JPS6163685A - 7-(alpha-(2-amino-4-thiazolyl)-alpha-(lower alkoxyimino)-acetamido)-3-substituted pyridiniomethel-delta3-cephem-4-carboxylate and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are lower alkyl) and its salt. EXAMPLE:(Z)-7-[alpha-(2-amino-4-thiazolyl)-alpha-methoxyiminoacetamido -]-3-(3-amino-4- methylpyridiniomethyl)-DELTA<3>-cephem-4-carb-o-xylate. USE:Antibacterial agent. PREPARATION:The objective compound can be prepared by (1) reacting 7- amino-3-halogenomethyl-ALPHA<3>-cephem-4-carboxylic acid of formula II (X is halogen) with the N,O-bis(tri-lower alkylsilyl)trifluoro-acetamide of formula III (R<3> is lower alkyl) and the disubstituted pyridine of formula IV (R<4> is H or amino- protecting group), (2) reacting the reaction product with the substituted oxyiminothiazolylacetic acid of formula V or its reactive derivative, and if necessary (3) removing the protecting group from the product.

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field of the Invention) The present invention relates to a cephalosporin type chemical substance or a salt thereof useful as a pharmaceutical having antibacterial activity, and a method for producing the same.

(Solution Means of the Invention) The compound of the present invention is represented by the following formula: 7-[α-(2-
Amino-4-thiazolyl)-α-(lower alkoxyimino)acetamide]-3-substituted hyridiniomethyl-Δeasily-cephem-4-carboxylate or salts thereof.

(In the above formula, + RI and R2 mean a lower alkyl group. The above is the same.) In addition, the production method of the present invention is represented by the general formula (wherein, X means a halogen atom. The same applies hereinafter). 7-amino-3-halogenomethyl-Δ3-
Cephemu-4-carboxylic acid is combined with N,O-bis(tri-lower alkylsilyl) trifluoroacetamide represented by the general formula (wherein R1 means a lower alkyl group. The same applies hereinafter) and the formula (wherein R2 is A lower alkyl group, and R4 means a hydrogen atom or a protecting group for an amino group. 7-[α-(2-Amino-4-thiazolyl)-α-(lower Alkoxyimino)acetamitoco-3
- Substituted pyridiniomethyl-Δ1-cephem-4-carboxylate or a salt thereof.

(Detailed Description of the Invention) In the compound of the above formula, the lower alkyl group meant by R1 and R2 includes a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.

It is a linear or branched alkyl group having 1 to 5 carbon atoms such as a pentyl group.

Furthermore, the two groups (amino group and R2 group) substituting the pyridinio group may be substituted at any position on the pyridine ring.

Compound (I) provided by the present invention has an α-(2-amino-4-thiazolyl)-α-(lower alkoxyimino)acetyl group in the side chain at position 7 of the cephalosporin heptad nucleus, and It is a new cephalosporin derivative with a chemical structural feature in that it has a di-substituted pyridinio group in the side chain at the 3-position.

(Effects and Utilization of Compounds) The compounds of the present invention exhibit excellent antibacterial activity as shown in Table IK below. In particular, the compounds of the present invention can be used as pharmaceuticals, especially antibacterial agents, and as feed additives, since they have been shown to have excellent efficacy against several important pathogenic bacteria belonging to Durham-positive and -negative bacteria.

It is useful as a preservative.

Table 1 (Minimum inhibitory concentration, γ/mt) The compounds of the present invention are available as they are or as their salts. Salts include salts with pharmaceutically acceptable non-toxic acids or bases.

As a salt with an acid, for example, a pyridinium salt represented by the general formula (herein, as a punion represented by Yo, for example, a halogen anion (C1e,
Io, etc.), Skrh nic acid 7 Nio 7 (H8O,”
.

504ee, etc.) and benzenesulfonate anions (C61(5SO3), acetate anions (C
H3COO”), fluoric acid te=, t7
Organic acid anions such as (HOOC-CH:CH2C00e)) are used. Salts with bases include salts at the carboxyl group represented by the general formula (for example, alkali metal salts such as sodium salts and potassium salts; ammonium salts; or dicyclohexylamine salts, cyclohexylamine salts, trimethylamine salts, triethylamine salts, and ethanolamine salts). Salts, salts with organic bases such as ornithine salts and lysine salts can be used.

The compound of the present invention or its salts can be administered orally or parenterally as an antibacterial agent.The dosage varies depending on the symptoms, body weight, etc.
(2), which is administered in 3 to 4 doses.

Suitable dosage forms for administration include injection tablets, capsules, syrups, and the like. These dosage forms are prepared by conventional methods by adding excipients, preservatives, stabilizers, etc. used in pharmaceutical formulation.

(Specific description of the manufacturing method) Compound (I) of the present invention is represented by the general formula 7-amino-4-halogenomethyl-Δ3-
N, O- shown in the general formula of cephemu-4-carboxylic acid
After reacting bis(trilower alkylsilyl) trifluoroacetamide and a substituted pyridine represented by the formula 9 and reacting the reaction product with a substituted oxyiminothiazolyl acetic acid (T) represented by the general formula or a reactive derivative thereof, 1. It can be produced by removing a protecting group from a reaction product, if necessary.

To carry out this production method, first, 7-amino-3-halochenomethyl-Δcosephem-4-carboxylic acid (n) or a salt thereof, N,O-bis(trilower alkylsilyl)trifluoroacetamide (m) and a di-substituted Pyridine (
IV) in an organic solvent inert to this reaction. The protecting group for the amine group in the di-substituted pyridine (IV) used here is not limited as long as it is commonly used in the synthesis of peptide compounds. The specific content thereof is as follows: the protecting group R4 for the amino group in compound (V) described below.
is the same as

Although N,O-his(trilower alkylsilyl)trifluoroacetamide (III) and substituted pyridine (IV) can be simultaneously reacted with compound (II), 9
It is also possible to react in stages.

This reaction proceeds easily at room temperature. When performing a stepwise reaction, perform the former reaction at room temperature.

Different conditions can be employed for each reaction, such as carrying out the latter reaction under cooling.

As the organic solvent inert to this reaction, dichloromethane, acetone, acetonitrile, tetrahydrofuran, etc. are used.

In this way, a compound (A) having a silyl-based protecting group is produced.

COO5i(Rυ.

Next, the reaction solution containing compound (A) is reacted with substituted oximinothiazolylacetic acid (V) or a reactive derivative thereof to obtain a compound represented by formula 9, and the protecting group is removed from this product. By this, the target compound (I) is obtained.

Here, as the protecting group R4 for the amino group in compound (V), for example, a tri-lower alkylinyl group such as a trimethylsilyl group, or a formyl group.

Acetyl group, propionyl group, tert-butoxycarbonyl group, methoxyacetyl group, methoxypropionyl group, benzyloxycarbonyl group.

Aralkyl groups such as p-nitrobenzyloxycarbonyl group, acyl group, benzyl group, benzhydryl group (diphenylmethyl group), )lythyl group (triphenylmethyl group), etc. are used.

The reaction between compound (A) and compound (V) is usually carried out in a solvent under cooling or at room temperature. There are no particular limitations on the solvent as long as it does not participate in the reaction.

In addition to the solvent used in the previous reaction, 1 Examples of commonly used organic solvents include dioxane, ether, ethyl methyl ketone, chloroform, dichloroethane, ethyl acetate, ethyl chloride, dimethylformamide, and dimethyl sulfoxide. Examples include solvents. These solvents can also be used as a mixture as appropriate.

Compound (V) is used in the form of a free carboxylic acid or is subjected to a reaction as a reactive derivative of a carboxylic acid. As reactive derivatives of carboxylic acids, active esters, mixed acid anhydrides, acid halides, active amides, acid anhydrides, acid azides, etc. are used. When compound (V) is used in the form of free carboxylic acid, N,! (-Dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide and the like are preferably used as condensing agents.

Depending on the type of reactive derivative of carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the 9 reaction to proceed smoothly. Examples of such bases include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and organic bases such as trimethylamine, triethylamine, dimethylaniline, and pyridine.

When the protecting group is a tri-lower alkylsilyl group, the protecting group can be easily removed from the product thus obtained by treatment with water. Furthermore, when using an aralkyl group such as a trityl group or various acyl groups, it can be easily carried out by hydrolysis with an acid.

Acids used at this time include formic acid, trifluoroacetic acid,
Hydrochloric acid and the like are preferred.

The salt of the compound of the present invention represented by general formula (I) is:

For example, it can be produced by using the salt of the raw material compound in advance in the above production method, or by applying a salt-forming reaction that is commonly used in modern needles to the free compound produced by the above production method. .

Isolation and purification of the compound (I) of the present invention and its salts are carried out according to conventional methods, including extraction with organic solvents, crystallization, column chromatography, and the like.

Example 1゜ , O.C.R.

1) 680,111 g of 7-amino-3-iodomethyl-Δ3-cephemu-4-carboxylic acid was added to 20 m of dichloromethane.
Add 1.24 ml of N,O-bis(trimethylsilyl)trifluoroacetamide and stir at room temperature for 30 minutes.
Stir for 1 minute to obtain a clear solution. To this solution, add 3-amino-
4-Methylpyridine [Chemical Abstracts Volume 63 1
4805e (1965) reference 216■ was added, stirred at room temperature for 3 hours, and trimethylsilyl 7-drimethylsilylamino-3-(3-amino-4-methylpyridiniomethyl)-Δ3-cephemu 4-carboxylate was added. Obtain a solution containing iodide.

ii) 886,111 g of (Z)-α-(2-tritylamino-4-thiazolyl)-α-methoxyiminoacetic acid was suspended in 20 m of dichlorontough and cooled to -5°C.

Add 416 mg of phosphorus pentachloride and stir at -5 to 0°C for 15 minutes (referred to as liquid A). On the other hand, trimethylsilyl 7-drimethylsilylamino-3-(3-amino-4-methylpyridiniomethyl)-Δ3-cephemu4 obtained in 1)
- After cooling the solution containing carboxylate iodide to -40°C, 0.8 ml of pyridine is added thereto, the above solution A is added thereto, and the temperature is raised to -15°C over 30 minutes.

to this reaction solution.

1N hydrochloric acid 5.4m4. Add 6.7 ml of water and 6.7 ml of tetrahydrofuran, and stir at OoC for 10 minutes. After stirring.

The reaction solution was concentrated under reduced pressure, and 66 ml of water was added to the residue.

Filter the precipitate.

iiD) Cool 20 ml of IJ fluoroacetic acid to 5°C, add the precipitate obtained in step 11) with stirring, add 1 ml of water, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 2 cal of ethanol was added to the residue, followed by 30 ml of ether to form a powder.

Filter to obtain 1.03 g of crude product. Add this to 50ml of water
Add 5 ml of 1N hydrochloric acid to dissolve, remove a small amount of insoluble matter by filtration, and subject the P solution to Diaion HP-200 column chromatography, first mixing water and then water-methanol at a ratio of 75:25. elute by changing gradually until
The fraction containing the target product was concentrated and lyophilized (Z
)-7-[α-(2-amino-4-thiazolyl)-α-
methoxyiminoacetamide)-3-(3-amino-4
-Methylpyridiniomethyl)-Δ3-cephemu 4-carboxylate (200 μl) is obtained.

ONMR (DMSO-d,) δppm: 2.24
3 H,s, -9CHs6.42 2
H, broad s.

6・651H・°・　阜8 7.14 2H, broads.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 mean lower alkyl groups.) 7-[α-(2-amino-4- thiazolyl)
-α-(lower alkoxyimino)acetamide]-3-
Substituted pyridiniomethyl-Δ^3-cephem-4-carboxylate or salts thereof. (2) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, X means a halogen atom.) 7-amino-3-halogenomethyl-Δ^3-
Cephem-4-carboxylic acid has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^3 means a lower alkyl group.) Fluoroacetamide and the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^2 is a lower alkyl group, and R^
4 means a hydrogen atom or a protecting group for an amino group. ) is reacted, and the reaction product has the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a lower alkyl group, and R^4 is a hydrogen atom or amino A general formula characterized by reacting a substituted oxyiminothiazolyl acetic acid or a reactive derivative thereof represented by (meaning a protecting group for a group) and then removing the protecting group from the reaction product as necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 have the above meanings.)
7-[α-(2-amino-4-thiazolyl) represented by
-α-(lower alkoxyimino)acetamide]-3-
A method for producing substituted pyridiniomethyl-Δ^3-cephem-4-carboxylate or salts thereof.