JPS59172494A - Beta-lactam antibacterial - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a group of microorganisms that have antibacterial activity and are of value in the treatment of infections in animals, especially mammals, including humans, caused by a wide range of microorganisms, especially Durham-negative microorganisms. The present invention relates to novel β-lactam derivatives. The invention also relates to processes for preparing such compounds, intermediates for use in preparing such compounds, and pharmaceutical compositions containing these antimicrobially active compounds.

The present invention relates to compounds of the formula (I) 1-1O HH (wherein Y is a compound of the formula (a), (b), (C) or C or (d)
It is a group represented by CI-13, and R and 1 are phenyl, substituted phenyl, cyclohexenyl, cyclohexagenyl, or hydroxy, amino, halogen, substituted amino, or C1
a 5- or 6-membered heterocycle containing up to 6 heteroatoms selected from oxygen, sulfur or nitrogen which may be substituted with -6 alkoxy; R2 is hydrogen or C1 which may be substituted -6 alkyl group, and R3
is an optionally substituted 5- or 6-membered heterocyclic group containing 1 or 2 nitrogen heteroatoms, or R
2 and R3 together with the nitrogen atom to which they are bonded form an optionally substituted 5- or 6-membered heterocyclic group containing 1 or 2 nitrogen heteroatoms, 1(, 4 is carbamoyl, carbamoyl (Ct a) Alkyl, ami/
(C16)alkyl, di(C+t,alkyl)amino(C,+s)alkyl, hydroxy(CI-s)alkyl, sulfo(C+-a)alkyl, C2-6alkenyl or carboxy(C1-e)alkyl; , and R5 is carbamoyl or C-6 alkyl), or its pharmaceutically suitable salt or ester that can be hydrolyzed in vivo.

Preferably substituted phenyl as Jl is cl-e alkyl, phenyl, halogen, C1-6 alkoxy, amino, nitro, hydroxy, C1-6 alkylamino, C
l-6 alkylcarbonyloxy, carbonyl, C1-
6 alkoxycarbonyl, C1-a alkoxycarbonyloxy, halo(Cr-a)alkyl, oxo(C1-
6) Alkyl, C1-6 alkylcarbonyl, aryloxy, aralkyloxy, arylcarbonyl, C
It is a phenyl group substituted with up to 6 groups selected from 1-6 alkylamino or di(Ct-6) alkylamino.

In formula (I), the group R1 is preferably phenyl-4-hydroxyphenyl, 6,4-di(C1-6alkylcarponyloxy)phenyl, 3,4-dihydroxyphenyl, 2-thenyl, 3-thenyl or 2-amino -4
- Thiazolyl.

Particularly preferred radicals R1 are phenyl, 6,4-dihydroxyphenyl and 3,4-diacetoxyphenyl.

Preferably R2 is hydrogen or C1-6 alkyl.

More preferably R2 is hydrogen.

Suitable substituents for R3 or R2 and R3 together as a 5- or 6-membered heterocyclic group include optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl groups; phenyl, oxo; hydroxyl group optionally substituted with alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, pyrimidyl or benzyl; optionally substituted mercapto group, alkylsulfonyl group, substituted imino group; or alkyl, Included are amine groups which may be substituted with alkenyl, cycloalkyl, phenyl, substituted phenylmodyl, habenzyl groups. Alternatively, two substituents on the ring may form additional carbocyclic or heterocyclic residues.

Preferably Y is a group of formula (a) or (b).

Preferably Y is a group of formula (a) or (d).

More preferably, Y is (wherein Z is carbamoyl, carbamoyl (Ct-a)
Alkyl, amino(C1-a)alkyl, di(CI-
e alkyl) amino (C1-s) alkyl, hydroxy (CI-s) alkyl, sulfo (CI-s) alkyl or C2-6 alkenyl).

Preferably, Z represents carbamoyl, carbamoylmethyl, aminomethyl, aminoethyl, dimethylaminomethyl, dimethylaminoethyl, hydroxymethyl, hydroxyethyl, sulfomethyl and ethynyl.

Other suitable values for Y include:

CH3 As used herein, the circled carbon atom in the formula is asymmetric, so the compound can exist as two optically active diastereomers. In general, those made from D@ chains have the highest antibacterial activity, so D compounds or DL mixtures are preferred, especially D compounds.

The compounds of the present invention can contain both ami7 groups and/or carboxyl groups, and therefore have a counterion (zwitteri
on) or can form salts with suitable acids or bases.

The formamide group has two preferred configurations, namely -
The hydrogen atoms of NH-C)10 can exist in cis or trans configuration, of which the cis configuration usually predominates.

While the β-lactam antibiotic compounds of the present invention are intended for use as pharmaceutical compositions, they are each in substantially pure form, e.g., at least 50% pure, more preferably at least 75% pure, and preferably It will be readily appreciated that it is provided with a purity of at least 95% (% is w/w). Impure formulations of compounds can be used to prepare purer forms for use in pharmaceutical compositions. Although the purity of the intermediate compounds of the present invention is not critical, it will be readily appreciated that substantially pure forms are preferred for β-lactam antibiotic compounds. Preferably, whenever possible, the compounds of the invention are obtained in crystalline form.

Examples of in vivo hydrolyzable ester groups that are suitable as pharmaceuticals include those that readily decompose in the human body to leave the original acid or salt thereof. Suitable ester groups of this type include sub-formulas (1), (11) and (song) RO-CO, CH-o, co, Rb, (+
>d/-Co CH-0)Lf 22 (song) (wherein Ra can be hydrogen, methyl or phenyl, Rb can be C1-6 alkyl, cl-a alkoxy or phenyl, or Bb is 1 together
or 1, which may be substituted with two methoxy groups,
forms a 2-phenylene group, Ro represents cl-6 alkylene optionally substituted with a methyl or ethyl group,
Rd and 1F independently represent 01-6 alkyl, Rf
represents C1-6 alkyl). Examples of suitable in vivo hydrolyzable ester groups include acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ω-acetogyethyl and Mata-pivaloyloxyethyl groups; ethoxycarbonyloxymethyl; and an alkoxycarbonyloxyalkyl group of α-ethoxycarbonyloxyethyl;
dialkylaminoalkyl, especially di-lower alkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl and second β-lactam antibiotics or β - Contains esters attached to lactamase inhibitors.

Suitable pharmaceutically suitable salts of the carboxy group of the compound of formula (I) include metal salts, for example aluminum salts, alkali metal salts such as sodium or potassium;
alkaline earth metal salts such as calcium or magnesium and ammonium or lower ammonium salts, e.g. lower alkyl amines such as triethylamine;
Hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, with cycloalkylamines such as dicyclohexylamine, or prooxyamines, dibenzylamine, N,
N-dibenzylethylenediamine, 1-ephenamine,
N-ethylpiperidine, N-benzyl-β-phenethylamine, dehydroabiethylamine, N,N'-bisdehydro-abiethylamine, ethylenediamine or bases of the pyridine type, such as pyridine, collidine or quinoline, or the known penicillins and cephalosporins. These include those with other amines that have been used to form salts with other amines.

Other suitable salts include lithium and silver salts, and some of the compounds of the present invention can be crystallized or recrystallized from water-containing solvents. In such cases, water of hydration is formed. The present invention includes within its scope stoichiometric hydrates as well as compounds containing varying amounts of water that can be prepared by methods such as lyophilization.

One particularly preferred subroutine encompassed by the present invention is
R1 and Y have the same meaning as in formula (I), and R6 represents hydrogen, CI-6 alkyl, substituted alkyl, aryl or aralkyl, and R7 and Y8 are the same or different and represent hydrogen, Cl- 6 alkyl, substituted alkyl, halogen, amino, hydroxy or C1-6 alkoxy, or R7 and R8 form a 5- or 6-membered carbocyclic or heterocyclic residue, or as a pharmaceutical thereof Provide a suitable salt or ester that can be hydrolyzed in vivo.

C1-a alkyl groups suitable as radicals R6, R7 and R8 in formula (II) include methyl, ethyl, n- and iso-propyl, n-1sec-, iso- and tert
-Contains butyl. Preferably, 6 is ethyl.

Preferably R7 and R8 are hydrogen.

Specific compounds encompassed by the present invention include the pharmaceutically acceptable salts and in vivo hydrolyzable esters described below.

a> 7β-(DL-2-(3,4-diacetoxyphenyl)-2-[:(4-ethyl-2,6-dioxopiperazin-1-yl)carbonylaminocoacetamide: 1-7a-formamide -3-((<S-hydroxy-4-methyl-5-oxo-4)]-1,2,4-)riazine-6-y/l/)thiomethyl]cefu 6-nimu 4-carboxylic acid, 3 -1m(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-70-[D-2-[(4-ethyl-2,ro-dioxopiperazin-1-yl)carbo'-ruamino]-2 -phenylacetamide]-7a-
-formamidocef-6-em-4-carboxylic acid and b) 7β-[]) ~2-[(4-ethyl-2,6-thioxopiperazin-1-yl)carbonylaminoyo2-
Phenylacetamide'1-7.1-formamide-3
-[(,Is-hydroxy-4-methyl-5-oxo-
4H-1,2,4-triazin-ro-yl)thiomethyl]cefu 6-nimu 4-carboxylic acid, 713-(:D-2-(4-acetoxyphenyl)-2
, -((4-ethyl-2,6-thioxohy.

perazin-1-yl)carbonylaminocoacetamide]-70L-formamide-6-[(6-hydroxy-
4-Methyl-5-oxo-4H-1,2,4-triazine-6-〇〇thiomethyl]cefu 6-nimo 4-carboxylic acid 1 7β-(DL=2-C(4-ethyl-2,6- thioxobiperazin-1-yl)carbonylamino]-2-(Checy-2-yl)acetamide]-7a--formamide-6-[(6-hydroxy-4-methyl-5-oxo-4H-1, 2,4-)Ryazin-6-yl)thiomethyl]Cef~6-nimu 4-carbonyl, 7β-[DL-2-[(4-ethyl-2,6-thioxopiperazin-1-yl)carbonylamino ]-2-(2
-fluorophenyl)acetamide]-7lowformamide 6-[(6-hydroxy-4-methyl-5-oxo-4)(-1,2,4-)riazin-6-yl)thiomethyl]cefu 6- Nimu 4-carboxylic acid, 71-[:D-2-(3,4-diacetoxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylaminocoacetamide]-7lowformamide 3-4(6-hydroxy-4-methyl-
5-oxo-4H-1,2,4-)riazin-6-yl)thiomethyl]cefu 3-emu 4-carboxylic acid, disodium, 3-((1-carboxymethyl-1H-tetrazol-5
-yl)thiomethyl]-7β-[D-2-(3,4-diacetoxyphenyl)-2-[(4-ethyl-2,3-
dioxobiperazin-1-yl)carbonylaminocoacetamide)-7,z-formamidocef-6-em-4-carboxylic acid and C)3-[(1-carbamoylmethyl-1-tetrazol-5- yl)thio-methyl)-7a-CD-2-((
4-ethyl-2,6-thioxopiperazin-1-yl)
carbonylamino]-2-phenylacetamide]-7
a, -formamidocef-3-em-4-carboxylic acid and d) 3-((1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-713-[D-2-(j
, 4-diacetoxyphenyl)-2-((4-ether-
2,3-dioxopiperazin-1-yl)carbonylamino]-7(L-formamidocephalo-em-4-carboxylic acid, and e)3-[:(1-carboxymethyl-1H-tetrazol-5- yl)thiomethyl')-713-CD-2-(
3,4-dihydroxyphenyl)-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamide/]acetamide:]-7m-formamide cef-
6-Em-4-carboxylic acid, 3-((1-dimethylaminoethyl-1H-tetrazol-5-IA/)thiomethyl]-713-D-2(4-ethyl-2,6-thioxobiperazine-1- yl)carbonylaminoco-2-phenylacetamido)-7a-
-formamidecef-ro-em-4-carboxylic acid, and f) 3-[(6-carbamoyl-2-methyl-5-oxo-48-1,2,4-)riazin-6-yl)thiomethyl]- 70-CD-2-((4-ethyl-2,3-dioxobiverazin-1-yl)carbonylamino]-
2-phenylacetamido]-7(L-formamidocef-3-em-4-carboxylic acid.

The antibiotic compounds according to the invention can be formulated for administration in any convenient manner for use in human or veterinary medicine according to techniques and methods known per se in the art in conjunction with other antibiotics. Therefore, within its scope, the present invention provides pharmaceutical compositions containing an antibiotic compound according to the present invention, such as a compound of formula (I) above, together with pharmaceutically suitable carriers and excipients.

The composition can be administered by any suitable route, such as oral or parenteral,
or by topical application. The compositions may take the form of tablets, capsules, powders, lozenges, creams or liquid preparations such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dosage form and may contain the usual excipients, such as syrup, acacia, gelatin, binders such as sorbitol, tragacanth or polyvinylpyrrolidone, lactose, Sugar, corn starch, calcium phosphate, fillers such as sorbitol or glycine, tableting lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or sodium lauryl sulfate. It can contain suitable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may take the form of, for example, aqueous or oily suspensions, solution emulsions, syrups or elixirs, or for reconstitution with water or other suitable vehicle before use. It may also be provided as a dry product. Such liquid preparations contain the usual additives such as sorbitol, methylcellulose, glucose syrup,
gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fat suspension agents, lecithin, emulsifiers such as sorbitan monooleate or gum arabic, almond oil, oily esters (e.g. glycerin), plastic A non-aqueous medium (which may include an edible oil) such as tetrapyrene glycol or ethyl alcohol, p
- Preservatives such as methyl or ethyl hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents may be included.

Suppositories may contain conventional bases such as cocoa butter or other glycerides.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water for injection, filter sterilized, and then filled into a suitable vial or ampoule and sealed.

Advantageously, agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To increase stability,
After the composition is filled into vials, it can be frozen and the water removed under vacuum. The dry lyophilized powder is then enclosed in a vial, which may be supplemented with an attached vial containing water for injection to reconstitute the liquid before use.

Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.

The compound can be sterilized by exposure to ethylene oxide prior to suspension in a sterile medium. Advantageously, surfactants or wetting agents are included to achieve uniform distribution of the compound.

Depending on the method of administration, the compositions can contain more than 0.1% by weight of active substance, preferably from 10 to 60% by weight. When the composition consists of dosage units, each unit preferably contains 5
It will contain from 0 to 500 μg of active ingredient. The dosage as used in the treatment of adults is preferably between 100 and 10,000 Tn9 per day, depending on the route and frequency of administration.
For example, it would be 1500m9 per day. Such a dose corresponds to 1.5 to 50 m9/9 per day. Suitably the dosage is 5 to 20 m9/9 per day.

The antibiotic compound according to the invention may be the sole therapeutic agent of the composition of the invention or may be used in combination with other antibiotics and/or β-lactamase inhibitors.

Advantageously, the composition also has the formula (III) wherein A is hydroxy, substituted hydroxy, thiol, substituted thiol,
or a pharmaceutically suitable salt or ester thereof.

Further advantageous compositions include the antibiotic compound according to the invention in combination with a β-lactamase inhibitor of formula (IV) or a pharmaceutically suitable salt or in vivo hydrolyzable ester thereof and a pharmaceutically suitable carrier or excipient. Included with excipients.

Other suitable β-lactamase inhibitors include 6β-brompenicillanic acid and its salts and in vivo hydrolyzable esters, and 613-iodobenicillanic acid and its salts and in vivo hydrolyzable esters. It will be done.

Such compositions of the invention containing β-lactamase inhibitors are formulated in a conventional manner.

The invention also encompasses methods of treating bacterial infections in humans and animals comprising administering a therapeutically effective amount of an antibiotic compound of the invention.

The antibiotic compounds of the present invention are active against a wide range of Gram-positive and Gram-negative bacteria and are particularly useful in the treatment of respiratory and urinary tract infections in humans and mastitis in cattle. A particular advantage of the antimicrobially active concentrated compounds of the present invention is that they are stable towards the β-lactamase enzyme, so that they are also effective against β-lactamase producing microorganisms.

The present invention further provides a method for producing a compound represented by formula (I), which method comprises the preparation of a compound of formula (V) 1 H (wherein l(, IXRlt, R3 and Y have the same meanings as above, (wherein any reactive group may be protected and R9 is a carboxyl protecting group that can be easily removed) and then if necessary follow step l) Any carboxyl protecting group. also removing R9, if) also removing any protective groups on R, 1, R2, R3 or Y, ++0 converting the product into a salt or an ester that can be hydrolysed in vivo. This includes doing the above.

Suitable formylating agents include mixed anhydrides such as formic acid anhydride. The reaction is preferably carried out at -50°C to 300°C.
e.g. dichloromethane, chloroform, at temperatures in the range of
It can be carried out in the presence of a tertiary base in an aprotic solvent such as dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethylsulfoxide.

Preferred tertiary bases used in the reaction are pyridine type bases, such as pyridine, lutidine or picoline.

Suitable easily removable carboxyl protecting groups for the group -CO□R9 in formula (V) include salts and ester derivatives of carboxylic acids. The derivative is preferably one that can be easily cleaved.

Suitable ester-forming carboxyl protecting groups can be removed under conventional conditions. Such groups as H,s include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2
, 2.2-) ligulomoethyl, 2,2.2-) ligulomoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur- 2-yl, tetrahydro e 5 c2-
yl, pentachlorophenyl, acetonyl, 1]-p-
Toluenesulfonylethyl, methoxymethyl, silyl,
a stannyl or chain-containing group, of the formula -N=CHRO, where:
RO includes aryl, an oxime group represented by (J heterocycle), or an ester group that can be hydrolyzed in vivo and has the same meaning as above.

The carboxyl group can be isolated from any of the above esters by conventional methods appropriate to the particular R9 group, e.g. by acid- and base-catalyzed hydrolysis, and also by enzyme-catalyzed hydrolysis. It can be played from here.

Ct U.S. Patent No. 3,962,214, British Patent No. 13'4898
No. 4 and European Patent Application No. 82303821.1 or similar to those disclosed.

Compounds of formula (I) are also preferably compounds of formula (VI) C) t.

HH (wherein Y has the same meaning as above, any reactive group here may be protected and the amino group may be substituted by a group capable of undergoing acylation) , and l (, 10 is hydrogen or a group R9 having the same meaning as above), a compound represented by the formula (
■1) R1-CH-C02B H (■) O / \ 1(,'1 11.3 (wherein, 11, R'' and R3 have the same meaning when referred to in formula (I) , where any reactive group therein may be protected), and if necessary, the following steps 1) Any carboxyl group: also removing the protecting group RIG; removing any protecting groups on tDR'', R2, R3 or Y; converting the i1+ product into an ester that can be hydrolyzed in its soil or in vivo. It can also be manufactured by performing the above steps.

Suitable groups capable of undergoing acylation and which may be present on the amide group of the starting material of formula (Vl) include N-silyl, N-stannyl and N-phosphorus groups, e.g. , trialkylsilyl such as trimethylsilyl, trialkyltin group such as tri-n-butyltin, -PRJa
R'' (wherein R3 is alkyl, alkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, and Bb is the same as B or a or is a halogen , or groups represented by Ra and I (.5 together form a ring), and preferred such groups include -P(OCtHa)z, -P(C2Ha)2
, is.

Reactive N-acylating derivatives of acids (■) are used in the above method. The choice of reactive derivative will of course be influenced by the chemistry of the acid substitution method.

Suitable N-acylating derivatives include acid halides, preferably acid chlorides or bromides.

Acid acylation is performed using an acid binder, such as a tertiary amine (
(eg triethylamine, pyridine or dimethylaniline), an inorganic base (eg calcium carbonate or sodium bicarbonate) or oxirane. The oxirane is preferably a (C1-o)-1,2-alkylene oxide, such as ethylene oxide or propylene oxide. The acylation reaction using an acid halide is performed from -50°C to +50°C, preferably from -20°C to +
aqueous or non-aqueous medium, at a temperature in the range of 20°C, □
For example, it is carried out in water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1.2-dichloroethane or mixtures thereof. Alternatively, the reaction can be carried out in water-immiscible solvents, especially aliphatic esters or ketones,
For example, it can be carried out in unstable emulsions of methyl ethyl ketone or butyl acetate.

Acid halides can be prepared by reacting M(■) or a salt thereof with a chlorinating agent (such as a chlorinating or brominating agent) such as pentachloride, thionyl chloride or oxalyl chloride.

Alternatively, the N-acylating derivative of the acid (■) may be a symmetrical or mixed anhydride.

Suitable mixed anhydrides are alkoxyformic anhydrides or, for example, carboxylic acid monoesters, trimethylacetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, acidic acids (such as phosphoric acid, or subacidic acid) or aliphatic or aromatic sulfonic acids. (e.g. T)-)cyansulfonic acid). When using symmetrical anhydrides, the reaction can be carried out in the presence of 2,6-lutidine as catalyst.

Other N-acylating derivatives of acids (■) include acid azide or 2-mercaptopyridine, cyanmethanol, p-
Nitrophenol, 2,4-dinitrophenol, thiophenol, halophenol (including pentachlorophenol), monomethoxyphenol, activated esters such as esters with N-hydroxysuccinimide or 8-hydroxyquinoline, N-acyl saccharin,
N-acylthiazoline-2-thione or N-acylphthalimide, or an alkylidene imino ester prepared by reacting an acid (■) with an oxime.

Reactive N-acylating conductors of other acids (■) include N, N
/-diethyl-, dibutetyl- or diisopropylcarbodiimide, N,N'-di-cyclohexylcarbodiimide or N-ethyl-N/-[(ro-(dimethylamino)propyl]carbodiimide), N,N '-carbonyldiimidazole or N,N
carbonyl compounds such as '-carbonyltriazole, N-ethyl-5-phenylisoxazolium-ro-
sulfonates or isoxazolinium salts such as N-1-butyl-5-methylisoxazolinium verchlorate, or N-alkoxycarbonyl-, such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Included are reactive intermediates formed in situ by reaction with 2-alkoxy-1,2-dihydroquinoline. Other condensing agents include Lewis acids (e.g. BB
phosphoric acid condensing agents such as r, -C6I-T, ) or diethylphosphoryl cyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxane or tetrahydrofuran.

The compound represented by formula (I) also preferably has the formula (■) C)10HH (■[) (wherein R1, RIO and Y have the same meanings as above, and the compound represented by the formula (IX) o2I-1 (wherein R2 and R3 are (having the same meaning as (in which any reactive groups may be protected)) and then, if necessary, the following step 1) one or more of the following: also removing the protecting group R1'; ii) removing any protecting groups on R1, R2', R3 or Y; fib converting the product into its salt or in vivo hydrolysable ester; It can be manufactured by performing the following steps.

The compound represented by the formula (■) in the present invention is particularly an intermediate of the compound represented by the formula (I) having the same meaning as above, but the compound represented by the formula (VI) can be converted into a compound represented by the formula (XT) ( In the formula, Bil is an amino protecting group), and then the protecting group R1
It can be manufactured by removing 11.

Suitable amino groups R1m are those which can be removed under conventional conditions without destroying the remainder of the molecule and are well known in the scale art.

Examples of amine protecting groups for R11 include C
1 or 2 selected from 7-4 alkyl, Cl-4 alkoxy, trifluoromethyl, halogen or nitro
Benzyl optionally substituted with substituents; C1
Included are -4 alkoxycarbonyl, such as tert-butoxycarbonyl; benzyloxycarbonyl which may be substituted as in benzyl above; allyloxycarbonyl; trityl or trichloroethoxycarbonyl.

Preferred examples of N-protecting groups included in R11 include those listed above that can be removed under acidic conditions in the presence or absence of a Group Ib metal.

The intermediate compound represented by formula (Vl) having the same meaning as above is preferably a compound represented by formula (■) H2 (wherein R9, R11 and Y have the same meaning as above). It can be prepared by formylation, followed by removal of the protecting group R11 and, if necessary, substitution with the group R'Q group RIO.

Suitable formylating agents and reaction conditions (as defined in Daio).

Compounds of the invention are also preferably of the formula (Xm) HO HH R2R,3, where R1, R2, R3 and B, io have the same meanings as above, in which any reactive groups are protected. and a compound represented by l (,12 is a leaving group) is reacted with a thiol represented by the formula (provided that when R.12 is an acyloxy group, -CO,B,12 is a free (must be in the form of an acid or a salt thereof).

Suitable leaving groups R,12 include hydrogen, such as iodide or bromide, or an acyloxy group, such as an acetyloxy group.

The thiol Y-S H can be reacted as a free compound or as a salt with an alkali metal such as sodium or potassium. This reaction is carried out in a filtration solvent. For example, water or organic solvents inert to the starting materials, such as dimethylformamide, dimethylacetamide, dioxane,
Acetone, the alcohol 11,2-dichloroethane, acetonitrile, dimethylsulfoxide or tetrahydroctane or mixtures thereof can be used. The reaction temperature and time will vary depending on the starting compounds and solvent used, among other factors, but generally the reaction will be carried out at a selected temperature within the range of 0 to 100° C. for a selected period of several hours to several days. . The reaction is preferably carried out at pH 3-7.

In order to prevent oxidation of the thio compound, it is advantageous to carry out the reaction in an inert gas atmosphere, for example nitrogen gas.

It will be appreciated from the above description that compounds of formula (VI) and protected derivatives thereof are valuable intermediates and form another preferred aspect of the invention.

Specific compounds included in formula (Vl) include the following or salts thereof.

713-amino-3-(:(1-carboxymethyl-1
) 1-tetrazol-5-yl)thiomethyl]-7-formamidoceph-3-em-4-benzene acid bis-diphenylmethyl ester, 7β-amino-((1-carbamoylmethyl-11-1-tetrazol-5-yl) yl)thiomethyl]-7m-formamidocef-3-em-4-carboxylic acid or diphenylmethyl ester thereof.

7β-amino/-3-[(1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl)thiomethyl:]
-7cc-formamide cef-6-em-4-carboxylic acid or its diphenylmethyl ester, and 7β-amino-3-4(6-carbamoyl-2-methyl-5-oxo-4H-1,2,4-) riazin-6-yl)thiomethylturf α-formamide cef-3-em-4-carboxylic acid ester or diphenylmethyl ester thereof.

The antibiotic compounds of the present invention are suitable for a wide range of Durham-negative and Gram-positive microorganisms, such as E. coli, PS8.
JT4, JT425 and NCTClQ 418; Ps
eudomonas Spp, e.g. PS.

aeruginosa (e.g. 10662) and Da
lgleish;5erratia marcesce
ns U332; Klebsiella aerog
Enes A; Enterobacter
cLoacae N1; Plmirabilis
s analogy (MaC977 and 339; P, morg
anii; P, rett-geri, B, 5ubtil
is; 5taph aureus, e.g. 0xfo
rd and FLussell'N, catarrhal
ts1502;5trep faecalis I
; β-HaemolyticStrep CN
Active against 10. M included in the examples below
The IC data are representative of the activity of the compounds of this invention.

The following examples illustrate the preparation and use of the compounds of the invention.

Example 1 7β-Amino-3-C(1-carboxymethyl-1H-
70 in tetrazol-5-yl)thiomethyl]-7-formamidecef-3-em-4-carboxylic acid disodium brine (12,5 ml) and acetone (5 ml").
-Amino-7a-formamide cephalosporanic acid trifluoroacetate C6001n9.1.4 mmo7)
was treated with saturated sodium bicarbonate solution until pH 6.5. 5-Mercapto-1H-tetrazole-1-acetic acid (2
78m9.1.7rrmolf) and -5N
It was adjusted to 6.5 with hydrochloric acid. Solution under argon at 6000
The mixture was heated for 6 hours, cooled, and the pH was adjusted to 6.5.

Evaporate the solvent and transfer the residue to Diaion HP20SS
The product was chromatographed with water and eluted with water. The title compound (385■, 60%) was obtained by making the active fraction lyophilic.
I got it. vmaX(KBr)630011760.16
00cfIL-1s Example 2 7β-(DL-2-(ro, 4-diacetoxyphenyl)
-2-114-ethyl-2,6-thioxopiperazin-1-yl)carbonylaminocoacetamide]-71-
Formamide-3-['(6-hydroxy-4-methyl-5-oxo-48-1゜2.4-)riazin-6-yl)thiomethyl]cefu 6-nimu-4-carboxylic acid, disodium salt (a )713-amiz-3,-(6-hydroxy-4-methyl-5-oxo-4H-1,2,4-
) riazin-3-yl)thiomethyl)-7(L-formamidecephalosporanic acid trifluoroacetate (0,836 g, 1,953 m
m0l), water (32F+11) and acetone (8m
6-hydroxy-3-mercapto-4-
Meth)I/-5-oxo-4H1,2°4-triazine (0,404 g, 2.569 mmol) was added. The pl of the solution was filtered, adjusted to 5, and the solution was heated at 60 °C in argon.
for 3.25 hours and then left at ambient temperature for 18 hours. p) (adjusted to 3.5 and the reaction mixture was approximately 5 n
Concentrated to rl and chromatographed on Diaion HP20S8. A light yellow solid (0,680,9) was obtained by freeze-drying both portions containing the title compound.

umax (KBr)3400.300.2890,1
700°1670, and 1590cm1, λmax (
H, O) 266 nm (16,700), δ((CD)s
sO] 3.20-3.50br (4H, NH3 and OH
1 exchange), 3.28 (3H, s, N, Me), 6.
47 and 3.57 (total 2)], 2XABq, J
16 and 14Hz (-hzoit, 2-cHt)
, 4.06 and 4.09 (total 2H, 2XAB
q, both J 14Hz, cH, S,) 4.93 and 5.01 (combined Te 1'n, each s, 6-H), 8.0
4 and 8.29 (combined in, each dSJ, 1 and 11Hz respectively, replaced with LNHCHo, 2XS), 8.95br and 9.11br (
In total, IH, d (JllHz) and S, ・N, CHO, exchange] and 12.45 b r (
1H, s, OH).

(b) 7f3-ami/-7(L-formamide-6-[
(6-hydroxy-4-methyl-5-oxo-4H-1
,2,4'-triazin-6-yl)thiomethyl)cef-6-em-4-carboxylic acid diphenylmethyl 7β-amino-s-[(6-hydroxy-4-methyl-5- Oxo-4H-1,2,4-)
riazin-6-yl)thiomethyl)-7(L-formamidocef-6-em-4-carboxylic acid CB28m9.2
mmo7) was heated to 0-5°C and purified with 5M hydrochloric acid.
Acidified to H2. The reaction mixture was evaporated to dryness under vacuum, the residue was redissolved in N,N-dimethylformamide (25 mA) and the resulting mixture was treated with a large excess of diphenyldiazomethane in dichloromethane for 24 h. Glacial acetic acid (5 mA) (drops) were added and the mixture was concentrated to low volume under vacuum.

The aqueous phase was further extracted with ethyl acetate (50ml), the extracts were combined, water (5X30ml) and saturated brine (30ml).
), drying over anhydrous magnesium sulfate and evaporation to give a dark red foam. silica gel 60
Chromatography on (230 mesh A8TM) eluting with ethyl acetate gave the title compound as a foam, which was solidified by trituration with ether as a white solid (287 mg, 25%, mp 1
35-140°C).

umax (CHCIs) 1780 and 171
0cm-1.

δ(CD CIs) 2.68 (2H,,br s
, NH2) 5.33 (3”, s, CH3) ,
3.35 and 3.53 (2H, ABq, positive 17
．． 2Hz, 2-H,), 3.88 and 4.30
(2F1, ABq, J13.7Hz, 3-c)],)
5.18 (IH, S, 6-1-1), 702 (
IHLS, CHSpH2), 7.20-7.61 (
10H, m.

aromatic) 8.18 (1H,S,CHO), 1o1a
-11,09 (1H, br s, OH).

(C) 7β-(DL-2-(3,4-diacetoxyphenyl)-2-((4-ethyl-2,6-thioxopiperazine-1-i/L7)carbonylami/)-7a-formamide -5-C(6--hydroxy-4-methyl-5
-oxo-4H-1,2,4-)riazine-ro-yl)
thiomethyl]cefu 6-nimo 4-carboxylic acid diphenylmethyl 773-amino-7a,-formamide-6-[(6-
Hydroxy-4-methyl-5-oxo-4H-'1,2
．． 4-triazin-6-yl)thiomethyl]Sefu 6
-Nimu 4-carboxylic acid diphenylmethyl (10omp
, o, 17 mMol) in tetrahydrofuran (
N,N-dicyclohexylcarbodiimide (No. 69, 0.19 m Mo
1e). To this mixture was added DL-2-(3,
4-diacetoxyphenyl)-2-((4-ethyl-2
,3-dioxopiperazin-1-yl)carbonylamino]68(75m9゜(3,'I, 7mMole)(
7) Nato5 human t'a furan (5-) solution was added dropwise. The mixture was stirred at room temperature for 24 hours, then insoluble materials were removed by filtration, thoroughly washed with tetrahydrofuran, and Solution F was evaporated to dryness under vacuum to give a yellow foam. Chromatography on silica gel 60 (230 mesh ASTM) and elution with 5% ethanol in ethyl acetate gave the two distinct diastereomers as a foam (combined 124 mz, 70%).

Isomer 1: umax (KBr), 3260br1
1780.1710.1690Sh, 1595.150
0,1368.1258 and 1180 cm-”;δ((
”D3) 2 CO) 1.16(3)(1t −, J
7 Hz, NCR2CH3), 2.24 (6
H1s.

2CH, CO2's), 2.84 and 3.08 (2
HXABq, stop 8Hz, 2-H,), 3.30 (
3H,s, NCHs), 3.48(2HXq,
J7Hz, NCR,CH,), 3.55-3.8
2 and 3.86-4.14 (4H12m1N (CH
2) N) , 3.85 and 4.58 (2HlAB
q 1J 14 Hz, 3-CH2S), 5.2
8 (I Hls, 6-H), 5.78 (11-L
d, J 8Hz, CH), 6.96 (IH, s,
CtanPh2), 7.10-7.80 (13H, m, aromatic), 8.29 (IH, s, CHO), 8.4
8 (IH, brs, NHCHO), 8.91 (I
H, brs.

C0NH,), 10.07 (IH,d, J8Hz,
Ndan CHCO), 11.34 (IH, b r s,
0I-1); Isomer 2: umax (CH
CI, )3240br, 1775.1710.1690
sh, 1595.1665.125B, and 1180
cm-1; δC(CH3)2CO]1.13 (3H.

t, J 7 Hz, NCH2CHs), 2.25
(6H,,S.

2C1,, Co,'s), 3.24-381 (
'9H, m, CH2CH3゜NCH, CH, N, NC)
I3, and 2-I(2), 3.85-4, j Q
(2H, m, NCl-1, C1% N), 4.40
and 408 (2H, ABq, J14Hz, 3-CH2
5) , 5.29 (111, S, 6-14.) , 5
．． 84 (IH,, d, , J 7Hz.

CHCO), 6.94 (1B, S, empH,)
, Z09-7.76 (13i (, m aromatic), 8.
23 (1H,s, CHO), 8.60 (IH,b
rs, NHCHO), 8.72 (iHlbrs.

C0NH), 10.00 (IH,, d, J7Hz,
Ndan CHCO).

11.36 (IHSbrs, OH).

(d) 713-[:DI, -2-(3,4-diacetoxypheni/I/)-2-[:(4-ethyl-2,6
-thioxopiperazin-1-yl)carbonylamino]
aceFamide]-7α-formamide-3-((6-hydroxy-4-methyl-5-oxo-4H-1,2,4
-) riazin-6-yl)thiomethyl]cefu 6-nimu 4-carboxylic acid disodium salt 7β-[:DL-2-(3,4-diacetoxyphenyl)-2-((2,3-dioxo-4 -ethylpiperazin-1-yl)carbonylaminocoacetamide)-7(
L-formamide-3-((6-hydroxy-6-methyl-5-oxo-4H-i, 2.4-)riazine-ro-
Diphenylmethyl 4-carboxylate (94■, (1lmMole))
! J7/'4# in acetic acid (5 ml) at room temperature until thin layer chromatography (silica gel, 5% ethanol in ethyl acetate) showed that no starting material remained (
The mixture was stirred for approximately 0.5 h) and the volatiles were removed under vacuum.

The residue was azeotroped with chloroform (3ix10m4) and redissolved in tetrahydrofuran (5ml) to give 1.93M2
-4-methylpentane in sodium ethylhexanoate-
solution in 2-one (0.2 ml, o, 2 m Mole
) and then treated with ether (50ml). The insoluble material (81μ, 99%) was collected by filtration, washed with ether and dried under vacuum.

umax (I(Br)3700-2500.1775
sh.

1765.170rosh, 1680,1560.140
0.1670.1204.1185Sh, and 113
0 cml; δD, 0 1.00-1.40 (3HXm
,, NCN2CHs ) 3.22 (<SR, b r
S, 2CH3CO2'S), 3.35 (RoH,
s.

NCHs), 3.35-4.10 (1OHSm,
, NCN2CH2NCH.

3-Ca128 and 2-I42), 5.22
(1) (XS, 6-Hn, 5.45 (IH, S
, CI-]) , ]7.20-7.55 (RoH
, m, aromatic), 8.09 (IH, brs, CHO
).

Example 6 (+)3-((1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-・7β-[2-[(4-
Ethyl-2,6-thioxopiperazin-1-yl)carbonylamino 1-2-phenylacetamide]-7α-
Formamidecef-6-em-4-carboxylic acid disodium salt 7β-[2-(4-ethyl-2,6-thioxobiperazine-1-carbonylamino)-2-phenylacetamide]-7loformamidecef γ Allosporanic acid sodium salt (0,088 mmol, 0.131 mmol) was dissolved in water (
6 ml) and acetone (2 ml) and 5-mercapto-1H-tetrazol-1-acetic acid (0,042 g,
0.252 mmol) was added.

After adjusting the pH of the solution to 6.5, it was heated to 10° C. for 5 hours in an argon atmosphere. The solution mixture was then concentrated under vacuum and taken up in a saturated solution of minor silver in sodium bicarbonate. The resulting solution was chromatographed on Diaion HP3QSS and the fraction containing all the desired product was lyophilized to give an amorphous light yellow solid (0,0
10,! The title compound was obtained as i').

umax (KBr)3400.6000.1765.
1710.1670 and 1620cm”,'δ(D
, 0) especially 1.18 (tXJ7Hz, N, CH,
, CH, ) , 3.18 (ABq, J17Hz,
2-C Notice), 3.49 (q, J 7 Hz, N
, CH2, CHa) 3.6-3.8 (rnlN,
CKt , CH2-N) -3,9-4-1(m
l(s-N-"N2-""t), 5.48 (s
, Ph, CH, NH), 7.3-7.45 (m
, aromatic H), and 8.10 and 8.41 (each
s, NH, CHO).

M I C (Pf17
fnl) is 0,25.

(l+)(a) 3-[(i-diphenylmethoxycarbonylmethyl-1H-tetrazol-5-yl)thiomethyl]-71CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl amino)-2
-Phenylacetamide'1-74-formamidoceph-6-em-4-carboxylic acid diphenylmethyl freshly prepared D-2-((4-ethyl-2°3-dioxopiperazin-1-yl)carbonylaminoco -2-
Phenylacetyl chloride [dry dichloromethane (3 drops) containing N1N-dimethylformamide (1/10 drop)]
ml) of the corresponding acid (0,092 g, 0.289 m
mol) to oxalyl chloride (0,073F, 0.57
7β-amino-3-((
Stirred solution of diphenylmethyl 1-diphenylmethoxycarbonylmethyl-1H-tetrazol-5-iA/)thiomethyl]-71L-formamidoceph-6-em-4-carboxylate (0.108 g, 0.145 mmol),
Then pyridine (0,0114 g, 0.145 mmo
A) was added. After 30 minutes, the mixture was diluted with dichloromethane, washed successively with an aqueous solution of Mg5O, dilute hydrochloric acid and saturated brine, dried (Mg5O, ) and evaporated. Chromatography of the residue on silica gel gave the title compound (0.113 g, 75%) as a gum.

umax (CH, CI,)3270.3170,30
50, 1785.1745.1715 and 1690em
l, δ [(CDs) x CO/D, 0] especially 1.18
(3H1t, J75Hz, N.

CH,,OH,) , 3.13 and 3.27 (
2H, ABqXJ16H1,2-CH2), 5.53
(2H, q, J 7.5Hz.

N-qHt-CH5), 3.6-3.8 and U
4.0-4.15 (each 2H, m, NCH2CH
2N), 4.27 and 4.35 (: total 1
H, 3-CH on the high magnetic field side, 8AB q (J 13.
5 Hz), respectively main and secondary rotamers], 4.48 and 4.52 [combined b t) TeIH1 low m field side (7)
3-CH, 8ABq (J13.5Hz), respectively main and secondary rotor r-], 5.28 and 5.35 (combined TeiH, each s, 6-)(), 5.54 (2H, 8
,NCH,CO,) ,5.68 (IH,s,NHC
HCO), 6.90.6.92.6.94 7.0 each
0 (combined 2H, 8 each, 2xCHPh, ), 7
．． 2-7.7 (15H, m, aromatic) and 8.19.
8,21.827 and 8.5 ro (total 1H, each s, NHCHO).

(b) 3-((1-carboxymethyl-1H-tetratol-5-yl)thiomethyl]-70-CD-2-((
4-ethyl-2,6-dioxo-piperazin-1-yl)carbonylaminoco-2-phenyl-acetamide]
-7α-Formamidocef-3-em-4-carboxylic acid disodium salt 6-[(1-diphenylmethoxycarbonylmethyl-1
H-tetrazol-5-yl)thiomethyl]-7β-[D
-2-[(4-ethyl-2゜3-dioxopiperazine-
1-yl)carbonylamino)-2-phenylacetamide]-7(L-formamide)-6-M-4-carboxylic acid After dilution, the solvent was evaporated under vacuum and the residue was dissolved in saturated sodium bicarbonate. The solution was taken in an aqueous solution.
The title compound (0,0531) was obtained as a white solid by subjecting it to aion HP208S (DrioT).

umax (KBr)3400.2980,1770,
1720°1710.1680.1620 and 14
90cm=, 6 (Dt O) 1.18 (3HSt
1j 7 HzSN, CHt CHs), 3
．． 01 and 3.03 (1H in total, 2- on the high magnetic field side
CH.

ABq, (positive 16.5H2) main and secondary rotamers respectively]
, 6.40 and 3.43 (1H in total, 2-CH, ABq (J 16.5Hz) on the low magnetic field side, main and secondary rotamers respectively), 3.50 (2H, 4117Hz)
, NCR,, CHa), 3.6-3.8 (2H
,m, NCH,CH,N) ,3.9-4.1 (3
H, m.

NCR, CH, N and 3-”H2S) on the high field side,
4.33 and 4.39 (total of 3 on the 1H1 low magnetic field side
-CH28ABqC113Hz), respectively main and secondary rotamers], 4.98 (2H-51NCH2CO2)
, 5.23 (1H-516-H) , 5,5Q (i
H,5XNHCHCO), 7.3-7.6 (5H.

m5Ph), 8.11 and 843 (Aisete 1
H, each S, NHC dan 01 each main and minor rotamer).

p, MIC for m1rabilis 889 (pg
/n is 0.06.

Example 4 7β-ami7-3-((1-diphenylmethoxycarbonylmethyl-1H-tetrazol-5-yl)thiomethyl)-7cL-formamidocef-6-em-4-carboxylic acid schiftenylmethyl 7L-amino-3 -((1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl]-7a-formamidoceph-6-em-4-carboxylic acid, thorium salt (120 μ) was dissolved in water (2−) and the pH was adjusted to 2 by addition of 5N hydrochloric acid. . The solvent was evaporated and the residue was dried under vacuum.

Acetonitrile (10ml) was added followed by excess diphenyldiazomethane. After 12 days, the mixture was treated with acetic acid (5 drops) for 1 hour. The mixture was diluted with ethyl acetate.
Pour into water, separate the organic layer, and saturated A (monohydrogen carbonate)
Washed with IJum aqueous solution and brine, dried and evaporated. The residue was washed with silica gel 60 (<230 mesh A8
TM) to give the title compound (59rn9.61%).

umax, 3400br, 1775.1775sh,
1710.1690cm-1;6 (CDCI,)2.
28 and 2.4 (total 2H, wide respective main and minor rotamers, replacing NH2, D, O), 3.54
(2H,s, ring 8-CH,), 4.36(2HSABq
1J13.3Hz1CH2-8-), 5.02 and
5.11 (2H1ABq-JLl 7.6Hz-N
-CHt), 5.13 (IH,s, 6H), 6
．． 3 and 6.42 (together IHN d SJ
12H1% and s1 main and hirmo-tamer, respectively;
(exchanging NH, D, O), 6.92 (IH, s, CH
Ph, ), 6.95 (IH, Szu””3 Pht )
, 7.21-7.58 (20H, m), 8.26 and 8.4 (total of 1HSs and dJ = 12H2, major and minor rotamers respectively, latter beam, becomes S by 0 exchange).

Example 5 7β-CD-2-[(4-ethyl-2,6-sioxobiperazin-1-yl)carbonylaminoco-2-phenylacetamide)-7a-formamide-3-((6-
Hydroxy-4-methyl-5-oxo-4H-1,2,
4-)Ryazin-3-yl)thiomethyl]77-3-emu-4-carboxylic acid disodium salt (a) 7β-CD-2-[(4--1-2,3-dioxopiperazine-1- yl)carbonylamino)-2-
phenylacetamide)-7-formamide-3-(
(6-hydroxy-4-methyl-5-oxo-4H-1
, 2゜4-triazin-6-yl)thiomethyl]cefu 6-nimo 4-carboxylic acid diphenylmethyl newly prepared D-2-((4-ethyl-2゜6-thioxopiperazine-1-yA/) carbonylmethyl]-2
-phenylacetyl chloride [corresponding acid (0,066
g, 0.207 mmol) of chloride (0
,053,! i+, 0.414 mmol) and N, N-
Dry dichloromethane (1 drop) with dimethylformamide (1 drop)
1-) was taken up in dichloromethane (Li2) and pyridine (0,011, l
70-amino-7a-formamide-3 in dichloromethane (3 m) containing i', 0.138 mmol)
-1:(6-hydroxy-4-methyl-5-oxo-4
H-1,2,4-)riazin-6-yl)thiomethyl]
Sefu 6-nimu 4-carboxylic acid diphenylmethyl (0
, 080 g, 0.138 mmol) into a stirred solution. After 90 minutes, the mixture was washed successively with dilute aqueous sodium bicarbonate solution, dilute hydrochloric acid, and saturated saline, and dried (
Mg8Q) was evaporated. Chromatography of the residue on silica gel yielded the title compound (0,071
g, 58%) as a cream solid.

υmax (Nujol) 3250.1775.171
5.1705, and 1680cm''''11δ ((CD
s)! Co) 1.19 (3H, t, J 7Hz,
NCR, CH,), 3.33 (3H.

s, NCH,), 3.25-3. (So (total of 4HSm, 2-OH, and N, CH,, CH,')
, 3.60-3.85 (2H, m.

N, Cp, -CH,, N), 3.95-4.15
(2HSm.

NC horse CHEN), 4.16 and 4.31
(2H, ABq, J14Hz, 3-CH,S), 5
．． 27 (IH, s, 6-H), 5.77 (1H,
dXJ 7Hz, Ph, Cdan, NH), 6.94 (I
H.

'1CH-Pht), 7.2-7.7 (15H1m
, aromatic), 8.29 and 8.56 (combined 1H, each s, NH, CIO.

(main and minor rotamers, respectively), 8.66 and 8.71 (1H,br,CONHC and NH,CHO, respectively), 10
．． 04 (1HSdSJ7Hz, CH, NH, Co) and 11.52 (IHbr, OH), (8.66.8.71.10.04 and 11.5 with the addition of D20)
(b) 713-CD-2-[(4-ethyl-2,6
-thioxobiberazin-1-yl)carbonylaminoco-2-phenylacetamide]-7lowformamide 3-((6-hydropxy-4-methyl-5-oxo-4
H-1,2゜4-triazin-6-yl)thiomethyl]
Cefu 3-emu 4-carboxylic acid disodium salt-7β-[:D-2-[: (4-ethyl-2,6-thioxobiperazin-1-yl)carbonylaminoco-2
-phenylacetamide)-7ct-formamide-3
-[(6-hydroxy-4-methyl-5-oxo-4H
-1,2,4-triazine-':r-ik)thiomethyl]cefu-6-nimo-4-carboxylic acid diphenylmethyl (
0,063,! ? , 0.072 mmol) was taken up in trifluoroacetic acid (5 ml) and left at room temperature. 45
After minutes, the solvent was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution.

The resulting cloudy solution was coated with Diaion HP2088 glue 0? The title compound (0,
007#) was obtained as a white solid.

umax (KBr)3400.6600.6000.
1770.1710.1680 and 1590cm1. δ
Φ20) 1.18 (3H, t, J7Hz, N, C
H,,CH,), 2.97 and 3.01 (total 1H, each d, J 16.5Hz, 2-Cdan H1 each main and secondary rotamer), 3.33-3.45 (combined set) T: 41H,m, N CH3 and 2CHH16
, 69), 6.48 (2H, q
SJ 7Hz.

N, CH2CH, >3.53-3.73 and 3.85-
4゜10 (each 2H, m, NCH2CH, N), 3.7
6 and 4.39 (2H.

ABq, J 14.1Hz, 3-CH,S), 5.1
7 and 5.22 (combined 1H1 each S, 6-H1 each main and minor rotamer), 5.45 and 550 (combined I
H, each sSPh, C1-1, NI4. 7.30-7.60 (5H,, m, aromatic), and 8.11 and 8.44 (combined 1H1 each S, major and minor rotamers, respectively).

M I C against P. m1rabilis 3139
(Pg, 4 is < 0.06.

Example 6 7β-CD-2-(4-acetoxyphenyl)-2-(
(4-ethyl/l/-2,3-dioxopiperazine-1-
carbonylaminocoacetamide]-7 monoformamide 3-((6-hydroxy-4-methyl-5-
Oxo-4H-1,2,4-triazin-ro-yl)thiomethyl]cefu 6-nimu 4-carboxylic acid disodium salt (a) 7β-[:D-2-(4-acetoxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylaminocoacetamide]-7(L
-formamido-6-[(6-hydroxy-4-methyl-5-oxo-4H-1,2,4-)riazin-6-yl)thiomethyl]sefu 6-nimu 4-carboxylic acid diphenylmethyl newly produced CD -2-(4-acetoxyphenyl>
-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-acetyl chloride
Corresponding acid 0.165 g, 0.438 mmol: ]
[produced as described in Example 5(a)] from the monoformamide 5-C of 713-amino-7 in dichloromethane (2 tM') containing pyridine (0,008 Ji', 0.103 mmol). 6-hydroxy-4
-Methyl-5-oxo-4H-1,2゜4-triazin-3-yl)thiomethyl]cefu 6-nimu 4-carboxylic acid diphenylmethyl (0,060,!i', 0.10
3 mmol). After 2 hours, the mixture was worked up as in Example 5 to yield the title compound (0,
071 g, 76%) was obtained as a white solid.

umax (Nujol) 3500.6270.1785
．． 1760.1720, 1710.1685 and 1
585 Cm-16 ((CDs)!) Especially 1.
18 (t, J 6.5Hz, N.

CH, CH, ) , 2.25 (S, 0COC'H8)
, 3.24 and 3.36 (ABq, J 18
Hz, 8-CH2), 3, filter 4 (S, N"Hs
), 3.45-5.60 (mXN, CH2, CH
3), 3.65-3.75 and 4.0-4.14
(each m, N CH2C) (21, N-) 4.1
t and 4.35 (ABq, J13Hz, 3-CH
28), 5.26 (S, 6-H), 5.76 (
d, J 10Hz, PhC NH) 6.95 (S
1CH-Ph2), 7.05-7.90 (m-aromatic, NHoCHOlCONHC, and OH), 8
．． 30 and 8.56 (each s XNH, CHO, major and minor rotamers respectively) and 10.07 (d, J
10Hz, CH, NH, CO).

(b) 7β-CD-2-(4-acetoxyphenyl)-
2-CC4-Ethyl-2,ro-dioxohyperazin-1-yl)carbonylaminocoacetamide]-7CL
-Formamide-3-[(6-hydroxy-4-methyl-5-oxo-4H-1,2,'4-triazine-6-
yl)thiomethyl]cefu 6-nimu 4-carboxylic acid disodium salt 7β-[2-(4-acetoxyphenyl)-2-C(4
-ethyl-2,6-thioxobiperazin-1-yl)carbonylaminocoacetamide]-7ct-formamide-3-[(6-human waxy-4-methyl-5-oxo-4H-1,2,4 -triazin-6-yl)thiomethyl]cefu-3-emu 4-carboxylic acid diphenylmethyl (0,063 g) was treated with trifluoroacetic acid (2TLl) and worked up as described in Example 5(b) to obtain the title Compound? 1 (20 .mu.) was obtained as a white solid.

umax (KBr)3380.3000.1760.
1710.1670 and 159[]Cm1, δ(D
2o) 1.18 (3H.

tXJ 7.5klzSN, C Peng CHs), 2
．． 33 (RoH%S'10COCH,) , 2.97
and 2.99 (total 1H, each dSJi7Hz
, AB q12- CH2 on the high magnetic field side, primary and secondary, respectively”
-tamer), 3.41 (1H, dSJ17Hz.

ABq12-CHt on the low magnetic field side), 3.42 (
Ro H, s, N.

CHa ), 3.51 (2H1q, J 7.5Hz
, N, CH, CH3), 3.60-3.80 and 3.90-4.10 (2H, m each.

N, CH2, CH,, N), 3.77 and 4.
40 (2H, ABqJ 1'4Hz, 3-C)r2
S), 5.18 and 5.22 (1H in total,
each s, 6-H, each main and each -tamer), 5.49
and 5.53 (1H in total, each s, NH0CH
0CO1 each (main and secondary rho each -), 7.17 and 759 (4H, ABq, J8.5Hz, aromatic), and 8.12 and 845 (total 1H1 each s, N
HCHO, major and minor rotamers respectively), P, MIC for m1rabilis 839 (
P, 9/mA) is 0.5.

Example 7 7β-(:DL-2-[:(4-ethyl-2,6-thioxopiperazin-1-yl)carbonylamino]-2-
(chedi-2-yl)acetamide) -75L-formamide-3-((6-hydroxy-4-methyl-5-
oxo-4H-1,2,4-)riazin-3'-yl)
thiomethyl]cefu 3-emu 4-carboxylic acid disodium salt (a) 7β-(DL-2-((4-ethyl-2,ro-dioxopiperazin-1-yl)carbonylamino]-2
~ (Chedz-2-yl)acetamido]-7a-formamide-3-[C6-hydroxy-4-methyl-5-
Diphenylmethyl oxo-4H-1,2,4-)riazine-ro-yl)thiomethyl]sefu-6-nimo-4-carboxylate (DL-2-(4-ethyl-2゜6-thioxapiperazine) 1-yl)carbonylamino)-2
-(Chedi-2-yl)acetyl tetralide (Example 5 (
The corresponding acid (0,131,f
, 0.403 mmol)
7β-amino-7a-formamide-3-((6-hydroxy-4-methyl-5-oxo-
4H-1,2,4-)riazine-6-y/I/)thiomethyl]cefu-3-emucarboxylic acid diphenylmethyl (
0.1165', 0.2 mmol). 6
After 0 minutes, work-up as in Example 5(a) gave the title compound (0.101 g, 57%) as a pale gum.

δ((CDa)2CO) 1.17 and 1.1
8 (Match H1 each t SJ 7HzlN, CHt
CHs), 2-85-3.05 (I H12-C
HH, obscured by HOD in solvent), 3.25-3
=4 Cl (I H, 2-CHH1 partially obscured by NC horse 6.36 and 3.35 (total 6H1 each s
, N, CHs), 3.4-3.6 (2H,m, N,
CH2,CH,), 3.6-3.8(2H,m, N
,C)1. , CH,, N) ,! 1.95-4.2
0 (3H.

m, N, CH2, CH,, N and high magnetic field side (7)
3-CH! ABq), 4.32 and 4.4IC(
Total 1H, low magnetic field side (D 3-CH, S ABq
(J14Hz) ], 5, 60 and 5.32 (total i
H, each 8.6-H), 6.06 and 6.08(
Total 1H1 each dSJ 9Hz, NH, CH, CO)
, 6.97.7 (16H,m, aromatic CH0Pht,
NHCHO and Co, NHoC), 8.27.8.
29.8.47 and 8.57 (total 1H, each s,
Nu, CH(Q, and 9.96(IH).

br, d, J9HzSCH, NH, CO).

(b) 7β-(DL-2-C(4-ethyl-2,3°-
Diogysobiperazin-1-yl)carbonylamine/]-
2-(chedi-2-yl)acetamide) -7'W-
Formamide 3-[:(6-hydroxy-4-methyl-5-oxo-4)1-1.2.4-)riazine-ro-
yl)thiomethyl]cefu 6-nimu 4-carboxylic acid disodium salt 7β-(:DL-2-[: (4-ethyl-2,3-
dioxopiperazin-1-yl)carbonylamino”]
-2-(chedi-2-yl)acetamide]-7a, -
Formamide-3-[(6-hydroxy-4-methyl-
Diphenylmethyl 5-oxo-4H-1,2,4-triazin-6-yl)thiomethyl)sefu 6-em-4-carboxylate (0,092 g) was added to trifluoroacetic acid (2T
The title compound (0,04
0p) was obtained as a white solid.

umax (nujiel-ru) 3500.6260.177
5.1710.1680. and 1590 Cm-1,
δ (Dz O) 1.19 (3H, t, J7.5Hz,
N, CH2, CH, ), 3.15 and 3.20 (total of 2-CH, ABq・J 1 BH on the 1H1 high magnetic field side
z) , 3.44 and 3.46 (3H in total,
each 5SNCH,), 3.40-3.55 (IH, 2-CH on the low magnetic field side, ABq, NH, and N, CH,,
Obfuscated by CH, 3.51 (2H,Q, J 7
．． 5Hz, N, CH,, CH3), 3.6-. 3.
9 (3+H, m, N, CH,, CH2, N
and 3-CH, S ABq) on the high magnetic field side, 3.95-
4.15 (2H, m.

N,C look,C)(,,N),4.43 and 4.
48 (total 1H1 low magnetic field side c7) 3-CHt
S' A B q 1J 14 H2), 5.19.
521.5.24 and 5.6j (combined 1H1 each 8.6-) 1), 5.7 B, 5.82.5.86
and 6.14 (1H in total, each s, NH6C, C
O), 7.0-Zl, 7.15-7.30 and Hifu, 4-7.55 (Jowasete 3H.

each m1 aromatic), and 8.11.8.16.8.22 and 8,46 (combined 1H, each s, NHCHO).

P, MIC against m1rabilis 8B9 (
1Lg/ml) is 0.06.

Example 8 7 13-(DL-2-((4-ethyl-2,6
-dioxopiperazin-1-yl)carbonylamino]
-2-(2-fluorophenyl)acetamide]-7 monoformamide 3-((6-hydroxy-4-methyl-5-oxo-4H-1,2,4-triazin-6-yl)thiomethyl]cefu 3-Emu-4-carboxylic acid disodium salt (a) 713-CDL-2-C(4-ethyl-2,6
-thioxopiperazin-1-yl)carbonylamino)
-,2-(2-fluorophenyl)acetamide)-7
(L-formamide-6-[(6-hydroxy-4-methyl-5-oxo-4H-1,2,4-)riazine-6
-yl)thiomethyl]cefu 6-nimo 4-carboxylic acid diphenylmethyl newly prepared (DL-2-(4-ethyl-2゜6-thioxopiperazin-1-yl)carbonylamino)-2
-(2-fluorophenyl)acetyl chloride [corresponding as described in Example 5(a)* (0,138
i 0.409 mmol)] was prepared from 70-amino-7(L-formamide-3-[(6-hydro;xy-4-methyl-5-oxo-4H-1,2,4 -triazin-6-yl)thiamethyl]cefu 3-emu 4-carboxylic acid diphenylmethyl (0.08A, 9.0.145 mmol), then added to pyridine (0.0115 &, 0.145 mmol)
moA) was added. After 15 minutes, the mixture was converted to Example 5 (a
), the title compound (
0,113,! i', 87%) was obtained as a white solid.

umax (CH2C12) Ro 250.30 Ro 0.17
85.1720.1710, and 1690 Cm-”
10 ((CDs)tCO) especially 1.18 and
1.19 (tSJ 7Hz, NCR, CH3), 3
．． 34 and 3.36 (each 5SNCHa), 3.4-
3.6 (m1NCH2CH3 and 2-CHt)
, 3.6-3.8 (m, NCR, CH, IN),
3.9-4.2 (m, NCH2CHtN), 4.
07.4.18.4, 63 and 4.44 (2xABq
, J 1.4Hz, 3-CH,,8) ,5.50.5
．． 31 and 5.66 (each 816-H), 5.98 (
dXJ8Hz.

NHCHCO), 6.94 and 6.96C each, s, C
Ph, ), 7.1-7.7 (m, aromatic), 8.17
．． 8.27.8.29 and 8.57 (each s, NHCHO
), 10. Obr (CONHCH).

(b) 7β-(DL-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbo/nylamino)-
2-(2-fluorophenyl)acetamide]-7α-
Formamide-5-CC6-hydroxy-4-methyl-
5-Oxo-4H-1゜2.4-')riazin-6-yl)thiomethyl]cefu 6-nimo 4-carboxylic acid disodium salt 7β-[DL-2-[(4-ethyl-2,3- dioxopiperazin-1-yl)carbonylamino]-2-(
2-Fluorophenyl)acetamido)-7a-formamide-3'-[:(6- and droxy-5-oxo-4
Diphenylmethyl H-1,2,4-,)riazin-3-yl]thiomethyl]cef-6.-M-4-carboxylate (0,1039) was treated with trifluoroacetic acid. 15
After minutes, the solution was worked up as described in Example 5(b) to give the title compound (0,044 g) as a white powder.

umax (KBr)3420.3000.1770.
1720.1700.16B[], 1610 and 159
0cm-1,6(D,O)1.19 (3HStXJ8
H, zSNCH2CH8), 3.09 and 3.16 (
Combined with IH, 2-CH2ABI on the high magnetic field side).

J 13Hz), 3.42 and 3.44 (total 3
H, each 51N-CHs), 3.51 (2Hlq
1J 8 Hz 1N Hz CHs), 3.4
-3.5 (I H, 2-CH2ABq on the low magnetic field side, N
Obfuscated by CH3 and NCH2CH3 3.60-
3.85 (3H1m, NCH, CH, N and high magnetic field side (7) 3-CH28ABq), 3.9-4.1
(2H, m, NCH, CH2N) , 4.43.44
6 (total of 1H1 low magnetic field side 3-CH, S ABq
.

J 15Hz), 5.17.5.20.5.26 and 5.43 (total 1H, each s, 6-H), 5.7
7.5.81.5.84 and 5.93 (together IH,
each s, NHCHCO), 7.1-7.6 (4H,
m, aromatic), 8.08.8.12.8.24 and 8.45 (combined 1H, each s, NHCHO).

P, MIC against m1rabilis 889 (
11g/mJ) is 0.5.

Example 9 7β-[D-2-(3,4-diacetoxyphenyl)=
2-((4-ethyl-2,6-thioxobiperazine-1
-yl)carbonylaminocoacetamide]-7a-formamide-3-((6-hydroxy-4-methyl-5
-oxo-4H-1゜2.4-)riazin-6-yl)
[thiomethyl]cefu 6-nimu 4-carboxylic acid disodium salt (a) 7β-CD-2-(3,4-thia t=)
-+diphenyl")-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminocoacetamide]-7-formamide-3-((6-hydroxy-4-methyl-5 -oxo-4H-1,2,4-)
riazin-3-yl)thiomethyl]cefu 6-nimu 4
-Diphenylmethyl carboxylate Freshly prepared D-2-(3,4-diacetoxyphenyl)-2-C(4-ethyl-2,6-thioxobiperazin-1-yl)carbonylaminocoacetyl chloride [
The corresponding acid (0,1
07,L O,216mm0A? 70-amino-7a,-formamide-3-[:(6-hydroxy-4-methyl-
5-oxo-4H-1,2,4-triazin-6-yl)thiomethyl]cefu-3-emu-4-carboxylic acid";'
Phenylmethyl (0,0957i, 0.164mm
ol) 2 additions, 2 additions, helicin (0,013g
, 0.164 mrnol) was added.

After 90 minutes, the mixture was worked up as described in Example 5(a) to yield the title compound (0,094 g).

58%) was obtained as a white solid.

umax (CHCI,)3280.3000,177
0°1720.1710 and 1685cm-”, δC(
CDs )2 CO:)1,17 (3H,t 1i
J7Hz, NCHxCHs), 2.24
<6H1s, 2xOCOCH,), 2. B-3,1(
IH, 2-CH, ABq on the high field side, obscured by HOD in the solvent 3.1-3.3 (I H,m, low field side] 2-CH,), 3.33 (3HSS, NMe )
, 3.4-3.6 (2H, m, NC!l!, CH,
), 3.6-3.8 and 3.9-4.1 (2HXm each,
NCH, CH, N), 4.13 and 4.37 (2H,
ABq, J14Hz, 3-CH, 8), 5.28 (I
H, S, 6-H), 5.72 (IH, S, NH
CHCO) 6.90 and 6.92 (total 1H1 each s
, C Ph,), 7.1-7.7 (11H,m, aromatic and NHCHO), 8.02 (IH,s, C0NH
C), 8.29 and 8.45 (combined 1H.

each s 5NHCHO1 each main and minor rotamer) (
By adding D20, 2-CH, becomes 2xABq (J16
(b) 70-CD-2-(3,4-diacetoxyphenyl)-2-[:(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco Acetamide] -
70,-formamide-3-((6-hydroxy-4-
Methyl-5-oxo-4H-1,2,4-)riazine-
6-yl)thiomethyl]cef-6-nimu 4-carboxylic acid disodium salt 7β-(D-2-(3,4-diacetoxyphenyl)-
2-1m(4-ethyl-2,6-thioxopiperazin-1-yl)carbonylaminocoacetamide]-7α-
Formamide-3-[(6-hydroxy-4-methyl-
5-oxo-4H-1゜2.4-)riazin-6-yl)thiomethyl]7-nohu-6-emu diphenylmethyl 4-carboxylate (0,088 g) was dissolved in trifluoroacetic acid (2
Processed with Go). After 10 minutes, the solution was worked up as in Example 5(b) to give the title compound (0,016
g) was obtained as a white solid.

umax (KBr)3420.2980.1760.
1720°1710.1670 and 1590 cm-1
,6(DtO) 1.18(3H,tSJ7Hz,
NCR2CH3), 2.60 and 2.61 (3H each,
s, 2x OCOCH,), 2.89 and 2.93 (total 1H1 each d, J 16,5HZ, high magnetic field side) 2-C, H2), 6.25-3.4o (H4, low magnetic field side ( 7) 2-CH,,obscured by NMe),
3.41 (3HSS, NMe), 6.50 (2H
1q, J7Hz, NCH2CH3), 3.55-3.
80 (2H, m,, NCH, CH2N), 3°80 and 4.39 (2H.

ABq, J14Hz, 3-CH, 8), 5.22
and 5624 (total 1H1 each 8.6-H),
5.50 and 5.52 (combined TIH, each 5SNHC
HCO), 7.2-7.6 (3H, m, aromatic) and 8.12 and 8.45 (combined 1H1 each s, NHC
HO, major and minor rotamers respectively).

MIC for Pomirabilis 889 (Pg
/m/) is 0.06.

Example 10 3-[(1-carboxyphenyl-1H-tetrazol-5-yl)thiomethyl]-7β-[D-2-(3,4-
diacetoxyphenyl)-2-[(4-ethyl A/-2,
3-Dioxopiperazin-1-yl)carbonylaminocoacetamide)-7a-formamidocef-6-em-4-carboxylic acid disodium salt (a) 3-[(1-diphenylmethoxycarbonylmethyl-1H-tetrazole5) -yl)thiomethyl]-7β
-(D-2-(3,4-diacetoxyphenyl)-2-
C(4-ethyl-2,3-dioxopiperazin-1-iA/)carbonylaminocoacetamide-7a,-formamidocef-6-em-4-carboxylic acid diphenylmethyl newly prepared D-2-(3 , 4-diacetoxyphenyl)-2-C(4-ethoxy-2,6-thioxopiperazin-1-yl)carbonylaminocoacetyl chloride [corresponding acid (0,047F).

0,108 mm01), N, N-zime7/lzt
Oxalichloride # (0,027,F) in dry dichloromethane (5 ml) containing Lum7
, 0.216 mmol) for 90 minutes] was taken up in dichloromethane C2ml'), and 71
-Amino-3-[(1-diphenylmethoxycarbonylmethyl-1H-tetrazol-5-yl)thiomethyl]-
7 (L-formamide cef-6-em-4-carboxylic acid diphenylmethyl (0,054,9,0,072mmo
7) to the stirred solution of pyridine (0,0061!
, 0.072 mmoJ). 90 minutes later, it was chaotic.

Dilute the hardware with dichloromethane and add hydrogen carbonate sequentially)
Washed with aqueous IJum solution, dilute hydrochloric acid and saturated brine, dried (MgSO4) and evaporated. The title compound (0
,046,! i', 55%) was obtained as a yellow foam.

umax (CHCI3)5290.6000.177
0.1745.1715 and 1690Cm-”, 6
((CDs)tcO)1.15-(3H,t,J 75
Hz, NCH2CH8), 2.21 and 2.22 (3 each) (,2s, 2xOcOcHs), 2.91
and 3.20 (2HXABq, J 17 Hz,
2-CHt), 3.49 (2H12Xq, J7
．． 5Hz, NC horse CHs), 6.6-3.8 and
3.95-4.10 (each 2H, m, N, CH,, C
H, N), 4.16 and 4.65 (2H, ABq
, J 13Hz, 3-CH,S), 5.22 (IH,
S, 6-H), 5.46 and 5.55 (2H
.

ABq, J 17.5Hz, NCR, Co), 5.7
6 (1H, d, J7Hz, NHCHCO), 6.86
．． 6.89 and 6.93 (combined t) Sete 2H, each s,
2xCHPh, ), 715-7.70 (24H, m,
Aromatic and Ndan, CHO), 8.02 (IH.

s, CONHC) 8.27 and 8.52 (Total 1H1 each 5SNHCHO, each main and secondary rotamer)
, and 10.08 (IH, d, J7Hz, CH, NH
, Co), (signal 10.08 disappeared with the addition of D20, while the signal centered at 5.73 collapsed to S) (b) 3-(1-hydroxymethyl-1H-tetrazo/
L/-5-yl)thiomethyl-7β-[D-2-(3,
4-diacetoxyphenyl)-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl)carbonylaminocore-7doamide)-70L-formamidecef-6-
Em-4-carboxylic acid disodium salt 3-[(1-diphenylmethoxycarbonylmethyl-1
H-tetrazol-5-yl)thiomethyl]-7β-CD
-2-(3,4-diacetoxyphenyl")-2-C(
4-ethyl-2,6-thioxopiverazin-1-yl)
carbonylaminocoacetamide]-74-formamidocef-6-em-4-carboxylic acid diphenylmethyl (
The solution was taken up in trifluoroacetic acid (21 nl) and the resulting solution was left at room temperature. After 10 minutes, the solvent was removed under vacuum and the residue was taken up in a saturated aqueous solution of bicarbonate. Add this solution to Diaion HP20SS
The title compound (
0.015 g) was obtained as a white solid.

umax (nujol)ro 300.1775.1765
．． 1720.1710.1690.1675 and 1
625cm-56(DzO)'+, 18(3H,
t, J 7.5Hz, NCH,CH,), 2.34
(6H, S, 2xOcOcH8), 2.91 and 2.95C combination IH, high magnetic field ([u) 2-CH
2ABq (J 1z'5Hz), main and secondary rotamers respectively], 3.64 and 3.37 [: 1H in total, 2-CH2ABq (J 17.5Hz) on the low magnetic field side, main and secondary rotors Y- respectively) , 3.51 (2H, q, J75H
z, NCH2C0□), 3.6-3.75 (2HSm
, NCH,CH,N) ,3.9-4.1 (3Hz
m-NC horse CH2N and 3-CH25ABq on the high magnetic field side
), 467 and 4.43C combined 1H1 low magnetic field side 6-CH, S ABq, (J 14Hz), respectively main and sub rotamer], 5.00 (2H, ABq, NC
H2C0□), 5.23 (1H.

516-H), 5.54 (1H, s,, NHC view C
o), 7.3-7.6 (3H, m, aromatic), and 8
09.812 and 845 (1H1 each s, NHCH
O).

MIC for P, m1rabilis 889 (p,
, 97mA) is 0.06.

Example 11 (a) 7β-amino-3-[(1-carbonylmethyl-
1H-tetrazol-5-yl)thiomethyl)-7a-formamidoceph-3-em-4-carboxylic acid sodium salt 7β-amino-7α-formamidocephalosporanic acid trifluoroacetate (516m9.1.2mmol)
was treated with saturated sodium bicarbonate solution in water (18 mA) and acetone (6 TL) until pH 6.5.5-
Mercapto-1H-tetrazol-1-7-11! )
7 Add mido (384mp, 2.4mmoA),
The pH was adjusted to 6.5. The solvent was heated to 60°C in argon.
Heat for an hour, cool and adjust pH to 6.5.

Evaporate the solvent and transfer the residue to Diaion 1-IP20S
Chromatographed on S2 and eluted with water. By making the active fraction lyophilic, the title compound 038m9.65
%) was obtained.

' (D20) 3.315 and 3.69 (2
H, ABq, Woodworking 16Hz, C) IzS), 5.1.
2 (IH, s, C-6), 5. ．． 28 (2H, S
, CH2C0M), 8.1. ．． 2 and 8.4
(1H1s in total, CHO); umax (KB
r) 3350.1760.1680.1600 cm1° (b) 7β-amino-3-, ((1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl:]-]
7a-Formamide Cefu 3-M4-carboxylic acid diphenylmethyl 713-amino-3-[(1-calicebamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-7(L-
Formamide cef-6-em-4-carboxylic acid sodium salt was dissolved in water (2 ml) and p
I learned H to 2. The precipitated solid was collected, washed with water and acetone and dried under vacuum (75 rru?). The solid was suspended in acetonitrile (8 ml) and excess diphenyldiazomethane was added. After 12 days, the mixture was treated with acetic acid (5 drops) for 1 hour. The mixture was poured into ethyl acetate-water and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried and evaporated. Chromatography of the residue on silica gel (<230 mesh ASTM) yielded the title compound (71rn
9) (50%) was obtained.

umax (nujol) 3400br, 3280, filter 2
50.3200.1750.1720.1710.16
90.1675 = -sδ(CD3), C0NH, obscured by solvent signal, 3.61 and 3.69 (2H
, ABq, J 17. I Hz, ring S-CH2)
, 4.22 and 4.47 (2H, ABq, J
13,3Hz), 5.16(2H,S), 5.22
(1H,S), 6.89 (1H1 wide S1D,
0), 6.90 and 6.93 (total 1
H1 Midan Ph, ), 7.18-7.69 (1'1
H1m, 1H, D, 0 exchanged), Z92 and 808
(In total, 'IH, d, J12Hz, and S1 respectively replace the main and minor rotamers, liver, D, 0'), 8.25
and 852 (combined 1 H, s and aJ 12 Hz; major and minor rotamers respectively, signal beam of the latter, collapses to S by O exchange) Example 12 (a) 713-amino-3-((1-(2-dimethyl aminoethyl)-1H-tetrazo/I/-5-yl)thiomethyl)-7cL-formamidocef-3-em-4-
Carboxylic acid sodium salt 713-amino-7lowformamidecephalosboranic acid trifluoroacetate (320
mg, 0.74 mmol) in water (11 ml) and acetone (filtered) with saturated bicarbonate solution)
Processed up to 16.5. 1-(2-dimethylaminoethyl)-1H-tetrazol-5-thiol (258 mg,
1.49 mmol) was added to adjust the volume to 6.5. The solution was heated to 60° C. in argon for 6 hours, cooled,
- was adjusted to 65. The solvent was evaporated and the residue was
on)1. 2% by chromatography on P2O8s
Elute with acetone-water. The active fractions were combined, acetone was removed by partial evaporation, and the mixture was made lyophilic to obtain the title compound (200 mg, 60%).

δ(D20) 3.20 (6Hls −, N (C”
s)2), 3.02, and ro77 (2H,A
Bq, J 17.6Hz, 2-H2), 382(
2H, t, J5, 6H2, N, C tool 2), 4.05
and 4.22 (2H, ABq, J 13,5Hz,
Dandan, STe t), 4.86 (2HtXJ5.
6H2, N-CI(,), 5.08 and 5.1
7 (combined IHlsXC-6), 8.15 and 8.45 (combined 1H, S, CHO); umax
(KBr) 3360, 1760.1600cm-”.

(b) 7β-Amino-3-((1-dimethylamineethyl-1H-tetrazol-5-yl)thiomethyl)-7c
L-formamidocef-6-em-4-carboxylic diphenylmethyl 7β-amino-3-[(1-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl]-7a-formamidocef-6-em-4- Sodium carboxylic acid salt (60 ml) was dissolved in water (2 ml), and - was adjusted to 2. The solution was evaporated and the residue was dried under vacuum, suspended in acetonitrile (5d) and treated with excess diphenyldiazomethane. After 27 hours, the mixture was poured into ethyl acetate-water, the organic layer was separated, washed with saturated aqueous bicarbonate solution and brine, dried, and evaporated. Chromatography of the residue on silica gel 60 (<230 mesh A8TM) gave the title compound (50 y, 63%).

umax (CHCIg)3400br, 1780,1
720sh1695cm'-1; δ(CDC13)2.
23 (6H,sSN (CHa)t)2.43 (2
H, wide s, Ndan,, replace D20), 2.7 (
2H,t, J7Hz, CH,N-) 3.62 (
2H% s, ring S""z), 4.17-4.37 (
3H,m, N-CD, +SCH.

IH) , 4.43 (IH, d, part of ABq, 514 Hz, SCH, (7) in) , 5.1
6 (IH1S16-H), 6.61 (1H,s,N
(exchanged D, O), 6.98 (1H, S.

, qtanPh2) , 7.2-7.6 (10H, m)
, 8.23 (IH, s.

0), the product is 20% of 70-370-3-l dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl]-7(L-formamidocef-2-em-4-carboxylic acid diphenylmethyl t- It was contained as a non-M substance.

Example 16 s-[1-carbamoylmethyl-1H-tetrasyl-5-yl)thiomethyl]-70-(2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino)-2- phenylacetamide)-74-formamidocef-6-nimu 4-carboxylic acid sodium salt 7β-11D-2-((4-ethyl-2,6-thioxopiperazin-1-yl)carbonylamino-2-phenylacetamide] -7a-formamide cephalosporanic acid sodium salt (0,070 &, 0.104 mmo
/) in water (6-) and acetone (2 ml),
-Mercapto-1H-tetrazol-1-acetamide (
0.039, 0.208 mmol) was added. The resulting solution was adjusted to 6.5 ml and the resulting solution was heated to 60° C. in an argon atmosphere for 11.5 hours. (saturated hydrogen carbonate) in a 9 um solution and then
I applied 20SS glue to ZY Togera Fie. The desired compound was obtained as a white amorphous solid (0,010 g) by lyophilization of both portions containing the title compound.

umax (KBr)3280.2970.1775.
1710°1670, and 1620cm1, δ(D2
0)1. ．． 19 (3H.

t, J 7Hz, N, CH2CH3), 3.
05 (2H, ABq, J16Hz12-CHt)
, 3.52 (2H1q1J7Hz,,N.

CH,, CHs) , 3.64-3.76 and 3
．． 94-4.07 (each 2H, m, diketopiheradi>
H), 4.25 (2H, ABqSJ14Hz, S
, CHt), 5.24 (IH, 516-H)
,5.28(2H,S,N,CH,,CO) ,5
．． 52 (IHXs, Pb.

CH, NH), 7.37-7.59 (5H, m, aromatic H), and 8.16 and 8.44 (together 1
H, each s, N)l, CHO)P, m1rabilis
The MIC (P9/frLl) for 889 is 0.12.

Example 14 3-4(1-rubamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-7β-[D-2-(3,4-
diacetoxy7dinyl)-2-((4-ethyl-2,6
-thioxopiperazin-1-yl)carbonylaminocoacetamide)-7a-formamidecef-ro-em-
Sodium 4-carboxylate (a) 3-[(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-7β-(D-2-(3
,4-Diacetoxypheny(9)--2-((4-ethy/I/-2,3-dioxopiperazin-1-yl)carbonylaminocoacetamide: ]-7(L-formamide cef-3- Diphenylmethyl em-4-carboxylate D-2-(3°4-diacetoxyphenyl)-2-C<4-ethyl- in dry dichloromethane (3 mA) at 0°C containing a catalytic amount of dimethylformamide. 2,6-thioxopiperazin-1-yl)carbonylamino]acetic acid (6
9my, 0.158mmoA) was cooled to 0°C and treated with oxalyl chloride (0,023mff1). After 5 minutes, the cooling bath was removed and the solution was kept at room temperature for an additional 45 minutes. The solvent was evaporated and the residue was dried under vacuum.

7β-amiz-3-C (1-carbamoylethyl-1H
Dry tetrahydrofuran (5 ml
) and pyridine (9 m9, 0.113 mmoA in tetrahydrofuran (1 m/l) was added.
After minutes, the mixture was poured into ethyl acetate-water and the organic layer was separated. The latter was washed successively with 0.1N salt solution, water, aqueous sodium bicarbonate solution and water, dried and evaporated to give the title compound (110), which contained traces of starting material. It was contained as an impurity.

(b) 3-1m(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-7β-CD-2-(
'5,4-diacetoxyphenyl)-2-((4-ethyl-2,3-dioxobipeperazin-1-yl)carbonylaminocore-7-doamide)-7(L-formamide cef-6-em- Sodium 4-carboxylate 3-[(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-71-(D-2-('5.4
-diaceF xyphenyl)-2-((4-ethyl-2,
Diphenylmethyl 6-thioxopiperazin-1-yl)carbonylaminocoacetamide]-70-formamidoceph-6-em-4-carboxylate (11011&, containing some of the corresponding 7β-amide compound) was dissolved in trifluoroacetic acid. . After 15 minutes, the solvent was evaporated and the residue was dried under vacuum. suspending the remaining solids in water;
- was adjusted to 6.5 with sodium bicarbonate solution. The solution was chromatographed on HP2088 using an acetone-water mixture. The active fractions were combined, the acetone was removed by partial evaporation, and then lyophilized to give the title compound (67■).

umax (KBr), Roro0[]br, 1775.
1680 br.

1625 cm4; δ (D, 0) especially 1.19 (filtration H
,t, J7.2Hz) ,2.33 (6H,s,2
x OCOCHs ), 2.8 and 3.18 (2H
, ABq, J 16.5Hz, 5-CH,), 3.
5'l (2H, q, J7.2Hz), 3.68
(2H, m) , 4.0 (2H, m) , 4.08
and 4.48 (2H, ABq, J14.6Hz, -
CH2-8), 5.22 (IH, S, 6-H), 5
．． 28 (2H, AA/, CH2C0N), 5.54
(IH,s, Ar0H), 7.27-7.58
(3H, m, aromatic'), 8.13 (1)s, C
HO).

MIC for P, m1rabilis is 0.12 P
It is iA.

Example 15 3-1m(1-carboxyphenyl-1H-tetrazol-5-yl)thiomethyl)-74-(D-2-(3,4
-dihydroxyphenyl), -2-((4-ethyl-2
,3-dioxopiperazin-1-yl)carbonylaminocoacetamide)-71L-formamidecef-6-
Em-4-carboxylic acid disodium salt 3-(:(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-70-[D-2-(3,4-
diacetoxyphenyl)-2-((4-ethyl-2,6
, -dioxopiperazin-1-yl)carbonylaminocoacetamide)-7 (L-formamidocef-6-em-4-carboxylic acid disodium salt (48)) in tetrahydro7rane (2d) and water (6 ) Sodium sulfite (1Z7) was added to the solution at -90 and the solution was stirred.The pH was kept at 90 and after 70 minutes sodium sulfite (2m9) was added to the bath.After a total of 2 hours, the pH 6.
7 and concentrate the solution, then DiaionHP2
088 chromatography. The title compound (23η) was obtained by making the active fraction lyophilic.

53%) was obtained as an amorphous white solid.

umax, (KBr)343012980,1765.
1675.1625.1524, and 1460Cm-
1,6(DtO) especially 1.18(3H,t,J
7Hz, N, CH,.

C! ! s ) 1 ((3,01 and 'CF 3.40)
and U (3,05 and H 3.45) together 2H, each AB q ,, J 17 Hz12-CH2, each main and minor rotamer], 3.50 (2H, q.

J7Hz1N, CH,, CHa), 3.6-
3.8 (2H, m, N.

CH,,CH,,N), 6.9-4.1 5
(3H, m, N, CH2.

"Ht -N NU High magnetism lJt side f) 3-CH2
8), 4.33 and 4.39 [Aisete 1H, low m
Hot water side) 3- CH2S A B q (J14Hz)],
5.00 (2H, s, N, CH2, C02), 5
．． 18 and 5.26 (total 1H, each 3,6-H
.

major and minor rotamers respectively), 5.26 and 5. Filter 1 (combined, each s, NH, CH, Co,
each k major H and minor rotamer), 6.8-7.1 (
3H, m, aromatic), 8.10 and 8.41 (together IH, each 51NH0CHO, major and minor rotamers respectively), P, MI versus m1rabilis 889
C<p-1/ml> is 0.12.

Example 16 3-((6-carbamoyl-2-methyl-5-oxo-
4H-1,2,4-)riazin-6-yl)thiomethyl]-70-CD-2-,[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-
Phenylacetamide]-7a-formacetamide 7-6
- Nimu 4-carboxylic acid sodium salt (a) 7β-ami7-3-((6~carbamoyl-2-
Methyl-5-oxo-4H-1,2,4=triazine-
3-yl)thiomethyl]-7mata-formamidecef-6
-M-4-carboxylic acid diphenylmethyl 7β-amino-7a-formamide cephalosporan trifluoroacetate (482 my, 1.13 mmoA) in water (6-) and acetone (3TLl) was diluted with p+( 6,0, 6-carbamoyl-2-methyl-5-oxo-4H-1,2,
4-)Ryazine-3-thiol (1861n9゜1mm
o7) was added, the pH was adjusted to 5.4 with 2N hydrochloric acid and the solution was heated to 60° C. under argon. After 2 hours and 45 minutes, the pressure was adjusted to 6.5, the mixture was filtered and the solvent was evaporated. The residue was chromatographed on a Diaion HP 2088, eluting with a water-acetone mixture. By making the active fraction lyophilic, 7β-amino-3-((6-
Carbamoyl-2-methyl-5-oxo-4H-1,2
,4-)riazin-6-yl)thiomethyl]-7α-formamidocef-6-em-4-carboxylic acid sodium salt (120m9) was obtained as a yellowish white solid.

umax(nujo-1”>3150,3000.176
0°1700.1690.1680.1610 and 1
550cm-1゜Dissolve the above salt in water and add p)1 to 6
, adjusted to 0.

An amorphous solid is obtained by making the obtained solution lyophilic,
This was suspended in acetonitrile (FILA') and treated with excess diphenyldiazomethane. 7 days later,
The mixture was treated with acetic acid (5 drops) for 1 hour. The mixture was poured into ethyl acetate-water, the organic layer was separated, washed with 9 um aqueous solution and brine, and dried (Mg
S04), evaporated.

Treat the residue with silica gel 60 (<230 mesh ASTM)
The title compound (
16■) was obtained as a white solid.

umax-(CHCl,)3470.6410.660
0.6000.1780.1710.1705.170
0,1650 and 1555Cm-1, δ((CD3
)2 C0)3.62 and 3.76 (2HSAB
q1J 17Hz, 2-CHv), 3.85(J
H,s,N,CHs), 4.14 and 4.5
4 (2H.

ABqXJ 14Hz, 3-CH,S), 5.11
and 5.20 (total of 1H1 each S, 6-H, each main and minor rotamer), 6.99 (IH, S, c
m, Ph, ), Z2-7.7 (12H, m, aromatic and 2x amide protons), 8.25 and 8.5
4 (combined 1H, each s, NH, CdanO, main and minor rotamers respectively), 8.99br (1H, amide proton), (8.99 signal disappears with the addition of DzO, while the signal of 72~Z7 things have decreased in strength).

(b) 3-((6-carbamoyl-2-methyl-5--
oxo-4H-1,2,4-)riazin-6-yl)thiomethyl]-7β-CD-2-((4-ethyl-2,6
-thioxobiverazin-1-yl)carbonylamino)
-2-Phenylacetamido)-7a-formamidoceph-6-em-4-carboxylic acid diphenylmethyl newly prepared D-2-C(4-ethyl-2゜6-thioxopiperazin-1-yl)carbonylaminoco -2-
Phenylacetyl chloride [corresponding acid (20,4■,
0.064 mmoA was added to dry dichloromethane (2
d) in oxalyl chloride (16,3■, o, 128
mm0A)] was taken up in dry dichloromethane (2d) and the 713-amino-5
-CC6-carbamoyl-2-methyA/-5-oxo-
4H-1,2,4-triazin-6-yl)thiomethyl]-7-formamidecef-6-emu 4-carboxylic acid diphenylmethyl (26 da, 0.0427 m+;')
to a stirred solution of in dichloromethane (1d) followed by the addition of pyridine (5,41n9, 0.0427 mmo)).

After 90 minutes, the mixture was washed successively with dilute hydrogen carbonate solution, dilute hydrochloric acid, and saturated saline solution, and dried (Mg5
Oa) evaporated. Chromatography of the residue on silica gel 60 yielded the title compound (19m9)
was obtained as a white solid.

δ((CDs)zco) 1.15 (3H,t,
J 7 Hz, N, CH,.

CHs ), 3.22 and 3.43 (2HX
ABq, J 16Hz.

2-”H2), 3.47 (2H,qlJ 7H
z 1N , CHz -cHs ) -3,6-3,
8 (2HSm, N, CH2, CH,, N), 3.82
and 3.84 (3H in total, each s, N, CH,,
3.95-4.10 respectively.
(2H, m,, N, C horse N) 4.17 and 4.53
(2H, ABq, J13.5Hz, Ro-CH2S)
, 5.27 and 5.30 (1H in total, 5 each
16-H1 (main and minor rotamers respectively), 5.70 (I
H.

d, J 7.5HzXNH6CH0Co), 6.96
(IH,s,CH.

P'h), 7.2-7.8 (17H,m, aromatic and 2 amide protons), 8.02 (IHSs,
C00NH, C), 8.27 and 8.53 (total 1H, each s, NH, CHO1 each main and secondary rotor Y-), 8.63 and 8.88br (total 1H, NHCHO1 each main and each −Tama→.

(C) 3-[(6-carbamoyl-2-methyl-5oxo-4H-1,2,4-triazin-6-yl)thiomethyl]-70-(D-2-(4-ethyl-2,6 -thioxopiperazin-1-yl)carbonylamino-2-phenylacetamide)-7cL-formamidecef-6
-M-4-carboxylic acid sodium salt 5-CC6-carbamoyl-2-methyl-5-oxo-4H-1,2,4
-) riazin-3-yl)thiomethyl]-70-CD-
2-((4-ethyl-2,3-dioxopiperazine-1
-yl)carbonylaminoco-2-phenylacetamide]-7ct-formamidoceph-6-em-4-carboxylic acid (19■) in trifluoroacetic acid 1g (2rr, l)
and left at room temperature. After 10 minutes, the solvent was evaporated and the residue was taken up in a saturated aqueous solution of hydrogen carbonate. The resulting white cloudy liquid was chromatographed on Diaion HP20SS and eluted with a water-acetone mixture.

The title compound (11■) was obtained as a white colorless solid by making the active fraction lyophilic.

umax, (KBr)3390.2990.2665
．． 236oJ 2325.1770.1680.155
5 and 1520Cm-1, δ(DtO)1.20 (
3H, t, J7Hz, N, CH7, C! l! , ), 6.
11 and 3.15' (total 1H1 each d,
Ji7Hz, high magnetic field side (7) 2-CHtABq.

The main and minor rotamers respectively>, 3.45-3.60<
A total of 3HXm, N, CH,, CH3 2-CH on the low magnetic field side.

ABq, q1 centered at 3.54 can be identified), 3.
6-3.8 (2H, mXN, CH,, CH,, N)
, 3.95 and 3.97 (total 3H, each S1N
, CH8, respectively main and sub rotor Y-), 3.9-4.
2 (Total 3HXm, N.

C, CH2,N and 3-CH25 on the high magnetic field side)
, 4.37 and 4.41 (total 1H, each d, J
14Hz, 3-CH28ABq on the low field side, main and secondary rotamers respectively) 5.25 and 5.28 (total 1
H, each S, 6-H.

major and minor rotamers), 5.47 and 5.5 respectively
2 (total iH, each 5SNH, C view, co, each main and secondary rotor), 7.4-7.6 (5H, m,
aromatic), 8.15 and 8.47 (combined 1H1
5SNH, C0, major and minor rotamers respectively), P, MIC for m1rabilis 839 < Pg
imi> is 0.25.

Example 17 3-,((1-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl-7β-[(2-D-(4-
Ethyl-2,6-thioxopiperazin-1-yl)carbonylamino)-2-7enylacetamide:]-]7
aL-borumamidocefu 6-nimu 4carboxylic acid sodium salt (a) 3-((1-diphenylaminoethyl-1H tetrazol-5-yl)thiomethyl]-70-((:2-D
-(4-ethyl-2,6-thioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide)
-70L-formamidocef-6-em-4-carboxylic acid diphenylmethyl newly prepared D-2-[(4-ethyl-2°6-thioxobiperazin-1-yl)carbonylaminoco-2-
Phenylacetyl chloride [corresponding acid (113rn9
．． 0.354 mmoA was added to dry dichloromethane (5-
) Medium plated oxalyl (898 mg, 0.707 mn
7β-amino-3-[(1-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl-7- Formamide safe
Diphenylmethyl 3-m-4-carboxylate (140
, 0.236mm0l) [corresponding delta of approximately 50%
2 isomers] and then pyridine (2o, 5mp, 0.259 mmol) was added. After 15 minutes, the mixture was diluted with dichloromethane, washed successively with aqueous IJ carbonate solution, dilute hydrochloric acid and saturated brine, dried (11V4gS04) and evaporated. Chromatography of the residue on silica gel afforded the title compound (1257n9), (containing approximately 50% of the corresponding delta-2 isomer) as a pale glass.

umax, (CHCI,)3300.3000.178
0.1720.1700 and 1685 cm-1,
δ (CDC13/D, 0) especially 1.20 (t, N
, CH2, C, ), 2.24 (2X S, NMe
2), 2.6-2.7 (t, , cn, , NMe
2), 5.50C5,6-H), 5.46 (S,N
H, CH, CO), 6.89 (s, CH, Ph2)
, 8.22 and 8.45 (each S, NH, CHO
, respectively the main and minor rotamers].

(b) 3-((1-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl]-713-(C2-D
-(4-ethyl-2,6-thioxobiperazin-1-yl)carbonylamino)-2-phenylacetamide]
-7cm formamide cef-6-em-4-carboxylic acid sodium salt 3-[(1-dimethylamineethyl-11(-tetracyl-5-yl)thiomethyl) -713-([2-D-
(4-ethyl-2,6-thioxopiperazin-1-yl)carbonyl)-2-phenylacetamide': l-7
ct-formamide cef-6-em-4-carboxylic diphenylmethyl [containing approximately 50% of the corresponding delta-2 isomer] (100 mp) was treated with trifluoroacetic acid (100 mp) for 10 min.
5 ml) and then the solvent was evaporated under vacuum.

The residue was mixed with water to form two layers, the texture was adjusted to 6.8, and the resulting suspension was stirred vigorously. P2
Purified with O88. By making the active fraction lyophilic, the title compound (62■) containing about 50% of the corresponding delta 2 isomer was obtained as a white solid.

umax, (KBr)3430.2985.1770.
1680.1610.1505.1460.195.
1665, and 1185Cm-1, δ (DtO) especially 1.19 (t, N, CH2°CH3), 2.9
5 (s, NMe2> , s, 14 [2-C on the high magnetic field side
H, ABq (J17Hz)), 5.26 (S, 6
-H), 5.5[] (s, NHoCH, CO),
7.3-7.6 (m1 aromatic), and 8.16 and 8roO (each s, NHoCIO).

MIC for P6mirabil 1s839 (
P9/1na is 1.0.

Agent Patent attorney Masaaki Akizawa Mitsunobu (Kaneda) 1 person (Kaneda) April 2-8, 1947 Official of the Japan Patent Office Relationship with one nobleman Suspension: Repulsion 1

Claims (1)

[Claims] (1) Formula (I) / \ R, 2R3 (wherein, Y is formula (a), +b), (c) or (d')
H3, R1 is phenyl, substituted phenyl, cyclohexenyl, cyclohexagenyl, hydroxy, amino, halogen, substituted amino or cl-
5 containing up to 3 heteroatoms selected from oxygen, sulfur or nitrogen optionally substituted with 6-flukoxy
or a 6-membered heterocycle, R2 is hydrogen or an optionally substituted C1-6 alkyl group, and R3 is an optionally substituted 5 or is a 6-membered heterocyclic group, or R2
and R3 together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-shell heterocyclic group containing 1 or 2 nitrogen heteroatoms, such as alkyl, C2-
5 alkenyl or carboxy(CI-a) alkyl, and R5 is carbamoyl or C1-6 alkyl), or a pharmaceutically suitable salt or in vivo hydrolyzable ester thereof. (2) Y is Z (wherein, Z is carbamoyl, carbamoyl (Ct-a)
Alkyl, amino(C1-s)alkyl, di(CI,
6alkyl)amino(Cr-s)alkyl, hydroxy(C1-s)alkyl, sulfo(CI-a)alkyl or C2-6fulkenyl). (3) The compound according to claim (1), wherein Y is. HO 6 (wherein R1 and Y have the same meaning as in claim (1), and R6 represents hydrogen, ci-s alkyl, substituted alkyl, aryl or aralkyl; R7 and R8 are the same or different, hydrogen,
represents C1-5 alkyl, substituted alkyl, no-rogen, amino, hydroxy or C1-6 alkoxy, or R7 and H,s form the residue of a 5- or 6-membered carbocyclic or hetep ring group); Claim No. (
A compound according to any one of items 1) to (3), or a pharmaceutically suitable salt or ester thereof that can be hydrolyzed in vivo. (5) The following a) 7β-(:DL-2-(3,4-diacetoxyphenyl)-2-((4-ethyl-dioxopiperazine-1
-yl)carbonylaminocoacetamide)-7a-formamide-6-[(6-hydroxy-4-methyA/-
5-oxo-4H-1,2,4-)riazin-6-yl)thiomethyl]Sefu6-nimu4-carboxylic acid 3-((1-carboxymethyl-1H-tetrazol-5
-yl)thiomethyl)713-CD-2-CC4-ethyl-2,6-sioxopiverazin-1-yl)carbonylamino]=2-phenylacetamide]-7ct-formamidecef-6-em-4-carvone acid b) 7
β-CD-2-((4-ethyl-2,6-thioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide]-7a-formamide-3-((6-hydroxy-4-methyl- 5-oxo-4H-1,2゜4
-triazin-6-yl)thiomethyl]cefu-3-emu-4-carboxylic acid, 7β-CD-2(4-acetoxyphenyl)-2-((
4-ethyl-2,6-thioxobiperadi>-1-yl)
carbonylaminocoacetamide)-7a-formamide-6-[(6-hydroxy-4-methyA/-5-oxo-4)(-1,2,4-)riazin-6-yl)thiomethyl]cefu 6- Nimu 4-carboxylic acid, 713-(DL-2-((4-ethyl-2,6-thioxobiperazin-1-yl)carbonylamino)-2-(
cefu 6- Nimu 4-carboxylic acid, 7β-(DL
-2-C(4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylamino)-2-(2-fluorophenyl)acetamide)-7a-formamide-6-[
(6-hydroxy-4-methyl-5-oxo-4H-1
,2,4-)riazin-6-yl)thiomethyl]cefu-6-nimo-4-carboxylic acid, 7β-[D-2-(3,4-diacetoxyphenyl)-
2-((4-ethyl-2,6-thioxobiperazine-1
-yl)carbonylaminocoacetamide]-7lowformamide 3-((6-hydroxy-4-methyl-5
~oxo-4H-1,2,4-)riazin-6-yl)
thiomethyl]cefu-3-emu-4-carboxylic acid, 3-((1-carboxymethyl-1H-tetomerazol-5-yl)thiomethyl]-71-[D-2-(3,4-
diacetoxyphenyl)-2-((4-ethyl-2,'
5-dioxopiperazine-1-yl)carbonylaminocoacetamide)-7(L-formamidocef-6-em-4-carboxylic acid, c) 3-(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl )-74-CD-2-((4-
Ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide”]-]7
a-Formamide Cefu 3-M-4-carboxylic acid, d)
3-[(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl]-71-CD-2-(3,4-
diacetoxyphenyl)-2...[(4-ethyl-2,
6-Shioxohi. perazin-1-yl)carbonylaminoco-fluorformamide cef-3-em-4-carboxylic acid, e) 3-((1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-7β-[D-2 -(3,4
-dihydroxyphenyl)-2-((4-ethyl-2,
6-thioxopiverazin-1-yl) carbonylaminocoacetamide: l-7(L-formamide cef-6-
Em-4-carboxylic acid, 3-((1-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl)-713-((2-D-(4
-ethyl-2,6-thioxopiperazin-1-yl)carbonylamino)-2-phenylacetamide:]-]
7cL-Formamide Cefu 6-nimu 4carboxylic acid or f) 3-[(6-carbamoyl-2-methyl-5-oxo-4H-1,2,4-)riazin-6-yA/)thiomethyl]- 7β-CD-2-[(4-ethyl-2,6-
thioxopiperazin-1-yl)carbonylamino]-
A compound according to claim (1) selected from (2-phenylacetamido)-74-formamidocef-6-em-4-carboxylic acid, or a pharmaceutically suitable salt thereof, or a salt capable of being hydrolyzed in vivo. ester. (6) A pharmaceutical composition containing the compound according to claim (1) together with a pharmaceutically suitable carrier or excipient. (A pharmaceutical composition according to claim (6), further comprising a β-lactamase inhibitor. (8) A compound according to claim (1) for use in the treatment of bacterial infections. ( 9) a) Formula (V) NH. H (where Bi, R2, H, s and Y have the same meanings as above, any reactive groups may be protected, and R9 is an easily removable carboxyl protecting group) or b) a compound of the formula HO 1 (wherein Y has the same meaning as above, any reactive groups may be protected and the amino group is acylated); and RIG is hydrogen or a group having the same meaning as above. O (■1) 2 R3 (wherein R1, R2 and R3 have the same meanings as in formula (I), and any reactive group therein may be protected) reaction with an N-acylating derivative of the acid, or HH (wherein R1, R10 and Y have the same meanings as above, and the 6-ami7 group is substituted with a group capable of causing acylation). and any reactive group may be protected) is a compound represented by the formula (TX) 2 R3 (where l(,2 and uta have the same meanings as above). and d) with an N-acylating derivative of an acid of the formula 0Gll) (, lHO (wherein 1(IX)( , 2, R, 3 and R9 have the same meaning as above, in which any reactive groups may be protected, and compounds of formula % (where , 2 is a leaving group) %)] (provided that when R12 is an acyloxy group, -Co2RIO must be in the free acid form or a salt thereof), then method a),
If necessary after either b), C) or d), the following steps 1) Removal of any carboxyl protecting group R9, +t) Any protection on R', R3 or Y. Claim (1) comprising one or more of the following: (1) converting the product into its salt or in vivo hydrolysable ester.
Method for producing the compound described in Section 1. C0) 7β-amino-34(1-carboxymethyl-1
H-tetrazol-5-yl)thiomethyl]-7-formamidocef-6-em-4-carboxylic acid bis-diphenylmethyl ester, 713-amino-3-[(1-carbamoylmethythyl-1H-tetrazol-5- )
thiomethyl]-7uform□amidecef-6-M-
4-carboxylic acid or its diphenylmethyl ester, 7β-amino-ro-((1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl)thiomethyl)
7a, -formamide heptafluoroem-4-carboxylic acid or its diphenylmethyl ester and 7β-amino z-3-[(6-cal]
Moyl-2-methyl-5-oxo-4H-1,2
,4-)riazin-6-yl)thiomethyl]-7(L-
The compound according to claim (1) or a salt thereof selected from hol-1, muchimidocef-6-em-4-carboxylic acid or diphenylmethyl ester thereof.