JPH032871B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel cephalosporin derivative represented by the following general formula and a salt thereof. [In the formula, R ₁ represents a single bond or a linear or branched lower alkylene group, R ₃ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, or a carboxy lower alkyl group, and R ₄ represents a hydrogen atom; Acetoxymethyl group; lower alkyl group, lower alkylamino lower alkyl group, carbamoyl lower alkyl group or carboxy lower alkyl group substituted tetrazolylthiomethyl group; or lower alkyl group or amino group substituted thiadiazolylthiomethyl group As a result of research on various cephalosporin derivatives, the present inventors completed the present invention after learning that the novel compound represented by the above formula () exhibits high antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria. The target substance () of the present invention can be produced, for example, by the method shown in the reaction formula below. In the formula, R ₁ , R ₃ , R ₄ and n are each the same as above, and R ₅ is an amino group used in peptide synthesis represented by trityl, formyl, tertiary butoxycarbonyl, p-methoxybenzyloxycarbonyl, etc. protecting group, R ₆ is hydrogen, lower alkyl, hydroxy lower alkyl protected with trityl, etc.
Carboxy lower alkyl protected with tertiary butyl, etc., as well as protecting groups for amino groups used in peptide synthesis such as trityl, formyl, tertiary butoxycarbonyl, p-methoxybenzyloxycarbonyl, etc., R ₇ is benzhydryl or tertiary
A protecting group for carboxylic acid used in peptide synthesis such as butyl, or x represents a halogen. In addition, the compound of the present invention (), the raw material compound (),
() and () have syn isomers (A), anti-isomers (B), and mixtures thereof, which have the following partial structures in their molecules. In the present invention, when syn isomer and anti isomer are conveniently explained in one expression, partial structure (C) It is expressed as Furthermore, although the thiazole moiety shown in the present invention is thought to have a tautomeric structure of a 2-aminothiazole form and a 2-iminothiazoline form, it will be described in the thiazole form in this specification. Next, in more detail regarding the present production method, the compound () of the present invention is produced by reacting the compound () or a reactive derivative thereof at the amino group or a salt thereof with the compound () or the reactive derivative at the carboxyl group thereof. , can be produced by removing the protecting group. Reactive derivatives of the amino group of the compound () include silyl derivatives obtained by reacting the compound () with a silyl compound such as trimethylsilyl chloride or bis(trimethylsilyl)acetamide. Further, examples of the salts of the compound () include organic amine salts such as triethylamine salt. Reactive derivatives at the carboxyl group of compound () include active esters, acid halides, acid anhydrides, active amides, etc. Examples of active esters include N-hydroxy compounds [1-hydroxybenzotriazole (hereinafter referred to as "HOBt ), N-hydroxysuccinimide, N-hydroxyphthalimide, etc.]. When compound () is reacted in the form of a free acid or its salt, a condensing agent such as N,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC") is used. The above reaction can be carried out in the presence of, for example, water, dimethylformamide (hereinafter referred to as "DMF"), tetrahydrofuran (hereinafter referred to as "THF"), or any other organic solvent that does not adversely affect the progress of the reaction. The elimination reaction of the protecting group is carried out by hydrolysis with an organic acid such as formic acid or trifluoroacetic acid or an inorganic acid such as hydrochloric acid, or by conventional catalytic reduction using a conventional catalyst such as palladium on carbon. In the case of hydrolysis,
You may use a solvent that does not adversely affect the reaction, or
It can also be carried out in the presence of a scavenger such as anisole. In the case of catalytic reduction, it is carried out in a solvent such as THF or alcohol that does not adversely affect the reaction. The compound () of the present invention can also be produced by reacting the compound () or a salt thereof with an acid halide () in the presence of a deoxidizing agent, and then deprotecting the compound under the conditions described above. You can. As the deoxidizer, an organic compound such as pyridine or an inorganic compound such as sodium carbonate is used, and as a solvent, a solvent that does not adversely affect the reaction, such as dichloromethane or DMF, is used. On the other hand, various methods for synthesizing the raw material compound can be considered, but an example of the synthesis of the raw material compound () is as shown in the reaction formula below. (In the formula, R ₁ , R ₅ , R ₆ and X are the same as above.) That is, piperazine or its derivative (),
In the presence of a deoxidizing agent such as N,N-dimethylaniline,
A product (2) is obtained by reacting acid chloride (2) in a solvent such as acetone. Further, by reacting N-hydroxyphthalimide () in a solvent such as acetonitrile in the presence of a deoxidizing agent such as triethylamine, a phthalimide derivative (XI) is obtained. Next, a hydroxyamine derivative (XII) obtained by reacting compound (XI) with hydrazine hydrate in a solvent such as alcohol is mixed with a thiazole-4-glyoxylic acid derivative (XII) in an organic solvent such as ethanol. By this, the raw material compound () can be produced. The compound of the present invention exhibits a broad antibacterial spectrum and high antibacterial activity, but is particularly resistant to conventional cefem compounds such as Pr. vulgaris, Ent. cloacae,
It also exhibits strong antibacterial activity against Ent. erogenes, Ser. marcetuscens, and Ps. aeruginosa. The antibacterial activity of several examples of the compounds of the present invention is compared with that of cefazolin, a known representative cefem compound, as shown in the following table. Antimicrobial Spectrum Minimum Inhibitory Concentration (MIC μg/
ml, bacterial amount 10 ⁶ /ml

【table】

[Table] Compound A: 7β-[2-{(piperazin-1-yl)
carbonylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride isomers). Compound B: 7β-[2-{(piperazin-1-yl)
Carbonylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt (syn isomer). Compound C: 7β-[2-{(piperazin-1-yl)
carbonylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-(5-amino-1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer). The present invention will be explained in more detail with reference to Examples below. Example 1 7β-[2-{(piperazin-1-yl)carbonylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl ) Thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): 1-(4-methoxybenzyloxycarbonyl)
31.1g of piperazine and N,N-dimethylaniline
29.5 g of bromoacetic acid bromide was added dropwise to 20.0 g of acetone solution under ice cooling and stirring. After stirring at the same temperature for 1 hour, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed successively with 10% citric acid, 5% sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and then ethyl acetate is distilled off to obtain 44.4 g of a brown oil residue. A solution of the above residue in acetonitrile was mixed with 19.1 g of N-hydroxyphthalimide and 16.3 g of triethylamine.
ml of acetonitrile solution under ice cooling and stirring. After stirring at the same temperature for 30 minutes and then at about 50°C for 3.5 hours, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with 5% sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and then the ethyl acetate is distilled off and the residue is washed with ether to obtain 36.6 g of phthalimide with a melting point of 154-156°C. . 34.3 g of the above product obtained and hydrazine hydrate
Reflux 3.8 g of ethanol solution for 2 hours. After cooling,
Insoluble materials are removed by filtration, the filtrate is dried, ethyl acetate is added to the residue, the mixture is washed with water, 5% sodium hydrogen chloride solution, and then saturated brine, dried over anhydrous sodium sulfate, and dried. The residue was purified by column chromatography using silica gel (solvent: mixture of chloroform and methanol) and then recrystallized from ether-petroleum ether to obtain 20.2 g of carbonylmethoxyamine with a melting point of 59-60°C. 4.0 g of the above product obtained and 2-[2-tritylaminothiazol-4-yl)glyoxylic acid
After stirring 5.12g in ethanol at room temperature for 45 hours,
Evaporate the solvent. Ethyl acetate was added to the residue, washed with 10% citric acid and then with saturated brine, and then the solvent was distilled off. When the residue is washed with ether, the melting point is 100-125℃.
Syn isomer of 2-[{4-(4-methoxybenzyloxycarbonyl)piperazin-1-yl}carbonylmethoxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid (decomposition) (referred to as "Compound Y.") 7.9 g were obtained. To a DMF solution of 0.9 g of the obtained compound Y and 169 mg of HOBt was added 258 mg of DCC under cooling, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was cooled with ice.
Amino-3-(1-methyl-1H-tetrazole-
A DMF solution of 452 mg of 5-yl)thiomethyl-3-cephem-4-carboxylic acid (hereinafter referred to as "Compound Z") and 417 mg of triethylamine was added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent, ethyl acetate is added to the residue, which is washed with 10-% citric acid and then with water, and the ethyl acetate layer is dried over anhydrous sodium sulfate and then evaporated to dryness. Ether was added to the residue and filtered. To the obtained powder (815 mg) was added 1.3 ml of anisole and then 50 ml of trifluoroacetic acid under ice cooling, stirred at room temperature for 2 hours, and then dried. 10% hydrochloric acid was added to the crude product obtained by washing the residue with ether, and after filtering off insoluble matter, it was dried.
The residue was subjected to high performance liquid chromatography (carrier: Micro Bondabac C ₁₈ , solvent: pH 3 by adding hydrochloric acid.
Purification with 15% methanol (adjusted to 15% methanol) gives the title target compound. IRν ^KBr _nax cm ^-1 : 1780, 1630 FT-NMR (D ₂ O, 200MHZ) δppm: 3.25 ~ 3.50, 3.80 ~ 4.00 (total 8H,

H in [Formula]) 3.80 [2H, dd, methylene at the 2nd position of the Cefem nucleus (C ₂
-H) ] 4.10 (3H, s, tetrazole-1-CH ₃ ) 4.25 (2H, dd, -CH ₂ -S-) 5.51 (2H, s, -OCH ₂ CO-) 5.28 (1H, d, C ₆ -H) 5・84 (1H, d, C ₇ −H) 7.29 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₁ H ₂₅ N ₁₁ O ₆ S ₃・2HCl・2H ₂ O
For counted value C34.44, H4.26, N21.03 Actual value C34.55, H4.09, N20.79 Example 2 7β-[2-{(4-methylpiperazin-1-yl)carbonylmethoxy imino}-2-(2-aminothiazol-4-yl)acetamide]-3
-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): N-(carboxymethoxy)phthalimide 6.0
g and N-hydroxysuccinimide 3.1 g THF
Add 6.2 g of DCC to the solution under ice cooling and stir for 2 hours. The precipitate collected by filtration is suspended in DMF, 3.0 g of N-methylpiperazine is added, and the mixture is stirred for 16 hours.
Insoluble materials are removed by filtration, the filtrate is dried, dilute sodium chloride water is added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue is washed with isopropyl ether to obtain 3.2 g of phthalimide having a melting point of 105-107°C. A methanol solution of 0.5 g of hydrazine hydrate is added to a dichloromethane solution of 2.5 g of the above-obtained product, and the mixture is stirred for 3 hours. After removing the insoluble matter by filtration, drying is carried out.
Saturated brine is added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and then chloroform is distilled off. The residue (yellow oil. 850 mg) was dissolved in 2-(2-
The mixture was added to an ethanol suspension of 1.02 g of tritylaminothiazol-4-yl)glyoxylic acid, stirred for 50 hours, and the ethanol was distilled off. The residue was washed with ether, the resulting white powder was suspended in methanol, and hydrochloric acid and methanol were added to adjust the pH to approximately 5.
After stirring, filtration yields 2-{(4-
1.0 g of the syn isomer of methylpiperazin-1-yl)carbonylmethoxyimino}-2-(2-tritylaminothiazol-4-yl)acetic acid is obtained. 684 mg of the above product and 162 mg of HOBt were obtained.
Add 250 mg of DCC to the DMF solution and stir for 5 hours.
Insoluble matter was removed by filtration, and the filtrate was added to a DMF solution of 328 mg of compound Z and 300 mg of triethylamine, and stirred for 20 hours. After drying, add saturated brine to the residue, adjust the pH to approximately 3 with 5% hydrochloric acid, and extract with THF. After drying over anhydrous sodium sulfate, the solvent is distilled off and ether is added to the residue. Add 1 ml of anisole to the filtered powder (approximately 950 mg), then add 20 ml of trifluoroacetic acid under ice cooling, and stir at room temperature for 2 hours. After distilling off trifluoroacetic acid, ether was added to the residue and filtered. The brown powder collected by filtration was suspended in 15% methanol, stirred, filtered, and the filtrate was dried to give a pale yellow powder (500%
mg). Dissolve in 15% methanol adjusted to pH approximately 2 with hydrochloric acid, remove insoluble matter by filtration, and dry. The residue was subjected to high performance liquid chromatography (carrier: Microbondapak _C18 , solvent: pH adjusted to approximately 2.5 with hydrochloric acid).
Purification with 15% methanol gives the title compound. IRν ^KBr _nax cm ^-1 : 1775, 1625 FT-NMR (D ₂ O, 200MHZ) δppm: 2.96 (3H, s,

[Formula]) 3.20, 3.63 (total 8H, each m,

H in [formula]) 4.08 (3H, s, tetrazole-1-CH ₃ ) 5.26 (1H, d, C ₆ -H) 5.83 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5 -H) Elemental analysis (%) C ₂₂ H ₂₇ N ₁₁ O ₆ S ₃・2HCL・H ₂ O
For Calculated value C36.26, H4.29, N21.15 Actual value C36.09, H4.37, N20.85 Example 3 7β-[2-[{4-(2-hydroxyethyl)piperazine-1 -yl}carbonylmethoxyimino]-2-(2-aminothiazol-4-yl)
Acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): 1-(2-hydroxyethyl)piperazine 9.1 g
and benzyloxycarbonyl chloride in a dichloromethane solution of 11.7 ml of triethylamine under ice cooling.
Drop 11.0ml. After stirring at room temperature for 2 hours, water was added and the mixture was separated, and the organic layer was washed with 10% citric acid and then with saturated saline, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue (yellow oil, 18.6 g) was dissolved in dichloromethane, 11.7 ml of triethylamine and then 17.6 g of trityl chloride were added, and the solution was dissolved at room temperature for 4 hours.
Stir for a while, add water and distribute. Wash the organic layer with water,
After drying over anhydrous sodium sulfate and drying, the residue was recrystallized from ethanol to give 1-
24.2 g of (2-trityloxyethyl)-4-(benzyloxycarbonyl)piperazine are obtained. 18.4 g of the above-obtained product was dissolved in a mixed solvent of ethyl acetate and ethanol, 10% palladium on carbon was added, catalytic reduction was carried out at room temperature and pressure, and the catalyst was filtered off.
The filtrate was dried to obtain 15.2 g of 1-(2-trityloxyethyl)piperazine as a yellow oil. By using the above piperazine compound in place of 1-(4-methoxybenzyloxycarbonyl)piperazine in Example 1 and carrying out the reaction in the same manner as in Example 1, 2-[ {4
-(2-trityloxyethyl)piperazine-1
-yl}carbonylmethoxyimino]-2-(2-
Tritylaminothiazol-4-yl)acetic acid (syn isomer) is obtained. Then, 842 mg of the above product obtained and HOBt175
Add 246 mg of DCC to 1 mg of DMF solution and stir overnight at room temperature. After removing insoluble matter by filtration, compound Z328 is added to the filtrate.
Add a DMF solution of 0.42 ml of triethylamine and
Stir overnight. After drying, the residue was washed successively with water, ethanol, and ether, and the resulting powder (1.09 g) was dissolved in 11 ml of formic acid and stirred for 1.5 hours. After removing insoluble materials by filtration, the filtrate is dried. The powder obtained by washing the residue with ether is suspended in 100 ml of water, and after adding 1 ml of 4N hydrochloric acid, insoluble matter is filtered off and the filtrate is dried. Wash off the residue with ether (576 mg),
Diaion HP-20 column chromatography (solvent: 5-10% THF), followed by high performance liquid chromatography (carrier: Micro Bonder Pack)
Purification with C ₁₈ , solvent: 15% methanol adjusted to pH approximately 2 with hydrochloric acid) yields the title target compound. FT-NMR ( _D2O , _200MH2 ) δppm: 3.10~3.48, 3.90~4.02 (total 8H, each m,

H in [formula]) 3.74 (2H, t, -CH ₂ CH ₂ OH) 4.10 (3H, s, tetrazole-1-CH ₃ ) 5.14 (2H, s, = N-OCH ₂ CO-) 5.27 (1H, d, C ₆ -H) 5.82 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₃ H ₂₉ N ₁₁ O ₇ S ₃・2HCL・
For 2H ₂ O Calculated value C35.59, H4.54, N19.85 Actual value C35.29, H4.58, N19.86 Example 4 7β-[2-[{4-(2-carboxymethyl) piperazin-1-yl}carbonylmethoxyimino]-2-(2-aminothiazol-4-yl)
Acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (syn isomer): 1-(4-methoxybenzyloxycarbonyl of Example 1) ) 2-[{4
-(tertiary-butoxycarbonylmethyl)piperazin-1-yl}carbonylmethoxyimino]-2
-(2-tritylaminothiazol-4-yl)
Obtain the syn isomer of acetic acid. Next, a reaction similar to that of Example 1 was carried out using the above-obtained product and Compound Z, and the obtained crude product was dissolved in dilute sodium chloride water and subjected to high performance liquid chromatography (carrier: microbonder). Purification with back C ₁₈ , solvent: 5% methanol) gives the title compound. IRν ^KBr _nax cm ^-1 : 1760 FT-NMR (D ₂ O, 200MHZ) δppm: 2.6 to 2.8, 3.5 to 3.7 (total SH,

[Formula] H) 3.14 (2H, s, > N-CH ₂ CO-) 4.05 (3H, s, tetrazole-1-CH ₃ ) 5.00 (2H, s, -OCH ₂ CO-) 5.11 (1H, d , C ₆ -H) 5.82 (1H, d, C ₇ -H) 7・10 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₃ H ₂₆ N ₁₁ O ₃ S ₃ Na ₂・3H For ₂ O Calculated value C35.43, H4.00, N19.76 Actual value C35.52, H4.23, N19.82 Example 5 7β-[2-[2-{(piperazin-1-yl) carbonyl}prop-2-oximino]-2-
(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): 1-(4-methoxybenzyloxycarbonyl)
2-(Hydroxyimino)-2 -(2-tritylaminothiazole-4
Potassium carbonate was added to a solution of 4.11 g of the syn isomer of ethyl acetate in dimethyl sulfoxide under a nitrogen atmosphere.
After adding 1.93g, stir vigorously and stir overnight. Focus the reaction solution in water, filter the precipitate,
The filtered material was dissolved in ethyl acetate, washed sequentially with 10% citric acid and water, and dried over anhydrous sodium sulfate.
Dry. Powder obtained by washing the residue with petroleum ether
After dissolving 6.9g in 60ml of methanol, 2N-NaOH9
ml and reflux. After distilling off the methanol, add water and add 20% citric acid to make the liquid acidic.
Extract with ethyl acetate. After washing the ethyl acetate layer with water,
Dry over anhydrous sodium sulfate and evaporate the solvent. When the residue was purified by silica gel column chromatography (solvent: mixed solvent of chloroform and methanol), 2-[2-
[{4-(4-methoxybenzyloxycarbonyl)
Piperazin-1-yl}-carbonyl]-probu-
960 mg of the syn isomer of 2-oximino]-2-(2-tritylaminothiazol-4-yl)acetic acid are obtained. Next, using the above-obtained product and Compound Z, reaction and purification are carried out in the same manner as in Example 1 to obtain the title target compound. IRr ^KBr _nax cm ^-1 : 1770, 1630 FT-NMR (D ₂ O, 200MHZ) δppm: 1.62 (3H, s, C-CH ₃ ) 1.65 (3H, s, C-CH ₃ ) 3.2~3.4, 3.6~ 4.5 (total 8H, each m,

H in [formula]) 4.10 (3H, s, tetrazole-1-CH ₃ ) 5.29 (1H, d, C ₆ -H) 5.83 (1H, d, C ₇ -H) 7.30 (1H, s, thiazole-5 -H) Elemental analysis (%) C ₂₃ H ₂₉ N ₁₁ O ₆ S ₃・2HCL・
For 2H ₂ O Calculated value C36.32, H4.64, N20.26 Actual value C36.16, H4.39, N19.98 Example 6 7β-[2-[1-{(Piperazin-1-yl ) carbonyl}eth-1-oximino]-2-(2
-aminothiazol-4-yl)acetamide]
-3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): 2-
When the reaction and purification were performed in the same manner as in Example 1 using promopropionyl bromide, the melting point
2-[1-[{4-(4-methoxybenzyloxycarbonyl)piperazine-1] at 100-103°C (decomposition)
-yl}carbonyl]eth-1-oxyimino]
The syn isomer of -2-(2-tritylaminothiazol-4-yl)acetic acid is obtained. Next, using the above-obtained product and compound Z, a reaction was carried out in the same manner as in Example 1, and finally high performance liquid chromatography (carrier: Microbondapak C ₁₈ , solvent: adding hydrochloric acid to PH2 Purification with 15% methanol (adjusted to 15% methanol) yields active form A and active form B of the title compound. Data for active form A Melting point 145-155℃ (decomposition) IRν ^KBr _nax cm ^-1 : 1770, 1630 FT-NMR (D ₂ O, 200MHZ) δppm: 1.55 (3H, d, > CH-CH ₃ ) 3.2-3.5 , 3.5~4.1 (total 8H,

H in [formula]) 4.09 (3H, s, tetrazole-1-CH ₃ ) 5.28 (1H, d, C ₆ -H) 5.38 (1H, d, C ₇ -H) 7.26 (1H, s, thiazole -5-H) Elemental analysis (%) C ₂₂ H ₂₇ N ₁₁ O ₆ S ₃・2HCL・
For 3H ₂ O Calculated value C34.55, H4.61, N20.15 Actual value C34.41, H4.48, N20.09 Data for active form B Melting point 145-155℃ (decomposition) IRν ^KBr _nax cm ^{- 1} :1780, 1630 FT-NMR ( _D2O , 200MHZ) δppm: 1.56 (3H, d, > CH- _CH3 ) 3.2-3.5, 3.6-4.1 (total 8H,

[Formula] H) 4.10 (3H, s, tetrazole-1-CH ₃ ) 5.30 (1H, d, C ₆ -H) 5.94 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5 -H) Elemental analysis (%) C ₂₂ H ₂₇ N ₁₁ O ₆ S ₃・2HCL・
For 2H ₂ O Calculated value C35.39, H4.45, N20.64 Actual value C35.21, H4.68, N20.33 Example 7 7β-[2-{(piperazin-1-yl)carbonyloxy imino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-Cefem-4-carboxylic acid hydrochloride (syn isomer): syn isomer of 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid
Suspend 4.3 g in dichloromethane, add 4 ml of isopropenyl methyl ether, stir for 1 hour, and then dry. The residue was dissolved in THF, 1.4 g of HOBt and then 2.1 g of DCC were added, stirred for 5 hours, and insoluble materials were filtered off. The filtrate was added to a DMF solution of 3 g of compound Z and 4 ml of triethylamine, stirred for 16 hours, and then dried under reduced pressure. Water is added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness. Add isopropyl ether to the residue to make a powder,
After filtering, 3.5 g of condensate was obtained. 3.5 g of the above-obtained product was dissolved in 25 ml of acetone, 10 ml of 2N hydrochloric acid was added, stirred for 1 hour, and then dried. Add a mixture of ethyl acetate and THF to the residue,
Insoluble materials are removed by filtration, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. After adding ether to the residue, the powder (2.3 g) obtained by filtration was dissolved in THF.
After adding 9 ml of diethylamine, isopropyl ether is added. Filter the precipitate,
After reprecipitation with THF-isopropyl ether and washing with ether, the melting point is 140-145℃ (decomposition).
7β-[2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]
1.8 g of the syn isomer of the diethylamine salt of -3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. In a dichloromethane solution of 1.2 g of the obtained above product and 0.4 ml of pyridine, 630 mg of 4-(4-methoxybenzyloxycarbonyl)piperazine-1-carbonyl chloride {prepared from 1-(4-methoxybenzyloxycarbonyl)piperazyl and phosgene } and stirred for 5 hours, then dried. The residue is dissolved in ethyl acetate, washed with water and then with 1% hydrochloric acid, dried over anhydrous sodium sulfate, and then evaporated to dryness. After adding isopropyl ether to the residue, it was collected by filtration, and to the obtained powder (1.2 g) was added 1 ml of anisole under ice cooling,
Next, add 20 ml of trifluoroacetic acid and stir for 1 hour. Trifluoroacetic acid was distilled off, ether was added to the residue, the precipitate was collected by filtration, dissolved in 30 ml of water, Amberlite-45 was added to adjust the pH to 3, and the resin was filtered off.
Adjust the pH to 1 with 5% hydrochloric acid. After drying, the residue is purified by high performance liquid chromatography (carrier: Microbondapak C ₁₈ , solvent: 15% methanol adjusted to pH 2 with hydrochloric acid) to obtain the title compound. IRν ^KBr _nax cm ^-1 : 1775, 1730 FT-NMR (D ₂ O, 200MHZ) δppm: 3.40, 3.86 (total 8H, each broad,

H in [formula]) 4.10 (3H, s, tetrazole-1-CH ₃ ) 4.24 (2H, s, C ₃ -CH ₂ -S-) 5.30 (1H, d, C ₆ -H) 5.90 (1H, d , C ₇ -H) 7.50 (1H, s, tetrazole-5-H) Elemental analysis (%) C ₂₀ H ₂₃ N ₁₁ O ₆ C ₃・2HCL・
For 1.5H ₂ O Calculated value C38.85, H3.98, N21.71 Actual value C33.80, H3.74, N21.31 Example 8 7β-[2-[2-{(Piperazine-1- yl)carbonyl}eth-1-oximino]-2-(2
-aminothiazol-4-yl)acetamide]
-3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): 1-{3(benzyloxycarbonylaminooxy)probionyl}-4-(tert-butoxycarbonyl)piperazine (11.1 g) was cooled on ice. Add 78 ml of 25% hydrogen bromide and acetic acid solution, stir for 20 minutes under ice-cooling and 40 minutes at room temperature, then add 100 ml of ether under ice-cooling and stirring, and decant the supernatant. After repeating the operation of adding ether to the residue and decanting it, 9.1 g of a white powder obtained by drying under reduced pressure over phosphorus pentoxide is dissolved in 32 ml of ice water.
While cooling with ice and stirring, add 34 ml of 2N sodium hydroxide and then 182 ml of dioxane. After returning to room temperature 2
-(tertiary butoxycarbonyloxyimino)-2
- Add 3.4 g of phenylacetonitrile and stir for 2 hours, then add 2.0 g of the same acetonitrile compound and stir for 2 hours. Dioxane is distilled off, the residue is made alkaline by adding sodium hydroxide, extracted with chloroform, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel chromatography (solvent: a mixture of chloroform and methanol) to obtain 5.3 g of ethoxyamine as a colorless oil. The above product obtained and 2-(tritylamino)
If the reaction is carried out in the same manner as in Example 1 using thiazole-4-glyoxylic acid, the melting point will be 125-135°C.
(Decomposition) of 2-[{4-(tert-butoxycarbonyl)piperazin-1-yl}carbonylmethoxyimino]-2-(2-tritylaminothiazole-
The syn isomer of 4-yl) acetic acid is obtained and then reacted and purified using the obtained product and compound Z in the same manner as in Example 1 to obtain the title target compound. IRν ^KBr _nax cm ^-1 : 1775, 1625 FT-NMR (D ₂ O, 200MHZ) δppm: 2.97 (2H, broad, -CH ₂ CO-) 3.33, 3.88 (total 8H, each broad,

H in [formula]) 4.10 (3H, s, tetrazole-1-CH ₃ ) 4.63 (2H, broad, -OCH ₂ -) 5.26 (1H, d, C ₆ -H) 5.82 (1H, d, C ₇ - H) 7.21 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₂ H ₂₇ N ₁₁ O ₆ S ₃・2HCl・2H ₂ O
For calculated value C35.39, H4.45, N20.64 Actual value C35.78, H4.40, N20.74 Example 9 7β-[2-{(piperazin-1-yl)carbonylmethoxyimino}- 2-(2-aminothiazol-4-yl)acetamide]-3-{1-(2-
dimethylaminoethyl)-1H-tetrazole-
5-yl}thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer): Compound Y and 7β-amino-3-{1-(2-dimethylaminoethyl)-1H-tetrazole-5 -yl}thiomethyl-3-cephem-4-carboxylic acid and purified in the same manner as in Example 1 to obtain the title compound. FT-NMR (D ₂ O, 200MHZ) δppm: 3.05 (6H, s,

[Formula]) 3.38, 3.86 (total 8H, each broad,

H in [formula]) 4.24 (2H, s, −C ₃ −CH ₂ S−) 4.94 (2H, t, −CH ₂ N(CH ₃ ) ₂ ) 5.15 (2H, s, −OCH ₂ CO−) 5.30 (1H, d, C ₆ -H) 5.85 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₄ H ₃₂ N ₁₂ O ₆ S ₃・3HCl・_2H2O
For Calculated value C35.67, H4.61, N20.14 Actual value C35.88, H4.90, N19.75 Example 10 7β-[2-{(Piperazin-1-yl)carbonylmethoxyimino}- 2-(2-aminothiazol-4-yl)acetamide]-3-{1-(carbamoylmethyl)-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer ): Compound Y and 7β-amino-3-{1-(carbamoylmethyl)-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid were used to react and react in the same manner as in Example 1. Purification yields the title compound. FT-NMR (D ₂ O, 200MHZ) δppm: 3.36, 3.86 (total 8H, each broad,

H in [Formula]) 5.12 (2H, s, = N-O-CH ₂ -) 5.26 (1H, d, C ₆ -H) 5.36 (2H, s, -CH ₂ CONH ₂ ) 5.82 (1H, d, C ₇ −H) 7.26 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₂ H ₂₆ N ₁₂ O ₇ S ₃・2HCl・2H ₂ O
For Calculated value C34.07, H3.90, N21.67 Actual value C33.96, H4.20, N21.34 Example 11 7β-[2-{(Piperazin-1-yl)carbonylmethoxyimino}- 2-(2-aminothiazol-4-yl)acetamide]-3-{1-(carboxymethyl)-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer ): Compound Y and 7β-amino-3-{1-(carboxymethyl)-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid were used to react and react in the same manner as in Example 1. Purification yields the title compound. FT-NMR (D ₂ O, 200MHZ) δppm: 3.36, 3.86 (total 8H, each broad,

H in [Formula]) 5.14 (2H, s, -OCH ₂ CO-) 5.24 (2H, s, >N-CH ₂ COOH) 5.28 (1H, d, C ₆ -H) 5.85 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5-H) Elemental analysis (%) C ₂₂ H ₂₅ N ₁₁ O ₈ S ₃・2HCl・2H ₂ O
For Calculated value C34.02, H4.04, N19.84 Actual value C34.22, H3・98, N19.45 Example 12 7β-[2-{(Piperazin-1-yl)carbonylmethoxyimino}- Sodium salt (syn isomer) of 2-(2-aminothiazol-4-yl)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid: Compound Y and 7β-amino-3-acetoxymethyl-3 -Cefem-4-carboxylic acid was used to react in the same manner as in Example 1, and the resulting crude product was subjected to column chromatography using Diaion HP-20 as a carrier (solvent: 5-20% ethanol). ,
Next, high performance liquid chromatography (carrier: Microbondapak C ₁₈ , solvent: 20% methanol)
Purification to give the title target compound. IRν ^KBr _nax cm ^-1 : 1770, 1730, 1635 FT-NMR ( _D2O , 200MHZ) δppm: 20.1 (3H, S, _-OCOCH3 ) 3.74-3.84, 3.16-3.30 (total 8H,

H in [formula]) 5.01 (2H, s, -OCH ₂ CO-) 5.25 (1H, d, C ₆ -H) 5.85 (1H, d, C ₇ -H) 7.10 (1H, s, thiazole-5- H) Elemental analysis (%) C ₂₁ H ₂₄ O ₈ N ₇ S ₂ For Na・3H ₂ O Calculated value C39.19, H4.70, N15.23 Actual value C38.81, H4.40, N15. 18 Example 13 7β-[2-{(piperazin-1-yl)carbonylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-{cephem-
4-Carboxylic acid hydrochloride (syn isomer): 720 mg of compound Y and 7-amino-3-cephem-
p-nitrobenzyl ester of 4-carboxylic acid
Dissolve 335mg in THF20ml and stir on ice.
After adding 135 mg of HOBt and 208 mg of DCC, the mixture was stirred at the same temperature for 1 hour and then at room temperature overnight. After filtering off insoluble materials, the residue was purified by silica gel column chromatography (solvent: chloroform and methanol mixture) to give 7β-[2] with a melting point of 130-138°C.
-[{4-(4-Methoxybenzyloxycarbonyl)piperazin-1-yl}carbonylmethoxyimino]-2-(2-aminothiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid p- Syn isomer of nitrobenzyl ester
Get 800mg. 800 mg of the above product obtained was dissolved in THF and 10
% palladium on carbon and catalytic reduction under normal pressure. After removing the catalyst by filtration, the filtrate was dried, ether was added to the residue, and 1 ml of anisole was added to the yellow powder collected by filtration.
Add 30 ml of ice-cold trifluoroacetic acid and stir for 2.5 hours. Trifluoroacetic acid is distilled off, ether is added to the residue, and 10% hydrochloric acid is added to the crude product obtained by filtration. After filtering off insoluble matter, it is dried. The residue was subjected to high performance liquid chromatography (carrier: Microbondapak _C18 , solvent: adjusted to pH 2.5 by adding hydrochloric acid.
Purification with 15% methanol gives the title compound. IRν ^KBr _nax cm ^-1 : 1770, 1630 FT-NMR (D ₂ O, 200MHZ) δppm: 3.34, 3.85 (total 8H, each m,

H in [formula]) 3.70 (2H, m, C ₂ −H) 5.10 (2H, s, −OCH ₂ CO−) 5.28 (1H, d, C ₆ −H) 5.92 (1H, d, C ₇ −H ) 6.70 (1H, m, C ₃ -H) 7.25 (1H, s, thiazole-5-H) Elemental analysis (%) C ₁₈ H ₂₁ N ₇ S ₂ O ₆・2HCl・3H ₂ O
For Calculated value C34.73, H4.37, N15.75 Actual value C35.10, H4.18, N15.35 Example 14 7β-[2-{(Piperazin-1-yl)carbonylmethoxyimino}- 2-(2-aminothiazol-4-yl)acetamide]-3-(5-amino-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (synisomer ): Compound Y and 7β-amino-3-(5-amino-
The title compound is obtained by reaction and purification in the same manner as in Example 1 using 1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid. IRν ^KBr _nax cm ^-1 : 1765, 1660, 1620 FT-NMR (D ₂ O, 200MHZ) δppm: 3.36 (4H, d,

H in [formula]) 5.12 (2H, s, -OCH ₂ CO-) 5.28 (1H, d, C ₆ -H) 5.83 (1H, d, C ₇ -H) 7.28 (1H, s, thiazole-5- H) Elemental analysis (%) C ₂₁ H ₂₄ N ₁₀ O ₆ S ₄・2HCl・
For 2.5H ₂ O Calculated value C33.24, H4.12, N18.46 Actual value C33.53, H4.02, N18.11 Example 15 7β-[2-{(piperazin-1-yl)carbonyl Hydrochloric acid of methoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid Salt (syn isomer): Compound Y and 7β-amino-3-(5-methyl-
The title compound is obtained by reaction and purification in the same manner as in Example 1 using 1,3,4-thiadiazol-2-yl)thiomethethyl-3-cephem-4-carboxylic acid. FT-NMR ( _D2O , 200MHZ) δppm: 2.74 (3H, s, thiadiazole-5- _CH3 ) 3.36, 3.85 (8H in total, each broad,

H in [formula]) 5.14 (2H, s, -OCH ₂ CO-) 5.28 (1H, d, C ₆ -H) 5.80 (1H, d, C ₇ -H) 7.30 (1H, s, thiazole- 5-H) Elemental analysis (%) C ₂₂ H ₂₅ N ₉ O ₆ S ₄・2HCl・2H ₂ O
For calculated value C35.29, H3.90, N16.84 Actual value C34.95, H4・09, N16.47

Claims (1)

[Claims] 1 formula [In the formula, R ₁ represents a single bond or a linear or branched lower alkylene group, R ₃ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, or a carboxy lower alkyl group, and R ₄ represents a hydrogen atom; Acetoxymethyl group; tetrazolylthiomethyl group substituted with lower alkyl group, lower alkylamino lower alkyl group, carbamoyl lower alkyl group or carboxy lower alkyl group; or thiadiazolylthiomethyl group substituted with lower alkyl group or amino group A cephalosporin derivative or a salt thereof represented by: