JPH0684310B2 - Anti-infective agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a medicine, and more particularly to a drug for protecting an organism from infection by enhancing the in vivo defense function.

[Conventional technology]

At present, infectious diseases are becoming a serious problem due to an increase in complex infectious diseases accompanied by various serious underlying diseases in addition to simple infectious diseases caused by invasion of simple pathogenic bacteria. For example, in the treatment of malignant tumors such as leukemia, although the cure rate has been improved by chemotherapy and radioactive irradiation, there have been reported cases of death due to so-called opportunistic infections. This is due to a decrease in the immune system of the living body due to the growth of tumors,
Treatment of such infectious diseases in cachexia patients is not possible with conventional chemotherapeutic agents alone, which is a major social problem.

On the other hand, substances having an acyl peptide structure have been extensively studied as antibacterial agents and immunostimulants. For example, D
-Lactoyl-L-alanyl-γ-D-glutamyl-L
-Mesodiaminopiperyl-L-glycine (FK-156) and heptanoyl-γ-D-glutamyl-L-mesodiaminopiperyl-L-glycine (FK-565) are known to have immunostimulatory action. (The Journal of Antibioti
cs, 36 (8), 1045 (1983); ibid.36 (8), 1051 (1983)
And 36 (8), 1059 (1983)].

[Problems to be solved by the invention]

However, effective drugs against these opportunistic infections and complicated infectious diseases have not yet been found, and their development has been desired.

[Means for solving problems]

The present inventors focused on the acyl tripeptide structure excluding the cyclic peptide portion of colistin and polymyxin which are peptide antibiotics, decomposed and separated them by an enzymatic reaction, and conducted research on these actions. ,
The inventors have found that this acyltripeptide exhibits an excellent antifungal effect against infectious diseases, and completed the present invention.

That is, the present invention provides the following general formula (I) The present invention provides an infection control agent comprising, as an active ingredient, an acyl tripeptide represented by the formula (wherein R represents a methyl group or an ethyl group) or a pharmaceutically acceptable salt thereof.

The acyl tripeptide of the general formula (I), which is an active ingredient of the anti-infective agent of the present invention, is a known compound, in which colistin or polymyxin B is dissolved in a solvent such as water, and a hydrolase such as nagase or colistinase is dissolved therein. It is produced by adding oxygen to the mixture [The Journal of Antib
iotics, Vol.33, No.12, 1551-1555 (1980)].

Since these degrading enzymes have the highest activity around pH 9, it is preferable to carry out the reaction near pH 9 using 0.01 M borate buffer as a solvent. The reaction is completed after 3 hours at 37 ° C. After the reaction, the pH is adjusted to around 4 and the reaction is stopped to carry out the following isolation and purification operation as soon as possible. For example, in order to isolate the acyl tripeptide using colistin, the following procedure may be performed, that is, butanol extraction from the reaction solution is repeated three times, the butanol layer is concentrated, and microbead silica gel (100 -200 mesh)
Chromatograph using. 0.1M for eluate
Use ethanolamine phosphate buffer 50% methanol solution
Two peaks are obtained using the absorbance at 230 nm as an index. The pre-eluted portion is isooctanoyl-L-2 derived from colistin B,
4-diaminobutyryl-L-threonyl-L-2,4-diaminobutyric acid (IOA-DAB-Thr-DAB) [wherein R is a methyl group in the formula (I)] and the post-eluting portion is 6-derived from colistin A. Methyloctanoyl-L-2,4-diaminobutyryl-L-threonyl-L-2,4-diaminobutyric acid (MOA-DAB-Thr-DAB)
[Wherein R is a methyl group]. These fractions are further subjected to gel filtration with Sephadex LH20 to obtain each purified colistin acyl tripeptide. If the same operation as described above is performed on polymyxin B, MOA-DAB-Thr-DAB derived from polymyxin B ₁ and IOA-DAB-Thr-DAB derived from B ₂ can be obtained.

MOA-DAB-Thr-DAB and IOA-DAB-Thr-DAB thus obtained
Table 1 shows the physicochemical properties of.

The pharmaceutically acceptable salts of these acyl tripeptides include, for example, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, ethanolamine salts, triethylamine salts, dicyclohexylamine salts, and other organic or inorganic salts, acetate salts. Acid addition with organic or inorganic acids such as, trifluoroacetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, hydrochloride, sulfate, nitrate phosphate, etc. Things can be mentioned.

The acyl tripeptide (I) thus obtained or a pharmaceutically acceptable salt thereof, either alone or in a mixture thereof, has an excellent anti-infective action as shown in Examples below.

In addition, a mixture of MOA-DAB-Thr-DAB and IOA-DAB-Thr-DAB (1:
As a result of examining acute toxicity (LD ₅₀ ) to mice in 1), 5
It was 0.9 mg / kg (intravenous).

In addition to the acyltripeptide (I) or a pharmaceutically acceptable salt thereof, the infection control agent of the present invention may be mixed with excipients, binders and the like which are generally used in various dosage forms. There is no problem.

The dosage form of the anticorrosive agent of the present invention can be used as intraperitoneal, intravenous, intraarterial, subcutaneous and intramuscular injections, as well as suppositories, tablets, capsules and powders, but injections are most preferred. . A dose of 0.1 to 50 mg / kg body weight / day is sufficient.

Due to the characteristics of this type of drug, the earlier the administration, the higher the effect.

[Operation and effect of the invention]

The acyl tripeptide (I), which is an active ingredient of the anti-infective agent of the present invention, does not exhibit an antibacterial effect by itself, but enhances the anti-fungal function of the living body by acting on immunocompetent cells such as macrophages, and indirectly causes pathogenic bacteria in vivo It suppresses the growth of the plant and, as a result, exhibits a protective effect against infectious diseases caused by various pathogenic bacteria.

Therefore, the infection control agent of the present invention, Pseudomonas aeruginosa, Escherichia coli, Streptococcus, Staphylococcus, Streptococcus pneumoniae, Klebsiella pneumoniae, Listeria monocytogenes,
It is also effective against bacterial infections caused by Salmonella, etc., deep-seated mycosis caused by Candida, etc., and complicated infections in which the causative bacteria are not clear. In addition, in complicated infections, the effect is further enhanced by the combined use with conventional chemotherapeutic agents such as antibiotics and anticancer agents.

〔Example〕

 Next, the present invention will be described with reference to examples.

Example 1 Effect of MOA-DAB-Thr-DAB on mouse Listeria monocytogenes infection The mice consisted of 10 male ddY mice (6 weeks old, body weight 25).
g) was used. The inoculum was Listeria monocytogenes Serotype 4b isolated from patients with infectious diseases. MOA-DAB-Thr-DAB 25 μg 7 days before infection with Listeria monocytogenes
Dissolve in physiological saline at a rate of / ml or 250 μg / ml, and
0.2 ml was administered intravenously. As a control, 0.2 ml of physiological saline was intravenously administered.

Listeria suspension (1 x 10 ⁷ /
(ml) was intravenously inoculated, and the survival rate was calculated from the number of survivors on the 14th day after infection. The results are shown in Table 2.

Example 2 Effect of IOA-DAB-Thr-DAB on mouse Listeria monocytogenes infection IOA-DAB-Thr-DAB was used as a sample and tested in the same manner as in Test Example 1. The results are shown in Table 3.

Example 3 MOA-DAB-Thr-DAB and IOA against mouse Listeria monocytogenes infection
-Effect of the mixture with DAB-Thr-DAB The mice consisted of 10 C57BL / 6 male mice (6 weeks old, body weight 2
0 g) was used. As the inoculum, the same strain as in Test Example 1 was used, and an acyltripeptide mixture (MOA-DAB-Thr-DAB: IOA-DAB-Th was used.
r-DAB = 1: 1) was intraperitoneally administered 4 days before intravenous infection with Listeria monocytogenes (7 × 10 ⁶ cells). The results are shown in Table 4.

[Brief description of drawings]

Figures 1 and 2 show MOA-DAB-Thr-DAB and IOA-DAB.
2 is a drawing showing an infrared absorption spectrum of -Thr-DAB.

Claims (1)

[Claims] 1. The following general formula (I): An infection control agent comprising an acyl tripeptide represented by the formula (wherein R represents a methyl group or an ethyl group) or a pharmaceutically acceptable salt thereof as an active ingredient.