JPS60226886A - Novel cephem compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) amino; R<2> is lower aliphatic hydrocarbon group; X is N or CH] or its salt. EXAMPLE:7-[2-Ethoxyimino-2-( 5-amino-1,2,4-thiadiazol-3-yl )acetamido]-3-(1,2,5,6- tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid. USE:Antibacterial agent. PREPARATION:The compound of formula II (or its salt) {e.g. 7-[2-ethoxyimino- 2-( 5-amino-1,2,4-thiadiazol-3-yl )acetamido]-3-( 1-pyridiniomethyl )-3-cephem-4-carboxylate, etc.} is reduced with a hydrogenation agent, preferably sodium borohydrate, etc., e.g. in an aqueous solvent.

Description

[Detailed description of the invention] "Industrial application field" This invention relates to novel cephem compounds and salts thereof.

More particularly, the present invention relates to novel cephem compounds and salts thereof having antibacterial activity, processes for their production, and pharmaceutical compositions containing them.

That is, one object of the present invention is to provide novel cephem compounds and salts thereof that have high activity against many pathogenic bacteria.

Another object of this invention is to provide a method for producing novel cephem compounds and salts thereof.

Yet another object of this invention is to provide a pharmaceutical composition containing the novel cephem compound and its salt as an active ingredient.

``Problems to be solved by the invention'' Many cephalosporin compounds have been known in the past, but many of them have problems with antibacterial activity and antibacterial spectrum, etc. This invention solves these problems, The aim is to develop even better medicines.

"Means for Solving the Problem" The novel cephem compound that represents the object can be represented by the following general formula (I).

(In the formula, B1 is amino or protected amino, R2 is a lower aliphatic hydrocarbon group, and X means N or CH, respectively).

According to the present invention, the novel cephem compound (I) can be produced by various production methods shown in the following reaction formula.

Production method 1 (II) or its salt or its salt production method 2 or its salt (Ia) or its salt production method 3 (Ib) or its salt (Ic) or its salt (in the formula, R1, R2 and , R3 is a lower alkyl group, R4 is a protected amino group, and Y is an acid residue).

Suitable salts of the target compound CI) are the customary non-toxic salts;
Examples include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts; for example triethylamine salts, pyridine salts,
Salts with organic bases such as picoline salts, ethanolamine salts, triethanolamine salts, organic amine salts such as dicyclohexylamine k,N,N''/benzylethylenediamine salts, and salts with organic bases such as hydrochlorides, hydrobromic acid Inorganic acid addition salts such as salts, sulfates, phosphates; for example, formates,
Organic carboxylic acid addition salts or organic sulfonic acid addition salts such as acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate; for example, arginine, asparagine Examples include salts with acids, basic amino acids such as curtamic acid, or bases such as salts with acidic amino acids, acid addition salts, quaternary salts, and the like.

The quaternary salt has the formula: wherein the nitrogen atom of the group represented by the formula: is substituted with a lower alkyl group such as methyl, ethyl, furobyl, butyl, pentyl, hexyl, etc., where R3 represents a lower alkyl group. is formed when a quaternary cationic group of the meaning ) occurs.

Suitable examples of the quaternary cation group include, for example, 1-
Methyl-1,2,5,6-tetrahydro-l-pyridinio, -ethyl-1.2.5.6-tetrahydro-1-
Pyridinio, 1-propyl-1,2,5,6-tetrahydro-1-pyridinio, 1-butyl-1゜2,5.6-
Examples include 1-(lower)alkyl-1,2,5,6-tetrahydro-1-pyridinio groups such as tetrahydro-1-pyridinio.

The quaternary salt may be formed, for example, between the quaternary cation group and the carboxy group of compound (I). In this case, suitable quaternary salts include, for example, 1-methyl-1, 2
, 5,6-tetrahydro-1-pyridinio carboxylate, l-ethyl-1,2,5,6-tetrahydro-
1-pyridiniocarboxylate, 1-propyl-1
, 2,5,6-tetrahydro-1-pyridinio carboxylate, 1-butyl], 1-(lower)alkyl-1,2°5.6 such as 2,5,6-tetrahydro-1-pyridinio carboxylate, 2,5,6-tetrahydro-1-pyridinio carboxylate -tetrahydro-l-pyridiniocarboxylate.

1” endogenous compounds (Il, (h), (rb) and (Ic)
The raw material compound ([1) includes a syn isomer, an anti isomer, and a mixture thereof.

For example, to explain [1 endogenous compound (I), the syn isomer has the formula: (wherein R1, R2 and X each have the same meaning as before)
refers to one geometric isomer having the partial structure represented by the formula: (wherein R1, R2 and X each have the same meaning as before)
means another geometric isomer having a partial structure represented by

Regarding the other compounds mentioned above, the syn isomer and the anti isomer have the same relationship as the geometric isomer explained for compound (I).

In the foregoing and following description of this specification, preferred examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below.

"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.

Suitable "protected amino" for R1 and R4 include acylamino or such as benzyl, trityl, etc.
Examples thereof include amines substituted with conventional protecting groups such as al(lower) alkyl which may have a suitable substituent.

Suitable acyl moieties in "acylamino" and "acyloxy" include carbamoyl, aliphatic acyl and acyl containing aromatic or heterocycles. Suitable examples of these acyls include lower alkanoyl groups such as fortriyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, invaleryl, oxalyl, succinyl, and pivaloyl; examples include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. , 1-cyclopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and other lower alkoxycarbonyl groups: Examples include mesyl, ethanesulfonyl, propanesulfonyl, Lower alkanesulfonyl groups such as isopropanesulfonyl and butanesulfonyl; Arenesulfonyl groups such as benzenesulfoninopetosyl; Examples fd'Aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, and indancarbonyl; such as phenyl Noal (lower) alkanoyl groups such as acetyl and phenylpropionyl; Examples include al (lower) alkoxycarbonyl groups such as ehapenzyloxyluponyl and phenethyloxycarbonyl.

The above acyl moiety, acyl (e.g. lower alkanoyl)
, halogens (e.g. chlorine, bromine, fluorine and iodine)
It may have appropriate substituents such as.

Suitable "lower aliphatic hydrocarbon groups" include lower alkyl, lower alkenyl, lower alkynyl, and the like.

Suitable "lower alkyl groups" have 1 to 6 carbon atoms, and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, and the like. , having 1 to 4 carbon atoms.

Preferred lower "alkenyl" groups are those having 2 to 6 carbon atoms, such as vinyl, allyl, impropenyl, 1-
Examples include 7'ropenyl, 2-y"tenyl, 3-pentenyl, etc., and preferably one having 2 to 4 carbon atoms.

Suitable "lower alkynyl groups" have 2 to 6 carbon atoms, and include ethynyl, 2-propynyl, 2--1 thynyl, 3-pentynyl, 3-hexynyl, etc., but preferably carbon atoms It has 2 to 4 pieces.

Suitable examples of Y include acyloxy, halogen (eg, chlorine, bromine, iodine, or acid residues such as fluorine, azide, etc.), and examples of the acyl moiety in "acyloxy" include those exemplified above.

Preferred embodiments of the target compound (1) are as follows.

Preferred embodiments of R1 are amine or acylamino,
More preferred is amino or lower alkanoylamino.

A preferred embodiment of R2 is a lower alkyl group.

The method for producing the object compound (I) or a salt thereof of the present invention will be explained in detail below.

Production method 1 The target compound (I) or a salt thereof can be produced by subjecting compound (II) or a salt thereof to a reduction reaction.

Suitable salts of compound (I) in this production method include:
Examples of the target compound (I)K include salts with bases or acid addition salts as exemplified above.

Suitable salts of compound (II) include target compound CI)
Examples include salts with bases or acid addition salts as exemplified above.

Examples of the reduction method in this reduction reaction include reduction using a hydrogenating agent, reduction using a combination of a metal and an organic acid, and catalytic reduction.

If a hydrogenating agent is used, suitable hydrogenating agents include, for example, alkali metal borohydrides such as sodium borohydride, alkali metal aluminum hydrides such as lithium aluminum hydride, sodium cyanofluoride, etc. Examples include alkali metal cyanoborohydrides, such as alkali metal hydrides such as tri(tert-butoxy)aluminum lyticum hydride.

The solvent used in this reaction can be selected depending on the type of hydrogenation agent used, and the reaction can be carried out with water, alcohols such as methanol and ethanol, and ethers such as diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane. It can be carried out in a solvent such as
The reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

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

When using reduction by a combination of metals and organic acids,
Suitable metals include iron, zinc, etc., and suitable organic acids include citric acid, acetic acid, etc.

When using catalytic reduction, suitable catalysts include, for example, platinum metal catalysts such as platinum oxide, palladium metal catalysts such as Baladicum carbon, and suitable solvents include alcohols such as methanol, ethanol, etc. , acetic acid, ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclohexane, water, ethyl acetate, N,N-dimethylformamide, etc., which are commonly used in this reaction.

Production method 2 Target compound (Ia) or its salt is compound (I) t
or its salt can be produced by reacting with the compound (iii).

Compound (I) and compound (Ia) in this production method
Suitable salts include the salts with bases or acid addition salts exemplified above for the target compound (I).

This reaction may be carried out in the presence of a silylating agent such as monotrimethylsilylacetamide, talolotrinotylsilane, and the like.

The reaction is usually carried out in a solvent such as water, acetone, diethyl ether, tetrahydrofuran, an alcohol such as methanol or ethanol, methylene chloride, ethylene chloride, N,N-dimethylformamide, but any solvent that does not adversely affect the reaction may be used. It can be carried out in any other solvent.

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

Production method 3 The target compound (Ic) or its salt can be produced by subjecting compound (Ib) or its salt to an amino-protecting group elimination reaction.

Suitable salts of compounds (Ib) and (Ic) include those exemplified above for the target compound (I).

This elimination reaction involves hydrolysis, reduction, and cleavage. When the protecting group is acyl, compound (Ib) is reacted with an iminohalogenating agent, then reacted with an iminoetherifying agent, and if necessary, This is carried out by conventional methods such as hydrolysis of the resulting compound. Examples of hydrolysis include methods using acids, bases, hydrazine, and the like. These methods may be selected depending on the type of protecting group to be removed.

In these methods, hydrolysis using an acid can be performed, for example, on substituted or unsubstituted alkoxycarbonyl groups such as pentyloxycarbonyl, butoxycarbonyl, alkanoyl groups such as formyl, cycloalkoxycarbonyl groups, such as benzyloxycarbonyl, Substituted or unsubstituted aralkoxycarbonyl groups such as substituted benzyloxycarbonyl, e.g. (lower) alkoxycarbonyl groups such as benzyl, trityl, etc.
This is one of the common preferred methods for removing protective groups such as alkyl groups.

Suitable acids are organic or inorganic acids, for example formic acid,
Examples include trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid, and preferred acids include, for example, formic acid, trifluoroacetic acid, and hydrochloric acid. The acid suitable for the reaction can be selected depending on the type of protecting group to be removed. When the elimination reaction is carried out by hydrolysis with an acid, it can be carried out in the presence or absence of a solvent. Suitable solvents include, for example, conventional organic solvents such as methanol, ethanol, tetrahydrofuran, water or mixtures thereof. When using trifluoroacetic acid, the elimination reaction is preferably carried out in the presence of anisole.

Hydrolysis using hydrazine is commonly applied for elimination when the protecting group is eg succinyl or phthaloyl.

Hydrolysis with a base is preferably applied to eliminate acyl groups, such as haloalkanoyl groups such as dichloroacetyl, trifluoroacetyl, and the like. Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkali metal hydroxides such as sodium carbonate and potassium carbonate; carbonates, e.g. alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, alkali metal acetates such as sodium acetate, potassium acetate, e.g. phosphoric acid; Inorganic bases such as alkaline earth metal phosphates such as magnesium, lucicum phosphate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc., trimethylamine, triethylamine, etc. Trialkylamines such as picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo(4,3,03non-5-ene, 114-diazabicyclo[2,2,2]octane, 1,5 −Diazabicyclo [
Examples include organic bases such as [5,4,0]kundecene-5 and the like. Hydrolysis with bases is often carried out in water, customary organic solvents or mixtures thereof.

Among the protecting groups, acyl is generally modified by the hydrolysis described above.
or by other conventional hydrolysis methods.

Acyl is a halogen-substituted alkoxycarbonyl group or 8
-quinolyloxycarbonyl groups, these are eliminated by treatment with heavy metals such as copper, zinc, etc.

Elimination by reduction includes, for example, haloalkoxycarbonyl groups such as 2-trichloroethoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.
It is applied to the removal of protecting groups such as 2-pyridylmethoxycarbonyl group.

Suitable reduction methods include, for example, reduction with an alkali metal borohydride such as sodium borohydride.

The reaction temperature is not particularly limited and may be appropriately selected depending on the type of amino protecting group and the type of the above-mentioned elimination method, and this reaction is preferably carried out under cooling, at room temperature, or under mild conditions such as slightly elevated temperature. .

"Effects of the Invention" The object compound of this invention (Il and its salts) is a new compound that exhibits high antibacterial activity and inhibits the growth of a wide range of pathogenic bacteria, including Durham-positive bacteria and Gram-negative bacteria, and is useful as an antibacterial agent. For therapeutic purposes, the compounds according to the invention may be present in pharmaceutically acceptable formulations such as organic or inorganic solid excipients or liquid excipients suitable for oral, parenteral or topical administration. The compound is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient.

Pharmaceutical formulations may be in solid form, such as capsules, tablets, dragees, ointments or halves, or in liquid form, such as solutions, suspensions or emulsions.

If desired, auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers, and other substances such as lactose, fumaric acid,
Such as citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol etc. Commonly used additives may also be included.

The dose of the compound varies depending on the age and condition of the patient, but the average single dose is about lθ■, 50q, 100~. 2
50■, 500~. The compounds of this invention were found to be effective in treating pathogenic bacterial infections.

Generally about 1 fng/individual to about 6.00 per day
0 ■/individual or more may be administered.

In order to explain the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

Minimum Inhibitory Concentration (A+ Test Method) In vitro antibacterial activity was measured by the following agar plate 2-fold dilution method.

Each test strain was cultured overnight in Trypticase Soy Pross, and a loopful of the culture (108 viable bacteria/me) was placed on Heart Infusion Agar (HI agar) containing a representative test compound at each concentration level. ) and incubated at 37°C for 20 hours, the minimum inhibitory concentration (MCC) was adjusted to μy/
It was expressed as me.

(B) Test compound (1) 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1,2,5,6-tetrahydro-1- pyridinio)
Methyl-3-cephem-4-carboxylate (syn isomer).

(C) Test results "Example" The present invention will be explained in more detail below according to examples.

Example 1 7-[2-ethoxyimino-2-(5-amino-1,2
,4-thiadiazol-3-yl)acetamide]-3
-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (6,0p) in water (300p)
mf') was adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate at 5°C, and then sodium borohydride (l, 6y) was added in portions to the pH 6.5.
Maintain pH 7-75 with N-hydrochloric acid. After the reaction is completed, the resulting solution is acidified with 6N hydrochloric acid, and a nonionic adsorption resin "Diaio: yHP-20J (trademark, manufactured by Mitsubishi Kasei Corporation) (200
column chromatography using me).

After washing with columnar water (11), it is eluted with a 30% methanol aqueous solution. The eluate containing the target compound is collected, methanol is distilled off under reduced pressure, and lyophilized to obtain 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl). Acetamide]-3-(1,2,5
,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) (3,5 gI) is crystallized from methanol.

mp: 150-155°C (decomposition) IR (nudial): 3400.3100. 176
0.1670°1600, 1530cm-1 NMR (D20 + DCl, δ 6.27-5.5 (
2L m), 5.90 (LH, d, J=4.5Hz)
, 5.37 (IH, d, J-"4.5Hz).

4.43 (2H + q, J = 7Hz) + 4.30 (2H
, br s).

4,0 3.6 (4Ht br s )+3.6-a
, 4 (2H2m)+2.7-2.3(2H,m)
, 1.36 (3H, t, J=7Hz) Example 2 +1+Similarly to Example 1, 7-[2-methoxyimino-2-(2-formamidothiazol-4yl)acetamide]-3-7 (1,2,5,6-tetrahydro-
1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) is obtained.

mp: 142-147°C IR (Nujol): 3200. 1775. 16
70. 1610°1540α-1 NmR (D,, o, δ): 8.53 (IH, s), 7
．． 43 (IH, s).

6.05-5.7 (2H, m), 5.83 (IH, d,
J=5Hz).

5.57 (IH, d, J=5Hz), 4.0 (3H,
s), 4.6 (2H.

overlaps with the H2O peak), 4.1-3.9 (2H, m
).

3.70 (2H, br s), 3.5-3.3 (2H,
m), 2.7-2.4(2H,m) (2) In the same manner as in Example 1, 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]- 3-(1,2,5,6-tetrahydro-1-
pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) is obtained.

mp: 145-150°C (decomposition) IR (nujol): 3300. 1775. 16
60. 1610°1530cm-1 NMR (D20.δ): 7.00 (LH, e), 6.
1-5.6 (2H, m) 15.90 (IH, d, J=5
Hz), 5.22 (IH, d, J=5Hz).

4, 5 (overlaps with 2H, H2O peak), 4.1-3
．． 9 (2H, m), 4.0 (3H, s), 3.1-3.
6 (2H, m).

3.5-3.3 (2H, m), 2.6-2.3 (2H,
m) Example 3 7-[2-ethoxyimino-2-(5-amino-1,2
,4-thiadiazol-3-yl)acetamide]-3
-(1,2,5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) (
500q) and monotrimethylsilylacetamide (
1,0y) in methylene chloride (10me) at 35°C, and then cooled to room temperature. Add methyl iocide (1
, 5 ml') are added under stirring at the same temperature and the mixture is stirred for 3 days. The solvent of the reaction mixture was distilled off, and water (50 m
Add e). Insoluble matter was removed, and the p solution was subjected to column chromatography using Diaion HP-20J (20 ml'). After washing with water (500me), the mixture is eluted with 30% aqueous methanol. Both methanol containing the target compound were distilled off and freeze-dried to obtain 7-[
2-ethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamide]-3-(1
-Methyl-1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-carboxylate (
Syn isomer) (350■) is obtained.

mp: 150-1558C (disassembly) Engineering R (nujol): 3300. 1770. 1660. 161
0°1530 cm-1 NMR (D20.δ): 6.1-5.8 (IH, m)
, 5.93 (IH, d.

J=5Hz), 5.83 and s, 50 (2H2
A Bqr J-13Hz)+5, 4 s, 3 (
I H2m) + 5-37 (I Hrd, J-5
Hz).

4.37 (2H, q, J=7Hz), 4.0-3.8
(2H, m).

3.7-3.4 (2H, br s), 3.1-2.9 (
2H, m).

3.00 (3H, s), 2.7-2.4 (2H, m).

1.35 (3H, t, J=7Hz) Example 4 +1) In the same manner as Example 3, ? -[2-Methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-(1-methyl-1°2,5.6-tetrahydro-1-pyridinio)methyl-3-cephem-
4-carboxylate (syn isomer) is obtained.

mp: 144-149°C (decomposition) Engineering R (Nujol): 3300. 1780. 16
70. 1610°1550c+++71 NMR (D20.δ): 8.57 (IH, s), 7.
47 (LH, s).

5.87 (IH, d, J = 5Hz), 6.1-5.7 (
2H, m).

5.37 (IH, d, J=5Hz), 5.47 and 5.30 (2LABq, J=13Hz), 4.03 (3
H,s), 4.1 3.7 (4H.

m), 3.6-3.3 (2H, m), 3.06 (3H
,s), 2.7-2.4(2H,m) (2) In the same manner as in Example 3, 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide] -3-(1-methyl-1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-
Obtain carboxylate.

mp+160~165°C (decomposition) Engineering R (Nujol): 3300. 1750. 16
60. 1610°1530cm-1 NMR (D20.δ): 7.00 (IH, s), 6.
1-5.8 (2H, m).

5.83 (IH2d, J=5H2), 5,33 (IH2
d, J-5H2).

5.50 and 5.30 (2H, ABq, J=13Hz
), 4.14-3, 9 (2H+ m ), 4.00
(3H9s), 3-83 (2H+brs).

3.65 3.40 (2H1m) + 3.00 (3H1
s).

2.67-2.35 (2H, m) Example 5 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-(1,2,
5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) (2,53!9
') in methanol (15m), concentrated hydrochloric acid (1m
Add e) and stir at room temperature for 3.5 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in water, and the pH is adjusted to 3.0 with saturated aqueous sodium bicarbonate solution. This solution is subjected to column chromatography using "Diaion HP-20" (100++7).
After washing with water, elute with 30% methanol aqueous solution. The eluate containing the target compound was collected, methanol was distilled off under reduced pressure, and lyophilized to give 7-[2-methoxyimino-2-(
2-aminothiazol-4-yl)-acetamide]
-3-(1,2,5,6-tetrahydro-l-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) (1,55P) is obtained.

mp: 145-150°C (decomposition) IR (nujol): 3300. 1775. 1660. 161
0°1530σ-1 NMR (D20.δ): 7.00 (IH, s), 6.
1-5.6 (2H, m).

5.90 (IH, d, J=5Hz), 5.22 (IH
, d, J=5H2).

4.5 (overlaps with 2H, H2O peak), 4.1-3
．． 9 (2H, m), 4.0 (3H, s), 3.1-3.
6 (2H, m).

3.5-3.3 (2H, m), 2.6-2.3 (2H,
m) Example 6 In the same manner as in Example 5, 7-[2-methoxyimino-2
-(2-aminothiazol-4-yl)-acetamide]-3-(1-methyl-1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer ).

mp: 160-165°C (disassembly) Engineering R (nujol): 3300. 1750. 1660. 161
0°1530cm' NMR (D, 0.δ): 7.00 (IH, s), 6.
1-5.8 (2H, m).

5.83 (IH, d, J=5Hz), 5.33 (LH
, d, J=5Hz).

5.50, 5.30 (2H, ABq, J-13Hz),
4.14-3.9 (2H.

m), 4.00 (3H, s), 3.83 (2H, br
s), 3.65-3.40 (2H, m), 3.00 (3
H, s), 2.67-2.35 (2H, m) Example 7 The following compound is obtained in the same manner as in Example 5.

(1) 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide], -3-(1,2,5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer).

mp: 150-155°C (decomposition) IR (Nujol): 3400. 3100. 17
60. 1670°1600, 1530c+++-1 NMR (D20 + DCl, δ): 6.27-5.
5 (2H, m), 5.90 (IH, d, J=4.5H
z), 5.37 (IH, d, J=4.5Hz).

4.43 (2H, q, J=7Hz), 4.30 (2H
, br e), 4.0-3.6 (4H, br s), 3
．． 6-3.4 (2H, m), 2.7-2.3 (2H, m
), 1.36 (3H, t, J=7Hz) +217-
[2-ethoxyimino-2-(5-asanino 1.2.4
-thiadiazol-3-yl)acetamide]-3-(
1-Methyl-1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer).

mp: 150-155°C (decomposition) IR (nujol): 3300. 1770. 1660. 161
0°1530cm' NMR (D20.δ): 6.1-5.8 (IH+m)
+5.93 (IH, d.

J-5Hz), 5.83 and 5. sQ (2H,
ABq, J=13T(z).

5, 4 5= 3 (I H+ m), 5.37 (
l Hld, J-5Hz).

4.37 (2H, q+ J=7Hz), 4.0-3.8
(2H, m).

3.7-3.4 (2H, bre), 3.1-2.9 (
2H, m).

3.00 (3H, s), 2.7-2.4 (2H, m).

1.35 (3H, t, J=7Hz)

Claims (1)

[Claims] 1) A novel cephem compound represented by the general formula: (wherein R1 is amino or protected amino, R2 is a lower aliphatic hydrocarbon group, and X is N or CH, respectively) and its salt. 2) Claim 1, wherein R'' is an amine or lower alkanoylamino, and R2 is a lower alkyl group.
Compounds described in Section 1, and quaternary salts thereof. 3) 7-[2-ethoxyimino-2-(5-ami7-1
．． 2.4-thiadiazol-3-yl)acetamide]
-3-(1,2,5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer), 7-[2-methoxyimino-2-(2-formamidothiazole- 4-yl)acetamido]-3-(1,2,
5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer), 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamide]- 3-(1, 2, 5,
6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn M form), 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3- yl)acetamide]-3-(1-methyl-
1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl) Acetamide]-3-(1-methyl-1,2,5,6-tetrahydro-1-pyridinio)
Methyl-3-cephem-4-carboxylate (syn isomer), 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetothymide L-3-(1-methyl-1
,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)
, 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1°2, 5.6
-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer), 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1 -Methyl-1,2,5,6-tetrahydro-1-pyridinio)methyl-3-cephem-4
-carboxylate (syn isomer), 7-[2-ethoxyimino-2-(5-amino-1,2
,4-thiadiazol-3-yl)acetamide]-3
-(1,2,5,6-tetrahydro-1-pyridyl)methyl-3-cephem-4-carboxylic acid (syn isomer) and 7-[2-ethoxyimino-2-(5-amino-1,2
,4-thiadiazol-3-yl)acetamide]-3
-(1-methyl-1,2,5,6-tetrahydro-1-
3. The compound according to claim 2, which is selected from the group consisting of: 4) Formula (1): (wherein R1 is amino or protected amino, R2 is a lower aliphatic hydrocarbon group, and X means N or CH, respectively) or a salt thereof is subjected to a reduction reaction. to obtain a compound or a salt thereof of the formula: (wherein Hl, R2 and X each have the same meanings as before, or (2) formula: (wherein Hl, R2 and ) or a salt thereof is reacted with a compound represented by the formula: (in the formula, R3 means a lower alkyl group and Y means an acid residue, respectively) to form a compound represented by the formula: (in the formula, Hl, R2, R3 and X each have the same meaning as before) or a salt thereof, or 1+l
? . (In the formula, Hl and X each have the same meaning as before, and R4 means a protected amine.) A compound represented by the formula or a salt thereof is subjected to an amino-protecting group elimination reaction to obtain the formula: ( A novel compound represented by the general formula (in which R11 and X each have the same meaning as before) or a salt thereof: A method for producing a cephem compound or its salt. 5) The active ingredient is a novel cephem compound represented by the general formula: (wherein R1 is an amino or protected amine, R2 is a lower aliphatic hydrocarbon group, and X is N or CH, respectively) or a salt thereof. Pharmaceutical composition.