JPH0332555B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cephalosporin derivative represented by the following general formula and a salt thereof. In the formula, R ₁ is

[expression] or

[Formula], R ₂ represents hydrogen or lower alkyl, and R ₃ represents hydrogen or lower alkyl. As a result of research on various cephalosporin derivatives, the present inventors found that the novel compound represented by the above formula [) exhibits high antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria, and completed the present invention. The thiazole moiety, which is a part of the structure of the compounds of the present invention and their synthetic intermediates, is thought to have tautomers of 2-aminothiazole and 2-iminothiazoline. Throughout this specification, structural and name references to 2-aminothiazole compounds are not meant to be limiting. Similarly, 1,2,4-triazole and 1,2,3-triazole, which are part of the structure of the compounds of the present invention and their intermediates, can have several types of tautomeric structures with different hydrogen substitution positions. It is believed that there is. In this specification, these are representatively explained as one type of structure, but this is not meant to be limiting. Furthermore, the compounds of the present invention having an oximino group and their synthetic intermediates have a syn isomer (J) and an anti isomer (K), and one or a mixture thereof can be obtained. However, in general, the syn isomer is superior in antibacterial activity.

【formula】

[Formula] Next, the method for producing the compound () of the present invention will be described in detail. formula (R ₄ represents a protecting group for an amino group used in the synthesis of peptides and β-lactam compounds, such as hydrogen, triphenylmethyl ( _abbreviated as trityl), formyl, and tertiary butoxycarbonyl.

[expression] or

[Formula], R ₆ is hydrogen or a protecting group for the amino group used in the synthesis of peptides and β-lactam compounds, such as trityl, formyl, and tertiary butoxycarbonyl), and is a compound represented by the formula By acylating the compound represented by the formula The compound shown is obtained. This acylation reaction can be carried out in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, the so-called Vilsmeier reagent produced from dimethylformamide and phosphorus oxychloride, and the like. Acylation can also be carried out after converting the compound () into a reactive derivative, such as an active form such as an acid halide or an active ester. Suitable examples include acid chloride, N-
Examples include esters with N-hydroxy compounds such as droxysuccinimide and 1-hydroxybenztriazole. The reaction is carried out in methylene chloride, tetradrofuran, ethyl acetate, dimethylformamide or other solvents that do not adversely affect the reaction. Further, these reactions are appropriately selected depending on the type of compound [] used. From the compound [] thus obtained, the compound represented by the formula [] can be obtained by removing the protecting group, if necessary. The protective group removal reaction can be carried out by water decomposition, reduction, or the like. Hydrolysis with acid is one of the most common methods and is the preferred method for removing protecting groups such as trityl, formyl, and tert-butoxycarbonyl. The acids used include organic acids such as formic acid and trifluoroacetic acid, or inorganic acids such as hydrochloric acid. In this case, a solvent that does not adversely affect the reaction may be used, and the reaction may be carried out in the presence of a scavenger such as anisole or thioanisole. Hydrolysis with a base is used to remove acyl groups, and an inorganic base such as sodium hydroxide or an organic base such as triethylamine is used. Further, in the case of a haloalkoxycarbonyl group such as trichloroethoxycarbonyl, the protective group can be removed by a reduction reaction. Also, using the compound [], the formula (R ₇ represents lower alkyl, R ₈ represents hydrogen or a protecting group for carboxylic acid used in the synthesis of β-lactam compounds such as tertiary butyl and benzhydryl)
By acylating the compound represented by the formula After obtaining the compound represented by the formula, removing the protecting group if necessary, the formula The compound shown can be obtained. The acylation reaction can be carried out in the same manner as when compound [] is acylated with compound [], and the protecting group removal reaction can be carried out under the same conditions as in the case of removing a protecting group from compound []. The compound [] obtained in this way and the formula The compound represented by the formula [) can also be obtained by reacting the compound represented by the formula [)].
This reaction between [] and [] may be carried out in the presence of sodium iodide, potassium iodide, sodium bromide, potassium thiocyanate, or the like. The reaction is also advantageously carried out in an aqueous solvent with a pH of 5 to 8. Furthermore, using the above compound [], the formula (X represents a halogen such as chloro or bromine) is acylated, and the formula There is a method to obtain the intermediate shown. The acylation reaction can be carried out in the same manner as when compound [] is acylated with []. Then, when the intermediate [X] is reacted with the above compound [], the formula The compound shown is obtained. This reaction can be carried out in acetone, dichloromethane, acetonitrile, or any other solvent that does not adversely affect the reaction. Next, after converting the sulfoxide of intermediate [XI] to sulfide, the protecting group is removed to form the compound [)
can be obtained. The reaction of deoxidizing a sulfoxide to form a sulfide can be carried out using reagents such as phosphorus trichloride, phosphorus tribromide, acetyl chloride and stannous chloride, and acetyl chloride and potassium iodide. Further, the reaction for removing the protecting group can be carried out in the same manner as in the case of removing the protecting group from the compound []. The compound of formula [] is reacted with an alkali metal, an alkaline earth metal, or a derivative thereof, such as a hydroxide or a carbonate, by a conventional method, so that the 4-position carboxylate becomes a salt of an alkali metal or an alkaline earth metal. It is also possible to obtain it as a summer type. The compound of formula [] can be formed into a suitable acid addition salt, for example, as a monohydrochloride or trihydrochloride, or as a salt with an organic acid such as formic acid or maleic acid. Compound [] used in the synthesis of compound [)
For example, the expression It can be obtained by reacting a compound represented by the formula with a compound represented by the formula NH ₂ OCH ₂ -R ₅ [ ]. As the reaction solvent, in addition to water and ethanol, any solvent that does not adversely affect the reaction can be used. The above compound [] can be produced by, for example, reacting _{N - hydroxyphthalimide} with a compound represented by the _formula By reacting with a reagent such as diethyl dicarboxylate, the formula After obtaining the compound represented by , it can be obtained by treating this compound with hydrazine or hydrochloric acid. In addition, if a compound [] in which R ₆ in the structure of R ₅ is hydrogen is subjected to a reaction to introduce a protecting group, and then treated with, for example, hydrazine,
Corresponding compounds in which R ₆ is trityl, formyl, tertiary butoxycarbonyl, etc. can be obtained. The compound of the present invention exhibits a broad antibacterial spectrum and high antibacterial activity, and is particularly characterized in that it also exhibits antibacterial activity against Ps. aeruginosa, which is resistant to conventional cefem compounds. The following table compares the antibacterial activity of some compounds of the present invention with that of cefotaxime.

[Process]

Ethyl N-trityl-1,2,4-triazole-3-carboxylate 0.86 g of ethyl 1,2,4-triazole-3-carboxylate is suspended in 40 ml of methylene chloride, 1.67 g of trityl chloride and 1.0 ml of triethylamine. was added dropwise and stirred at room temperature for 1 hour.
Wash with 10% citric acid solution, then saturated saline, and dry over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.69 g of the title compound as a pale yellow oil. CW-NMR (CDCl3 _, ppm) 1.37 (3H, t, J-7Hz, _CH2CH3 ) 4.46 (2H, q, J-7Hz, _CH2CH3 ) 7.1-7.4 ₍ 15H, _m , trityl) 8.02 (1H, s, H at the 5th position of triazole) [Step] 3-[hydroxymethyl)-N-trityl-1,
2,4-Triazole 0.23 g of lithium aluminum hydride is added to 30 ml of tetrahydrofuran, and a solution of 2.65 g of the compound obtained in [Step] in 10 ml of tetrahydrofuran is added dropwise to this suspension while stirring under ice cooling. Heat to reflux at 80℃ 1
Cool after an hour. Add water. After filtering, drying the filtrate under reduced pressure and washing the residue with ether, the melting point is 208-212℃.
1.30 g of the title compound is obtained. CW-NMR (CDCl ₃ , ppm) 4.73 (2H, s, -CH ₂ OH) 7.0-7.4 (15H, m, trityl) 7.95 (1H, s, H at the 5th position of triazole) Elemental analysis O ₂₂ H ₁₉ N ₃ Calculated value for O C 77.39, H 5.61, N 12.31 Actual value C 77.29, H, 5.85, N 12.12 [Step] 3-(phthalimidoxymethyl)-N-trityl-1,2,4-triazole Obtained in [Step] 1.02g of the compound was dissolved in 30ml of tetrahydrofuran by heating, and 0.49g of N-hydroxyphthalimide and triphenylphosphine were added.
0.79 g and 0.57 g of ethyl azodicarboxylate are sequentially added at room temperature and stirred overnight. After evaporation of the solvent, column chromatography using silica gel as a carrier (first time, chloroform:methanol-19:1;
2nd time, with ethyl acetate:benzene = 1:4)
If purified twice, the title compound with a melting point of 254-257°C would be 0.56
get g. IR ν ^KBr _nax cm ^-1 : 1780, 1730, 1490, 1440 CW-NMR (CDCl ₃ ppm) 5.28 (2H, s, NOCH ₂ ) 7.0-7.4 (15H, m, trityl) 7.75 (4H, s, phthalimide) 7.97 (1H, s, H at the 5th position of triazole) [Step] 3-(aminooxymethyl)-N-trityl-
1,2,4-triazole 0.55g of the compound obtained in [Step] was dissolved in ethanol 20
After adding an ethanol solution of 60 mg of hydrazine hydrate, the mixture was heated and stirred at 80°C for 1.5 hours. The precipitated crystals were removed by filtration, and the solvent was distilled off. Chloroform is added to the residue, insoluble materials are removed by filtration again, and the filtrate is washed with saturated brine. Dry over anhydrous sodium sulfate, evaporate into solvent, and wash the residue with ether to obtain the title compound with a melting point of 105-110°C.
Obtain 0.40g. CW-NMR (CDCl ₃ , ppm) 4.80 (2H, s, NOCH ₂ −) 5.60 (2H, br, H ₂ NO−) 7.1-7.4 (15H, m, trityl) 7.93 (1H, s, triazole 5-position H) [Step] 2-(2-tritylaminothiazol-4-yl)-2-{(N-trityl-1,2,4-triazol-3-yl)methoxyimino}acetic acid Compound obtained in [Step] 0.40g of ethanol15
ml of (2-tritylaminothiazole-
Add 0.40 g of 4-yl)glyoxylic acid and stir at room temperature for 1 hour. After evaporating the solvent, the residue is dissolved in chloroform and dried over anhydrous sodium sulfate.
After evaporating the solvent and washing the residue with ether, the melting point is 128.
0.73 g of the title compound is obtained at ~135°C. IR ν ^KBr _nax cm ^-1 : 1710 CW-NMR (CDCl ₃ , ppm) 5.50 (2H, s, NOCH ₂ −) 6.75 (1H, s, H at the 5th position of thiazole) 7.0-7.4 (15H, m, trityl) 8.03 (1H, s, H at the 5th position of triazole) [Step] 7β-[2-(2-aminothiazol-4-yl)
-2-{(1,2,4-triazol-3-yl)
Methoxyimino}acetamide]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) Add dimethylformamide to methylene chloride under ice cooling.
Add 0.77ml and phosphorus oxychloride 0.91ml, total 10ml
Prepare a reaction mixture of Dissolve 0.76 g of the compound obtained in [Step] in 8 ml of methylene chloride, and cool on ice.
Add 2.0 ml of the above reaction mixture and stir for 45 minutes.
This reaction solution was mixed with 0.75 g of 7β-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrochloride and bis(trimethylsilyl).
The mixture was added to a solution of 0.9 ml of acetamide in 8 ml of acetonitrile under ice cooling, then the mixture was returned to room temperature and stirred for 1.5 hours.
The reaction solution is diluted with chloroform, washed with water, then with saturated brine, and dried over anhydrous sodium sulfate.
After evaporating the solvent, the residue was washed with ether to obtain 730 mg of a light brown powder. This powder is added to an ice-cooled mixture of 8 ml of 9% formic acid and 0.4 ml of concentrated hydrochloric acid, and after 10 minutes the mixture is allowed to warm to room temperature and stirred for 1 hour. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. Dissolve the residue in water and add Diaion HP-
Column chromatography using 20 as a carrier (2.5
% tetrahydrofuran), and then purified by high performance liquid chromatography (carrier: Partsil (manufactured by Watmann); solvent: 10% methanol).
The title compound is obtained. IR ν ^KBr _nax cm ^-1 : 1770, 1660, 1610 FT-NMR (D ₂ O, ppm, 200MHz) 3.14 (1H, d, J = 18Hz, C ₂ -H) 3.63 (1H, d, J = 18Hz, C ₂ -H) 5.25 (1Hz, d, J = 5Hz, C ₆ -H) 5.36 (2H, s, B-O-CH ₂ ) 5.38 (1H, d, J = 14Hz,

【formula】) 5.59 (1H, d, J = 14Hz,

[Process]

Ethyl N-trityl-1,2,3-triazole-4-carboxylate 3.47 g of ethyl 1,2,3-triazole-4-carboxylate and 7.55 g of trityl chloride
Dissolve g in 100 ml of chloroform. Add 377 ml of ice-cold, stirred triethylamine dropwise to this, and let it stand for 30 minutes at room temperature.
Stir for a minute. After chloroform was distilled off, the residue was dissolved in ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Distill the ethyl acetate,
A crystalline solid is obtained. If this is purified by column chromatography (silica gel: 100g, solvent: benzene and then chloroform), the melting point is 201 to 203.
The title compound (8.37 g) is obtained. IR ν ^KBr _nax cm ^-1 : 1730 CW-NMR (CDCl ₃ , ppm) 1.37 (3H _, t, J = 7.5Hz, CH ₂ CH ₃ ) 4.39 (2H, q, J = 7.5Hz, CH 2 CH ₃ ) 8.01 (1H, s, H at the 5th position of triazole) [Step] 4-(hydroxymethyl)-N-trityl-1,
2,3-Triazole After suspending 1.29 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, 13.0 g of tetrahydrofuran was obtained by suspending 1.29 g of lithium aluminum hydride in [Step] under ice-cooling and stirring.
Add 300 ml of solution (partial suspension) dropwise and stir at room temperature for 3 hours. Carefully add 1.3 ml of water, then 1.3 ml of a 15% aqueous sodium hydroxide solution, and then 3.0 ml of water to the reaction solution. After filtration, the filtrate is dried under reduced pressure to precipitate a pale yellow solid. N-hexane is added to this and the solid is collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 11.4 g of a compound having a melting point of 205-207°C. CW-NMR (CDCl ₃ , ppm) 4.78 (2H, s, OCH ₂ ) [Step] 4-(phthalimidoxymethyl)-N-trityl-1,2.3-triazole 17.5 g of the compound obtained in [Step], N- 8.4 g of hydroxyphthalimide and 14.8 g of triphenylphosphine were dissolved in 700 ml of tetrahydrofuran, and 9.8 g of diethyl azodicarboxylate was dissolved under stirring at room temperature.
g and stirred at room temperature for 1 hour. After distilling off the solvent, chloroform was added to the residue and the mixture was dried under reduced pressure to precipitate a slight solid. Addition of diethyl ether precipitates a large amount of solid. This is collected by filtration, dried under reduced pressure, and then methylene chloride is added. Filter the insoluble matter,
Drying under reduced pressure yields 24.5 g of powder. If this is purified by column chromatography (silica gel: 500g, solvent: chloroform), the melting point is 195~
14.2 g of the title compound are obtained at 200°C. IR ν ^KBr _nax cm ^-1 : 1790, 1730 CW-NMR (CDCl ₃ , ppm) 5.36 (2H, s, OCH ₂ ) [Step] 4-(aminooxymethyl)-N-trityl-
1,2,3-triazole 16.2g of the compound obtained in [Step] was dissolved in methanol.
Suspend in 300ml, add 17g of hydrazine hydrate,
Stir for 1.5 hours at room temperature. After filtration, the solvent is distilled off.
After adding chloroform to the residue and filtering off insoluble materials, the filtrate is dried under reduced pressure (this operation is repeated 3 to 4 times).
The residue is purified by column chromatography (silica gel: 200 g, solvent: chloroform) to obtain 9.5 g of the title compound having a melting point of 144-145°C. CW-NMR (CDCl3 _, ppm) 4.79 (2H, s, _OCH2 ) 4.80-5.80 (2H, br, _NH2 ) 7.45 (1H, s, H at the 5th position of triazole) [Step] 2-(2-totyl aminothiazol-4-yl)
-2-{(N-trityl-1,2,3-triazol-4-yl)methoxyimino}acetic acid 2.58g of the compound obtained in [Step] was dissolved in methanol.
2.4 g of (2-tritylaminothiazol-4-yl)glyoxylic acid dissolved in 100 ml and stirred at room temperature.
Add and stir for 16 hours. Solvent evaporation. The residue is dissolved in ethyl acetate, washed with a PH4 aqueous hydrochloric acid solution and brine, and then dried over anhydrous sodium sulfate. The solvent is distilled off. The residue was dissolved in a small amount of chloroform, n-hexane was added thereto, and the precipitated solid was collected by filtration. n
- Washed with hexane and dried under reduced pressure, melting point 138-145℃
(Decomposition) 4.05 g of the title compound is obtained. IR ν ^KBr _nax cm ^-1 : 3600-2700, 1720 CW-NMR (CDCl ₃ , ppm) 5.27 (2H, s, COH ₂ ) 6.55 (1H, s, H at 5-position of thiazole) [Process] Sodium 7β- [ 2-(2-aminothiazole-
4-yl)-2-{(1,2,3-triazole-
4-yl)methoxyimino}acetamide]-3-
Acetoxymethyl-3-cephem-4-carbochyto (syn isomer) 2.26 g of the compound obtained in [Step] was dissolved in methylene chloride.
After adding 0.62 g of dicyclohexylcarbodiimide, 0.41 g of N-hydroxybenztrial and 0.98 g of tertiary butyl 7-amino-3-acetoxymethyl-3-cephem-4-carboxylate under stirring at room temperature. , stir at room temperature for 2 hours. After filtering off insoluble materials, the solvent is distilled off. The residue was purified by column chromatography (silica gel: 45 g, solvent: chloroform) to obtain 2.40 g of foam. Dissolve this in anisole (3 ml), add 24 ml of trifluoroacetic acid while stirring on ice,
Stir for 1.5 hours at room temperature. Dry under reduced pressure. Formic acid in the residue
Add 25 ml and stir at room temperature for 1 hour. Dry under reduced pressure.
Diethyl ether was added to the residue and the precipitated solid was collected by filtration. After washing with diethyl ether and drying under reduced pressure, 0.88 g of powder was obtained. This powder was used in the next [step] without further purification. A portion (0.2 g) is dissolved in a 5% aqueous sodium bicarbonate solution and purified by high performance liquid chromatography (carrier: Partsil (manufactured by Watmann), solvent: 2% methanol) to obtain the title compound. IR ν ^KBr _nax cm ^-1 : 3650-2600, 1760, 1655, 1600 F-NMR (D ₂ O, ppm) 2.10 (3H, s,

[Process]

7β-[2-(2-aminothiazol-4-yl)
-2-{(1,2,3-triazol-4-yl)
Methoxyimino}acetamide]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) 632 mg of the compound obtained in [Step] was added to 0.45 mg of pyridine.
ml, dissolved in 93 mg of sodium carbonate and 0.75 ml of water, add 2.34 g of sodium iodide, and stir at a nitrogen atmosphere bath temperature of 70-75°C for 1.5 hours. After cooling, acetone is added and the precipitated solid is collected by filtration. After washing with acetone and drying under reduced pressure, 470 mg of powder was obtained. Dissolve this in a small amount of water, perform column chromatography using Diaion HP-20 (80ml) as a carrier (5% tetrahydrofuran, then 20% tetrahydrofuran), and then perform high performance liquid chromatography (carrier: C ₁₈ Micro Bonder Pack). (manufactured by Waters), solvent:
Purify with 7.5% MeOH) to obtain the title compound. IR ν ^KBr _nax cm ^-1 : 3600-2500, 1770, 1610 FT-NMR (D ₂ O, ppm) 3.13 (1H, d, J = 18Hz, C ₂ -H) 3.60 (1H, d, J = 18Hz, C ₂ -H) 5.23 (1H, d, J = 5Hz, C ₆ -H) 5.38 (1H, d, J = 14Hz,

[Formula]) 5.39 (2H, s, OCH ₂ ) 5.58 (1H, d, J = 14Hz,

[Formula]) 5.84 (1H, d, J = 5Hz, C ₇ - H) 7.04 (1H, s, H at the 5th position of thiazole) 8.02 (1H, s, H at the 5th position of triazole) 8.13 (2H, t, J =7Hz, H at the 3rd and 5th positions of pyridine) 8.63 (1H, t, J = 7Hz, H at the 4th position of pyridine) 8.98 (2H, d, 7Hz, H at the 2nd and 6th positions of pyridine) Elemental analysis C ₂₁ H ₁₉ N Calculated values for ₉ O ₅ S ₂・3H ₂ O: C 42.34, H 4.23, N 21.17 Actual values: C 42.38, H 3.80, N 21.08.

Claims (1)

[Claims] 1 formula Cephalosporin derivatives and salts thereof represented by (R ₁ : [Formula] or [Formula] R ₂ : hydrogen or lower alkyl; R ₃ : hydrogen or lower alkyl). 2 7β-[2-(2-aminothiazol-4-yl)-2-{(1,2,4-triazol-3-yl)methoxyimino}acetamide]-3-(1-pyridiniomethyl)-3-cephem 2. The compound according to claim 1, which is the syn isomer of -4-carboxylate or a salt thereof. 3 7β-[2-(2-aminothiazol-4-yl)-2-{(1,2,3-triazol-4-yl)methoxyimino}acetamide]-3-(1-pyridiniomethyl)-3-cephem 2. The compound according to claim 1, which is the syn isomer of -4-carboxylate or a salt thereof.