JPS6052757B2 - Novel antibacterial compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporin derivatives or salts thereof.

In the compound of the above general formula, R and R2 may be the same or different and may be substituted with a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, or both may be substituted with a lower alkyl group.
- means a butadienylene group, R3 is a hydrogen atom or a methoxy group,

. ζElectric R・The present invention is based on the general formula 25-1 Cape’ [I] R.

represents a lower alkyl group, n represents 0, 1 or 2, and the dotted line in ring A represents a double bond or a single bond, respectively.

Examples of the lower alkyl group include, for example, a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, and examples of the sulfur-containing heterocyclic group represented by ring A include 1,3-dithiolan-2-yl group, 1,3-dithiolan-2-yl group, 1 , 3-dithien-2-yl group,
Examples include 1,3-dithian-2-yl group, 1,3-benzodithiol-2-yl group, and 1,3-dithioevan-2-yl group.

Compound [1] provided by the present invention is a chemically structurally completely new cephalosporin derivative in that it has a 5- to 7-membered sulfur-containing ring in the side chain at position 7 of the cephalosporin nucleus, and has excellent antibacterial activity. It is promising as an antibacterial agent.

The antibacterial activity (minimum effective antibacterial concentration) of compound [1] is shown below in comparison with commercially available cefazolin (CEZ).

The compound [1] of the present invention exhibits antibacterial activity against a wide range of pathogenic bacteria, and as is clear from Table 1 above, excellent efficacy is observed particularly against several important pathogenic bacteria belonging to Gram-negative bacteria.

Therefore, the compound [1] of the present invention is useful for pharmaceuticals, especially antibacterial agents,
It is useful as a feed additive and preservative. The compound of the present invention is available as it is or as a salt thereof.

Preferred salts are salts with pharmaceutically acceptable non-toxic bases, such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. ; Examples include ammonium salts or salts with organic bases such as synchlohexylamine salts, cyclohexylamine salts, trimethylamine salts, triethylamine salts, ethanolamine salts, ornithine salts, and lysine salts. The compound of the present invention or its salt is
It is administered orally or parenterally as an antibacterial agent.

The dosage varies depending on symptoms, body weight, etc., but for adults it is usually about 250 to 3000 Tn9 per day, divided into 3 to 4 doses. Dosage forms suitable for administration include injections, tablets, capsules, syrups, and suppositories, but these dosage forms are prepared using excipients, preservatives, stabilizers, etc. used for pharmaceutical purposes. can be added and carried out in a conventional manner.

According to the present invention, the compound [1] can be produced by the following method.

First method (wherein R5 means a hydrogen atom or a carboxyl group protecting group).

Further, R1, R2, R3, R4, n and the dotted line of ring A have the above meanings. ) In this method, a compound [ ] is prepared by reacting a 7-amicephalosporin derivative [ ] or a salt thereof with a carboxylic acid [ ] or a reactive derivative of the carboxylic acid, and R5 of the compound is a protective carboxyl group. If it is a group, then this is done by removing it. In the reaction between the above compound [old and [], the compound [
] can be converted into a reactive derivative of the carboxylic acid and then subjected to reaction.

Suitable reactive derivatives include acid halides, mixed acid anhydrides, active esters, active amides, acid anhydrides, acid azides, and the like.

When reacting the compound [] in a free state, it is preferable to use a condensing agent. Suitable condensing agents include N,N-dicyclohexylcarbodiimide, N,N''-diethylcarbodiimide, etc.The reaction between the compound [formerly compound] or its reactive derivative is carried out under heating or cooling.
When a compound [] in which R3 is a methoxy group is used as a raw material, it is preferable to carry out the reaction at a low temperature, particularly at -20°C or lower, in order to avoid epimerization of this methoxy group during the reaction. The thus generated cephalosporin compound having a sulfur-containing 5- to 7-membered heterocyclic group in the 7-position side chain [
] is then removed to obtain the target product [1]
can lead to. Second Method The object compound [1] of the present invention can also be produced by the method of the following formula.

(In the formula, R6 represents an acyl group such as an acetyl group or a carbamoyl group.

Further, R1, R2, R3, R4, n and the dotted line of ring A have the above meanings. ) This method is carried out by reacting a cephalosporin derivative [V] or a salt thereof with lower alkyltetrazole-5-thiol [] or an alkali metal substituted in its mercapto group. The reaction is usually carried out in a solvent at room temperature or at elevated temperature. Solvents that do not participate in this reaction include, for example, acetone, dimethylformamide, methanol, ethanol, water, and phosphate buffer, but these may be used in combination if necessary.

The reaction is preferably carried out near neutrality. When lower alkyltetrazole-5-thiol is used in free form as a starting material, it is preferable to carry out the reaction in the presence of a base such as alkali hydroxide, alkali carbonate, alkali hydrogencarbonate, trialkylamine, pyridine, dimethylaniline, etc. . In order to isolate the product after the reaction is completed, the reaction solution is made acidic and the precipitated product is collected, or a method using solvent extraction is used. Although two methods for producing the target compound of the present invention have been described above, the target compound of the present invention can also be produced by other methods. These will be explained in Examples as appropriate. Example 1 330 m9 of 1,3-dithiane-2-carboxylic acid was dissolved in 10 ml of benzene, 718 m9 of thionyl chloride was added, and after reacting at 50°C for 3 hours, the solvent was distilled off under reduced pressure.
1,3-dithiane-2-carboxylic acid chloride 355Tn
I got a 9.

7-amino-3-(1-methyltetrazol-5-ylthiomethyl-Δ3-cefemu-4-carboxylic acid benzhydryl ester) (hereinafter abbreviated as 7-A-3-MTCA).

)618m9 was dissolved in 6ml of methylene chloride and heated to -25°C.
225 m9 of pyridine was added, and then 1,3-
355 mg of dithiane-2-carboxylic acid chloride was added and reacted for 1 hour, and further 45 m9 of pyridine was added and reacted for 2 hours. The reaction solution was washed successively with cold 1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then methylene chloride was distilled off to obtain 659 mg of a crude caramel product. Fractions containing the target product were collected using a silica gel column effluent solvent (5 benzene: 1 part ethyl acetate) to obtain 566 m9 of caramel. Add 530 m9 of this caramel to 1 m1 of methylene chloride.
The mixture was dissolved in water, cooled to -20°C, and 27 ml of a mixture of 4 parts trifluoroacetic acid and 1 part anisole was added to react with the three powders. Methylene chloride, trifluoroacetic acid, and anisole were distilled off under reduced pressure.
1,3-dithiane-2-carboxamide)-3-(1-
223 m9 of pale yellow powder of methyltetrazol-5-ylthiomethyl)-Δ3-cefemu-4-carboxylic acid was obtained. Nuclear magnetic resonance spectrum (Ppm) 7.88 (1H, d, NH) 5.78 (1H, dd, C7-H) 5.06 (1H, d, C6-H) 4.39 (2H, s, 3 position CH2) 3.93 (3H, s, N-CH3) 3.74 (2H, s, C2-H2) 3.1-3. &2.6~2.8,2.0~2.2(6H
, m, Example 2 In Example 1, 71A-3-MTC
7β-amino-7α-methoxy 3-(1-
Methyltetrazol-5-ylthiomethyl)-Δ3-cepheme 4-carboxylic acid (hereinafter referred to as 71A-J) carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cepheme 14
Dye carboxylic acid was obtained.

Nuclear magnetic resonance spectrum (Ppm) 9.15 (1H, s, NH) 5.40 (1H, s, C6-H) 4.35 (2H, s, 3rd position CH2) 3.94 (3H, s, N-CH3) 3.60 (2H, s, C2-H2) 3.52 (3H, s, 7th position 0CH3) 3.4-3.6, 2.5-2.7, 2.0-2. 2 (6
H, m, Example 3 In Example 1, 1,3-dithiolane-2-carboxylic acid was used instead of 1,3-dithiane-2-carboxylic acid, and 7-1 was used instead of 7-A-3-MTCA. Perform the same operation using A-Jyo l-3-MT'CA,
7β-(1,3-dithiolan-2-yl)carboxamide 7α-methoxy-3-(1-methyltetrazole-
5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid was obtained.

Nuclear magnetic resonance spectrum (Ppm) 9.08 (1H, s, NH) 5.08 (1H, s, C6-H) 4.30 (2H, s, 3rd position CH2) 3.94 (3H, s, N -CH3) 3.56 (21{, S, C2-H2) 3.50 (3H, s, 7th position 0CH3) Example 4 In Example 1, 5- in place of 1,3-dithiane-2-carboxylic acid Methyl-1,3-benzodithiol-2-
carboxylic acid, also 7-A-3-MTCA instead of 7-A-3-MTCA.
Perform the same operation using 1A-JYo1-3-MTCA,
7α-methoxy7β-(5-methyl-1,3-benzodithiol-2-yl)carboxamide 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid was obtained.

Nuclear magnetic resonance spectrum (Ppm) 7.76 (1H, s, NH) 5.02 (1H, s, C6-H) 4.43 (2H, q, 3rd position CH2) 3.93 (3H, s, N -CH3) 3.46 (2H, s, C2-H2) 3.46 (3H, s, 7th position 0CH3) Example 5 198 m9 of 4,5-dicyano-1,3-dithiol-2-carboxylic acid was dissolved in 20 m1 of methylene chloride. Then, 218 m9 of phosphorus pentachloride was added and the mixture was allowed to react at room temperature for 1 hour.

Then, the temperature was cooled to -40 to -50°C, 1.2 mL of pyridine was added, and then 1 g of 71A-J Yoko l-3-MTCA benzhydryl ester was added to 10 ml of methylene chloride.
Add the solution dissolved in 1 dropwise. The three powders are reacted at 30 to -40°C, 10 ml of precursor monohydrochloric acid is added dropwise, and the methylene chloride layer is separated.

After washing twice with 10 ml of water and drying over anhydrous magnesium sulfate, methylene chloride is distilled off to obtain a crude caramel product 6.
Obtain 50m9. It was subjected to silica gel column chromatography, and the elution solvent (chloroformrimethanol, 100%
Collect fractions containing the target product in step 5) and distill off the solvent to obtain 500 m9 of caramel. Then, it is dissolved in 5 ml of methylene chloride and cooled to -20°C. 0.5 ml of anisole and 0.8 ml of trifluoroacetic acid are added dropwise to this, and the mixture is reacted at 0 to 5° C. for 1 hour. After the reaction, the solvent anisole trifluoroacetate was distilled off, and 10 ml of ether was added to the residue, which was then powdered to give 7β-(4,5-dicyano-1,3-dithio-2-yl)carboximide 7α-methoxy-3-( 1-methyltetrazole-5
A pale yellow powder 3687-19 of 3687-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid is obtained. Infrared spectrum (KBr tablet) ~2210 cm-1 (nitrile), 17
751c1-1 (lactam) nuclear magnetic resonance spectrum ((
X3-DMSO) (Ppm) 9.46 (1H, s, NH
) 5.17 (1H, s, C6-H) 4.31 (2H, s, C3-CH2-) 3.92 (3H, s, N-CH3) 3.40 (3H, s, 0CH3) 4,5-dicyano 1,3 used in Example 5
-Dithio-2-carboxylic acid was produced by the method of the following reference example.

Reference Example 1 960 m9 of 50% sodium hydride is added to 60 mt of dimethoxyethane, cooled, and 6.24 y of short acetic acid is added at 10° C. or lower to react.

(Formation of sodium salt of short acetic acid) Furthermore, 3.72 g of disodium 1,2-dicyanoethylene dithiolade is added at 10° C. or lower.

Then, the mixture was stirred and reacted overnight at room temperature. The solvent dimethoxyethane is distilled off to obtain a dark brown residue. Add 50 ml of water to dissolve this, and extract and wash twice with 30 ml and 20 ml of ethyl acetate. The obtained aqueous layer was made acidic (PHI) with Beau's hydrochloric acid and extracted twice with 50 ml of ether. 100 ml of petroleum ether was added to the ether solution washed with 30 ml of saturated sodium chloride water, and the precipitated tar was removed by decanting. After drying the ether solution over anhydrous magnesium sulfate and distilling off the ether and petroleum ether, crude 4,5-dicyano 1,3-dithiol-2-
3.17V of carboxylic acid is obtained. The fraction containing the target product is collected by applying it to a silica gel column using an elution solvent (ethyl acetate-n-hexane 2:1) and distilling off the solvent to obtain 4,5-dicyano-1,3-dithiol-2- with a melting point of 137-140°C. 2.46y (62.1%) of carboxylic acid is obtained. Nuclear magnetic resonance spectrum (↓-DMSO) (Ppm) 6
．． 14 (1H, s, C2-H) infrared spectrum (KB
r5) 2220cm-1 (nitrile), 1720C77! -1
(carboxylic acid) mass spectrum (m/e) Ml98M+
-CO2l54 Example 6 Product of Example 5 230Tng
and add 5ml of cold concentrated hydrochloric acid (+5~0℃) to it.
Hydrolysis is carried out by stirring at room temperature for an hour.

After the reaction is completed, 10 ml of ice water is added and the mixture is extracted twice with 20 ml and 110 ml of n-butanol/ethyl acetate (11). The organic layer was washed twice with 10 ml of saturated sodium chloride water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography using eluting solvent (chloroformimethanol lyformic acid = 85:15).
:2 (volume ratio)), the solvent is distilled off, and the resulting residue is powdered with ether to obtain 7β-(4,5-dicarbamoyl-1,3-dithiol- 2-carboxamide)-7α-methoxy3-(1
-Methyltetrazol-5-ylthiomethyl)-Δ3-
20 m9 of light brown powder of cefhemu 4-carboxylic acid are obtained. Nuclear magnetic resonance spectrum (D6-DMSO) (Ppm)
9.27 (1H, s, NH) 8.08, 7.76 (each?, amide) 5.10 (1H, s, C6-H) 4.28 (2H, q, C3-CFL.-) 3 .92 (3
H, s, NCH3) 3.40 (3H, s, 0CH3)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 are the same or different, and represent a hydrogen atom,
A cyano group, a carbamoyl group, a carboxyl group, or both together may be substituted with a lower alkyl group 1
, 4-butadienylene group, R_3 is a hydrogen atom or a methoxy group, R_4 is a lower alkyl group, n is 0, 1 or 2, and the dotted line bond in ring A is either a double bond or a single bond. It means something. ).