CA1305487C - Intermediates for preparing 3-propenylcephem derivatives - Google Patents

Abstract

ABSTRACT

A 3-propenylcephem derivative of the following formula:

wherein R1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A
represents a cyclic or an acylic ammonio group, or a pharmaceutically acceptable salt thereof, exhibiting excellent anti-bacterial activities against both Gram-positive bacteria and Gram-negative bacteria;
Process for the preparation thereof; Anti-bacterial composition; Intermediate for the 3-propenylcephem derivative; and Process for the preparation of the intermediate.

Description

:1 3C~ 7 S P E: C I F I C A T I O N

TITLE OF T~IE INVENTION
-3-Propenylcephem derivative BACKGROiJND OF THE INVENTION
Field of the invention:
The present inven,tion rela-tes to novel cephem derivative useful for anti-bacterial agents. More particularly, the presen-t invention relates to 3-propenylcephem derivative. The present inven-tion also provides process for the preparation of the 3-propenylcephem derivative, anti-bacterial agents, intermediate for the 3-propenylcephem derivative, and process for -the preparation of the intermediate.

Descrip-tion of the prior art:
;
- Cephem deriva-tives having ammonio group have been conventionally known Erom Japanese Patent Appli-cation Laid-open Nos. 174,387/83; 198,490/83; 130,295/84;
172,~93/84; 219,292/84; 97,983/85; 197,693/85, 5,084/86, etc.
ParticuIarly, cephem derivative having an ammonio-propenyl group at the 3~position thereof, similar to the compound of the presen-t invention, have been disclosed in Japanese Patent Application Laid-open ~;~ Nos. 17Z,493/84 and 5,084/86.

, ' : : ~

`.

;~ 305'~

S~MMARY OF TIIE INVF,NTION

The pr~sent inventors have found -that cephem derivative having an ammoniopropenyl group at the 3-position thereof and a Eluoro-substituted lower alkoxyimino group or a cyano-substituted lower alkoxyimino group in a side chain at the 7-position thereof have excellent anti-bac-terial activities, leading to comple-tion of the present invenl:ion.
An object of the present invention is therefore to provide novel cephem compounds useful as anti-bac-terial agents; a process for -the preparation thereof; pharmaceutical composition containing the same;
intermediates for -the derivatives; and a process for the prepara-tion of the intermediates.

DETAILED DESCRIPTION OF THE INVENTION
AND PREFERED EMBODIMENTS

The present invention rela-tes to 3-propenylcephem derivative of the following formula (I):

: ~ C ~ CON~ ,S
~: H2N~S~ ~CH=CHCH2-A (I) O-R, COO-:
:~ wherein Rl represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A
represents a cyclic or acycllc ammonio group, and a : pharmaceutically acceptable salt thereof.

. . , , ~ . , . ~ , .

~l3VS~'7 As illustrative examples of the Eluoro-substituted lower al.kyl group represented by Rl in the formula (1), may be mentioned fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, l-fluoroethyl, 2-fluoropropyl, l-(fluoromethyl)-2-fluoroethyl, 3-Eluoropropyl and the like with fluoromethyl being particularly p~eferred.

Regarding the cyano-subs-titu-ted lower alkyl group represented by R~ in the formula (I), there may be enumerated cyanomethyl, 2-cyanoe-thyl, 3-cyanopropyl, and the like.
As illustrative examples of the acycli.c ammonio group represen-ted by A in the formula (I) may be mentioned a group of the following formula:

N - R

:~ in which R2, R3 and R4 are the same or : different and mean individually a group ~ selected from the group consisting of lower :: :
, ~::

: ~ 3 '~:
: ~ :

; : .

alkyl, hydroxyl-substituted lower alkyl, carbamoyl-substituted lower alkyl, cyano-substituted lower alkyl, amino, (lower alkyl)carbonylamino-substituted lower alkyl, aminosulfonylaminocarbonyl-substituted lower alkyl,--(lower alkyl)sulfonylaminocarbonyl-substituted lower alkyl, (lower alkyl)aminocarbonyl-substituted lower alkyl, hydroxyl- and carbamoyl-substituted lower alkyl, hydroxyl- and hydroxy(lower alkyl)aminocarbonyl-substituted lower alkyl, (lower alkyloxy)aminocarbonyl-substituted lower alkyl, hydroxyaminocarbonyl-substituted lower alkyl, carbamoy.l(lower alkyl)aminocarbonyl~substituted lower alkyl, hydroxy(lower alkyl)aminocarbonyl-substituted lower alkyl, (lower alkyl3amino-substituted lower alkyl, carboxylate(lower alkyl)di(lower alkyl)-ammonio-substituted lower alkyl,di(lower alkyl)amino-substituted lower alkyl, di(lower alkyl)amino- and hydroxyl-substituted lower alkyl, ureido, hydroxyl, carboxyl-substituted lower alkyl, hydroxyl- and carbamoyl-substituted lower alkyl, lower alkyloxy-substituted lower alkyl, di(lower alkyl)amino-' ;
- .
~ ~ 25 ~a~4~!~

carbo~yl-substituted lower alkyl, dicarbamoyl-substituted lower alkyl, : bis[hyd~oxy(lower alkyl)]aminocarbonyl-substituted lower alkyl, dihydroxyl-substituted lower alkyl, trihydroxyl-substituted lower alkyl, bis[hydroxy(lower alkyl)amino-substitu-ted lower alkyl, amino-substituted lower alkyl, oxo-substituted lower alkyl, di-lower alkyl-substituted lower alkyl, 5-membered he-terocycle-substituted lower al.kyl wherein said heterocycle stands for pyrazolyl, imidazolyl, oxadiazolyl or te-trazolyl.

Fur-ther, illustrative of a cyclic ammonio group represented by A in the Eormula (I) may include, for example, a group of the following formulae:
. .

:
S

~: :

..,. : : :

13~5~87 R~ -~N N

~ N~ ~N ~ -\ ~ ~ N~N~

+ ` ~? ~ ~ ~, ~o ,~
Rs ~ / 5 + ~ N~

; ~ in which R5 means a group selec-ted from :~ lower aIkyl, carbamoyl-substituted lower ; :

: :
~;
~; :: ::

~ . , ~L~3Q54~7 alkyl, amino-substituted lower alkyl, hydroxyl-substituted lower alkyl, carboxyl-substituted lower alkyl, cyano-substituted lower alkyl, dihydroxyl-substituted lower alkyl and ureido-substituted-lower alkyl groups, said cyclic ammonio group optionally containing on the ring thereof one or more substituents selected from hydroxyl-substituted lower alkyl, hydroxyl, formyl~ sulfonic, carboxyl-substituted lower alkyl, carbamoyl, sulfamoyl, carboxyl, hydroxyimino-substituted lower alkyl, imino-substituted lower alkyl, bis[hydroxy(lower alkyl)]aminocarboxyl, hydroxy(lower alkyl)aminocarboxyl, amino, morpholinocarbonyl, carboxy(lower alkyloxy)-substituted lower alkyl, carboxy lower alkylthio and lower alkyl groups.

Illustrative of the lower alkyl group in the definition for A (R2 - R5) in the formula (I) : :

: '' ~:
~. .

~3~)54~37 may include alkyl groups having 1 - ~ carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec~butyl and t-butyl.
As non-toxic salts of the compounds of the ~o;-mula (I) may be mentioned their pharmaceutically acceptable salts, for example, alkali metal salts such as sodium salts and potassium salts;
ammonium salts; quaternary ammonium such as tetraethyl-ammonium salts and betaine salts; alkaline earth metal salts such as calcium salts and magnesium salts;
inorganic acid salts such as hydrochlorides, hydro-bromides, hydroiodides, sulfates, carbonates and bicarbonates; organic carboxylates such as acetates, maleates, lactates and tartrates; organic sulfonates such as methanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfonates, taurine salts, benzene-sulfonates and toluenesulfonates; amino acid salts such as arginine salts, lysine salts, serine salts, aspar-tates and glutamates; amine salts such as trimethyl-amine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, N-methyl-glucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts and phenethylbenzylamine salts; etc.

. 8 .~

3~5~1~37 Each of the compounds of the Eormula (I), which pertain to the present invention, has its syn-isomer (2) and anti-isomer (E) with respect to its stereoscopic conEiguration at the following moiety:

-C- ..
N
O -R
~lthough both isomers are included in the present invention, the syn-isomers are desired owing to their antibacterial activitiesO
The compounds of this invention can be produced by the following process.
Namely, the compounds of the formula (I) and their pharmaceutically acceptable salts can individually be obta1ned by reacting a compound, which is represented by the formula (II):

N~rC-CONH~S~
H 1~S~ N~CH-CHCH2~ (II) 2 ' O--R, COOH

; wherein Rl means a fluoro-substituted lower alkyl group or a cyano-substitu-ted lo~wer alkyl group, and X denotes a halogen atom, a compound wherein the amino and/or carboxyl groups are protected with protecting group(s), or a salt thereof wi-th a compound represented : by the formula (III):

A' (III) g - . ' ' :
:

~3~S~L15~7 wherein A~ mea~ls an amlne corresponding to A a compound wherein the functional group(s) are protec-ted with protec-ting group(s) or a salt thereof; followed by optionally removing the protecting group(s).
As halogen atoms represented by X in the above Eormula (II) may be mentioned iodine a tom bromine atom and chlorine ~tom.

The above reaction may be carried out at a reaction temperature of -10C - 60C,preferably, 0C
- 40C. ~s a reaction solvent, an anhydrous organic solvent is desired. As usable organic solvents, may be mentioned lower alkylnitriles such as acetonitrile and propionitrile; halogenated lower alkanes such as chlorornethane, dichioromethane and chloroform; ethers such as tetrahydro~uran, dioxane and ethyl ether;
amides such as dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarhons such as benzene; alcohols such as methanol and ethanol; and sulfoxides such as dimethylsulfoxide; as well as mixed solvents thereof.
The removal of the protecting group(s) may be carried out by a method known per _ in the art in accordance with the kind(s) o~ the protecting grou~?(s) used, such as hydrolysis or reduction.
As the salts of the compounds of the formulae (II) and (III) and the protecting groups for , 10 54~

the compounds, those employed routinely may also be used SQ long as they do not impair the above reaction.
Exemplary protecting groups for the amino group may include formyl group, acetyl group, chloroacetyI
group, dich]oroacetyl group, phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxy-carbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group, benzylidene group, p-nitro-benzylidene group and m-ch]orobenzylidene group. As illustrative protecting groups for the carboxyl group, may be mentioned p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, 2,2,2-trichloro-ethyl group, diphenylmethyl group and pivaloyloxymethyl group. Here, use of a silylating agent such as N,O-bis(trimethylsilyl)acetamide, N-methyl-N-(trimethyl-silyl)acetamide, N-methyl-N-(trimethylsilyl)trifluoro-acetamide or N-(trimethylsilyl)acetamide is convenient because such a silylating agent can protect botil amino and carboxyl groups at the same time.
As salts of the compounds of the formulae (II) and (III), suitable selection may be made from their salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts;
ammonium salts; quaternary ammonium salts such as triethylammonium salts and betaine salts; inorganic - ' 13(15~37 acid salts such as hydrochlorides, hydrobromides, sulfates, carbonates, hydroiodides and bicarbonates;
organic carboxylates such as acetates, trifluoro-acetates, maleates, lactates and tartrates; organic sulEonates such as rnethanesulEonates, hydroxymethan.e-sulEonates, hydroxyethanesulfollates, taurine salts, benzenesulfonates and toluenesulfonates; amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline sa].ts, di.cyclohexylamine salts, N,N'-dibenzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, trlethanolamine salts, tris(hydroxymethylamino)methane salts and phenethylbenzylamine salts; amino acid salts such as arginine salts, aspartates, lysine salts, glutamates, serine salts and glycine salts; etc.
The compounds of this invention show strong antibacterial activities against both gram-positive and gram-negative bacteria and are hence useEul as anti-bacteria1 agents. The compounds are used ~or treating a disease caused by bac-teria.
When using the compounds of this invention as injections, they may be administered generally at a daily dose o~ 100 mg - 10 g in 1 - 4 portions either intravenously or intramuscularly. Meedless to say, the dose may be increased or decreased depending on the age and conditions of disease.
Their injections may be produced by a method :13~5~L~3'7 known ~ se ln the art. For example, each compound of this inventioll may be formulated into an injection by dissolving same in distilled water, if necessary, in the presence oE an isotonic agent, solubilizer and/or the like. They may each be filled as powder in a vial or the like, thereby providing injections which require dissolution before use. These injections are hence dissolved in distilled water for injection, physio-logical saline, glucose injection, amino acid infusion or the like upon administration.
A compound of the above-mentioned formula (II) i.e. an lntermedia-te; a compound wherein the amino and/or carboxyl group(s) are protected with a protective group; or salts of these compounds are all novel compounds.
These compounds can be prepared by the following process.
That is -to say, the compounds can be prepared by reacting a compound oE -th~ formula:

N \\ C - COOH
J ~ / N (IV) H2N S ~O - Rl wherein Rl has the same meanings as mentioned above, a reac-tive acid derivative thereof, a compound wherein an amino group is protected wi-th a protective group or ; a salt of the compound with a compound of the formula:

~ 13 :

13~5~8'7 (V) O ~-- ~ \
C~l = C~IC~l2X
COOH

wherein X has the same meanings as defined above, a compound wherein a carboxyl group is protected with a protective group, or a sal-t thereof, followed by optionally removing the pro-tective group, and/or convertin~ a halogen a-tom represented by -the symbol X
into the o-ther halogen atom.
The above-mentioned reaction can be conducted in accordance with a conventional reaction condition for an N-acylation. ~or example, the reaction can ke carried out at a temperature from -50C to 50C in an inert solvent such for example as tetrahydrofuran, ethyl acetate, acetone, N,N-dimethyl formamide, acetnitrile, dioxane or a mixed solvent thereof.
As for a reactive acid derivative of -the compound of the formula (IV), there may be exemplified an acid halide such as acid chloride, acid bromide, etc.
symmetrlcal acid anhydride, a mixed acid anhydride, ~ ~ an active ester, an active acid amide, and the like.
: When a free carboxylic acid of -the formula ~IV) or a salt thereoe is used in the reaction, it is preferable to conduct the reaction in -the presence of :a conventional condensing agent such as N,N'-:~ ~
~ 14 , .

~3~ '7 dicyclohe,Yylcarbodiimide, p-tuluene sulfonic acid, and the like, for example.
The conversion of a halogen atom represented by X into the other halogen atom is carried out in a conventional manner. For example, -there can be prepared a compound of the formula (II) wherein X
represents iodine atom, when a compound of the formula (II) wherein X represents chlorine atom is reacted with an alkali metal iodide.
Further, the intermediates of -the under-men-tioned formula (VI) are also novel compounds, such as a compound of the formula:

N \\ C -- 6 ~ N N ( VI ) wherein R6 represents carboxyl group, a halogenocarbonyl ~roup, carbamoyl group, or cyano group, a compound wherein amino and/or carboxyl group(s) are pro-tected with a pro-tective group, or a salt thereof.
Illus-trative oE protec-tive grloups for -the amino qroup and the carboxyl group may include a similar group as exemplified in the compound of -the formula (II).
The above-mentioned compounds can be prepared by ~ the following exemplary process.

:

: :
, :

.

3(~5~t7 OH (VII ) H 2 N S ~ ~ ( X I V ) NC - C - CONH 2 .
N

~ OCH E~ ~ VIII ) NC - C - CN - N ~CI --COX
N ( IX ) H2N ~OCH2F
~ OCH2F ,~ ( X: halogen atom ) / (XV) `~ . ~ ~ /
N ~ COOH

H 2 N \ C C C N H 2 N ~S / \ ( X I I I ) ; HN N (X) . OCH2F
\ OCH2F / ~
: .

f ~\S / N\

~ C CN /~7 ( X I I ) H2N S" N
: \OCH F

; : ( XI ) :::

:~ :
o :

' ~ `
.

13~ t~

The compound of the formula (VIII) can be prepared by reacting a compound of the formula (VII) with a halogeno fluoromethane in an inert solvent.
As the halogeno fluoromethane, there may be exempliied bromo fluoromethane, iodo E]uoromethane, and the like.
The reaction is 'carried out a-t a tempera-ture ranging rom -30C to 100C.
The compound of the formula (IX) can be prepared by reacting a compound of the formula (VIII) with a dehydrating agent in an inert solvent. As the reaction tempera-ture, it is preferable to use room tempera-ture or above. A dehydrating agent may include oxyphosphorus chloride, thionyl chloride, etc.
The compound of the formula (X) can be prepared by reacting -the compound of the formula (IX) with ammon1a and/or ammonium salt in an inert solvent such as wa-ter, a lower alcohol, acetone, chloroform, etc.
Suitable reaction temperature may range from -20C to room temperature. Ammonium salt may include ammonium chloride, ammonium aceta-te, ammonium sul.fa-te, and the like.
:
The compound of the formula (XI) can be prepared by reacting tbe compound of the formul2 (Xj with a halogenatina agent such as gaseous bromine, gaseous chlorine, etc. to effect t~e halogenation, follo.~ed ~ 7 ;~ .
.
'. :: ' : ~- :

' ' , ' - ~ :

.

~3~5~ 7 by reacting it with an allcali metal thlocyanate, pre-ferably in the presence of a base. Suitable reaction temperature may range from -20C to room temperature. As an alkali metal thiocyanate, -there may be used potassium thiocyanate, sodium thiocyanate, and the like.
A compound of thé formula (XII), a compound wherein amino group is protected with a protective group, or a salt -thereof can be prepared by hydrolyzing a compound of the formula (XI), a compound wherein amino group is protected with a protective group, or a salt thereof in -the presence of an oxydizing agent and a base, followed by optionally removing the protective group.
The reac-tion can be carried out at a reaction temperature of from 0C to 70C in water, a buffer solu-tion or a mixed solvent of the former with a lower alcohol.
There may be used hydrogen peroxide, oxygen, etc.
; as an oxydizing agent; and sodiurn hydroxide, po-tassium hydroxide, etc. as base.
A compound of the formula (XIII), a compound wherein amlno group is pro~-tected with a protective group, or a salt thereof can be prepared by hydrolyzing a compound of the formula (XII), a compound wherein amino group is ~; protected with a pro-tective group, or a salt thereof ; in -the presence of a base, followed by op-tionally removing the protective group.

~: .

, .. ~

, 13~'S4~'7 Tlle types of the base, solvents, the reaction tempera-tures, etc. may be the same as those described in -the reaction sequence from the compound of the formula (XI) to that of the formula (XII).
Fur-thermore, a compound of the formula (XIII), a compound wherein amino group is protected with a protec-tive group, or a salt thereof can be also prepared by reacting a compound of the formula (XIV) wherein amino and/or carboxyl group(s) are protected by a pro-tected group, with a halogeno fluorome-thane, followed by optionally removing the protective group.
The halogeno fluoromethane may indlude bromo fluoromethane, iodo fluorome-thane, chloro fluoro-methane.
The reaction can be carried out in an inert solvent at a reaction temperature ranging from -30C to 100C.
Illustrative examples of the inert solvent to be used may include sulfoxides such as dimethyl sulfoxlde, etc., amides such as N,N-dimethylacet-amide, for~amide, hexamethylphosphoryl triamide, etc., ke-tones such as ace-tone, etc., or a mixed solvent thereof.
; :: :

. :
, ~: :
~, ' ~ ~ ' ' : - ' . :
' .

, ~3~4~

A compound of the Eormula (XV)~ a compound wherein arriino group i~s protected with a protec-tive group, or a salt thereof can be prepared by reacting a compound of the formul.a (XIII), a compound wherein amino group is protected with a protective group, or a salt thereof with a halogena-ting agent.
Illustra-tive examples of the halogenating agent may include phosphorus pentaoxide, thionyl chloride, -thionyl bro~ide, oxyphosphorus chloride, and the li!ce The above reaction can be carried out in an inert solven-t such for example as dichloromethane, te-tra-hydrofuran, ethyl acetate, chloroform or a mixed solvent thereof at a reaction temperature of from -50C to 50C.
The present invention will next be descri.bed : in fur-ther de-tail by the followina Experiments and ~xamples.

~ ' :: :
~ .
; 20 ~ .

~ .

~ :L3~ '7 Experiment l (Synthesis of` the raw material compound) Ethyl 2-(5-tritylamino-1,2,4-thiadiazol-3~yl)-(Z)-2-fluoromethoxyi~ino acetate @~- CHN~ COOC2Hs \OCH2 F

Ethyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(z)-2-hydroxyimino acetate (60.4 g) was dissolved in dimethyl sulfoxide (210 ml), and then potassium carbonate (96.1~8g) was added thereto under ice-cooling. The solution was stirred for lO minutes.
Thereafter, bromofluoromethane (19 g) was added thereto, and the solution was stirred for 3 hours at room temperature.
Ethyl acetate (1 liter) was added to the reaction solution and the solution was washed with water and then with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off, and ethanol (120 ml) was added to the residue. Crystals deposited were collected by filtration, and washed with ethanol to obtain the object ~; product (58.2 gj.

Experiment 2 (Synthesis of the,raw material compound) 2-(5-Tritylamino-lJ2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyimi~no acetic acid : ~ ~

:
;: :

~HN~ 5 ~ ~
~ `OCH2F

Into a mixed solution contai.ning sodium hydroxide (2.04 g), ethanol (146 ml) and water (29 ml) was added the compound (17.87 g) prepared in Experiment 1, and the solution was stirred for 20 minutes under reflux. After the soluticn was concentrated under reduced pressure, ethyl acetate (.200 ml) and lN hydro-chloric acid (77 ml) were added thereto. The ethyl acetate layer was separated to collect and washed with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off to obtain crystals. The crystals were crushed with addition of petroleum ether, and then recovçredby filtration to obtain the object product (16.55 g).

Experiment 3 (Synthesis of the raw material compound) p-Methoxybenzyl 7~-[2-(5-tritylamino-1,2,LI-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido~-3-~(Z)-3-chloro-l-propen-l-yl]-3-cephem-4-carboxylate C-CONH~S,~Cl bCH2F -IOOCH2~0CH3 - :
, .

.

~3~
Dime-thyl~ormamide (348 ~1) and tetrahydrofuran (4.1 ml) were cooled to -10C, and phosphorus oxychloride (418~1) was added thereto, and stirred for 90 minutes under ice-cooling.
To this solution was added a solution of the compound (1.73 g) prepared in Experiment 2 in tetrahydrofuran (5.5 ml) with cooling to -10C, and the resulting solution was stirred for 90 minutes under ice-cooling. The reaction solution was cooled to -20 C,and a mixed solution containing p-methoxyben 7~-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (1.78 g), N-(trimethylsilyl)acetamide (2.95 g), ethyl acetate (18 ml) and tetrahydrofuran (5.5 ml) was added thereto, and the resulting solution was stirred for one hour at -10C. To the reaction solution was added ethyl acetate (100 ml), and the resulting solution was washed succesively with water, a saturated aqueous sodium hydrogencarbonate and a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the object product (2.65 g).

::
Experiment 4 (Synthesis of the raw material compound) p-Methoxybenzyl 7~-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido~-3- t(E)-3-iodo-l-propen-l-yl~-3-cephem~4-carboxylate , ~; ~ 23 ::
:

.

L3(?~L8 C - CONH S
~N'~N ~F~, I
~D ~OCHzF (~OOCH2~0CH3 The compound (10.11 g) prepared in Experiment 3 was dissolved in acetone (212 ml), and sodium iodide (9.03 g) was added thereto under ice-cooling. The resulting solution was stirred for 15 minutes under ice-cooling and for additional 90 minutes at a room temperature. The solvent was distilled off, and the residue was extracted with ethyl acetate (500 ml). The extract was washed with a saturated aqueous sodium thiosulfate solution and with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure and n-hexane was added thereto. The resulting precipitates were collected by filtration to obtain the object product (10.92 g).
.
Experiment 5 (Synthesis of the raw material compound) p-Methoxybenzyl 7~-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-difluoromethoxyiminoacetamido)-3-~(Z)-3-chloro-l-propen-l-yl]-3-cephem-4-carboxylate N~C-CONH~CI
'OGHF2 OOCH2 ~OCH3 S~'7 In the sarne marlller as described in Experiment 3, 2-(5-tritylamino-1,2,~l_thiacliazol-3-yl)-(Z)-2-difluoromethoxyimino-acetic acid (2.00 g) was reacted with p-methoxybenzyl 7~-arnino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephein-4-carboxylate hydrochloride (1.795 g) to obtain the object product (3.17 g).

Experiment 6 (Synthesis of the raw material compound) p-Methoxybenzyl 7~~[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-difluoromethoxyiminoacetamido)-3-~(E)-3-iodo-l-propen-l-yl]-3-cephem-4-carboxylate ~) C-CON~I S
~(~HN~S~
\OCHFz COOCHz~OCH~

In the same manner as described in Experiment 4, the compound (3.00 g) preapred in Experiment 5 was reacted with sodium iodide (2.62 g) to obtain the object product (2.92 g).

Example 1 7~G'-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamidoJ 3 t(E)-3-(carba~oylmethyl-ethylmethylammonio)_l-propen_l_yl]-3-cephem-4-carboxylate ~ 25 :~

~ ~3~1S~

~C-CONH ~ S `, I
H2N~S' N ~ N~ I~CONH2 \O-CH2F COO- CH3 The compound (550 mg) prepared in Experiment 4 was dissolved in a mixed solution containing ethyl acetate (20 ml) and ethyl ether (lO ml), and then ethylmethylamino-acetamide (117 mg) was added thereto. The resulting solution was stirred at room temperature for 4 hours and 30 minutes.
Isopropyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration and dried to obtain the yellowish brown powder (400 mg).

The powder was stirred in a mixed solution of trifluoro-acetic acid (4.5 ml) - anisole (4 ml) for one hour under ice-cooling, and ethyl ether was added thereto. The resulting precipitates were collected by filtration and washed with ethyl ether. The precipitates were suspended in water (5 ml). The suspension was adjusted to pH 5.5 - 6.5 with sodium acetate. Insolubles were removed by filtration, and the filtrate was purified by reversed phase chromatography to obtain the object product (49 mg).

~xample 2 7~-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(E)-3-[1-(2-hydroxyethyl)-4-carbamoyl~l-piperidinio]-1-propen-1-yl]-3-cephem-4-carboxylate .

, ~ .

-3~3~S~7 0~1 ,,~C-CONH ~ S
HzN S N ~G~/N~CO~Hz \O-C~T~F COO-The compound (700 mg) prepared in the Experiment 4 was dissolved in dimethylformamide (3 ml), and a solution of 1-(2-hydroxyethyl)isonipecotamide (194 mg) in dimethylformamide (0.5 ml) was added thereto. The solution was stirred overnight.
The reaction solution was added to ethyl ether (120 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (680 mg).
To this powder was added anisole (4.5 ml), and trifluoro-acetjc acid (5.3 ml) was added drop by drop over 30 minutes with stirring under ice-cooling. After the dropping was completed, the mixture was stirred for additional one hour and 30 minutes.
To the reaction solution was added isopropyl ether (50 ml), and ; ~ the resulting precipitates were collected by filtration.
The precipitates were suspended in water (30 ml), and the suspension was adjusted to pH 7.0 with sodium acetate. The result:ing insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the following two types of isomers of the subject compound: -~; Isomer (2-1) 21 mg Isomer (2-2) 20 mg ~ 1 Mixture of the two isomers 50 mg : ~: 27 :

~3~ '7 Example 3 7~-[2-(5-Amirlo-1,2,4-thiad.iazol-3-yl)-(Z)-2-fluorom~thoxyiminoacetamido3-3-~(E)-3-~lS-carbam~ylethyl~
dimethylammonio]-1--PrPen-l-yl~-3-cephem_~_carboxylate (3-1) rC-CONH ~S CH3CH~
H~N ~ ll ~ N ~J ~'`.'N ~ CONH2 \OCH2F COO~ dH3 7~-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoximino-acetamido]-3- L( E)-3-[(lR-carbamoylethyl)dimethylammonio]-l-propen-l-yl~-3-cephem-4-carboxylate (3-2) C-CONH ~ 9~ OH

\OCH2F COO- dH3 ~ ' The compound (600 mg) prepared in Experiment 4 was dissolved i.n a mixed solution con~aining ethyl acetate (20 ml) and ethyl ether (10 ml), and then 2-dimethylaminopropylamide (150 mg) was added thereto. The resulting solution was stirred for 3 hours at room temperature. Isopropyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration, followed by drying to obtain yellowish brown ;

~ powder (50 mg).

. ~

~ ~ 2~

,~ ., : .

:~3~ 7 This powder was stirred in a mi,ced solution containing trifluoroacetic ~cid (5.5 n~l) and anisole (5 rnl) for one hour under ice-cooling and, thereafter, ethyl ether was added thereto.
The resulting precipitates were collected by filtration and washed with ethyl ether. The precipitates were suspended in water (5 ml), and the suspension was adjusted to pli 5.5 ~ 6.5 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purif~ied by reversed phase silica ~el column chromatography to obtain the object products of 8 mg of the (3-1), 7 mg of the (3-2), and Ll mg of the mixture (1:1) of the (3-1) and the (3~2).

Example 4 7~-[2-(5-A~ino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamidO~-3-~(E)-3- ~(2-hydroxypropyl) dimethylammonio]-l--propen-l-yl]-3-cephem-4-carboxylate N ~\ C--CONH~ ~S~ ~ I OH
H2N'4S~ 11 ~N~N~
\OCH2F COO- CH3 CH3 The compound (550 mg) prepared in Experiment Ll was dissolved I in a mlxed solution containin~ ethyl acetate (20 ml) and ethyl ether (10 ml), and then 3-dimethylamino-2-propanol (0.124 ml) .
was added thereto. The resulting solution was stirred at room temperature ~or one hour and 30 minutes. Isopropanol was 2~

~3~f~7 added to the reactiotl solution. The resulting preclpitates wer-e collected by filtration and dried to obtain y~llowish brown powder (530 mg).
This powder was stirred in a mixed solution containing trifluoroaceticacid (5.5 ml) and anisole (5 ml) for one hour under ice-cooling. Thereafter, ethyl ether was added thereto.
The resulting precipitates were collected by filtration and washed with ethyl ether. ~The precipitates were suspended in water (5 ml). The suspension was adjusted to pH 5.5 - 6.5 with sodium acetate. Insolubles were removed by filtration and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (70 mg).

Example 5 7~-C2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamidO~-3- ~(E)-3- ~(lR-carbamoyl-2-hydroxyethyl)dimethylammonio]-1-propen-1-yl]-3-cephem-4-carboxylate ~C-CONH S I H3 OH
H2 ~S ' N ~_,~ N ~H
\OCH2 F ~OO- bH CONH2 The compound (1.00 g~ prepared in Experiment ll was dissolved ::

~: :
: :~
~ ~ ~ 3 ~ ~:

~ ~ '.' . ' .

~3~ 37 in dimetllylformaide (2 ml). A solution of ~ dimethyl-D-serinamide was prepared by dissolving N,N-dimethyl-D-serinamide trifluoroacét~te (590 mg) in methanol (5 ml), adding lN-aqueous sodium hydroxide solution (2.4 ml) thereto, followed by distilling off the solvent under reduced pressure,~and extractir;g the residue with acetonitrile (2 ml). The N~N-dimethyl-D-serinamide solution was added to the solution of the compound prepared in Experiment 4 in dimethylformamide under ice-cooling. Th2 resulting solution was stirred for 30 minutes. The reaction solution was added to ethyl ether, and the resulting precipitates were collected by filtration to obtain yello~ powder (1.1 g).
To this powder was added anisole (8 ml), and trifluoroacetic acid (9 ml) was dropped over 30 minutes with stirring under ice-cooling, followed by stirring for additional one hour and 30 minutes. Ethyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration.
The precipitates were suspended in water (10 ml). The suspension was then adJusted to pH 7 with sodium acetate.
The isolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (30 mg).

Example 6 7~-[2-(5-Amino-1,2,4-thi,adiazol-3-yl)-(Z)-2-fluoromethoxyiminoace~amido~-3-~(E)-3-(4R-hydroxy-2R-hydroxymethyl-l-methyl-l-pyrrolidinio)-l-propen-l-yl]-3-cephem-il-carbOxylate ~: :
;: ::

~: :

.

'7 N\\ C-CONH ~ \ r H2N~Sy 11 ~ N ~ , OCI-12F (~00- , CH~OH

The compound (700 mg) prepared in E~periment 4 was dissolved in acetone (4 rnl),and a solution of N-methyl-cis-LI-hydroxy-D-prolinol (89 mg) in acetone (2 ml) was added thereto. The resulting solution was stirred overnight. The reaction solution was added to ethyl ether (100 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (700 mg).
To this powder was added anisole (4.5 ml), and trifluoro-acetic acid (5.3 ml) was dropped over 30 minutes with stirring under ice-cooling, and stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (50 ml). The resulting precipitates were collected by filtration.
The precipitates were suspended in water (30 ml), and the suspension was adjusted to pH 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the following two types of isomers (relating to a nitrogen atom of pyrrolldine):

Isomer (6-1) 27 mg Isomer (6~2) 100 mg ~; :
~ ~ 32 .:;; :

~.

`-~13~5~

Example 7 7~-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(E)-3[4R-hydroxy-1-(2-hydroxyethyl)-2S-hydroxymethyl-1-pyrrolidinio]-1-propen-1-yl]-3-cephem-4-carboxylate OH
C-CONH ~ S ~ OH
H2 N~ 11 ~ N ~ N~J
\ OCH2F COO- ~
C~ OH

The compound (2.0 g) prepared in Experiment 4 was added to a solution containing (R)-4-hydroxy-1-(2-hydroxyethyl)-(S)-2-hydroxymethylpyrrolidine (450 mg) in dimethylformamide (5 ml). The resulting solution was stirred overnight. The reaction solution was added to ethyl acetate. The resulting precipitates were collected by filtration to obtain yellow powder (1.65 g).
, :
~ To the powder was added anisole (10 ml~, and then ; trifluoroacetic acid (11.7 ml) was dropped over 30 minutes with stirring under ice-cooling, and further stirred for ~ additional one hour and 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting ~; ~ precipitates were collected by filtration. The precipitates were suspended in water (4.5 ml), and the suspension was adjusted to pH 7 with sodium acetate. ~he insolubles were removèd by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to :
~ ~ 33 :

~: ~

ol)tain two l;ypes of the isorners (relating to a nitrogen atom of pyrrolidine) of` the subject compound as follows:

:[somer (7-1) 96 mg Isomer (7-2) 207 mg Example 8 7~-[2~(5-l\mino-1,2,LI-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoa~etamido~-3-t(E)-3-(4R-hydroxy-2s-hydr methyl-l-methyl-l-pyrrolidinio)-l-propen-l-yl]-3-cephem-4-carboxylate CH3 ,~OH

H2N S N ~ ~ ~
\OC~ F COO~ CH2OH

The compound (700 mg) prepared in Experiment 4 was dissolved in acetone (4 ml), and a solution of N-methyl-trans-4-hydroxy-L-prolinol (89 mg) in acetone (2 ml) wa`s added thereto, and the resulting solution was stirred overnight. The reaction solution was added to ethyl ether (100 ml), ancl the re~sulting precipitates were collected by f~iltration to obtain yellow powder (700 mg).
To the powder was added anisole (4.5 ml), and trifluoro-acetic acid (5.3 ml) was dropped with stirring under ice-cooling over 30 minutes, and then the mixture was stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (50 ml), and the resulting precipitates were collected by filtration. The precipitates were then suspended ~:

::
' . ' ' .

-:

in water (30 rnl). The s~lspension was acljusted to p~l 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object compound (92 mg).

E~ample 9 7~-[2-(5-Arnino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido~-3-~(E)-3-(1-carbamoylmethyl-3-hydroxy-l-pyrrolidinio)-l-propen-l-yl]-3-cephem-4-carboxylate ~N ~ C CON ~ ~ ~ ~ OH

'OCE~2~ COO

The compound (1.0 g) prepared in Experiment 4 was dissolved in dimethylformamide (4 ml), and a solution of N-carbam methyl-3-hydroxypyrrolidine (186 mg) in dimethylformamide (2 ml~
~was added thereto. The resulting solution was stirred overnight.
The reaction solution was addedto ethyl ether (200 ml). The resulting precipitateg were collected by filtration to obtain yellow powder (970 mg).
To the powder was added anisole (9.0 ml), and then trifulooroacetic acid (10.6 ml) was dropped over 30 minutes with stirring under ice-cooling. The mixture was further stirred for additlonal one hour and 30 minutes. To the reaction solution :: : :

:: :
:
~",..,:

was added isopropy~. ether (80 ml), and the resulting precipitates were collectdd by filtration. The precipitates were suspended in water (50 ml). The suspension was adjusted to pH 7 with sodium acetate. The i.nsolubles were removed by filtration1 and the filtrate was purified by reversed phase silica gel column chromatography to obtain the respective types of isomers (relati.ng to a nitrogen atom, and carbon atom on the 3-position of pyrrolidine, and there are four types on high pressure liquid chromatography) of the subject compound as follows:
Isomer (9-1) 71 mg (mixture of two types) Isorner (9-2) 70 mg (sihgle material) Isomer (9-3) 54 mg (single material) Example 10 7~-~2-(5~Amino-1,2,4-thiadiazol-3 yl)-(%)-2-fluoromethoxyiminoac2tamido~-3-~(E)-3-tl-m~thyl-4 sulfo-l-piperazinio)-l-propen-l-yl]-3-cephem-4-carboxylate ~ \~ C-CONH ~ S~ ~r-~
H2N ~ S~ N ~ N ~ ~_~N~_~N-SO3H
\OCH2F 00-:
The compound (2.0 g) prepared in Experiment 4 was added to a mixed solution containing 4-methylpiperazinosulfonic acid I sulfate (718 mg), N-methyl-N-(trimethylsilyl) trifluoroacetamide (2 ml) and dimethylformamide (6 ml), and the rFsulting solution ' ...~,:

~ ~3~
was stirred overnight. To the react;ion solution was added methanol (2 ml), and the insolubles were removed by filtration.
The filtrate was added to a mixed solution containing ethyl acetate (50 ml) and ethyl ether (50 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (1.79 g).
To this powder was added anisole (10.9 ml), and trifluoro-acetic acid (12.7 ml) was dropped over 30 minutes with stirring under ice-cooling. The resulting solution was further stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (100 ml), and the resulting precipitates were collected by filtration. The precipitates were suspended in water (4.5 ml), and the suspension was adjusted to pH 7 with sodium acetate. Insolubles were removed by filtration and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (50 mg).

~ Example 11 ;~ 7~-[Z-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-~fluoromethoxyiminoacetamido~-3--~(E)-3-(1-carbamoylmethyl-4-hydroxy-1-piperidinio)-1-propen-1-yl~-3-cephem-4-carboxylate :
: : 'CON~2 ,~Cj-CONH~S~ N/~OH
Hz~l~ S N : d-\ OCH2F COO-:

~ ` 37 : : :

~3~
The compound (1.0 g) prepared in Experiment 4 was dissolved in acetone (9 ml), and N-carbamoylmethyl-4-hydroxypiperidine (206 mg) was added thereto. The solution was stirred overnihgt. The reaction solution was added to a mixedsolution (lO0 ml) containing ethyl ether and isopropyl ether (2:1), and the resulting precipitates were collectecl by filtration to obtain yellow powder (l.0 g).
To this powder was added anisole (9.0 ml), and trifluoro-acetic acid (10.6 ml) was~dropped over 30 minutes with stirring under ice-cooling, and the resulting solution was further stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (80 ml), and the resulting precipitates were collected by filtration. The precipitates were suspended in water (5 ml)~ and the suspension was adjusted to pH 7.0 with sodium acetate. Insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (166 mg).

Example 12 7~-[2-(5-Amino-l,2,4-thiadiazol~3-yl)-(Z)-2-fluoromethoXYiminoacetamido~-3-~E)-3-(S~aza-l-methyl-2,8-dioxabicycloC3.3.1~nona-5-io)-1-prlopen-1-yl)-3-cephem-4-carboxylate N C-CONH , ~ S ~ --o H~N~ S~ N ~L N~ ~CH3 OCH2F COO- ~' 3~
: ~ :

.

The compound prepared in Experirnent 11 was dissolved in d~methylformamide (10 ml), 5-aza-]-methyl-2,8-dioxabicyclo [3.3.1]nonane (800 mg) was added theretc at room temperature.
The resulting solution was stirred for 20 minutes. ~he reaction solution was diluted with ethyl acetate (25 ml) and the solution was added to ethyl ether to obtain brown precipitates (3.85 g).
The precipitates were dissolved in anisole (23 ml), and tr:ifluoroacetic acid (26 ml) was added thereto uncler ice-cooling.
The solution was stirred for 30 minutes at the same temperature.
Ethyl ether was added to the reaction-solution, and resulting precipitates were collected by filtration. The precipitates were suspended in water (40 ml), and the suspension was adjusted to pH 7.0 with sodium acetate. Insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product ( L108 mg).
In the same manner as described in the Examples 1 - 12, the following compounds in Examples 13 - 113 were preapred:

~ C-CONH S
HN ~ S~ N ~ ~ I

OCH2F COOCH2 ~ OCH3 (compound in Experiment 4) : ~ A' (amine corresponding to A) ~ . :

~ H2N ~ N ~ ~ A
\OCH2F COO--: :
:

:~3C~
~ 'lur~ Lsomers may be formed due to the portion of ammonio group on A. When these isomers were separated~ the respective yields were shown for the respective isomers individually..
The following abbreviations were used:
Boc: t-butoxy carbonyl group t~u: t-butyl group Bh: benzhydryl group .
Tr: trityl group ~: : : : :
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` ~3~54~'7 ple 114 7~-~2-(5-~mino-1,2,4-thi?~-liazol-3-yl)-(Z)-2-di~luoromethoxy-iminoacetamido~-3,~(E)-3-(dirnetllylcarbamoylmethylammonio)-1-propen-l-y]~-3-cep~em-4-carboxylate N ~ C - CONH ~ ~S ~7H3 2 ~ C~I3 The compound (500 mg) Or Experiment 6 WaB dissolved in a mixed solution Or ethyl acetate (10 ml~ and ethyl ether (10 ml). To the solution was added dimethylglycine amide (160 mg), followed by stlrring for 30 minutes at a room temperatureO To the reaction solution was added iso-propyl ether. The resulting precipitate was recovered by filtration, and dried to obtain yellowish brown powder (400 mg)0 This powder was stirred under an lce-cooling in a mixed ~olution Or trlrluoroacetic acid (5 ml) and anisole (4.5 Dll) for one hour. To the reaction solu-tion was added ethyl ether, and the resultlng precipitate was recovered by riltration, rollowed by washing with ethyl e~ther, This precipitate was suspended in water (5 ml), followed by adJusting its pH to 505 - 605 with sodium acetate, The insolubles were removed by filtration, and the riltrate was puriried through a reversed pha~e silica gel chromatography to obtain the obJec~t product (55 mg).
I~ the same manner as described in Example 114, there were produced the compounds of' the f`ollowing Examples 115 - 117.

~ . .

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' :~3~:~S~8'7 Experiment 7 (Synthesis of Raw Material Compound):
p-methoxybenzyl jB- ~2~(5-tritylami.no-102,4-thiadiazol-3-yl)-(Z),2-[2,2,2-trifluoroethyl)oxyiminoacetamido3-3- L(Z)-3-chloro-1-~ropen-1-yl~3-cephem-4-carboxyla-te:

~ N \~-C--CON~ S e ~S~
OCH2CF3 ~2~0CEI;

A mix-ture solution comprising dimethylformamide (0.247 ml) and -tetrahydrofuran (3 ml) was cooled to -10C, and phosphorus oxychloride (0.297 ml) was added thereto and stirred for 40 m.inutes wi.th ice-cooling. To the resulting solution was added the tetrahydrofuran solution (4 ml) of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetic acid (1.36 g), followed by stirring for fur-ther one hour at the said temperature.
The resulting reaction solu-tion was added to a mix-ture solution comprising p-methoxybenzyl 7B-amino-3- t(Z)-3-chloro-l-propen-l-yl~-3-cephem-4-carboxylate hydrochloride (1.145 g), N-(tri.methylsilyl)acetamide (2.09 g) and ethyl acetate (10 ml), with cooling at -20C, followed by e]evating the temperature up to 0C with s-tirring for one hour. After ethyl acetate was added to -the reaction solu-tion, this was washed : ~ :
~ with water and dried with anhydrous sodium sulfate~

~ : 10~

: ~
.

'7 The solvent ;~as evaporated out and the residue was purified by silicagel column chromatography to obtain the desired product (1.43 g).

Example 118 7B-~2-(5-~nino-1,2,4-thiadia~ol-3-yl)--(Z)-2-fluoro-methoxyimlnoacetamido~-3- t(E)-3-(carbamoylme-thyldimethyl-: ammonio)-l-propen-l-yl]-3-eephem-4-carboxylate:

N~-C-CONH ~/S CH, boo The compound (500 mg) obtained in Experiment' 4 was dissolved in a mixture solu-tion comprising methanol (3 ml) and di.emthylformamide (l ml), and N,N-dimethylglyeinamide (71.3 mg) was added thereto wi-th ice-cooling and then stirred overnight at room temperature.
The resulting reaction solution was added to a mixture solution comprising ethyl aeetate (5~ ml) and ethyl ether ~. ~
(50 ml) and the preeipitate formed was eollected by filtration : and dried to obtain an yellow powder (382 mg).

This powder: was added to a mixture solution : comprising trifluoroace-tic acid (2.7 ml) and anisole (2.3 mll, ~: ~: followed by stirring for 2 hours with iee~cooling. The ::
.
: :

:; : :

.

3~3~ii4L~'7 reaclion solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate Eormed was collected by filtration and washed with ethyl ether. The thus--obtained precipitate was suspended in water (4.5 ml), followed by adjus-ting the p~l of the resulting suspension to the range of Erom 5.5 to 6.5 with sodium aceta~e, and -the insoluble subs-tances were removed by Eiltration. The filtrate was purified by reversed phase-silicagel column chromatography to ob-tain the desired product (94 mg).
Example 119 7~-~2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido3-3- r(E)-3-(1-methyl-4-sulfamoyl-l-piperazinio)-l-propen-l-yl~-3-cephem-4-carboxylate:

N ~ -H2~S N`oC~ F ~LN~ , ,N ~N SO2N~
COO-The compound (500 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol i3 ml) and dime-thylformamide (1 ml), and N-sulfamoyl-N'-methylpiperazine (116 mg) was added thereto with ice-cooling and then stirred overnight a-t room tempera-ture.

: ~:

: ::

~3~59L87 The reaction solutlon was adcled to a mixture solution comprising ethyl acetate (50 ml) and ethyl etller (50 ml), and the precipitate formed was collected by filtration and dried to obtain an yellow powder (402 mg).
The powder was added to a mixture solution comprising trifluoroacetic acid (2.8 m]) and anisole (2.5 ml) and stirred for 2 hours with ice-cooling. The reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was co]lec-ted by filtration and washed with ethyl ether. The resulting precipitate was suspended in water (4.5 ml), followed by adjusting the pH of -the resulting suspension to -the range of from 5.5 to 6.5 with sodium acetate, and the insoluhle substances were removed by filtration. The Eiltrate was purified by reversed phase-silicagel column chromatography to obtain the desired produc-t (58 mg).
Example 120 73- ~-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyimi~oacetamido]-3- ~E)-3- ~(1,3,4-oxadiazol-2-yl)methyldimethylammonio3-1_prOpen-l-yl~-3-cephem 4-carboxylate:

, ~ ~q CONH~ ~ CH, ~3~5~'7 The compoulld ~50!~ mg~ obtained in Experiment 4 was dissolve~ in a mixture solution comprising methanol (1 ml) and ethyl ace-tate (4.8 ml), and the ethyl aceta-te solution (1 ml) of 2-dlmethylaminomethyl-1,3,4-oxadlazole (88.8 mg) was added thereto wi-th ice-cooling and then stirred overnight at room temperature. The resulting reaction solution was addéd to a mix-ture solution comprising ethyl acetate (~0 ml) and ethyl ether (50 ml), and the precipltate formed was collec-ted by filtra-tion and dried to obtain an yellow pow~der (443 mg).
The powder was added to a mixture solution comprising trifluoroacetic acid (3.1 ml) and anisole (2.7 ml) and stirred for 2 hours with ice-cooling. The resulting reaction solu-tion was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipita-te formed was collected by filtration and washed , ; ~ with ethyl ether. The thus-obtained precipita-te was suspended n water (4.5 ml), followed by adjusting the pH of the resul-ting suspension to -the range of from 5.5 to 6.5 with sodium aceta-te, and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-sllicagel column chromatography to obtain the desired product (92 mg).
:
xample 121 7B-~2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z~-2-fluoro-~:
~ :

::

.

~ 3~t3~

methoxyiminoacetamidoJ-3- ~E)-3-(1-methyl-9-carbamoyl-l-piperazinlo)-l-propen-l-yl~-3-cephem-~-carboxyla-te:

N ~ N ~l CONHz COO

The compound (500 mg) ob-talned in Experim'ent 4 was dissolved in a mix-ture solution comprising methanol (3 ml) and d;methylformamide (1 ml), and N-methyl-N'-carbamoylpiperazine (100 mg) was added thereto with ice-cooling and then stirred overnight a-t room temperature.
The reaction solution was added -to a mixture solution comprising ethyl aceta-te (50 ml) and ethyl ether (30 ml), and the precipitate formed was collected by filtration and dried to obtain an yellow powder (425 mg).
The powder was added to a mixture solution comprising trifluoroace-tic acid (3.0 ml) and anisole (2.6 ml) and stirred for 2 hours with ice-cooling. The reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collec~ed bs~ filtration and washed with ethyl ether. The precipitate was suspended in water (4.5 ml), followed by adjusting the pH of the resulting suspension -to the range of from 5.5 to 6.5 with sodium acetate, and the insoluble subs-tances were :
:

~ .

13~

removed by filtra-tion. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (107 rng)~
~xamp]e 122 7B- ~2-(5-~nino-1,2,4-thiadiazol-3-yl)-(Z~-2-fluoromethoxy iminoacetamido~-3-((E)-3-(1,2-dimethyl-1-pyrazolidinio)-l-propen-l-ylJ-3-cephem-4-carboxylate (Isomers: A and B)-M~ CONH~S CH, H2~S `0(~I2F c~ N~\6~/+~ N
C00 CH~

The compound (783 mg) obtained in Experiment4 was dissol-~ed i.n a mix-ture solution comprising ; me-thanol (1.5 mll and e-thyl acetate (7.1 ml), and -the ethyl acetate solution (1.5 ml) o~ N,N'-dimethylpyrazolidine (103 mg) was added thereto with ice-cooling and then stirred overnigh-t at room temperature. The reaction solution was added to a mixture solution comprising ethyl ace-ta-te (50 ml) and ethyl ether (S0 ml), and the pre~ipitate formed was ~ ~ collected by filtration and dried to obtain an yellow powder - (631 mg).
The powder was added to a mixture solution comprising trifluoroacetic acid (4.5 ml) and anisole (3.8 ml) and s~irred ~ ~ for 2 hours wi-th ice-cooling. The reaction solution was ::: : ~ :

:: :

: ::: ::
' ' :

~3~ S ~L~ 7 added to a mixture solutiotl comprising ethyl ether (2S ml) and isopropyl ether (25 ml), and -the precipitate formed was collected by filtration and washed with ethy] ether. The precipitate was suspended in water (4.5 ml~, followed by adjus-ting the pll of the resul-ting suspension to the range of from 5.5 to 6.5 with sodium acetate, and the insol~ble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromat;ography to obtain the desired isomer A (37 mg) and isomer ~ (27 mg).
Example 123 7~-t2-(5-~nino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido~-3- ~(E)-3-(1-me-thyl-4-formimidoyl-l-piperazinio)-l-propen-l-yl~ -3-cephem-4-carboxylate hydrochloride:

N ~C- CONH~ S ~ (~3 H,N `OCH~F (r~ N ~I-C~ H

The compound ~750 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (4.5 ml) and dimethylformamide (1.5 ml), and N-methyl-N'-formimidoylpiperazine hydrochloride (l5a mg) was added thereto with ice-cooling and then stirred overnight at .
,, : 111 ~ .

room temperature. The reac-~ion solution was added to a mixture soluti,o~ comprising ethyl acetate (50 ml) and ethyl ether (3n ml), and the precipi-ta-te formed was collected by filtration and dried to obtain an yello~ powder (485 mg).
The powder was added to a mixture solution comprising trifluoroacetic acid (3.4 ml) and anisole (3 0 ml) and stirred for 2 hours wi-th ice-cooling. The reaction solu-tion was added -to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and -the precipitate ~ormed was collected by filtra-tion and washed with ethyl ether.
The precipitate was suspended in water (4.0 ml), and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatoyraphy to obtain the desired product (58 mg).
In the same manner as Examples 118 to 123, the cornpnunds of the following Examples 124 -to 140 were synthesized.
Example 124 7BL2-(5-Amino-1,2,4-thiadiazol~3-yl)-(Z)-2-fluoromethoxy-iminoacetamido~-3-[(E)-3-(l~methyl-1-piperazinio)-1-propen-l-yl~-3-cephem-4-carboxylate:

N--C-CONH
H~N S ~ F ~
COO-.

~ ~ 112 The compound (750 mg) obtained in Experimen-t 4 was reac-ted with N-methylpiperazine (116 ~1), ollowed by removing the protective group, to obtain the desired product (16 mg).
Example 125 7B-~2-(5-~mino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido~-3- [(E)-3-(4-carboxypyridinio)-l-propen-l-y~ -3-cephem-4-carboxylate: .

H2N S `OCH2F ~ N~COOH
COO

The compound (750 mg) obtained in Experiment:
4 was reacted with isonicotinic acid tl98 mg), followed by removing the protective group, to obtain the desired product (143 mg).
Example 125 7~-~2-(5-Amino-1,2,4-thiadiazol-3 yl)-(Z)-2-fluoro-methoxyiminoace-tamido~-3-~E)-3-(1-methylpyrrolidinio)-1-propen-l-y~ -3-cephem-4-carboxylate:

H2NJ~ S ' N~
boo-:, ~;

:: :

3..3~

The compound (500 mg) obtained in Exp~riment 4 was reacted with N-methylpyrrolidine (55.8 ~1), followed by removing -the protective group, to obtain the desired produc-t (21 mg).
Example 127 7B- t2-(5--Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamid~ -3- [(E)-3-(4-carbamoylpyridinio)-l-propen-l-yl~-3-cephem-4-carboxylate:

M- ~ C-CONH r S
HzN S N~ocH F~rN ~ vN~ CO~
COO

The compound ~500 mg) obtained in Experiment 4 w~s reacted with 4-carbamoylpyridine (131 mg), followed by removing the protective group, to ob-tain the desired product (42 mg).
Example 128 7B-~2-(5-A~nino-1,2,4-thiadiazol-3-yl)-~Z)-2-fluoro-methoxyiminoacetamido3-3- t(E)-3-(trime-thylammonio)-l-propen-l-yl~-3-cephem-4-carboxylate:

N~C-CONH _,S CHJ
/~ S' ~ CH~
H2N 1 `O~I F 0~ N~\~/CHJ
::

:: :
~ 114 :
~ - ~

~ . .

~3~ 4~ ~

The compound (500 mg) obtained in Experiment 4 was reacted with trimethylamine (whcareupon tri-methylamine hydrochloride (57 mg), as neutralized, was used), Eollowed by removing the protec-tive group, to ob-tain the desired product (79 mg).
Example 129 7B- ~2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-~luoro-methoxyiminoacetamido~-3- ~(E)-3-(1,4-diazabicyclo-~2,2,2J octan-l-io)-l-propen-l-yl~-3-cephem-4-carboxyla-te:

HtN S ~`OC~ F O~N~\~/N'/\--The compound (500 mg) obtained in Experimen-t 4 was reac-ted with 1~4-diazabi~yclo~2~2~2~octane ~72 mg), followed by removing the protective group, to ob-ta:in the desired product (61 mg).
Example 130 7B- ~2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxy-iminoacetamido3-3- ~(E)-3-(1,5-diazabicyclo ~3t3~0~ octan-l-io)-1-propen-l-yl~-3-cephem-4-carboxylate:

N~C- CONH~ S
HZ1 S `OCHtF ~ N `~

'7 The compound (500 mg) obtairled in Experiment 4 w~s reacted with 1,5-diazabicyclo ~3,3,0~octane (120mg~, followed by removing the protective group, to obtain the desired product (32 mg).

, ~ .
Exarnple 131 7B-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyim;.noacetamido~-3- [(Ej-3-(4-methylthiomorpholine-1,1-dioxid-4-io)-1-propen-1-yl~-3-cephem-4-carboxyalte:

~C-CONH~r~s~ CH, ~2N S `OC~IIF ~ N` ~,~y~, ~ o The compound (250 mg~ obtained in Experiment.
4 was reacted with 4-me-thylthiomorpholine-1,1-dioxide (52 mg), followed by removing the pro-tective group, -to obtain the desired produc-t (17 mg).
Example 132 7B-t 2-(5-~mino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido~-3- [IE)-3-(1,4-dimethyl-l-piperazinio)-l-propen-l-yl~-3-cephem-4-carboxylate:

H..7`1 S `O~I~F ~
coo :

:

The compourld (500 mg) obtained in Experi.Ment.
4 was reacted ~ th 1,4-dimethylpiperazi.ne l94 lul), followed by removing the protective group, to obtain the desired product (35 mg).
Example 133 7B-r2-(5-Z~mino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido~-3- ~(E)-3- ~(2-aminoethyl)dime-thyl-ammonio3-1-propen~l-yl~-3-cephem-4-carboxylate;:

N ~C-CONH _~ S~ CH3 H2N S `OCH~F ~ b - I--NH2 The compound (750 mg1 ob-tained in Experiment~
a was reacted with N,N-dimethylethylenediamine (115 lul), followed by removing.the protec-tive group, to obtain the desired product (15 mg).
Example 134 7B-~2-(5-Amino-1,2,4-thiadiazol-3-yl)-~Z)-2-~luoro-methoxyimlnoacetamido~-3- [(E)-3- t(tetrazol-5-yl)methyl-dimethylammonio3-1-propen-1-yl~-3-cephem-4-carboxylate:

: N~C-CONH~S~ C~ N--N
H2N ` ~OCH2F o~ ~ N
:

:: :

: 117 :

gL&i'7 rh compoulld (soo mg) obtained in E,cperimant d ~as reacted with 5-dime-thylaminomethyltetrazole (150 mg1, followed by removing the protective group, to obtain -the desired product (37 mg).
~xample 135 71~-~2-(5-~mino-1,2,4-thiadiazo].-3-yl)-(Z)-2-fluoro-metho~yiminoace-tamido~-3- ~E)-3-(3-sulEopyridinio)-l-propen-l-yl~-3-cephem-4-carboxyla-te:

N -~-C-CONH ~ ~S ~ ~ ~H
H2N S N`oc~ F ~N~\~/
COO

: The compoun~ (750 mg) obtained in Experiment 4 was reacted with 3-pyridinesulfonic acid (384 mg), followed by removing the pro-tective group, to obtain the desired produc-t (68 mg).
: Example 136 7B- ~2-(5-Amino-1,2,4-thiadiazol-3-yll-(Z)-2-fluoro-methoxyiminoacetamido~-3- [(E)-3- ~(2-dimethylaminoe-thyl)-~: dimethylammonio~ propen-l-yl~-3-cephem-4-carboxylate:

:~ N ~ ll_CONH ~,S~ CH3 H,.'\~ S N`oc~; F ~N`~'\~/ 1 N

:: :

~ 118 :::
:

.`

. . , .

. ~ . . .

~.3~,~S9~7 The compound (500 mg) obtalned in Experiment 4 was reac~ed wi.h N,N,N',N'-tetramethylethylene-diamine ~105 pl), Eollowed hy removing the protective group, -to obtain the desired produc-t (22 mg).
Example 137 7B-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido~-3- ~(E)-3- ~(2-oxopropyl)dimethyl-ammonio~ propen-l-y.l~-3-cephem-4-carboxylate:

N ~ C-The compound (500 mg) obtained in Experiment 4 was reac-ted with (dime-thylamirlo)acetone (80 lul), ~ollowed by removing the pro-tective group, to obtain the desired product (60 mg).
Example 138 7B-~2-(5~Amino-1,2,4~thiadiazol-3-yl)-(ZJ-2-fluoro-methoxyiminoacetamido]-3- [(E)-3-(4-carbamoylquinuclidinio)-l-propen-l-yl~ -3-cephem-4-carboxylate:
~: N ~- C- CONH;~ ~N;~CONH2 :.

The compound (500 mg) obtai.ned ln E:~periment 4 was reacted ~ith 4-carbamoylquinucli.dine (107.6 mg), followed by removing the protective group, to obtain the desi.red product (77 mg).

Examp]e 139 713-t2-(5-~mino-1,2,4-th,iadiazol-3-yl)-(Z)-2-Eluoro-methoxyiminoace~amido~-3- t(E)-3- ~1-methyl-2-(2-hydroxy-ethyl)pyrrolidinio~-l-propen-l-yl~-3-cephem-4-carboxylate (Isomers: A and B):

'~ S N N~ V/~,~
CHZC~20H

The compound (500 mg) obtained in Experim~nt 4 was r~acted with 1-methyl-2-(2-hydroxyethyl)-pyrrolidine (83.3 mg), followed by removing the protective . .
group, to obtain the desired isomer A (24 mg) and isomer B (26 mg).
Example 140 7B-L2-(5-~mino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoacetamido3-3- r(E) -3-(4-carboxyme-thylpyridinio)-l-propen-l-yl~ -3-cephem-4-carboxylate:

C-CONH ~S
N Z,LN ~3CH2COOH
HZN S ~CH2F O
~ ~ coo :; ~

~, . . : . , :

`

~3~5487 The compound ~500 mg~ obtained in Experiment.
4 was reacted with 4-pyridyl. acetic acid hydrochloride (280 mg), followed by removing the protective group, to obtain the desired product 15 mg).
Example 141 7B- t2-(5-~mino-1,2~4-thiadiazol-3-yl)-(Z)-2-fluoro-methoxyiminoace-tamido~-3- L(E)-3-(1,4,4-trimethyl-1-.
piperazinio)-l-propen-l-yl~-3-cephem-4-carhoxylate iodide:

~N ~ 1 CONH ~ r ~ ~ CH~

The compound (1.0 g) obtained in Bxperiment 4 was suspended in ethyl ether (100 ml), and the ethyl aceta-te solution (40 ml) of 1,4-dimethylpiperazine (189 jul) was dropwise added there-to and s-tirred overnight.
The precipitate formed was collec-ted by filtra-tion, and this was fur-ther re-prec;.pitated in tetrahydrofuran/ethyl acetate and then washed wi-th ethyl acetate to obtain an yellow powder (992 mg). This was dissolved in dichloromethane (2 ml), and :~ me-thyl iodide (4 ml) was added thereto with ice-cooling and then stirred overnight at the same temperature. The reaction solution was pu-t into e-thyl acetate, and the precipitate formed :

':

~3~ 37 WdS co~.lected by filtration. to obtain an yellowlsh brown powder (190 mg).
This powder was added to a mixture solution comprising triE~uoroacetic acid (1.35 ml) and anisole ~1.16 ml) and stirred for 2 hours with ice-stirring. The reaction solution was added to a mixture soluti.on comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and -the precipitate formed was collected by filtra-tion and washed witll ethyl ether. The resulting precipitate was suspended-in water (4.5 ml), and the insoluble substances was removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (23 mg).
Example 142 7B-~2-(S-Amino-1,2,4-thiadiazol-3-yl)-~Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetamido~-3- [(E)--3-(carbamoyl-methyldimethylammonio)-l-propen-l-yl~ -3-cephem-4-carboxylate:

CH~
N C--CONEI~ S~
T ~ CO~DH2 ~2N OCH CF ~

~ ~ The compound (1.43 g) obtained in Experiment '~ ~
:
12,~

.
, ~, ~;~q~5~h~7 7 was dissolved in acetone (20 ml), and sodium iodide (0.927 ~) was added thereto with ice-cooling and stirred Eor 10 minutes at the same temperature and successively for 1 hour and 30 minutes at room temperature. The solvent was evaporated out, and after ethyl acetate was added to the resulting residue, this was washed with a dilute~sodium thiosulfate solution and saturated brine and then dried with sodium sulfa-te as added. The brine was evaporated out, and the residue was dissolved in ethyl acetate (~0 ml).
~fterwards, dimethylgycinamide (237 mg) was added to the resulting solution and stirred for one hour at room -temperature.
To the resulting solu-tion was added isopropyl ether, and the precipi-ta-te formed was collected by filtrat;on, to obtain an yellowish brown powder (1.07 g).
The powder was added to a mixture solution comprising -trifluoroacetic acid (8 ml) and anisole (6 ml) and stirred for one hour with i.ce-cooling. Ethyl e-ther was added to the resulting reaction solution, and the precipita-te Eormed was collected by filtration. This precipitate was suspended in water (10 ml), followed by adjusting -the p~ of the resulting suspension to the range of Erom 5.5 to 6.5 with sodium acetate, and the insoluble substances were removed by filtration.
The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product ~268 mg).

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Example 14~
7~-[2-(5-Amino-1,2,4-thiadiazol-3-yl~-(Z)-2 fluoromethoxyiminoacetamido~-3- ~(E)-3-¦tris(2-hydroxyethyl)ammonio]-l-propen-l-yl] 3-cephem-4-carboxylate \~ C--CoNH \ pH

'O--CH:.FC~fJoo \ ~
OH .

400 Mg of the compound prepared in the Experiment 4 was dissolved in 4 ml of ethyl acetate, and 96 mg of triethanolamine solution in 4 mQ of ethyl acetate was added thereto. The resulting solution was stirred for 6 hours at the room temperature. To the reaction solution was added 24 mQ of diisopropyl ether, and the resulting precipitates were collected by filtration. This precipitates were added to 4.5 m~ of a mixed solution containing trifluoro acetic acid and anisole (1:1) under ice-cooling. The mixture was stirred for one hour and 30 minutes ~t the room temperature. To the reaction solution was added 18 mQ of dilsopropyl ether. The resulting precipitates were collected by filtration, and washed with diisopropyl ether. This precipitates were suspended,in 3 mQ of water, and sodium acetate was added thereto to adjust the resulting solution to pH 6. Insolubles were removed by filtration, and the filtrate was purified by a reversed-phase silica gel column .

~ 131 ~3~S4~7 chromatography to obtain 17 mg of the objective product.

Example 144 7~-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(E)-3-[bis(2-hydroxyethyl)methylammonio]-1-propen-1-yl]-3-cephem-4-carboxylate /OH
N-~ C--CONH ~,~ ~ ~
l~SyN o~N~WN--C~3 O--CH2F C013- --\OH

In the same manner as the Example 143, 500 mg of the compound prepared in the Exeriment 4 was reacted with 150 mg of N-methyldiethanolamine, and the protecting group was eliminated to obtain 15 mg of the objective product.
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E~periment 8 (Synthesis of the raw material compound) 2-(5-Tritylamjno-l,2,4-thiadiazol-3-y])-(Z)-2-cyano-me~hoxyiminoacetic acid C - ~00~
~3CHN~3~N

~ ..

8.00 g of N-cyanomethoxyphthalimide was suspended in 50 ml of ethanol and 1.93 ml oE hydrazine monohydride was added thereto at roorn temperature. The resulting mixture was stirred for 1 hour and 45 minutes. Then a saturated brine and ethyl ether were added thereto. The mixture was made basic with conc. aqueous ammonia and then extracted with ethyl ether. The ethyl ether layer was washed with a saturated brine solution and dried over anhydrous sodium sulfate. Subsequent]y the solvent was distilled off.
To the residue, 350 ml oE methanol and 6,50 g of 2~(5-tritylamino-1,2,4-thidiazol-3-yl)glyoxylic acid were aclded and the resulting mixture was stirred at room temperature Eor one hour. After clistilling off the solvent, the residue was dissolved in ethyl ace~tate and then washed with 0.1 N hydrochloric acid~followed by with a saturated brine solution~ After drying the organic layer over ;anhydrous sodium sulfate, the solvent was distilled off.
Thus 7.64 g of the ob~ective compound was ohtained.
Experiment 9 (Synthesis~of the raw materia.l compound) p-Methoxybenzyl 7~-[2-(5-tritylamino-1,2,~-thiadiazol-3-8'~

yl)-(Z)-2-cyanometlloxyiminoacetamido]-3-[~Z)-3-chloro-1-propen-1-y1~-3-cepllem-4-carboxylate ~r N~7-CON~sl rC
6~H~ S ~ N~O
O-C~H2CN
~D COOCH~OCH~
.::
1.51 ml oE dimethylEormamide and 18 ml oE tetrahydro-furan were cooled to -10 C and 1.82 ml oE phosphoryl chloride was added thereto. The resulting mixture was stirred for 40 minutes under ice-cooling. Then a solution of 7.64 g of the compound of Experiment 8 in 24 ml of tetrahydrofuran was added thereto and the resulting mixture was stirred at the same temperature for additional one hour.
A solution comprising 6.00 g of p-methoxybenzyl 7~7-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride, 12.8 g of N-trimethylsilyl-acetamide and 60 ml of ethyl acetate ~las cooled to -25 C.
Then the above-~,entioned reaction mixture was added thereto and the resulting mixture was stirred for 40 minutes while raising the temperature to 0C. This reaction mixture was extracLed with ethyl acetate and the organic layer was washed with a saturated brine solution and dried over anhydrous sodium sulfate. After distilling off the solvent, ~ ::
the residue was purified with silica gel column chromatographyO Thus 7.80 g of the objective compound was obtained.

Experim~nt 10 ~Synthesis of the raw ma-te~ial compound) p-Methoxybenzyl 7~-~2-(5-tritylamino-1,2,4-thiacliazol-3-yl~--(Z)-2-cyanomethoxyiminoacetamido]-3-[(E)-3-iodo-1-propen-1-yl~-3-cephem-4-carboxylate . ~D ~,~C-~N~S
~ S N c~N~
~(~

~D C~H2 ~

To a solution of 7.80 g of the compound of Experiment 9 in 120 ml of acetone, 6.9 g of sodium iodide was added under ice-cooling. The resulting mixture was stirred Eor 10 minutes and then for additional 1 hour and 30 minutes at room temperature. The solvent was distilled off and the residue was extracted with ethyl acetate. The extract was washed with a dilute aqueous soltuion of sodium thiosulfate followed by with a saturated brine solution and then dried over anhydous sodium sulfate. The solution was concentrated and added dropwise to a mixture of isopropyl ether and ethyl ether. The precipitate thus formed was filterd out to thereby give 6.50 g of the objective compound.
Example l45 7~-[2-(5-Amino-1l2,4-thiadiazol-3-yl)-(Z)-2-cyanomethoxy-: ~

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iminoacetamido]-3-t(E)-3-[~15-carbamoyl-2-hydroxyethyl)-dimethylammonio]-l-propen-l-yl]-3-cephem-4-carboxylate ~C-CONH~S CH~ H

H~N S ~OGH CN~LN~NH2 00- . ' 1.0 g of the compound of Experimentlo was dissolved in 2 ml of dimethylformamide and 210 mg oE (IS-carbamoyl-2-hydroxyethyl)dimethylamine was added thereto at room temperature. The resulting mixture was stirred for one hour and then diluted by adding 10 ml of ethyl acetate thereto.
The resulting solution was added dropwise to 100 ml of ethyl ether to thereby give 710 mg of a brown precipitate.
This precipitate was stirred in a mixture of 6 ml of anisole and 6.5 ml of trifluoroacetic acid under ice-cooing for one hour. Then ethyl ether was added to the reaction mixture to thereby give 430 mg of a brown precipitate. This precipitate was suspended in 10 ml of water and the pH value of the obtained suspension was adjusted to 7.0 with sodium acetate. After filtering off the insoluble matters, the filtrate was purified with reverse phase silica gel column chromatography to thereby give 50 mg of the objective compound.
Example 146 7~-[2-l5-~mino-1,2,4-thiadiazol-3-yll-(Z)-2-cyanomethoxy-13l ~ . . ` '''' ' "

:

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iminoacetamido]-3-[(E)-3-(1 methyl-2R-hydroxymethyl-4R-hydroxy-1-pyrrolidinio)-l-propen-1-yl]-3-cephem-4-carboxylate bCH~

1.0 g of the compound of Experimentlo was dissolved in a mixture of 10 ml of ethyl acetate and 8 ml of ethyl ether~
Then 167 mg of N-methyl-4R-hydroxy-D-prolinol was added thereto and the resulting mixture was stirred overnight.
The reaction mixture was added to 100 ml of ethyl ether and the precipitate thus Eormed was filtered out to thereby give 840 mg of a yellow powder.
To this powder, 6 ml of anisole was added and 8 ml of trifluoroacetic acid was added dropwise to the ~esulting mixture under ice-cooling for 30 minutes. Then the mixture was stirred for additional 1 hour and 30 minutes. 100 ml of ethyl ether was added to the reaction mixture and the preclpitate -thus formed was filtered out and suspended in 4 ml of water. The pH value of -the resulting suspension was adjusted to 7.0 with sodium acetate. After filtering off the insoluble matters, the filtrate was purified with :
reverse phase silica gel column chromatography to thereby give 24 mg of the objective co~pound.

~ ~ 130 ;::

3~ 7 The following comp-unds of Examples 147 - 154 were obtained in the same manner as those described in Examples 145 and 146, ONH~
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: In a case where plural isomers were formed depending on : the ammonio group of A, the yield of each isomer, if ~ isolated, was given.

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J1~3~.~5 ~xamPle 155 7~-[2 (5-~mino-1,2,LI-thiadiazol-3-yl)-(Z)-2-cyano-methoxyim:Lnoacetoamido]_3_[(E)_3-carbamoylmethyldimethyl-ammonio)-l-proPen-l-yl~-3-cephem-4-carboxylate IN~ I ~ONH r~ S ~ CHa H2N S N, ~g N~ ~N~coNH2 Dimethylglycinamide (64 mg) was added to a solution of the compound (390 mg) of Experiment loin ethyl acetate (15 m~) 9 and this mixture was stirred at a room temperature for 1 hour.
Ethyl ether was added to the reaction solution and the produced precipitate was filtered and dried, thus providing a yellowish brown powder (260 mg).
A mixture of trifuloroacetic acid (2 m~) and anisole (1.5 m2) was added to this powder and stirred for 1 hour under an ice-cooling condition. Ethyl ether was added to the resulting solution, and the produced precipitate was filtered and washed with ethyl ether. This precipitate was suspended into water (5 m~) and pH of the suspension was adjusted to 5.5 to 6.5, following which the insoluble material was filtered off. The filtrate~was refined in a reversed phase chromatography, thus providing the desired material (37 mg).

:

' ~ ' '7 E.Yample 156 7~-[2-(5-Arnino-l,2,4-thiadiazol-3-yl)--(Z)-2-cyano-methoxyiminoacetoamido]-3-[(E)-3-(l methyl-4-sulfamoyl-l-piperazinio)-l-propen-l-yl)-3-cephem-4-carboxylate The compound (500 mg) of ExperimentlO was dissolved into a mixture of dichloromethane (5 mQ) and methanol (l m~, and N-sulfamoyl-N'-methylpiperazine (145 mg) was added thereto, and the whole was stirred at a room temperature for 4 hours.
The resulting solution was concentrated, and ethyl ether was added thereto. The produced precipitate was filtered and dried, thus providing a yellowish brown powder (450 mg).
A mixture of tr1fluoroacetic acid (3.5 m~) and anisole (3 m~) was added to this powder, and the whole was stirred for l hour. Ethyl ether was added to the resulting solution, and the prod~uced precipitate was filtered and washed with ethyl ether. The preoipitate was suspended into water (5 rn~) and the pH of the suspension was adjusted to 5.5 to 6.5, following ~; which the insolubIe material ,was fiItered off. The filtrate was refined in a reversed phase chromatography, thus providing the~ desired material (39 mg).
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`S~W~r Example 157 7~-[2-(5-Amino-1,2,ll-thiadiazol-3-yl)-(Z)-2-cyano-methoxyiminoacetoamido]-3-[(E)-3-(1,4-diazabicyclo[2,2,2]
octane-l-io)-l-propen-l-yl~-3-cephem-~-carboxylate N-~C--CONH-~_~S
H~N `O-~2CN ~3LN i co(r The compound (500 mg) of Experiment lOwas dissolved into a mixture of ethylacetate (6 m~) and methanol (0.5 mR), and 1,4-diazabicyclo[2,2,2]octane (90 mg) was added thereto and stirred at a room temeprature for 20 minutes. Ethyl ether was added to the resulting solution, and the produced precipitate was filtered and dried, thus providing a yellowish brown powder (330 mg).
A mixture of trifluoroacetic acid (3 mQ) and anisole (2.5 m~) was added to this powder, and the whole was stirred for 1 hour under a ice-cooling condition. Ethyl ether was added to the resulting solution, and the produced precipitate was filtered iand washed with ethyl ether. The precipitate was suspended :~ into water (5 m~) and the pH of the suspension was adjusted to 5;.5 to 6.5, following which the insoluble material was filttered off. The filtrate was refined in a reversed phase chromatography, thus providing the desired material (48 mg).
Compounds of the following Examples 158 to 161 were provided in the same manner as in Examples 155 to 157.

:: : :

Example 158 7~-t2-(5-Amino-1,2,LI-thiadiazol-3-yl)-(Z)-2-cyano-methoxyiminoacètoamido¦-3-[(E)-3-(4-carbamoylpyridinio)-l-propen-l.-yl~-3-cephem-4-carboxylate N~C-CONH S +
HZN S N ~ N J~/N~CONH2 coo- .

The compound (600 mg) of Experimentlowas reacted with 4-carbamoylpyridine (235 mg), and the protective group was removed to provide the desired material (37 mg).

Example 159 7~ [2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-cyano-methoxyiminoacetoamido~-3_C(E)-3-(1,3,4-oxadiazol-2-yl)methyldimethylammonio]-l-propen-l-yl3-3-cephem-4-carboxylate N~rC-CONH r~S~ C~3 N~
H~N S N ~J\~\/~\J~ oJ
O CHzCN I oo- CH~
; The compound (600 mg) of ExperimentlO was reacted with : 2-dlmethylaminomethy~ 3~4-oxadiazol (163 mg), and the protective group was removed 'to provide the dasired material ; (54 mg).
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'7 Example 160 7~-[2-(5-Amino~ L~-tili~di~zol-3-yl)-(z)-2 methoxyiminoacetoamido]-3-[(E)-3-(1,2-dimethyl-1-piperazinio)-l-propen-l-yl~-3-cephem-4-carboxylate (i~omers: A and B) ~ I--CONH ~/S~ ~Hl "
H2N `0-CH2CN ~
oo CHl The compound (510 mg) of ExperimentlO wàs reacted with 1,2-dimethylpyrazolidine (0.4 mQ), and the protective group was removed to provide the desired isomer A (20 m~) and the desired isomer B (20 mg).

Example 161 ~ 7~-[2-(5-Amino-1,214-thiadiazol-3-yl)-(Z)-2-cyano-; ; methoxyiminoacetoamid]-3-[(E)-3-(1,5-diazabicyclo ~ ~ [3.3.0]octane-1-io)-1-propen-1-yl~-3-cephem-4-carboxylate :
CI--CONH~f S~ ~
H2N S No ~ N~J\~/~N
COO

The compound (600 mg) of ExperimentlO was reacted with 1,5_dlazablcyclo[3,3,0]octane (220 mg), and the protective group was removed to provide the desired material (39 mg).

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Experiment 11 (Synthesis of the raw material compound) 2-(5-Tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetyl chloride hydrochloride ~1J N ~ C--COCl ~CHN ~ ~N N HCl S ` OCH2F

Phosphorous pentachloride (395 mg) was dissolved in dichloromethane (2.9 mQ) and cooled to -5C. To the solution was added the compound (627 mg) of Experiment 2, and agitated for 2 and half hours at the same temperature as described above. The reaction solution was added to a mixture of n-hexane (9.4 m~) and n-octane (9.4 m~). The resulting crystalline substance was collected by filtration, and washed with n-octane to obtain the objective product (325 mg).

Melting point: 139 - 140C (decomposition) Mass spectrum (m/e): M+....... 480 (35CQ), 482 (37C~) In~rared absorption spectrum (cm 1, Nujol): 1795, 17~0, 1740, 1630 NMR spectrum (~, DMSO-d6): 5.79(2H, d, J=54Hz), 7~31 (15H, s), lO.O9(1H, s) ~: :

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Experiment 12 (Syn-thesis of the raw material compound) 2-(5~Amino-1,2.4-thiadiazol-3-yl) (Z)-2-fluorome-thoxy iminoacetic acid ~thYl ester N \~ C - COOC2H6 ~z ~ S' N ~ oCE2F
The compound ( 2.00 g) of Experiment 1 was agitated .in tri-fluoroacetic acid at room temperature for 30 millutes. The solvent was distilled off, and the residue was purified bY
silica gel column chromatography to obtain the objective product (405 mg).
~lel-tincJ Point: 172 - 173C
Infrared absorPtion spectrum (cm 1, Nujol): 1730. 1615 NMR sPectrunl (~. DMSO-d6): 1.28t3H. t. J=7.0Hz). 4.34(2H. q, J-7.0Hz). 5.83(2H, d. J=54.5Hz). 8.27t2H. brs ~i ~

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ExFeriment 13 (Synl:hesis oE the raw material comPUnd) 2-(5-~mino-l~2~4-thiadiazol-3-yl)-(z)-2-fluorometh iminoace-tic acid N ~ C--COOH
H2N~S~N N~OCHF

The comPound (200 mg) of Experimen-t 12 was suspended in mixture oE ethanol (6 mQ) and water (2 mQ). IN aqueous sodlum hydroxide solution 1l.75 mQ) was added thereto, and s-tirred at 60C for I hour. Ethanol was distilled off from the reac-tion solution. and the solution was adjusted to PH 2 with the use of IN hYdrochlorlc acid. The resul-tin~ solution was Purified bY

means of "Dia-lon SP207" (trade mark for nonionic adsorPtion resin manufactured bY Mitsubishi Chemical Industries, Ltd.) to obtain the objective product (30 mg).
Infrared absorPtion sPectrum (cm l, Nujol): l720, 1620 NMR sPectrum (~, DMSO-d6): 5.74~2H, d, J=55 Hz), 8.24(2H, br) :

~ ~ 155 , ' Experiment 14 (Synthesis of the raw material compaund) P-Methoxybenzyl 7~-[2-(5-tritylamino-1,2,~-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate ~3 N~ C-CONH ~S rCl (~HN S `OCXzF oJ N ~
@l COOC~I~ ~OCEs To a mixture of ethyl acetate (37 mQ), tetrahydrofuran (5 mQ), and dichloromethane (15.7 mQ) were added N-(trimethylsilyl)acetamide (8.17 g) and p-methoxybenzyl 7~-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (3.33 g) to dissolve the latter materials. The solution was cooled to -20C, then the compound of Experiment 11(3.80 g) was added thereto, and agitated at lO~C for 1 hour. After the addition of ethyl acetate (500 m~) to the reaction solution, the mixture was washed successively with water, a saturated a~ueous sodium bicarbonate solution, lN
hydrochloric acid, and a saturated brine solution, and then anhydrous magnesium sulfate was added thereto to dry the same. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the objective product (4.33 g~.

The infrared absorption spectrum and the NMR spectrum of the resuItant product coincided with those of Experiment 3.

, ~

~ 156 ~ . ~

' .

.?~4~7 \
periment :L5 (Syntllesis of the raw material cornpound):

2-Cyano-2-E:Luoromethoxyiminoacetamide NC- C - CONHz N

\ OCH2F

2-Cyano-2-hydroxyiminoacetamide (22.6 g) was dissovled in dirnethyl sulfoxide (100 ml), and then potassium carbonate (55.2 g) was added thereto with stirring at room temperatureJ and the solution was Eurther stirred for additional 20 minutes Fluorobromomethane (27 g) dissolved in dimethylformamide (20 ml) was then added to -the solutionr and the solution was stirred for 20 hours at room temperature and -then allowed to cool. The reac-tion solution was added to iced water (1 liter)~ and extracted -twice with ethyl acetate (150 ml)c The organic layer was washed twice with a satura-ted brine, and dried with addition of anhydrous magnesiurn sulfa-te, followed by distilling off the solvent, The residue was washed with e-thyl ether, and dried -to obtain the objective product (14,4 g)~
Melting point: 124 - 125C, : : ; Infrared absoprtion spect~um (cm , Nujol):
: 3410, 3290, 3150J 1690~ 1590 NMR spctrum ( ~, DMSO-d6):
5.94 (2H, d, J=54.0 Hz), 7.85 - 9.40 (2H, b) :: ~
~: ~
.:

, Experiment 16 (Synthesis oE the raw material compound) 2-Fluoromethoxyiminopropanedinitrile NC-- C--C~N

N
\ OCH2F
A mixture con-taining the compound (14.0 g) prepared in Experiment 15, acetonitrile (15 ml), sodium chloride (lS g) and phosphoryl chloride (14 ml) was reacted under reflux for 2 hours.
To the mixture was added phosphorylchloride (5 ml), and the whole was reacted for 2 hours. The reaction solution was, after cooling, added to lced water ~200 ml) and stirred at room temperature for one hour. The solution was extracted twice with methylene chloride (50 ml). The extract was washed with 5% aqueous solution of sodium bicarbona-te, and with a sa-turated brine, and then dried wi-th addition of anhydrous magnesium sulfate. The solvent was distilled off. The resulting oily product was subjected to distilla-tion under reduced pressure to obtain a colorlessoily objective product (9.1 g).

~oiling point: 69 - 70C/25 mmHg NMR spectrum (~, CDC13): 5.85 (2H, d, J=52.0 Hz) `
:::

:: :

: , :

Experirnent 17 (Synthesis of the raw material compound) 2-Cyano-2-fluoromethoxyiminoacetamidine ~2N ~
C- C - CN
HN D l¦

A mixed solution con-taining 28% aqueous ammonia (50 ml), amrnonium chloride (8 g) and ethanol (50 ml) was cooled to -5C.
and the compound (9.1 g) prepared in Experiment 16 was added thereto with stirring, and -then Eurther stirred at the same tempera-ture for additional 3 hours. Water ~100 ml) was added -to the reaction solution. The solution was extracted thrice with methylene chloride t50 ml). After drying the extract with addi-tion of anhydrous magnesium sulfate, the solvent was distilled off. The residue was washed with ethyl ether and dried to obtain -the obejctive product (3.4 g).
A portion of the product was dissolved in ethanol, and glacial acetic acid was dropped thereto_with stirring. The resultant precipitates were recovered by fil-tration and washed with ethanol, followed by drying to obtain an acetate of the subject compound. The following data of physical properties are those of the acetate.
Melting poln~t: 125 - 127C
Infrared absorp-t1on spectrum (cm 1, Nujol):
3200, 1670, 1570 NMR spectrum ( ~, DMSO-d6) 1.90 (3H, s), 5.95 (2H, d, J=54.0 Hz), 7.40 (3H, b) :

~: : :

r~ 3 ~
~xperlment 18 (SynLhesis of the raw material cornpound) 2-(5-Amino-1,2,~1-thiadiazol~3-yl)-(E)-2-fluorometoxyimino-acetonitrlle, N- C CN

N N
H2N ~ S'/
OCH2F "
The compound (3.0 g) prepared in Experiment 17 was dissolved in methanol (50 ml), and triethylamine (4.2 g) was added thereto, After cooling the solution to -5C, bromine (3.5 g) was dropped to the solution. A solution of potassium thiocyanate (2.1 g) in methanol was -then dropped thereto at a -temperature from -3C
to -5C, and the solution was stirred at the same temperature for 2 hours. The resulting precipitates were recovered by filtration and washed with wa-ter and with methanol. The precipitates were then recrystallized from acetone to obtain -the objectlve product (3.4 g).
Melting point: 236 - 238c.
Infrared absorption spectrum (cm 1, Nujol) 3450, 3250, 3075, 1610, 1520 NMR spectrum (~`, DMSO-d6):
6.02 (2H, d, J=54.0 Hz), 8.32 (2H,b) ::: :

~ ' :

:

.

..xperiment 19 (Synthesis of the raw materi.al compound) 2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetam..ide N ll C CONH2 N N
H2N \ / OCH2F

To a solution of sodium hydroxide (0.23 g) in water (18 ml) was added 35% aqueous hydrogen peroxide (7.4 ml). And;~ the compound ~2.0 g) prepared in Experiment 18 was added -thereto with stirring at room temPerature. The solut.ion was further stirred at a temperature from 2SC to 30C for additional 8 hours. The precipitates deposi-ted were recovered by filtration, and washed with water and with acetone, followed by drying to obtain the objective produc-t (1.3 g).

Mel-ting point: 210 - 211C.
In~rared absorp-tion spectrum (cm 1, Nujol):
3450, 3260, 3180,1690, 1610 :~ MNR spectrum (~ , DMSO-d6):
5.73 (2H, d, J=55.0 Hz), 7.69 (2H, br), 7.98 (lH, br), 8.10 (lH, br) ;~

~ 161 )'s~

E.Yperirnent 20 2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoY~yiminoacetic acid N , C - ---------COOI]
~ N N
/ \S / ~OCH2F' ~l2N

A mixture containing the compound (1.1 g) prepared in Experiment 19 and 2N aqueous sodium hydroxide solution (10 ml) was stirred at 50C for 5 hours. The react~on mixture was cooled, and adjusted to pH l.0 with concentrated hydrochloric acid, followed by extraction thrice with ethyl acetate (20 ml). After addition of anhydrous magnesium sulfate to the extract, followed by dryingJthe solvent was ditilled off. The residue was washed with isopropyl ether to obtain a crude product (0.8 g). The crude produc-t was purified by reversed phase silica gel colurnn chromatography to ohtain the objec-tive product (0.4 g).
The infrared absorption spec-trum and NMR spectrum were identical with t~hose of Experiment 13.

:

16~

, , t7 xample 162 (Preparation of an injection) The compound (10 g) prepared in Example 1 was dissolved in distilled water (50 ml). The solution was divided and infused, so that the respective vial rnay contain 5 ml o-f the solution.
This solution was lyopllilized to give an injection.

Example 163 (Preparation of an injection~
The compound tlO g) prepared in Example 151 was dissolvbd in distilled water (50 ml). The solution was divided and;infused, so as -to contain 5 ml per one vial. This solution was lyophili~ed to give an injection.
The acu-te toxici-ty and the anti-bac-terial activity of the compounds according to this invention were determined as follows:
(1) Acute toxici-ty in mouse:
The compoundsaccording to this inven-tion dissolved in a physiological saline solution were intravenously dosed to five ICR male 6 weeks-old mouse. As the result, the values of acute toxicity o~ the compounds prepared in the following Examples were all ln excess of 2g/kg.
Example Numbers:
1, 2-1, 2-2, 3-1, 3-2, 5, 6-1, 6-2, 7-~, 7-2, 9-1, 9-2, 9-3, 10, 11, 12, 13-1, 13-2, 96, 121, 137, 145J 146, 150, 151, 159 and 155 (2) Anti-bacterial activity (MIC):
MIC (~Ug/rnl) were determined by an agar dilution method [Chemo~therapy (Japan), 29, 76 - 79, 1981~. Overnight cultures of the bacterial strains in Mueller-Hinton broth were diluted -to . ~

::

5''~

final concentratioll of about 106 CFU/ml, and 5~1 of each bacterial suspension was spotted onto Mueller-Hinton agar plates that contained twofold serial dilutions of antibio-tics. MICs were measured after incubation for 18 hours at 37C.
As the controls, CAZ (Cefatazidime) and CTM (Cefotlam) were selected.

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~ O ~D ~ O O O C~ ~ O O ~ ~
X E X O O O O O O O O O O
Q.
__-_ .......... _ ... _ . .. - ._ ._ U.
U ~ OOO'C~OOOOOO
~ :~ ~
~ _ . _ .. _ ._ _ . . .___ ~: :~1 :~

~U N O O O O O O O O O O
= Ul _ ~: ~ /~ ~

~ ~ U) ~ E E ~ ,,1 ~ Ul N ~ ~, ~ ~: ~ _ _~ U _ : .___ ~_ 1 ~0 ~ ' ~.3~ B~
__ ._ I_ __ _ .. . .. ..
~u, ~ O o U~
~ CLI U~ CO U~ .~, U~ oo o~
U ~ ~ o ~ o o c :~ Lr) ~n ~ ~ Q. _ ~ ~ _ ~ O ' O ~
h O ~3 O O O O O O O O
__ . - ., E~ cl \ - L~ U In ~ ~ C~
~ ~ ~ v~ o o o o o o o o E W
~ .

t ) ~ I L ~ C~ ~ C~
E ~D O _ _ O O O O O
~ ~ o o o o o o o o ,_, c ~11 ~1 .

;~ . ., ~ -- --- -r~ , C~
: o ~ _ ~ o o o o o ~; 1~ o o o o o o . o o ~s~ z ~1 ~1 . .

a~ ~
~ l o o o o o o o o ~ o u~

1 ~1 '; ~ ~ , :

U~C~ ~ '7 ~ ~ ~ o a. ~a il.1 o ___~ ~

~ ~ I~~
h h a, o o 1 \ ~
~ E
._. _ ~ . .

c~~ I c ~ ~ ~
' ~ ~ o o . . _ .. _ . _ ___.____.. ~
~0~ ~ ~
U I Z o' o 1 ~ 1 ~ ~
~iY, , / ~

;''` ' : :
~ ~ ' ~3~S~

3. Antl-bacterial activity (MrC):
Comparison tests oE the anti-bacterial activities were conducted between the compounds of the following ~ormula according to the present invention and the corresponding control compounds wherein Rl represents methyl group. Measurements of MIC are the same as described in the above item 2. The results are shown in the following table.

N , --- C CONH~ S

H2NJ~ ~ O--Rl ~--CH=CHCH2-A
COO

~: :

a3 :

~3~-~ t~

__.__ .. ,_ ~0 ~ o n C~ ~ r-l ~D O ~I Ul ~I O
_ . . , /\,_ U~
_ (~1 ~ 111 0 U) ~O U~
E L, O r~ O o u ) o ,~ (~1 m ,-1 N

~ ~Y I~ ~ ~ ~
~'U O o O O o ~ O O
~ ... _ . .___ . __ ~D . .
,~ ~ r-l ~ U~ In ~ U~

V~ 111 W r~ ~D ~ ~D ~D ~1 ~1 ~D
: ~D ... .. _ _ ,_ a~ ,~ ~ ,~ ~ ,~ ~ ,~ ?
,_~ ~4 E h CL~ E Ccl 6 ~? ~ E ~?
~ ~: ~ t, 3 ~. . ~ ~ ? 3 ~ n? ~ C v~ , ~: t ,~ - ~

, ~ ~

` ~ ;' , . . . . .

.
.
.

, , ,

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula:

wherein R6 represents carboxyl, a halogenocarbonyl, carbamoyl or cyano group, a compound wherein said amino and/or carboxyl group is protected with a protective group, or a salt thereof.

2. A process for the preparation of a compound of the formula:

a compound wherein said amino and/or carboxyl group is protected with a protective group, or a salt thereof, which comprises (1) reacting a compound of the formula:

wherein said amino group and carboxyl group are protected with a protective group, or a salt thereof, with a halogeno-fluoro methane, followed by optionally removing the protective groups;
or (2) hydrolyzing a compound of the formula:

a compound wherein said amino group is protected with a protective group, or a salt thereof in the presence of a base followed by optionally removing the protective group.