.6 IR spectrum (in paraffin oil) (carbonyl range): 1,775 (shoulder), 1,76
0 (shoulder), 1.735.1, 680.1, 610 and 1
,550-1,520crn-'O NMR signal (in CD30D), r=2.1-2.9
(10f(), 4.2-4.35 (LH), 4.4(
IH), 5.0-5.2 (3H), 6.1 (4H),
6.5-6.7 (2H) and s, oppm (3H).

This substrate was prepared according to the method of Preparation Example 13.1 from 1-amino-2-oxo-imidazolidine hydrochloride (14.0 parts by weight) and 2-fluorobenzaldehyde (12.7 parts by weight). did.

Yield: 17.6 parts by weight.

Melting point = 214-216°C (Kofler bench).

1-(2-fluorobenzylideneamine)-2-oxo-imidazolidine (6.0 parts by weight), benzonitrile (
50 parts by volume) and triethylamine (8 parts by volume) was mixed with phosgene (4.2 parts by volume). The IJL (10 parts by volume) solution was added dropwise while cooling with ice/water and stirring.

The mixture was then stirred for a further 3 hours at 20°C.

The precipitate was separated, washed with ether, and diluted with methylene chloride (approx.
(20 parts by volume) (this was suspended, separated again, and dried.

Yield = 5.6 parts by weight.

Melting point: 230°C (Kofler bench).

IR spectrum (Co C1): 1,800cr
rt-'.

(There is a shoulder at about 1,815).

This substrate was not able to completely remove triethylamine hydrochloride, but this did not interfere with further reactions.

This penicillin was prepared using empicillin trihydrate (10 parts by weight) and 1-chlorocarbonyl-
Prepared from 2-oxo-3-(2-fluorobenzylidene-amino)-imidapridine (0.8 parts by weight).

Yield: 0.55 parts by weight of the sodium salt of crystalline α-[(2-oxo-3-(2-fluorobenzylidene-amino)-imidapridin-1-yl)-carbonylaminoco-benzylpenicillin.

β-Lactam Content: According to the 90 NMR spectrum, the substrate contained approximately 2.9 molar equivalents of H20.

This was taken into account in the analysis. Calculated value: C49,4H4,9
N12.8 84.9 Analysis value: C49,4H4,9N1
2.6 85.3IR spectrum (in paraffin oil) (
carbonyl range): 1,793 (1,775),
1,740 (1,70011,680 both shoulders), 1
, 660.1.610.1,560 and 1,520cI
rL-”.

NMR signal (in CD30D), r = 1.8-3
．． 1 (10), 4.4 (IH), 4.4-4.65 (
2H), 5.8(if(), 6.0-6.3(4f(
), 8.45 (3H) and 8.51) I) Ill (3f
().

This cephalosboron was prepared using cephaloglycin dihydrate (1.5 parts by weight) according to the methods of Production Examples 1.3 and 1.6.
was prepared by reacting with 1-chlorocarbonyl-2-oxo3-(2-fluorobenzylideneamino)-imidazolidine (1.07 parts by weight).

When acidified to pH 2, some of the cephalosporin was obtained as a free acid insoluble in water and ethyl acetate (0.2
Parts by weight: ■R spectrum (in paraffin oil) (carbonyl range): 1,780.1,745.1.670 and 1
, 540crrt').

The generated Tase 77'0sporin is dissolved in the organic phase, and from it 7-(Dα-[(2-oxo-3-o-fluorobenzylideneamino-imidapridin-1-yl)-carbonylaminoco-phenylacetamide)- 3-acetoxymethyl-ceph-3-em-carboxylic acid (IJ) was obtained in a yield of 0.8 parts by weight.

The following data relate to the sodium salt.

β-lactam content: 91@ According to the NMR spectrum, the substrate contained approximately 2.8 molar equivalents of H20 and 0.55 molar equivalents of sodium 2-hexanoate.

This was taken into account in the analysis. Calculated value: C49,2H4,5
N11.7 84.5 Analysis value: C49.1f (4.3N
11.7 84.9IR spectrum (in paraffin oil)
(Carbonyl range): 1,78011,730.1,
670.1.610 and 1.530 crIL'.

NMR signal (in d7-DMF), r=1.8-2.
9 (IOH), 4.0-4.4 C2H), 4.8-5
．． 1 (3H), 5.8-6.2 (4H), 6.5-6
．． 75 (2H) and Hif, 95 ppm (3H).

47.5 parts by weight of 2-oxo-imidazolidine, 38.0 parts by weight of nitrous acid, and 82.5 parts by weight of zinc powder were treated as in Preparation Example 2.1 to obtain 64.0 parts by weight of 2-chlorobenzaldehyde. Reacted with parts by weight.

15.0 parts by weight of 1-(2-chloro)-benzalimino-2-oxo-imidapridine was obtained and recrystallized from ethanol.

Melting point 216-17° C01-(2-chloro)-benzalimino-2-oxo-imidapridine 50.0 parts by weight and triethylamine 73.0 parts by weight anhydrous dioxane 4
A solution of 72.7 parts by weight of trimethylchlorosilane in 150 parts by weight of anhydrous dioxane, and 44.5 parts by weight of phosgene were reacted as in Preparation Example 2.2.

37.2 parts by weight of 1-chlorocarbonyl-2-oxo-3-(2-chloro)-benzalimino-imidapridine was obtained and recrystallized from acetonitrile.

Melting point 233-7°c. IR (paraffin oil): 1,
800crnt.

Calculated value: C46,18f (3,17N14.68 C1
24,7B analysis value: C46,I H3,2N14.6
14.1 parts by weight of ampicillin in 150 parts by volume of C124780 aqueous THF was added as in Preparation Example 13.
-Rita was reacted with 5.0 parts by weight of carbonyl-2-oxo-3-<2-oxo-3-benzalimino-imidazolidine.

6=(-D-α-[(2
11.3 parts by weight of sodium -oxo-3-(2-chloro)-benzalimino-imidazolidin-1-yl)-carbonylamino]-phenylacetamido)-penicillanate was obtained.

β-lactam content: 83 IR (KBr): C765, 1,730, 1,675*
* and 1,605 crIL'.

NMR- (CD30D): 7.92 (S + with exchangeable proton disturbance, 2H), skin, 7.3 (8H) center, 5.55 (s, LH), 5.42 (AB system, 2H)
, 4.12 (s, LH), 3.83 (S, wide width, 4H)
, 1.58 (s, 3H), 1.50 (s, 3H) δ
.

C27H26CIN6Na06S -2H20 calculated value:
C49,36H4,60N12.79 Analysis value: C49,
4H4,6N12,7 16.4 6.3 parts by weight of amoxicillin trihydrate in 80 parts by volume of 80% aqueous THF was prepared in Preparation Example 1.4. The mixture was reacted with 2.9 parts by weight of l-chlorocarbonyl-2-oxo-3-(2chloro)-benzalimino-imidazolidine as in .

6-(D-α-[(2-oxo-3-(2-chlor)-
8.5 parts by weight of sodium benzalimino-imidazolidin-1-yl)-carbonylaminoco-4-hydroxy-phenylacetamido)-pe**nidylanate were obtained.

IR (KBr): 1,760.1,720.1,65
5 and 1,600 crrL'.

NMR (CD20D): 7.95 s (IH), 7
．． 5-6.8 (8H), 5.5 (m, 3H), 4.20
(s, LH), 3.92 (s, wide width 4H), 1.
60 (s, 3H), 1.50 (s, 3H) δ
.

Cefrazine 10.5 in 100 parts by volume of 80% aqueous THF
Parts by weight were reacted with 5.7 parts by weight of l-chlorocarbonyl-2-oxo-3-42-chloro)benzalimino-imidazolidine as in Preparation Example 1.3.

7-(D-α-[(2-oxo-3
-(2-chlor)-benzalimino-imidazolidine-
1-yl)-carbonylaminoco-cyclohex-1,
10.9 parts by weight of sodium 4-genyl(1)acetamido)-3-methyl-cef-3-em-4-carboxylate was obtained.

IR (KBr): 1,770.1,735.1,66
5 and 1,590CIrL-10 C2□H26CIN6NaO6S, 2H20 calculated value: C
49,36H466N1279S4.88 C15,
39 Analysis value: C48,9H4,5N12.4 S4.4
5.0 parts by weight of cephaloglycin dihydrate in 100 parts by volume of C15,380% aqueous THF was prepared in Preparation Example 1.6. l-chlorocarbonyl-2-oxo-3(2
-chloro)-benzalimino-imidapridine (3.3 parts by weight).

7-(D-α-[(2-oxo-3(2-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl- with a decomposition temperature of 195-200°C. Cef 3-M-4
- 6.7 parts by weight of sodium carboxylate was obtained.

I R (KBr): 1,760.1,725.1,
670 and 1,600 crf L-1° NMR (CD30D/D20): 7.2-8.0 (aromatic protons and -CH=N-), 5.65 (d,
IH), 5.50 (s, IH), 5.05 (d
, superimposed on the exchangeable proton signal), 3.8
(6H), 2.10(s, 3H)δ.

C2g H26ClN6NaOBS, H20 calculated value: C50,lI H4,21N12.09 S4.
63 analysis value: C50, L H4, I N12.1
848 Production Example 17 47.6 parts by weight of 2-oxo-imidapridine, 34.5 parts by weight of sodium nitrite, and 78.4 parts by weight of zinc powder were added to Production Examples 1 and 1. and stirred overnight with 77.0 parts by weight of 3-tri**olbenzaldehyde.

65.7 parts by weight of 1-(3-chloro)-benzalimino-2-oxo-imidazolidine having a melting point of 210-212 DEG C. was obtained.

I R (KBr): 3,23013,120.1,
715.1.475 and 1,405CrfL'.

NMR(daDMSO)rn, about 7
．． 5 centers (aromatic protons, -CH=N- and NH:6
H), 3.65 (m, 4H) δ0 Calculated value: C53,70H4,51N18.79 C21
5,85 analysis value: C54, OH4,7N18.4 C
! '16.2 1-(3-
A solution of 43.3 parts by weight of trimethylchlorosilane in 80 parts by volume of anhydrous dioxane is added warmly to a boiling solution of 30.0 parts by weight of chloro)-benzalimino-2-oxo-imidapridine and 43.4 parts by weight of triethylamine; The mixture was prepared in Preparation Example 2.2. It was reacted with 26.4 parts by weight of phosgene as in .

16.2 parts by weight of l-chlorocarbonyl-2-oxo-3-(3-chloro)-benzalimino-imidazolidine having a decomposition temperature of 190°C was obtained.

The product still had a small amount of starting material.

IR (paraffin oil): 1,800crfL-1°80% aqueous THF 100 parts by volume Ampicillin 9.3
The parts by weight are determined from Production Example 1.3. The mixture was reacted with 8.7 parts by weight of 1-chlorocarbonyl-2-oxo-3-(3-chloro)-henzaliminoimidazolidine as in .

6(D-α-[(2-oxo-3-(3-chloro)benzalimino-imidazolidin-1-yl)carbonylaminoco-phenylacetamide)**-sodium penicillanate with a decomposition temperature of 215-220°C5. 0 parts by weight were obtained.

IR (KBr): 1,760.1,720. 1,6
60 and 1,600 crfL-1° 3.8 parts by weight of cephaloglycine dihydrate in 100 parts by volume of 80% aqueous THF were prepared in Preparation Example 1.6. l-chlorocarbonyl-2-oxo-3(3-chloro) as in
-Reacted with 2.5 parts by weight of benzalimino-imidazolidine.

7-(D-α-[(2-oxo-3(3-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamido)-3-acetoxymethyl- with a decomposition temperature of 212-218°C. Cef 3-M-4
-2.1 parts by weight of sodium carboxylate were obtained.

IR (KBr): 1,765.1,735.1,
665 and 1,61OcfrL-1°C2H26CIH6NaO8S, 3H20 calculated value: C4
7,65H4,42N11.49 Analysis value: C47,6H
4,8N11.5 2-oxo-imidazolidine 47.6 parts by weight, sodium nitrite 34.5 parts by weight and zinc powder 78.4 parts by weight,
and 87.5 parts by weight of 3,4-dichlorobenzaldehyde in Production Example 1゜1. The reaction was carried out as shown in .

50.4 parts by weight of 1-(3,4-dichloro)-benzalimino-2-oxo-imidazolidine having a melting point of 178 DEG to 181 DEG C. was obtained.

IR (KBr): 3,240. 1,710C
Wide width) 11.470.1,400 and 1,260 crI
L'.

NMR (d6 DMSO) = 7.95 (s, LH), 7
．． 7 (m, 3H), 7.37 (s, wide width, IH), m,
3.7 (4H) center.

Calculated value: C46, 46H3, 56N16.28 C12
7,47 analysis value: C46,4H3,6N16. l C
A solution of 30.0 parts by weight of 127,4l-(3,4-dichloro)-benzalimino-2-oxo-imidazolidine and 37.8 parts by weight of triethylamine in 250 parts by volume of anhydrous dioxane, 37.7 parts by weight of trimethylchlorosilane 80 parts by volume solution of anhydrous dixane and 23.1 parts of phosgene
The parts by weight are shown in Production Examples 2 and 2. The reaction was carried out as shown in .

l-chlorocarbonyl-2 with a decomposition temperature of 224-230°C
11.2 parts by weight of -oxo-3-(3,4 dichloro)-henseliminoimidazolidine were obtained and recrystallized from acetonitrile.

IR (paraffin oil): 1,800 CrrL'.

Calculated value: C41, 80H2, 82N13.07 C13
3,07 analysis value: C41,9H2,8N12.9C
9.4 parts by weight of ampicillin in 100 parts by volume of 132,880% aqueous THF were added to Preparation Example 1.3. Like in 1-
It was reacted with 5.0 parts by weight of chlorocarbonyl-2-oxo-3-(3,4-dichloro)-benzalimino-imidazolidine.

6-(D-α-[(2-oxo-3-(34-dichloro)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-penicillanic acid s**Thorium 5.3 parts by weight I got it.

I R (KBr): 1,765.1,725.1,
660 and 1,605cIrL-1O NMR (CD30D) near, 3-7.7 (aromatic protons and -CH=N'-), 5.61 (S, IH), 5.
50 (q, 2H), 4.18 (s, IH), 3.
85 (s, wide width, 4H), 1.58 (s, 3H)
, 1.50 (s, 3H)δ.

9.4 parts by weight of ampicillin trihydrate in 100 parts by volume of 80% aqueous THF were prepared in Preparation Example 1.3. The mixture was reacted with 3.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-(3°4-dichloro)-benzalimino-imidazolidine as in .

7-(D-α-[(2-
5.3 parts by weight of sodium oxo-3(3,4-dichloro)-benzalimino-imidazolidin-l-yl)-carbonylaminoco-phenylacetamide)-penicillanate was obtained.

IR (KBr): 1,765.1,740.1,66
5 and 1,615 crrL”.

Calculated value: C48,95N11.80 017.99 Analysis value: C49,ON11.7 018.12-oxo-
27.8 parts by weight of imidazolidine, 2 parts by weight of sodium nitrite
0. Production Example 1.1. The reaction was carried out as shown in .

22.4 parts by weight of 1-(4-bromo)-benzalimino-2-oxo-imidazolidine having a melting point of 250-2°C was obtained.

IR(KBr): 3,24013,12011,74
0.1.705.1,595.1,475.1,415
and 1.270 crfLl.

NMR (d6-DMSO): 7.67 (aromatic protons and -CH-N-), 7.30 (s, wide width, LH),
m, 3.6 (4H) δ center.

Calculated value: C44,80N3.76 N15.47 Analysis value: C44,9N3.7N15.3 l-(4-bromo)-benzalimino-2-oxo-imidazolidine 21.7 parts by weight and triethylamine 26.3 parts by weight Preparation Example 2.2. A solution of 250 parts by volume of anhydrous dioxane, 26.2 parts by weight of trimethylchlorosilane in 80 parts by volume of anhydrous dioxane, and 16.0 parts by weight of phosgene. The reaction was carried out as shown in .

1-chlorocarbonyl-2-oxo-3(4-bromo)
37.2 parts by weight of -benzalimino-imidazolidine were obtained and recrystallized from acetonitrile.

Melting point 177-180°C. IR (paraffin oil): L
800crfL-1゜cephaloglycin dihydrate 5.7
Parts by weight and l chlorocarbonyl-2-oxo-3-(4
-bromo)-benzalimino-imidazolidine (4.2 parts by weight) of Production Example 18.3. The reaction was carried out as shown in .

7-(D-α-[(2-oxo-3-(4-from)-benzalimino-imidazolidin-1-yl)-carbonylaminocophenylacetamide)-3-acetoxy with a decomposition temperature of 190-3°C Methylcef-3-M-4-
3.5 parts by weight of sodium carboxylate was obtained.

IR (KBr): 1,760.1,725.1,65
5 and 1,600CrfL-1゜47.6 parts by weight of 2-oxo-imidazolidine, 34.5 parts by weight of t-IJium nitrite, 78.4 parts by weight of zinc powder, and 60.1 parts by weight of 4-methylbenzaldehyde. Manufacturing Example 1.1. The reaction was carried out as shown in .

52.2 parts by weight of 1-(4-methyl)-benzalimino-2-oxo-imidazolidine having a melting point of 235-6°C were obtained.

**IR(
KBr): 3,23013,110,1,710 (wide width), 1,475.1,410. 1,270 (wide) C
IrL-1°NMR (d6-DMSO): 7.2-7.8 (aromatic proton, -CH=N-, NH: 6H), m, 3.7
(4H) center, 2.40 (s, 3H)δ.

Calculated value: C65,00H6,45N20.68 Analysis value:
C65,OH6,3N20.8 1-'(4-methyl)-benzalimino-2-oxo-
20.8 parts by weight of imidazolidine, 33 parts by weight of triethylamine
．． 3 parts by weight, 32.1 parts by weight of chlorotrimethylsilane and 19.8 parts by weight of phosgene were added to Production Example 19.2. The reaction was carried out as shown in .

19.6 parts by weight of l-chlorocarbonyl-2-oxo-3-(4-methyl)-benzalimino-imidazolidine having a melting point of 265-8°C was obtained.

IR (paraffin oil): 1,800cm'.

Calculated value: C54, 24H4, 55N15.82 C11
3,34 analysis value: C54,2H4,5N15.8 (
, '13.6 ampicillin trihydrate 8.1 parts by weight and 1
-chlorocarbonyl-2-oxo-3-(4-methyl)
2.7 parts by weight of benzalimino-imidazolidine was added to Production Example 2.3. The reaction was carried out as shown in .

Sodium 6-(D-α-[(2-oxo-3-(4-chloro)-benzalimino-imidazolidin-1-yl)-carbonylaminocophenylacetamide)-penicillanate with a decomposition temperature of 220-225°C5. 0 parts by weight were obtained.

I R (KBr): 1,76011,725.1,
660 and 1,600 c/rL-1° NMR (CD30D): 7.1-7.8 (aromatic protons and -CH=N-), 5.60 (s, LH)
, 5.45 (q, 2H), 4.17 (s, l
'H), 3.60 (s, wide, 4H), 2.18 (s
, 3H), 1.58 (s, 3H), 1.50
(s, 3H)δ.

C23H2g N6 Nap6S, 2H20** Calculated value: C5282N5.22 N13.2OS5.0
3 analysis value: C52,6N5.3 N12.8 85.
Production Example 10.5. The reaction was carried out as shown in .

6-(D-α-[(2-oxo-3-(4-methyl)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-4-hydroxyphenyl-acetamidoyopenicilane with a decomposition temperature of 230-5°C Sodium acid6.
8 parts by weight were obtained.

IR (KBr): 1,765.1,730. 1,6
65** and 1,61OcrIL-1O NMR (CD30D): 7.6-6.7 (aromatic proton and -CH=N-), 5.5 (m, 3H), 4,
18 (s, IH), 3.6 (m, 4H), 3.25 (
s, 3H), 1.55 (s, 3H), 1.5
0 (s, 3H)δ.

C28H2,N6NaO7S,2H20 Calculated value: C51,53N5.09 N12.87 84
．． 91 analysis value: C51,2N5.2 N12.7 8
5.5.0 parts by weight of cephaloglycine dihydrate in 50 parts by volume of 180% aqueous THF was added to Preparation Example 1.6. The reaction mixture was reacted with 3.3 parts by weight of l-chlorocarbonyl-2-oxo-3-(4-methyl)-hemethyliminoimidazolidine as in .

7-(D-α-[(2-oxo-3-(4methyl)-benzalimino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl- with a decomposition temperature of 178-80°C. Cef-3-M-4
- 5.5 parts by weight of sodium carboxylate were obtained.

I R (KBr): 1,760.1,725.1,
660 and 1,615C77L-1°C30H2g N6 NaOB S, H20 calculated value:
C53,41N12.47 Analysis value: C53,4N12.5 Production example 21 21.1 47.6 parts by weight of 2-oxo-imidazolidine, 34.5 parts by weight of sodium nitrite, and 78.4 parts by weight of zinc powder,
and 77.1 parts by weight of 4-carboxybenzaldehyde in Production Example 1.1. The reaction was carried out as shown in .

(2) 82.8 parts by weight of -(4-carboxy)-benzalimino-2-oxo-imidazolidine was obtained.

This was suspended in 200 parts by volume of methanol, and an ether solution of cyasimicun was added until the yellow color was maintained.

A short time after the clear solution has been removed, the melting point is 245-6°.
1-(4-methoxycarbonyl)-benzalimino-2-oxo-imidazolidine of C was crystallized.

IR (KBr): 2,240.1,700 (1,720
Shoulder to crfL-1) NMR (d6-DMSO): 7.6-8.1 (AB
system and s, 7.63: 5H), 7.20(s,
Wide IH), 3.88 (s, 3H), m, 3.7
(4H) δ Nakadomari・.

Calculated values: C58, 29H5, 30N17. OO019,
41 analysis value: C58, 7H5, 2N17.3 019.
6■-(4 methoxycarbonyl)benzalyl* *Minnow 2-oxoimidazolidine 17.4 parts by weight,
22.8 parts by weight of triethylamine, 22.7 parts by weight of chlorotrimethylsilane and 13.9 parts by weight of phosgene were added to Production Example 19.2. The reaction was carried out as shown in .

Decomposition temperature! 1-chlorocarbonyl-2 at 210-215°C
19.6 parts by weight of oxo-3-(4-methoxycarbonyl)-benzalimino-imidazolidine were obtained.

IR (paraffin oil): 1,800cx-".

6.2 parts by weight of empicillin trihydrate and l-chlorocarbonyl-2-oxo-3-(4-methoxycarbonyl)
- 4.6 parts by weight of benzalimino-imidazolidine in Production Example 2.3. The reaction was carried out as shown in .

6-(D-α-[(2oxo-3-44-methoxycarbonyl)-benzalimino-
imidazolidin-1-yl)-carbonylaminoco-phenylacetamido)-sodium penicillanate 5.4
Parts by weight were obtained.

IR (KBr): 1,760.1,720,1,66
5** and 1,595 cm'.

NMR (CD30D): 8.0-7.1 (aromatic protons and -CH=N-, 10H), 5. '58 (s
, IH), 5.45 (q, 2H), 4.15 (s
, IH), m, approximately 3.8 (4H), 2.30 (s
, 3H), 1.57 (s.

3H), 1.50 (s, 3H)δ.

C2, H2oN6NaO8S, 3H20 Calculated value: C49,86H5,05N12.02 S4
．． 58 analysis value: C49,7H5,2Nl 1.9 8
4.2.3 parts by weight of cephaloglycine dihydrate in 40 parts by volume of 480% aqueous THF were prepared in Preparation Example 1.6. 1-chlorocarbonyl-2-oxo-3-(4methoxycarbonyl)-benzalimino-imidapridine 2.2
Reacted with parts by weight.

7-(D-α-[(2-oxo-3-(4-methoxycarbonyl)-benzalimino-imidazolidin-I-yl)-carbonylaminoco-phenylacetamide)-3-acetoxy with a decomposition temperature of 195-200°C 1.0 parts by weight of sodium methyl-cef-3-em-4-carboxylate was obtained.

I R (KBr): 1,755.1,725.1,
665 and 1,600crfL-1°C31H2g H6Na010 S, 3 H20 calculated value: C49,34H4,67N11.1484.25
Analysis value: 4.9.1 4.5 11.1 4
．． 4 Production Example 22 A solution of l-amino-2-oxoimitazolidine (3.0 parts by weight) in water (30 parts by volume) was diluted with 5-acetoxymethyl-
Furan-2-artich (5.0 parts by weight) in water (50 parts by weight)
30 parts by volume) into the suspension while stirring and cooling with ice/water.
It was added over a period of minutes.

The mixture was then stirred for a further 20 hours at 20° C., then the precipitate was filtered off and washed with isopropanol.

The substrate was dried with P2O5 under vacuum and 70°C.

Yield: 6.6 parts by weight.

Melting point = 146°C. Calculated value: C52, 6H5, 2N16.
7 025.5 Analysis value: 52.6 5.3 1
6.8 25.8l-(5-acetoxymethyl~furfurylideneamino)-2-oxo-imidazolidine (6
, 6 parts by weight), benzene (60 parts by volume) and triethylamine (4.1 parts by volume) are added dropwise to a mixture boiling under reflux of a benzene solution of trimethylchlorosilane (3.2 parts by weight), The mixture was boiled for a further 20 hours.

The triethylamine hydrochloride was then filtered hot, rinsed with benzene, and the combined furnace liquor was added with phosgene (1.6 parts by volume).
A solution of benzene (10 parts by volume**) was added with cooling.

The mixture was left at 20° C. for 20 hours and the product was filtered out.

Yield: 4.3 parts by weight.

Melting point -184 to 85°C6IR spectrum (in paraffin oil) (carbonyl range): 1,810 and 1,745
crfL'.

Calculated value: C45,9H3,8C'11.3 N13.4
025.5 analysis value: 46.4 3.9 tl,
+ 13.4 25.3 This penicillin was produced in Production Example 1.
．． 3. empicillin trihydrate (2.0 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(
It was prepared by reacting 5-acetoxymethyl-furfurylidene-amino)-imidapridine (1.75 parts by weight) with each other.

Yield: D-α-([2-oxo-3-(5-acetoxymethylfurfurylideneamino]-imidapridine-l-
Ilyocarbonylamino)-benzylpenicillin2.
8 parts by weight.

Melting point: The substrates stuck together at about 190° C. and then gradually decomposed.

NMR signal, r = 2.37 (L H), 2.5
2.85 (5H), 3.15-3.30 (d, IH),
3.40-3.55 (d, IH), 4.43 (
IH), 4.43-4.70 (AB, 2H), 4.93
(2H), 5.87 (IH), 5.98-6.30 (
4H), 7.94 (3H), 8.45 (3H) and 8.
52p disorder (3H).

IR spectrum (in paraffin oil) (carbonyl range)
:1,767 (shoulder), 1,734.1,66011.6
00 and 1,530-1,510 crn'.

β-lactam content: 92%.

This cephalosporin was produced in Production Example 1.3. and cephaloglycine dihydrate (2,0 parts by weight) and 1 chlorocarbonyl-2-oxo-3-(5-acetoxymethyl-furylidene-amino) according to the method described for penicillin in 1.6° - prepared by reacting imidapridine (1.5 parts by weight) with each other.

When acidified, part of the cephalosporin was obtained as a precipitate insoluble in water and in the organic phase (ethyl acetate): (yield: o, i parts by weight: sticky at mp -205°C, 260
Gradual decomposition down to °C, no melt formation: ■R spectrum (
(in paraffin oil) (carbonyl range): 1.770.1
,726.1,678.1,600 and 1.528cr
fL').

Cephalosboron could then be precipitated from the organic phase as described.

Yield near-D-α/([2-oxo-3-(5-acetoxymethyl-furfurylidene-amino)-imidazolidine-l-ylyocarbonylamino)-phenylacetamide/-3-acetoxymethyl-cef-3 -M-4
-2.7 parts by weight of sodium carboxylate.

β-lactam content: 86%.

IR spectrum (carbonyl range): 1,770 (shoulder)
, 1,760 (shoulder), 1,730.1,680.1.6
10,1,550 (shoulder) and 1.530 crrL'.

NMR signal, r=2.33 (IH), 2.45-
2.85 (5H), 3.15-3.25 (IH), 3.
4-3.52 (IH), 4.24-4.48 (2H)
, 4.92 (2H), 5.0-5.22 (3H), 6
．． 06.27 (4H), 6.55-6.75 (2H)
, 7.96 (3H) and 8.02p yen (3H).

Melting point = 220'C and decreases with decomposition.

Preparation of 2-chlorofuran-5-aldehyde by H Example 1.1. Reacted with l-amino-2-oxo-imidazolidine as in .

1-(5-Chlorfurylideneamino)-2-oxoimidazuridine having a melting point of 173-175°C was obtained.

NMR (d6 DMSO)”, 7.45 (s, IH
), 7.26 (s, wide, IH), 6.77 (d,
IH), 6.60 (d, LH), 3.55 (m,
4H) δ.

Calculated value: C45, ON3.7 N19.7 Cl1
6.6 Analysis value: 45.5 3.8 20.0
16.2l-(5-chlorfurylideneamino)-2-
20.0 parts by weight of oxo-imidazolidine, 31.8 parts by weight of triethylamine, 31.8 parts by weight of chlorotrimethylsilane
Parts by weight and 18.6 parts by weight of phosgene were added to Production Example 1.2. The reaction was carried out as shown in .

After recrystallization from acetonitrile, the decomposition temperature is 193 ~
1-chlorocarbonyl-2-oxo-3-(
5-Chlorfurylideneamine)-imidazolidine 16.
5 parts by weight were obtained.

Calculated value: C125,68 Analytical value: C125,7 80% aqueous TI (1-chlorocarbonyl-2-oxo-3-(5-chlorofurylideneamino) in 100 parts by volume of F
- 3.9 parts by weight of imidapridine and 5.0 parts by weight of empicillin trihydrate were added to Production Example 1.3. The reaction was carried out as shown in .

Sodium 6-(D-α-[(2-oxo-3-(5-chlorofurylideneamine)-imidazolidin-1yl)-carbonylaminoco-phenylacetamide)-penicillanate 4 with a decomposition temperature of 210-220°C .7 parts by weight were obtained.

IR (KBr): 1,76011,720,1,66
0.1.60011,525.1,470.1,405
．． 1,270 and ** and 1,225 cr/L'.

NMR (CD30D) Near, 55 (s, L H
), 7.3 (m, 5H), 6.52 (a, tH), 6.
35 (d.

IH), 5.56 (s, IH), 5.43 (pseudoq, 2H), 4.12 (s, IH), 3.
82 (s.

Wide width, 4H), 1.55 (s, 3H), 1.48
(s.

3H) δ.

C25H24CIN6NaO7S・1-H2O2 Calculated value: C47,06H4,27N13.18 S5
．． 04 analysis value: 47.1 4,7 13.2
5.0 parts by weight of cephaloglycine dihydrate and l-chlorocarbonyl-2-oxo-3-(5-chlorfurylideneamino)- in 100 parts by volume of 280% aqueous THF.
3.5 parts by weight of imidazolidine were reacted as in Preparation 16°.

7-(D-α-[(2-
Obtained 4.3 parts by weight of sodium oxo-3-(5chlorfurylideneamino)-imidapridin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em-4-carboxylate. Ta.

I R (KBr): 1,765.1,720.1,
66011.595.1, 520.1, 405 and 1,
225crrL-1°NMR (CD30D/D20):
7.48 (S) and 7.37 (m, total 6H), 6.7
8 (LH), 6.34 (IH), 5.65 (IH), 5
．． 43 (IH), 4.95 (overlaps with exchangeable proton signal), 3.8 (s, wide, 4H), 3.6
(overlaps with solvent signal), 2.06 (s, 3
H) δ.

Water adjusted to pH 5 with sulfur-IJium hydroxide solution 350
To a solution of 1-amino-2-oxo-imidazolidine hydrochloride in parts by volume was added 33.5 parts by weight of 2-bromo-furan-5-aldehyde dissolved in parts by volume of THF IOO, and the mixture was stirred overnight.

The precipitate was filtered out, washed with water, and recrystallized from methanol.

30.0 parts by weight of 1-(5-promfurylideneamino)-2-oxo-imidazolidine having a decomposition temperature of 153 to 158°C was obtained.

IR (KBr): 1,720,1,58011,41
0°1.265 and 1,245crrL-1°NMR (
do DMSO) near, 55 (s, IH)
, 7°31 (s, IH), 6.80 (AB, 2H
), m.

Approximately 3.6 (4H) δ.

1-(5-promfurylideneamino)-2-oxo-imidazolidine 30.0 parts by weight, triethylamine 37,
8 parts by weight, 36.8 parts by weight of chlorotrimethylsilane and 23.0 parts by weight of phosgene in Production Example 1.2. The reaction was carried out as shown in .

After recrystallization from acetonitrile, the decomposition temperature was 190-
1-chlorocarbonyl-2oxo-3-(
5-promfurylideneamino)imidapridine 21,6
Parts by weight were obtained.

IR (paraffin oil): 1,815cIrL'.

1-chlorocarbonyl- in 80 parts by volume of 80% aqueous THF
3.2 parts by weight of 2-oxo-3-(5-promfurylideneamino)-imidapridine and 6 parts by weight of empicillin trihydrate
．． 1 part by weight was added to Production Example 1.3. The reaction was carried out as shown in .

Sodium 6-(D-α-[(2-oxo-3-(5-promphurylideneamino)-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-penicillanate with a decomposition temperature of 220-228°C 3.7 parts by weight were obtained.

*IR(KBr): 1,76011,725.1,
660°1600.1,400 and 1,225cIrL
'.

NMR (CD30D) near, 60 (s, LH), 7.4
6 (s, 5H), 6.83 (d, IH), 6.52 (d
.

LH), 5.58 (s, LH), 5.50 (AB
.

2H), 4.18 (s, IH), 3.85 (s,
Wide width, 4H), 1.57 (s, 3H), 1.50
(s,3H)δ.

4.5 parts by weight of cephaloglycine dihydrate and 1-chlorocarbonyl-2- in parts by volume of 80% aqueous THF IOO
3.3 parts by weight of oxo-3-(5-promfurylideneamino)-imidazolidine were reacted as in Preparation 1.6°.

7-(D-α-[(2-oxo-3-(5-bromofurylideneamino)-imidazolidin-l-yl)-carbonylaminoco-phenylacetamido)-3-acetoxymethyl with a decomposition temperature of 187-196°C -Seph-3-M-
3.3 parts by weight of sodium 4-carboxylate were obtained.

I R (KBr): 1,775.1,715.1,
655.1.450 and 1,275CrrL-1°NM
R (CD30D/D20) Near, 55 (s,
L H), 7.4 (m, 5H), 6.80 (d'-
, LH), 6.50 (d, LH), 5.6 s (a
, tH), 5.50 (s.

IH), 4.96 (d, IH), 4.92 (overlaps with the exchangeable proton signal), 3.80 (s.

Wide width, 4H), 3.4 (overlaps with solvent signal), 2
．． 08 (s, 3H)δ.

Production example 25 Water adjusted to pH 4.5 with sodium hydroxide solution 100
2-Methyl-furan-5-aldehyde to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 0 parts by volume 98.
3 parts by weight were added and the mixture was stirred overnight.

The precipitate was filtered out, washed with water, and recrystallized from methanol.

1(5-methylfurylideneamino) with melting point 194-6°C
126 parts by weight of -2-oxoimidazolidine was obtained.

I R (KBr): 3,32011,735.1,
710.1.480.1, 420.1, 395 and 1,
245cm'ONMR(d6-()MSO):
7.57 (s, l H), 7.22 (s, wide,
IH), 6.67 and 6.25 (AB series, 2H), 3.
65 (m, 4H), 2.38 (s, 3H) δ.

Calculated value: C55,95N5.74 N21.75 Analysis value: 56.0 5.8 21°31-(5
-Methylfurylideneamino)-2-oxo-imidazolidine (50.0 parts by weight), triethylamine (84.3 parts by weight), chlorotrimethylsilane (84.0 parts by weight) and phosgene (51.4 parts by weight) in Production Example**1.2. The reaction was carried out as shown in .

After recrystallization from acetonyl-IJ, the decomposition temperature was 18
50.7 parts by weight of 1-chlorocarbonyl-2-oxo-3-(5-methylfurylideneamino)imidazolidine having a temperature of 0S-186°C was obtained.

IR (paraffin oil) 1,815crrL-1゜80%
2.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-(5-methylphenol)-imidazolidine and 6 parts by weight of empicillin trihydrate in 80 parts by volume of aqueous THF
．． 1 part by weight was added to Production Example 1.3. It reacted like this.

Sodium 6-(D-α-[(2-oxo-3-(5-methylfurylideneamino)-imidazolidin-1-yl)-carbonylaminoco-phenylacetamido)penicillanate 4 with a decomposition temperature of 210-220°C .2 parts by weight were obtained.

* * IR (KBr): 1,760.1,720,1,66
01.600.1,525 and 1,410CrrL'.

NMR (CDsOD)”, 7.62 (s, IH), 7.
35 (m, 5H), 6.75 (d, IH), 6.
13 (d.

LH), 5.60 (s, IH), 5.45 (A
B, 2H), 4.18 (s, LH) 3.83 (s
, wide width, 4H), 2.35 (S, 3H), 1.56
(s, 3H), 1.49 (s, 3H).

Production Example 1: 4.4 parts by weight of cephaloglycine dihydrate and 2.6 parts by weight of l-chlorocarbonyl-2-oxo-3-(5-methylfurylideneamino)-imidazolidine in 80 parts by volume of 80% aqueous THF. .6. The reaction was carried out as shown in .

7-(D-α-[(2-oxo-3-(5-methylfurylideneamine)imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3-acetoxymethyl-cef-3-em- 4-Sodium carboxylate 4
．． 4 parts by weight were obtained.

I R (KBr): 1,76011,725.1,
66011.600.1, 525.1, 405 and 1,
225cfrt-1°NMR (CD30D) near, 70
(s, IH), 7.40 (m, 5H), 6.80 (d
, LH), 6.20 (d.

IH), 5.75 (d, LH), 5.68 (s,
LH), 4.95 (m, overlaps with the exchangeable proton signal), 3.88 (s, wide, 4H), 3.45 (
overlaps with the solvent signal), 2.35 (S, 3H), 2
．． 04(S,3H)δ.

Production Example 26 14.0 parts by weight of 5-methyl-3-formyl-isoxazole was added to Production Example 25.1. 1-amino-2-oxo-imidazolidine hydrochloride 25% in 100 parts by volume of water as in
．． 6 parts by weight.

After 90 minutes, the filtrate was separated, washed with water, dried, and recrystallized from anhydrous acetonitrile.

12.5 parts by weight of 1-(5-methyl-isoxazol-3-ylmethyleneamino)-2-oquin-imidazolidine having a melting point of 195-7°C was obtained.

IR (paraffin oil): 3,22011.695 and 1
, 610crnt.

NMR (CD30D)”, 7.65 (s, IH), 7.
47 (s, wide width, IH), 6.53 (s, IH)
, 3.7 (m, 4H), 2.50 (s, 3H) δ
.

Calculated value: C49,48H5,19N28.85 Analysis value:
49.6 5.2 29.2* 1-(
12.0 parts by weight of 5-methyl-isoxazol-3-yl-methyleneamino)-2-oxo-imidazolidine, 21.0 parts by weight of triethylamine, 20.8 parts by weight of chlorotrimethylsilane and 12.3 parts by weight of phosgene were produced. Example 1.2. The reaction was carried out as shown in .

19.8 parts by weight of 1-chlorocarbonyl-2-oxo-3-(5-methyl-isoxazol-3-yl-methyleneamino)-imidazolidine having a melting point of 199-203°C was obtained.

This compound still contained a small amount of triethylamine hydrochloride which did not need to be removed as it did not interfere with subsequent reactions.

IR (paraffin oil): 1,790cm t08
Ampicillin trihydrate 1 in 100 parts by volume of 0% aqueous THF
6.5 parts by weight and l-chlorocarbonyl 2-oxo-3
9.5 parts by weight of -(5-methylisoxazol-3-yl-methyleneamino)-imidapridine was added to Preparation Examples 1 and 6. The reaction was carried out as shown in .

7(D-α-[(2-oxo-3-(methylinxacil-3-yl-methyleneamino)-imidapridine-1
-yl)carbonylaminoco-phenylacetamide)
- 1.0** parts by weight of sodium penicillanate were obtained.

IR (KBr): 1,760.1,730,1,66
0.1.60011, 525.1,395 and 1,22
5CrrL'.

NMR (CDsOD/D20) Near, 72 (
s, lH); 7.38 (s, 5H)
, 6.62 (s, IH), 5.53 (s, IH)
, 5.43 (m, 2H), 4.13 (s.

IH), 3.90 (m, 4H), 2.45 (s
, 3H), 1.53 (s, 3H), 1.48
(s, 3H) 18.1 parts by weight of cephaloglycine dihydrate in 150 parts by volume of 80% aqueous THF and l-
Chlorcarbonyl-2-oxo-3-(methylisoxazol-3-yl-methyleneamino)-imidazolidine 9
．． 5 parts by weight were reacted as in Preparation Example 16.

7-(D-α-[(2oxo-3-(methylisoxazol-3-yl-methyleneamino)-imidazolidin-1-yl)carbonylaminoco-phenylacetamide)- with a decomposition temperature of 215-220°C. 3-acetoxymethyl-
2.2 parts by weight of sodium Cef-3-M-4 carboxylate was obtained.

I R (KBr): 1,760.1,730 (shoulder), 1.670. 1,595 and 1,395CrfL
'.

NMR (CD30D/D20) Near, 74 (S, LH
), 7.38 (s, 5H), 6.63 (s,
IH), 5.65 (d, tH), 5.50 (s,
LH), 4.95 (overlaps with exchangeable proton signal), 3,90 (s, wide, 4H), 3.4 (overlaps with solvent signal), 2.45 (s, 3H),
2゜05(s,3H)δ.

Production Example 27 Water (216 parts by volume) and concentrated H2So4 (108 parts by weight)
1-Diacetoxymethyl-5-nitro-furan (48.6 parts by weight) in a mixture of was boiled under N for 15 minutes, then the mixture was cooled and the 5-nitrofurfuraldehyde formed was trapped in ether. After removing the ether, it was dissolved in 100 parts by volume of methanol.

To this solution was added 1-amino-2-oxoimidazolidine hydrochloride (27.5 parts by weight) in water (100 parts by volume).
A solution of was added.

After 4.5 hours, the fractionated product was filtered, washed with water, and dried.

** Yield: 42.1 parts by weight.

Melting point = 259-260°C (Kofler bench).

Calculated value: C42,9H3,6N25.0 028.6 Analysis value: 42.8 3.7 25.2 29.
1 8.0 parts by weight of the above product (27,1) was added to Production Example 1.
．． 2. and reacted with phosgene (2.6 parts by volume) as described in .

Yield: 5.2 parts by weight.

Melting point -188-1900C (Kofler Bench).

This standard contained a small amount of triethylamine hydrochloride (mostly removed by washing with methylene chloride), but this did not interfere with the subsequent reaction.

This penicillin was produced in Production Example 1.3. Empicillin trihydrate (1.5 parts by weight) and l-chlorocarbonyl-2-oxo-3-(5-nitrofurfurylidene-amino)-imidazolidine (1.1 parts by weight) were mixed together as described in . It was produced by reacting.

After the treatment, 0.7 parts by weight of crude sodium salt was obtained.

To purify this, it was suspended in a small amount of water.
The undissolved material was separated in the oven and dried (first yield 20.3
parts by weight).

The aqueous FFj was covered with ethyl acetate and acidified to pH 1.5, then the sodium salt was precipitated by the method described above (second yield: 0.2 parts by weight).

Total yield: D-α-((2-oxo-3-(5-nidrofurylideneamino)-imidazolidine 1-ylyocarbonylamino)-benzylpenicillin sodium salt 0.
5 parts by weight.

β-lactam content (according to NMR spectrum and elemental analysis): 44%.

This substrate contained an additional 44% of product with the β-lactam ring open (the reaction mixture was left at 20° C. for several hours after acidification).

According to NMR spectra and analysis, the substrate contained 4.8 molar equivalents of water (including water consumed in cleavage of the β-lactam ring).

This was taken into account in the analysis. Calculated value: C42,4H4,8
N13.8 84.5 Analysis value: 42.1 4.8
13.8 4.3 Melting point - gradually decomposes from about 260°C.

IR spectrum (carbonyl range): 1,775 (shoulder)
, 1,745.1,665, ■, 5.90 and 1.51
5C1rL'O (in Nujol).

This cephalosporin was produced in Production Example 1.3. and cephaloglycin dihydrate (4,0 parts by weight) and l-chlorocarbonyl-2-oxo-3-(5-nidrofurylidene-amine) according to the method described for penicillin in -Imidazolidines (2.5 parts by weight) were reacted with each other.

When the reaction mixture without tetrahydrofuran was made acidic, only a portion of the cephalosporanic acid dissolved in ethyl acetate.

The other part precipitated.

The sodium salt was obtained from both components according to the method described above.

Yield near-D-α/([2-oxo-3-(5nitrofurfurylidene-amino)-imidapridin-1-ylyocarbonylamino)-phenylacetamide/-3
2.8 parts by weight of sodium -acetoxymethyl-cef-3-em-4-carboxylate.

Melting point = decomposition from about 230°C to 260°C (Kofler bench) without obvious melting.

β-lactam content (determined by iodometry): 84%0
**NMR
Signal (in d6-DMF), r=1.92.9 (8
H), 4.14.5 (2H), 4,95.2 (3H)
, 6.0 (4H), 6.6-6.85 (H and s, op
pm/3H).

IR spectrum (carbonyl range): 1,76 (shoulder),
1,725.1,670.1,600 and 1.510c
x' (Nujol) Preparation Example 28 28.1 This substrate was prepared by preparing 1-amino-2-oxo-imidazolidine (1
, 2 parts by weight) and 5-methoxycarbonyl-furfural (1.8 parts by weight) at 20°C for 60 minutes.

Yield = 2.7 parts by weight.

Melting point = sticky from 88°C (Kofler Bench).

Production Example 1: 2.6 parts by weight of the above product (29,1,)
22, and then reacted with phosgene (0.8 parts by volume).

Yield: l, 5 parts by weight.

Nene melting point = (crude product - still contains some triethylamine hydrochloride) = decomposed at about 220°C (Kofler Bench).

This penicillin was produced in Production Example 1.3. empicillin trihydrate (0.87 parts by weight) and lchlorocarbonyl-2-oxo-3-(5-methoxylfurfurylidene-amino)-imidapridine (0.65 parts by weight) as described in
parts by weight) with each other.

Yield: D-α-([2oxo-3-(5-methoxylponylfurfurylideneamino)-imidazolidine-1-
yl]carbonylamino)-benzylpenicillin 0.5
Weight part.

β-lactam content (determined by iodometry) = 80%.

Melting point = 185-210' C1 decomposition (Kofler bench)
.

IR spectrum (carbonyl range): 1,770.
1.730.1,670, 1,605 and 1,530c
rrL1 (in Nujol) Preparation Example 29 This material is prepared from 1-amino-2-oxo-imidazolidine (1,3 parts by weight) and **5-ethoxycarbonyl-furfural (2,6 parts by weight) in aqueous methanol. Manufactured.

Yield: 3.1 parts by weight.

Melting point (crude product) = 135-138°C (Kofler bench).

2.85 parts by weight of the above product (29,1) was added to Production Example 1.
2. As in (however, dioxane is used as a solvent)
It was silylated and reacted with phosgene (0.9 parts by volume).

* * Yield: 1.1 parts by weight.

Melting point (crude product) = 230-33°C (Kofler bench).

29.3 This penicillin was prepared according to Preparation Example 1.3. empicillin trihydrate (1.3 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(5-ethoxycarbonyl-furfurylidene-amino)-imidazolidine (1.0 parts by weight) as described in . They were produced by reacting with each other.

Yield: D-α-([2-oxo-3-(5-ethoxycarbonylfurfurylideneamino]-imidazolidine-1
-Ilyocarbonylamino)-benzylpenicillin 0
．． 8 parts by weight.

β-lactam content (determined by iodometry) = 92% (this substrate contained approximately 6% of the product from which the β-lactum ring was cleaved).

) Melting point - approx. 220°C, decomposition (Kofler bench).

IR spectrum (carbonyl [circled): 1,775-1,
790, 1,740.1, 675.1, 610 and 1.
520-1,540cm' (in Nujol).

According to analysis and NMR data, the penicillin contained 4.3 molar equivalents of Hondori and 0 of sodium 2-ethylhexanoate.
．． It contained 16 molar equivalents.

This was taken into account in the analysis.

Calculated value: C46,7N5.3 N11.2 84.3
Analysis value: C46,7N5.6 N11.2 84.5
Preparation Example 30 This intermediate product was obtained by 1N hydroxylation of l-amino-2-oxo-imidazolidine hydrochloride (6.9 parts by weight) I
It was prepared by dissolving in Jum solution (50 parts by volume), adding 4tert-butyl-benzaldehyde (8.0 parts by weight) and stirring the mixture for 24 hours at 20<0>C.

The precipitated product was recrystallized from acetonitrile.

Yield: 5.9 parts by weight.

Melting point = 208°G (Kofler bench).

This substrate was prepared in Preparation Example 1.2. By silylation with triethylchlorosilane (4.4 parts by weight) and subsequent reaction with phosgene (2.1 parts by volume), but using dioxane as solvent, the above product (30
, 1,).

* * This substrate still contained some triethylamine hydrochloride.

IR spectrum (COCl): 1,808 crfL
'(Nujol).

This penicillin is produced in Production Example ①, 3. Reacting empicillin trihydrate (2.2 parts by weight) and 1-chlorocarbonyl-2-oxo-3-(4-tertbutyl-benzalimino)-imidapridine (2.0 parts by weight) with each other as described in . Manufactured by.

Yield: D-α-([2-oxo-3-(4-tert-
2.7 parts by weight of butyl-benzalimino-imidazolidin-1-yl]-carbonylamino)benzylpenicillin.

β-lactam content (determined by iodometry): 83% (this penicillin contains approximately 1% β-lactam cleavage product)
0% content).

Melting point - Sticky from about 240'C, dark melt at about 259°C, which solidifies rapidly as a result of decomposition.

** NMR signal (in CD20D), r=2
．． 152.8 (IOH), 4.4 (LH), 4.4-4
．． 65° (2H), 5.85 (LH), 6.3 (wide width,
4H), 8.45 (3H), 8.52 (3H) and 8.
75pI)m(9H).

According to the NMR spectrum, this substrate contained 1.8 molar equivalents.

This was taken into account in the analysis.

Calculated value: C55, L H5, 8N12.4 84.7
Analysis value: 55.1 5,9 12.4 4.
8IR spectrum (carbonyl range): 1,772
．． 1.730. 1,672.1,610 and 1,51
5-1.530ctrt' (in Nujol).

Production Example 30' This cephalosporin was prepared in Production Examples 1, 3. and cephaloglycine dihydrate (1,5 parts by weight) and lchlorocarbonyl-2-oxo-3-(3-pyridyl-methylidene-amino)-imidazo according to the method described for penicillin in 1,6° It was prepared by reacting lysine (0.8 parts by weight) with each other.

After removing THF and acidifying the mixture to pH 1,5,
The free cephalosporanic acid was isolated as a precipitate (0.8 parts by weight), insoluble in water and in ethyl acetate: mp ca.
Decomposition starts at ℃, does not clearly melt until 260℃: ■
R absorption band: 1,77011.745.1,675 and 1
, 520-1,550 crIL-' (Nujol method).

The acid was dissolved in a small amount of dimethylformamide and 1.3 parts by volume of methanol-containing ether solution of about IM2-sodium ethylhexanoate was added to precipitate the sodium salt of the cephalosporin with ether.

Yield near 1D-α-[(2-oxo-3-/3-pyridyl-methylideneamino/-imidazolidin-1-yl)
-carbonylaminoco-phenylacetamide)-3-
0.6 parts by weight of sodium acetoxymethyl-cef-3-em-4-carboxylate.

Melting point=The fine powder sample jumped from 242°C on the Koffler heating bench, immediately became a clear melt, then quickly decomposed and solidified, not melting again below 260°C.

IR spectrum (carbonyl range): 1,770 (shoulder)
, 1,760.1,73011, 670.1,605 and 1,530-50crrt' (in Nujol).

According to the NMR spectrum, this substrate contains 5.5 molar equivalents of Honsori and 0.26 molar equivalents of st-IJ2-ethylhexanoate.
It contained molar equivalents.

This was taken into consideration in the analysis.

Calculated value: C45.9N5.2 N12.5 Analysis value: C
45°9 N5.3 N12.4 β-Lakucum content (determined by iodometric titration): 82%.

Preparation Example 31 7-(D-α-amino-phenylacetamido)-3-hydroxymethyl- in 80% aqueous THF I OO parts by volume
11.0 parts by weight of cef-3-M-4-carboxylic acid and 1
-Chlorocarbonyl-2-oxo-3-furylideneaminoimidapridine 6.1 parts by weight was added to Production Example 1.6. Reacted and processed as in.

7-(Dα-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)-3 with a decomposition temperature of 215-220°C
-Hydroxymeth*holosefu 6.9 parts by weight of sodium 3-M-4-carboxylate was obtained.

NMR (CDaOD)”, 7.80 (s, l
H), 7.70 (s, IH), 6.97 (q, IH
), 5.75 (d.

IH), 5.63 (s, LH), 5.37 (overlaps with easily exchangeable protons), 4.40 (s, 2
H), 3.95 (s, wide, 4H), solvent peak (δ)
overlaps with the C-2 proton.

Preparation Example 32 7-(D-α-amino-phenylacetamide)-3-((3-methyl-
thiadiazol-5-yl)-thiomethylosef-3-
7.5 parts by weight of em-4-carboxylic acid and 6.1 parts by weight of l-chlorocarbonyl-2-oxo-3-furylideneaminoimidazolidine were added to Preparation Example 1.6. Reacted and processed as in.

7-(D-α-[(2oxo-3-furylideneamino-imidazolidin-1-4)-carbonylaminoco-phenylacetamide 13- with a decomposition temperature of 200-205°C
5.2 parts by weight of ((3-methyl-thiadiazol-5-yl)-thiomethylyoseph-3-em-4-carboxylic acid) were obtained.

I R (KBr): 1,76011,720.1,
660.1.595.1, 525.1, 475.1, 4
10.1,275 and 1,230CrrL-1O NMR (CD30D): 7.70 (s, LH), 7.
64 (d, IH), 7.33 (m, 5H), 6.
86 (d.

LH), 6.50 (dd, IH), 5.65 (d
, LH), 5.55'(s, IH), 4.90
(d, LH), 4.02 (pseudoq, 2H), 3.
85 (s, wide Fil, 4H), **3.4 (overlapping with solvent peak), 2.52 (s, 3H) δ.

Preparation Example 33 7-(D-α-amino-phenylacetamido)-3-((1-methyl-tetrable-5-yl)-thiomethyl]cefu 3-emu 4 in 100 parts by volume of 80% aqueous THF
-5.0 parts by weight of carboxylic acid and 1-chlorocarbonyl-
2-oxo-3-furylideneaminoimidazolidine 6
．． 1 part by weight was added to Production Example 1.6. Reacted and processed as in.

7-(D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylaminoco-phenylacetamide)- with a decomposition temperature of 215-220°C
3.2 parts by weight of sodium 3-((1-methyl-tetrable-5-yl)-thiomethylyosef-3-em-4**-carboxylate was obtained.

I R (KBr): 1,76011,720.1,
66011.61011,520.1,475.1,4
10 and 1.230C1rL-1°NMR (CDaOD)'', 7.73 (s, I
H), 7.63 (d, LH), 7.38 (m, 5
H), 6.88 (d.

IH), 6.54 (q, IH), 5.67 (d, I
H), 5.56 (s, IH), 4.9 (overlaps with exchangeable protons), 4.32 (s, 2H),
3.95 (s.

3H), 3.85 (s, wide, 4H), 3.45 (overlapping with solvent peak) δ.

Preparation Example 34 7-(D-αamino-phenylacetamido)-3-((5trifluoromethyl-134-thiadiazol-2-yl)-thiomethylyosef-3-em4 in 100 parts by volume of 80% aqueous THF -8.0 parts by weight of carboxylic acid and 1
6.1 parts by weight of -chlorocarbonyl-2-oxo-3-furylideneaminoimidazolidine were reacted and worked up as in Preparation Example 1.6.

7-( with a decomposition temperature of 220 °C and a β-lactam content of 76%).
D-α-[(2oxo-3-furylideneaminoimidapridin-1-yl)-carbonylaminoco-phenylacetamide)-3-((5-t-liproluomethyl-1
, 7.8 parts by weight of sodium 3,4-thiadiazol-2-yl)-thiomethylyosef-3-em-4-carboxylate were obtained.

IR (paraffin oil) dicarbonyl range: 1.765.
1,720, 1,66011.600 and 1.53QC
rrL'.

* To summarize the matters related to the present invention, be.

11 Formula (I) as follows [wherein R represents hydrogen or methoxy, Z represents a group, provided that R1 and R2 may be the same or different, and hydrogen,
optionally substituted alkyl or alkenyl group, optionally substituted cycloalkyl group, cycloalkenyl or cycloalkagenyl group, optionally substituted aralkyl, optionally substituted aryl group, optionally substituted beterocyclic group, carboxyl, methoxy carbonyl, ethoxycarbonyl,
Cyano, nitro, lower alkylcarbonyl group, or formula -CONH2, -CONHCH3, C0N(CH2)
2, SO2NH2, -8O2NHCH2 or -5O2
represents a group of N(CH3)2, or R1 and R2 together with the carbon atom to which they are bonded represent an optionally substituted saturated or unsaturated 3- to 7-membered carbon ring or hetero 1, A is -CH2-CH2--CH2-CH2-CHB represents an optionally substituted phenyl, cyclohexenyl or cyclohexagenyl group, and X is S, N, -80,802
or -CH2-, with the proviso that the carbon atom having a carboxyl group is bonded to the nitrogen atom of the β-lactam ring, and T is hydrogen, an alkenyl group C0-
0-, pyridinium, aminopyridium, carbamoyloxy, azide, cyanide, hydroxyl, an optionally substituted -S-phenyl group, or -8-ne, where net is an optionally substituted 5-membered or represents a 6-membered heterocycle], and the two possible R types regarding the asymmetric center C'' are
- and S- forms or in the form of mixtures of diastereomers resulting therefrom, and especially when Z represents the radical R2>C=N- and R1 and R2 are different, with respect to the imino group. syn or ant
β-, present in i-form or its hydrate or salt form
lactam.

2. R represents hydrogen, a group, provided that R1 represents hydrogen; and R2 represents halogen, alkyl having 1 to 4 carbon atoms, and
4 alkoxy, nitro, cyan, alkylsulfonyl having 1 to 4 carbon atoms, or phenyl optionally substituted with CH300C-; or optionally halogen, NO2, alkyl, alkoxycarbonyl having 1 to 4 carbon atoms, or CH3
furyl or chenyl substituted with COOCH2; or pyridyl, and A represents -CH2-CH2-; and B represents phenyl, hydroxyphenyl or cyclohexagenyl; and Y represents a group, with T being hydrogen , -0-Co-CH3 represents thiadiazolylthio or tetrazolylthio optionally substituted with hydroxyl or alkyl having 1 to 4 carbon atoms or CF2, and C is present in the D-=R- form, compound.

3, R2 represents halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyano, alkylsulfonyl having 1 to 4 carbon atoms, or phenyl optionally substituted with CH300C, or halogen or CH3CO0
A compound according to 2 above, which represents a furyl, chenyl or pyridyl group optionally substituted with CH2-; and T represents hydrogen, -0-CO-CH3 or hydroxyl.

4, R, A, B and Y have the same meaning as above 1: X represents S; R1 and R2 are the same or different and each is hydrogen; optionally substituted alkyl or alkenyl; optionally substituted cycloalkyl, cyclo alkenyl or cycloalkagenyl; optionally substituted aryl or optionally substituted heterocyclic group; and T is hydrogen, alkyl-COO-pyridinium, aminepyridinium, carbamoyl, azide, cyano, optionally substituted- The compound of 1 above, wherein 8-phenyl or Het represents an optionally substituted 5- or 6-membered heterocyclic ring.

5, R, A and B are as defined in 2 above, and R2 represents phenyl optionally substituted with halogen, alkoxy having 1 to 4 carbon atoms, nitro, cyan, or alkylsulfonyl having 1 to 4 carbon atoms, or halogen represents a furyl or chenyl group optionally substituted with; and T is -C)-CO-CH3
The compound of 4 above, which represents.

31 A pharmaceutically acceptable salt of any of the compounds 6 to 26 above.

32 A pharmaceutically acceptable salt of the compound of any of 27 to 30 above.

33 Solu-IJum salt of any of the compounds 6 to 26 above.

34 Solu-IJum salt of any of the compounds 27 to 30 above.

35 Compounds of 1 above as specifically described.

36 Compound 1 above as described in Table A.

37 number A I a (1) J A I a (3) ~ (7
) : A Ib (1) : A It (7) ~ (9
) and (18) ; A In(1) ? (4) and (5), AIV(1)-(8); AIV(i)-(3)
, (6) and (7), B I (aXl) , (
3) and (6), B I b (1); B II α9)
and B V (1), (6) and (7), the compound of 1 shown in Table A above.

38 Production Examples 13-15; 23-26, 38-35゜43
;44;53;63-66;73-75;83
; The compound of 1 described above in either 93 or 103.

39 Production example 84, 85; 94, 104, 105° 113
〜116,123;133〜16:143;144;1
53;154;163-166;173;174;18
3;184;193;203-205;213;214
; The compound of 1 described above in either 223 or 224.

40 Production Example 233; 234; 243.244
;253;254.263;264.273
.

274; The compound of the above 1 described in any of 283.293.303 and 31-35.

41 In the presence of a solvent and optionally an acid binder, a compound of the formula [wherein R, B, C, , , Z and A are as defined in 1 above, and W represents a halogen, azide or other removable nucleophilic group] and optionally convert the obtained β-lactam into a salt, or A method for producing the compound according to item 1 above, which comprises converting the obtained salt into an acid.

42. The method of 41 above, wherein the reaction is carried out at a temperature of -20 to +50°C.

43. The method of 41 or 42 above, characterized in that the compound is as defined in 2 or 40 above.

44. The method of 43 above, wherein the compound is as defined in 3, 27-30 and 39 above.

45. The method of 36 or 37 above, characterized in that the compound is as defined in 4-26, 37 or 38 above.

46 A method for producing the compound of 1 above, substantially as described above in any of the production examples shown in 38 above.

47 A method for producing the compound of 1 above, substantially as described above in any of the production examples shown in 39 above.

48 A method for producing the compound of 1 above, substantially as described above in any of the production examples shown in 40 above.

49 The above 1 produced by any of the methods 41 to 48 above
compound.

50 Contains any of the compounds 1 to 40 and 49 above as an active ingredient, mixed with a solid or liquefied gas diluent, or mixed with a liquid diluent excluding a solvent with a molecular weight of 200 or less except in the presence of a surfactant. A pharmaceutical composition characterized in that:

51. A pharmaceutical composition comprising any of the compounds of 1 to 40 and 49 above as an active ingredient in the form of a sterile or isotonic aqueous solution.

52 The composition of 50 or 51 above, characterized in that the active ingredient is contained in an amount of 0.5 to 95% by weight.

53 activity is above 3,27~30,32,34゜36
．． 39. The composition of 50 to 52 above, characterized in that it is any one of the compounds of 39.

54 active fraction is above 4~26,31,33,37°38
The above-mentioned 50-
52 compositions.

55. A drug in dosage form, characterized by containing any of the compounds of 1 to 40 and 49 above, either alone or in admixture with a diluent.

56 A tablet containing any of the compounds of 1 to 40 and 49 above alone or in combination with a diluent;
Drugs in pill, dragee, capsule, ampoule or herbal form.

57 The compound is 3,27-30,32,34°36
．． 56. The drug according to 55 or 56 above, which is any one of the compounds described in 39.

58 The compound is 4-26,31,33,37°38
The drug according to 55 or 56 above, which is any one of the compounds.

59. For the treatment of bacterial diseases in soil and animals, characterized in that the active compound of any of the above 1 to 40 and 49 is administered to the animal alone or in admixture with a diluent or in the form of a drug according to 55 or 56 above. Eradication method.

59. The method according to claim 59, characterized in that the active compound is administered in an amount of 20 to 200 kg/ky body weight/day.

61. The method of 59 or 60 above, characterized in that the active compound is administered orally or parenterally.

62 active ingredients listed above 3,27-30,32.34°36
．． 62. The above-mentioned methods 59 to 61, characterized in that the compound is any one of 39.

63 active fraction is above 4~26,31,33,37°38
The above-mentioned 59-, characterized in that it is any one of the compounds
61 methods.

64. A drug-containing food characterized by comprising a nutritional substance and the compound 1 or 2 above as an active ingredient.

65 active ingredients are the above 3,27-30,32,34°36
, 39.

66 active fraction is above 4~26,31,33,37°38
64 above, characterized in that it is a compound of
food.

Claims (1)

[Claims] 1 Formula (1) Here, R1 represents hydrogen, and R2 is optionally halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyan, or 1 to 4 carbon atoms. a phenyl group or β-phenylethynyl group optionally substituted with alkylsulfonyl or methoxycarbonyl; 5 optionally substituted with methyl
or 6-membered heterocyclic group, B represents an optionally substituted phenyl, cyclohexenyl or cyclohexagenyl group, X represents S, SO or SO2, with the proviso that a carboxyl group is bonded to the nitrogen atom of the β-lactam ring, and T is hydrogen; alkyl-CO-O
-, pyridinium, aminopyridinium, carbamoyloxy, azide, cyano or hydroxyl group; optionally substituted -S phenyl group; or -8-He, where Het is optionally substituted 5- or 6-membered [representing a heterocyclic ring of members], and the two possible R types with respect to the irregular center C
- and S-configuration or in the form of a mixture of diastereomers resulting therefrom, and the group "2) with respect to c = N-, syn or a
β-lactams, which may be in any of the nti forms, or exist in the form of their hydrates or salts. 2 R2 is optionally halogen, alkyl having 1 to 4 carbon atoms,
Alkoxy having 1 to 4 carbon atoms, nitro, cyano, 1 carbon number
phenyl optionally substituted with ~4 alkylsulfonyl or methoxycarbonyl: or optionally halogen, NO
2, represents furyl, chenyl or pyridyl in which alkyl or alkoxy having 1 to 4 carbon atoms may be substituted with alkoxycarbonyl or acetoxymethyl having 1 to 4 carbon atoms, and B is phenyl, hydroxyphenyl or cyclohexagenyl represents; and represents, where T is hydrogen and -0-C! 0-0H3 represents thiadiazolylthio or tetrazolylthio optionally substituted with hydroxyl or alkyl having 1 to 4 carbon atoms or CF3; and the C rice is in the D-(-R,-) configuration. A compound according to claim 1. 3 R2 is optionally halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyano, or 1 to 4 carbon atoms
4 represents phenyl optionally substituted by alkylsulfonyl or CH300C-, or represents a furyl, chenyl or pyridyl group optionally substituted by halogen or CH3CO0CH2-; and T is hydrogen, -0-00 A compound according to claim 2, which represents -CH3 or a hydroxyl group. 4R', B and Y have the same definitions as in claim 1; X represents S; R2 is an optionally substituted phenyl group as defined in claim 1; is a heterocyclic group which may be 2. A compound according to claim 1, wherein Het represents an optionally substituted heterocyclic 5- or 6-membered ring. 5 Even if the definitions of R1 and B are the same as in claim 2, and R2 is optionally substituted with halogen, alkoxy having 1 to 4 carbon atoms, nitro, cyano, or alkylsulfonyl having 1 to 4 carbon atoms, 5. A compound according to claim 4, which represents a phenyl group or a furyl or chenyl group optionally substituted with halogen; and T represents 0-Oo-OH3.