JPS5911595B2 - New cephalosporin derivatives - Google Patents

Description

Detailed Description of the Invention *Ho□s-CH2Coj [In the formula, B means an acetoxy group or a formula -S-R1 (wherein R1 means a thiadiazolyl group or a tetrazolyl group which may be substituted with a lower alkyl group).

), the present invention has the general formula (I)-□CH.

-B(I) 35 means a heterocycle thio group.

The present invention relates to novel cephalosporin derivatives, salts thereof, and methods for producing the same.

In the compound (I) of the present invention, the lower alkyl group that each of the thiadiazolyl group or tetrazolyl group represented by B may have is specifically a methyl group,
These include ethyl group, propyl group, isopropylene group, etc.

Furthermore, examples of non-toxic salts of the compound (I) of the present invention include alkali metal salts, ammonium salts, and salts with bases such as triethylamine and synchlohexylamine.

Examples of the novel cephalosporin derivatives of the present invention include the following.

(1) 7-(6-hydroxy-3-pyridyl)thioacetamidocephalosporanic acid (47-(2-hydroxy-4-pyridyl)thioacetamidocephalosporanic acid (3) 7-(6-hydroxy-3- pyridyl)thioacetamide-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid (4) 7-(2-hydroxy-4-pyridyl)thioacetamide-3-(1-methyl Tetrazol-5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid According to the present invention, novel cephalosporin derivatives (
l) To obtain the general formula () [wherein X means a halogen atom and B is the same as above.

The same applies hereinafter] and the general formula () [In the formula, A means a hydrogen atom or a group represented by the formula D-S-.

A method of reacting a compound represented by [the same applies hereinafter] in the presence of a base (hereinafter abbreviated as the first method).

) and the compound (1) of the present invention has the general formula (I)' (wherein R1
is the same as above), a cephalosporanic acid derivative represented by the general formula (IV) and a general formula (V)
[In the formula, M means a hydrogen atom or an alkali metal, and R1 is the same as above.

The same applies hereinafter] (hereinafter abbreviated as the second method).

). The first method of the present invention described above is carried out as follows.

That is, compound () and compound () are reacted in the presence of a base, usually under cooling or at room temperature, in an organic solvent that does not participate in the reaction, water, or a mixture thereof.

The bases used include aliphatic, aromatic or heterocyclic nitrogen bases or alkali metal carbonate or bicarbonate salts, such as triethylamine, N-N-dimethylaniline, N-ethylmorpholine, pyridine, colicin, 2,6-lutidine, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, and the like are used. Examples of the halogen atom of X in the compound () include a chlorine atom, a bromine atom, a fluorine atom, and the like. The amount of compound () to be used is equimolar to excess molar relative to compound (), but preferably about 1 to 2 times the molar amount. Specifically, organic solvents that do not participate in the reaction include methanol, chloroform, methylene chloride, ethylene chloride, acetone,
Examples include tetrahydrofuran, dimethylformamide, and the like. The second method of the present invention is carried out as follows.

That is, compound () and compound () are reacted.

This reaction is preferably carried out near neutrality, and is reacted with equimolar to excess molar amount of compound () relative to compound ().
The alkali metal of M in compound (V) is sodium;
Examples include potassium. In addition, when using a compound in which M is a hydrogen atom in the compound (), in the presence of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, and a base such as trialkylamine, pyridine, dimethylaniline, etc. It is preferable to do so. The reaction is usually carried out in an organic solvent that does not participate in the reaction, such as acetone, dimethylformamide, methanol, or ethanol, or in water or a mixture thereof, or in a phosphate buffer at room temperature or under heating. The compound (1) of the present invention has the general formula () (in the formula R
2 means a protecting group for a carboxy group, and is the same as above.

The same applies hereinafter) and the compound represented by the formula (B) or a reactive derivative of its carboxy group by an equal mole to an excess mole, preferably twice the mole, are reacted in an organic solvent that does not participate in the reaction, preferably in the presence of a base. , if the product has a protecting group R2, it can also be obtained by removing it.

The compound of the present invention thus obtained can be converted into a pharmaceutically acceptable non-toxic salt.

To form a salt, it is sufficient to follow a commonly used method, for example, by adding a solution of alkali metal 2-ethylhexanoate in n-butanol, and then adding an organic solvent with a different solubility such as ether or ethyl acetate. Compound (1
) by adding and reacting the alkali metal salt of the present invention with an organic base such as synchlohexylamine, triethylamine, cyclohexylamine, trimethylamine, etc. in an equivalent amount or in a slight excess, and by adding aqueous ammonia. Ammonium salts of the compounds of the present invention can be obtained. The compound (1) of the present invention or its salt may be isolated and purified by conventional methods.

The compound (1) of the present invention produced in this manner is an antibiotic having excellent antibacterial activity against both Gram-positive and Gram-negative bacteria and is useful as a medicine.

The antibacterial activity (minimum effective inhibitory concentration) of the compound (1) of the present invention is as follows: A comparison is shown with thiadiazol-2-yl)-thiomethyl-Δ3-cephem-4-carboxylic acid (generic name: cefazolin).

Therefore, the compound (1) of the present invention can be used orally or parenterally as a therapeutic agent for bacterial infections in humans and animals caused by these bacteria and other bacteria that exhibit the virulence of the compound of the present invention, specifically, injections, It is administered in various dosage forms such as tablets, liquids, and external preparations. These preparations can be manufactured by conventional methods. Example 1 170 η of bis(6-hydroxy-3-pyridino(he)disulfide, 1.2 ml of 1N sodium hydroxide and 5 ml of water were mixed together, 60 η of sodium borohydride was added while stirring under ice cooling, and the mixture was heated to room temperature. Stir for 4 hours.

This solution was combined with 450 η of 7-promoacetamidocephalosporanic acid, 90 mg of sodium bicarbonate and 10 d of water.
was added to the mixed solution while stirring under ice cooling, and then a 0.1 N phosphoric acid aqueous solution was immediately added dropwise to adjust the pH to 7.
Adjust to 5. After stirring this solution at room temperature for 1.5 hours, a 0.1N aqueous solution was added to adjust the pH to 2. 50ml each of a mixture of O and n-butanol-monoethyl acetate (volume ratio 1:1)
Extract 3 times. The extracts were combined, washed twice with water, then twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium marrow acid, and the solvent was distilled off under reduced pressure to give 7-(6-hydroxy-3-pyridyl)thio. Acetamide cephalosporanic acid 360T! Get 9. Nuclear magnetic resonance spectrum (
D6-DMSO) δ (P.p.m.): 2.02 (Sl3H), 3.20-3.70 (Ml4H
), 4.72-5.20 (Ml3H), 5.50 (Ql
lH), 6.30 (DllH), 7.48 (Ml2H)
Example 2 7-(6-hydroxy-3-pyridyl)thioacetamidocephalosporanic acid 330-, 5-mercapto-1-
Methyltetrazole 115w, sodium bicarbonate 14
5η and 15 m2 of pH6.86 phosphate buffer were mixed, stirred at 60°C for 12 hours, and filtered.

The P solution was made acidic with 3 ml of 3.5% hydrochloric acid, and the precipitate was washed away.
The filtrate is extracted with 50 ml of a mixture of n-butanol and ethyl acetate (1:1 by volume) and then with 40 ml. The extracts were combined and washed twice with water, then washed twice with a saturated aqueous sodium chloride solution,
Dry over anhydrous magnesium sulfate, and remove the solvent under reduced pressure.
The obtained residue was subjected to silica gel column chromatography and developed using a solution prepared by sequentially adding methanol to a mixture of chloroform-isopropanol-formic acid (volume ratio 90:10:3) as an eluent.

Fractions containing the target compound were collected and the solvent was distilled off to obtain 7-(6-hydroxy-3-biridyl)thioacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid. Obtain 90TI19. Nuclear magnetic resonance spectrum (D6-DMSO) δ(P
．． p. m. ); 3.44 (s, 2H), 3.68 (Ql2H), 3.9
4 (Sl3H), 4.32 (m, 2H), 5.08 (D
llH), 5.64 (QllH), 6.30 (d, 1H
), 7.50 (Ml2H) Example 37-promoacetamidocephalosporanic acid 160η, 2-hydroxy-
100 W of 4-mercaptopyridine, 5 ml of pH 6.86 phosphate buffer, 105 η of sodium bicarbonate and 15 Tn of methanol are mixed and stirred at room temperature for 5 hours.

Methanol in the reaction solution was distilled off, and then sodium hydrogen carbonate was added to adjust the pH to 9, followed by filtration. 1.5% in P solution
Add hydrochloric acid to make it acidic. -Ptanoichi, L. Extract twice with 25 ml each of a mixture of ethyl monoacetate (1:1 by volume). The extracts were combined and washed twice with water, then twice with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting powdery residue was decanted with ethyl acetate and then ether to give 7-(2-hydroxy-
4-pyridyl)thioacetamidocephalosporanic acid 7
8η is obtained. Nuclear magnetic resonance spectrum (D6-DMSO)
δ (P.p.m.): 2.02 (s, 3H), 3.52 (q, 2H), 3.8
0 (Sl2H), 4.62-5.14 (Ml3H), 5
．． 66 (QllH), 6.08 (DllH), 6.12
(m, 2H), 6.20 (s, 1H), 7.22 (Dl
lH) Example 4 7-bromoacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid 113TI19, 2-hydroxy-4-mercaptopyridine 40W9, sodium hydrogen carbonate 46TI9,
Mix 10 ml of methanol and 5 ml of water, and stir at room temperature.
Stir the time.

After distilling off methanol, add sodium hydrogen carbonate to pH 9.
After adjusting to
n-butanol-ethyl acetate (volume ratio 1:1) mixture 60
Extract with WLt. The extracts were combined, washed with saturated aqueous sodium chloride solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 7-(2-hydroxy-4-pyridyl)thioacetamide.
100 mf of 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephem-4-carboxylic acid? Ru.
Nuclear magnetic resonance spectrum (D6-DMSO) δ (P.p.
m. ); 3.68 (q, 2H), 3.80 (s, 2H), 3.9
2 (s, 3H), 4.28 (Ql2H), 5.04 (D
llH), 5,66 (QllH), 6.04 (DllH
), 6.14 (SllH), 7.20 (DllH) Example 5 7-bromoacetamido-3-(5-methyl-1.3.
Mix 1.63 f7 of 4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid, 0.457 of 2-hydroxy-4-mercaptopyridine, 50 mj of water, and 1001.1111 of methanol, and stir on an ice bath. After further adding 0.59 V of sodium hydrogen carbonate, the mixture was stirred at room temperature for 2 hours.

Methanol was distilled off under reduced pressure, the mixture was filtered, acidified with dilute hydrochloric acid, and then extracted with 200 ml of a mixture of n-butanol and ethyl acetate (volume ratio 1:1).

The extract is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. A lot of precipitated crystals were collected, washed with ethyl acetate, and dried to give 7-(2-hydroxy-4-pyridyl)thioacetamide-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl. 1.23 V of -Δ3-cephem-4-carboxylic acid is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (P.p.
m. ); 2.68 (Sl3H), 3.66 (Ql2H), 3.8
4 (Sl2H), 4.36 (Ql2H), 5.08 (d
, 1H), 5. ．． 62 (q, 1H), 6.14 (Dll
H), 6.24 (SllH), 7.28 (DllH)

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, B is an acetoxy group or the formula -S-R^1 (in the formula R^
1 means a theadiazolyl group or a tetrazolyl group which may be substituted with a lower alkyl group. ) means a heterocycle thio group. ] A novel cephalosporin derivative or a salt thereof. 2
The compound according to claim 1, wherein B is a 1-methyltetrazol-5-yl group.