JPH0128038B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cephalosporin derivatives. The compound of the present invention is represented by the following general formula. In the formula, R ₁ is hydroxy, alkyloxy,
Indicates amino, alkylamino, dialkylamino, hydrazino, alkylhydrazino or dialkylhydrazino. R ₂ represents a 1-methyl-1H-tetrazol-5-yl group. Conventionally, various Cefem derivatives have been developed as antibacterial agents, but the present inventor discovered that when a group having an α-diketone group is attached to the amino acid at the 7th position of Cefem, as shown in formula (1), it is effective against a wide range of Gram-positive and -negative bacteria. The present invention was completed based on the discovery that it has strong antibacterial activity. The compound () of the present invention can be synthesized by various methods, but for example, the compound () of the formula (R ₂ is the same as above.) 7β-[2-
Amino-2-(2-aminothiazol-4-yl)acetamide]-3-heterocyclic thiomethyl-3
-Cefem-4-carboxylic acid with the formula (In the formula, R ₁ is the same as above.) When acylating with an acid represented by the formula or an active derivative thereof (e.g., an acid halide, an active ester, or a mixed acid anhydride), this acylating agent is combined with a coupling agent (e.g., The compound of the present invention can be produced by reacting in the presence or absence of dicyclohexylcarbodiimide (dicyclohexylcarbodiimide) and then removing the protecting group, if necessary. As an example, an embodiment will be described in which an acid halide, which is an active derivative, is used. Compound () is trimethylsilylated in acetonitrile at room temperature by adding N,O-bis(trimethylsilyl)acetamide, and then cooled by adding a base such as propylene oxide or triethylamine as a deoxidizing agent. -20 to 10℃, preferably -10 to 5℃ in this reaction solution
C. Add the acid chloride of the compound all at once or in several portions and stir for 1 to 2 hours. Then, if necessary, the mixture is further stirred at room temperature for 0.5 to 1 hour. After the reaction,
The solvent is distilled off either immediately or after addition of a water-containing solvent such as water-tetrahydrofuran. A solvent such as water or hydrous alcohol is added to the concentrated residue to isolate the crude product, and the crude product is purified by reprecipitation with a solvent or column chromatography using a suitable carrier such as Amberlite XAD or silica gel.
The target compound can be obtained. The cefem derivative of the present invention thus produced is 2
- Since the carbon atom to which the aminothiazole group is bonded is an asymmetric carbon atom, an optically active substance can be produced. From the viewpoint of effectiveness, the 2-aminothiazole glycine moiety is preferably in an optically active form, particularly in the D form, but it may also be in a racemic form. The compound of the present invention has a broad antibacterial spectrum as described above, and exhibits particularly high antibacterial activity against Gram-negative bacteria. It exhibits strong antibacterial activity against Ent. cloacae, Ent. erogenes, and Ser. marcetuscens, which are resistant to conventional cefem-based compounds, and also exhibits antibacterial activity against Ps. aeruginosa. The antibacterial activity of several examples of the compounds of the present invention is compared with that of the known representative cefem compound cefazolin as follows. Compound A: 7β-[DL-2-{(2-ethoxy-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-
Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid compound B: 7β-[DL-2-{(2-amino-1,2-dioxoethyl)amino}-2-(2- aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid compound C: 7β-[DL-2-{(2-hydrazino -1,2-
dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid/hydrochloride compound D: 7β-[DL-2-{(2-hydroxy-1,2
-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid

[Table] Example 1 7β-[DL-2-amino-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (484 mg) was suspended in 50 ml of anhydrous acetonitrile, and then N,O-bis(trimethylsilyl)acetamide was added to this.
After adding 1.0 g of trimethylsilylation, add 160 mg of propylene oxide. To this was added 160 mg of oxalic acid chloride ethyl ester while stirring under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After adding 1 ml of water to the reaction solution, it was concentrated to dryness under reduced pressure. Add 3 ml of water to the residue and filter off the insoluble matter to obtain 390 mg of powder. If the obtained powder is purified by repeating the procedure of dissolving it in tetrahydrofuran and acid precipitation with ether,
7β-[DL-2-{(2-ethoxy-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazole-5- yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. IRν ^KBr _nax cm ^-1 : 1760, 1680, 1620 NMR (90MHz, δ value in DMSO- _d6 ): 1.25 (3H, t, CH ₃ of ethyl group) 3.65 (2H, broad, 2-H) 3.94 (3H , s, tetrazole 1-CH ₃ ) 5.05 (1H, m, H ₆ ) 5.41 (1H, d, J=9.0Hz, CH of glycine) 5.66 (1H, m, H ₇ ) 6.52 (1H, s, thiazole 5 -H) Elemental analysis C ₁₉ H ₂₁ N ₉ O ₇ S ₃・H ₂ O Calculated value C 37.93, H 3.85, N 20.95 Actual value C 38.30, H 3.64, N 20.55 Example 2 7β-[DL- 2-amino-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (387 mg) and oxamyl chloride (100 mg) were reacted in the same manner as in Example 1, and the resulting crude product was used as Amberlite XAD.
column and developed with 20-30% methanol.
After collecting the relevant fractions, concentrate to dryness under reduced pressure. Add methanol to the residue and filter the insoluble matter to obtain 7β-[DL-2
{(2-amino-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)
A powder of [acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. IRν ^KBr _nax cm ^-1 : 1760, 1670 NMR (90MHz, δ value in DMSO- _d6 ) 3.73 (2H, broad, 2-H) 3.96 (3H, s, tetrazole 1-CH ₃ ) 4.30 (2H, s, S-CH ₂ ) 6.60 (1H, s, thiazole 5-H) Elemental analysis C ₁₇ H ₁₈ N ₁₀ O ₆ S ₃ H ₂ O Calculated value C 35.66, H 3.52, N 24.46 Actual value C 35.52, H 3.72, H 24.14 Example 3 (a) 178 mg of oxamic acid was dissolved in dimethylformamide.
After dissolving in 10 ml and adding 230 mg of N-hydroxysuccinimide and then 413 mg of dicyclohexylcarbodiimide under ice cooling, the mixture was stirred at room temperature overnight. After removing insoluble materials by filtration, the filtrate was concentrated to dryness under reduced pressure. If ether is added to the residue and the insoluble matter is filtered out, N
- Crude form of (oxamyloxy)succinimide
332 mg are obtained as a white powder. IRν ^KBr _nax cm ^-1 :3450, 3340, 1730 (b) 7β-[DL-2-amino-2-(2-aminothiazol-4-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
Suspend 515 mg in 10 ml of 50% tetrahydrofuran,
While stirring under ice-cooling, 0.15 ml of triethylamine and then 239 mg of crude N-(oxamyloxy)succinimide were added, followed by stirring at the same temperature for 1 hour. THF is distilled off under reduced pressure. After adding water to the remaining aqueous layer, it is extracted with ethyl acetate.
The aqueous layer was taken, acidified with citric acid, and then extracted with ethyl acetate. After drying the ethyl acetate portion with anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure. After washing the residue with ethanol, it is dissolved in a mixture of methanol and tetrahydrofuran, reprecipitated by adding ether, and the precipitate is filtered to obtain 7β-[DL-2-
{(2-amino-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid is obtained as a powder. Example 4 7β-[DL-2-amino-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (967 mg) and N,N-diethyloxamyl chloride (540 mg) were reacted in the same manner as in Example 2, and purified to give 7β-[DL-
2-{(2-diethylamino-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid was obtained. IRν ^KBr _nax cm ^-1 : 1770 NMR (90MHz, δ value in DMSO- _d6 ) 1.08 (6H, m, ethyl CH ₃ ) 3.33 (4H, m, ethyl CH ₂ -) 3.66 (2H, broad, 2 -H) 3.93 (3H, s, tetrazole 1-CH ₃ ) 4.30 (2H, broad, -CH ₂ -S-) 5.06 (1H, m, H ₆ ) 5.70 (1H, m, H ₇ ) 6.43 (1H, s, thiazole H ₅ ) Elemental analysis C ₂₁ H ₂₆ N ₁₀ O ₆ S ₃・2H ₂ O Calculated value C 39.00, H 4.68, N 21.66 Actual value C 38.93, H 4.48, N 21.38 Example 5 (a) tert .-Butoxycarbonylhydrazine 2.0g
was dissolved in 10 ml of tetrahydrofuran, and a solution of 16 ml of oxalyl chloride dissolved in 50 ml of tetrahydrofuran was added to this under stirring at about -10°C, and the mixture was stirred at the same temperature for 20 minutes. After concentration under reduced pressure to dryness, the residue was dissolved in 30 ml of tetrahydrofuran. 7β-[DL-2
-amino-2-(2-aminothiazole-4-
yl)acetamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
2.9 g of 3-cephem-4-carboxylic acid was suspended in 100 ml of anhydrous acetonitrile, and then N,
O-bis(trimethylsilyl)acetamide
Trimethylsilylation was carried out by adding 6.0 g. The above tetrahydrofuran solution was added to this while stirring at -10°C, and the mixture was stirred at the same temperature for 1.5 hours. After concentrating to dryness under reduced pressure, water is added to the residue, stirred, and insoluble matter is filtered off to obtain 3.2 g of brown powder. This powder was subjected to silica gel column chromatography, and chloroform:tetrahydrofuran=
Develop with 1:1 solvent. Collect the relevant fraction,
If concentrated to dryness under reduced pressure, 7β-[DL-2-{(2-
tert-butoxycarbonylhydrazino-1,2
-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3
-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. IRν ^KBr _nax cm ^-1 : 1770, 1680 NMR (90MHz, δ value in DMSO- _d6 ) 1.43 (9H, s, (CH ₃ ) ₃ C-) 3.73 (2H, broad, 2-H) 3.98 (3H, s, tetrazole 1-CH ₃ ) 4.33 (2H, broad, -CH ₂ S-) 5.10 (1H, m, H ₆ ) 5.45 (1H, m, CH of glycine) 5.75 (1H, mH ₇ ) 6.60 (1H, s, H ₅ of thiazole) Elemental analysis C ₂₂ H ₂₇ N ₁₁ O ₆ For S ₃ Calculated value C 39.46, H 4.06, N 23.01 Actual value C 39.85, H 4.30, N 22.61 (b) 55 ml of acetic acid and concentrated hydrochloric acid Add 7β-[DL-2-{(2-tert.-butoxycarbonylhydrazino-1,2-dioxoethyl)amino}-2-(2-aminothiazole-) to 5 ml of the mixed solvent under ice-cooling and stirring.
Add 1.5 g of 4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid,
Stir at the same temperature for 2 hours. After concentrating to dryness under reduced pressure, ether is added to the residue and filtered to obtain a powder. If the obtained powder is purified by repeating the procedure of dissolving it in methanol and reprecipitating it with ether, 7β-[DL-2-{(2-hydrazino-1,
2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-
3-(1-methyl-1H-tetrazole-5-
650 mg of thiomethyl-3-cephem-4-carboxylic acid hydrochloride is obtained. IRν ^KBr _nax cm ^-1 : 1770, 1690, 1630 NMR (90MHz, δ value in DMSO- _d6 ) 3.75 (2H, broad, 2-H) 3.99 (3H, s, tetrazole 1-CH ₃ ) 4,35( 2H, broad, -CH ₂ -S) 5.15 (1H, m, H ₆ ) 5.60 (2H, m, H ₇ and CH of glycine) 6.91 (1H, s, H ₅ of thiazole) Elemental analysis C ₁₇ H ₁₉ N ₁₁ O ₆ S ₃・HCl・H ₂ O Calculated value C 32.72, H 3.55, N 24.69 Actual value C 33.05, H 3.72, N 24.29 Example 6 660 mg of oxalic acid mono-tert.butyl ester was dissolved in 20 ml of tetrahydrofuran. Then, under ice-cooling and stirring, a solution of 945 mg of dicyclohexylcarbodiimide and 530 mg of N-hydroxysuccinimide dissolved in 10 ml of tetrahydrofuran was added, and the mixture was stirred at the same temperature for 3 hours. Insoluble matter is filtered off to obtain a clear filtrate. 7β-[DL-2-amino-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-carboxylic acid 483mg
Suspend in 15 ml of 50% tetrahydrofuran, add and dissolve 0.2 ml of triethylamine while stirring under ice cooling, and then add the above filtrate. The reaction solution was stirred for 2 hours under ice cooling and then for 2 hours at room temperature. After distilling off tetrahydrofuran under reduced pressure, 5% aqueous sodium bicarbonate was added, and the mixture was washed with ethyl acetate. The aqueous layer was taken, acidified with citric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, then dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. Add ether to the residue and filter it to obtain a pale yellow powder. If this is dissolved in tetrahydrofuran and purified by reprecipitation with the addition of ether, a colorless powder of 7β-[DL-2-{(2-tert.-butoxy-1,2-dioxoethyl)amino}-2 can be obtained.
264 mg of -(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. IRν ^KBr _nax cm ^-1 : 1760, 1680 NMR (90MHz, δ value in DMSO- _d6 ) 1.50 (9H, s,

[Formula]) 3.97 (3H, s, tetrazole 1-CH ₃ ) Elemental analysis C ₂₁ H ₂₅ N ₉ O ₇ S ₃ H ₂ O Calculated value C 40.19, H 4.01, N 20.08 Actual value C 39.88, H 4.10, N 19.90 Example 7 Add 7β-[DL-2-{(2-tert.-butoxy-1,2-dioxoethyl)amino}-2- to a mixture of 5 ml of trifluoroacetic acid and 1 ml of anisole while stirring on ice.
(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1H-tetrazole-
Add 210 mg of 5-yl)thiomethyl-3-cephem-4-carboxylic acid and stir for 2 hours. After concentrating to dryness under reduced pressure, ether was added to the residue and filtered to obtain a light brown powder. Add water to this, add 5% sodium bicarbonate solution and adjust the pH.
8 and washed with ethyl acetate. The aqueous layer was made acidic with 10% citric acid, and insoluble matter was removed by filtration. The filtrate was applied to an Amberlite XAD column, developed with 5% tetrahydrofuran, and the relevant fractions were collected and concentrated to dryness under reduced pressure. Add ethyl acetate to the residue and filter it.
7β-[DL-2-{(2-hydroxy-1,2-
dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1
114 mg of -methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-carboxylic acid is obtained as a white powder. IRν ^KBr _nax cm ^-1 :1765, 1650 NMR (90MHz, δ value in DMSO- _d6 ) 3.94 (3H, s, tetrazole 1-CH ₃ ) 4.30 (2H, s, S-CH ₂ -tetrazole) 6.42, 6.57 (1H, thiazole 5-H in total) Elemental analysis C ₁₇ H ₁₇ O ₇ N ₉ For S ₃・H ₂ O Calculated value C 35.59, H 3.34, N 21.98 Actual value C 35.90, H 3.60, N 21.68

Claims (1)

[Claims] 1 formula A cephalosporin derivative represented by or a salt thereof. However, R ₁ is hydroxy, alkyloxy,
Indicates amino, alkylamino, dialkylamino, hydrazino, alkylhydrazino or dialkylhydrazino. R ₂ represents a 1-methyl-1H-tetrazol-5-yl group. 2 7β-[DL-2-{(2-ethoxy-1,2-
dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-carboxylic acid or a salt thereof. 3 7β-[DL-2-{(2-amino-1,2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-(1-
The compound according to claim 1, which is methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof. 4 7β-[DL-2-{(2-diethylamino-
1,2-dioxoethyl)amino}-2-(2-
Aminothiazol-4-yl)acetamide]-
The compound according to claim 1, which is 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof. 5 7β-[DL-2-{(2-hydrazino-1,2
-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-
The compound according to claim 1, which is (1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-carboxylic acid or a salt thereof. 6 7β-[DL-2-{(2-tert.-butoxy-
1,2-dioxoethyl)amino}-2-(2-
Aminothiazol-4-yl)acetamide]-
The compound according to claim 1, which is 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof. 7 7β-[DL-2-{(2-hydroxy-1,
2-dioxoethyl)amino}-2-(2-aminothiazol-4-yl)acetamide]-3-
The compound according to claim 1, which is (1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-carboxylic acid or a salt thereof.