JPS5854157B2 - New derivatives of cephalosporin compounds and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporin derivatives represented by the general formula or salts thereof and methods for producing them.

In the compound of the above general formula, A is a group represented by the formula (wherein R2 means a lower alkyl group which may have a hydroxyl group as a substituent) or a formula (wherein 3 and R4 are the same - Alternatively, R5 is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a cyano group, a carboxy group, a carbamoyl group which may have a lower alkyl group as a substituent, or a bond; means an atom or a bond.

However, R3 does not mean a bond, and R4 and R5 mean different substituents), and R1 means a hydrogen atom or a lower alkyl group.

Therefore, the following can be cited as representative examples of A.

4-cyano-3-hydroxy-5-inchazolyl group,
3-hydroxy-4-phenyl-5-isothiazolyl group, 3-amino-4-cyano-5-isothiazolyl group, 4
-cyano-3-methoxy5-isothiazolyl group, 3-hydroxy-4-dimethylaminocarbonyl-5-inchazolyl group, 3-hydroxy-5-inchazolyl group,
4-carbamoyl-3-hydroxy-5-inchazolyl group, 3-hydroxy-4-hydroxymethyl 5-inchazolyl group, 4-carboxy-3-hydroxy-5-
Inthiazolyl group, 4-cyano-3-methylthio-5-inchazolyl group, 4-cyano-2-methyl-3-oxo-2,3-dihydro-5-isothiazolyl group, 4-cyano-2-hydroxyethyl-3-oxo -2,3-dihydro-5-isothiazolyl group, 3-hydroxy-4hydrazinocarbonyl-5-inchazolyl group, 4-aminomethyl-3-hydroxy-5-isothiazolyl group, '41
0-rho 3-hydroxy-5 isothiazolyl group.

Among the inthiazolyl groups represented by A, those having a hydroxyl group at the 31-position include keto-enol isomers represented by the following formula, and the present invention includes both of these.

Next, the salts of the compound represented by the above general formula (I) include pharmaceutically acceptable non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, ammonium salts, dicyclohexylamine salts, cyclohexylamine salts, etc. Examples include salts with organic bases such as amine salts, trimethylamine salts, triethylamine salts, ethanolamine salts, ornithine salts, and lysine salts.

Cephalosporin derivatives (I) provided by the present invention
) or its salts are new compounds that have antibacterial activity against both Gram-positive and Gram-negative bacteria, and are especially effective against the latter, so they are used as pharmaceuticals, feed additives, and preservatives for foods and chemical industrial products. Useful.

Now, its antibacterial activity (minimum effective inhibitory concentration) is determined by cefazolin (chemical name: nia-(α(IH-tetrazol-1-yl)acetamide) 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl -Δ3-cephemu-4carboxylic acid (abbreviated as CEZ in Table 2) is as follows.

Among the compounds of the present invention, for example, the compounds of Examples 9, 10 and 11 further exhibit excellent antibacterial activity against the following various microorganisms.

As described above, the compounds provided by the present invention have excellent antibacterial activity against a wide range of pathogenic bacteria.

These compounds are administered orally or parenterally;
The dosage for adults is usually about 250 to 300 doses per day, divided into 3 to 4 doses.

However, the dosage should be adjusted as appropriate depending on age, symptoms, and body weight, and a higher dose may be administered if necessary.

According to the present invention, the compound represented by the general formula (I) can be produced by the following method.

First method: The reaction formula for this method is as follows.

(In the formula, X means a halogen atom.

Moreover, A and R1 have the above-mentioned meanings.

) The reaction for producing the object compound (I) of the present invention by the first method is an alkali metal salt of mercaptoisothiazole which may have a substituent on the 7-valoacetamidosephalosporin derivative (II-a) or a salt thereof. This is done by activating the

The reaction is usually carried out in a solvent.

The solvent is not particularly limited as long as it does not participate in the reaction; for example, water, methanol, acetone, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof may be used.

The reaction is also preferably carried out at room temperature or under cooling in the presence of a base.

The compound of (I[I-a) can usually be used as an alkali metal salt of the mercapto group of mercaptoisothiazole, but it can be used as is.* When it is used as a base, for example, triethylamine, N/N-dimethylaniline, N
- aliphatic, aromatic or heterocyclic bases such as ethylmorpholine, pyridine, collidine, 2,6-lutidine or sodium carbonate, potassium carbonate, sodium bicarbonate,
It is carried out in the presence of an alkali metal carbonate or bicarbonate such as potassium bicarbonate.

Examples of the halogen atom for X in the 7-valoacetamidosephalosporin derivative (I[-a) include a chlorine atom, a bromine atom, and a fluorine atom.

The ratio of compounds (II-4) and (III-a) used in this reaction is
a) 1 to 2 mol is suitable.

Isolation of the product from the reaction solution is carried out by conventional methods, such as separation by chromatography or extraction with a solvent.

Second method: This method is shown by the following reaction formula.

(In the formula, R6 means a hydrogen atom or a protecting group for a carboxy group.

Moreover, A and R1 have the above-mentioned meanings.

) The reaction for producing the object compound (I) of the present invention by the second method is a reaction involving a 7β-aminocephalosporin derivative (I
I-b) or a salt thereof is reacted with isothiazolylthioacetic acid (III-b) having a substituent or a reactive derivative thereof at the carboxy group to prepare a compound represented by formula (■), and R6 of the compound is When is a protecting group for a carboxy group, this is then removed.

The reaction between the above compound (n-b) and (I[I-b) is usually carried out in a solvent.

Preferred solvents include acetone, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, ethyl acetate, ethyl formate, and the like.

These solvents can be used alone or in combination,
Water-soluble ones can also be used by mixing with water.

i* Preferred reactive derivatives of the carboxyl group of thioacetic acid in compound (III-b) include acid halides, mixed acid anhydrides, active esters, active amides, acid anhydrides, acid azides, and the like.

When compound (m-b) is used in a free state, a condensing agent may be used.

Suitable condensing agents include N-N'-dicyclohexylcarbodiimide and N-N'-diethylcarbodiimide.

The 7β-acylaminocephalosporin derivative (IV) produced in this reaction is isolated from the reaction solution by a conventional method and, if necessary, purified by chromatography or the like.

Further, when the carboxy group of the 7β-acylaminocephalosporin derivative (■) thus obtained is protected, it can be removed by a conventional method to lead to the target compound (I).

Third method: The object compound (I) of the present invention can also be produced by the reaction of the following formula.

(In the formula, R7 represents an acetyl group or a carbamoyl group.

Moreover, A and R have the above-mentioned meanings. ) This method is 7
β-acylamide-cephalosporin derivative (n-c)
Or its salts include 1-methyl-IH-tetrazole-
This is carried out by reacting 5-thiol or its mercapto group with alkaline earth substitution on hydrogen.

The reaction is carried out at room temperature to elevated temperature, usually in a solvent.

Solvents that do not participate in the reaction include acetone, dimethylformamide, methanol, ethanol, water, and phosphate buffer, and these may be used in combination if necessary.

This reaction is preferably carried out near neutrality.

1-Methyl-1H-tetrazole-5- as starting material
When using thiol in its free state, alkali hydroxide,
It is preferable to carry out the reaction in the presence of a base such as an alkali carbonate, an alkali hydrogen carbonate, a trialkylamine, pyridine, or dimethylaniline.

To isolate the product after the reaction is completed, the reaction solution is made acidic and the precipitated product is collected, or solvent extraction is used.

A typical target compound of the present invention obtained by the above method is 7β-(4-cyano-3-hydroxyisothiazole-
5-yl)thioacetamide-7α-methoxy-3-(
1-methyltetrazol-5-yl)thiomethyl-Δ3
-Cephemu 4-carboxylic acid 7β-(3-hydroxyisothiazol-5yl)thioacetamide-7α-methoxy-3(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu4-
Carboxylic acid 7β-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamide-7α-methoxy-3
-(1-methyltetrazol-5-yl)thiomethyl-
△3-cephemu-4-carboxylic acid
*(DL-7β-[α-(4-cyano-3-hydroxyisothiazol-5-ylthio)propionamide]-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4
-Carboxylic acids These compounds can be converted into their non-toxic salts by conventional methods.

A commonly used method is, for example, by adding an n-butanol solution of alkali metal 2-ethylhexanoate to these compounds, and then adding an organic solvent with different solubility such as ether or ethyl acetate. Alkali metal salts of compounds, also dicyclohexylamine,
By adding and reacting an organic base such as triethylamine, cyclohexylamine, trimethylamine, arginine, lysine, ornithine, jetanolamine, etc. in an equal amount to a small excess amount, the present invention can add the organic base of the target compound and further add aqueous ammonia. There is a method to obtain ammonium salt.

Next, the manufacturing method of the present invention will be specifically explained with reference to Examples.

Although most of the isothiazole derivatives used as raw materials in the following examples are compounds not described in literature, they are used in the production of 4-cyano-3-hydroxy-5-mercaptoisothiazole, which is a known inthiazole derivative. Method (W,
R.

Hatchard et al., J. Org. Chem.
(28), 2164), or by further processing the thus obtained isothiazole derivative by a conventional method.

Example 1 123 ml of disodium salt of 3-hydroxy-5-mercaptoisothiazole was dissolved in 5 ml of methanol, and 7β-bromoacetamide-7α-methoxy-3-(1-methyltetrazole-5- A solution of 250 μl of 3-cephemu-4-carboxylic acid dissolved in 4M methanol was added dropwise, and the mixture was allowed to return to room temperature and stirred for 2 hours.

After the reaction is completed, the reaction solvent is distilled off under reduced pressure, a small amount of water is added, and the pH is adjusted to 1 with 5% hydrochloric acid.

Extract with a mixture of n-butano-ethyl acetate (volume ratio 1:1), and the organic layer is washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixture of chloroform-methanol-formic acid (volume ratio 80:20:3) to obtain 7β.
-(3-Hydroxythiazol-5-yl)thioacetamide-7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ -cephem-4-carboxylic acid 153 µ is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (ppm
); 3.38 (3H), 3.60 (2H) 3.9
0 (3H), 3.94 (3H) 4.30 (2H), 5.10 (IH) 6.61 (LH), Example 2 Disodium of 4-cyano-3-hydroxy-5-mercaptoisothiazole 140cm of salt and 6m of tanol
A solution of 250 μl of 7β-bromoacetamido-7α-methoxy-3(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid dissolved in 4 ml of methanol was added to this solution under water cooling. was added dropwise, and the mixture was allowed to return to room temperature and stirred for 2 hours.

After completion of the reaction, the same operation as in Example 1 was performed to obtain 7β(4-cyano-3-hydroxyisothiazol-5-yl)thioacetamide-7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3 -Cephemu 4-carboxylic acid 1601v is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (ppm)
; 3.39 (3H), 3.59 (2H) 3.92
(3H), 4.11 (2H) 4.28 (2H), 5.10 (IH) According to Example 2 above, the following compounds were synthesized.

The obtained compound is shown together with its physicochemical properties.

Example 9 270 W1f/4-carboxy-5ethylthio-3-hydroxyisothiazole was suspended in 10 ml of liquid ammonia, cooled to -50'C, and 100 ml of sodium metal was suspended in 10 ml of liquid ammonia.
Add (2) and stir at -50 to -33°C for 30 minutes.

Liquid ammonia was distilled off, and the resulting residue was dissolved in 20rrLl of methanol, and 7β-bromoacetamido-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carvone was dissolved under water cooling. Add 10 TfLl of acid 600 instant methanol solution dropwise,
Stir for another 30 minutes under water cooling, then return to room temperature for 30 minutes.
Stir for a minute.

After the reaction is completed, the pH is adjusted to 4 with 4N hydrochloric acid, and the reaction solvent is distilled off under reduced pressure.

Water was added to the residue, the pH was adjusted to 1 with 4N hydrochloric acid, and 50ml of a mixture of butanol and ethyl acetate (volume ratio 1:1) was added.
Extract with 1.

The organic layer was washed twice with water, then saturated with chloride with >*). After washing once with an aqueous solution of IJum, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

Add 30ml of ether to the residue, filter the precipitate, wash with 20ml each of ether three times, and dry under reduced pressure.
β-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamide 7α-methoxy-3-(
1-methyltetrazol-5-yl)thiomethyl-△3
- 560 ml of powder of cephemu-4-carboxylic acid are obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (ppm
); 3.41 (3H), 3.58 (2H) 3.9
3 (3H), 3.99 (2H) 4.28 (2H), 5.10 (IH) According to Example 10 above, the following compounds were synthesized.

The obtained compound is shown together with its physicochemical properties.

Example 12 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4
300 ml of -carboxylic acid benzhydryl ester are dissolved in 7yrLl of methylene chloride, cooled to -3Q DEG C. and 460 ml of pyridine are added.

Then, (4-cyano-3-methoxyinthiazole-
5-yl) Potassium thioacetate (240 μ) to methylene chloride (1)
Oxalyl chloride 170r suspended in 01rLl
rI9, an acid chloride solution prepared from dimethylformamide drops was added dropwise at -30°C to -20°C, and after stirring at the same temperature for 1 hour, 30ml of chloroform was added, and the solution was diluted twice with 2% hydrochloric acid and then with saturated sodium chloride water. After washing twice, the organic layer is dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform-impropatol (volume ratio 10:1) to obtain 7β-
(4-cyano-3-methoxyisothiazol-5-yl)thioacetamide-7α-methoxy-3-(1methyltetrazol-5-yl)thiomethyl-8*Δ3-cephem-4-carboxylic acid benzhydryl ester 190 ■
get.

Dissolve 170 ml of this material in 2 ml of methylene chloride, and add anisole trifluoroacetate mixture at 1.6 mA! (Capacity ratio 3
:1) is added dropwise at -15 to -5°C.

After stirring at the same temperature for 40 minutes, the solvent was distilled off under reduced pressure, and the resulting residue contained 10 ml of ether! Add and stir for 20 minutes.

Next, the precipitate obtained by filtration under reduced pressure was thoroughly washed with ether and dried under reduced pressure to obtain 7β-(4-cyano-3-methoxyinthiazol-5-yl)thioacetamide-7α-.
Methoxy-3-(1-methyltetrazol-5-yl)
Thiomethyl-△3-cephemu-4-carboxylic acid powder 1
Get 20 ■.

Nuclear magnetic resonance spectrum (D, -DMSO) δ (ppm)
: 3-40 (3H), 3.58 (2H) 3.92
(3H), 3.99 (3H) 4.15 (2H), 4.18 (2H) 5.12 (IH) The following compounds were synthesized according to Example 13 above.

The obtained compound is shown together with its physicochemical properties.

Claims (1)

[Claims] The group or arm represented by the general formula 1 (meaning a lower alkyl group which may have a hydroxyl group as a substituent) is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a cyano group, a carboxy group, a carbamoyl group which may have a lower alkyl group as a substituent, or a bond, and R5 means a hydrogen atom or a bond. However, R3 does not mean a bond, and R4 and R5 mean different substituents), and R1 means a hydrogen atom or a lower alkyl group. cephalosporin derivative. 2 A is 4-cyano-3-hydroxyisothiazole-
The compound according to claim 1, which is a 5-yl group. 3. The compound according to claim 1, wherein A is 3-hydroxyisothiazol-4-yl group. 4. The compound according to claim 1, wherein A is 4-carboxy-3-hydroxyisothiazol-5-yl group. 5 Compounds represented by the general formula (wherein, X represents a halogen atom and represents a lower alkyl group) and the general formula (% represents a lower alkyl group which may have a hydroxyl group as a substituent) A group or formula represented by *Differently, a hydrogen atom, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amine group, a cyano group, a carboxy group, a carbamoyl group which may have a lower alkyl group as a substituent, or R5 means a hydrogen atom or a bond. However, R3 does not mean a bond, and R4 and R5 mean different substituents. A method for producing a novel cephalosporin derivative represented by the general formula (wherein A and R1 have the above-mentioned meanings), the method comprising reacting the compound represented by the above formula. 6 Claim 5, characterized in that X in the compound represented by general formula (II-a) is a bromine atom
Manufacturing method described in section. 7 A compound represented by the general formula (in the formula, R6 means a hydrogen atom or a protecting group for a carboxy group) and a lower alkyl group which may have a hydroxyl group as a substituent of the general formula) group or formula (in the formula, R3 and R4 are the same or *different and have a hydrogen atom, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, an amino group, a cyano group, a carboxy group, or a lower alkyl group as a substituent) R5 means a hydrogen atom or a bond. However, R3 does not mean a bond (and R4 and R5 mean mutually different substituents. ), R1 means a hydrogen atom or a lower alkyl group] or a reactive derivative of its carboxy group is reacted with the general formula (wherein A, R' and R6 are A compound represented by the general formula (wherein A and R1 have the above meanings) is obtained by removing R6 when it is a protected *protecting group for a carboxy group. 8. A method for producing a novel cephalosporin derivative represented by the general formula (n-b). 8. A method for producing a novel cephalosporin derivative represented by the general formula (n-b), wherein R6 is a benzhydryl group.
8. The method according to claim 7, wherein the reactive derivative of the carboxy group in the compound m-b) is an acid halide or a mixed acid anhydride.