JPS60181090A - 7-(alpha-(2-amino-4-thiazolyl)-alpha-cyanomethoxyiminoacetamido)-3- substituted-pyridiniomethyl-delta3-cephem-4-carboxylate and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I and its salt. USE:Antibacterial agent against Gram-positive and Gram-negative bacteria, feed additive, and preservative. PREPARATION:The objective compound can be prepared by (1) reacting 7-amino- 3-halogeno-DELTA3-cephem-4-carboxylic acid of formula II (X is halogen) with N,O- bis(tri-lower alkylsilyl)trifluoroacetamide of formula III (R<1> is lower alkyl) and the substituted pyridine of formula IV (R<2> is H or amino-protecting group), (2) reacting the reaction product with the substituted hydroxyiminothiazolylacetic acid of formula V (R<3> is same as R<2>) or its reactive derivative, and (3) removing the protecting group from the product.

Description

Detailed Description of the Invention The present invention provides 7-[α-(2-amino-4-thiazolyl)-α-cyanomethoxyiminoacetamide]-3-substituted pyridiniomethyl-Δ represented by the quintic formula (I). -Cephem-4-carboxylate or its salts and a method for producing the same.

The amine group in the above pyridinio group may be substituted at any position of the pyridinio group.

Compound (I) provided by the present invention has an α-(2-amino-4-thiazolyl)-α-cyanomethoxyiminoacetyl group in the side chain at position 7 of the cephalosporin core,
In addition, it is a new cephalosporin derivative having a chemical structural feature in that it has a pyridinio group in the side chain at the 3-position.

This compound exhibits excellent antibacterial activity as shown in Table 1 below, and is therefore promising as an antibacterial agent. In particular, the compounds of the present invention have been shown to have excellent efficacy against several important pathogenic bacteria belonging to Durham-positive and -negative bacteria.
Pharmaceutical products.

It is particularly useful as an antibacterial agent, feed additive, preservative, etc.

Table 1 (Minimum Inhibitory Concentration, γ/ff1t) The compounds of the present invention are available as such as their salts. Salts include salts with pharmaceutically acceptable non-toxic acids or bases.

Examples of salts with acids include pyridinium salts represented by the general formula (herein, the anion represented by Yo is, for example), rogen anion (C'I
, I, etc.), sulfonic acid anion (ISO4rso4”
etc.) and hihenzenesulfonic acid anions (C,H5So3L, acetate anions (cH3coo
)) y fumarate anion (HOOC-CH:CH
Examples include organic acid anions such as 3COO).
is 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). Examples include salts with organic bases such as salts, ornithine salts, and lysine salts.

The compound of the present invention or a salt thereof is administered orally or parenterally as an antibacterial agent. The dosage varies depending on the symptoms, body weight, etc., but for adults it is 250 to 3,000 r/day.
1 g, which is divided into 3 to 4 doses and administered.

Dosage forms suitable for administration include injections9 tablets, capsules, syrups, etc., but these dosage forms are prepared by adding excipients, preservatives, stabilizers, etc. used in pharmaceutical sciences, and using conventional methods. This can be done by any method.

Next, two aspects of the present invention will be explained in detail.

The production method of the present invention is represented by the general formula 7 (wherein, X means a halogen atom).
-amino-3-halogenomethyl-Δ-cephemu-4-carboxylic acid, N, O-bis(tri-lower alkylsilyl) trifluoroacetamide represented by the general formula (in the formula, R1 means a lower alkyl group) and Formula (in the formula R
2 means a hydrogen atom or a protecting group for an amino group. ) The two reaction products are substituted oxyiminothiazolyl acetic acid represented by the general formula (in the formula, R3 means a hydrogen atom or a protecting group for an amino group) or the reaction thereof. 7-[α-(2-amino-4-thiazolyl) represented by the general formula, which is characterized in that the protecting group is removed if necessary from the two reaction products after the two reaction products are reacted.
-α-cyanomethoxyiminoacetamide]-3-substituted pyridiniomethyl-Δ-cephem-4-carboxylate or salts thereof.

To perform this production method, first, 7-amino-3-halogenomethyl-Δ-cephemu-4-carboxylic acid (II) or its salt, N,O-bis(tri-lower alkylsilyl) trifluoroacetamide (■) and Substituted pyridine (2-
, 3- or 4-aminopyridine (IV) in an organic solvent inert to this reaction. The protecting group for the amine group in the substituted pyridine (IV) used here is not limited as long as it is one commonly used in the synthesis of peptide compounds. Their specific contents are as follows: Compound (V)
This is the same as the protecting group R3 for the amine group in .

N,O-bis(trilower alkylsilyl)trifluoroacetamide (III) and substituted pyridine (IV)
can be reacted with compound (II) simultaneously, or can be reacted in two steps.

This reaction proceeds easily at room temperature. - When reacting in stages, 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.

Next, by reacting the reaction solution containing the compound (A) with substituted oxyiminothiazolyl acetic acid (V) or a reactive derivative thereof, and removing the protecting group from the product,
The target compound (I) is obtained.

Here, as the protecting group R3 for the amine group in compound (V), for example, a tri-lower alkylsilyl group such as a trimethylsilyl group, or a formyl group.

Acetyl group, globionyl group, tert-butoxycarbonyl group, methoxyacetyl group, methoxyglobinyl group, benzyloxycarbonyl group.

Aralkyl groups such as p-nitrobenzyloxycarbonyl group, nato(7)acyl group, benzyl group, benzhydryl group (diphenylmethyl group), trityl group (1-IJ phenylmethyl group), and the like 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 solvents used in the previous reaction, commonly used solvents include dioxane, ether, ethyl methyl ketone, clopform, dichloroethane, methanol, ethanol, ethyl acetate, ethyl formate,
Examples include organic solvents such as dimethylformamide and dimethylsulfoxide. 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 nolides, active amides, acid anhydrides, acid azides, etc. are used, and among these, acid halides and active esters are preferred. In this case, acid chlorides are preferred as acid chlorides.

Suitable active esters include esters with 1-hydroxybenzotriazole. When compound (V) is used in the form of a free carboxylic acid, it is preferable to use a condensing agent such as N,N-dicyclohexylcarbodiimide or N,N-diethylcarbodiimide.

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 two reactions 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 commonly used in the art 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゜(Z)-α-(2-tritylamino-4-thiazolyl)
- 377 mg of α-cyanomethoxyiminoacetic acid was suspended in 4 ml of dichloromethane, and 1661 mg of phosphorus chloride was suspended under water cooling.
Add 11 g and stir for 30 minutes. (Liquid A) On the other hand, 7-amino-3-iodomethyl-Δ3-cephemu 4
- Suspend 340 mg of carboxylic acid in 10 ml of dichloromethane, add 0.5 6 m4 of N,0-bis(trimethylsilyltrifluoroacetamide, and stir at room temperature for 30 minutes to obtain a solution. (Liquid B) Separately, 1 g of 3-aminopyridine is added in dichloromethane Dissolve in 1 ml and add 0.27 mA of N,0-bis(trimethylsilyl)trifluoroacetamide.

Prepare a solution (solution C) that was stirred at room temperature for 5 minutes.

Add this to Solution B and stir at room temperature for 5 hours. Next ((After cooling this reaction solution to -40°C, add 0.32 ml of pyridine.
and -15 over 30 minutes after adding the above solution A to this.
Increase temperature to °C. To this reaction solution were added 2 ml of tetrahydrofuran and 2 mt of IN-hydrochloric acid, and the mixture was stirred for 10 minutes under water cooling. After distilling off the solvent under reduced pressure, 20 ml of water is added to the residue and the precipitate is filtered off.

After washing the precipitate with water and drying it, the crude product 42O with a protecting group was obtained.
Get n1g. To this, 10% trifluoroacetic acid was added under water cooling.
After adding ml and 5 rnl of water, the mixture was stirred at room temperature for 1 hour.

The insoluble material was filtered once, the P solution was dried under reduced pressure, and the remaining residue was powdered by adding 50 mt of ether.
Get rr1g. Suspend this in 50n+t of water, 1
After adding N-hydrochloric acid to adjust the pH to 2 and stirring well, it was subjected to column chromatography using Diaion HP-20 (manufactured by Mitsubishi Kasei).
The fraction containing the target product was concentrated and lyophilized (z+ -7-cα-(2-amino-4-thiazolyl)-α- Cyanomethoxyiminoacetamide]-3-
17111 g of (3-amino-1-pyridiniomethyl)-Δ3-cephemu 4-carboxylate are obtained.

NMR (DMSO-d6) patent applicant Yamanouchi Pharmaceutical Co., Ltd. agent Patent attorney Shozo Nagai

Claims (2)

[Claims] (1) 7-[α-(2-amino-4-thiazolyl) represented by the general formula
-α-cyanomethoxyimino acetamidocou 3-substituted pyridi-omethyl-Δ3-cephem-4-carboxylate or salts thereof. (2) 7 represented by the general formula (wherein, X means a halogen atom)
-Amino-3-halogenomethyl-Δ-cephemu-4-carboxylic acid, N, O-bis(tri-lower alkylsilyl) trifluoroacetamide represented by the general formula (in the formula, R1 means a lower alkyl group), and formulaerNH
Substituted pyridine represented by R'' (in the formula, R2 means a hydrogen atom or a protecting group for an amine group) is reacted with the two reaction products to give a general formula (wherein R3 means a hydrogen atom or a protecting group for an amine group). 7-[α- (2-amino-4-thiazolyl)
-α-cyanomethoxyiminoacetamide]-3-substituted pyridiniomethyl-Δ3-cephem-4-carboxylate or a salt thereof.