JPS6251688A - Novel cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X is H or pivaloyloxymethyl; Y is group of formula II, III or IV) or its salt. EXAMPLE:7-[2-( 2-Aminothiazol-4-yl )-2-(syn)-methoxyiminoacetamido]-3-(3-fluoro-4-hydroxypheyn-l)-fluoro- 4-hydroxypheynl) methyl-DELTA<3>-cephem-4-carboxylic acid. USE:An antibacterial agent effective for the remedy of bacteriosis. Suitable for oral administration. It exhibits excellent antibacterial activity. PREPARATION:The compound of formula I can be produced by acylating 7-amino-3- substituted-cephalosporin of formula V with an acylation agent consisting of the acid chloride of the acid of formula VI [R is (protected) amino group] in an organic solvent such as dichloromethane at -20-0 deg.C to obtain the compound of formula VII and esterifying the carboxylic acid salt of the compound with pivaloyloxymethyl halide.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel cephalosporin compounds that have value as antibacterial agents when administered parenterally or orally.

More particularly, the present invention relates to novel 3-cephem compounds containing a 7-(2-(2-aminezol-4-yl)-2-methquiniminoacetamide) group.

BACKGROUND OF THE INVENTION Cephalosporins are a well-known group of antibiotics that have recently become widely used in the treatment of pathogenic infections in humans and animals. In the past, a large number of cephalosporins have been provided by varying the substituents at the 3- or 7-position of the cephalosporin backbone. However, the search for a group of compounds that have high activity and stability as well as absorbability upon oral administration is still ongoing.

Japanese patent application 1986-17! Cephalosboria species represented by the general formula (1) are disclosed in No. %263C% Publication No. 1987-9Q592; published on June 21, 1982).

C0OR□ [In the formula, R is a hydrogen atom or a carboxyl atom; R2 is an aryl, acylamino, which may have a substituent,
R3 is a hydrogen atom or a lower alkokene group; R4 is a hydrogen atom or a halogen. R5 is a hydrogen atom or an amino group which may be protected or substituted; R5 is an atom or an alkyl group, and the wavy line (~) is /.

2 is a sulfur atom or S→0; and the dotted line in the cephalosporic/skeleton is between the 43rd position and the 34th position is a double bond. represents.

In the specification, R2 mentioned includes 7enyl, 4-hibiroquinphenylsocitechenyl group. A preferred example of R□ mentioned is the pivaloyloxymethyl group. In the statement.

Among the disclosed compounds, 1% is specifically specified as a compound represented by formula (II).

The present inventors have discovered that an oral drug that has antibacterial activity against Durham-positive bacteria and Durham-negative bacteria, especially bacteria that are frequently isolated from clinical materials, and also shows good serum concentrations when administered orally. With the intention of creating a cephalosporin for human use, as a result of extensive research, we discovered the following series of compounds and completed the present invention.

The novel 3-cephem compounds of the present invention are compounds represented by formula (nI) and pharmaceutically acceptable salts thereof.

σX)X [wherein, X is a hydrogen atom or a pivaloyloxymethyl group, and y is selected from. ] Individual compounds encompassed by the present invention include 7-(2-(2-aminothiazol-4-yl)-2-
(dino)-methquiniminoacetamide]-3-(3,
4-Dihydroquinphenyl)methyl-Δ33-cephem-4-carboxylic acid (1) 7-[2-(2-aminothiazol-4-yl)=2-(n/)-methquiniminoacetamide]- 3-(3-fluoro-4-human 20
quinphenyl)methyl-Δ 3-cephem-4-carbo/acid 7-(2-(2-aminothiazol-4-yl)-
2-(syn)-methquiniminoacetamide 9]-3-
(2-Aminomethylth/-5-yl)methyl-Δ3-
Cephemu 4-carbo/acid (3) and their pivaloyloxymethyl esters.

The present invention also provides a method for administering to a mammal a composition comprising a compound of formula (n+1) and a pharmaceutically acceptable diluent or carrier, and an antimicrobially effective amount of a compound of formula (Ill). %
It also covers methods for treating bacterial infections by administering the drug orally.

Although the present invention is contained in the general disclosure in the above-mentioned prior art documents, none of the compounds of the present invention have been specifically disclosed in said documents and therefore should not be considered novel compounds. I can do it.

When compared with the prior art compounds of formula (If), the individual compounds of the invention all exhibit antibacterial activity superior to the compounds of formula (II) against Durham-positive and Durham-negative bacteria. Table 1 shows the measurement results of in vitro MC (minimum inhibitory concentration). Here, the susceptibility of clinical 5+ isolates of bacteria to coating compounds is tested using the well-known disk plate method. MC refers to the minimum concentration at which bacterial growth is inhibited when observed with the naked eye.

Table 1 In vitro antibacterial activity Ent, cloacae 182HIZ5
3.13 3.13 6.25 Serratiobacterium aeruginosa 11fil (P, aeruginosa) 76
9I, and Enterococcus faecalis (Str, faecalis)
428N for all compounds at 100 mcg/
The minimum inhibitory concentration north of rrtl was shown.

a: N Non-production of β-lactamase H High production of β-lactamase L Low production of β-2 lactamase b: The compound number corresponding to the compound number is the same as above), Compound (4)
) refers to prior art compounds of formula (II). A compound of formula (nr) in which x is a pinoζroyloxy group is easily hydrolyzed in the mammalian body to give the corresponding cephalosporin 7, a compound of formula (III') in which X is a hydrogen atom.

The in vitro activity of these cephalosporin VII has been demonstrated by measuring the minimum inhibitory concentration. formula(
The in vivo effectiveness of the esters of the compound m) is as follows:
Evaluation is based on the pharmacokinetics of these esters. Pharmacokinetics can be determined by standard techniques, in which serum concentrations of hydrolyzed antibiotic are measured upon oral administration of the ester to rats at 50 μg/kg. In all cases serum samples are taken at defined time intervals and assayed according to standard bioassay methods.

Compound (1) is E, coli NIHJ, compound (2
) and (4) are assayed using Streptococcus pyogenes Cook (E3. pyogenes Cook) as a constant bacterium.

The measurement results are shown in Table 2.

Table 2 Rat serum drug concentration sample collection time Average drug concentration (mag/1
ll) (after hours) Compound 1) Compound 2)
Compound 4) 0.5 6.20 2.9
5 2.301.0 7.95 4
．． 80 4.60ZO11,158,657,00 3,016,2519,5015,504,015,5
016,0014,50 As is clear from the results in Table 2, the compound of formula 1 (m) (in the formula, This indicates a high serum concentration of the corresponding free acid.

Thus the clinical utility of the compound of formula (10).

First, to determine the in vitro antibacterial activity of the compounds in their free acid form against clinical isolates of bacteria, as well as their serum concentrations obtained upon oral administration of the corresponding esters. It was exemplified by.

According to the present invention, a compound of formula (Tll), in which X is a hydrogen atom, is unnulated at the 7-position of a 7-amino-3-substituted cephalosporin with a suitably protected unnulating agent. by introducing a 2-aminothiazol-4-yl-2-methquiniminoacetyl group, followed by removal of the protecting group if necessary.

The product of formula (m) is then converted to the cibaroyl oxene ester by esterification, which itself is a method known to those skilled in the art.Process for the preparation of compounds of formula (m) The flowchart below shows how to make an AK reservation.

〔Ma〕

In the chemical formula b, R is an amino group or a protected amino group, and x is the same as previously defined.

Starting material (IV) is obtained in a conventional manner. That is, υ is synthesized by reacting 7-ACA with a suitable substituent (for example, 1) in the presence of a Lewis acid. In preparation for the unarylation step to obtain the compound of formula (Vl), the carboxylic acid group of compound (V) is activated by any standard method, eg mixed anhydride.

It can be converted to acid chlorides, acid imidazolides, activated esters, etc. Suitable reactive derivatives are acid halides 9 such as acid chlorides. The unruling reaction is typically carried out using the acid chloride of acid (V) 9 at low temperature (-20° to θ°C) 1 in an organic solvent such as dichloromethane.

Additionally, if the carboxylic acid group at position 2 of the cephem backbone (tV) is already protected as a pivaloyl oxine ester or other easily eliminated ester form, the condensing agent (
For example, DCC) can be used. Many commonly used carboxylic acid protecting groups can be used in this unruling step. Such protecting groups include t-butyl, inzhi)
J IJ le, benodyl, p-methquin benodyl mosi te p
-Nitrobenzyl, etc. All of these can be removed using conventional methods. The amino groups present in the compounds of formula (V) are also preferably protected with easily removable protecting groups prior to unarylation. For this purpose, the amino group is, for example, trichloroethquine carbonyl.

It is conveniently protected by groups such as t-methquinecarbonyl, benodylmethoxycarbonyl, trimethylsilyl, p-methquinepenzyloquine, and chloroacetyl. A particularly preferred protecting group is the chloroacetyl group.

The pivaloyluochine ester of formula (m) is compound (Vl)
It can be manufactured from These esters are usually carboxylates of compounds of formula [■] and pivaloyl oxine methyl halide.
can be obtained by reacting with K). Suitable carboxylic acid salts include alkali metal salts (eg, sodium, potassium salts), amine salts (eg, triethylamine salt), and tetraalkylammonium salts (eg, tetra-n-butylammonium salt).

A typical esterification reaction is carried out by contacting the reactants in an organic solvent such as N,N-dimethylformamide 9 at a temperature of o'-so°C. Conveniently, the carboxylate reactant is formed in solution during the esterification reaction. In this case, the reactants are brought into contact with each other in the presence of an amine (eg triethylamine versus diimpropylamine). The product of formula (Tll) is isolated according to conventional methods. If the initial product is a salt conductor of compound CIII) with the amine group protected, removal of the protecting group can be carried out in standard manner to provide the desired cephalosporin.

An alternative method for preparing compounds of formula (m) is formula (IV)
K may also lead to compound (III) K by first esterifying the compound of formula (V), followed by acylation with a compound of formula (V), but if necessary removing the amino protecting group. As will be understood by those skilled in the art, the same methods and conditions used for the acylation and esterification steps described above are used.

Isolation or purification of reaction intermediates and final products is 70-
There is almost no difference from each process shown in chart A.

It can be understood that compounds of formula CV) or formula (m) exist as geometric isomers due to the geometric isomerism of the iminoether group. In structural formula (VI), only the syn isomer is shown, and this is preferred, but the anti isomer also exists. Both isomers and mixtures thereof are within the scope of the present invention.

Compounds of formula (m) (in which R is a hydrogen atom, i.e., a carboxylic acid) form a base salt.Since the compound has an amino group, the acid can also form a salt.Furthermore, these compounds have zwitterions. These acids also exist as compounds.
Base salts as well as zwitterions are also within the scope of this invention.

These salts can be prepared by standard methods used for penicillin and cephalosporin compounds using a wide range of non-toxic, pharmaceutically acceptable acids or bases commonly used by those skilled in the art.

Typical examples of such acids are mineral acids such as hydrochloric acid and sulfuric acid; organic carboxylic acids such as oxalic acid, formic acid, and trichloroacetic acid; p-) sulfonic acids such as luenesulfonic acid, metasulfonic acid, and sulfosalicylic acid. etc. Typical examples of bases are alkaline hydroxides, bicarbonates, carbonates, hydrides: alkaline earth metal hydroxides, carbonates, hydrides such as alcoquinides; and ammonia, organic amines such as triethylamine, Trimethylamine.

tributylamine/, pyridi/, diethylamine/.

N-methyl piperidy, N-methylmorpholine.

Diethylamine, dicyclohexylamine, Flokai 7
% dibe/:) ruamiy, N, N-dibe/silethylenediamine, 1-α-7 enami/as N-ben:) ru β
-7 enetelami/etc.

In addition, easily hydrolyzed esters of the compound [■] (wherein X is a hydrogen atom) also fall within the technical scope of the present invention. Like the p-20yloxy ester, these esters are easily hydrolyzed in vivo to give the parent antibiotic itself. Such ester residues are known to those skilled in the art. A typical example is 3-
7-talidyl, 4,-crotonolactonyl, r-butyrolact-4-yl, acetoxymethyl, hivaloyloxyethyl, and 5-methyl-2-oxo-L3-dioxole/-4-ylmethyl.

The above-mentioned compound of formula (III) and its pharmaceutically acceptable salts are used in mammals including humans.

It is effective in treating various bacterial infections. Compound [l] (
(wherein X is a hydrogen atom) can be administered parenterally, ie, intramuscularly, subcutaneously, intraperitoneally, intravenously, etc. Because of this route of administration, it is usually administered alone or with a pharmaceutically acceptable carrier.

A sterile solution of the active ingredient is used.

The compound of formula (III) (wherein R is a pivaloyloxy group) is preferably administered orally. For oral administration, the compound is given in tablets, capsules.

Dosage forms such as rosé/lozenges, powders, syrups, elixirs, aqueous solutions and suspensions are used.

The appropriate needle for administration in humans is determined by the physician and depends on the individual patient's age, weight, response to the drug, and condition. The cephalosporins of the present invention will typically be administered orally at a dosage of about 10 to about 400 μ/day.
When administered parenterally, the dosage is approximately 9 kg (body weight) per day.
It can be administered in dosages of 0 to about 200 cm/yu (body weight).

Hereinafter, the present invention will be specifically explained with reference to Examples and Production Examples, but these Examples are merely given for illustrative purposes and are not intended to limit the present invention.

Nuclear magnetic resonance absorption spectra of monohydrogenated sulfoxide' (
Measured at 60 MHz in DMSO-a6) solution. And peak positions are reported in ppm downstream from tetramethylsilica (TMS).

The following abbreviations are used to describe the shape of the peak.

B-single-l/M%d-double, t-triple, q-quartet, m-multiple, q-quadruple, m-multiplet.

Example 1 7-(2-(2-chloroacetamidothiazole-4-
yl)-2-(shi/)-methoxyiminoacetamide]
-3-(34-dihydroxyphenyl)methyl-Δ33
-Cefem-4-carbo/acid (synthesized according to Preparation fPJ1) 0.467 N in sodium acetate trihydrate 0
．． Water-acetonitrile containing 328 Ii (231 each)
To this was added 0.1531 thiourea. Cuffed at room temperature for 166 hours. The reaction solution was concentrated under reduced pressure to about half its volume, and 23 mA' of water was added thereto. Furthermore, IN hydrochloric acid was added to adjust the pH to 25. Remove the precipitate and wash with water. Drying under reduced pressure yielded 0.2429 of the title compound (60).

IR (KBr Desk) 1770, 1670.163
0cm-1NMR818-4,3(m), 3.85(
s, 3H), 5.16(Lll, J-4Hs, I
H), 5.73 (rla, , T-4Hz, 8H.

IH), 6.4-6.9 (m), 7.2 (bs).

Alternatively, the same compound was prepared as follows. N
, N-dimederacetamito” (DMAc) 1,74
Phosphoryl chloride (l) and 651 Ll (651 Ll) were added to 6.12 ml of dichloromethane and dichloromethane at 0°C. After cuffing at 0°C for 300 minutes, the mixture was cooled to -15°C. Add to this 2-(2-
1.81 f of 7minothiazol-4-yl)-2-(cy/)-methoxyiminoacetic acid was added. cuff agitation 205
Continued for + time. Add pivaloyloxymethyl 7 to this reaction solution.
-amino-3-(3,4-dihydroxyphenyl)methyl-Δ33-cephem-4-carboxyle) 3.3
4. Add 715ttte solution of F in dichloromethane,
The temperature was increased to O'C and held at this temperature for 1 hour.

The reaction solution was concentrated to an oil, and this oil was dissolved in acetic acid-ethyl water (301 ml each). The pH of the solution was adjusted to 70 with saturated sodium bicarbonate solution. The organic phase was separated and washed with water. Water was added and the pH was adjusted to 1.5 with 6N hydrochloric acid. After separating the organic phase and washing with water, add anhydrous sulfuric acid)
After drying with IJum and distilling off the solvent, a viscous oily substance 195
．． I got a 9. When it was purified on a silica gel column using acetate/dichloromethane as the eluent, the title compound 1.
30.9 was obtained.

Example 2 In Example 1, 7-(2-(2-chloroacetamidothiazol-4-yl)-2-(cy/
)-methoxyiminoacetamide]-3-(3-fluoro-4-human90xyphenyl)methyl-Δ 3-cephem-4-carbo/acid, the same operation was repeated to obtain the title compound. Ta.

Engineering R (KEr disk 21760cm-1NMRa
Z9-4.1 (ml, 3.84 (a, 3H), 5.1
7 (d, J-4Hz, IH), 5.77 (dd, J-4
1 (g, 8Hz.

IH entry 6.76 (e, IH), 6.8-7.
4 (ml, 9.56 (d.

J-8Hz, IH).

Example 3 7-(2-(2-chloroacetamide 9thiazole-4
-yl)-2-(cy/)-methoxyiminoacetamide-
1-3-(2-chloroacetamidomethylche/-5-
yl) methyl-Δ 3-cephem-4-carbo/acid 12
: lV of sodium acetate trihydrate 76■ and thiourea 85
Water-acetonitrile containing η (0, fyxl-1,
2 wl).

Cuffed at room temperature for 166 hours. 10 rnl of isopropanol was added to the reaction solution. The precipitate was collected in a furnace, washed with Impropatol, and then dried under reduced pressure to obtain 101'my of the title compound (97%) in the form of 1 mol of Impropatol.

Engineering R (KBr disk) 1760cm-'NMRδ
1.05 (d, J-7H2, isopropyl/-A
/).

2.9-4.7 (ml, 3.84 (s, 3H)
), 5.02 (d, J-4Hz.

IH), 5.56 (m, iH), 6.75 (li), 6
．． 6-7.4 (m).

Example 4 Piparoyloxymethyl 7-(2-(2-chloroacetamido3fazol-4-yl)-2-(cy/)-methoxyiminoacetami)]-3-(a4-:)hydroxyphenyl)methyl -Δ3-Cefemu 4-carboxylate 1051S' ethanol α5d% acetonitrile 1.0 mA! , 34ml of thiourea and 62ml of IJium trihydrate were added to a mixed solution of 0.55ml of water. The reaction was cuffed at room temperature for 200 hours. This was diluted with water and the precipitate was washed with water and dried under reduced pressure to obtain the title compound (71) of 66.1 cape.

Engineering R (KBr disk) 1780, 1755, 16
65CWL-INMRa 1.15 (g, 9H), Z
8-4.2 (m), 3.82 (s, 3H), 5.22 (
d, J-4Hz, IH), 5.5-6.1 (6.3 m)
-7.0 (m), 7.20 (bs).

Example 5 In Example 4, piparoyloxymethyl 7-C2-(2-chloroacetamido 3fazol-4-yl)-2-(syn)-methoxyiminoacetamito]-3-(3- The same operation was repeated using fluoro-4-hydroxyphenyl)methyl-33-cephem-4-carboxylate to obtain the title compound.

Engineering R (KEr disc) 1780.1755cm-
1MNRδ i, 15 (8J 9 H), 3-2-
40 (m)e, 3-82(e, 3H), 5.19(
d, J-4H2, IH), 5.60-6.00 (m, 3
H), 6.7-7.3 (m).

Production Example 1 2-(2-chloroacetamibiteazol-4-yl) acid
-2-(cy/)-methoxyiminoacetic acid 3.451 DM
1.14 MLt of Ac16d solution 1c-20'C't'[phosphoryl] was added. The reaction solution was kept at the same temperature and stirred with a cuff for 1 hour. On the other hand, 6.29 m of trimethylsilylchloride) was added to a 4.0.9 DMA c 16d solution of 7-amino-3-(44-dihydrogycyphenyl)methyV-Δ33-cephem-4-carbo/acid, and the solution 1 at room temperature
The cuff was agitated for an hour. This solution was added dropwise to the above prepared solution at -20°C. After cuff stirring the reaction mixture for 1 hour, add 130 ml of water.
I poured dK.

The precipitate was separated, washed with water, and dried under reduced pressure to form the title compound 2.
．． 41! i was obtained as a crude product. Aceto this/
The insoluble matter was removed from each house. The p solution was treated with activated carbon and concentrated to yield the amorphous title compound 1.71I.

IR (KBr disk) 1770, 1680.15
40cm-”NMRa Z8-4.2 (m), 3.8
9 (s, 3H), 4.40 (a, J-4Hz, IH),
5.78 (aa, J-4, 8Hz.

IH), a4-6.9 (m), 7.48 (s, IH).

Production Example 2 According to the method of Production Example 1, a suitable 7-amino-3-[converted-
Δ 3-Cefem-4-carbo/acid and 2-(2-chloroacetamidothiazol-4-yl)-2-(cy/)-
Reaction with methoxyiminoacetic acid gave the following compound.

7-(2-(2-chloroacetamidodeazole-4-
Irun-2-(shi/)-methoxyiminoacetamide]
-3-(3-Fluoro-4-human 90xyphenyl) mesol-Δ 3-cephem-4-carboxylic acid, this compound exhibits the following physical properties.

IR (KBr disk) 1770cm-”NMRδ
3.2-4.2 (m), 3.89 (s, 3H), 4.
38 (a, 2H), 5.20 (d, J-4Hz, IH
), 5.80 (cud.

J-4Hz, 8Hr;, IH), 6.7-7.3(m,
) 7.45 (S.

IH), 9.63 (a,, T-8Hz, IH).

7-(2-(2-chloroacetamide 9y-azole-
4-yl)-2-(syn)-methoxyiminoacetamide]-3-(2-chloroacetamibimederde/-5
-yl)methyl-Δ 3-cephem-4-carbo/acid.

This compound exhibits the following physical properties.

Engineering R (KBr disk) 1780, 1680, 15
40cIrt-”NMRδ 3.0-4.7(m), 3
．． 90 (8, 3H), 4.08 (a, 2H), 4.40
(s, 2H), 5.20 (d, J-4Hz.

IH), 5.82 (ad, J-4H2, 8Hz, IH
), 6.82 (a, 2H), 7.46 (s, IH), &
80 (t, IH).

9.70 (d, 1) 1).

Production Example 3 7-C2-(2-chloroacetamidodeazole-4-
yl)-2-(syn)-methoxyiminoacetamide)
-3-(34-:)hydroxyphenyl) mesol-Δ3
3-cephem-4-carbo/a! DMA 2116Mg
cO, 5dK dissolved. Torie fnt ami 721 at 0℃
119 and further iodine 9 mesol bivalate 51'
Added q. The reaction solution was cuffed at 0° C. for 900 minutes, and after death, 5 d of water was added, and the resulting precipitate was collected. When this was washed with water and dried under reduced pressure, 121 mg (81%) of the title compound was obtained.
) was obtained.

IR (KBr disk) 1780.1750c++
t-”NMRa 1.15 (s, 9H), 3. (14
, 1 (m), 3.90 (s, 3H), 4.39 (s, 2
H), 5.25 (d, J-4Hz.

IH), 5.6-6.2 (m), 6.4-6.9 (
m), 7.45 (s.

IH).

Production Example 4 In Production Example 3, 7-(2-(2-chloroacetamidothiazol-4-yl)=2-(cy/
)-methoxyiminoacetamide]-3-(3-fluoro-4-hydroxyphenyl)methyl-Δ 3-cephem-4-carbo/acid and repeating the same operation,
The title compound was obtained.

Engineering R (KBr disc) 1780.1750cm-
"NMRa Li2 (e, 9H), 3.2-4.
1 (m), 3.85 ('e 3H), 4.38 (town 2
)1), 5.13((1, J-4Hz.

IH), a7-6.1 (m, 3H), 6.8-7.2 (
m, 7.42 (a, IH) with 3H, 9.65 ((1,
J-8H2, IH).

Production Example 5 To a mixture of catechol 60.7.9 and 15% boron trifluoride acetonitrile solution 600 id, 7-amicose 7 allosbora/acid ioo,v was added at -20°C.

The reaction solution was heated to -5°C and maintained at this temperature for 16 hours. This was poured into 600 mg of water and the pH was adjusted to 3.5 with a 25% aqueous ammonia solution. Isolate the precipitate and
Thiacetoni) was washed with an aqueous IJ solution, then washed with water, and dried under reduced pressure to yield the title compound 107.3.9 (9
1%).

Engineering R (K B r disk) 1770m-”NMR
δ 2.80-4.20 (m), 4.73-5.0
0 (d, J-5Hz), 6.40-7.00
(m).

Production Example 6 The title compound was obtained from 0-fluorophenol in substantially the same manner as in Carbo/Acid Production Example 5.

Engineering R (KBr disk) 1780cm-”NMRδ
3.1-4.2 (m), 4.78 (d, J-4
Hz, IH).

5.03 (d, J-4Hz, IH), 6.8-7
．． 4 (m, 3H).

Production Example 7 In the same manner as in Production Example 5, the title compound was obtained from 2-chloroacetamibimethylthiophe/.

Engineering R (KBr disc) 1800.1659cm-
"NMRδ 3.25, 3.60 (ad,, T-17H
z), 3.68° 4.02 (aa, J-15Hz), 4
．． 10 (s, 2H), 4.40 (d.

J-5,5Hz), 4.75 (d, J-5H2), 5.
00((1,5,0H2), 6.81(8,3H), &
78 (bs).

Production Example 8 7-amino-3-(a4-:)hibiloxyphenyl)methyl-Δ 3-cephem-4-carbo/acid 11.6! i
Triethylamine 75,5 d in a DMAc 81 m solution of
at 0°C followed by iodo-9-methyl biverret) 6.
35- was increased by 01. The reaction solution was cuffed at 0° C. for 2 hours, and then washed with water and ethyl acetate (900 mA each). The organic phase was separated and washed with water. The ethyl acetate solution was dried over magnesium oxide and concentrated under reduced pressure to obtain a crude product.

This was subjected to silica gel column chromatography and eluted with aceto/-dichloromethane (1:2) to obtain the title compound 3.34.
．． I got a 9.

IR (KBr disk) 1780.1750cm-
"NMRδ 1.20 (B, 9") $ 3.2
-4.2 (m) + 4.70 (d, J-4Hz, IH
), 4.95 (d, J-4Hz, IH).

5.95 (θ=2H), 6.75 (bs).

(5 other people)

Claims (4)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X represents a hydrogen atom or pivaloyloxymethyl group, and y is ▲ There are mathematical formulas, chemical formulas, tables, etc. There are ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Selected from the group consisting of. ] or a pharmaceutically acceptable salt thereof. (2) 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
(3,4-dihydroxyphenyl)methyl-Δ^3-
The compound according to claim 1, which is cefem-4-carboxylic acid or its pivaloyloxymethyl ester. (3) 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
(3-fluoro-4-hydroxyphenyl)methyl-Δ
The compound according to claim 1, which is ^3-cephem-4-carboxylic acid or its pivaloyloxymethyl ester. (4) 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
(2-aminomethylthien-5-yl)methyl-Δ^3
-Cefem-4-carboxylic acid or its pivaloyloxymethyl ester.