JPS604127A - Antibacterial agent - Google Patents

Abstract

PURPOSE:An antibacterial agent consisting of an L-ascorbic acid derivative, and, if necessary, a salt of a divalent transition metal. CONSTITUTION:An ascorbic acid derivative shown by the formula I (X1-3 is H, 2-21C acyl, polyfluoroacyl, or 7-21C aromatic acyl; at least one of it is not H) is used as an antibacterial agent. The acyl group in the formula I is generally shown by the formula II (R is 1-20C alkyl, polyfluoroalkyl, or 6-20C aryl). The antibacterial activity of the ascorbic acid derivative shown by the formula I is raised by the addition of a divalent transition metal (e.g., copper, iron, Mn, etc.). Especially a copper salt such as CuSO4, Cu(NO3)2, CuCl2, etc. is preferable.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antibacterial agent, and more particularly to an antibacterial agent comprising a trJ, L-ascorbic acid derivative and optionally a salt of a divalent transition metal.

It is known that L-ascorbic acid, ie, vitamin Cfi, exhibits antibacterial activity in the coexistence of divalent transition metal salts.

While conducting research on L-ascorbic acid derivatives, the present inventors discovered that certain derivatives themselves have antibacterial activity.
It has been discovered that the activity is enhanced by the presence of a salt of a divalent transition metal, and the present invention has been completed.

That is, the gist of the present invention is the formula: represents an aromatic acyl group of 7 to 21, at least one of which is not hydrogen.

The acyl group in formula (I) generally has the formula: co-(U) [wherein R represents an alkyl group or polyfluoroalkyl group having 1 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms. ] It is indicated by.

Among the derivatives (I) of the present invention, fluorine-free acyl derivatives include, for example, Pharmaceutical Journal, Vol. 86, No. 5, 376-3.
83 (1966), or produced according to the method described in the same document.

Moreover, polyfluoroacyl derivatives can be easily produced according to the method described in the same document.

For example, the 6-ester can be obtained by reacting L-ascorbic acid with a carboxylic acid represented by the formula: RCOOH (wherein ■ has the same meaning as above) in concentrated sulfuric acid, for example at room temperature. The 6-ester can also be obtained by reacting L-ascorbic acid with the acid chloride of the above acid in a solvent such as dimethylformamide or acetonitrile in the presence of an ion exchange resin.

The 2,6-diester and 2,5,6-) diester are obtained by combining the acid chloride or acid anhydride of the above acid and L-ascorbic acid in the presence of a base (for example, pyridine, picoline or triethylamide). It can be obtained by reacting at room temperature or under water cooling.

The 2-ester is obtained by reacting 5,6-inguropylidene-ascorbic acid with the above acid chloride in the presence of a base such as pyridine.

L-ascorbic acid derivative (I) itself has antibacterial activity, but when a divalent transition metal salt is co-present, the activity may be increased or the antibacterial spectrum may be expanded.

Preferred examples of salts of divalent transition metals include sulfates, nitrates, and norogenoides (e.g., chlorides and bromides) of copper, iron, manganese, zinc, etc. Among them, copper salts,
For example, Cu804, Cu(NO3)2, CuC12,
Particularly preferred are CuBr2 and the like.

When a salt of a divalent transition metal is coexisting, the amount added is as follows:
It can be determined as appropriate depending on the type and concentration of derivative (I), the type of bacteria, etc.

Next, a production example will be shown to illustrate a method for producing an ester containing a polyfluoroacyl group among derivatives (1,).

Production example Ascorbic acid 4.7 g'f:: Acetonitrile 40-
and pyridine 45, and then 242 g of perfluorooctanoic acid chloride was added dropwise while cooling with water. After the dropwise addition was completed, stirring was continued for 10 hours. The solvent was evaporated under reduced pressure, and the candy-like residue was dissolved in a mixed solvent of ether/chloroform (volume ratio 1:2), washed with dilute aqueous hydrochloric acid solution and subsequently with water, and then dried over sodium sulfate. n-
Hexane was added and the precipitated powder was reprecipitated with ether/n-hexane to obtain 13.5 g of 2,6-di(perfluorooctanoyl)ascorbic acid.

Melting point: 162-5°C.

Next, Examples will be shown to explain the antibacterial activity of the derivative (I) of the present invention.

Example 1 The antibacterial activity of the compounds shown in Table 1 was tested in the following manner in combination with bacteria.

The test bacteria were added to 0.02 M) Lis-HCl buffer (pH 7.4).
) at a concentration of 1 to 4 x 107 cells/-, and add the compound solution to this at a concentration of I
They were mixed so that the ratio was x1σ4M. Then C of 1×1σ
The cells were incubated for 60 minutes at 37°C in the presence or absence of u2+. After that, take a portion of the liquid and dilute it (
NaC11g, Mg5O+・7f (20o, 25 g
, 0.03 g of gelatin, and diluted 100 times or more with O,Q 1M phosphate buffer (pH 7,0) 11) to stop the reaction.

The antibacterial activity of the compound was evaluated by counting the number of colonies before and after the reaction using a conventional method, and calculating the residual rate of bacteria. Note that I x 10'M Cu2+ alone had no antibacterial activity.

The results are shown in Table 1.

In the table, the bacterial abbreviations indicate the following bacteria: B: Escherichia coli BS 1
: Lactobacillus casei 81
101: Escherichia coli NI
J JC-2102: Proteus vulgar
is IFO3988103: Proteus mo
rganii IFO3168106: Salmon
ella typhimurium LT-2110:
Micrococcus flavus IFO32
421l: 5taphylococcus a
ureus FAO209P Example 2 Eschr of various compounds was determined by the same procedure as in Example 1.
ichia coli, B (B) and Lacto
The antibacterial properties in the presence of Cu'' (I x 10'M) against Bacillus casei 81 (81) were investigated. The results are shown in Table 2.

Table 2 Table 2 (Continued) Procedural amendment (, 2) October 19, 1988 Patent application No. 112331) No. 2 Name of invention Antibacterial agent 3 Relationship with the person making the amendment Case Patent applicant Address: Osakayama I, Osaka Prefecture (1st ward, 7! if l'j
'(l i-2, il,'')Ol)rlJ, <Keep hill name phaseゝ (285) Gui'! ”':l:leaf:゛1
Shikikai Reiyu Representative Yama [11 Minoru 4, Agent 7, I am making the following amendments to the detailed explanation of the invention in the statement of contents of the amendment.

(1) = 4 lines from the bottom of page 1, after “triethylamide”, “
Insert ".

(2) Three lines from the bottom of page 7, [NIJJ is
Corrected with J.J.

(3) Page 9, Table 1, bottom row of the column “Compound (I)”, “X1
=X =Ci-J COJ [Xl-X3=C7F1
5CO” 3 7 15 corrected.

+4110 page 3 line, “Eschricbia J [
Corrected with Escherichia J.

North of

Claims (1)

[Scope of Claims] X20- Cl-1 H2OX3 [In the formula, X, , X2 and Represents an aromatic acyl group, at least one of which is not hydrogen. ] Antibacterial AIL2 consisting of an ascorbic acid derivative shown by
The antibacterial agent according to claim 1, further comprising a salt of a divalent transition metal. 3. The antibacterial agent according to claim 2, wherein the divalent transition metal is copper, iron, manganese or zinc. 4. The antibacterial agent according to claim 3, wherein the divalent transition metal is copper. The salts of 5 divalent transition metals are Cu5O1, CuCl2, C
The antibacterial agent according to claim 4, which is uBr2 or Cu(NO3)2.