JPS6219593A - Novel cephem compound - Google Patents

Abstract

NEW MATERIAL:A compound (syn isomer) shown by the formula I [R<1> is (protected)amino; R<2> is lower alkyl; R<3> is H, salt-forming cation or carboxyl- protecting group; R<4> and R<5> are H, lower alkyl or halogen], its salt or its ester. EXAMPLE:7-[ 2-Methoxyimino-2-( 2-aminothiazol-4-yl )-acetamido ]-3-[2-(thiozol-2-yl)vinyl]-3-cephem-4-carboxylic acid. USE:An antibacterial agent against Gram-positive, Gram-negative bacteria and resistant bacteria. PREPARATION:A compound shown by the formula II or a reactive derivative at its amino group or its salt is reacted with a compound shown by the formula III or a reactive derivative at its carboxyl group or its salt.

Description

[Detailed description of the invention] (Industrial application field) The present invention is a novel β-lactam antibacterial compound.

and its pharmaceutically acceptable salts and esters. More specifically, the present invention relates to a novel Cepha'6 sporin compound having antibacterial activity.

and pharmaceutically acceptable salts and esters thereof and antibacterial compositions thereof.

(Prior art and problems to be solved by the invention) Examples of β-lactam compounds closely related to the novel cephemide of the present invention include, for example, JP-A-Sho! j-/211790β-
Publication, Japanese Patent Application Publication No. Sho Jt-/22JrJ and Japanese Patent Application Publication No. Sho! Compounds such as those described in Turf 4Or3 are known. Similar to these known near-green compounds, the compound of the present invention has a β-substituted vinyl side chain at the 3-position of the cephem ring; It is a novel cephalosporin having a β-(substituted or unsubstituted thiazolyl novinyl group) at the 3-position with a different type of β-substituent on the vinyl side chain.

Cephalosporin antibiotics are Durham-positive bacteria.

It exhibits broad antibacterial activity1 against Durham-negative bacteria, and various semi-synthetic cephalosporin compounds are already commercially available1 and are used clinically as therapeutic agents for various infectious diseases. However, among these known compounds, there are only a few compounds that exhibit antibacterial activity and antibacterial activity against Pseudomonas aeruginosa and M. aeruginosa and can be put to practical use therapeutically. Additionally, these known compounds are unstable against β-lactamases produced by resistant bacteria;
It has drawbacks such as low antibacterial activity against resistant bacteria, which is currently a clinical problem (W, 'Er, Wick,
”0ephalospori-ns and P
en1c fins, Chemistry and
Biology”.

Edited by L. H. Flynn, Academic Pres.
s, New York, NeY11ri72. 1st
/*).

(Means for Solving the Problems 1 Actions and Effects) The present inventors have succeeded in creating a new cephem compound represented by the general formula (I) below, which has an extremely wide range of antibacterial properties. It has a strong antibacterial activity not only against Durham-positive bacteria but also against Durham-negative bacteria and resistant bacteria, and has low toxicity and is highly absorbable when administered orally or parenterally. The present invention was completed based on the discovery that the antibacterial effect can be exerted for a long time in the body without being degraded until the antibacterial activity is lost in the body.

That is, one aspect of the present invention is represented by the following formula (1) [wherein, Rfl is an amino group or a protected amino group; R2 is a lower alkyl group; and R3 is a hydrogen atom.

V:R4 is a salt-forming cation or a carzexyl group-protecting group.
is a hydrogen atom, a lower alkyl group or a halogen atom:
A new cephem compound (syn isomer), or a pharmaceutically acceptable salt thereof; Or provided by Estel-kai.

In the compound (1) of the present invention, the thiazolyl group bonded to the β-position of the vinyl group at the 3-position of the cephem ring is a thiazole-noyl group, a thiazole-gooyl group or a thiazole-gooyl group having no substituent on the thiazole ring. Thiazole! -yl group or a single alkylthiazole group! −
yl group, 4cm halothiazole-! -yl group or Kotsugu, ・Dino 10 thiazole-! -yl group is preferred.

The compound of the present invention has cis isomers and trans isomers depending on the difference in the steric position in which the substituent on the substituted vinyl group at the 3-position coordinates around the 2-type packing of the vinyl group. The invented compound is a cis isomer.

Includes trans isomers or mixtures thereof.

Suitable examples included in the various definitions in the above and below explanations will be explained in detail as follows.

Unless otherwise specified, the term "lower" in lower alkyl groups refers to i- carbon atoms. Regarding R, the protecting group for the amino group in the protected flat amino group is a tertiary butoxycarzenyl group, an acyl group such as formyl, chloroacetyl, or a trityl group, etc. It is a common amine protecting group that can be easily removed. When TL3 is a salt-forming cation, examples thereof include cations such as alkali metal salts, alkaline earth metal salts, and ammonium salts. Is R also Cal?纺、If it is a syl protecting group.

Examples of such protecting groups include aryl groups, lower alkyl groups, lower alkoxymethyl groups, lower alkylthiomethyl groups, and lower alkanoyloxymethyl groups.

Protecting groups commonly used for cephalosporins can be mentioned. Furthermore, it also includes metabolically unstable protecting groups that can be hydrolyzed and removed in vivo. Examples of such protecting groups include lower alkoxycarzenyloxyalkyl groups, lower alkylcarzenyloxyalkyl groups, and substituents. (2-oxo-/, J-dioxolene-butyl-ylnomethyl groups, etc.).When R and/or R are a halogen atom, the halogen atom includes a fluorine atom, a Examples include a atomic atom, a bromine atom, and an iodine atom, but a chlorine atom is preferred.

Specific examples of the compounds of the present invention include [,7-[nomethoxyimino-2-(coatcutylaminothiazole-μm ylinoacetamide)-3-(X-(thiazole-noyl λ vinyl]-3-cephem-μm Carzenic acid cyphenyl methyl ester (syn isomer, 7=chi-methocheleimino-2-(no-aminothiazole-hiro-ylfuacetamide)-j-[-2-(thiazole-noylnovinyl)]-3-cephem- μm calzenic acid (syn isomer), 7-[nomethoxyimino-,2-(,?-tritylaminothiazole-l-ylnoacetamide]-j
-[''No(thiazole-μm ylnon♂yl]-3-cephem-hiro-carzenic acid p-methoxybenzyl ester (syn isomer) (cis isomer>), 7-(no methoxyimino-2-(no aminothia Zorudaylfuacetamide]-3-[no(thiazol-hiro-yl)vinyl]-3-cephemu≠-carzenate sodium salt (syn isomer) (cis isomer J, 7-(nomethoxyimino-2- (Noaminothiazol-μ-yl]-acetamide]-J-(J-(thiazole-guylnohynyl)
-3-Se7 emug carzenic acid piparoyloxymethyl ester (syn isomer) (cis isomer), 7-[no methoxyimino no (no tritylaminothiazole-μ-ylno acetamide 3-J-C No (no methylthiazole!-ilnovinyl)-3-cephem-≠
-carzenic acid diphenylmethyl ester (syn isomer)
(cis isomer, trans isomer.

or cis-trans isomer mixture J, 7-(J-methoxyimino-(no-aminothiazol-l-yl 2
-acetamide] -J-C2-<nomethylthiazole-yyllambyl vinyl]-3-cephemul-carzenate sodium salt (syn isomer) (cis isomer, trans isomer, or cis-t, trans 7-[nomethoxyimino-2~(noaminothiazole-μm-7cetamido)-3-Cno(nomethylthiazole-yylnohynyl)-3-cephemu-carzenic acid (,1 -Methyl-nooxo/, 3-dioxolene-t-yltmethyl ester (syn isomer) (cis isomer, trans isomer, or cis-trans isomer mixture 7.7-(λ-methoxyimino 2- (No-aminothiazole-μm ylnoacetamide)-JC-2-(
≠-Methylthiazole! -ylnovinyl]-3-cefe, A-≠-carzenic acid (!-methyl-no-okine-/
, J-dioquinlene-hiro-ylzmethyl ester (syn isomer) (cis isomer, trans isomer, or cis isomer)
trans isomer mixture), 7-(J-methoxyimino-2-
(notritylaminothiazole-l-ylnoacetamide)-J-(nor(thiazol-y-ylJvinyl)-3-cephem-≠-carzenic acid diphenylmethyl ester (syn isomer) (cis isomer), 7 -1'a-Methoxyiminoco-(no-aminothiazole-μm ylnoacetamide)-J-Cno(thiazole-!-ilfuhinyl)-3-cephem-μm carzenate sodium salt syn isomer) (cis isomer) 7-[Nomethoxyiminoco-(noaminothiazole-≠-ylnoacetamide)-J-(no(thiazole-!-ilnovinyl)-3-cephem-≠-carboxylic acid hivaloyloxymethyl ester ( syn isomer) (cis isomer), 7
-(,,2-methoxyimino-no(notritylaminothiazole-l-ylnoacetamide)-3-[λ
-・<a-Chlorthiazole-! -ilnohynil]-3
-cephem-μm carzenic acid p-methoxybenzyl ester (syn isomer) (cis isomer).

7-[λ-Methoxyimino 2-(no-aminothiazole-l-ylnoacedo epsilon)-J-(,2-(4A
-Chlorthiazole-! y-[x-methoxyimino-(λ-aminothiazol-μ-yl]-acetamide) -J-(
No(4!-Chlorthiazol-!-yl]hinyl]-
3-Cefemudarcarzenic acid piparoyloxymethyl ester (syn isomer) (cis isomer), 7-[nomethoxyiminoco-(-monotritylaminothiazole-daryl]-acetamide) -J- (J-(J, 4(-
Dichlorthiazole! -ylnovinyl]-3-cephem-←carboxylic acid p-methoxybenzyl ester (syn isomer) (cis isomer).

7-(,2-Methoxyimino-(λ-aminethiazole-yl-yl)-acetamide]-'J-[no(9μm dichlorothiazol-yl]vinyl]-3-
Cephem-μm carzenate sodium salt syn isomer)
(cis isomer), and 7-[nomethoxyimino-2-
(No-aminothiazole-Hiro-ylnoacetamide)
-J-(no(2+μm dichlorothiazol-!-yl λ vinyl))-3-cephem-hiro-carzenate piparoyloxymethyl ester (syn isomer) (cis isomer), and the like.

The compounds of the present invention can be produced by the following method.

That is, the adduct of formula (I) is a compound represented by the following formula (wherein R3, R4, and R5 have the same meanings as above), or a reactive derivative thereof at the amino group, or a salt K thereof.

A method comprising reacting a compound represented by the following formula [phase] [wherein al and R2 have the same meanings as above] or a reactive derivative or a salt thereof at the carxyl group!
/c can be manufactured. Suitable examples of reactive derivatives at the amino group of compound (1) are:

Schiff base-type imino or its tautomeric enamine-type isomer produced by the reaction of compound ■ with carzenylated compounds such as aldehydes and ketones; Examples include silyl derivatives; or compounds (derivatives produced by reaction of ID with phosphorus trichloride or phosgene).

Suitable salts of compound ■ and haze include salts with organic acids (
For example, acetates, maleates, tartrates, benzenesulfone Ii salts), luenesulfonates, etc. or salts with inorganic acids (e.g. hydrochlorides, hydrobromides, sulfates, phosphates, etc.). acid.

Addition salt: alkali metal salt or alkaline earth metal salt (7
2: For example, sodium salt, potassium salt, calcium salt,
Examples include metal salts such as magnesium salts; ammonium salts; organic amine salts (such as triethylamine salts and dicyclohexylamine salts).

Suitable examples of reactive derivatives at the carxyl group of the compound [phase] include acid halides, acid azides, acid anhydrides, activated amides, activated esters, and more particularly acid chlorides, acid anhydrides, etc. Bromides: substituted phosphoric acids (e.g. dialkyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl sulfite, sulfite, thiosulfuric acid, sulfuric acid, alkyl carbonate ('fc, e.g. methyl carbonate, ethyl carbonate, etc.), fats. Group carbenoic acids (e.g. piparic acid, valeric acid.

Isovaleric acid, no ethyl acetic acid. mixed acid anhydrides with acids such as trichloroacetic acid (such as trichloroacetic acid) or aromatic carzenic acids (such as benzoic acid); imidazole;

Active amides with dimethylpyrazoles, triazoles or tetrazoles: or active esters ('fe,!-, t-cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl ((OH3)2N=OH-) esters, hinyl esters, solonosokyls ester, p-nitrophenyl ester, 22 μm dinitrophenyl ester, trichlorophenyl ester.

Pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, calzexymethyl thioester, hyranyl ester, hyridyl ester, piperidyl ester,
r-quinolyl thioester), or iN- and droxy compounds (eg, N,N-dimethylhydroxyamine, l-hydroxy-no(/)l-nopyridone).

Examples include esters with N-hydroxysuccinimide, N-hydroxy 7-talimide, l-hydroxy-6-chloro-/H-benzotriazole, and the like. Kon
Their reactive derivatives are the reactant compounds to be used (IllD
It is selected as appropriate depending on the σ type.

The reaction between this compound (ID and phase) is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydro7rane, ethyl acetate, N, N
- in conventional solvents such as dimethylformamide, pyridine, or other organic solvents that adversely affect the reaction. These solvents can also be used mixed with water.

In this reaction, when the compound a[D is used in the free acid form or in the salt form, C as the condensing agent, for example N,
N'-dicyclohexylcalcediimide: N-cyclohexyl-N'-morpholinoethylcalcediimide: N-
Cyclohexyl-N'-<a-)ethylaminocyclohexylnocarzediimide; N.

N'-dimethylformamide: N, N'-diisopropylcalzediimide: N-ethyl-N'-(J
-dimethylaminopropyl]calzediimide; N.

N-carbunylbis(nomethylimidazolene; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine: ethoxyacetylene; l-alkoxy-l-chloroethylene: trialkyl phosphite; ethyl polyphosphate; polyphosphoric acid Isopropyl; phosphorus oxychloride; phosphorus acid chloride; thionyl chloride;
Oxa chloride 1) /l/ : ) IJ phenylphosphine; no ethyl-7-hydroxypenzin xazolium salt: no ethyl! -(m-sulfophenylnoinixazolium hydroxide inner salt 'e' -(p
-chlorobenzenesulfonyloxyno-6-chloro-1
H-hensitriazole: Examples include the so-called Guillsmeyer reagent obtained by reacting dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, and the like.

This reaction may also be carried out in the presence of an inorganic or organic base, examples of which are alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal carbonates. (e.g. calcium carbonate, etc.), tri(lower noalkylamines (e.g. triethylamine, trimethyl, lyamine, etc.), pyridine, N-(lower noalkylmorpholine, N, N, J
--7 (lower non-alkylbenzylamine, etc.).

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

In addition, in the compound (1) of the present invention obtained by the above reaction, if necessary, the carxyl protecting group and/or the amine protecting group may be removed according to a conventional method. Depending on the situation, the carzexyl group may be converted to a metabolically unstable non-toxic ester group. The method for removing the carxyl protecting group and/or the amino protecting group is appropriately selected depending on the type of protecting group to be removed. For the elimination reaction of the amino protecting group, hydrolysis and reduction are used. For compounds where the protecting group is an acyl group, a method of reacting with an iminohalogenating agent, then an iminoetherifying agent, and then hydrolyzing as necessary. Any commonly used method can be applied. The method of hydrolysis using an acid is one of the general methods and is applied to the elimination of groups such as 7c, for example, alkoxy groups such as ruzenyl group, formyl group, and trityl group. Further, as the acid to be used, formic acid, trifluoroacetic acid, acetic acid, hydrochloric acid, etc. are appropriately selected depending on the type of amine protecting group. The reaction can be carried out without a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed medium thereof. Further, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. Any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of the carzexyl protecting group. Subhydrolysis using an acid is a general method for eliminating groups such as silyl groups, diphenylmethyl groups, etc. The metabolically unstable esterification method is a commonly used method known per se, for example, a method in which a metal salt of carzenic acid is reacted with a compatible alkyl halide such as piparoyloxymethyl halide in a solvent. .

Suitable examples of pharmaceutically acceptable salts of the target compound (1) are the usual pharmaceutically acceptable non-toxic salts, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.) and metal salts such as alkaline earth metals (e.g. calcium, magnesium, etc.),
Ammonium salts, salts with organic bases (4 examples are triethylamino salts, trimethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, salts with organic acids (7 examples are acetic acid) salt, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate.

formate, toluenesulfonate, etc.], salts with inorganic acids (
For example, hydrochloride, hydrobromide, sulfate.

These include phosphates, salts with amino acids (eg, arginine salts, aspartate, glutamate), etc.

Next, the pharmacological effects of some of the compounds of the present invention will be shown.

/No Antibacterial Effect Table 1 shows the minimum inhibitory concentration measured using the agar dilution method.

, 2) Urinary recovery rate of test compound in mice (IOR″41 male, 4 withdrawn) 1
Orally administered at a dose of -0.3q per animal, and the urinary recovery rate was determined. The results are shown in Table 2.

In addition, in all test compounds, the ester group on the 2-position carzene acid group was easily detached in vivo after absorption.

Since the corresponding free calzenic acid was obtained, the amount of the compound of the present invention in the form of free calzenic acid excreted in the urine was quantified and determined as the urinary recovery rate. A high urinary recovery rate indicates that the amount of the test compound decomposed in the body before losing its antibacterial activity is low.

Administration method: The test compound was suspended in fO02*OMO aqueous solution and then administered orally.

Quantification method: Pe-1R-disk method (test bacteria: E.

The amount of the test compound in the urine was measured using E.coli K-/Cotco34).

Table λ O-μ Time Average of 3 cases When the objective adduct of the present invention or its pharmaceutically acceptable salt or ester is administered for therapeutic purposes, the above-mentioned compound should not be contained as the total active ingredient. , mixed with a pharmaceutically acceptable carrier such as an organic or inorganic, solid or liquid excipient suitable for oral, parenteral or topical use, and formulated into a fungicidal composition, according to the conventional methods. It can be administered in the form of formulations, such as capsules and tablets.

Examples include ointments, suppositories, solutions/suspensions, and emulsions.

Furthermore, if necessary, the above-mentioned preparation may contain adjuvants, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

EXAMPLES Next, the production of the compound (I) of the present invention will be explained in detail with reference to Examples. In addition, the production of the raw material compound (ID or [phase]) is shown as a reference example.

Reference example/μm chloro! -Production of thiazole calgoxyaldehyde Drop phosphorus oxychloride (/2λ, 7f) k into dimethylformamide P·(7J,/f) under water cooling. After stirring for 30 minutes after dropping, thiazolinco, 4A-dione (2
3. Add Hiroshi 2) and heat at 100°C for 3 hours.

Cool the reaction solution to room temperature and pour into a drain (200f).

After neutralizing by adding sodium acetate, methylene chloride
Extract around O-≠. After washing the methylene chloride solution with a small amount of saturated sodium bicarbonate solution.

Dry with anhydrous magnesium sulfate. Concentrate under reduced pressure and separate and purify by silica gel column chromatography (eluent: benzene:ethyl acetate = io:i). The title compound (/, IO?) was obtained as pale yellow crystals.

NMR δ value (CD (M3J: L? J (/
H, d.

J=/Hz), 10.03(/H,d, J=/Hz)M
S m/e/IL I (M+/) Reference example Coco, <L-dichloro-y-thiazole Production of ruzexaldehyde Dimethylformamide (7J,/t) in dichloroethane <-2oo, 1) Add a solution of dichloroethane <-2oo, under water cooling. Bovine phosphorus chloride (/
Drop J2, 7f). After stirring for 30 minutes after the dropwise addition, thiazoline-1, kudione (23,4 LP) was added, and the mixture was heated under reflux for 7 hours. After cooling the reaction solution to room temperature, pour it onto ice (CO00f). After neutralization by adding sodium acetate, extract with methylene chloride (200 ml, 3 times 2. The methylene chloride solution is washed with a small amount of saturated hydrogen carbonate) +7um solution, and then dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and separate and purify using silica gel column chromatography (eluent: benzene:ethyl acetate=/0:/). Hiro - Kuroro! - dialdehyde (0,3uf) in thiazolecalce and the title compound (co, o ty
) was obtained as pale yellow crystals.

NMR, δ value (CDC23): Ta, Ta 0 (/H,,
) M S , (m/e): ltko (M+ten/)
Reference example 3 p-methoxybenzyl 7-phenylacetamide-3
-[No(4C-chlorothiazole-!-ylnovinyl]-3-cephem-μ-ruzexilate (cis isomer), p-methoxybenzyl 7-phenylacetamide-3
-Chloromethyl-3-se7em-11 cardaxylate (j, 2 Aj f, 4.7 / mmorph and triphenyl *sphere (/J j P F , 7.0
! Sodium iodide (1, Oj4?.

Add 7.0 j mmol) and stir for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and then diluted with methylene chloride (i.

- Add Nowo. This solution was added with μm chloro-
! -thiazole calxaldehyde (/, / 00
f) Add f, then add saturated aqueous sodium bicarbonate solution (/0rd). After stirring at room temperature for t hours, the layers were separated, and the aqueous layer was extracted with methylene chloride (/Odl). ) Isolate and purify by flash column chromatography (eluent: 24% ethyl acetate = J2/J) to obtain the title compound (s, r P it , 7 a %). do.

NMR δ value (0DO1S:3./J'(/H,,,,d
.

J”/I Hz), J,gco(/H,d
=/rHz).

Jj/ (2H,s), J,7g(JH,
s),! ,00(/H,d,J=jHz
),! ,04(2H,s).

! J4A(/H, dd, J=jl(j, 9Hz), t
, /4L(/H, d, J=PHz) , J,,
27 (/H, d, J=l coHg), A,
14 (/H, d, J=-/2Hz) μ, 7-4
．． 7! (2H, m), 7.0!
-7,4A (7H,m)sl,! 0
(/H, 3) Reference example Hiro p-methoxybenzyl 7-amino-3-[λ-(≠-
Chlorothiazole! -yl)hinyl]-3-cephemu μ-calxylate (cis isomer) p-methoxybenzyl 7-phenyl 7 obtained in Reference Example 3
- to amyl'-3-[λ-(4L-chlorothiazol-y-ylλvinyl]-3-cefemoglucal?xylate (cis-R form) (-2,4'j, f4t, co / millimorno methylene chloride solution (10td) f-30
Add pentachloride 7 (J, A J Orlco, t3 mmorno and pyridine (J, 4'+d, μλ mmolf) to a methylene chloride solution (4'osg) at °C.

The reaction solution was stirred for 3 hours under water cooling, then added to methanol cooled to -3oC and stirred at room temperature for 1 hour. Then, under water cooling, saturated brine (700 yd) and methylene chloride (100-) and stir for an hour.

After separation, the aqueous layer is extracted with t-hydrogenated methylene (jO,z), and the extract is combined with the organic layer. This organic layer is washed with a fully saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate.

After concentration under reduced pressure, Lv isolation and purification was performed by flash column chromatography using Wako gel 0-JOO (+109) f (leaf solution: benzene:ethyl acetate = 3:i). Titled appendix (/, j4tJP 7 Tachino is obtained.

NMRa value (ooaz3): /, 7j
(2F(, broadS,] , j, J 0 (/
H, d, J=/rHz), J, 4t
4t(/H, d, J==/J'Hz), J, 7
J (j Hg 8 ) +! ,77(/H,d
, J=J'Hz), 4t, Ta 7(/H.

d,”J=,rHx),!,O
r(,2H,s), 13/(
/H, d, J = / Ko H Sugi J, Otsu, Yu! '(/H"wd+
J = / JHz], 4.7-AJ! (2H, m)
,7. /-7,Jj(JH,mJ', !,!0(
/H,s) Reference example! p-Methoxybenzyl 7-phenylacetamiF'-
Preparation of J-[λ-(Co,Hiro-dichlorothiazol-z-ylnhinyl]-3-cephem-≠-calcexylate (cis isomer) p-methoxybenzyl 7-phenylacetamide-3
-Chloromethyl-3-cephemo-gcalxylate and Reference Examples Kodefu 72: Ko, 4t-dichloro! -thiazole calgoxyaldehyde 1, the title adduct (7rts) was obtained in the same manner as in Reference Example J.

NMRδ value (oDai3): 3-/
ta (/)I, d, J=/l1lz),
3,410 (/H, d, J”:/KHz)
.

! , 0/ (/H, d, J=jHz
), S, Ota (2H.

s), shrl (/H, dd, J=jHz,
rikh).

A, / 0 (/H, d, J = RiH 尤), t, ko2
(/H.

d, J=/2Hz), 4.4c6 (/H, d
, J=/koHz), 7.7-7Jj (2H, m),
7. /-7,u! ).

(7H, m) Reference example t p-methoxybenzyl 7-amino-J-(J-(co2
μm dichlorothiazole! -Ilnovinyl)'-J-
Preparation of cephemu μm calxylate (cis isomer) p-methoxybenzyl 7-phenylacetamide-3
-[No(co,4L-dichlorothiazol-!-yl λvinyl]-3-cephemubutsu-calcexylate (cis isomer synthesis) The title compound (73
I was disappointed.

NMRδ value (aoot3): iJ O(2
H, broadS), 3.20 (/H, d, J=/rH
1), 3. Hiroko (/H, d, J=/rHz),! ,7
j(JH,S).

g, 7 ta (/H, d, J=jHz), 4A
, Ta t (i H.

d, J=! Hz),! , 10(2H,s), A, Kot(/H,d, J=L2Hz), 4,4<4<
(/H,d.

J=/2Hz), 7.7-7, r! (AH, m), 7.
/-7,≠(7H,m) Example 1 p-Methoxybenzyl 7-[Nomethoxyimino-(coat lythylaminothiazole-μm ylnoacetamide]-3-(J-(Hiro-chlorothiazole-!- ilnohynil]-3-cephem-μ-ruzexylate (
Production of p-methoxybenzyl 7-amino-3-[no (4t
-chlorothiazole-! -ylnovinyl]-3-cephem-μ-carboxylate (cis isomer) (/, coOJ
f, co, t O mmol” and 2-(not tritylaminothiazole no λ-methoxyiminoacetic acid (syn isomer)
(/, / r J t , 2.t O millimoles of methylene chloride solution (JOml) at -20"C:, pyridy (0,14'mj , / 0.IA mi1
3% Le J and phosphorus oxychloride (θ, Jjml, J, 6≠
1 mol Jt-add sequentially. After stirring the reaction solution at t-θ℃ for 0 minutes, ice water (100 dl) and ethyl acetate (/
00yd) and after stirring, separate the organic layer. Organic layer tube saturated hydrogen carbonate) Washed with IJum aqueous solution,
Dry with anhydrous magnesium sulfate. After concentration under reduced pressure, it was isolated and purified by Wako Gel 0-300 (109) T-fc7 column chromatography (lW eluate: benzene: ethyl acetate = j: / J. The title compound (/, l, t!f, 72%) is obtained.

NMRδ value (0DO13): J, 20
(/F(,d, J=/KHz), 3.
414A (/H, d, J==/IHz).

7.74 (JH,s), 41.03 (JH,
s), 37.07(-2H,s)
,! , 01r (/H, d, J=jHz).

! , ta a (t H* da + J =
' Hz + 2Hz), iJ J(/H, d,
J=-/2H1), A,jri(/H,d.

J=/JHz), 17 - 7.44
(J 2 H, m), r, t.

(/H, s) Example core [no methoxyimino λ-(no aminothiazole-glyloacetamide)]-3-[no(Hiro-chlorothiazole-yoyylfuhinyl)]-3-cephemu μ
-Preparation of sodium caldenate (syn isomer, cis isomer) p-methoxypencil 7- (': ≠-chlorothiazole-!-ilnohynyl]-3-cephem-hiro-cal-xylate (syn isomer, cis isomer) (o, r J-a
Anisole C-2m with t, o, and t2 mmorno
1) Add trifluoroacetic acid (rtd)'11- to the solution under water cooling.
Drip. After stirring in water cooling for 7 hours.

Add inpropyl ether (!0td). The resulting precipitate was collected by filtration and washed with inopropyl ether.

Dry under reduced pressure. The title compound (calzenic acid) is obtained as trifluoroacetate (O6j r & ?)
.

water (3-) and carboxylic acid) IJum (O, 1j
Fat? Add and dissolve the Diamond Ion HP-J O resin (Mitsubishi Kasei) column and isolate and purify by Niji chromatography (eluent: water, then 30% acetone water).The fraction containing the target product is concentrated under reduced pressure and freeze-dried. The title compound (Oo, μJJf, ?λ%) is obtained.

NMR δ value (D20): J, GJ (/H, d, J=
/KHz ノ,! ,70(tH,d,J=/rHz
).

41. OJ (JH, S), 1.172 (tH,
d, J=jHz), j, FO(/H, d
, J=! Hz), A', <41(tH,d
, J=/2Hz), A,7/(tH, rl.

J = / J Hz) + 7- □ A (
'H,s) *'-1' 7 ('H-
) Example 3 Piparoyloxymethyl 7-[2-methoxyimino-
Preparation of 2-(no-aminothiazole-hiro-yl diacetamide)-J-(λ-(μm chlorothiazole-yylfuvinyl)-3-cephemu μ-calcexylate (syn isomer, cis isomer) 7 -[Nomethoxyimino-2-(2-aminothiazole-≠-ylnoacetamide]-J-(2-(Hiro-chlorothiazole-yo-ylnovinyl: -3-cefemu-Hiro-carzenate sodium (syn isomer, cis Isomers] (
o, ioμf, 0. /♂rmmol dimethyl formamide (Jd
/t, 0.2μ mmol and sodium iodide (Oo-♂coF,i,rr mmol could be reacted in acetone) in dimethylformamide F'(/
m/) Add solution/stir for θ minutes. Add ice water (20-) and ethyl acetate (-20-) to the reaction solution, stir well, and then separate the mixture. The organic layer is washed with water (10 ad, 2 times) and saturated brine (/Omt) and dried over anhydrous magnesium sulfate. Wako gel a-3oo after concentration under reduced pressure
Isolate and purify using flash column chromatography (W! I eluent: ethyl acetate J) using (iot)2.

The title compound (o, riμOf, 71chino) is obtained.

NMR, δ value C0DO13) ; /, / J (riH
t') w3.30 (tH, d, J=/KH
z), J, j/ (tH.

・d, J=/rHz),
,t,/7(tH,d,J::jHz
j, Hiroj (2H, broads),! ,7j(/H+d
*J=6 H2), J, lr O(/
H, d, J=jHz).

4.04(tH, ad, J-=tHz, 2H
z), A, 4AO(tH, d, J=/koHz), t, A
A(tH,d.

J=/2Hz), &,7r(tH,s),7.6! (t
H, d, J=2Hz), lr, ju (tH, s) Example Hirota The following compounds were prepared in the same manner as in Example 1.

Example Hirodiphenylmethyl 7-[Nomethoxyiminoco-(
2-Tritylaminothiazole-μm ylnoacetamide'3-j-C (thiazole-λ-ylnohynyl)
-3-se7m-ruzexylate (syn isomer,
3. Manufacturing yield of trans isomer) NMRa value (ODCt3); Hiroj (
tH, d , J = /J'HzJ , J, A7 (tH, d
, J=/KHz).

! ,O&(JH,s),! , /J(tH,d,J:=j
Hz), j, 7 (tH, d d, J=j
Hz, 2Hz).

t, し”('H*a) + IIG-
7J (tH,s), AJ! (tH,
s ), t, F −7, s r (2
P H,m ), 7,7u(tH,c
f, J=jHz) Example! diphenylmethyl-,,7-(nomethoxyimino-
2-(2-trityl(aminothiazol-≠-yl)acetamide)-3-(x-(x-methylthiazol-y-ylnohynyl)-3-cephem-μ-forcexylate (syn isomer, trans isomer) Production yield of 61r NMI'L δ value (cDct3); x
, Otsu 3 (JH,s).

3J/s (λH, broad, s), 101
7 (JH, s).

j,06 (tH,d, J=!Hz), j,I
re (tH.

dd, J=jHz, 9Hz), 6.73 (tH
,s).

A, lr2 (/H, d, J=/AHz), t,
Ta r (tH.

3), 7.0-7. t (H, 2
Ta, m) Example 6 Diphenylmethyl 7-(J-methoxyimino-2-(
2-) lythylaminothiazole-Hiro-ylnoacetamide)-J-(u-(2-methylthiazol-s-yl)
hinir]-3-cephem-φ-cal day? Production yield of gysylate (syn isomer, cis isomer)
O(JH,sJ.

J, J7 (jH, d, J-=/rHz), J,
ui (jH.

d, J=/J'Hz), μ, O# (jH, aJ,
j, /d(/H,d,J=!Hz),! ,ri7(
jH, dd.

J = j Hz', 2Hz), t, /
3 (jH, d, J=/ Hz), i@/(jH, d
, J-=/-2Hz), A,7/(jH,s)
, 4JJ(jH,s), A, Tar-7.3(21rH
, m) Example 7 p-methoxybenzyl 7-(J-methoxyimino-2
-(2-tritylaminothiazole-hiro-ylnoacetamide)-j-['no(thiazole-guylnohynyl]-3-cephem-butsu-calxylate (syn isomer, cis isomer) f) Production yield Rate yzqb NMRδ value C0DOL,) : J, 4tO(/H,
d.

J=/fHz), JjJ(jH, d, J=/rH
x).

, J, 77 (JH#l!), u, Ou
(JH,s), j,10(jH,d
, J=1Hz), j, / / (koH,,s
).

jJri(/H, d d, J=jHz, 9'Hz
), 6.13 (JH, 3), t, 7-7
,! (2JH, m), rjj (jH, d, J
=2H1) Example r diphenylmethyl 7-[”J-methoxyimino-
(Cotelylaminothiazole-guylfacetamide)-3-(no(thiazol-z-yl)hinyl)-3-cephemu μ-ruzexylate (sin J1
Production yield of NMR δ value LODOt, ): J, core (/) (, d
.

J=/rHX), J, Hiro 4 (jH,d
, J=/rH1).

u, 04A (/H, d, J==jHz)
, j, ta 4 (jH.

' d d, J = jHz, 2Hz)
, Fu, Ko J (jH, d, J==/ 2Hz), &J
O(jH, d, J=/2Hz).

4.7/(jH,a)t4. Za 3 ('H+s)+'
-Tar 7-! (j 7 He m)
e7-t/(/H+
s).

IJ 7 (/H, s) Example p-Methoxybenzyl 7-[No-methoxyimino-(notritylaminothiazole-≠-ylnoacetamide)-J-(-2-(co,4L-cyclothiazole-J -/flunohynyl)-j-cephem-gukal-
Xylate (syn isomer.

Production of cis isomer) Yield 11% NMRδ value (OD(M3J: J, co/(jH, d.

J=/KHz), ! , 4C (jH, d, J
=/KHz).

J, 74 (JFf, sJ,!, θ e (J H,
s].

1.0 ta (/H, d, J=!Hz), j
, //(koH,s).

! , ta j (jH, d d , J=-tH,, 2Hz)
,t,J! (jH, d, J=/2Hz)
, i4L 7(jH,d.

J=/coHz), 6.7-7.44 (JJH, m) Example 10-/! All of the following compounds (IJium salt or ToI fluoroacetate) were manufactured in the same manner as in Examples.

Example 10 7-[nomethoxyimino-(noaminothiazole-l-ylnoacetamide)]-3-[no(thiazole-noylnovinyl°)-3-cephem-hiro-sodium cardinate (syn isomer, trans Production yield of rxts NMRa value (D20.): J, male (2H, broa
d*s), 4C1(7J (J H, @)
, j , J j (' H+ d rJ=!H1)
, ! , lr j (/H, d, J=jHz)
.

6. Tata (jH, d, J=/4Hz), 7.
OJ (/H.

s), 7.4AA (jH,d, J=/AH
z), 7. II (/H, d, J=JHz)
, 7.74 (/H, d, J= J
Hz) Example 1/7-[No-methoxyimino-2-(no-aminothiazole-hiro-ylnoacetamide]-3-(co-(2-methylthiazol-!-ylnovinyl)-3-cephem-glucarboxylic acid trifluoro Production yield of acetate (syn isomer, trans isomer) RR value NMRa value (OD3SOOD3);
).

j, 7 j (2H, broad, s
),,i,r,i<3H,s).

j, / r (/ H, d, completion=!Hz),
j, 7t (/H.

d d, J=jHz, 2Hz), A, 7j
(jH,s).

7, /j(2H,s), 7j O(
jH,s), ta3r(jH,d,J=2
Hz) Example/,2 7-[,2-methoxyimino-2-(no-aminothiazole-≠-ylfacetamide]-3-(,2-(J-
Production yield of methylthiazol-j-yl λvinyl]-3-cephem-μ-calP acid trifluoroacetate (syn isomer, cis isomer) 71 ￤NMRδ value (CD, 5OOD3); ri(jH.

s ), j, 4(/ (jH, d, J=/1rHz
), JJJ (jH, d, J=irHz), J,
I4A (JH,s).

! , 2♂(jH, d, J=rHz),! , 12 (jH.

d d, J=jHz, J=riHz), JJJ(j
H.

d, J=/2Hz), 4. jj(jH, d, J=/J
H1), 4.73 (/F(,S), 7.j
7 (jH, 8).

9.60 (jH, d, J = Hz) Example 13 7-(X-methoxyimino-2-(27aminothiazole-μm ylnoacetamide)-3-[no(thiazole-μm ylnovinyl)-3-cephem - Production yield of μm sodium calgenate (syn isomer, cis isomer) HI NMRδ value (D20); 3. Hiro j (jH, d
, J=/rHz), Ljr (jH,d, J=
/rHz).

4A,03(JH,s),! , J! (jH,d
, J=jHz), ! , r II (/
H, d, J=jHz), J, tJ(jH,
d, J=/uHz), A, yt (i
H, d.

J=/2Hz), 7.06 (jH,s
), 7. jj(/H, d, J=
= JHz) , r, ta (jH, d.

J=2Hz) Example 1μ 7-[Nomethoxyimino(2-aminothiazole-≠-ylnoacetamide)]-3-[2-(thiazole-yo-ylnovinyl-to-3-cephem-μm sodium carboxylate (synisomer Production yield of 7r-isomer, cis isomer) NMI'L δ value (D20); 3.μ
F(jH, d, J=/rHz), 3.70 (j
H, d, J=/rHz).

G, Oj (jH, s), j, jj (/) (, d,
koJ=jHz) ,! , Ta 0 (jH, d, J
=jHz), 6. J ta(jH, d, J=/2H
z), if/ (jH, d.

J=/JHz), 7.01 (jH,s
), 7. r 4 (jH,s)
, r, ta 0 (/H, s) Example/
j 7-(j-methoxyimino-(2-aminothiazole-hiro-ylnoacetamide)-J-[no(2,4A
Production yield of -dichlorothiazole-yo-ylnovinyl-3-cephemuder sodium caldenate (syn isomer! cis isomer) 71q6 NMR δ value (D20); 3. ≠J(jH, d, J=/K
Hz),jj7(jH,d,J=/jHz
).

4A, O$(jH, s ), j, 4j(jH,
d, J=JHz), j, ta/
(/H, d, J==jHz)
, +, g t(jH, d, J=/2Hz
), 144L (jH, d.

J=/2Hz), 7,0. t(' / H, s
) The following compounds were prepared in the same manner as in Example 3.

Example 1t (j-methyl-nooyasol, 3-dioquinlene-μ
m-Irutmethyl 7-[:j-methoxyimino-(
2-aminothiazole-guylnoacetamide]-3
-Cλ- (no-methylthiazole-!-ilnohynyl)
-3-cefemugoocalcexylate (syn isomer,
Production yield of trans isomer) NMRδ value C0DCL5): =2. ．． 2
/ (j H, s).

j, 7ri (JH, s), J, evening (jH, d, J=/♂
H2), ! , 7! (jH, d, J=/KH
z).

@, 04(jH,s), 4ζ, Ta J
(/H, d, J=/AHz),
j, / 2 (/H, °J=jHz)
,! , /II(jH,d, J=/AHz)
, j, 4c (JH, broad).

! , ta ta (/H, dd, J”jHz, J
=riHz).

4.1r/(/H,s),
B, ter 2 (jH, d, J = / tHz),
7,244 (/T(, d, J=/
AHz].

7.1! (/H,s), 7.6≠(jH,
d', J=riHz) Example/7 (j-methyl-1-ogiso/, J-dioxolene-guylzmethyl 7-[λ-methoxyimino(2
-Aminothiazole-μmylnoacetamide)-J-
(J-(2-methylthiazol-!-yl)vinyl]-
3-cephem-μ-cal N-z sylate (syn isomer,
Production yield of cis isomer) 22cm NMRδ value (ODO15): Co, 01
(JH, s).

2ju (3H, s), J, uj (jH, d, J=/
IrHz), J, Hirohiro (jH, d, J=〆 tHz
).

Il, 0u (JH, s), IIJO (jH, d, J=/
JH2), ≠, ta (jH, d, J=/
AHz).

! , 22 (/H, d, J=jHz
), jJ (uH.

broad), 6. / 0 (d d
, J=jHt, 2Hz).

A, /7(jH,d','J=/2Hz), AjqJ/
H.

d, J=/-2Hz ノ, 17J'(jH,s
), 7.4 Otsu l;(/H,s)
, 7.7 2 (jH, d, J= 2'flz)
Example it Piparoyloxymethyl 7- (
Production yield of 3-cephem-hiro-calcexylate (syn isomer, cis isomer J 7λ coefficient NMR δ value (ODOt3): /, / 4 (riH,
s).

J, ul(jH,d, J=/1rHz), 3.61(j
H.

' r J = / J' Hz)
, 4t, 011(jH,s) , j
,/t(jH,d, J=!Hz),! , 7!
(jH,d.

J=tHz), j, r l, (jH,
d, J=6Hz).

! , Ta 44 (jH, dd, J=jH2, 2Hz),
61/(jH,d, J=/2Hz), t, 11
(jH,d.

J=/2Hz), AJI (jH,s), 7.
/P(jH, d, J=JHz), J'jA(jH, d,
J=2Hz) Example/P Pinomaloyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazole-μm ylnoacetamide)-j-(-2-(thiazol-y-yl) vinyl2-3- Cephem-4-forcerzegicylate (syn isomer,
Production yield of cis isomer) NMRδ value (0DOt3): /, /j(PH,s
).

! , 32 (/H,d, J=7KHz), 3jO(
jH.

d, J=/KHz), 4', 04A(JH,s
), ! ,/ri(/H, d, J=!Hz
),! , 74t (jH, d, J=tHz),
j, ♂/ (/H, d, J=tHz), 6
．． 02(/H, dd, J=jHz, taHz), t, J j (/I(.

d, J=/jHz], 6. t ♂ (jH, d
, J=/-2Hz), t, Ir I (
jH,s), 7.4t/(/
l(,d.

J=riHz), 7.7! (jH,s),
r, AA (jH.

S) Example λO pivaloyloxymethyl 7- [j-methoxyimino-2-(2-aminothiazole-μm ylnoacetamide)-j-C1-(co,guzik:rolothiazole-yylnovinyl]-3- Production yield of 7F'M-μmm calxylate (syn isomer, cis isomer) 7/NMR δ value (oDot3);
).

3.30 (jH, d, J=/♂Hz), 3. J
2 (/H.

d, J=/KHz), 4t, o sir
(jH,s), L/t(/H
, d , J=AHz) ,! , 7F (jH, d, J=
AHz), jJ / (/H, d, J=6Hz)
, A, Or(jH, dd , J=!Hz, 2Hz
), t, jJ'(jH.

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is an amino group or a protected amino group; R^2 is a lower is an alkyl group; R^3 is a hydrogen atom, a salt-forming cation, or a carboxyl group-protecting group; R
^4 is a hydrogen atom, a lower alkyl group, or a halogen atom; R^5 is a hydrogen atom, or R^5 represents a lower alkyl group or a halogen atom which may be the same or different from R^4] A cefem compound (syn isomer), a salt thereof, or an ester thereof. 2, R^1 is an amino group, R^2 is a methyl group, and R^3 is sodium, pivaloyloxymethyl group, or (5-methyl-2-oxo-1,3-dioxolene-4
-yl) methyl group, R^4 is a hydrogen atom, a methyl group, or a chlorine atom, and R^5 is a hydrogen atom, a methyl group, or a chlorine atom; syn isomerism of the compound according to claim 1; body. 3,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(thiazol-2-yl)vinyl]-3-cephem-4-carboxylic acid ( The compound according to claim 2, which is a syn isomer). Sodium 4,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(thiazol-4-yl)vinyl]-3-cephem-4-carboxylate The compound according to claim 2, which is a salt (syn isomer) (cis isomer). 5,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-[2-thiazol-4-yl)vinyl]-3-cephem-4-carboxylic acid pivalo yloxymethyl ester (syn isomer)
(cis isomer). 6,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(2
-Methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium salt (syn isomer) (cis isomer, trans isomer, or mixture of cis and trans isomers) Compound according to item 2. 7,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(2
-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester (syn isomer) (cis isomer, trans isomer, or a mixture of cis and trans isomers). 8,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium The compound according to claim 2, which is a salt (syn isomer) (cis isomer). 9,7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid pi The compound according to claim 2, which is baloyloxymethyl ester (syn isomer) (cis isomer). 10,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(
The compound according to claim 2, which is 4-chlorothiazol-5-ylvinyl]-3-cephem-4-carboxylic acid sodium salt (syn isomer) (cis isomer). 11,7-[2-methoxyimino-2-(2-aminothiazol-4-ylno-acetamide]-3-[2-(
The compound according to claim 2, which is 4-chlorothiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (cis isomer). 12,7-[2-methoxyimino-2-(2-aminothiazol-4-ylno-acetamide]-3-[2-(
2,4-dichlorothiazol-5-yl)vinyl]-3
-Cefem-4-carboxylic acid sodium salt (syn isomer) (cis isomer). 13,7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]-3-[2-(
2,4-dichlorothiazol-5-yl)vinyl]-3
-Cefem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (cis isomer).