CA1197838A - Cephalosporins and processes for preparation thereof - Google Patents

Abstract

TITLE OF THE INVENTION
Novel Cephalosporins and Processes for Preparation Thereof ABSTRACT OF THE DISCLOSURE
Disclosed are novel cephalosporin derivatives having an excellent antibiotic activity against pathogenic bacteria belonging to the genera Pseudomonas, Serratia and Enterobacter, and processes for the preparation thereof.

Description

~7~

BACKGROUND OF THE INVENTION
(1) Field of the Invention:
The present invention relates to novel cephalosp~rin derivatives valuable as medicines and processes for the preparation thereof.
More particularly, the present invention relates to novel cephalosporin derivatives having an excellent antibiotic activity against pathogenic bacteria belonging to the general Pseudomonas, Serratia and Enterobacter, and processes for the preparation thereof.

(2) Description of the Prlor Art:
Japanese Patent Application Laid-Open Specification No. 148795/79 ~Richardson-Merrell Incorporated) discloses that a compound represented by the following ~ormula has ar.
excellent antibiotic property:

[ ~1 J--A--CH--C-NH,S~ ~
1. o ~ CH2R3 wherein A is selected from the group consisting of sigma bond, phenylene and phenylenethio, R1 is selected from the group consisting of hydrogen, phenyl, amino, hydroxyl, carboxyl and sulfo, R2 is selected from the group consisting of hydrogen,formyloxymethyl and alkanoyloxymethyl (in which ; 25 the alkanoyl group has 2 to 5 carbon atoms), and R3 is selected from the group consisting of hydrogen, hydroxyl, acetoxy~
5-methyl-1,3,4-thiadiazol-2-yl-thio, 1-methyl-1,2,3,4-tetrazol '7~38 5-yl-thio and 1,2,3-triazol-4-yl-thio.
It is suggested by the above laid-open specification that when a 1,3-dithiolan-2-imino group is introduced into a known cephalosporin compound, the antibiotic activity against gram-ne~ative bacteria and gram-positive bacteria is enhanced.
The compound disclosed in the above laid-open specification is very low in effect in the curing of infectious diseases caused by, Pseudomonas, Serratia and Enterobacter, which are now regarded as.being difficult to cure.
i A series of cephalosporin compounds are disclosed in Japanese Patent Ap?~ication Laid-Open Speci~ications Nos.
822B6/76, 110592/76, 15398/78, 79895/78 and 39D91/7g (all filed by Bayer A.G.), but cephalosporin compounds having a 1,3-dithiolan-2-imino group are not disclosed in any of these laid-open specifications.

SUMMARY OF THE INVENTION
In accordance with one fundamental aspect of the present invention, there is provided a novel cephalosporin represented by the following formula:

1 ~ ~N-N N-CONH-CH-CO NH ~ ~ (I) R2 S ~ B ~N ~ CH2-R
COOR' wherein R represents a hydrogen.atom, an acyloxy group, a carbamoyloxy group, a substituted or unsubstituted pyridinium group or a group -S-Het in which Het represents a substituted or unsubstituted, hetero atom-containing, a ~, 78~3 5- or 6-membered heterocyclic group, R' stands for a hydrogen atom, an al~ali metal, an organlc amine or an ester molety, R1 and R2, whlch may be the same or different, stand ~or a hydrogen atom or a lower alkyl group, and B stands for a 1,4-cyclohexadienyl group, a group Z ~ `in which Y stands ~Y
for a hydrogen atom, a group OH or a group -O-C-R~ in which R5 represents an a~kyl group having 1 to 5 carhon atoms, an aryl group or an alkoxy group having 1 to 4 carbon atoms, Z stands for a hydrogen or halogen atom and p is an integer of 1 or ~, a furan group~ or a thiophene group.
In accordance with another aspect of ~he present t invention, there is provided a process for the preparation of novel cephalosporins represented by the above ormula (I), which comprises reacting a compound (II) r~presented by the following formula:
~H -C~-CONH ~ 51 (II) B N ~ CH2-R
COOR' wherein B, R and R' are as defined above, with a reactive derivative of a compound (III) represented by the following formula:

R1 ~ ~ N-N N-COOH . (III) wherein R1 and R2 are as defined above, ~`? - 4 -

3~3 and, if necessary, acylating or esterifying the resulting reaction product.
In accordance with still another aspect of the p~esent invention, there is provided a process for the preparation of novel cephalosporins represented by the above formula (I), which comprises reacting a compound (IV) represented by the following formula:

NH~ ~ S-~ (IV~

10~ /~ N ~ H2-R
. CQOR' wherein R and R' are as defined above, with a compound (V) represented by the following formula:

r ~N-N N-CONH-CH-COOH ~V) 15R2l SJ ~ B

wherein B, R1 and R2 are as defined above, or a reactive derivative thereo, and, if necessary, acylating or esterifying the resulting reaction product.
In accordance with a further aspect of the present invention, there is provided a process for the preparation of novel cephalosporins represented by the above formula ~I), which comprises reacting a compound (VI) represented by the following formula:

1 ~ ~ N-N ~ N-CO NH-CH-COWH-__~S
R2 S O B ~ ~ ~ E2~ VI) COOR"' 8~
wherein R" stands for an acyloxy group, R"' stands for a hydrogen atom, an alkali metal or an ammonium group, and B, R1 and R2 are as defined above, with a compound (VII) represented by the following formula:
M-S-Het (VII) wherein M stands for a hydrogen atom or an alkali metal, and Het is as defined ahove, and, if necessary, acylating or esterifying the resulting xeaction product.
In accordance with a still further aspect of the present invention, there is provided a novel intermediate represented by t~e foiiowing formula:

1 ¦ ~ N-N IH (VIII) wherein R1 and R2 are as defined above, which is used for the above-mentioned preparation processes.
In accordance with a still further aspect of the present invention, there is provided a reactive derivative of a novel intermediate represented by the following formula:

¦ ~ N-W ~ 1_COOH (III) wherein R1 and R2 are as defined above, which is used for the above-mentioned preparation processes.
In accordance with a still further aspect of the present invention, -there is provided a compound represented by the following formula or a reactive derivative thereof:

7~3~

R S l l I1 ~ N-N N-CO-NH-CH-COOH (V) R SJ ~

wherein B, R1 and R2 are as deined above, which is used for the above-mentioned preparation processes.

DETAILED DESCRIPTION O~ THE PREFERRED EMBODIMENTS
The present invention relates to novel cephalosporin derivatives and processes ~or the preparation thereof.
0 L More particularly, the present invention relates to novel cephalosporin derivatives having an excellent antibiotic activity against pathogenic ~acteria belonging to the genera Pseudomonas, Serratia and Enterobacter, and processes for the preparation thereof.
The intended novel cephalosporin derivatives of the precent invention are novel compounds represented by the ~ollowing ~ormula:

R r S ~ N-N ~ N-CONH-CH-CO NH ~ CH~-R (I) COOR' wherein R represents a hydrogen atom, an acyloxy group, a carbamoyloxy group, a substituted or unsubstituted pyridinium group or a group -S-Het in which Het represents a substituted or unsubstituted, hetero atom-cont~in;ngr a 5- or 6-membered heterocyclic group, R' stands for a hydrogen atom, an alkali metal, an organic amine or an ester moiety, R~ and R2, which may be the same or dif~erent, stand for a ~.

~y~ogen atom or a lower alkyl group, and B stands or a 1,4-cyclohexadienyl group or a group Z P in which ~Y
Y stand~ for a hydrogen atom, a qroup -OH, a group -O-C-R5 S ln whlch R5 represents an alkyl group having 1 to 5 carbon a~oms, an aryl group or an alkoxy group having 1 to

4 carbon atoms, Z stands for a hydrogen or halogen atom and p is an lnte~er or 1 or 2, a furan group or a thiohene group.
Pharmaceutically accepta~le salts, hydrates and organic solvent solvated products of the foregoing compounds are naturally included within t~e technical scope of the present invention.
The individual groups generally shown in the formula (I) will now be described in detail.
Group R
By the acyloxy group as R is meant a group R4-CO-O-in which R4 stands ~or an alkyl g~oup having 1 to 4 carbon atoms or a substituted or unsubstituted aryl group. A
compound of the formula (I) ln which R4 is methyl group is especially preerred be~ause 7-ACA used for the preparation o th~s compound is easily commercially available and the antibiotic activity of this compound is especially excellent.
By the substituted pyridinium group as R is meant a group ~ ~ R6 wherein R6 stands for a hydrogen atom, 2~ -N ~
a lower alkyl group, a carboxyl group, a lower alkoxy group, a carbamoyl group, a halogen atom or a sulfamo~l group.

By the group -S-Het as R, there can be mentioned, or e~ample, the following yroups:
N--N N--N N--N
- s J~ ,N ,- S ~ ,N ,- S J~ I
CH3 CH2-COOH CH2-CH2N< 3 N N N
- s J~ , N - S -¢,N
N
CH -CH -NHCOCH

N i; - N N--N
-Sll~ N ,-S ~ o _S_I]~ oJl-CH3 N

- S ~ , - S ~
S N o N--N N--N CH N--N
_S-I~ s~l-NHCOCH3 ~ -S-l~s ~-N< CH and -S- ~S ~ R3 Namely, as is apparent from the above formulae, Het represents a substituted or unsubstituted, hetero atom cont~;n;ng, 5- or 6-membered heterocyclic group. Incidentally, R3 stands for a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms.

_ g ~97~3~8 Group R' The group R' is explained as the group -CQOR'~
Namely, as the group -COOR', there can be mentioned a free carboxyl group, salts thereof with alkali metals such as sodium and potassium, salts thereof with organic amines such as triethylamine, diisopropylamine and dicyclohexylamine, and methyl, ethyl, benzyl, acetoxymethyl, a-acetoxyethyl, pivaloyloxymethyl,' ~-ethoxycarbonyloxymethyl, ~-methoxy-carbonyloxymethyl, ~-methoxycarbonyloxyethyl, benzhydryl, 1-in~anyl, phthalidyl, dimethylaminoethyl and trimethylsilyl esters thereof.
Groups R1 and R~
R1 and R2 stand for a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, which may be branched, such as methyl, ethyl, propyl and butyl groups.
Group B
B stands for a 1,4-cyclohexadienyl group, a furan group or a thiophene groups. Furthermore, B stands for a group represented by the following general formula:
zp wherein Y stands for a hydrogen atom, a group -OH
or a group -O-C-R5 in which R5 is an alkyl group having O c 1 to 5 carbon atoms, an aryl group or an alkoxy group having 1 to 4 carbon atoms, Z stands for a hydrogen or halogen atom 33~

and p is an integer of 1 or 2.
As specific examples, there can be mentioned a p-hydroxyphenyl group and a 4-hydroxy-3-chlorophenyl group, and acyl esters thereof, such as acetic acid, propionic acid, butyric acid, caproic acid, benzoic acid, methylcarbonic acid, propylcarbonic acid and butylcarbonic acid esters.
Processes for PreDaration of Novel Cephalosporins The intended novel cephalosporin derivatives of the present invention are generally prepared according to the following three processes.
First Process The intended derivatives can be prepared by reacting a compound represented by the following formula:

NH -CH-CONH I r ~
2 , ~ N ~ CH2-R (II) COOR' wherein R, R' and B are as defined above, with a compound lIII) represented by the ollowing formula:

R - - S
1 ~=N-N N-COOH (III) R2---S / ~

wherein R1 and R2 are as defined above, or a reactive derivative thereof.
In the case where B is a p-hydroxyphenyl group ~Y = -OH) or R' is a hydrogen atom lR' = ~, acylation or esterification of the ob~ained reaction product is carried out i necessary.
The compound (III) which is used as the starting compound may be obtained by preparing from a compound of the following formula:

NH -N ~ H
a compound represented by the following formula:
¦ )=N-~ NH (VIII) wherein R1 ~nd R2 are as defined above, silylating the comp~und (VIII) and subjecting the silylated product chlorocarbonylation with phosgene or trichloromethyl chloroformate.
Second Process The intended derivatives can be prepared by reacting a compound (IV) represented by the following formula:

NH2 ~ 1 ~IV) ~ N ~ CH2-R
COOF~ ' whereln R and R' are as defined above, with a compound (V) represented by the following formula:

R1 1 ~N-N ~ -~ONH-CH-COOH (V) R2 S ~ B

wherein R1, R2 and B are as defined above, 783&~

Acylation or esterification is carried out, if necessary, as described above with respect to the first process.
The compound (V) may be obtained by reacting a reactive derivative of the above-mentioned compound (III) with a compound (X) represented by the following ~ormula:

NH2-CH-COOH (X) B

wherein B is as defined above.
Third Process The intended derivatives can be prepared by reacting a comp~und tVl`) represented by the following formula:

1 ¦ ~=N-N N-CONH-CH-CONH ~ ~ (VI~

COOR'n wherein R1, R2 and B are as defined above, R"
stands for an acyloxy group and R"' stands for a hydrogen atom, an alkali metal or an ~m~on;um group, 20 with a compound (VII) represented by the following formula:
M-S-Het (VII) wherein Het is as defined above and M stands ~or a hydrogen atom or alkali metal.
A compound ~I') represented by the following formula:
1 r ~N-~l-CONH--CH-CONH~S
R2 - S ~ B . ~ ~ CH2-S Het ~I') COOR' . .

can be prepared by subjecting the resultin~ compound to acylation or esterification, if necessary, in the same manner as described above with respect to the first process, The processes for the preparation of the novel cephalosporin derivatives will now be described in detail while referring to novel intermediates used for these preparation processes.
The starting compound (A) can easily be prepared, for example, by subjecting 1-benzalimino-2-oxo-imidazolidone (B) to steam distillation under a sulfuric acid-acidified condition according to eu;tomary procedures.
This process is represented by the followiny reaction formula:

~ -CH=N-N NH ~ NH2-N NH ~ ~ HO
O O
(B) (A) Isolation and purification of the compound (A) may be performed according to eustomary proeedures.
~he starting compound (VIII) that is used in the present invention is a novel eompound, and this compound can be synthesized aeeording to the following three processes.
Process (a):
NH2-~NH + R1 S Rl S
~ ¦ , s r ~=N-N NH ~VIII) 2~ R2 S R2 S y ~A) 3~

Process (b): I 1 Rl---S~
NH -N NH ~ S-CH X
2 ~ R2---S~ 3 (A) R11S~

Process (c): ~ ~ SM
NH -N NH HN N-N=C ~
2 ~ ~ ~ \ SM
(A) o O

X-CS-C~ =N-N NH /VIII) In the above reaction formulae, R1 and R2 are as defined above, X ~ stands for a halogen ion, M stands for sodium or potassium, and X stands for a halogen atom.
According to the process (a), the compound (A) is mixsd with 1,3-dithiolan-2-thione or a herivative thereof at a substantially eguimolar ratio in the absence o~ a solvent, the mixture is heated at 80 to 1~0CC until generation o hydrogen sulfide is stopped, and the reaction product is puri~ied according to customary procedures.
Accoraing to the process (b3, S-methyl-1,3-dithiolan-2S 2-thione halide ~iodide) or its derivative obtained by reacting 1,3-dithiolan-2-thione or its derivative with an alkyl halide, ordinarily methyl iodide~ is reacted with the ` ~ ....~ - .: ,. .
, - , ' .:
.

7~3&~

compound ~A) at -10 to 80C, preferably -5 to 30C, in the presence of a tertiary amine such as triethylamine in an appropriate organic solvent such as methanol, ethanol, dimethylformamide, dimethylacetamide or acetonitrile, completion of the reaction is confirmed by thin layer chromatography and the reaction product is isolated and purified aecording to customary procedures.
In the above reaction, S-methyl-1,3-dithiolan-2-~hione halide (iodide) or its derivative is used in an amou~t of about 1.0 to about 1.5 moles per mole of the compound (A), preferably in an equimolar amount to the compound (A), and the tertiary amine is used in an amount of about 2 moles per mole of the compound (A).
According to the process (c), at first, the compound (A) is reacted with carbon disulfide at -10 to 50~C in the presence of an alkali metal hydroxide for about 1 to about 10 hours. In this reaction, the alkali metal hydroxide is used in an amount of about 2 moles per mole of the compound (A). The alkali metal hydroxide may be added at one time at the start of the reaction or it may be added at two times ~about one mole at each time). Carbon disulfide is added in an amount of 1 to 3 moles per mole of the compound (A).
Then, the resulting reaction product is reacted with an ethylene halide such as ethylene bromide or ethylene chloride or its derivative in an amount of 1 to 3 moles per mole of the compound (A) at 20 to 100C, preferably 30 to 35C, for about 1 to about 10 hours, and the resulting 7~33~

reaction pxoduct is isolated and purified according to customary procedures.
A compound (III') shown below, which is a reactive derivative of the compound (III), is prepared in a high yield with a good quality according to a process represented by the following reaction formula:

)=N-I~NH silylating agent o 1 0 ~ S ~ COC12 _ ~=N-N N-Si(CH3)3 >
R2_ O(CCl30COCl) 1 ¦ ~N-N ~ -COCl R2 S ~ (II~) As the silylating agent to be used for this reaction, there are preferably employed trimethylsilyl chloride, hexamethyldisilazane and bistrimethylsilyl acetamide. Ater the silylation xeaction, the reaction product is dissolved in an organic solvent such as tetra-hydrofuran, dioxane or dichloromethane and contacted with phosgene or its precursor such as trichloromethyl chloroformate, whereby the novel compound`(III') can easily be obtained.
In this reaction, when phosgene-gas is used, reaction is carried out at room temperature for about 2 to about 8 hours by using phosgene gas in an excessive amount over the silylated product of the compound f~III). When a 3~

phosgene precursor is used, reaction is carried out at -25 to 30C for about 1 to about 7 hours by using the precursor in an amount of about 1/2 mole per mole of the silylated product.
The compound (III') may be purified by recrystalliza-tion from an inert organic solvent. According to the above reaction, however, the compound (III') can be obtained at such a high purity that the as-obtained compound tIII') can conveniently be used directly for the subsequent reac~ion.
The compouna (V) can easily be prepared by reacting the compound (III') with a substantially equimolar amount o the compound (X~ or its silylated derivative in an appropriate solvent in the presence of an deacidifier.
As the solvent that is used for this reaction, there can be mentioned water, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethylacetamide, acetonitrile, dichloromethane and mixed solvents thereof. The deacidifier is used in a substantially equimolar amount. As the deacidifier, there may be used sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethyl-amine, pyridine and dimethylaniline. The reaction is carried out at -10 to 50C for about 30 minutes to about 2 hoursO
The so-obtained compound (V) is isolated and purified according to customary procedures.
Some of compounds of the formula (II~ are marke~ed as Cephalexin, Cephaloglycin and derivatives thereof~ and other compounds of the formula (II) can be prepared acco~ding ~' i~9~

to known techniques~
Novel cephalosporin derivatives of the present invention can be prepared by using the startiny compounds (intermediates) prepared according to the above-mentioned processes.
In the first process, a salt o the compound (II) with, for example, sodium, potassium/ triethylamine, pyridine or dimethylaniline or a silylated product of the compound ~II) is reacted with the compound (III) or its reactive deri~ative (III') at a substantially equimolar ratio in water, ethyl ether, ~e~rahydrofuran, dioxane, acetone, acetonitrile, dimethylformamide, methylene chloride or a mixed solvent thereof at a low temperature, ordinarily -50 to 30C, for about 30 minutes to about 3 hours.
~he so-obtained product is isolated and purified according to known methods.
In the second process, the compound ~V) synthesized according to the above-mentioned process is co~den5ed with a substantially equimolar amount of the compound (IV). It is ordinarily preferred that a reactive derivative of the compound (V) be used. As the reactive derivative, there are used an acid halide, a mixed acid anhydride and an active ester. The free carboxylic acid may be directly used. In this case, it is preferred that an appropriate condensing agent be used in a substantially equimolar amount. As the condensing agent, there can be used N,N'-~icyclohexylcarb~diimide, N,N'-carbonylimidazole, phosphorus oxychloride and Vilsmeier ';J8~3 reagent. These condensing agents are well-known reagents used in the fields of chemistry of penicillins, chemistry of cephalosporins and chemistry of peptides.
This reaction is ordinarily carried out in an appropriate solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetonitrile, acetone, dimethylsulfoxide, water or a mixed solvent thereof. The reaction temperature is ordinarily -50 to 30~C, though the reaction temperature changes to some extent according to the kind of the reactive derivative or condensing agent. The reaction time is about 30 minutes to about 3 hours.
The so-obtained compound (I) can easily be isolated and purified according to known methods.
In the third process, the compound (VI) is contacted with the compound (VII) in an amount of 1 to 2 moles per mole of the compound ~VI) in water or a mixture of water and water-miscible organic solvent. It is preferred that this reaction be carxied out under a substantially neutral condition.
When the thiol is used in the free state, the reaction mixture is kept substantially neutral by appropriately adding an alkaline compound such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal dihydrogenphosphate or an alkali metal monohydrogenphosphate. The reaction is ordinarily carried out at 20 to 70C.
Completion of the reaction is confirmed by thin ~- .

~78;~

layer chromatography.
Since the obtained compound (I') is dissolved in the form of a water-soluble alkali metal salt in the reaction mixture liquid, if the reaction mixture liquid is made slightly acidic by addition of an acid, the compound (I') is precipitated. The obtained crude product is purified by a method well-known in the art.
In the present invention, if desired, the compounds ~I) and ~') prepared according to the above-mentioned first, second and third processes may be acylated according to custormary procedures when they have a free hydroxyl group, or they may be converted to pharmaceutically acceptable salts or esters according to customary procedures.
The compounds of the formula (I) prepared according to the present invention have a high antibiotic activity but they have no toxicity at an effective administration dosage (the LD50 value is at least 5 g/kg in the intravenous administration to mice). Accordingly, the compounds of the present invention are valuable as medicines. For example, the compounds of the present invention have an excellent antibiotic activity against a variety of pathogenic bacteria such as gram-negative bacteria including Pseudomonas and gram-positive bacteria.
Accordingly, the novel cephalosporin derivatives of the present invention can be effectively utilized ~or remedy and prevention of various infections diseases caused by the above-mentioned pathogenic bacteria in men and An ~ mA 1 S .

1~9'i~3~

The cephalosporin derivatives of the present invention can be orally or non-orally administered to men or animals according to various known administration methods.
The derivatives of the present invention may be used singly or in combination with a pharmaceutically acceptable adjuvant, liquid diluent, binder, lubricant or moisture-reserving agent in the form o~ an ordinary pharmaceutic preparation such as a tablet, granule, sugar-coated tablet, powder, capsule, gel, dry syrup, syrup, ampoule, suspension, liqui~, emulsion, ointment, paste, cream or suppository.
~ As additives that can be incorporated into the derivatives of the present invention, there can be mentioned dissolution-retarding agents, absorption-promoting agents and surface active agents. Namely, in the present invention, there can be used all of known pharmaceutically acceptable additives.
The novel cephalosporin derivatives of the pxesent invention may be used singly or in the for~ of mixturesof two or more of diferent derivatives in an amount of about 20 0.1 to about 99.5% by weight, preferably 0.5 to 95% by weight, based on the total weight of the pharmaceutical composition~
The p~armaceutical composition of the present invention may comprise other pharmacologically active compounds - as effective ingredients in addition to the above-mentioned ~5 novel cephalosporin derivative(s).
The daily dose of the novel cephalosporin derivative of the present invention is changed according to the patient ~, ~ 22 -78~3 or the kind of the animal, the body weight and the disease to be cured, but the daily dose of the cephalosporin derivative is ordinarily in the range of from about 1 to about 1000 mg, preferably about 10 to about 800 mg, per kg of body weight.
The present invention will now be described in detail with reference to the following Examples that by no means limit the scope of the invention.
Reference Example 1 Preparation of 1~amino-2-oxo-imidazolidine A liquid mixture of 208 g of 1-benzalimino-2-oxo-imidazolidine, 2 l o~- water and 12~ ml of concentrated sulfuric acid was subjected to steam distillation for 4 hours, ! and at this point, distillation of benzaldehyde was substan-tially stopped. The liquid reaction mixture was filtered and extracted with chloroform. The aqueous solution was neutralized with sodium hydroxide and evaporated to dryness.
The residue was extracted with 5 l of chloroform and chloroform was distilled from the chloroform layer. The resulting crude crystal was recrystallized from ethanol to obtain 62 g ~the yield being 55 %) of the intended compounds. The melting point was 110 - 112.SC.
H-NMR (CDCl3 + d6-DMSO)~: 3.3 - 3.5 (4H, m, CH2x2), 6.44 (2H, broad-s, NH2), 7.97 (1H, broad-s, -NH-) Reference Example 2 Preparation of 1-~1,3-dithiolan-2-imino)-2-oxo-imidazolidine 7~3~

In 30 ml of water was dissolved 13.6 g of 1-amino-2-oxo-imida~olidine, and a solution of 7~63 g of potassium hydroxide in 10 ml of water was added to the so-formed solution. Then, 12;4 g of carbon disulfide was added dropwise to the mixture over a eriod of 1 hour. The liquid mixture was stirred for 1 hour at room temperature and for

5 hours at 45C. Then, excessive carbon disulfide was distilled under reduced pressure, and a solution of 7.63 g of potassium hydoxide in 10 ml of water was a~ded to the resi~ue and the mixture was stirred at room temperature for 30 minutes. Then, 25.6 g of ethylene bromide was added dropwise to the mix~ure under ice cooling, and the mixture was stirred at room temperature for 10 hours. Water was added to the liquid reaction mixture containing the precipitated crystal and the mixture was heated to form a solution. Petroleum ether was added to the solution to effect washin~, and the solution was extracted with chloroorm and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized rom ethyl alcohol to obtain 9~8 g ~the yield being 35 %) of the intended compound. The melting point was 219 - 220C.
IR (KBr) cm : vNH3260~ vc=o1690 MS (m/e): 203 ~M ) H-NMR ICDCl3 + d6-DMSO)~ : 3.42 (4H, s,CH2x2~, 3.53 ~4H, s, CH2x2),

6.97 (lH, broad-s, ~NH) Elementary analysis values as C6HgON3S2 133~3 Found value: C = 35.71, H - 4~45, N = 20.43 Calculated value: C = 36.00, H = 4.50, N - ~0.70 Referential Example 3 Preparation of 1-(1,3-dithiolan-2-imino~2-oxo-imidazolidine A mixture of 3.03 g of 1-amino-2-oxo-imidazolidine and 3.407 g of 1,3-dithiolan-2-thione was heated and stirred in a nitrogen current on an oil bath maintained at 110C
for 3 hours. Then, warm water was added to the reaction mixture to form a solution, and the solution was washed with a benzene-hexane mixture and filtered. Water was removed from the filtrate bi distillation under reduced pressure and the residue was recrystallized from ethanol to obtain 3.6 g (the yield being 72.5 %) of the intended compound. The 15 melting point was 219 - 220C.
Referential Example 4 Preparation of 1-(1,3-dithiolan~2-imino~2-oxo-imidazolidine In 50 ml of dimethylformamide was dissolved 6.46 g of 1-amino-2-oxo-imidazolidine, and 20 ml of triethylamide was added to the solution and the mixture was cooled to ~5C.
Then, 19.46 g of S-methyl-1,3-dithiolan-2-thione iodide was added to the solution with stirring over a period of 3 hours.
The mixture was stirred at room temperature for 2 hours and dimethylformamide was removed by distillation under reduced pressure. The residue was dissolved in water, washed with benzene and extracted with chloroform. The chloroform layer ;r~rj~

~ ~5 -1331~

was drled wl~h anhydrous sodlum sulfate and chloroform ~as removed by dlstillation. The res~due wa~ recrystallized from ethanol to ob~aln 6.8 g ~the yield ~eing 5~ ~) of the lntended compound. The melting point was 219 - 220C.
Referential ~xample S
Preparatlon o~ 1-(4-methyl-1,3 -dithiolan-2-i~ino)-~-oxo-imidazolidine In the same manner as descr~bed in Referential Exam~le 2, 6.00 g of 1-amino-2-oxo-imidazolidine was reacted with ~ 88 g of potasslum hydroxide, 6.9 g of carbon disulfide and 12.1 g o 1,2~ibromopropane.- The reaction product was puri ied ~y silica gel chro~atography and recrvstalli~ed rom benzene to obtain 2.09 g (the yleld bein~ 16 ~) of the intended compound. The meltlng point was 123 - 126C.
1; IR ~Br) cm 1 ~3~20, ~C o1690 ~--~M~ (CDC13 ~ d6-DMS0)~: 1. 50 (3H, t, ~=7 H2,--CU3), 6.60 llT~, s, ~) Referentlal Example 6 Preparation of 1-chlorocarbonyl-2-o~o-3-~1,3-d~thiolan-2-imino)-imidazolidine A mlxture of 3.5 ~ o 1- ~1 ,3-dithiolan-2-imino)-2-o~o-imiaazolidlne and 7.4 ml of hexamethyl~ lazane was heated and refluxed ~n a nitrogen current ~or 6 hours, and e~cesslve hexamethyldisilazane was d~stilled under reduced pressure. Then, 50 ml of tetrahydrofuran was added to the residue to form a 5olutlon ana phosgene w~s introauced into the solution at room temperature for 5 hours. The reaction ~:!

l~g'7~3~

vessel was sealed and the mixture was stirred overnight.
The liquid reaction mixture was subjected to distillation under reduced pressure to remove the volatile components completely, whereby 4.89 g of a crude crystal of the intended compound having a melting point of 126C was obtained.
Referential Example 7 Preparation of 1-chlorocarbonyl-~-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine In 50 ml of dry dichloromethane was suspended 3.0 g~(0.015 mole) of 1-11,3-dithiolan-2-imino)-2-oxo-imidazolidine, and 2.~ ml l0.016 mole) of triethylamine and 2.3 ml (0.016 mole) of trimethylchlorosilane were added to the suspension at room temperature and the mixture was stirred for 1.5 hours. The liquid reaction mixture was 1S cooled to -25C and 1 ml (0.0083 mole) of trichloromethyl chloroformate was added to the mixture, and the temperature was elevated to -5C over a period of about 1 hour and the mixture was stirred at room temperature for 3 hours. Active carbon was added to the liquid reaction mixture and the mixture was concentrated at 30C under reduced pressure.
Active carbon was removed by filtration and the filtrate was subjected to distillation under reduced pressure to obtain a light yellow solid. Dry dioxane was added to the obtained solid, insoluble substances were removed by filtration and dioxane was distilled from the resulting solution. A
small amount of aichloromethane was added to the resulting light yellow oily product to form a solution and dry ether ~,, , . ~
- 2~ ~

~L~g'7~338 was added to the solution to obtain 3.1 g (the yield being 78.8 %) of a white crystal of 1-chlorocarbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine having a melting point of 126 - 127.5C.
H-NMR ~CDCl3)~: 3.59 (4H,s, CH2x2), 3.69-4.22 (4H, m, CH2x2) - IR (KBr) cm 1: ~C=o1~00, 1760, 1700 Referential Example 8 Preparation of 1-chlorocarbonyl-2-oxo-3-(4-meth~l-1,3-dithiolan-2-imino)-imidazolidine A mixture of 2~0 g of 1-(4-methyl-1,3-dithiolan-2-imino)-2-oxo-imidazolidine and 3.88 ml of hexamethyl-disilazane was heated and refluxed or 6 hours in a nitrogen current. Then, excessive hexamethyldisilazane was distilled ; 15 under reduced pressure. Then, 5C m} of tetrahydrofuran was added to the residue to form a solution. Phosgene was introduced into the solution at room temperature for 2 hours.
The reaction vessel was sealed and the reaction mixture was stirred overni~ht. Volatile components were completely distilled from the reaction mixture under xeduced pressure to obtain 2.88 g of a viscous crude crystal. This crude crystal was directly used for the next reaction without isolation.
Referential Example 9 Preparation of D~ a-{[2-oxo-3-(1,3 dithiolan-2-imino)-imidazolidin-1-yl]-carkoxamide~-phenylacetic acid 3~

In 10 ml of 2N sodium hydroxide and 30 ml of water was dissolved 2.57 g of D~ -phenylglycine, and the pH
value was adjusted to 7.6 by addition of 10 ml of 2M hydro-chloric acid to precipitate D-(-)-a-phenylglycine in the finely dispersed state. To the resulting suspension was added 4,89 g of the crude crystal of 1-chloroc~onyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine. The pH value was maintained at 7.7 by addition of 2N sodium hydroxide while the mixture was being stirred. Then, the mixture was ~iltered, and the filtrate was washed with chloroform and the pH value was adjusted to 2 by addition o 2N hydro-chloric acid under '~e cooling to obtain 5.1 g ~the yield being 78.9 %) of a crystal ha~ing a melting point of 227 -230C.
1~ IR (KBr) cm : vNH3325, vc=o1740, 1650 MS (m/e): 380 (M ) H-NMR (d6-DMSO~CDCl3)~: 3.57 (4H, s, CH2x2), 3.71 (4H, s, CH2x2), 5.37 (1H, d, J=6.8Hz, ~-H),

7.35 (5H, s, phenyl nuclues~H),

8.94 [iH, d, J-6.8Hz, -CONH) Elementary analysis values as C15H16O4N4S2:
Calculated: C = 47.30, H = 4.24, N = 14.73 Found: C = 46.70, H = 4.17, N = 14.30 ~ Re~erential Example 10 Preparation of D-~-)-a{tZ-oxo-3-~1,3-aithiolan-2-imino) -imidazolidin-1-yl3-carboxyamido}-4-hydroxy-phenylacetic acid 3783~3 In 150 ml of dry dichloromethane was suspend

9.2 g of D-(-)-4-hydroxyphenylglycine, and 23.8 ml of triethylamine was added to the suspension. Then, 21.7 ml of trimethylchlorosilane was dropped to the mixture under ice cooling below 10C over a period of 15 minutes. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Then, 16.1 g of the crude crystal of 1-chlorocarbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine was added to the mixture under ice c~oling over ~ period of 10 minutes. The mixture was stirred at room temperature for 4 hours, and 100 ml of water was added and the mixture was stirred to precipitate a crystal. The crystal was recovered by filtration, washed with water and dried to obtain 18.71 g (the yield being 94.5 %) o~ the intended compound. The melting point was 230.5 - 231.5C.
IR ~KBr) cm 1 vNH oH3250 3800~ ~C=O
MS IF~) m/e: 396 (~ ) H-NMR (CDCl3~d6-D~ISO)~: 3.55 (4H, s, CH2x2), 3.69 (4H, s, CH2x2), 5.25 (lH, d, J=7Hz, C -H), 6.73, 7.20 (4H, d, J=8Hz,:C6H~), 8.78 (lH, d, J=7H2f NHCO) Elementary analysis values as C15H15N~O5S~:
Found: C = 45.01, H = 4.02, N = 14.10 Calculated: C = 45.45, H = 4.04, N = 14.14 Example 1 ~713;3~

Preparation of 7-{D~ a- ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-~-yl)-carboxamido]-(1,4-cyclo-hexadien-1-yl)-ace~amido}-3-methyl-3-cephem-4-carboxilic acid In 60 ml of 80 % aqueous tetrahydrofuran was suspended 1.837 g o cephaladine hydrate, and 0.607 g of triethylamine was added to the suspension to form a solution.
Then, 1.735 g of 1-chlorocaxbonyl-2-oxo-3~(1,3-dithiolan-2-imino)-imidazolidine was added little by little to the solut~on with stirring under ice cooling, and simultaneously, triethylamine was`drcp~e~ to adjust the pH value to 7.0 to 7.5. Reaction was conducted ~or 1 hour and 100 ml of water r was added to the mixture to adjust the pH value to 7.
- Tetrahydrofuran was distilled under reduced pressure, and the residue was filtered and 2N hydrochloric acid was added to the filtrate under ice cooling to adjust the pH value to 2. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum aesiccator to obtain 2.585 g ~the yield being 89 ~) of the intended compound~
The melting point was 160 - 170C (decomposition).
IR ~KBr) cm 1 C=ol770 (lactam),1720, 1675 (COOH, CON<) NMR (D6-DMSO)~: 2.02 (3H~ s, C~3), 2.4-2.8 (~H, m, cyclohexadiene, nucleus t (CH2X2 )~
3.20-3.90 (lOH, m, CH2x5), 5.04 (lH, d, J=5Hz, 6-H~, 5.45-5.85 (5H, m, 7-H, a-H, cyclo-hexadiene nucleus, CHx3), rv-,~

7~

8.50 (1H, d, J=8Hz, NHCO), 9.16 (1H, d, J=8Hz, NHCO) Example 2 Preparation of 1-ethoxycarbonyloxyethyl-7-{D~
~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-(1,4-cyclohexadien-1-yl)-acetamido}-3-methyl-3-cephem-4-carboxylate In 10 ml of dimethylsulfoxide was dissolved 0.81 g of the compound obtained in Example 1, and 0.18 ~ of potassium carbonate and U.02 g of 18-Crown-6 (crown ether supplied by Nippon Soda Ko K.') were added to the solution and the mixture was stirred at room temperature ~or 1 hour. Then, 0~32 g of diethyl ~-chlorocarbonate was added to the mixture and the mixtuxe was stirred for 4 hours in a nitrogen gas current on a water bath maintained at 35C. Then,, 100 ml of ice water was added to the reaction mixture, and the mixture was extracted with 150 ml of dichloromethane, washed with water two times and driea with anhydrous sodium sulfate. The solvent was removed by distillation to obtain a syrup-like product. The product was dissolved in a small amount of dichloromethane and the solution was dropped into 100 ml of,ethyl ether with stirring to effect crystallization. The crystal was recovered by filtration and dried to obtain 0.36 g (the yield being 37 ~) of the intended compound. The melting point was 124 - 128C (decomposition).
IR (gBr) cm 1: ~C=o1760 ~lactam), 1720, 1678 (ester, amide~

~'7~

H-NMR (d6-DMSO)~: 1.22 (3H, t, J=7Hz, -CH2-CH3), 1.48 ~3~, d, J=6Hz, -CH-CH3), 2.03 (3H, s, -CH3), 2.4-2.8 (4H, m, cyclohexadiene nucleus, CH2x2), 3 60 (8H, broad-s, CH2x4), 4.15 (2H, q, J=7Hz, -CH2-CH3), 4.98 ~lH, d, J=5Hz, 6-H), 5.46-5.83 (5H, m, 7-H, -H, cyclohexadiene nucleus r CHx3), 6.58-6.90 (lH, m, -O-CH-O-), 8.46 (1H, d, J=8Hz, CONH), 9.13 ~1H, d, J=8Hz, CONH) Example 3 Preparation of 7-tD-(-)-a-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-phenyl-acetamido}-3-methyl-3-cephem-4-carboxylic acid Reaction was carried out in the same m~nner as described in Example 1 by using 1~827 g of cephalexin hydrate, 1.593 g of 1-chlorocarbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine and 0.607 g of triethylamine to obtain 2.9 g of the intended compound. The melting point was 162 170~C
(decomposition).
IR (KBr) cm 1- vc=~ 1770 (lactam), 1720, 1680 ~COOH, CON
NMR (d6-DMSO)~:
2~00 (3H, s, CH3), 3.24, 3.48 ~2H, ABq, J=16Hz, 2-CH2), 3.62 (8H, broad-s, CH2x4~, ~r 1~783~

4.92 (lH, d, J=5Hz, 6-H~, 5.49-5.70 (2~, m, 7-H, ~-H), 7.20-7.42 (SH, m, C6H5), 8.84 (1H, d, J=8Hz, NHCO), 9.37 (lH, d, J=8H~, NHCO) Example 4 Preparation o~ 7-{D-(-)-a- r(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxy-phenylacetamido}-3- L( 1, 2,3-triazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid ~ In 50 ml of dichloromethane was suspended 4.35 g of a methanol adduct of ?-[D-(-)-~-amino-4-hydroxyphenyl-acetamido]-3-[(1,2,~-tria~ol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid, and the suspension was cooled to O~C on an ice-sodium chloride bath and 17.2 ml of N,O-bis(trimethylsilyl) acetamide was dropped to the suspension with stirring. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. While the mixture was cooled to -3C on an ice-sodium chloride bath, 2.34 g of 1-chloro-carbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine was added. The mixture was stirred at -3C fox 40 minutes and at room temperature for 2.5 hours. Dichloromethane was distilled under reduced pressure at room temperature, and 300 ml of water was added to the residue and the precipitated crystal was dissolved by addition of 2N sodium hydroxide. A
small amount o~ active carbon was added to the solution and the mixture was filtered, and the pH value of the precipitate was adjusted to 2 by 2N hydrochloric acid. The precipitated . . . - - -,~,r ~9'7~33~

crystal was recovered by filtration, washed with water and dried in a vacuum desiccator to obtain 4.635 g (the yield being 76 ~) of the intended compound. The melting point was 177 - 1 86C (decomposition). The melting point of the 5 dicyclohexylamine salt of the intended compound was 176 to 182C (decomposition).
IR (KBr) cm 1: vc=ol775 (lactam), 1715, 1680 (COOH, C~
NMR (d6-DMSO)~:
3.58 (10H, broad~s, CH2x5), 3.82-4.03 (2H, m, ~ 3-CH2), 4.96 (lH, d, J=5Hz, 6-H1, 5.33-5.~0 (2H, m, 7-H, ~-H), 6.66, 7.18 (4H, d, J=8Hz, C6H4-), 7.86 (lH, s, triazole CH), 8.72 ~1H, d, J=8Hz, NHC
~.24 (1H, d, J=8Hz, NHCO) 15 Example 5 Preparation of 7-{D-(-)-~- [(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-acetoxy-phenylacetamido}-3-r(1,2,3-triazol-5-yl)-thiometh~l]-3-cephem-4-carboxylic acid To a suspension of 2.075 g o the compound obtained in Example 4 in 25 ml of water was added 6 ml of 1N sodium hydroxide to form a solution. Then, 0.674 g of acetic anhydride was dropped to the solution with stirring over a period of 20 minutes while the pH value was maintained at 7 to 8 by addition of 1N sodium hydroxide. The mixture was stirred under ice cooling for 1.5 hours while the pH value was maintained at 7 to 8. The mixture was filtered and the 1~783~

pH value was adjusted to 2 under ice cooling by 2N hydrochloric acid. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator to obtain 1.46 g (the yield being 66 %) of the intended compound. The melting point was 166 to 175~C tdecomposition).
IR (KBr) cm 1 ~C o1760 tlactam), 1720, 1685 (ester, amide), VC o1200 ( ~ O~CH3) NMR (d6~DMSO)~: ~
~ 2.25 (3H, s, -C-CH3), 3.59 ~lOH, broad-s, CH2x5), 3.8~-4.02 ~2H, m, 3-CH2), 4.97 ~lH, d, J=5~z, 6-H), 5.45-5.78 (2H, m, 7~ H), 7.07, 7.42 (4H, d, J=8Hz, C6H4-), 7.86 (lH, s, triazole nucleus CH), 8.88 (lH, d, J=8Hz, NHCO), 9.40 (lH, d, J=8Hz, NHCO) Example 5b Preparation o 1-ethoxycarbonyloxyethyl-7-{D~
~(2-oxo-3-~1,3-dithiolan-2-imino)-imidazolidin-1-yl)-ca~boxamide~-4-acetoxyphenylacetamido}~3-t(1,2,3-triazol-5-yl)-thiomethyl3-3-cephem-4-carboxylate In 30 ml of dimethylsulfoxide was dissolved O.86 g of the compound obtained in Example 5a, and O.121 g of potassium carbonate and 0.01 g o 18-Crown-6 (crown ether supplied by Nippon Soda K. K.) were added and the mixture i~9783~3 was stirred at room temperature or 20 minutes. Then, 0.268 g of diethyl a-chlorocarbonate was added to the mixture and the mixture was stirred in a nitrogen gas current at room temperature for 17 hours and at 30C or 9 hours~ The reaction mixture was poured into 100 ml of water and extracted with 150 ml of dichloromethane. The extract was washed with water two times and dried with anhydrous sodium sulfatet and the solvent was removed by distillation. The resulting oily residue was purified by silica gel column chromatography (chlo~oform/ethanol mixture was used as the solvent). The resulting oily produc~ was dissolved in a small amount of dichloromethane and ether was added to the solution to - effect crystallization and obtain 0.21 g (the yield being 21 %) of the intended compound. The melting point was 105 to 111~C (decomposition).
IR (KBr) cm 1: vc=o1775, 1760 (lactam), 1720, 1680 (ester,amide), VC o1200 ( ~ OCCH3) NMR ld6-DMSO)~:
1.04-1.58 ~6H, m, -CH2-CH3, -CH~CH3), 2.23 (3H, s, -CCH3), 3.58 (10H, s, -CH2x5), 4.13 (2H, q J J-7Hz, -CH2-CH3), 5.01 l1H, d=5Hz, 6-H), 5.40-5.74 (2H, m, 7 H, -H)-, 7.05, 7.38 (4H, d~ J=8Hz, -C6H4-), 8.15 (1H, s, triazole nucleus CH~, 8.86 ~lH, d, J=8Hz, CONH), 9.42 (1H, d, J=8Hz, CONH) Example ~
Preparation o~ 7{D-(-)-a- [(2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid In 60 ml of ~0 % aqueous tetrahydrofuran was suspended 2.433 g of cephaloglycin, and 0.607 g of triethyl-amine was added to the suspension to form a solution. Then, 2.88 g of a crude crystal of 1-chlorocarbonyl-2-oxo-3-(4-meth~l-1,3-dithiolan-2-imino)-imidazolidine was added little by little to the solution under ice cooling, and simultaneously, the pH value was maintained at 7.0 to 7.5 by addition of triethylamine. The addition was completed in 30 minutes.
Reaction was conducted for 1 hour, and 100 ml o water was added to the reaction mixture and the pH value was adjusted to 7. Tetrahydrofuran was removed by distillation under reduced pressure and the residue was filtered. The pH va~ue of the filtrate was adjusted to 2 under ice cooling by 2N
hydrochloric acid. The precipitated crystal was recovered by filtration, washed with water and dried in a xeduced pressure desiccator to obtain 3.75 g (the yield being 96 %~
of the intended compound. The melting point was 175 -178~C
(decomposition).
IR (KBr) cm 1: ~C o1775 (lactam)~ 1720, 1700, 1685 (ester carboxylic acid, amide) H-NMR ~d6-DMSO)~:
1.45 (3H, d, ~=6Hz, CH-CH3)~

'';~

.
- . . .

~9'~t8 2.00 (3H, s, -CCH3), CH3 3.22-3.91 ~9H, m, CH~x4, -CH-CH2-), 4.61, 4.95 (2H, ABq, J=12Hz, 3-CH2), 4.96 (1H, d, J=5Hz, 6-H), 5.50-5.90 (2H, m, 7-H, 6-H), 7.36 (5H, broad-s, C6H5), 8.88 11H, d, J=8Hz, CONH), 9~41 ~1H, d, J=8Hz, CONH) Example 7a Preparation of 7-{D-(-)-a- ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazoli~in-1-yl)-carboxamido]-phenyl-acetamido}~3~aCetx~ethYl-3-cephem-4-carboxylic acid In 40 ml o~ dichloromethane was suspended 3.12 g (0.0077 mole) of anhydrous cephaloglycin, and 2.12 ml of triethylamine was added to the suspension under ice cooling to form a solution. Then, 1.96 ml of trimethylchlorosilane was added to the solution and the mixture was stirred at 15 to 20C for 1 hour. Then, 2.0 g (0.0075 mole) of 1-chloro-carbonyl-2-oxo-(1,3-dithiolan-2-imino)-imidazolidine was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 20 ml of water was added and the mixture was stirred for 20 minutes, and the pH value was adjusted to 7 to 8 by a dilute aqueous solution of sodium hydrogen carbonate ana the mixture was washed with ethyl acetate. The pH value of the aqueous layer was adjusted to 2 by addition o 4N HCl. The formed white precipitate was recovered by filtration, washed with water and dried in vacuo to obtain 3.22 g (the yield being ~9.4 ~) of ~ r;~

- 39 ~

,:

:

8;~3 7-{D-(-)-~-[(2-oxo-3-~1,3-dithiolan-2-imino)-imidazolidin-1~yl-carboxamido~-phenylacetamido}-3-acetoxymethyl-3-cephem-~-carboxylic acid in the form of a white powder having a melting point of 174 to 1 85DC (decomposition).
IR ~KBr) cm 1 vc o1780 (lactam) ~xample 7b Preparation of dicyclohexylamine salt of 7-{D-( )-~-t(2-oxo-3-(1,3-dithiolan-2-imino)-imiaazolidin-1-yl)-carboxamido]-phenylacetamido}-3-acetoxymethy1~3-~ cephem-4-carboxylic acid In 20 m~ of a liquid mixture of ethyl acetate and ethanol was dissolved 1.1 g of 7-{D-(-)-~-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid, and 15 insoluble substances were removed by filtration~ Then, 0.88 ml of dicyclohexylamine was added to the solution, and the mixture was concentrated and acetone was added to the concentrate. The mixture was allowed to stand still in a refrigexator, and the formed precipitate was recovered by filtration and washed wi~h acetone to obtain 0.9 g (the yield being 63.8 %~ of a dicyclohexylamine salt of 7-{D-~ [~2-oxo-3-(1,3-dithiolan-2~imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of a white crystalline powder having a melting point of t62 to 164~C (decomposition).
IR (KBr) cm 1: ~C=~1780 ~lactam~
H NMR(C~C13+~6 -DMso ) `:~

7~38 0.89-2.38, 2.77-3.41 ~m, H o~ dicyclohexyl group), 1.99 (3H, s, -CH3), 3.30-3.21 (2~, m, 2-CH2), 3.61 (8H, broad-s, CH2x4), 4.91-4.83 (3H, m, -CH2~ at 3-position, 6-H), 5.45-5.74 (2H, m, -H, 7-H), 7.22-7.62 (5H, m, phenyl nucleus H), 8.94 (lH, d, J=7.8Hz, CON~), 9.36 (1H, J=8.8Hz, CONH) D2O-Added~:
0.89-2.24, 2.77-3.41 ~m, H of dicyclohexyl group), ~ 2.02 (3H, s, -CH3), 3.31-3.21 (2H, m, 2-CH2), 3.62 (8E', s, CH2x4), 4.84-4.90 (3H, m, 3-CH2, 6-H), 5.54-5.64 (2H, m, a-H, 7-H), 7.22-7.26 (5H, m, phenyl nucleus-H) Example 7c Preparation and purification of sodium 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-acetoxymethyl-3 cephem-4-carboxylate (hereinafter referred to as In 10 cc of dry dime~hylformamide was dissolved 0.5 g of a dicyclohexylamine salt of 7-{D~(-)-a- t~2-oxo-3-(1,3-dithiolan-2-imino)-imidoazolidin-1-yl~-carboxamido~-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid, and 0.8 ml of a 1M solution of sodium 2-ethylhexanoate in isopropanol was aaded to the above solution. The mixture was stirred fQr 5 minutes and dry ether was added to the mixture to form a white precipitate~ The precipitate was -- ~1 --3~

recovered by filtration, washed with dry ether and dried in vacuo to obtain 0.4 g (the yield being 89.28 %) of a dimethylformamide adduct of sodium 7-{D-(-)-~- L(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point of 220 to 222~C (decomposition).
IR (KBr) cm 1: vc=o1760 (lactam~
In 10 ml of a 1/5 liquid mixture of dry dimethyl-forma~ide/methanol was dissolved 1.0 g of the so-obtained dimethylformamide addu~t o sodium 7-{D-(-)-a-L(2-oxo-3-~1,3-dithiolan-2- amino)-imidazolidin-1-yl)-carboxamido3-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylate, and the solution was subjected the decoloring treatment with active carbon and a 10 g solution of methanol in ether was added to the solution to form a precipitate. The precipitate was recovered by filtration, washed with a liquid mixture of dry methanol and ether and then with dry ether and dried in vacuo to obtain 0~6 g (the yield 20 being 62.5 %) of sodium 7-{D-( )-~-L(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-phenylac~tamido}-3-acetoxymethyl-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point of 219 to 222C (decomposition).
The sodium salt was purified by using Sephadex LH-20 (methanol was used as the developing solvent) to obtain sodium 7-{D-(-)~ (2-oxo-3-(1,3-dithiolan-2-imino)-i ~f `-_ 33~3 imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-acetoxymethyl-3-cephem-4-carboxylate in the form of a white crystalline powder having a meltin~ point of 218 to 221C ~decomposition).
Elementary analysis values as C25H25N6O8S3Na-1/2H2O:
Calculated: C=45.11, H = 3.94, N = 12.63 Found: C = 44.95, H = 4.10, N = 12.94 IR (KBr~ cm 1 vc=o1760 (lactam), 1720, 1680 (amide) H MR (d6 D SO) :
1.99 (3H, s, -CH3), 3.58 ~2H, broad-s, 2-CH2), ~ 3.62 ~8H, broad-s, CH2x4), 4.88 (lH, d, J=4.88Hz, 6-H), 4.87 ~2H, s, 3-CH2), 5.40-5.72 (2H, m, 7-H, ~-H), 7.36 (5H, broad-s, phenyl-H), 8.90 (1H, d, J=7.32Hz, CONH), 9.32 (lH, d, J=7.33Hz, -CONH-) D2O-Added~:
1.99 (3H, s, -CH3), 3.31 (2H~ broad-s, 2H, 2-CH2), 3.62 (8H, broad-s, CH2x4), 4.85 (1H, d, J=4.88Hz, 6-H), 4.85 (2H, s, 3-CH2), 5.53 (1H, d, J=4.88Hz, 7-H), 5.63 (1H, s, ~H), 7.37 (5H, s, phenyl-H) 13C_NM~(d~-12c-DMso)~:
20-66 (q, -CH3), 25.08 (t, 2-C), 35.99, 44.31 (t, imidazolidine nucleus~CH2), 37.81, 38.85 ~t, dithiolan nucleus CH2), 56.01 ~d, 6-C), 57.31 ~d, ~-C), 58.09 (a, 7-C), 64.32 (t, C~2 at 3-position), 113~18 (s, 4-C), 126.57 Id, 2', 6'-phenyl nucleus C), 127.87 ~d, 4l-phenyl nucleus C~, ,. "

~978;~

128.39 (d, 3', 5'-phenyl nucleus C), 134.24 (s, 3-C), 138.26 (s, 1'-phenyl nucleus C), 151.~6 (s, ~NCONH-), 155.03 (s, dithiolan nucleus ~C=N), 162.95 (s, 8-C), 164.51 (s, CO~Na), O
170.49 (s, imidazolidine nucleus C=O and -CCH3), 181.53 (s, -CONH-) Example 8a Preparation of 7-{D-(-)-a- [~2~oxo-3-t1~3-dithiolan-2-imino)-imida~olidin-1-yl)-carboxamido]-phenyl-~ acetamido}-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~7-3 ~ 4 carboxylic acid To a mixture of 1 g of 7-{D-(-)-a-[2-oxo-3-(1,3-dithiolan-2-imino)imidazolidin-1-yl)tcarboxamido]-phenyl-acetamido}-3-acetoxy~ethyl-3-cephem-4 ~ ~ylic acid and 0.273 g of 5-mercapto-1-methyl-1H-tetrazole was added 50 ml of water, and 1N sodium hydroxide was added to the mixture to form a solution and adjust the pH value to 6.5. The mixture was heated on an oil bath maintained at 60C for 17 hours while incroducing nitrogen gas. The pH value was always maintained at 6.5 during the r~A~inn- The reaction mixture was filtered and the pH value was adjusted to 2 under ice cooling by 2N hydrochloric acid. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator. The crystal was dissolved in ethyl acetate under heating and ethyl ether was added to the solution to cause precipitation and obtain 0.55 g(the yield being 50 %j of the intended compound. The melting point was 15~ to 164~C (decomposition.) l~ 9~v3~

IR (KBr) cm 1: vc=o1780 ~lactam), 1720, 1680 (-COOH, -CON<) Example 8b Preparation of 7-{D-(-)-a- [~-oxo-3-(1,3-dithiolan-2-imino)-imidaæolidin-1-yl)-carboxamido~-phenyl-acetamido}-3-~t1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid In 10 ml of dry methylene chloride was suspended 1.0 g (0.0026 mole) of D-(-)-a-{[2-oxo-3-(1,3-dithiolan-2-imino~-imidazolidin-1-yl~-carboxamido}-phenylacetic acid, and under ice coolin~,G.366 ml (0.0026 mole) of triethylamine was added to the suspension and 0.317 ml (0.0026 mole) of trimethylchlorosilane was then added. The mixture was stirred at room temperature for 1 hour, and it was cooled to about -20C and 0.2 ml (0~0026 mole) of dry dimethyl-formamide and 0.17 ml (0.0014 mole~ of trichloromethyl chloroformate were added. The mixture was stirred at -20 to -15C for 4.5 hours.
Separately, 1.3 ml of N,O-bis(trimethylsilyl)acetamide was added to a suspension of 0.86 g (0.0026 mole) of 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid in 7 ml of dry methylene chloride, and the mixture was stirred at room temperature for 4 hours. The resulting solution was cooled to -20~C and added to the above-mentioned chioride-formed solutionv and the mixture was stirred at -20 to -15C for 1 hour. Then, 16 ml of water was added to the mixture and the mixture was stirred to form ~9'~ 5138 a precipitate. When a 10 ~ aqueous solution of sodium hydrogen carbonate was added to adjust the pH value to 7.0, the precipitate was dissolved again. The methylene chloride layer was separated, and the obtained aqueous layer was washed with ethyl acetate. The aqueous layer was subjected to the decoloring treatment with active carbon and 3N hydrochloric acid was added thereto to adjust the pH value to 2Ø The formed precipitate was recovered by filtration, washed with water and dried in vacuo to 1~ obtain 1.28 g (the yield being 70.5 ~) of 7-{D-(-)-~-[(2-oxo-3-(1,3-dithiolxn-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-~1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid in the form of a white powder having a melting point of 162 to 169C (decomposition).
IR (KBr) cm 1: ~C=O 1780 (lactam) Example 8c Preparation of dicyclohexylamine salt of 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin 1-yl)-carboxamido]-phenylacetamido}-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid According to the method described in Example 7b, 1.0 g (the yield beiny 66.05 %) of a dicyclohexylamine salt of 7-{D-(-)-a- t(2-oxo-3-(1~3-dithiolan-2-imino)-imidazolidin-1 carboxamido~-phenylacetamido}-3- U1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethy~ -3-cephem-4-carboxylic acid was prepared in the form of a white crystalline powder having a melting point 158 to 161C (decomposition) by using 1o2 g of ~ . , 7-{D~ [~2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3- [~1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid.
IR (KBr) cm : Vc O 1780 (lactam) H-NMR(CDCl3+d6-DMSO)~:
0.94~2.13, 2.79-3.08 (m, H of dicyclohexyl group), 3.45 (2H, broad-s, 2-CH2), 3.60-3.69 (8H, m, CH2x4), 3.92 (3H, s, -CH3), 4.54-4.21 t2H, m, 3-CH2), 4.84 (1H, d, J=4.88Hz, 6-H), 5.44-5.73 (2H, m, ~ 7-H, ~-H), 7.~7-7.70 (5H, m, phenyl nucleus H), 8.96 (~, d, J=7.8Hz, 1H, -CONH-), 9.34 (lH, d, J=8.30Hz, -CONH) D2)-Added~:
0.94-2.13, 2.79-3.08 (m, H ofdicyclohexyl group), 3.44 (2~, broad-s, 2H, 2-CH2), 3061-3.71 `t8H, m, CH2x4), 3.94 (3H, s, CH3), 4.54-4.21 (2H, m~ 3-CH2), 4.85 (lH, d, J=4.88~Iz, 6-H), 5.63 ~lH, d, J=4.88Hz, 7-H), 5.64 (1H, s, a-H), 7.08-7.74 (5H, m, phenyl nucleus H) 20 Example 8d Preparation and purification of sodium 7-{D-(-)-~-[(2-oxo-3-(1,3-dithiolan-2-imino~-imida~olidin-1-yll-carboxamido]-phenylacetamido}-3- [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylate ~hereinafter referred to as KI-6248) According to the method described in Example 7c, 2.1 g (the yield being 93.33 ~) of a dimethylformamide adduct '~

l~t7~`3~

of sodium 7-{D~ a- ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl~carboxamido~-phenylacetamido}-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylate was prepared in the form of a white crystalline powder having a melting point of 194 to 198C ~decomposition) by using 2.5 g of a dicyclohexylamine salt of 7-{D-(-)-a-~(2-oxo-3-(1,3-dithilan-2-imino)-imidazolidin-1-yl)-carbox2mido]-phenylacetamido}-3- [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid.
~ IR (KBr) cm 1 vc=O 1760 (lactam) In the same manner as described above, 1.4 g (the yield being 73.68 ~) of sodium 7-{D-(-)-~-[~2-oxo-3-(1,3-dithiolan-2-imino)-imidazolin-1-yl)-carboxamido~-phenyl-acetamido}-3~ methyl-1,2,3,5-tetrazol-5-yl)-thiomethyl]-3-~ephem-4-carboxylate was prepared in the form of a white crystalline powder having a melting point OI 196 to 199~C
(decomposition) from 2.1 g of the dimethylformamide adduct of sodium 7-{D-(-)-~- [(2-oxo~3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-t(1-methyl-1,2,3,4-tetrazol-5-yl~thiomethyl]-3-cephem-4-carboxy-late.
IR ~KBr) cm : vC=O 1760 ~lactam) The above sodium salt was purified in the same manner as described above to obtain a sodium 7-{D-(~)-a-[(2-oxo-3-(1,2-dithiolan-2-imino)-imidazolidin-1-yl~-carboxamido~-phenylacetamido}-3- r (1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylate in the form of a - 4~ ~

7~

white crystalline powder having a melting point of 198 to 199C (decomposition).
Elementary analysis values as C25H25N10O6S4Na H2O:
Calculated: C = 41.09, H = 3.72, N = 19.17 Found: C = 41.15, H = 4.55, N = 19.71 C = O 1760 (lactam), 1720 1610 ( id H-NMR(DMSO-d6)~:
3.62 (10H, s, CH2x5~, 3.91 (3H, s, CH3), 4.33-4.29 (2H, m, 3-CH2), 4.86 (lH, d, J=4.88Hz, ~ 6-H), 5.70-5.44 (2H, m, 7-H, ~-H), 7.36 (5H, broad-s, ~henyl nucleus H), 8.91 (1H, d, J=7.81Hz, CONH), 9.42 ~1H, d, J=7.8Hz, CONH) , D2O-Added ~:
3.5g (10H, broad-s, CH2x5), 3.91 ~3H, s, -CE3), 4.33 (2H, m, 3-CH2), 4.85 ¦1H, d, J=4.88Hz, 6-H), 5.56 ~1H, d, J=4.88Hz, 7-H), 5.61 (lH, s, a-H), 7.37 (5H, broad-s, phenyl nucleus-H) 3C_NMR(d6_12c_D~so) ~
26.25 (t, 2-C), 33.53 (q, -CH3), 35.99, ~ 44.31 It, imidazoline nucleus-CH2), 36.65 (t, -CH2S-), 37.81, 38.85 ~t, dithiolan nucleus CH2), 56.01 (d, 6-C), 57.18 (d, ~-C), 57.96 (d, 7-C), 115.39 ~s, 4-C), 126.57 (d, 2', 6', phenyl nucleus C)j 127.87 (d, 4'-2~ phenyl nucleus C), 128.39 (d, 3', 5', phenyl ~ucleus C), 133.46 (s, 3-C), 138~26 (s, 1'-phenyl nucleus C), 151.26 (s, ~NCON~, _ ,~9 _ 7~

154.51 (s, tetrazole nucleus 5-C), 155.03 (s, dithiolan nucleus C=N), 162.83 (s, 8-C), 164.25 (s, -COONa), 170.23 (s, imida ZGli dine nucleus C=O), 181.53 (s, -CONH-) Example 9a Preparation of 7-{D-(-)-~- L(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxy-phenylacetamido}-3- L( 1 -methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid 7-{D-(-)-a-~(2-oxo 3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxyphenylacetamido}-3- L(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl] 3 cephem-l; 4-carboxylic acid was prepared in an amount of 1.20 g (the yield being 67.4 %) in the form of a white powder having a melting point of 174 to 179C (decomposition) in Lhe same manner as describea in Example 8b except that 1.0 g (0.0025 mole) of D-(-)-a-~[2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl1-carboxamido}-4-hydroxyphenylacetic acid and 0.83 g (0.0025 mole) of 7-amino-3- ~(1-methyl~
3,4-tetrazol~5-yl)-thiomethyl~-3-cephem-4-carboxylic acid were used and trimethylchlorosilane and triethylamine were used in molar amounts two times the molar amounts used in Example 8b.
IR ~KBr) cm 1 vc_O 1780 (lactam) Example 9b - 5~ -~7~

Preparation o dic~clohexylamine salt of 7-{D-(-)-a- [(2-oxo-3-(1,3-dithiolan-2-i~ino)-imidazolidin-1-yl)-carboxyamido]-4-hydroxyphenylacetamido}-3-[(1-methyl-1,2,3,4 tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid According to the method described in Example 7b, 0.3 g (the yield being 39.63%) o a dicyclohexylamine salt of 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-4-hydroxyphenylacetamido}-3-[(1-methyl-1,2,3~4-tetrazol-5-yl~-thiomethyll-3-cephem-4-carboxylic acid was prepared in the form o~ a white crystalline powder having a melting point of-i~7 to 170C (decomposition) by using 0.6 g of 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-4-hydroxyphenylacetamido}-3- [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid. When acetone was used as the reaction solvent, the intended compound was obtained in a yield of 63.7 ~.
IR ~KBr) cm : vC=O 1770 llactam) H-NMR (CDCl3+d6-DMSO)~:
0.73-2.34, 2.66-3.28 (m, H of dicyclohexyl group), 3.45 (2H, broad-s, 2-CH2), 3.58-3.74 (8H, m, CH2x4), 3.91 ~3H, s~ -CH3), 4.2~-4.58 (2H, mJ
3-CH2), 4.85 ~1H, d, J=4.88Hz, 6-H~, 5.37-5.94 (2H, mj 7-H, ~-H), 6073 (2H~ d, J=8.3Hz, 3'~ 5'-phenyl nucleus H), 7.37 (2H, d, J=8.3Hz, 2', 6'-phenyl nucleus H), 8.69 (1H~ d, J-9.28Hz~
-CONH), 8.89 (tHr d, J=6.84 Hz, -CONH~

:~9783~

D2O-Added~:
0.73-2.34, 2.66-3.28 (m, H of dicyclohexyl group), 3.45 (2H, broad-s, 2-CH2), 3.57-3.7S (8H, m, CH2x4), 3.89 (3H, s, -CH3), 4.20-4.58 (2H, m, 3-CH2), 4.85 (lH, d, J=4.88Hz, 6-H), 5.53 (1H, s, a-H), 5.66 (1H, a, J=4.88Hz, 7-H), 6.78 (2H, d, J=8.78Hz, 3', 5'-phenyl nucleus H), 7.27 (2H, d, J=8.78Hz, 2', 6' phenyl nucleus H) Example 9c Preparation and purification of sodium 7-{D-(-)-~-L ( 2-oxo-3-(1~3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxyphenylacetamido}-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylate (hereinafter to as KI-6269) According to the method described in Example 7c, 0.8 g ~the yield being 88.88 % of a dimethylformamide adduct of sodium 7-{D-~-)-a-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxyphenylacetamido}-3-~(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-cephem-4-carboxylate was prepared in the form ofa white crystalline powder having a melting point of 215 to 218C (decomposition~
by using 1.0 g of a dicyclohexylamine salt of 7-{D-(-)~n-L(~-oxo-3- (1 ,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-4-hydroxyphenylacetamido}-3-[(1-methyl-1,2,3,4-5 tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylic acid.
IR (KBr) cm : ~C=O 1760 (lactaml In the same manner as described above, 1.1 g .

~9'7~3~

(the yield being 80.88 %) of sodium 7-{D-(-)- ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-hydroxyphenylacetamido}-3- [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylate was prepared in the form of a white crystalline powder having a melting point of 215 to 218C (decompositi n) from 1.5 g of the dimethyl-ormamide adduct of sodium 7~D-(-)-~-[(2-oxo-3-(1,3-dit~iolan-2-imino)-imidazolidin-1-yl~carboxamido]-4-hydroxyphenylacetamido}-3- ~(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylate.
IR (KBr) cm : vc=O 1760 (lactam) In the san.e manner as described above, the above sodium salt was purified to obtain sodium 7-{D-(-)-a-[~2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido]-4-hydroxyphenylacetamido}-3- [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl~-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point of 221 to 222C (decomposition).
Elementary analysis values as C25H25N1007S4Na~H20:
Calculated: C = 40.21, H = 3.64, N = 18.76 Found: C = 40.08, H = 3.71, N = 19.20 IR ~KBr) cm t: vc_O 1760 ~lactam), 1720, 1680 (amideJ
H-NMR( a~-DMso)~
3.62 (lOH, s, CH2x5), 3.91 (3H, s, CN3), 4.06-4.59 (2H, m, 3-CH2J, 4.85 (1H, d, J=4.88Hz, 6-H), 5.29-5.79 (2H, m, 7-H/ ~HJ, 6.71 (2H, d, J=8.3Hzt 3', 5'-phenyl nucleus H1, 1~9'783~3 7.19 (2H, d, J=8.3Hz, 2', 6'-phenyl nucleus H), 8.76 ~1H, d, J=7.81Hz, -CONH), 9.23 (1H, d, J=6084Hz, -CONH), 9.63 ~lH, s, phenyl nucleus 4'-OH) D2O-Added ~:
3.61 (lOH, s, CH2x5), 3~91 t3H, s, -CH3), 4.06-4.57 (2H, m, 3-CH2), 4.84 (1H, d, J=4.88Hz, 6-H), 5.47 (1H, s, ~H), 5.53 (1H, d, J=4.88Hz, 7-H), 6.72 (lH, d, ~ J=8.3Hz, 3I, 5'-phenyl nucleus H), 7.20 (1H, d, J=8.3Hz, 2', 6'-phenyl nucleus H) 13C_NMR (d -12C-DMSO)~
26.25 (t, 2-C), 33.53 lq, -CH3), 35.99, 44.31 (t, imidazolidine nucleus CH2), 36.65 (t, -CH2S), 37.68, 38.85 ~t, dithiolan nucleus CH2), 55.49 (d, 6-C), 57.18 (d, a-C), 58.09 (d, 7-C), 115.13 (s, 4-C), 115~13 (d, 3', 5'-phenyl nucleus C), 127.74 (d, 2', 6'-phenyl nucleus C), 128.26 (s, 1'-phenyl nucleus C), 133.46 (s, 3-C), 15i.26 (s, NHCONH), 154.51 (s, tetrazole nucleus 5-C), 155.03 (s, dithiolan nucleus C=N), 157.11 Is, 4'-phenyl nucleus C), 162.83 (5, 8-C), 164.12 (s, COONa), 170.75 (s, imidazolidine nucleus C=O~ -181.41 (s, -CONH) Example 10 ~g~ 33~3 Preparation of 7-{D-I-)-a- ~(2-oxo-3 (1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-4-acetoxyphenylacetamido}-3~ meth~1-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid In 50 ml of water was dissolved 3.82 g of the sodium salt obtained in Example 9c, and reaction was carried out .in the same manner as described in Example 5a by using 1.07 g of acetic anhydride to obtain 3.17 g (the yield being 81 ~) of the intended compound. The meltin~ point was 159 to 162DC
(deco~position).
IR (KBr) cm l : `'C=O 1770 (lactam), 1720, 1680 (COOH, CONc), vC=O 1200 ( ~ OOCCH3) NMR (d6-DMSO)~: O
2.24 ~3H, s, C-CH3), 3.30-3.80 (10H, broad-s, CH2x5), 3.92 ~3Ht s, N-CH3), 4.27 ~2H, broad-s, 3-CH2), 4.98 ~lH, d, J=SHz, 6-H), 5.45-5.85 (2H, m, 7-H, a-H), 7.09, 7,43 ~4H, d, J 9Hz, C6H4), 8.91 (lH, d, J=8Hz, NHCO), 9.44 (lH, d, J=8Hz, NHCO) Example 11 The m;niml1m inhibitory concentrations ~MIC) of the compounds obtained according to the present invention were determined according to the standard-method o~ the Japanese Chemotherapeutic Association.
Cefotiam, cephalexin and cephalothin were used as the control compounds.
m e obtained results are shown in Table 1.

5~ -Table 1 M; n; m~m Inhibitory Concentration (MIC) (mc~/ml) Inoculum size: 1 o6 cells/ml ~acteria Gram-Positive Bacteria KI-6203 KI-6248 KI-6269 CTM**CEX** CET**
Staphylococcus aureus 209-P 0.78 0.78 1.56 0.39 1.56 0.20 Staphylococcus aureus TERAJIMA1.56 0.78 1.56 0.78 1.56 0.20 Staphylococcus epiderm~dis ATCC12228 0.39 0.39 0.39 0.39 1.56 ~0.10 Bacillus subtilis ATCC 6633 0.78 0.73 0.78 0.39 0.78 <0.10 ~n Gram-Negative Bacteria Escherlchia coli N I H J <0.10 <0.10 <0.10 <0.103.13 0.39 0 Escherichia coli MEGAWA 25 6.25 6.25 6.25 ~100 ~100 Ç~
Proteus vulgaris 6.25 1.56 0.78 0.39 12.5 6.25 Proteus ~organii IID 602 6.25 3.13 3.13 0.39 >100 >100 Pseudomonas aeruginosa IFO 13739 12.5 12.5 6.25 ~100 ~100 ~100 Pseudomonas aeruginosa IFO 30803.13 1.56 1.56 >100 ~100 >100 Table 1 (continued) Bacteria KI-6203 KI-6248KI-6269 CTM**CEX** CET**
Pseudomonas pudita IID 5121 50 25 25 ~100 >100 >100 Klebsiella pneumoniae IID 865 0.39 c0.100.20 <0.10 1.56 0.78 Salmonella enteritidls IID 604 6.25 3.131.56 -0.20 6.25 1.56 Salmonella paratyphi IID 605 6.25 1.56 . 1.56 <0.10 12.5 3.13 Salmonella typhimurium IID 1000 3.13 0.78 1.56 <0.10 3.13 0.78 Shigella bcydi~ IID 627 1.56 0.39<0.10 <0.10 3.13 0.78 Shigella sonnei IID 969 1.56 0.780.20 <0.10 6.25 6.25 Sh1gel1a dysenterLae IID 633 0.78 0.20<0.10 ~0.10 3.13 0.78 Enterobacter aerogenes IID 5206 12.5 3.13 1.56 1.56 >100 ~100 Enterobacter cloacae IID 977 12.5 3.133.13 3.13 >100 ~100 Serratia marcenscens IFO 12648 6.25 3.131.56 25 >100 ~100 ~7~338 Note *: weight concentration **: potency concentration CTM: cefotiam CEX: cephalexin CET: cephalothin Example 12 Preparation of 7-{D-(-J-a-~(2-oxo-3~ 3-dithiolan 2-imino)-imidazolidin-1-yl)-carboxamide~-p-hydroxy-~ phenylacetamido}-3-[(1-carboxymethyl-1,2,3,4-tetrazoi-5~yl)-thiomethyl ~-3-cephem-4-carboxylic acid In 100 ml of dry methylene chloride was suspended 8.721 g t22 millimoles) of D-(-)-a-~[2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl~-carboxan~ido}-p-hydroxyphenylacetic acid, and 4.452 g (44 millimoles) of triethylamine and 5.019 g (46.2 millimoles) of trimethylchlorosilane were added to the suspension and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -20C and 1.6t g (22 millimoles) of dimethylformamide and 2.39 g (12.1 millimoles) of trichloromethyl chloroformate were added to the reaction mixture. The mixture was stirred at -10 to -15~C for 5 hours. Separately, 6.679 g (66 milli-moles) of triethylamine and 7.684 g ~70.4 millimoles) of trimethylchlorosilane were added to a suspension of 8.192 g (22 millimoles) of 7-amino-3- [~1-carboxymethyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid in 150 ml of dry methylene chloride, and the mixture was stirred ~' . . .

`7~33~

at room temperature for 2 hours to form a solution. The solution was cooled to -30C and was added to the above chloride-formed solution. The mixture was stirred at

-10 to -15C for 1 hour, and was then poured into 200 ml of ice water and stirred to cause precipitation. When a 10 ~ aqueous solution of sodium hydrogen carbonate was added to adjust the pH value to 7.0, the precipitate was dissolved again. The methylene chloride layer was separated, and the resulting aqueous layer was washed with ethyl acetate.
The aqueous layer was subjected to the decoloring treatment with active carbon and 3N hydrochloric acid was added thereto to adjust the pH value to 1.5. The resulting precipitate was recovered by filtration, washed with water and dried in vacuo to obtain 13.99 g of a light yellow crude crystal of 7-{D-(-)-- U2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-p-hydroxyphenylacetamido}-3-~l1-carboxy-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid. The crude crystal was purified by silica gel column chromatography (~eveloping solvent: chloroform/
methanol/formic acid = 50:10:3 ~ 50:15:10) to obtain 7.91 g (the yield being 47.9 %) of a puriied white crystal having a melting point of 190C (decomposition).
IR ~KBr) cm : 1715, 1760-1780 (C=O) H-NMR (DMSO-d6)~:
3.60 ~10H, broad~s, C~2x5), 4.20-4~40 (2H, m, 3-CH2), 4.96 (1H, d, J=5Hz, 6H), 5~20 (2H, s, N-CH2-), 5.43-5.8D (2H, m, 7-H, a-H), 7~33~3 6.72, 7.20 ~4H, d, J-8~z, -C6H4-), 8.76 (lH, d, J=7.6Hz, CONH), 9.32 (1H, d, J=7.6Hz, CONHI
~2O-Added ~:
3.60 (lOH, broad-s, CH2x5), 4.20-4.40 (2H, m, 3-CH2-), 4.96 (lH, d, J=5Hz, 6H), 5.20 (2H, s, N-CH2-), 5.44 (1H, s, a-H~, 5.68 (1H, d, J=5Hz, 7-H), 6.72, 7.20 (4H, d, J=8Hz, -C6H4-) Example 13a io ~ Preparation of 7-{D-(-)-a- ~(2-oxo-3-~1,3-dithiolan-2-imino)-imida~olidin-1-yl)-carboxamido]-phenyl-acetamido}-3- ~1,3,4 thiadi a201 -2-yl~-thiomethyll-3-cephem-4-carboxylic acid In 60 ml of 80 ~ aqueous tetrahydrofuran was suspended 2.31 g of 7- ID- (-) -a-aminophenylacetamido]-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, and 0.607 g of triethylamine was added to the suspension to form a solution. The solution was cooled by ice and 1.593 g of 1-chlorocarbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine was added little by little to the solutionwith stirring while the pH value was maintained at 7.0 to 7.
by appropriately adaing triethylamine. The addition of the acid chloride was completed within about 3~ minutes. ~he reaction mixture was stirred under ice cooling~r 1 hour while the pH value was maintaine~ at 7.0 to 7.5 by addition of ~riethylamine. Then, 100 ml of water was added to the liquid reaction mixture and the pH value was adjusted to 7, ': ~

1~97~3~

and tetrahydrofuran was distilled under reduced pressure on a water bath maintained at 30C. The residue was filtered, and the pH value was adjusted to 2 under ice cooling by addition of 2N HCl. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator to obtain 1.73 g of the intended compound. The melting point was 160 - 165C (decomposition). The yield was 50 %.
IR (KBr) cm 1: ~C=O 1780 (lactam) 0 Example 13b Preparation of 7-{D-(-)-~-[(2-oxo-3-11,3-dithiolan-2~imino)- midazolidin-1-yl)-carboxamido]-phenyl-acetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxylic acid In 18 ml of dry methylene chloride was suspended 1.0 g (0.0026 mole) of D-(-)-~-{12-oxo-3-(1r3-dithiolan-2-imino)-imidazolidin-1-yl~-carboxamido}-phenylacetic acid, and under ice cooling, 0.366 ml (0.0026 mole) or triethylamine was added and 0.317 ml (0.0026 mole) o trimethylchloxosilane was then added. The mixture was stirred at room temperature for 1 hour and cooled to about -20C, and 0.20 ml (000029 molel of dimethylformamide and 0.17 ml ~0.0014 mole~ of trichloro-methyl chloroformate were added to the mixture. Then, the mixture was stirred at -20 to -15C for 4.5 hours. Separately ~1.28 ml of N,O-bis(trimethylsilyl)acetamide was added to a suspension of 0.87 g (0.0026 mole) o~ 7 amino-3-~1,3,4-thiadiazol-2-yl~-thiomethyl~-3-cephem-4-carboxylic acia in - 61 ~

1~9'7~ 8 7 ml of dry methylene chloride, and the mixture was stirred at room temperature for 4 hours to form a solution. The solution was cooled to -20~C and added to the above chloride-formed solution, and the mixture was stirred at -20 to -15C
for 1 hour. Then, 17 ml of water was added to the mixture and the mixture was stirred to form a precipitate. Then, a 10 % aqueous solution of sodium hydrogen carbonate was added to adjust the pH value to 7.50 and dissolve the precipitate again. The methylene chloride layer was separated, and ~he resulting aqueous layer was washed with ethyl acetate and subjected to the dec~loring treatment with active carbon.
Then, the pH value was adjusted to 2.0 by addition of 3N
hydrochloric acid, and thef~rmed precipitate was recovered by filtration, washed with water and dried in vacuo to 15 obtain 1.25 g (the yield being 68.4 ~) of 7-{D-(-)-a-~(2-oxo-3-(1,3-dithiolan-2-iminoj-imidazolidin-1-yl)-carboxamido~-phenylacetamido}-3-C(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid in the form of a white powder having a melting point of 164 to 167~C
(decomposition).
IR (XBr) cm : vC=O 1780 (lactam) Example 13c Preparation of dicyclohexylamine salt of 7-{D-(-)-a-t(2-oxo-3-(1,3-dithiolan~2-imino)-imidaæolidin-1-yl)-czrboxamido]-phenylacetamido}-3- [(1,3,4-thiadiazol-2-yl)-thiome~hyl]-3-cephem-4-carboxylic acid ~' i~7~33~

In 20 ml of a liquid mixture of ethyl acetate and ethanol was dissolved 0.8 g of 7-{D~ -[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido}-3- r (1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, and insoluble substances were removed by filtration. Then, 0.54 ml of dicyclohexylamine was added to the filtrate, and the mixture was concentrated and acetone was added thereto. The mixture was allowed to stand still in a refrigerator, and the ormed precipitate was ~ecovered by filtration and washea with acetone to obtain 0.7 g (the yiela being 70 %) of a dicyclohexylamine salt of 7-{D-(~ (2-oxo-3-(1,3-dithiolan-2-imino)-( imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-~l1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem~4-carboxylic acid in the form of a white crystalline powder having a melting point of 162 to 165C (decomposition).
IR (KBr) cm 1 ~C=o1780 (lactam) H-NMR (CDCl3~d6-DMSO)~:
0.98-2~27, 2.68-3.22 (m, H of dicyclohexyl group), 3.47 (2H, broad-s, 2-CH2), 3.61 (8H, broad-s, CH2x4), 4.49 (2H, broad-s, 3-CH2), 4.87 (1H, d, J=4.88Hz, 6-H), 5.47-5.72 (2H, m, 7-H, a-H), 7.12-7.67 (5H, m, phenyl nucleus-H), 8.94 (1H, d, J=7.32Hz, CONH), 9O3B (lH, d, J~7.32Hz, -CONH), 9.37 (1H, s, thiadiazole nucleus 5-H) :l~g~38 D2O-Added~:
0.99-2.27, 2.68-3.22 (m, H of dicyclohexyl group), 3.44 (2H, broad-s, 2-CH2), 3.61 (8H, broad-s, CH2x4), 4.47 (2H, broad-s, 3-CH2), 4.85 (1H, d, J=4.88Hz) 6-H), 5.59 (1H, d, J=4.88Hz, 7-H), 5.63 (1H, s, a-H), 7.12-7.67 (5H, m, phenyl nucleus H), 9.34 tlH, s, thiadiazole nucleus 5-H) Example 13d Preparation and purification of sodium 7-{~
i ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamidoJ-phenylacetamido}-3-r(1,3,4-thiadiazol-2-yl)-thicmethyl~-3-cephem-4-carboxylate In 20 cc of dry dimethylformamide was dissolved 2.0 g of a dicyclohexylamine salt of 7-{D-(-)-a- [(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3- E( 1,3,4-thiadiazol-2-yl)-thiomethylJ-3-cephem-4-carboxylic acid, and 2.96 ml of a 1M solution of sodium 2-ethylhexanoate in isopropanol was added to the solution and the mixture was stirred for 5 minutes. When dry ether was added to the solution, a white precipitate was formed. The precipitate was recovered by filtration, washed with dry ether and dried in vacuo to obtain 1.7 g Ithe yield being 94.4 %) of a dimethylformamide adduct of sodium 7-{D-(-)-a- ~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1 yl)~
carboxamido]-phenylacetamido}-3- t~1,3, -thiadiazol-2-yl)-thiomethy~ -3-cephem-4-carboxylate in the form of a white crystalline powder havin~ a melting point of 160 - 199C
(decomposition).

~ 6~ -~g~838 IR (KBr) cm 1: ~C=o1760 tlactam) In 10 ml of a 1:5 liquid mixture o dry dimethyl-formamide:methanol was dissolved 1.7 g of the above dimethylformamide adduct of sodium 7~P-t~ 2-oxo-3-l1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3- C(1,3.4-thiadiazol-2-yl~-thiomethyl~-3-cephem-4-carboxylate, and the solution was subjected to decoloring treatment with active carbon and a dry 10 %
solution of met~anol in ether was added to the solution to fo~m a precipitate. The precipitate was recovered by filtration, washed with a dry liquid mixture of methanol and ether and then~with dry ether and dried in vacuo to obtain 1.0 g (the yield being 64.9 %) of sodium 7-{D-(-)-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point o~ 1Q5 to 199C
(decomposition) IR (KBr) cm : vc=o1760 (lactam) The s~-obtained sodium salt was purified by using Sephadex LH-20 Ideveloping solvent: methanol) to obtain sodium 7-{I~ L~2-oxo-3- (1 ,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-phenylacetamido}-3-~1,3,4-thiadia20l-2-yl)-thiomethyl~-3-~ephem-q-carboxylate in the form of a white crystalline powder having a melting point of 195 to 202C
~decomposition).
Elementary analysis values as C25H~3N806S5Na H20:

.. . . .. .. . . . .

~$783~
.

Calculated: C = 40.97, H = 3.44, N = 15.29 Found: C = 40.84, H = 3.43, N = 15.53 IR (KBr) cm 1 YC=o1760 (lactam), 1710, 1670 (amide) H NMR (d6 DM O) :
3.63 (10H, broad-s, CH2x5), 4.51 (2H, broad-s, 3-CH2), 4.89 (lH, d, J=4.88Hz, 6-H), 5.52-5.67 (2H, m, 7-H, a-H)j 7.37 15H, s, phenyl nucleus-H), 8.87-8.99 (lH, m, -CONH), 9.52 (1H, s, thiadiazole nucleus 5-H), ~ 9.61-9.35 (1H, m, -CONH) D2O-Addëd~:
3.61 (10H, broad-s, CH~x5), 4.39-4.48 (2H, m, i 3-CH2), 4.86 (1H, d, J=4.88Hz, 6-H), 5.53 (lH, d, J=4.88Hz, 7-H~, 5.61 (lH, s, a-H), 7.36 (5H, broad-s, phenyl nucleus-H), 9.49 (1H, s, thiadia~ole nucleus 5-H) 3c-NMR (d6-12C-DMSO)~:
26.51 (t, 2-C), 35.99, 44.31 (t, imidazolidine nucleus CH2), 37.29 (t, -CH2S), 38.85, 37.68 tt, dithiolan nucleus CH2), 56.00 Id, 6-C), 57.31 (d, a-C), 57.96 (d, 7-C), 114.61 (s, 4-C), 126.44 ~d, 2', 6~-phenyl nucleus C), 127.74 (d, 4'-phenyl nucleus C), 128.39 Id, 3',5'-phenyl nucleus C), 133.98 (s, 3-C), 138.26 (s, 1'-phenyl nucleus C~, 151.26 (s, NCONEI), 153.99 (d, thiadiazole nucleus 5-C), 155.03 ~s, dithiolan nucleus C=N)g 162.70 (s, 8-C), ;~9~838 164.12 (s, -COONa), 166.33 (s, thiadiazole nucleus 2-C), 170.23 (s, imidazolidine nucleus C=O), 181.53 (s, -CONH) Example 14 Preparation of 7-{D-(-)-~- [(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetoamide}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxylic acid (hereinafter referred to as TO-180) i To a mixture of 20 ml of anhydrous acetone and 2.66 g of 7-{D-(-)-~-~(2-~x-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl¦-carboxamido}-phenylacetic acid were ( added 0.96 ml of triethylamine and one drop of 2-dimethyl-aminoethanol, and the mixture was cooled to -40C and 0.794 g 15 of methyl chloroformate was added thereto. A solution formed by adding 4 ml of 2N sodium hydroxide to a mixture of 5 ml of water and 2.772 g of 7-amino-3-t5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid under ice cooling and further adding 7 ml of acetone, which was cooled to -20C, was added at one time to the above solution, and the mixture was stirred until the temperature was naturally elevated to room temperature. Then, 100 ml of water was added to the mixture, acetone was removed by distillation, and the residue was filtered and the pH value was adjusted to 2 under ice cooling by addition of 2N hydrochloric acid. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator. The crystal was dissolved in ~9~33l~

ethyl acetate under heating and ethyl ether was added to the solution to precipitate 4.25 g (the yield being 86 %) of a crystal of the intended compound having a melting point of 157 to 160C ~decomposition).
IR (KBr) cm 1: vc=O 1770 (lactam), 1715, 1675 (COO~, -CON<) ( 6 2.66 (3H, s, -CH3) t 3.58 (10H, broad-s, CH2x5), 4.12, 4.44 ~2H, ABz, J=12Hz, 3-CH2), ~ 4.96 ~1H, d, J=5Hz, 6-H), 5.50-5.7~ (2H, m, 7-H, a-H), 7.32 ~5H, broad-s, C6H5-), 8.84 ~1H, d, J=8Hz, NHCO), 9.40 (lH, d, J=8Hz, NHCO) Example 15 Preparation of 7-{D~ t~2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido~-phenylacetamido}-3-~5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl}-3-cephem-4-carboxylic acid To a mixture of 1.945 g of 7{D~-)-a- [12-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido ~3-acetoxymethyl-3-cephem-4-carboxylic acid, 0.531 g of 5-methyl-2-mercapto-1,3,4-thiadiazole and 60 ml of water was added lN sodium hydroxide to form a solution having a p~ value of 6.5. The solution was heated and stirred at 60C in a nitrogen gas current f~r 22 hours while maint~; n; ng the p~ value at 6.5. Then the pH value of the reaction mixture was adjusted to 2 under l~g7~

ice cooling by 2N hydrochloric acid, and the precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator to obtain 1.895 g (the yield being 89 %) o the intended compound. The melting point was 140 to 146C (decomposition).
IR ~KBr) cm ~: vc=o1780 (lactam), 1720, 1680 (-COOH, -CON<) H-NMR(d6-DMSO)~:
1.45 (3H, d, J=6Hz, -CH-CH33, 2.65 (2H, s, ~ thiadiazole nucleus CH3), 3.20-3.94 (9H, m, CH2x4,iCH-CH3), 4.15, 4.50 (2H, ~Bq, J=13Hz, 3-CH2), 4.98 (lH, d, J=SHz, 6-~), 5.46-5.88 (2H, m, 7-H, a-H), 7.33 (5H, broad-s, C6H5-), 8.88 (1H, d, J=8Hz, CONH), 9.40 (lH, d, J=8Hz, CONH) Example t6 The mi n; mnm inhibitory concentrations (MIC) of the compound obtained according to the present invention were det~rm;ned according to the standard method of the Japanese Chemotherapeutic Association.
Cefotiam, cephalexin and cephalothin were used as the control compounds.
The obtainea results are shown in Table 2.

~.

Table 2 ~";mllm Inhibitory Concentration (MIC) Imcg/ml) 6 Inoculum size: 10 cells/ml Bacteria Gram-Positive Bacteria TO-180* CTM**~ CEX** CET**
Staphylococcus aureus 209-P 0.39 0.39 1.56 0.20 Staphylococcus aureus TERAJIMA 0.39 0.78 1.56 0.20 Staphylcoccus epidermidis ATCC 12228 0.39 0.39 1.56 <0.10 Bacillus subtilis ATCC 6633 0.78 0.39 0.78 <0.10 Gram-Negative Bacteria Escherichia coli NI~J <0.10 ~0.10 3.13 0.39 Escherichia coli MEGRWA 6.25 6.25 >100 ~100 Prote~s vulgaris 1.56 0.39 12.5 6.25 I . Proteus morganii IID 602 1.56 0.39 >100 >100 o Pseudomonas aeruginosa IFO 137396.25 >100 ~100 >100 Pseudomonas aerugi~osa IFO 3080 1.56 >100 >100 >100 Pseudomonas pudita IID 5121 25 >100 >100 >100 G~
Klebsiella pneumoniae IID 865 0.39 <0.10 1.56 0.78 r Salmonella enteritid~s IID 604 1.56 0.20 6.25 1.56 Salmonella paratyphi IID 605 1.56 <0.10 12.5 3O13 Salmonella typhimurium IID 1000 1.56 <0.10 3.13 0.78 Shigella boydii IID 627 0.39 <0.10 3.13 0.78 Shigella sonnei IID 969 0.39 <0.10 6.25 6.25 Shigella dysenterlae IID 633 0.39 <0.10 3.13 0.78 EnterGbacter aerogenes IID 5206 3.13 1.56 >100 ~100 Enterobacter cloacae IID 977 3.13 3.13 >100 >100 Serratia marcenscen~ IFO 12648 1.56 25 >100 >100 7133~3 Note * : weight concentration ** : potency concentration CTM : cefotiam CEX : cephalexin CET : cephalothin Example 17a Preparation of 7-{D~ a-1(2-oxo-3~ 3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido]-phenyl-~ acetamido{-3-[5-methyl-11,3,4-thiadiazol-2-yl)-thiomethyl]-3-c~phem-4-carboxylic acid According to the method described in Example 13b, i 4.11 g (the yield being 76.8 %) of 7-{D-(~ [12-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido}-3-~5-methyl-(1,3,4-thiadiazol-2-yl]-3-cephem-4-carboxylic acid was obtained in the form of a white powder having a melting point of 164 to 165C (decomposition~ by using 3.0 g (0.00757 mole) of D-(-)-a-{[2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl]-carboxamido}-phenylacetic acid and 2.7 g (0.00762 mole) of 7-amino-3-~(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 : 1780 (lactam) Example 17b Preparation of dicyclohexylamine salt of 7-{D-(-)-a-[(2-oxo-3-~1,3-ai-thiolan-2-imino)-Lmiaazolidin-l-yl)-carboxamido]-phenylacetamido}-3- r 5-methyl-(1,3,4-thiadi~zol-2-yl)-thiomethyl]-3~cephem-4-carboxylic acid ~'7~8 In 70 cc of dry acetone was dissolved 1~7 g of 7-{D-~ -oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, and 1.1 ml of dicyclohexylamine was added to the solution and the mixture was allowed to stand still in a refrigerator overnight. The ~ormed precipitate was recovered by filtration and washed with acetone to obtain 1.0 g (the yield being 46.9 %) of a dicyclohexylamine salt of 7-{D-(-)-a-](2-oxo-3-~1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid in the form of a white crystalline powder having a melting point of 162 to 164~C (decomposition).
IR (KBr) cm : VC=o 1780 (lactam) 'H-NMR(CDC13+d6-DMSO)~ : 0.7~2.36, 2.85~3.25~m, H of dicyclo-hexyl group), 2.66(3H, S, -CH3), 3.61 (lOH, broad-S, ~H2x5), 4.17~4.63(2~, m, 3-CH2), 4.88(lH, d, J=4.88Hz, 6-H), 5.03~5.90(2H, m, 7-H, a-H), 7.38(5H, broad-S, phenyl nucleus-H), 8.93(1H, d, J=7.81Hz, CONH~, 9.40(1H, d, J-7.33Hz, -CONH~
D20-Added ~ : 0.86~2.13, 2.93~3~08(m, ~ of-dicyclv-hexyl group), 3.62(1OH~ broad-S, CH2x5) r 4.19~4.50(2H, m, 3-CN2), 4.87(1~, a, J-4.88Hz, 6-~), 5~8~
d, J=4.g8Hz, 7-~), 5.64(lH, S, ~-H)I

.
,. ,~

1~7~38 7.36(5H, broad-S, phenyl nucleus-H) Example 17c Preparation and puri~ication of sodium 7-{D-t-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido~-3-~5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxylate (hereinafter referred to as KI-6271) According to the method described in Example 13d, 1.5 g (the yield being 83.33 ~) of a dimethylformamide adduct of sodi~ 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl)-car~oxamido]-phenylacetamido}-3-~5~methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate was i obtained in the form of a white powder having a melting point of 190 to 195C (decomposition) by using 2,0 g of a dicyclo-hexyl~ salt of 7-{-D-(-)-a-t(2-oxo-3-(l~3-dithiolan-2-imin imidazolidin-l-yl)-carboxamido]-phenylacetamido}-3-t5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 : vc=O 1760 (lactam) In the same m~nn~ as described ahove, 1.1 g (the yield being B0 %) of sodium 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan~
2-imino~imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxy--late was obtained in the form of a white crystalline powder having a melting point of 194 to 197C (decomposition) from 1.5 g of the dimethylformamide adduct of sodium 7-{D-(-?-a t~2-oxo-3-(1,3-dithiolan~2-~miro)-imidazolidin-1-yl~-carboxamido~-phenylacetamido~ 3-t5-methyl-(1,3,4-thiadiazol-2-yl)-~'7~33~

thiomethyl]-3-cephem-4-carboxylate.
IR (KBr) cm : v C 0 1760 (lactam) In the same manner as described above, the above sodium salt was purified to obtain sodium 7-{D~ (2-ox~-3-(1,3-dithiolan-2-Lmino)-imidazolidin-l-yl)-carboxamido]-phenyl-acetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point of 194 to 197C (decomposition).
Elementary analysis val~es as C26H2506N8S5Na-2H20:
~ Calculated : C = 40.83, H = 3.82, N = 14.65 Found : C - 40.84, H - 3.60, N = 14.65 IR (KBr) cm 1 : v C=O 1760 (lactam), 1720, 1670 (amide) 'H-NMR(d6-DMSO)~ : 2.66(3H, S, thiadiazole nucleus-CH3), 3.62(10H, broad-S, CH2x5), 4.43(2H, broad-S, 3-CH2), 4.88(lH, d, J=4.88Hz, 6-H), 5.70~5.45(2H, m, 7~Hr ~-H), 7.36(5H, S, phenyl nucleus-H~, 8.90(1H, d, J=3.32Hz, -CONH~ .39(lH, d, J=8.30Hz, -CON~-), D20-Added ~ : 2.66(3H, S, thiadiazole nucleus-C~3), 3.63 ~lOH, broad-S, -CH2x5), 4.42(2H, broad-S, 3-CH2), 4.86(1~, d, J=4.88Hz~ 6-H), 5.55 (lH, d, J=4.88Hz, 7-H), 5.62(1H, S, ~-H), 7.37(5H, S, phenyl nucleus-H) 13C-NMR(d6-12C-DMSO)~ : 15~201q, -CH3), 26.51(t 2-c), 35.99 44.31 (t, imidazolidine nucleus), 37.17 (tp -CH2-S), 37.81, 38.B5 (t, dithiolan nucleus CH2), 56.Q1 ~d, 6-C~, 57.31 (d, ~-C), 7!33~3 57.96 (d, 7-C), 115.13(S, 4-C), 126.57(d, 2', 6'-phenyl nucleus), 127.87(d, 4'-phenyl nucleus), 128.39(d, 3', 5'-phenyl nucleus), 133.7~(Sr 3-C), 138.26(S, 1'-phenyl nucleus), 151.26(S, >N-CO-NH-), 155.03(S, C=N), 162.83(S, 8-C), 164.25(S, -COONa~, 165.29(S, 5'-thiadiazole nucleus), 165.94(S, 2'-thiazole nucleus), 170.23(S~
imidazolidine nucleus C=O), 181.53(S, ~. --CON~--) Example 17d Preparation of l-ethoxycarbonyloxyethyl 7-~D~ a-[(2-oxo-3-(1 r 3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate In 20 ml of dimethylsulfoxide was dissolved 2.12 g o the compound obtained in Example 14, and 0.373 g of potassium carbonate and 0.02 g of 18-Crown-6 (crown ether supplied by Nippon Soda K~ K.) were added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 0.686 g of diethyl a-chlorocarbonate was added to the mixture and the mixture was stirred for 3 hours on a water bath maintained at 50C in a nitrogen gas current.
Then, 200 ml of ice water was added to the reaction mixture r and the mixture was extracted with 200 ml of dichloromethane 7 washed with water 2 times and dried `~ /
,~

~'7~33~3 with anhydrous sodium sulfate. The solvent was removed by distillation, and 1.84 g of the obtained oily product was dis-solved in a small amount of dichloromethane and the solution was dropped into 150 ml of ethyl ether with stirring to effect crystallization. The formed crystal was recovered by fil-tration and dried to obtain 1.14 g (the yield being ~6 %) of the intended compound. When the obtained product was purified by silica gel column chromatography ~developing solvent:
benzene/acetone = 2/1), two kinds of oily products were obtalned. Each oily product was dissolved in a small amount of dichloxomethane ànd the solution was dropped into ether to e~fect crystallization. Thus, there were obtained 0.410 g of a steric isomer A in the form of a white powder having a melting point of 125 to 128C and 0.230 g of an isomeric isomer B in the form of a white powder having a melting point of 110 to 113C.
Isomer A (melting point = 125 - 128C) IR (KBr) cm Vc~o 1760(lactam), 1720, 1680(ester, amide) 'H-NMR (d6-DMSO)~ : 1.23(3H, t, J=8Hz, -CH2-CH3), 1.55 (2H, d, J=6Hz, -CH-CH3), 2.70(3H, S, Thiadiazole nucleus-CH3), 3.50~3~83(10H, broad-S, CH2x5), 3.93~4.57(4H, m, 3-CH2, -CH2-CH3) t 5.06(1H, d, J=5Hz, 6-H), 5.50~6~.00(2H, m, 7-H, ~

6.66~7.13(1~, m, -CH-O ), $7838 7.20~7.53(5H, m, C6H3-), 8.93(1H, d, J=8Hz, -NHCO-), 9.50(lH, d, J=8Hz, -NHCO-) Isomer B (melting point = 100 - 113C) IR (KBr) cm Vc-o 1760~lactam), 1720, 1680(ester, amide) 'H-NMR(DMSO-d6)~ : 1.23(3H, t, J=8Hz, -CH2-CH3), 1.50(2H, d, J=6Hz, -CH-CH3), 2 72(3H, S, thiadiazole nucleus-CH3), 3.46~3.83(1OH, broad-S, CH2x5) 4.00~4.37(4H, m, 3-CH2, -CH2-CH3), 4.96~5.33(1H, m, 6-H), 5.47~5.80~2H, m, 7-H, ~-H), 6.46~6.90(lH, m, -CH-O-), 7.16~7~30(5H, m, C6H5-), 8.93(1H, d, J-8Hz, -NHCO~), 9.57(lH, d, J=8Hz, -NHCO-) Example 18a Preparation of 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido~-p-hydro- 0 xyphenylacetamido}-3-[(1,3,4~thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid 7-{D-(-)-a-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidaæolidin-l-yl)-carboxamido]-p-hydroxyphenylacetamido}-3 [(lr3,4-~hiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid was prepared in an amount of 4.0 g (~he yield being 74.6 %) in the form of a whi~e powder having a meltîng point of 171 to 176C (decomposition) in the same manner as described in Example 136 except that 3~0 g (0.0075 mole) of D~
{[2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl]-carbox-amido}-p-hydroxyphenylacetic acid and 2.49 g (0.0075 mole) of 7-amino-3-~(1,3,4-thiadiazole-2-yl)-thiomethyl~-3-cephem-4-carboxylic acid were used and trimethylchlorosilane and triethylamine were used in molar amounts two times the molar amounts used in Example Bb.
IR (KBr) cm : vC=O 1780 (lactam) 0 Examp~e 18b Preparation of dicyclohexylamine salt of 7-{D~
~(2-oxo-3 ~1,3-di~hiolan-2-imino)-imidazoliain-1-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethylJ-3-cephem-4-carboxylic acid In 250 cc of a liquid mixture of acetone and ethanol was dissolved 4.0 g of 7-{D-~ (2-oxo-3-~1,3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido]-p-hydroxyphenylacetami~o~
-3-[(1,3,4-thiadiazol-2-yl)-thiomethyll-3-cephem-4-carboxylic acid, and 2.08 ml of dicyclohexylamine was added to the solution and the mixture was allowed to stand still in a cold place overnight. The formed precipitate was recovered by fil-tration and washed with acetone to obtain 2.2 g tthe yield being 44 ) of a dicyclohexylamine salt of 7-{D~ [~2-oxo-3-(1,3 dlthiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydro~
xyphenylacetamido}-3-1(1,3,4-~hiadiazol-2-yl)-thiome~hyll-3~
cephem-4-carboxylic acid in the form of a white crys~

~7~38 powder having a melting point of 173 to 175~C (decomposition).
IR (KBr) cm 1 : Vc o 1780 (lactam) 'H-NMR(COCL~+d6-DMSO)~ : 1.17~2.39, 2.70~3.29(m, H of dicyclo-hexyl group), 3.57~3.66(m, lOH, CH2x5), 4.49(broad-S, 2H, 3-CH2), 4.85(d, J=4.88Hz, lH, 6-H), 5.65~5.77(m, 2H, 7-H, a-H), 6.70(d, J=8.30Hz, 2H, 3',5'-phenyl nucleus), 7.24(d, J=8.30Hz, 2H, 2', 6'-phenyl nucleus), 8.80~9.06(m, ~ 2H, 2X-CONH-), 9.16(S, lH, H of thiadiazole nucleus) D2O-Added ~ : 1.17~2.12, 2.00~3.30(m, H of dicyclo-hexyl group), 3.57~3.68~m, lOH, CH2x5), 4.51(broad-S, 2H, 3-CH2), 4.85(d, J=4.88~z, lH, 6-~0, 5.6~(broad-S, lH, 7-H, a-H), 6.71(d, J=8.30~z, 2H, 3', 5'-phenyl nucleus), 7.25(d, J=8.30Hz, 2H, 2', 6'-phenyl nucleus), 9.15~S, lH, H of thiadiazole nucleus) Example 18c Preparation and purification of sodium 7-{D-(-)-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl~-carbox~midoJ-p-hydroxyphenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate Z5 (hereinafter to as KI-5261) According to the method aescribed i~ Example 13d, 1.6 g(the yield being 80.4 ~) of a aimethylfor~amide adduct of ~ ~ -~, ~'7~338 sodium 7-{D~ (2-oxo-3-(1,3~dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyli-cephem-4-carboxylate was prepared in the form of a white crystalline powder having a mel-ting point of 203 to 215C (decomposition) by using 2.2 g of a dicyclohexylamine salt of 7-{D-(~ -[(2-oxo-3-(1,3-dithiolan-- 2-imino)-imidazolidin-1-yl3-carboxamido]-p-hydroxyphenylacet-amido}-3-l(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
IR (K~r~ cm 1 : vc=O 1760 (lactam) In the same manner as described above, 1.1 g (the yield being 75.8 %) of sodium 7-~D-(-)-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydro-xyphenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl~-3-cephem-4-carboxylate was prepared in the form of a white crystalline powder having a melting point of 217 to 220C
(decomposition) from 1.6 g of the dimethylormamide adduct of sodium 7-{D-(-)~ (2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamidol-p-hydroxyphenylacetamido}-3-[(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate.
IR (KBr) cm 1 : vc=O 1760 llactam) In the same m~nner as described above, the above sodium salt was purified to obtain sodium 7-{D~ [(2-oxo-3-(1,3-dithiolan-~-imino)-imidazolidin-1-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[~1,3,4-thiadiazol-2-yl)-thiomethyll-3-cephem-4-carboxylate in the form of a white c.rystalline powder having a melting point of 214 to 216 ~C (decomposition)~

7~jl3~

Elementary analysis values as C25H23N8O7S4Na^H2O:
Calculated: C = 40.10, H = 3.37, N = 14.96 Found : C = 39.81, H = 3.44, N = 14.85 IR (KBr) cm 1 : Vc o 1760 (lactam) 1720, 1670 (amide) 'H-NMR(DMSO-d6)~ : 3.62~10H, broad S, CH2x5), 4.47(2~, broad-S, 3-CH2), 4.89(1H, d, J=4.88Hz, 6-H), 5.56~
5.44(2H, m, a-~, 7-H), 6.72~2H, d, J=8.30Hz, 3', 5'-phenyl nucleus), 7.20(2H, d, J=8.30Hz, 2',6'-phenyl nucleus), 8~77(lH, dl J=7.81Hz, -CONH-), 9.25(1H, d, J=7.32Hz, -CONH-), 9.50~1~, S, thiadiazol nucleus ~I) D2O-Added ~: 3.62(1OH, broad-S, CH2x5), 4.41(2H, broad-S, 3-CH2), 4.86(1~, d, J=4.88Hz, 6-H), 5.48 (lH, S, a-H), 5.55(lH, d, J=4.88Hz, 7-~), lS 6.72(2H, d, J=8.30Hz, 31, 5'-phenyl nucleus), 7,20(2H, d, J=8.30Hz, 2',6'-phenyl nucleus), 9.47(lH, S, thiadiazole nucleus H) 3C-NMR( C-DMSO-d6)~ : 26.51~t, 2-C~, 35,99; 44.31 (t, ~ imidazolidine nucleus-C~2), 37.30(t, -CH2-S), 37~68; 38.85(t, dithiolan nucleus-CH2), 55.48(d, 6-C), 57.31(d, ~-C), 57.96(d, 7-C), 114.35(S, 4-C), 115.26(d, 3',5'-phenyl nucleus), 127.74(d, 2',6'-phenyl nucleus), 128.26(S, l-phenyl nucleus), 134.11(S, 3-C), 151.26(S, >N-CO-NH-), 153.86(d, 5'-thiadiazole nucleus), 155.03(S, C=N)o 157.24 (S~ 4'-phenyl nucleus), 162.83(S, 8-C), .~.~ .

- -i~7~38 164.12(S, -COONa), 166.3~(S, 2' thiadiazole nucleus), 170.75(S, imidazolidine nucleus C=O), 181.41(S, -CON~-) Example l9a Preparation o~ 7-{D~ -[(2-oxo-3-tl,3-dithiolan-2-imino)-imidazoliain-l-yl)-carboxamido~-p-hydroxy-phenylacetamido}-3-[[5-methyl-1,3-4-thiadia-~-yl)-thiomethyl]-3-cephem-4-carboxylic acid 7-{d-(-)-a-t~2-oxo-3-(1,3-dithiolan-2-imino)-~. imidazolidin-l~yl)-carboxamido]-p-hydroxyphenyl-acetamido~3-[( 5-methyl-1,3,4-thiadia-2-yl)-thio-methyl]-3-cephem-4-carboxylic acid was prepared in an i ~ount of 3.26 g (the yield being 60 ~1 in the form of a white powder having a melting point of 171 to : 15 174C (decomposition) in the same ~nner as described in Example 13b except that 3.0 g of n~ { [2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl]-carbo-xamido}-p-hydroxyphenylacetic acid and 2OS9 g o~ 7-amino-3~(5-methyl-1,3,4-thiadiazol-2-yl)-thiometh~ll-3-cephem-4-carboxylic acid were used and trimethylchlorosilane and triethylamine were used in molar amounts two times the molar amounts used in Example 13b~
; IR (KBr) cm 1 vc=O 1780 (lactam) Example l9h Preparation of dicyclohexyl~m;ne salt of 7-{D~
[(2-oxo-3-(1,3-aithio-lan-2-imino)-imidazolidin-1-yl~

, ~ ~
~ 2 -~9~33~3 carboxamido]-p-hydroxyphenylacetamido}-3-](5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephe~-4-carboxylic acid According to the method described in Example 17b, 2.3 g (the yield being 73.71 %~ of a dicyclohexylamine salt of 7-{D~ [(2-oxo-3-(1,3-dithiolan-2-imino)-Lmidazolidin-l-yl)-car~oxamido]-p-hydroxyphenylacetamido}-3-~(5-methyl-1,3,4-thiadiazol-2-yl)-th;om~thyl]-3-cephem-4-carboxylic acid was prepared in the form of a white crystalline powder having a melt~ng point of 173 to 174C tdecomposition~ by using 2~5 g of 7-{D-(-)-~-[(2-oxo-3-tl,~dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[(5-methyl-1,3,4-thiadiazol 2-yl)-~1iomethyl]-3-cephem-4-carboxylic acid.
IR (KBr) cm : vC=O 1780 (lactam) 'H-NMR(CoCL3+d6-DMSO)~ : 0.92~2.23; 2.86~3.22(m, H of dicyclo-hexyl group), 2.70(3H, S, -CH3), 3.57~3.72(10H, m, CH~x5), 4.43t2H, broad-S, -3-CH2), 4.84~1~, d, J=4.88Hæ, 6-H), 5.36~5.97(2H, m, 7-H, ~-H), 6.70(2H, d, J=8.30Hæ, 3',5'-phenyl nucleus H), 7.25~2~, d, J=8.30Hz, 2l,6'-phenyl nucleus H), 8.50~9.29(2H, m, 2x-CON~-) D2O-Added ~ : 0.85~2.47; 2.89~3.14(m, ~ of dicyclo-he~yl ~roup~, 207U (3Ht Sr -C~3) t 3.57~3.73tlOH, m, CH2x5), 4~43(2~, broad-S, 3-C~2), 4.84~1~, d, J=4.88Hz, .

'7838 6-H), 5.68(1H, d,J=~.88Hz, 7-H), 5.65(1H, S, ~-H), 6.72(2H, d, J=8.30Hz, 3',5'-phenyl group H), 7.25(2H, d, J=8.30Hz, 2',6'-phenyl group H) Example l9c Preparation and purifica-tion of sodium 7-{D-(-)-~-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido-]-p-hydroxyphenylacetamido3-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]`-3-cephem-4-~ carboxylate (hereinafter referred to as KI-6276) AGcording to ~he method described in Example 13d, 1.80 g (the yield being 90 ~) of a dimethylormamide adduct of 1 sodium 7-{D-(-)-~-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-l-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[5-methyl-~1,3l4-thiadiazol-2-yl)-thiomethyll-3-cephem-4-carboxylate was obtained in the form of a white powder having a melting point of 214 to 218C ~decomposition) by using 2.3 g of a dicyclohexylamine salt o~ 7-{D-(-)-a-1~2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydroxy phenylacetamido}-3-tS-methyl-(1,3,4-thiadiazol-2-yl) thiomethyl]-3-cephem-4-carboxylic acid.
IR (RBr) cm : vc_ol760 (lactam) In the same m~nnPr as described above, 1.30 g (the yield being 79 ~) o~ sodium 7-{D-(-)-a-t(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carbQxamido~-p-hydroxy-phenylacetamido}-3-[5-methyl-~1,3,4-thiadiazol-2-yl)-thio~Pthyl]-3-cephem-4-carboxylate was obtained in the form of '~"r"~
``~1~, - 8~ -7~338 \

a white crystalline powder having a mel~ing point of 217 to 220~C (decomposition) from lo 80 g of the dimethylformamide adduct of sodium 7~{D~ -[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[5-methyl-(1,3,4-thia~iazol-2-yl)-thiomethyl]-3-cephem-4-carboxylateO
IR (KBr) cm : Vc ol760 (lactam) In the same manner as descxibed above, the above sodium salt was purified to obtain sodium 7-{D-(-)-~-~(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-p-hydroxyphenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2~yl)-thiomethyl3-3-cephem-4-carboxylate in the form of a white crystalline powder having a melting point of 218 to 221~C
(decomposition).
Elementary analysis values as C26H25O7N8S5Na-2H2O:
Calculated : C = 39.99, H = 3.74, N = 14.35 Found : C = 40 16, H = 3.53, N = 1~.41 IR (KBr) cm 1 : vc=O 176n (lactam), 1720, 1670 (amide) 'H-NMR(DMSO-d6)~ : 2.66(3H, S, -CH3), 3.62(10H, broad-S, 5xCH2), 4.42(2H, broaa-S, 3-CH2), 4.87(1H, d, J=4~88Hz, 6-H),5.56~5.42(2H, m, ~-H, 7-H~, 6.71(2H, d, J=8~30Hz, 3'J5~-phenyl nucleus H), 7.19(2H, d, J=8.30Hz, 2',6'-phenyl nucleus H), 8.77(lH, d, J=7.33Hz, -CON~
9.25(lH, d, J=10.25Hz, -CONH-) D2O-Addea ~: 2.66(3H, S, -CH3), 3.62~10H, broad-S~ 5xCH2)~
4~37(2Hg broad-S, 3-C~2) 4.86(1H, d~ J-4.88Hz, 3~3 6H), 5.53~1H, d, J=4.88Hz, 7-H), 5.48(1H, S, a-H), 6.73t2H, d, J=8.79Hz, 3',5'-phenyl nucleus H), 7 22(2H, d, J=8.79Hz, 2i,6'-phenyl nucleus H) C-NMR( C-DMSO-d6)~ : 15.20(q, -CH3), 26.51(t, 2-C), 35.99;
44.31 (CH2 of imidazolidine nucleus) 37.17(t, -CH2S), 37.81 ; 38.85~t, CH2 ; of dithiolan nucleus), 55.49(d, 6-C), 57.44(d, ~-C) 57.96(d, 7-C~, 114.87 (S, 4-C), 115.26(d, 3'5'-phenyl nucleus), 127.74(d, 2',6'-phenyl nucleus), 128.26 ~S, l'-phenyl nucleus), 133.72(S, 3-C), 151.26(S, ~NCONH), 155703(S, C-N), 162.95(S, 8-C), 164.38(S, -lOONa~
165.42(S, 5'-thiadiazole nucleus), 165.94(S, 2'-thiadiazole nucleus), 170.75(S, imiaazoline nucleus C=O), 181.53(S, -CONH-) Example l9d ~0 Preparation of 7~{D-(-)-a [(2-oxo-3-(1,3-dithiolan-~-imino)-i~nidazolidin-l-yl)-carboxamido~-p-acetoxy-phenylacetamido}-3-r5-methy~ 3~4-thiadiazol-2-yl) thiomethyl]-3-cephem-4-carboxylic acid ~o a suspension of 2 0 g of the compound obtained in Example l9a in 25 ml of water was added 2.7 ml of lN sodium hydroxide to form a solution having a p~ value of 8.0, and 0.6~2 g of acetic anhydride was droppad to the solution with .l~g7~3~

stirring under ice cooling over a period of 40 minutes while maintaining the pH value at 7 to 8 by addition of IN sodium hydroxide. The mixture was stirred under ice cooling for 1.5 hours while maintaining the pH value at 7 to 8. The reaction mixture was filtered and the pH value was adjusted to 2 by 2N
HCL. The precipitated crystal was recovered by filtration, washed with water and dried in a vacuum desiccator to obtain 1.912 g (the yield being 90.3 ~) of the intended compound. The melting point was 160 to 163C ~decomposition).
IR (KBr) cm 1 : vc=O 1760 (lactam), 1720, 1680(ester, amide) NHR(d6-DMSO)~ : 2.~7(3H, S, -~-CH3) 2.69(3H, S, CH3 of thiazole nucleus), 3.63(lOH, broad-S, CH2x5), 4.20 4.50(2H, m, 3-CH2), 5.05(lH, d, J=6Hz~ 6-H), 5.50~5.90(2H, m, 7-~, a-H), 7.17, 7.53(4H, d, J=8Hz, C6H4-) 9.02(1H, d, J=8Hz, -COHN-), 9.55(lH, d, J=8Hz, -CONH-) Example l9e Preparation of phthaliayl 7-{D-(-)--[(2-oxo-3-(1 r 3~
dithiolan-2-iminff)-imidazolidin-l-yl)~carboxamido]
hydroxyphenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate In 10 ml of dimethylformamide was dissolved 1.4g y (2 mi~limoles~ of sodium 7-{D~ [(2-oxo-3-(1,3-dithiolan-2--i~
.
- ~7 -3~

imino)-imidazolidin-l-yl)-carboxamido]-p-hydroxyphenyl-acetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate at room temperature,and 0.014 g of potassium carbonate was added to the solution and the mixture was maintained at 0 to 5C with stirring. Then, 0.47 g (2.2 millimoles) of phthalidyl bromide was added to the mixture and stirrin~ was conducted at the same temperature for 2.5 hours.
The reaction mixture was poured into 500 ml of ice ~ater, and the precipitate was recovered by filtration, washed with water and d~ried in vacuo in a desiccator by phosphorus pentoxide to ob~ain 1.248 g (the yield being 72.98 %) of a crude crystal of phthalidyl 7-{D-(~ (2-oxo-3-(1,3-dithiolan-2-imino)-imidazolid~n-l-yl)-car~oxamido]-p-hydroxyphenylacetamido}-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate. The crude product was purifièd by silica gel column chromatography (developing sol~ent : methanol/chloroform = 1/9) to obtain 0.495 g (the yield being 28.94 %) of a pure product having a melting point of 163C (decomposition).
IR (KBr) cm : 1780(VS),`1720tVS), 1675~S), 1510(S), 1390(S), 1258(S), 970(S) 'H-NMR~DMSO-d6)~ : 2.65(S, 3H, -CH3), 3.19~3.88(m, 12H, CH~x6), 4.99(d, J=6.0Hz, lH, 6-H), 5.33~5.60~m, 2H, ~-H, 7-H~, 6.68, 7.15td, 4Ht J=8.0Hz, C6H4-), 7.33~8.06(m, 5H, H of phthalidyl group), 8.70(d, J=8.OHz, lH, -CONH), 9.25(d, J=8.0Hz, lH, -CONH) ,'~
,. ~

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of novel cepha-losporin represented by the following formula:

(I) wherein R is hydrogen, acyloxy of formula R4COO-, in which R4 is alkyl of 1 to 4 carbon atoms; carbamoyloxy, a pyri-dinium radical of formula in which R6 is hydrogen, alkyl having 1 to 4 carbon atoms, carboxy, lower alkoxy, carbamoyl, halogen or sulfamoyl or a group -S-Het in which Het is and in which R3 is hydrogen or alkyl having 1 to 4 carbon atoms, R' is hydrogen, alkali metal, an organic amine or an ester moiety, R1 and R2 are the same or different and are hydrogen or lower alkyl and B stands for a 1.4-cyclohexadienyl group, a group in which Y is hydrogen, -OH or in which R5 is alkyl having 1 to 5 carbon atoms, or alkoxy having 1 to 4 carbon atoms, Z is hydrogen or halogen and p is an integer of 1 or 2, a fu?an group or a thiophene group, which comprises a) reacting a compound (II) represented by the following formula:
(II) wherein B, R and R' are as defined above with a compound (III) represented by the following formula or a reactive derivative thereof:

(III) wherein R1 and R2 are as defined above, and if necessary, acylating or esterifying the resulting reaction product;
or b) reacting a compound (IV) represented by the following formula:

(IV) wherein R and R' are as defined above, with a compound (V) represented by the following formula:

(V) wherein B, R1 and R2 are as defined above, or a reactive derivative thereof, and, if necessary, acylating or ester-ifying the resulting reaction product; or c) when R represents -S-Het in which Het is as defined in (a), R', R1, R2 and B are the same as defined in (a), which comprises reacting a compound (VI) represented by the following formula:

(VI) wherein R" stands for acyloxy of formula R4COO-, in which R4 is alkyl of 1 to 4 carbon atoms, R''' stands for a hydrogen atom, an alkali metal or an ammonium group, and B, R1 and R2 are as defined above, with a compound VII
represented by the following formula:
M-S-Het (VII) wherein M stands for a hydrogen atom or an alkali metal, and Het is as defined above, and if necessary, acylating or esterifying the resulting reaction product.

2. A process which comprises reacting 1-chloro-carbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine with cephalidine hydrate to give the compound 7-{D-(-)-? -[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin -1-yl)-carboxamido]-(1,4-cyclohexadien-1-yl)-acetamido}-3-methyl - 3-cephem-4-carboxylic acid.

3. A process which comprises reacting 7-[D-(-)-?-amino-4-hydroxyphenyl-acetamido]-3-[(1,2,3-triazol-5-yl)-triomethyl]-3-cephem-4-carboxylic acid with 1-chlorocarbonyl -2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine to give the compound 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)carboxamido]-4-hydroxyphenylacetamido}
-3-[1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid.

4. A process which comprises reacting cephaloglycin with 1-chlorocarbonyl-2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidine to give the compound 7{ D-(-)-?-[(2-oxo-3-(4-methyl-1,3- dithiolan-2-imino)-imidazolidin-1-yl) -carboxamido]-phenylacetamido} -3-acetoxymethyl-3-cephem-4-carboxylic acid.

5. A process which comprises reacting cephaloglycin with 1-chlorocarbonyl-2-oxo(1,3-dithiolan-2-imino)-imidazo-lidine and converting the resulting product into a sodium salt to give the compound sodium 7- { D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolin-1-yl)-carboxamido]-phenylacetamido} -3-acetoxy-methyl-3-cephem-4-carboxylate.

6. A process which comprises reacting 7- { D-(-) - ? -[2-oxo-3-(1,3-dithiolan-2-imino)imidazolldin-1-yl) carboxamido]-phenyl-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid with 5-mercapto-1-methyl-1H-tetrazole and converting the resulting product into sodium 7-{ D(-) - ? -[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido] phenylacetamido} -3-[(-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylate.

7. A process which comprises reacting D-(-)-?- { [2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl]-car-boxamido} -4-hydroxyphenylacetic acid with 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carbo-xylic acid, and converting the resulting product into sodium 7- { D-(-)- ? -[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin 1-yl)-carboxamido]-4-hydroxyphenylacetamido}
-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem--4-carboxylate.

8. A process as claimed in claim 7 which comprises treating the sodium salt with acetic anhydride to give the compound 7-{ D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)carboxamido]-4-acetoxyphenylacetamido)-3 [(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid.

9. A process which comprises reacting 7-[D-(-)-?-aminophenylacetamido]-3-[1,3,4-thiadiazol-2-yl-)thio-methyl]-3-cephem-4-carboxylic with 1-chlorocarbonyl-2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidine and converting the resulting product into sodium7-{ D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido } -3-[1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate.

10. A process which comprises reacting 7-{ D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl]-carboxamido} -phenylacetic acid with 7-amino-3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid to give 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido} 3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid.

11. A process which comprises reacting 7-{D-(-)-?-[(2-oxo-3-(4-methyl-1,3-dithiolan-2-imino )-imidazolidin-1-yl)-carboxamido]-phenylacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid with 5-methyl-2-mercapto-1,3,4-thiadiazole to give 7-{D-(-)-?-[(2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-phenyl-acetamido} -3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid.

12. A novel cephalosporin represented by the follow-ing formula:

(I) wherein R is hydrogen, acyloxy of formula R4COO-, in which R4 is alkyl of 1 to 4 carbon atoms; carbamoyloxy, a pyri-dinium radical of formula in which R6 is hydrogen, alkyl having 1 to 4 carbon atoms, carboxy, lower alkoxy, carbamoyl, halogen or sulfamoyl or a group -S-Het in which Het is and in which R3 is hydrogen or alkyl having 1 to 4 carbon atoms, R' is hydrogen, alkali metal, an organic amine or an ester moiety, R1 and R2 are the same or different and are hydrogen or lower alkyl and B stands for a 1.4-cyclohexadienyl group, a group in which Y is hydrogen, -OH or in which R5 is alkyl having 1 to 5 carbon atoms, or alkoxy having 1 to 4 carbon atoms, Z is hydrogen or halogen and p is an integer of 1 or 2, a furan group or a thiophene group, whenever prepared by the process of claim 1 or its obvious chemical equivalents.

13. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is 7-{ D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)carboxamido]-1,4-cyclohexadien-1-yl)-acetamido}-3-methyl-3-cephem-4-carboxylic acid, whenever prepared by the process of claim 2 or its obvious chemical equivalents.

14. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula(I) is 7-{ D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-1-yl)carboxamido]-4-hydroxyphenylacetamido}-3-[(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid, whenever pre-pared by the process of claim 3 or its obvious chemical equivalents.

15. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is 7- { D-(-)-?[(2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-lyl-)carboxamido]-phenylacetamido} -3-acetoxy-methyl-3-cephem-4-carboxylic acid, whenever prepared by the process of claim 4 or its obvious chemical equivalents.

16. A novel cephalosporin as set forth in c1aim 12, wherein the compound represented by the formula (I) is sodium 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imida-zolin-1-yl)-carboxamido]-phenylacetamido } -3-acetoxymethyl-3-cephem-4-carboxylate, whenever prepared by the process of claim 5, or its obvious chemical equivalents.

17. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is sodium 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazo-lidin-1-yl)-carboxamido]-phenylacetamido}-3-[(1-methyl-1,2,3,4-tetrazol -5-yl)-thiomethyl]-3-cephem-4-carboxylate, whenever prepared by the process of claim 6 or its obvious chemical equivalents.

18. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is sodium 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imida-zolidin-1-yl)-carboxiamido]-4-hydroxyphenylacetamido} -3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxy-late, whenever prepared by the process of claim 7 or its obvious chemical equivalents.

19. A novel cephalosporin derivative as set forth in claim 12, wherein the compound represented by the general formula (I) is 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imidazolidin-1-yl)-carboxamido]-4-acetoxyphenylacetamido}
-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid, whenever prepared by the process of claim 8 or its obvious chemical equivalents.

20. A novel cephalosporin as set forth inclaim 12, wherein the compound represented by the formula (!) is sodium 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)-imida-zolidin-1-yl)-carboxamido]-phenylacetamido} -3-[(1,3,4-thia-diazol-2-yl)-thiomethyl]-3-cephem-4-carboxylate, whenever prepared by the process of calim 9 or its obvious chemical equivalents.

21. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is 7-{D-(-)-?-[(2-oxo-3-(1,3-dithiolan-2-imino)imidazolidin-1-yl)-carboxamido]-phenylacetamido} -3-[5-methyl(1,3,4-thia-diazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, whenever prepared by the process of claim 10 or its obvious chemical equivalents.

22. A novel cephalosporin as set forth in claim 12, wherein the compound represented by the formula (I) is 7-{ D-(-)- ? -{(2-oxo-3-(4-methyl-1,3-dithiolan-2-imino)-imidazolidin-1-yl)carboxamido]-phenylacetamido} -3-[5-methyl-(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid whenever prepared by the process of claim 11 or its obvious chemical equivalents.