JPS5839688A - 7alpha-methoxy-3-cephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) of formulaI. EXAMPLE:7beta-[D-2-(6,7-Dihydroxychromone-3-carboxamido)-2-phenylaceta mido]- 7alpha-methoxy-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-c arboxylic acid. USE:An antimicrobial agent for Gram-positive and Gram-negative bacteria, e.g. Pseudomonas aeruginosa, Serratia marcescens or Proteus morganii, and microorganisms producing beta-lactamases. PROCESS:A 7beta-(D-2-amino-2-phenylacetamido)-7alpha-methoxy-3-(1-carboxymethyl-5- tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid (salt), e.g. trifluoroacetate, is reacted with a 6,7-dihydroxychromone-3-carboxylic acid (reactive derivative), e.g. acid chloride, to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 7α-methoxy-3-cephem I conductor and its non-toxic salt.

The compound of the present invention has excellent antibacterial activity and is effective against not only Durum-positive bacteria but also Durum-negative bacteria.

%, is effective against clinically refractory bacteria such as Pseudomonas aeruginosa, Serratia marcescens, and Proteus morgani, as well as β-lactamase-producing bacteria.

The compound of the present invention can be produced by the method shown below.

The compound of the present invention represented by the formula (1) can be obtained by reacting the compound represented by the formula or its salt with the compound represented by the formula or its reactivity-conductor.

In the above reaction, one example is when a substitute compound which is a carboxylic acid (-COOH) is used.

N,N'-dicyclohexylcarbodiimide+N+N'
-diethylcarbodiimide, N-cyclohexyl-N-
The reaction is preferably carried out in the presence of a condensing agent such as morpholinoethylcarbodiimide, ethyl phosphite, phosphorus oxychloride, or oxalyl chloride. In addition, 2 types (2
) When using a reactive derivative at the carboxyl group of the compound (2), examples of the di-reactive derivative include acid compounds such as acid chloride and acid bromide; symmetrical acid anhydrides; and bilitel carbonate.

Mixed acid anhydrides with carboxylic acids such as trimethylacetic acid and diphenylacetic acid; 2-mercaptopyridine.

Active esters such as cyanomethanol, P-nidophenol, 2,4-dinitrophenol, and pentachlorophenol; active acid amides such as N-acylsaccharin and N-acylphthalimide are used.

The above reaction is carried out at -500C to 50C in an inert solvent in the presence or absence of a basic reagent or silylating agent.
1 Preferably, it can be carried out at a temperature of -20°C to 30°C.

Examples of the inert solvent include acetone, tetrahydrofuran, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, chloroform, benzene, toluene, ethyl acetate, or a mixed solvent thereof.

Examples of basic reagents include alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; amines such as triethylamine, pyridine, dimethylaniline, and N-methylmorpholine. can give.

Examples of silylating agents include N, O-bis(trimethylsilyl)acetamide, hexamethyldisilazane,
Examples include trimethylsilylacetamide.

Examples of the non-toxic salts of the present invention include sodium salts, potassium salts, calcium salts, ammonium salts, triethylamine salts, zinclohexylamine salts, proline salts, and the like. These salts can be formed by 2 formulas (
It can be obtained from the compound I).

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 7β-(D-2-(6,7-cyhydroxychromone-3
-carboxamide)-2-phenylacetamide]-7
α-methoxy-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid 7β-(D-2-amino-2-phenylacetamide)
-7α-methoxy-3-(1-carboxymethyl-5-
Tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid trifluoroacetate (60 ~) was stirred in tetrahydrofuran (3 ml), and 102 μl of N,O-bis(trimethylsilyl)acetamide was added and poured into a water bath. The mixture was stirred for 10 minutes, and 6,7-cyhydroxychromone-3-carbonyl chloride (24In9
) was further stirred at the same temperature for 1 hour and 20 minutes. The reaction solution was concentrated to about 1 ml, and dissolved in 0.2N hydrochloric acid (20 ml), once with 50 ml of ethyl acetate, and once with 20 mg of ethyl acetate.
Extracted twice. The extract was washed four times with water (2 QmJ) and four times with saturated saline (20 ml), dried over magnesium sulfate, and then the solvent was distilled off. The residue was dissolved in tetrahydrofuran (2 m
The mixture was dissolved in ether (30 ml) under stirring, and then hexane (1 Q ml) was added dropwise. The resulting solid was collected, washed with ether at °C, and then dried under vacuum to obtain the desired product (45 °C).
rn9) was obtained.

Infrared absorption spectrum (CrIL-'+ Neungyol) = 1750-1780.1640-1650.160
5NMR spectrum (δ, DMSO-d,): 3.24
(IH, d, J=18Hz).

3.38 (3H, s).

3.61 (IH, d, J=18Hz).

4.08 (1, H, d, J=14Hz).

4.49 (IH, d, J-=14Hz).

5.01 (IH, a).

5.28 (2H, B).

5.79 (IH, d, J = 7 Hz).

6.86 (IH, s).

7.38 (IH, s).

7.2-7.6 (5H, m).

8.83 (IH, a).

9.77 (IH, a).

10.10 (IH, br, s).

10.27 (IH, d, J = 7 Hz).

10.76 (IH, br, s ) Example 2 7β-(D-2-(6,7-cyhydroxychromone-3
-carboxamide)-2-phenylacetamide]-7
α-methoxy-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid cina, thorium salt 7β-(D-2-(6,7-cyhydroxychromone-3-carboxamide) -2-phenylacetamide]-7α-methoxy-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-carvone m (37In9) was added to methanol (9,5
mg), and a methanol solution of sodium acetate (IM, 0.11 ml) was added at room temperature, followed by stirring for 10 minutes. Methanol was distilled off, ethanol was added to the residue to solidify it, the residue was collected, washed with ether, and dried under vacuum to obtain the desired product (30In9).

Infrared absorption spectrum (CrrL-', Nujol)
:1745-1780.1650-1670.161O
NMR spectrum (δ, DMSO-d6): 3.08 (
IH, d, J = 18Hz).

3.40 (3H, s).

3.46 (LH, d, J=18Hz).

4.60 (2H, s).

4.90 (IH,s).

5.80 (IH, d, J = 8 Hz).

6.83 (IH, s).

7.28 (IH, s).

7.1 7.6 (5H, m).

8.75 (IH, s).

9.66 (IH, br, s).

10.44 (IH, d, J-8Hz) Antibacterial activity (MIC, tigAnl): Staphylococcus aureus 209-P 25 (5taph,
aureus) Escherichia coli NIHJ
O,2 (Eacher, coli) Klebsiella pneumoniae EK-60.05CK
leb, pneumonLae) Proteus morgani EP-140,4 (Proteua morgan
ii) Pseudomonas aeruginosa EP-174
0.4 (Pseud, aeruginosa) Serratia marcescens ES-75 < 0.05 (Serom
arcescens ) Proteus vulgaris E-18*0.4 (Proteus vulgaris
us vulgarii ) * β-lactamase producing bacteria Patent applicant Eisai Co., Ltd. 8

Claims (1)

[Claims] 7α-methoxy-37-cephem derivative represented by formula (1) and its non-toxic salt