JPH0453868B2 - - Google Patents

Description

[Detailed description of the invention]

This invention describes the general formula useful as an antibacterial substance. [wherein R ¹ is amino or protected amino, R ² is lower alkenyl or lower alkynyl, R ³ is amino, lower alkanoylamino or lower alkyl, R ⁴ is hydrogen or lower alkyl, or, R ¹ has the same meaning as before, R ² means methyl group or ethyl group, R ³ means ethyl group, R ⁴ means hydrogen, or R ¹ has the same meaning as before, R ² , R ³ and R ⁴ each represent a methyl group], salts thereof, methods for producing them, and agents for preventing and treating bacterial infections containing them as active ingredients. According to the present invention, the novel cefem compound () can be produced by the method described below. [In the formula, R ¹ , R ² , R ³ and R ⁴ each have the same meaning as before, R ⁵ is the formula

[Formula] (wherein R ³ and R ⁴ each have the same meanings as above), a group that can be substituted by a group, R ^3a means lower alkanoylamino, and R ^3b means amino, respectively] Target compound [], Regarding [a] and [b] and the starting compound [], the target compound and the starting compound include syn isomers, anti-isomers, and mixtures thereof.
For example, for the target compound [ ], the syn isomer has the formula: [In the formula, R ¹ and R ² have the same meanings as before] means a geometric isomer having the partial structure, and the anti-isomer has the formula: [In the formula, R ¹ and R ² have the same meanings as above] means other geometric isomers having the partial structure. Regarding the other compounds mentioned above, their syn and anti isomers refer to the same geometric isomers as the syn and anti isomers described for compound []. Preferred salts of the target compound [ ] are conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts. , organic amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, e.g. acetates, trifluoroacetates, maleates, tartrates, methane Organic acid salts such as sulfonate, benzenesulfonate, formate, and toluenesulfonate; inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; or Examples include salts with amino acids such as arginine, aspartic acid, and glutamic acid. In the foregoing and following descriptions 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" means 1 to 6 carbon atoms unless otherwise specified. Preferred "protected amino" is an amino substituted with a conventional protecting group such as acylamino or al(lower)alkyl which may have at least one substituent such as benzyl or trityl. Contains groups. Preferred acyl moieties in "acylamino" and "acyloxy" may include carbamoyl, aliphatic acyl groups, and acyl groups containing aromatic or heterocycles. Preferred examples of the acyl include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, and pivaloyl; for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, Lower alkoxycarbonyl having 2 to 7 carbon atoms such as isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, hexyloxycarbonyl; arenesulfonyl such as benzenesulfonyl, tosyl; e.g. benzoyl, toluoyl, xyloyl , naphthoyl, phthaloyl, aroyl such as indancarbonyl; for example, al (lower) such as phenyl acetyl, phenylpropionyl, etc.
Alkanoyl; examples include alkoxycarbonyl (lower) such as benzyloxycarbonyl and phenethyloxycarbonyl. The acyl moiety may be substituted with at least one suitable substituent such as halogen (chlorine, bromine, fluorine and iodine), lower alkanoyl, and the like. Preferred acyls having substituents include lower alkanoyl (eg, acetoacetyl, acetopropionyl, etc.). Suitable "lower alkyl" is alkyl having 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
Examples include -butyl, pentyl, t-pentyl, hexyl, etc., preferably alkyl having 1 to 4 carbon atoms. Suitable "lower alkenyls" have 2 to 6 carbon atoms, and include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, etc., but preferably 2 to 6 carbon atoms.
~4 pieces. Suitable "lower alkynyl" has 2 to 6 carbon atoms, examples include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, etc., but preferably 2 to 6 carbon atoms. ~4 pieces. Preferred examples of the "lower alkanoyl" moiety in "lower alkanoylamino" include the "lower alkanoyl" listed as examples of the acyl group. Suitable R ⁵ include acid residues such as the aforementioned acyloxy, halogen (eg, chloro, fluoro, bromo or iodo), and azide. Preferred specific examples of the target compound () are R ¹ is amino, R ² is lower alkenyl or lower alkynyl, R ³ is amino, lower alkanoylamino or lower alkyl, R ⁴ is hydrogen or lower alkyl, or R A compound in which ¹ is amino, R ² is methyl or ethyl, R ³ is ethyl, and R ⁴ is hydrogen, or R ¹ is amino and R ² , R ³ and R ⁴ are each methyl. The method for producing the object compound of the present invention will be explained in detail below. Method 1 The target compound [ ] or its salts can be produced by reacting the compound [ ] or its salts with the compound [ ] or its salts. As the preferred salts of the compound [] and [], the same ones as exemplified for the compound [] can be used. This reaction is typically carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, Although the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction, it is preferable to carry out the reaction in a strongly polar solvent. Among these solvents, hydrophilic solvents may be used in combination with water.
This reaction is preferably carried out in a neutral solvent.
When the compound [ ] is used in free form, this reaction can be carried out using bases such as inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, organic bases such as trialkylamines, etc. It is desirable to carry out the test in the presence of The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, under heating, or under heating. This reaction is preferably carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide, or an alkali metal thiocyanate salt such as sodium thiocyanate or potassium thiocyanate. Method 2 The target compound [b] or its salts can be produced by subjecting the compound [a] or its salts to a lower alkanoyl group elimination reaction. As preferred salts for compounds [a] and [b], the same salts as exemplified for compound [] can be used. This elimination reaction can be carried out by hydrolysis; a conventional method such as reacting the compound [a] with an iminohalogenating agent, then reacting with an iminoetherifying agent, and subjecting the product to a hydrolysis treatment as necessary. This is done by For hydrolysis, a method using an acid, a base, etc. can be used. Among these methods, hydrolysis with acids is one of the preferred methods, suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid. Preferred acids include formic acid,
These include trifluoroacetic acid and hydrochloric acid. When performing an elimination reaction using an acid, the reaction may be performed in the presence of a solvent or without using a solvent. Suitable solvents are customary organic solvents, water or mixtures thereof. When using trifluoroacetic acid,
Preferably, the elimination reaction is carried out in the presence of anisole. Suitable bases used for hydrolysis with bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, magnesium hydroxide,
Alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate. Inorganic bases such as alkali metal acetates such as bicarbonate, sodium acetate, potassium acetate, etc., organic bases such as trialkylamines such as trimethylamine, triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, etc. Can be mentioned. Hydrolysis with bases is often carried out in water, customary organic solvents or mixtures thereof. The reaction temperature is not particularly limited, but usually under cooling,
It is desirable to carry out the process at room temperature or under mild conditions such as being slightly heated. The compounds thus obtained according to Methods 1 and 2 above can be converted into pharmaceutically acceptable salts by conventional methods. 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 the cefem compounds () or salts thereof of this invention are administered for therapeutic purposes, they 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 in order 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: μg/
ml) Test compound (1) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3,5-dimethyl-1-pyridiniomethyl) -3-Cefem-4-carboxylate (syn isomer). (2) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3,4-dimethyl-
1-pyridiniomethyl)-3-cephem-4-
Carboxylate (syn isomer).

[Table] The present invention will be explained below with reference to production examples and examples. Production example 7-[2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]cephalosporanic acid (syn isomer) was reacted with sodium acetate in a conventional manner to form 7-[2
-methoxyimino-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide]
The sodium salt of cephalosporanic acid (syn isomer) is obtained. mp185-190℃ (decomposition) IR (nujiol): 3150, 1765, 1745, 1670,
1550, 1400, 1355, 1290, 1250, 1055 cm ^-1 Reference example 1 A mixture of 3-formamide pyridine (5.1 g), sodium iodide (36 g), phosphoric acid (1.24 g), water (6 ml) and acetonitrile (18 ml) The sodium salt of 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid (synisomer) was heated to 65-70°C with stirring. body) (10g)
Add. The mixture was stirred at 70-72 °C for 1.5 h,
Dilute with water (50ml). Cool the aqueous solution, adjust the pH to 3 with 6N hydrochloric acid, and dilute to 200 ml with water.
The aqueous solution was mixed with chloroform and ethanol (2:
Wash 5 times with the mixed solvent (150 ml) of 1) and concentrate to 300 ml under reduced pressure. Insoluble matters were removed, and the liquid was subjected to column chromatography using a nonionic adsorption resin "Diaion HP20" (registered trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (300 ml). After washing the column with water,
Elute with % aqueous methanol. The eluates containing the target compound were combined, methanol was distilled off under reduced pressure, and lyophilized to give 7-[2-methoxyimino-2-(5
-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-formamide-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (5.20 g) is obtained. mp.158-163℃ (decomposition). IR (Nujiyor): 3400-3100, 1770, 1670,
1600, 1530 cm ^-1 NMR (D ₂ O, δ): 3.20 and 3.73 (2H, ABq,
J = 18Hz), 4.03 (3H, s), 5.28 (1H, d, J
= 5Hz), 5.30 and 5.67 (2H, ABq, J = 14
Hz), 5.88 (1H, d, J=5Hz), 7.9~8.2 (1H,
m), 8.3~8.6 (1H, m), 8.45 (1H, s), 8.6~
8.8 (1H, m), 9.5 (1H, m) Reference example 2 7-[2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamido]-3-(3-formamido-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (4.48 g) in methanol (45 ml)
Concentrated hydrochloric acid (1.7 ml) is added to the suspension and the mixture is stirred for 75 minutes. The solvent was evaporated, the residue was triturated in acetone, and the resulting powder was suspended in water (100 ml).
Adjust the pH to 4-5 with an aqueous solution of sodium bicarbonate,
Subject to column chromatography using a nonionic adsorption resin "Diaion HP20" (registered trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (135 ml). After washing the column with water, elute with 15% aqueous isopropyl alcohol and
The eluates containing the target product were combined, the isopropyl alcohol was distilled off under reduced pressure, and the product was freeze-dried to give 7-[2-
Methoxyimino-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]-
3-(3-amino-1-pyridiniomethyl)-3-
Cefem-4-carboxylate (syn isomer)
(3.10g) is obtained. mp177-182℃ (decomposition). IR (Nujiyor): 3350, 3200, 1770, 1640~
1590, 1510 cm ^-1 NMR (D ₂ O, δ): 3.15 and 3.65 (2H, ABq,
J=18Hz), 4.04 (3H, s), 5.2~5.4 (2H,
m), 5.23 (1H, d, J=5Hz), 5.85 (1H, d,
J=5Hz), 7.6-7.7 (2H, m), 8.0-8.1 (1H,
m), 8.2 (1H, m) Reference example 3 7-[2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide] cephalosporanic acid sodium salt (syn isomer) (12.0 g), 3-methylpyridine (4.68
g), sodium iodide (44.4 g), phosphoric acid (1.48
g), water (73ml) and acetonitrile (22.4ml)
The mixture is stirred for 1 hour at 72-76°C. Add water to the reaction mixture to dilute to 300ml, and adjust the pH to 3 with 6N hydrochloric acid.
and wash with ethyl acetate. Separate the aqueous solution and use the nonionic adsorption resin “Diaion HP-20” (360
ml) and subjected to column chromatography. After washing the column with water, elute with 25% aqueous methanol.
The eluates containing the target compound are combined and concentrated to 20 ml under reduced pressure. N,N-dimethylformamide (20 ml) was added to the aqueous solution and mixed, and while stirring,
Add to acetone (470ml). The resulting precipitate is filtered off, washed with acetone and dried. Precipitate with water (80
ml) and passed through acidic alumina (22.5 g).
Freeze-dry to give 7-[2-methoxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-(3-amino-1-
pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (4.81 g) is obtained. mp150-154℃ (decomposition). IR (Nujiyor): 3650-3100, 1770, 1670,
1640-1610, 1520 cm ^-1 NMR (D ₂ O, δ): 2.52 (3H, s), 3.15 and
3.65 (2H, ABq, J=18Hz), 4.02 (3H, s),
5.27 (1H, d, J = 5Hz), 5.25 and 5.55
(2H, ABq, J=14Hz), 5.87 (1H, d, J=
5Hz), 7.73-8.10 (1H, m), 8.23-8.50 (1H,
m), 8.63-8.83 (1H, m) Example 1 The following compound is obtained in the same manner as in the above reference example. (1) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-ethyl-1-pyridiniomethyl)-3-cepheme-4 - Carboxylate (syn isomer), mp 160-165°C (decomposition). IR (Nujiyor): 3300, 3150, 1770, 1670,
1610, 1530, 1285, 1140, 1040cm ^1- NMR (D ₂ O, δ): 1.30 (3H, t, J = 7Hz),
2.92 (2H, q, J=7Hz), 3.22 and 3.68
(2H, ABq, J=18Hz), 4.05 (3H, s),
5.28 (1H, a, J=5Hz), 5.28 and 5.58
(2H, ABq, J = 14Hz), 5.88 (1H, d, J
=5Hz), 7.82~8.13 (1H, m), 8.30~8.57
(1H, m), 8.63-8.90 (2H, m) (2) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-( 3-Ethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 150-155°C (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1670,
1610, 1530, 1510, 1290, 1150, 1040cm ^-1 NMR (D ₂ O, δ): 1.30 (6H, t, J = 7Hz),
2.93 (2H, q, J=7Hz), 3.17 and 3.68
(2H, ABq, J = 18Hz), 4.37 (2H, q, J
=7Hz), 5.30 (1H, d, J = 5Hz), 5.28 and 5.58 (2H, ABq, J = 14Hz), 5.88 (1H,
d, J=5Hz), 7.80-8.15 (1H, m), 8.30
~8.60 (1H, m), 8.65 ~ 8.92 (2H, m) (3) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3 -(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 146-150°C (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1665, 1610, 1530 cm ^-1 NMR (D ₂ O, δ): 2.48 (6H, s), 3.22 and
3.55 (2H, ABq, J=18Hz), 4.03 (3H, s),
5.25 (1H, d, J = 5Hz), 5.28 and 5.43
(2H, ABq, J = 14Hz), 5.85 (1H, d, J
=5Hz), 8.15 (1H, s), 8.60 (2H, s) (4) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide] -3-(3,5-dimethyl-
1-pyridiniomethyl)-3-cephem-4-
Carboxylate (syn isomer), mp198~203
°C (decomposition). IR (Nujiyor): 3250, 3160, 1770, 1665,
1610, 1525, 1290, 1170, 1150, 1060, 1010
cm ^-1 NMR (D ₂ O, δ): 2.48 (6H, s), 3.15 and
3.60 (2H, ABq, J=18Hz), 4.7~4.9 (2H,
m), 5.25 (1H, d, J=5Hz), 4.9-5.7
(4H, m), 5.75-6.40 (1H, m), 5.87 (1H,
d, J=5Hz), 8.15 (1H, s), 8.57 (2H,
s) (5) 7-[2-(2-propynyloxyimino)-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3,5-
dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
mp175-180℃ (decomposition). IR (Nujiyor): 3400, 3250, 3050, 2110,
1775, 1660, 1610, 1530 cm ^-1 NMR (DMSO−d ₆ + D ₂ O, δ): 2.47 (6H,
s), 3.43 (1H, t, J=2Hz), 3.12 and
3.45 (2H, ABq, J=18Hz), 4.73 (1H, d,
J=2Hz), 5.03 (1H, d, J=5Hz), 5.17
and 5.52 (2H, ABq, J=14Hz), 5.68
(1H, d, J=5Hz), 8.23 (1H, s), 9.00
(2H, s) (6) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-ethyl-1-pyridiniomethyl) -3-Cefem-4-carboxylate (syn isomer), mp 195-200°C (decomposition). IR (Nujiyor): 3270, 3160, 1770, 1665,
1610, 1530, 1280, 1145, 1060cm ^-1 NMR (D ₂ O, δ): 1.28 (3H, t, J = 7Hz),
2.86 (2H, q, J=7Hz), 3.17 and 3.58
(2H, ABq, J=18Hz), 4.6-4.8 (2H, m),
5.25 (1H, d, J=5Hz), 5.1~5.8 (4H,
m), 5.90 (1H, d, J = 5Hz), 5.8-6.5
(1H, m), 7.8-8.1 (1H, m), 8.2-8.6
(1H, m), 8.7-8.9 (1H, m), 8.80 (1H,
s) (7) 7-[2-(2-propynyloxyimino)-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido-3-(3-ethyl-1-pyridiniomethyl)-3-cephem-
4-carboxylate (syn isomer), mp165
~170℃ (decomposition). IR (Nujiyor): 3400, 3250, 3150, 2090,
1770, 1660, 1610, 1520 cm ^-1 NMR (DMSO−d ₆ +D ₂ O, δ): 1.33 (3H, t,
J=7Hz), 2.90 (2H, q, J=7Hz), 3.17
and 3.55 (2H, ABq, J=18Hz), 3.50
(1H, t, J=2Hz), 4.80 (2H, d, J=
2Hz), 5.12 (1H, d, J = 5Hz), 5.25 and 5.67 (2H, ABq, J = 14Hz), 5.75 (1H,
d, J=5Hz), 7.93-8.23 (1H, m), 8.37
~8.67 (1H, m), 9.17 ~ 9.40 (2H, m) (8) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-(2,4-dimethyl-
1-pyridiniomethyl)-3-cephem-4-
Carboxylate (syn isomer), mp115-117
°C (decomposition). IR (Nujiyor): 3280, 3180, 1760, 1675,
1635, 1610, 1520 cm ^-1 NMR (D ₂ O, δ): 2.59 (3H, s), 2.78 (3H,
s), 3.20 and 3.50 (2H, ABq, J=18
Hz), 4.81 (2H, d, J=6Hz), 5.27 and
5.55 (2H, ABq, J=14Hz), 5.28 (1H, d,
J=5Hz), 5.93 (1H, d, J=5Hz), 5.1−
5.6 (2H, m), 5.7-6.3 (1H, m), 7.5-7.9
(2H, m), 8.60 (1H, d, J = 7Hz) (9) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-(3-Methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 115-117°C (decomposition). IR (Nujiyor): 3300, 3160, 1770, 1670,
1610, 1530 cm ^-1 NMR (D ₂ O, δ): 2.56 (3H, s), 3.20 and
3.40 (2H, ABq, J=18Hz), 4.80 (2H, d,
J=6Hz), 5.30 (1H, d, J=5Hz), 5.1~
5.8 (4H, m), 5.92 (1H, d, J=5Hz),
5.8-6.5 (1H, m), 7.8-8.9 (4H, m) (10) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]- 3-(3,4-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 117-122°C (decomposition). IR (Nujiyor): 3280, 3150, 1770, 1665,
1635, 1610, 1525 cm ^-1 NMR (D ₂ O, δ): 2.43 (3H, s), 2.55 (3H,
s), 3.20 and 3.60 (2H, ABq, J=18
Hz), 4.05 (3H, s), 5.26 (1H, d, J=5
Hz), 5.22 and 5.47 (2H, ABq, J=14
Hz), 5.87 (1H, d, J=5Hz), 7.6-8.0
(1H, m), 8.3-8.8 (2H, m) (11) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3,4-dimethyl-
1-pyridiniomethyl)-3-cephem-4-
Carboxylate (syn isomer), mp157-161
°C (decomposition). IR (Nujiyor): 3270, 3160, 1770, 1670,
1635, 1610, 1520 cm ^-1 NMR (D ₂ O, δ): 2.33 (3H, s), 2.54 (3H,
s), 3.20 and 3.63 (2H, ABq, J=18
Hz), 4.80 (2H, d, J=6Hz), 5.30 (1H,
d, J=5Hz), 5.1-5.8 (4H, m), 5.92
(1H, d, J=5Hz), 5.8-6.5 (1H, m),
7.81 (1H, d, J = 7Hz), 8.60 (1H, d, J
=7Hz), 8.68 (1H, s) (12) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-formamido-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
mp163-168℃ (decomposition). IR (Nujiyor): 3400-3100, 1770, 1670,
1610, 1560-1500 cm ^-1 NMR (DMSO-d ₆ + D ₂ O, δ): 3.05 (1H, t,
J = 2Hz), 3.15 and 3.70 (2H, ABq, J
= 18Hz), 4.87 (2H, d, J = 2Hz), 5.23
(1H, d, J=5Hz), 5.27 and 5.63 (2H,
ABq, J = 14Hz), 5.84 (1H, d, J = 5
Hz), 7.9-8.1 (1H, m), 8.42 (1H, s), 8.3
~8.8 (2H, m), 9.4 ~ 9.5 (1H, m) (13) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),
mp158-170℃ (decomposition). IR (Nujiyor): 3350~3150, 1770, 1660~
1590, 1510 cm ^-1 NMR (D ₂ O, δ): 3.15 and 3.67 (2H, ABq,
J=18Hz), 4.90 (2H, s), 5.0~5.6 (2H,
m), 5.28 (1H, d, J=5Hz), 5.88 (1H,
d, J=5Hz), 7.6-7.7 (2H, m), 8.0-8.2
(2H, m) Example 2 7-[2-methoxyimino-2-(5-amino-
Powder of 1,2,4-thiadiazol-3-yl)acetamide]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (50 mg) was mixed with water ( 25ml) and leave it in the refrigerator for several days. The resulting crystals are collected and used as crystal seeds. 7-[2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetamide]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.58 g) was dissolved in water (1.6 ml), add the crystals of the standard product obtained earlier as crystal seeds, and leave in the refrigerator overnight. The resulting crystals are collected, washed with cold water, and dried to form colorless crystals.
-[2-methoxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (370 mg) is obtained. Similar to Example 2, crystal forms of other compounds of the above examples are also obtained.

Claims (1)

[Claims] 1. General formula: [wherein R ¹ is amino or protected amino,
R ² is lower alkenyl or lower alkynyl, R ³
means amino, lower alkanoylamino or lower alkyl, R ⁴ means hydrogen or lower alkyl, respectively, or R ¹ has the same meaning as before, R ² is a methyl or ethyl group, R ³ is an ethyl group, R ⁴ each represents hydrogen, or R ¹ has the same meaning as above, and R ² , R ³ and R ⁴ each represent a methyl group] and salts thereof.