JPH0261479B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides compounds useful as antibacterial substances with the general formula: K0728 [wherein R ¹ is amino or a protected amino group,
R ² is lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkenyl, and the formula

The group represented by [Formula] each represents a heterocyclic cation group containing 2 to 3 nitrogen atoms, which may be substituted with 1 to 3 substituents selected from lower alkyl, amino, lower alkenyl, halogen, and hydroxy. means. (However, if R ² is lower alkyl, the formula

The group represented by the formula is 2-lower alkyl-1-pyrazolio and 3-lower alkyl-1-
Not Triazolio. )] The present invention relates to novel cefem compounds shown in the following, salts thereof, and methods for producing them. The above-mentioned novel cefem compound () according to this invention
can be produced by the method shown below. K0731 K0732 K0733 K0734 (In the above formula, R ¹ , R ² and the formula

Each group represented by [formula] has the same meaning as before; R ³ is of the formula

A group that can be substituted by a group of [formula];

The compound of [Formula] is a heterocyclic compound containing 2 to 3 nitrogen atoms optionally substituted with 1 to 3 substituents selected from lower alkyl, amino, lower alkenyl, halogen, and hydroxy (however,
If R ² is lower alkyl, then the formula

The compound represented by the formula is not 2-lower alkyl-1-pyrazole or 3-lower alkyl-1-triazole. ); R ⁴ is a protected carboxy group; K0739 K0740 K0741 K0742 K0743 (In the above formula, R ¹ , R ² , R ⁴ , X,

[Formula] Compounds and formulas

Each group in [Formula] has the same meaning as before) Target compound () and starting compound (),
With respect to (), (), (), () and (), these target and starting compounds include syn isomers, anti-isomers and mixtures thereof. For example, taking the target compound (),
Syn-isomer means a geometric isomer having a partial structure of the following formula K0746 (wherein R ¹ and R ² have the same meanings as before), and anti-isomer means a geometric isomer having a partial structure of the following formula K0747 (formula (wherein R ¹ and R ² each have the same meaning as above) means the other geometric isomer having the partial structure shown. The starting compounds mentioned above (), (), (), ()
,
Regarding () and (), the syn isomer and anti isomer respectively refer to the same geometric isomers as exemplified for compound (). Conventional non-toxic salts are suitable as the salts of the target compound (), and specific examples include alkali metal salts (e.g., sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.). salts, etc.), ammonium salts, organic base salts (e.g., trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N-dibenzylethylenediamine salts, etc.), organic acid salts (e.g. , acetate,
maleate, tartrate, methanesulfonate,
benzenesulfonate, formate, toluenesulfonate, etc.), inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.),
Or salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.). Explanations and preferred specific examples of the various definitions used in this specification will be described in detail. "Lower" means carbon number 1 to 1 unless otherwise specified.
It means 6. Suitable examples of "protected amino" represented by R ¹ include acylamino and conventional protecting groups such as aryl lower alkyl (e.g. benzyl, trityl) which may have at least one suitable substituent. Examples include amino groups substituted with . Preferred examples of the acyl moiety in "acylamino" and "acyloxy" include carbamoyl, aliphatic acyl groups, and acyl groups having an aromatic or heterocyclic ring, and preferred specific examples of such acyl include lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl) , tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.), arenesulfonyl (e.g.,
benzenesulfonyl, tosyl, etc.), aroyl (e.g., benzoyl, triooyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.), aryl lower alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.), aryl lower alkoxycarbonyl (e.g., benzyl) oxycarbonyl, phenethyloxycarbonyl, etc.). The above acyl moieties may have at least one suitable substituent (such as acyl such as lower alkanoyl, halogen such as bromine, fluorine and iodine). Suitable "lower alkyl" has 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
Examples include butyl, pentyl, tert-pentyl, hexyl, etc., and those having 1 to 4 carbon atoms are preferred. Suitable "lower alkenyl" has 2 to 6 carbon atoms, and specific examples include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3
-pentenyl, etc., and those having 2 to 4 carbon atoms are preferred. Suitable "lower alkynyl" has 2 to 6 carbon atoms, and specific examples include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, etc., and lower alkynyl has 2 to 6 carbon atoms. is preferred. Suitable "lower cyclo alkenyl" includes those having 3 to 6 carbon atoms such as cyclopentenyl and cyclohexenyl;
Preferably. Suitable R ³ include acid residues such as acyloxy, halogen (e.g. chlorine, bromine, iodine or fluorine), azide, where "as the acyl moiety in acyloxy, mention may be made of those exemplified above". Suitable heterocyclic cationic groups containing 2 to 3 nitrogen atoms include saturated or unsaturated, monocyclic or polycyclic heterocyclic cationic groups containing 2 to 3 nitrogen atoms. Preferred as the heterocyclic cation group containing 2 to 3 nitrogen atoms are unsaturated 5- to 6-membered heteromonocyclic cation groups containing 2 to 3 nitrogen atoms, such as imidazolio, pyrazolio, triazolio (e.g.,
2,3-triazolio, 1,3,4-triazolio or 1,2,4-triazolio), pyridazinio, pyrimidinio, pyrazinio, triazinio (e.g. 1,2,3-triazinio, 1,2,4
-triazinio or 1,3,5-triazinio), etc.; unsaturated fused heterocyclic cation groups containing 2 to 3 nitrogen atoms, such as indazolio,
benzimidazolinio, cinnonilio, phthalazinio, quinazolinio, quinoxalinio, 1,5-naphthyridinio, etc., and these heterocyclic cation groups containing 2 to 3 nitrogen atoms include hydroxy, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.) aminohalogens (e.g. chlorine,
(bromine, iodine or fluorine), lower alkenyl as mentioned above, etc., and may be substituted with 1 to 3 suitable substituents. Suitable "protected carboxy" includes "esterified hydroxy", and suitable ester moieties in "esterified hydroxy" include lower alkyl esters (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.),
Lower alkenyl esters (e.g. vinyl esters,
allyl ester, etc.), lower alkynyl ester (e.g., ethyl ester, propynyl ester, etc.), mono(or di- or tri)halo-lower alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.) Lower alkanoyloxy lower alkyl esters (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, -propionyloxyethyl ester, etc.), lower alkanesulfonyl lower alkyl esters (e.g., mesyl methyl ester, 2-mesylethyl ester, etc.), aryl lower alkyl esters, even if substituted with one or more suitable substituents. Good phenyl lower alkyl esters (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,
Phenethyl ester, trityl ester, diphenyl methyl ester, bis(methocacyphenyl)
Methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.) Aryl ester (e.g., fluorine ester) which may have one or more suitable substituents enyl ester, tolyl ester, t-
butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.). The heterocyclic compound containing 2 to 3 nitrogen atoms means a heterocyclic compound corresponding to the above-mentioned heterocyclic cation group containing 2 to 3 nitrogen atoms. As suitable acid residues for X, mention may be made of those mentioned above. Preferred embodiments of the target compound () are as follows: A preferred embodiment of R ¹ is amino, R ² is lower alkyl, lower alkenyl, lower alkynyl or cyclo lower alkenyl, and has the formula

The group represented by the formula is triazolio, imidazolio, pyrimidinio, pyrazolio, pyridazinio or pyrazinio, and these groups include one lower alkyl, amino, lower alkenyl,
Optionally substituted with halogen and hydroxy. The method for producing the object compound of the present invention will be described in detail below. Method 1 The target compound () or its salts can be produced by reacting the compound () with the compound () or its salts. Suitable salts for compound () include those exemplified for compound (). This reaction consists of water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene,
Methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol,
It can be carried out in a solvent such as ether, tetrahydrofuran, dimethyl sulfoxide, or other organic solvents that do not adversely affect the reaction, preferably in a highly polar solvent. Of these solvents,
Hydrophilic solvents may be used in mixtures with water. The reaction is preferably carried out in a medium near neutrality. When compound () is used in free form, the reaction is preferably carried out in the presence of a base. Examples of bases that can be used include unbasic bases such as alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates, and organic bases such as trialkylamines. Although there is no particular restriction on the reaction temperature, the reaction is usually carried out at room temperature, with heating, or under heating. This reaction is preferably carried out in the presence of an alkali metal halide (eg, sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (eg, sodium thiocyanate, potassium thiocyanate, etc.). Method 2 Compound () or its salts are compound ()
can be produced by subjecting it to an elimination reaction of the carboxy protecting group. For this elimination reaction, any of the conventional methods used for eliminating carboxy protecting groups, such as hydrolysis, reduction, elimination using a Lewis acid, etc., can be applied. When the carboxy protecting group is an ester, hydrolysis or elimination using a Lewis acid can be employed. Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include both inorganic and organic bases. Suitable acids include organic acids (e.g. formic acid, acetic acid,
propionic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not particularly limited and can be appropriately selected depending on the type of carboxy protecting group and the elimination method. Elimination using a Lewis acid is carried out by allowing the Lewis acid to act on the compound (). Lewis acids include boron trihalide (e.g., boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g., titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g., titanium tetrachloride, etc.). tin, tin tetrabromide, etc.), aluminum halides (e.g., aluminum chloride, aluminum bromide, etc.), trihaloacetic acids (e.g., trichloroacetic acid, trifluoroacetic acid, etc.)
etc. can be used. This elimination reaction is preferably carried out in the presence of a cation scavenger (e.g., anisole, phenol, etc.), and is usually carried out in the presence of nitroalkanes (e.g., nitromethane, nitroethane, etc.) or alkylene halides (e.g., methylene chloride, ethylene chloride, etc.). ), diethyl ether, carbon trisulfide, or other solvents that do not adversely affect the reaction. These solvents may be used as a mixed solvent. Although there is no particular restriction on the reaction temperature, the reaction is usually carried out under cooling, at room temperature, or under heating. Elimination by reduction involves halo-lower alkyl (e.g. 2
-Iodoethyl, 2,2,2-trichloroethyl, etc.) esters, aryl lower alkyl (eg, benzyl, nitrobenzyl, etc.) esters, etc. are preferably applied to removal of protecting groups. Reduction methods that can be applied to this elimination reaction include, for example, combining metals (e.g., zinc, zinc amalgam, etc.) or chromium alkyl salts (e.g., chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g., acetic acid, propionic acid, hydrochloric acid, etc.); as well as conventional metal catalysts (e.g. palladium/
conventional catalytic reduction in the presence of carbon, Raney nickel, etc.). This reduction can be performed using water, alcohol (e.g. methanol,
The reaction is usually carried out in a solvent such as ethanol, tetrahydrofuran, or other solvent that does not adversely affect the reaction. These solvents may be used as a mixed solvent. There is no particular restriction on the reaction temperature, but usually cooling,
The reaction is carried out at room temperature or under heating. The production of the starting compound () will now be described in detail. Production method 1 Compound () is a compound () or its salts with the formula

It can be produced by reacting a compound represented by the formula. This reaction can be carried out in a manner similar to Method 1. Production method 2 Compound () can be produced by reducing compound (). This reduction occurs in cephalosporin compounds.

This can be carried out in the presence of a conventional reducing agent capable of reducing the group ##STR1## to the group -S-, for example a phosphorus halide such as phosphorus trihalide (eg phosphorus trichloride). The object compounds of this invention () exhibit high antibacterial activity and inhibit the growth of numerous microorganisms, including Gram-positive and Gram-negative pathogens. When using the target compound () as a medicine,
It may also be used in the form of pharmaceutically acceptable salts. When administered for therapeutic purposes, the cefem compounds of this invention () or salts thereof may be administered in a pharmaceutically acceptable medium, such as an organic or inorganic, solid or liquid, suitable for oral, parenteral or topical administration. It is used in the form of a preparation mixed with excipients. Such preparations include solid preparations such as capsules, tablets, granules, ointments, and suppositories, and liquid preparations such as solutions, suspensions, and emulsions. Furthermore, if desired, adjuvants may be added to the formulation.
Stabilizers, wetting agents or emulsifiers, buffering agents, other conventional additives, etc. can also be included. Although the dosage of the active compound will vary depending on the age and condition of the patient, average single doses of the compounds of this invention are approximately 50 mg, 100 mg, and 250 mg.
Amounts of 500 mg and 500 mg are effective in treating infections caused by many pathogenic bacteria. Generally, daily doses of 1 mg to about 1000 mg or more may be administered. Next, test data regarding the antibacterial activity of representative compounds according to the present invention will be shown to demonstrate the usefulness of the target compound (2). Test method In vitro antibacterial activity was determined by the agar plate dilution method described below. Trypticase soy broth (bacteria count 10 ⁸
One platinum loop of each test strain, grown overnight in 1000 g/ml), was inoculated onto heart infusion agar (HI-agar). This medium contained antibacterial agents at various concentrations, and the minimum inhibitory concentration (MIC) was measured after culturing at 37°C for 20 hours. (Unit: Kg/ml) Test compound (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridazine) niomethyl)
-3-Cefem-4-carboxylate (syn isomer) (2) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-( 1-pyridaziniomethyl)
-3-Cefem-4-carboxylate (syn isomer) Test results

[Table] The present invention will be explained below with reference to production examples and examples. Production example 1 Phosphorus pentachloride (16.6g) in methylene chloride (150ml)
2-Ethoxyimino-2-(5
-Amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (17.3g) was added and the mixture was stirred at -13-10°C for 15 minutes. Meanwhile, a mixture of 7-amino-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (25.1 g) and trimethylsilylacetamide (80 g) in methylene chloride (400 ml) was heated to form a clear solution.
Cooled to -10°C. This cold solution was added to the above activation mixture and the resulting mixture was stirred at -10°C for 1 hour. Add the reaction mixture to sodium bicarbonate (42 g)
The mixture was poured into an aqueous solution (450 ml) of and stirred at room temperature for 1 hour. Separate the aqueous layer and adjust the pH to 2 with 6N hydrochloric acid.
Extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was triturated with diethyl ether to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamide]-3
-acetoacetoxymethyl-3-cephem-4-
Obtained 24.5 g of carboxylic acid (syn isomer).
mp101-106℃ (decomposition). IR (Nujol): 3400, 3300, 3170, 1770, 1710,
1660, 1620, 1525, 1145, 1035 cm ^-1 Example 1 A mixture of sodium iodide (12.25 g), 5-methylpyrimidine (1.867 g), water (2.5 ml) and acetonitrile (7.5 ml) was stirred at 60°C. while 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0g)
was added and stirring continued for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, diluted with a mixture of water (150 ml) and ethyl acetate (100 ml), then PH'd with 1N hydrochloric acid.
Adjusted to 2. The aqueous layer was separated, washed with ethyl acetate, ethyl acetate was removed by evaporation, and then subjected to column chromatography using a nonionic adsorption resin Diaion HP-20 (150 ml). After washing the column with water, elution was performed with a 30% methanol aqueous solution. The eluate containing the target compound was collected, concentrated under reduced pressure to 40 ml, passed through acidic alumina (10 g), and lyophilized to give 7-[2-ethoxyimino-2-(5-amino-1,2,4- Thiadiazol-3-yl)acetamido]-3-(5-methyl-1-pyrimidiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.45 g) was obtained. mp135~140
°C (decomposition). IR (Nujol): 3250, 3150, 1770, 1660, 1610,
1520cm ^-1 NMR (D ₂ O, δ): 1.32 (3H, t, J = 7Hz),
2.58 (3H, s), 3.28 and 3.72 (2H,
ABq, J = 18Hz), 4.33 (2H, q, J =
7Hz), 5.30 (1H, d, J=5Hz), 5.37 and 5.60 (2H, ABq, Jw14Hz), 5.90
(1H, d, J=5Hz), 9.25 (2H, s),
9.60 (1H, s) Example 2 The following compound was obtained in the same manner as in Example 1. (1) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridaziniomethyl)
-3-Cefem-4-carboxylate (syn isomer), mp 155-160°C (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1610,
1530, 1350, 1040cm ^-1 NMR (D ₂ O, δ): 1.23 (3H, t, J = 7Hz),
3.03−3.92 (2H, m), 4.20 (2H, q, J=
7Hz), 5.10 (1H, d, J = 5Hz), 5.4-5.9
(2H, m), 5.77 (1H, d, J = 5Hz) 7.67
(1H, m), 8.42 (1H, m), 9.20 (1H,
m), 9.52 (1H, m) (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyraziniomethyl)-
3-Cefem-4-carboxylate (syn isomer), mp 165-170°C (decomposition). IR (Nujol): 3250, 3150, 1770, 1660, 1610,
1520cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
3.27 and 3.72 (2H, ABq, J=18Hz),
4.33 (2H, q, J=7Hz), 5.30 (1H, d,
J = 5Hz), 5.47 and 5.75 (2H, ABq, J
= 14Hz), 5.90 (1H, d, J = 5Hz), 9.13
(2H, bs), 9.45 (2H, bs) (3) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1- pyridaziniomethyl)
-3-Cefem-4-carboxylate (syn isomer), mp 165-170°C (decomposition). IR (Nujol): 3400−3100, 1770, 1660−1580,
1530, 1040 cm ^-1 NMR (D ₂ O, δ): 3.47 and 3.83 (2H, ABq,
J=18Hz), 4.05 (3H, s), 5.25 (1H,
d, J=5Hz), 5.72 (2H, broad s),
5.87 (1H, d, J=5Hz), 8.5−8.7 (2H,
m), 9.4-9.6 (1H, m), 9.7-9.9 (1H,
m) (4) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(2-methyl-1-pyrazoliomethyl)-3- Cefem-4-carboxylate (syn isomer), mp 165-175°C (decomposition). IR (Nujol): 3200, 3100, 1770, 1670, 1610,
1520cm ^-1 NMR (D ₂ O, δ): 3.20 and 3.60 (2H, ABq,
J=18Hz), 4.13 (3H, s), 4.60−4.93
(2H, m), 5.30 (1H, d, J=5Hz),
5.16−5.63 (4H, m), 5.8−6.4 (2H, m),
6.80 (1H, t, J = 3Hz), 8.20 (2H, d,
J=3Hz) (5) 7-[2-ethoxyimino-2-(2-propynyloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridaziniomethyl)-3-
Cefem-4-carboxylate (syn isomer), mp 160-165°C (decomposition). IR (Nujol): 3250, 3200, 3100, 1770, 1660,
1620, 1520cm ^-1 NMR (D ₂ O, δ): 3.03 (1H, t, J = 2Hz),
3.48 and 3.83 (2H, ABq, J=18Hz),
4.93 (2H, d, J=2Hz), 5.27 (1H, d,
J=5Hz), 5.73 (2H, broad s), 5.88
(1H, d, J=5Hz), 8.60 (2H, m),
9.47 (1H, m), 9.83 (1H, m) (6) 7-[2-(2-propynyloxyimino)-
2-(5-Amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(2-methyl-1-pyrazoliomethyl)-3-cephem-
4-carboxylate (syn isomer), mp160
~170℃ (decomposition). IR (Nujol): 3250−3100, 1760, 1670, 1610,
1520cm ^-1 NMR (D ₂ O, δ): 3.05 (1H, t, J = 2Hz),
3.20 and 3.58 (2H, ABq, J=18Hz),
4.13 (3H, s), 4.97 (2H, d, J=2Hz),
5.30 (1H, d, J = 5Hz), 5.27 and 5.57
(2H, ABq, J=14Hz), 5.92 (1H, d,
J = 5Hz), 6.80 (1H, t, J = 3Hz),
8.23 (2H, broad s) (7) 7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamide]-
3-(2-methyl-1-pyrazoliomethyl)-3
-Cefem-4-carboxylate (syn isomer), mp 155-160°C (decomposition). IR (Nujol): 3250, 3100, 1770, 1660, 1605,
1525cm ^-1 NMR (D ₂ O + CD ₃ OD, δ): 1.83−2.63 (4H,
m), 3,20 and 3.43 (2H, ABq, J=
18Hz), 4.12 (3H, s) 5.17 (1H, d, J
=5Hz), 5.13-5.67 (3H, m), 5.80 (1H,
d, J=5Hz), 5.73−6.33 (2H, m),
6.77 (1H, m), 8.20 (2H, m) (8) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(2 -Allyl-1-pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp 130-140°C (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1610,
1530cm ^-1 NMR (D ₂ O, δ): 1.32 (3H, t, J = 7Hz),
3.13 and 3.46 (2H, ABq, J=18Hz),
4.31 (2H, q, J=7Hz), 5.0−5.3 (4H,
m), 5.20 (1H, d, J = 5Hz), 5.29 and 5.39 (2H, ABq, J = 14Hz), 5.82 (1H,
d, J=5Hz), 5.8−6.2 (1H, m), 6.8
(1H, m), 8.2 (2H, m) (9) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3- Chloro-1-pyridaziniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 145-150°C (decomposition). IR (Nujol): 3300−3100, 1775, 1670, 1610,
1530cm ^-1 (10) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-methyl-1-(1,3,
4-triazoliomethyl)]-3-cephem-4
-Carboxylate (syn isomer), mp153~
157℃ (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1610,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.22 (3H, t, J=
7Hz), 3.3-3.7 (2H, m), 4.05 (3H, s),
4.13 (2H, q, J=7Hz), 4.7−5.3 (2H,
m), 4.98 (1H, d, J=5Hz), 5.63 (1H,
2d, J=5 and 8Hz), 8.10 (2H, broad
s), 9.30 (1H, s) 9.33 (1H, d, J=
8Hz), 10.25 (1H, s) (11) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-methyl-1 -(1, 2,
4-triazoliomethyl)]-3-cephem-4
-Carboxylate (syn isomer), mp159~
164℃ (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1605,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.23 (3H, t, J=
7Hz), 3.1-3.8 (2H, m), 3.91 (3H, s),
4.12 (2H, q, J=7Hz), 4.98 (1H, d,
J = 5Hz), 5.0-5.5 (2H, m), 5.63 (1H,
2d, J=5 and 8Hz), 8.13 (2H, broad
s), 9.03 (1H, s), 9.31 (1H, d, J=
8Hz), 10.25 (1H, s) (12) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxy-1 -pyridaciniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 159-163°C (decomposition). IR (Nujol): 3400−3100, 1775, 1670, 1610,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.27 (3H, t, J=
7Hz), 3.56 (2H, broad s), 4.16 (2H,
q, J=7Hz), 4.9−5.6 (3H, m), 5.82
(1H, 2d, J=5 and 8Hz), 6.91 (1H,
d, J=9Hz), 7.6 (1H, m), 8.09 (2H,
broad s), 8.44 (1H, d, J = 4Hz),
9.54 (1H, d, J = 8Hz) (13) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)
Acetamide]-3-(3-methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate (syn isomer), mp 156-165°C (decomposition). IR (Nujol): 3300, 3150, 1770, 1660, 1605,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.23 (3H, t, J=
7Hz), 3.12 and 3.54 (2H, ABq, J=
18Hz), 3.86 (3H, s), 4.15 (2H, q, J
= 7Hz), 5.02 (1H, d, J = 5Hz), 5.02
and 5.18 (2H, ABq, J=14Hz), 5.66
(1H, 2d, J=5 and 9Hz), 7.65 (1H,
s), 7.97 (1H, s), 8.25 (2H, broap
s), 9.32 (1H, s), 9.45 (1H, d, J=
9Hz) Example 3 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3- in trifluoroacetic acid (20 ml)
(3-Methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate diphenylmethyl ester trifluoroacetate (syn isomer)
(3 g) and anisole (7.5 ml) was stirred for 20 minutes while cooling in an ice bath. This mixture was poured into cold diisopropyl ether (120 ml) with stirring, and the precipitate was collected by filtration. This powder was suspended in water (50 ml) and diluted with aqueous sodium bicarbonate solution.
The pH was adjusted to 4 to 5, and insoluble matter was filtered off. The filtrate is treated with Diaion Hp-20, a nonionic adsorption resin.
(100ml) was subjected to column chromatography. After washing the column with water, elution was performed with a 20% methanol aqueous solution. The eluate containing the target compound was collected, methanol was removed by vacuum evaporation, and lyophilized to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl).
Acetamide]-3-(3-methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate (syn isomer) (1.46 g) was obtained. mp156~
165℃ (decomposition). IR (Nujol): 3300, 3150, 1770, 1660, 1605,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.23 (3H, t, J=
7Hz), 3.12 and 3.54 (2H, ABq, J=
18Hz), 3.86 (3H, s), 4.15 (2H, q, J
= 7Hz), 5.02 (1H, d, J = 5Hz), 5.02
and 5.18 (2H, ABq, J=14Hz) 5.66
(1H, 2d, J=5 and 9Hz), 7.65 (1H,
s), 7.97 (1H, s), 8.25 (2H, broad
s), 9.32 (1H, s), 9.45 (1H, d, J=
9Hz) Example 4 The following compound was obtained in the same manner as in Example 3. (1) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(5-methyl-1-pyrimidiniomethyl)-3- Cefem-4-carboxylate pyrimidiniomethyl, mp135-140℃
(Disassembly). IR (Nujol): 3250, 3150, 1770, 1660, 1610,
1520cm ^-1 (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridaziniomethyl)
-3-Cefem-4-carboxylate (syn isomer), mp 155-160°C (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1610,
1530, 1350, 1040 cm ^-1 (3) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyraziniomethyl)-
3-Cefem-4-carboxylate (syn isomer), mp 165-170°C (decomposition). IR (Nujol): 3250, 3150, 1770, 1660, 1610,
1520cm ^-1 (4) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridaziniomethyl)
-3-Cefem-4-carboxylate (syn isomer), mp 165-170°C (decomposition). IR (Nujol): 3400−3100, 1770, 1660−1580,
1530, 1040cm ^-1 (5) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-1-pyrazoliomethyl) -3-Cefem-4-carboxylate (syn isomer), mp 165-175°C (decomposition). IR (Nujol): 3200, 3100, 1770, 1670, 1610,
1520cm ^-1 (6) 7-[2-(2-propionyloxyimino)
-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-pyridaziniomethyl)-3-cephem-4-carboxylate (syn isomer), mp160 ~165℃
(Disassembly). IR (Nujol): 3250, 3200, 3100, 1770, 1660,
1620, 1520cm ^-1 (7) 7-[2-(2-propionyloxyimino)
-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(2-methyl-1-pyrazoliomethyl)-3-cephem-4-carboxylate (syn isomer),
mp160-170℃ (decomposition). IR (Nujol): 3250−3100, 1760, 1670, 1610,
1520cm ^-1 (8) 7-[2-(2-cyclopenten-1-yloxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamide]-
3-(2-methyl-1-pyrazoliomethyl)-3
-Cefem-4-carboxylate (syn isomer), mp 155-160°C (decomposition). IR (Nujol): 3250, 3100, 1770, 1660, 1605,
1525cm ^-1 (9) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(2-allyl-1-pyrazoliomethyl-3-cepheme -4-carboxylate (syn isomer), mp130-140℃ (decomposed). IR (Nujol): 3400-3100, 1770, 1660, 1610,
1530cm ^-1 (10) 7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-chloro-1-pyridaziomethyl)-3- Cefem-4-carboxylate (syn isomer), mp 145-150°C (decomposed). IR (Nujol): 3300−3100, 1775, 1670, 1610,
1530cm ^-1 (11) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[3-methyl-1-(1,3,
4-triazolylmethyl)]-3-cephem-4
-carboxylate (syn isomer), mp153~
157℃ (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1610,
1530cm ^-1 (12) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[4-methyl-1-(1,2,
4-triazolylmethyl)]-3-cephem-4
-Carboxylate (syn isomer), mp159~
164℃ (decomposition). IR (Nujol): 3400−3100, 1770, 1660, 1605,
1530cm ^-1 (13) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)
Acetamide]-3-(3-hydroxy-1-pyridaziniomethyl)-3-cephem-4-carboxylate (syn isomer), mp159-163℃
(Disassembly). IR (Nujol): 3400−3100, 1775, 1670, 1610,
1520cm ^-1 Production example 2 Phosphorus pentachloride (54.6g) in methylene chloride (500ml)
2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (54.0
g) was added. The mixture was stirred at -15-12°C for 30 minutes and then at -5°C for 2 hours. Diisopropyl ether (500ml) was added to the resulting reaction mixture containing a precipitate of the desired compound at -5°C and the mixture was stirred at -5 to -10°C for 30 minutes. The deposited precipitate was collected by filtration, washed with diisopropyl ether,
Dry to give 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (60.17 g)
I got it. mp125-127℃ (decomposition). IR (Nujol): 1785, 1625, 1055 cm ^-1 Analysis value: (C ₆ H ₈ O ₂ N ₄ SCl ₂ ) C H N S Cl Calculated value: 26.57 2.95 20.66 11.81 26.20 Actual value: 26.13 2.99 20.49 11.77 26.41 Manufacturing example 3 7-Amino-3- in methylene chloride (300 ml)
Chloromethyl-3-cephem-4-carboxylic acid.
N,N-dimethylaniline (36.2 g) was added to a suspension of diphenyl methyl ester hydrochloride (27 g) while cooling in an ice bath to 5°C. 2-ethoxyimino-2-(5-amino-1,2,
4-Thiadiazol-3-yl) acetyl chloride hydrochloride (syn isomer) (16.2 g) was added in portions below 11°C and the mixture was stirred at 5°C for 45 minutes. The reaction mixture was diluted with a mixed solvent of methylene chloride (100 ml) and water (200 ml), and the pH was adjusted with 1N hydrochloric acid.
Adjusted to 2. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem- 4-Carboxylic acid diphenyl methyl ester (syn isomer) (32.4g)
I got it. mp120-125℃ (decomposition). IR (Nujol): 3300, 3150, 1780, 1725, 1675,
1625, 1530, 1495 cm ^-1 NMR (DMSO-d ₆ , δ): 1.28 (3H, t, J=
7Hz), 3.68 (2H, broad s), 4.23 (2H,
q, J=7Hz), 4.47 (2H, s), 5.27 (1H,
d, J = 5Hz), 5.97 (1H, 2d, J = 5 and 8Hz), 7.0 (1H, s), 7.2−7.7 (10H,
m), 8.17 (2H, broad s), 9.62 (1H, d,
Preparation Example 4 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) in a mixed solvent of methylene chloride (100 ml) and acetic acid (10 ml)
Acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) (10 g) was added to a cold solution of 30% hydrogen peroxide (1.84 ml) and sodium tungstate (0.3 g) was added. The mixture was stirred in an ice bath for 45 minutes and then poured into diethyl ether (300ml). The deposited precipitate was collected by filtration and washed with diethyl ether.
-[2-ethoxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid-1-oxide diphenylmethyl ester (syn isomer) (8.9 g) was obtained. mp150～
155℃ (decomposition). IR (Nujol): 3280, 3170, 1785, 1723, 1667,
1628, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J=
7Hz), 3.90 (2H, broad s), 4.23 (2H,
q, J=7Hz), 4.58 (2H, broad s),
5.12 (1H, d, J=5Hz), 6.10 (1H, 2d,
J=5 and 8Hz), 7.02 (1H, s), 7.20
−7.73 (10H, m), 8.15 (2H, broad s),
9.00 (1H, d, J = 8Hz) Production example 5 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4
- Sodium iodide (8.22 g) was added to a cold solution of carboxylic acid-1-oxide diphenyl methyl ester (syn isomer) (9.85 g) in acetone (222 ml), and the mixture was stirred for 2 hours while cooling in an ice bath. did. After evaporating the solvent under reduced pressure, the residue was dissolved in a mixed solvent of methylene chloride (200 ml) and water (100 ml). The organic layer was separated, washed successively with an aqueous sodium thiosulfate solution and water, dried over magnesium sulfate, and evaporated to dryness. The residue was triturated in diethyl ether to give 7-[2-ethoxyimino-2-(5-
Amino-1,2,4-thiadiazol-3-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylic acid-1-oxide diphenylmethyl ester (syn isomer) (10.39 g) was obtained. . mp159-163℃ (decomposition). IR (Nujol): 3250, 3150, 1780, 1720, 1670,
1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.29 (3H, t, J=
7Hz), 3.95 (2H, m), 4.25 (2H, q, J
=7Hz), 4.50 (2H, m), 5.12 (1H, d,
J=5Hz), 6.05(1H, 2d, J=5 and
9Hz), 7.00 (1H, s), 7.4 (10H, m),
8.13 (2H, broad s), 8.96 (1H, d, J=
9Hz) Preparation Example 6 K0751 K0752 7-[2-ethoxyimino-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetamide]-3
A mixture of -iodomethyl-3-cephem-4-carboxylic acid-1-oxide diphenylmethyl ester (syn isomer) (4 g) and 1-methylimidazole (0.5 g) was stirred at room temperature for 40 minutes. The deposited precipitate was collected by filtration, washed with tetrahydrofuran, and dried to give 7-[2-ethoxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-(3-methyl-1-
Imidazoliomethyl)-3-cephem-4-carboxylate-1-oxide diphenylmethyl ester iodide (syn isomer) (4.20 g) was obtained. mp105-114℃ (decomposition). IR (Nujol): 3250, 3150, 1790, 1720, 1670,
1610, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.21 (3H, t, J=
7Hz), 3.77 (3H, s), 4.10 (2H, m),
4.15 (2H, q, J=7Hz), 5.1 (3H, m),
6.07 (2d, 1H, J=5 and 8Hz), 6.87
(1H, s), 7.33 (11H, m), 7.60 (1H,
s), 8.00 (2H, broad s), 8.91 (1H, d,
Preparation Example 7 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide] in acetonitrile (40 ml) -3-(3
-Methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate-1-oxide diphenylmethyl ester iodide (syn isomer) (4 g) and N,N-dimethylaniline (1.21
Phosphorus trichloride (1.37 g) was added dropwise to the mixture with g) at a temperature lower than 8° C. while stirring and cooling in an ice bath. After the resulting mixture was stirred at the same temperature for 2.5 hours, diethyl ether (45ml) was added to it. The deposited precipitate was collected by filtration, washed with diethyl ether, and dried to give 7-[2-ethoxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-methyl-
1-imidazoliomethyl)-3-cephem-4-
Carboxylate/diphenyl methyl ester/
Iodide (syn isomer) (4.18 g) was obtained.
mp115.5~120.5℃ (decomposition). IR (Nujol): 1780, 1720, 1680, 1630, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 1.22 (3H, t, J=
7Hz), 3.09 (3H, s), 3.86 (2H, m),
4.18 (2H, q, J=7Hz), 5.18 (3H, m),
6.05 (1H, 2d, J=5 and 9Hz), 6.94
(1H, s), 7.4 (15H, m), 9.60 (1H, d,
Preparation Example 8 7-[2-ethoxyimino-2 in a 1:1 mixed solvent of tetrahydrofuran and methanol (10 ml)
-(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(3-methyl-1
-imidazoliomethyl)-3-cephem-4-carboxylate diphenylmethyl ester iodide (syn isomer) (3.9 g) was mixed with an ion exchange resin [Amberlite IRA-400 (trademark, Rohm & Co., Ltd.)]. The mixture was passed through a column packed with trifluoroacetate form (manufactured by Haas) (40 ml). Elution was carried out with the same solvent (80 ml) and the eluate was evaporated to dryness. The residue was triturated in diethyl ether to give 7-
[2-ethoxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide]-3-[3-methyl-1-imidazoliomethyl)-3-cephem-4-carboxylate diphenylmethyl ester trifluoroacetate (syn isomer) (2.74g) was obtained. mp110~119.5℃
(Disassembly). IR (Nujol): 3250, 3150, 1790, 1720, 1690,
1670, 1630, 1530, 1500 cm ^-1 Example 5 The following compound was obtained in the same manner as in the previous example. 7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-(2-amino-1-pyrimidinioniomethyl)-3-cephem-4-carboxylate (syn isomer), mp195-200℃ ( Disassembly). IR (Nujol): 3280, 3160, 1765, 1660, 1635,
1610, 1565, 1520, 1030 cm ^-1 NMR (DMSO-d ₆ , δ): 1.34 (3H, t, J=
7Hz), 3.40 and 3.83 (2H, ABq, J=
18Hz), 4.14 (2H, q, J = 7Hz), 4.70 and 5.45 (2H, ABq, J = 14Hz), 5.08
(1H, d, J = 5Hz), 5.70 (1H, dd, J
=5 and 8Hz), 7.0 (1H, m), 8.1 (2H,
broad s), 8.5 (1H, m), 8.7 (1H, m),
9.46 (1H, d, J = 8Hz).

Claims (1)

[Claims] 1 1 General formula K0711 [In the formula, R ¹ is amino or a protected amino group,
R ² is lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkenyl, and the group represented by the formula [formula] is 1 to 3 substituents selected from lower alkyl, amino, lower alkenyl, halogen, and hydroxy. Each term refers to an optionally substituted heterocyclic cationic group containing 2 to 3 nitrogen atoms. (However, when R ² is lower alkyl, the group represented by the formula [Formula] is 2-lower alkyl-1-pyrazolio and 3
-Not lower alkyl-1-triazolio. )] A novel cefem compound and its salts. 2. A syn isomer of the compound according to claim 1, wherein the [Formula] group is [Formula]. 3. A novel cefem compound characterized in that a compound represented by the general formula K0718 or a salt thereof is obtained by reacting a compound represented by the general formula: [Formula] with a compound represented by the general formula K0716 or a salt thereof. Manufacturing method. [In the above formula, R ¹ is amino or a protected amino group, R ² is lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkenyl, and the group represented by the formula [formula] is lower alkyl, amino, lower alkenyl, halogen and a heterocyclic cationic group containing 2 to 3 nitrogen atoms which may be substituted with 1 to 3 substituents selected from hydroxy (however, if R ² is alkyl, The groups are 2-lower alkyl-1-pyrazolio and 2-lower alkyl-1-
Not Triazolio. ), R ³ is a group that can be substituted by a group of formula [formula], and the compound of formula [formula] is substituted with 1 to 3 substituents selected from lower alkyl, amino, lower alkenyl, halogen, and hydroxy. A heterocyclic compound containing 2 to 3 nitrogen atoms (however, when R ² is lower alkyl, the compound represented by the formula 1
- Not a triazole. ) respectively. [4] A method for producing a novel cefem compound, which comprises subjecting a compound represented by the general formula K0724 to an elimination reaction of a carboxy protecting group to obtain a compound represented by the general formula: K0725 or a salt thereof. [In the above formula, R ¹ is amino or a protected amino group, R ² is lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkenyl, and the group represented by the formula [formula] is lower alkyl, amino, lower alkenyl, halogen and a heterocyclic cationic group containing 2 to 3 nitrogen atoms optionally substituted with 1 to 3 substituents selected from hydroxy (however, if R ² is lower alkyl, it is represented by the formula The groups are 2-lower alkyl-1-pyrazolio and 3-lower alkyl-1-
Not Triazolio. ), R ⁴ represents a protected carboxy group, and X represents an acid residue, respectively. ]