JPH08283159A - Resistance conquering agent - Google Patents

Abstract

PURPOSE: To obtain a resistance conquering agent comprising a prescribed compound and/or its salt, useful for chemotherapy of cancers and infectious diseases because of its excellent resistance conquering action on resistant cancers and resistant pathogenic microorganisms. CONSTITUTION: This resistance conquering agent comprises a compound of the formula (R is amino or a substitutable phenylmethylazo which may contain an N atom in a ring) and/or its salt as an active ingredient. 1-Amino-4- dibenzosuberylpiperazine, etc., are preferable as the compound of the formula. The compound, for example, is obtained by reacting dibenzosuberyl chloride with nitronsopiperazine in an organic solvent in the presence of an alkali under heating and reducing the reaction product. Hydrochloride of the compound of the formula is preferable as the salt of the compound of the formula. A daily dose of the objective agent is preferably 10-500mg/adult.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug for overcoming resistance and a pharmaceutical composition containing the drug for treating or preventing infectious diseases caused by cancer or pathogenic microorganisms.

[0002]

2. Description of the Related Art The present age is the age of longevity, and the average life expectancy is far higher than 60 years old for both sexes. Along with this, various new diseases are emerging. Of these,
The most threatening to humanity is cancer. First of all, the definitive therapeutic drug has not been developed, and the developed therapeutic drug will soon develop a resistant strain,
This is because its efficacy is significantly reduced. Among these, various treatments for resistance to resistant strains have been developed in recent years, and great expectations were placed on the novelty of the mechanism, but the side effects such as action on the circulatory organ, stability, and strong action are expected. Further improvements have been desired in terms of size.

Further, in recent years, many multidrug-resistant strains have appeared in regard to infectious diseases, which have been considered to be threatened by the advent of therapeutic agents for infectious diseases such as antibiotics. It is casting a cloud over the world of chemotherapy. In particular, diseases caused by methicillin-resistant Staphylococcus aureus and chloroquine-resistant malaria parasite are life-threatening serious diseases, and it has been desired to cope with them.

On the other hand, although the substance represented by the following general formula (I) has been known to have an action on the circulatory system and an anticonvulsant action, it is known to have an action to overcome tolerance. It wasn't done.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of such a situation, and overcomes the resistance acquired by cancer or pathogenic microorganisms, and the action of anti-cancer agents or anti-pathogenic microorganism agents is An object of the present invention is to provide a resistance overcoming agent which can be returned to a level and a pharmaceutical composition containing the same.

[0006]

In view of the above-mentioned circumstances, the inventors of the present invention have conducted extensive studies in search of a novel resistance overcoming agent, and as a result, have such an action on the compound represented by the following general formula (I). I found that there was, and completed the invention. That is, the present invention relates to a resistance overcoming agent comprising a compound represented by the general formula (I) and / or a physiologically acceptable salt thereof.

[0007]

[Chemical 6]

(1) Resistance Overcoming Agent of the Present Invention The resistance overcoming agent of the present invention comprises the compound represented by the above general formula (I) and / or a physiologically acceptable salt thereof.
Examples of the compound represented by the general formula (I) include 1-
Amino-4-dibenzosuberylpiperazine (structure 1,
Resistance overcoming agent 1), 1-dibenzosuberonyl-4-piperonylideneaminopiperazine (Structural formula 2, resistance overcoming agent 2), 1-dibenzosuberonyl-4-benzylideneaminopiperazine (Structure formula 3, resistance overcoming) Agent 3) and 1-dibenzosberyl-4- (2-pyridylmethyleneamino) piperazine (Structural formula 4, resistance overcoming agent 4) can be preferably exemplified,
These are all known substances, and their manufacturing methods are already well known.

[0009]

[Chemical 7]

[0010]

Embedded image

[0011]

[Chemical 9]

[0012]

[Chemical 10]

These compounds can be easily synthesized by the method shown in Formula 1. That is, dibenzosuberanyl chloride and nitrosopiperazine are heated and reacted with an alkali in an organic solvent to give 1-dibenzosuberanyl-4-nitrosopiperazine, which can be reduced by a conventional method to obtain the resistance represented by Structural Formula 1. Overcoming agent 1 is obtained. When this is reacted with various aldehydes and acetic acid or the like as a catalyst, a compound in which R in the general formula (I) is an arylmethylideneamino group can be obtained. These can be easily purified by column chromatography, recrystallization or the like and used as a resistance overcoming agent. Further, since they have both piperazine structures, they can be made into a salt together with an acid, and can also be used as a salt in a resistance overcoming agent. The salt is not particularly limited as long as it is physiologically acceptable, and examples thereof include mineral acid salts such as nitric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and organic acid salts such as citric acid, lactic acid, oxalic acid and acetic acid. And the like can be preferably exemplified. The most preferable of these is the hydrochloride from the viewpoint of economy and stability.

These agents for overcoming resistance of the present invention include resistant cancers that have acquired resistance to anticancer agents, pathogenic microorganisms that have acquired resistance to chemotherapeutic agents such as methicillin-resistant Staphylococcus aureus, chloroquine-resistant malaria parasites, resistant Escherichia coli, and It acts on drug-resistant African trypanosomes and the like, and has the effect of suppressing resistance to drugs and improving sensitivity to anticancer drugs and chemotherapeutic drugs. When the present resistance overcoming agent is used together with an anti-cancer agent or a chemotherapeutic agent, the sensitivity of resistant cancer or resistant pathogenic microorganisms to these drugs can be improved, and the treatment performance can be enhanced. The preferred dose of these resistance overcoming agents varies depending on various conditions such as age, weight, physical condition, and type of pathogenic bacteria, but is 1 per adult per day.
It is suitable to administer ˜2000 mg. More preferably, it is 10 to 500 mg. The administration route is not particularly limited, and oral administration, intravenous administration, intraarterial administration, portal vein administration, subcutaneous administration, intraperitoneal administration, sublingual administration, and rectal administration are all possible. Further, these may be used for treatment after infection or for prevention of infection. In addition, if given before the administration of anti-cancer agents or chemotherapeutic agents,
Administration may be simultaneous or delayed.

(2) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing at least one of the above-mentioned resistance overcoming agents. The pharmaceutical composition of the present invention may contain optional components necessary for formulation in addition to the above-mentioned resistance overcoming agent. Examples of the optional component include a coating agent, a binder, a disintegrating agent, a lubricant, a flavoring agent, a bulking agent, a coloring agent, a stabilizer, an isotonic agent, a solubilizing agent, a dispersing agent, and a solubilizing agent. Furthermore, a pharmaceutical composition in which an anticancer agent or a chemotherapeutic agent is previously mixed with a resistance overcoming agent is also one of the pharmaceutical compositions of the present invention. Such anti-cancer agents include anti-cancer antibiotics such as adriamycin, bleomycin, neocarzinostatin,
Antimetabolites such as 5FU and tegafur, substances derived from crude drugs such as taxol, platinum complexes such as cisplatin and the like can be exemplified. Examples of the chemotherapeutic agent include malarial drugs such as chloroquine, mefloquine and fancidal, and antibiotics such as methicillin, norfloxacin, cephalosporin and tetracycline.

Example 1 Test Example Using MRSA strain A8427 isolated clinically, the action to overcome resistance to antibiotics was confirmed. That is,
The effect of various antibiotics on MRSA in the presence and absence of 100 μg / ml of the resistance overcoming agent of the present invention was measured by MIC.
Was obtained by measuring. The test bacterium was inoculated into a broth for susceptibility measurement, precultured under the condition of 37 ° C. for 24 hours, adjusted to a cell count of 10 ⁶ cells / ml, and inoculated into a modified Mueller Hinton medium. The resistance overcoming agent of the present invention was dissolved in 1 ml of DMSO to give a final concentration of 100 μg / m 2.
l was added to the medium. A 10% DMSO medium solution was used as a negative control. Various antibiotics having the highest concentration were prepared, and the concentration at which the growth of bacteria was completely suppressed was determined as MIC by doubling the dilution. The maximum concentrations (as final concentrations) of various antibiotics were as follows. Methicillin: 800 μg / ml, Cefmetazole: 100 μg /
ml, fosfomycin: 400 μg / ml, norfloxacin: 200 μg / ml, ciproxacin: 10
It was 0 μg / ml. None of the agents for overcoming the resistance of the present invention showed an antibacterial action. The results are shown in Table 1. From this, it is clear that the resistance overcoming agent of the present invention has an action of decreasing the resistance of MRSA.

[0017]

[Table 1]

Example 2 Action on Resistant Cancer The action on mitomycin was examined using the cultured cancer cells AUXB1 derived from Chinese hamster and its resistant cell CHRC5. That is, α containing 10% FCS
A cell dispersion was prepared in MEM medium at a concentration of 2 × 10 ⁴ cells / ml, and 100 μl was dispensed to each 96-well plate and cultured at 37 ° C. for 1 day. Adjust mitomycin as an anticancer agent so that the final concentration is 10 ^-3 to 10 ^-11.
0 μl was added. After culturing at 37 ° C. for 3 days, 10 μl of MTT reagent dissolved in PBS was added and left at 37 ° C. for 4 hours. The culture solution was removed, 100 μl of DMSO was added and mixed, and the absorbance at 570 nm was measured to determine the survival rate. Based on this value, the 50% survival concentration was determined. The 50% survival concentration for CHRC5 was divided by the 50% survival concentration for AUBX to obtain a resistance overcoming value. Table 2 shows the results. From this, it is understood that the drug for overcoming resistance of the present invention has an excellent effect of suppressing the resistance of resistant cancers to anticancer drugs.

[0019]

[Table 2]

Example 3 Action against chloroquine (multi-drug) resistant malaria Using experimentally prepared chloroquine resistant murine malaria, the method of Tanabe et al. (Exp. Prasitol., 7
0,419-426,1990), and the resistance overcoming action was examined. That is, ICR mice were injected with 10 ⁸ malaria parasites through the tail vein to infect them, and then 4 days after 3 days.
10% of chloroquine and the resistance overcoming agent of the present invention on consecutive days
It was dispersed in a DMSO physiological saline solution and administered. The dose is 3 mg / Kg / day for chloroquine, and 50 for the drug to overcome tolerance.
It was mg / Kg / day. 10% DMSO saline solution (vehicle) was substituted for the chloroquine control group in place of the resistance overcoming agent, vehicle was substituted for chloroquine in the control group for the resistance overriding agent, and chloroquine was used for the experimental control group Vehicle was administered instead. The results are shown in Table 3. From this, it is understood that the drug for overcoming resistance according to the present invention is also effective for resistant malaria.

[0021]

[Table 3]

Examples 4 to 7 Preparation Examples Granule preparations were prepared according to the formulations shown in Table 4. That is, the prescription ingredients were weighed in a Glad granulator, and 100 ml of 50
% Fluidized bed granulation while gradually adding a% ethanol solution,
After drying with air blowing at 40 ° C. for 48 hours, the particles were sieved to obtain granules.

[0023]

[Table 4]

Examples 8 to 11 Preparation examples Granule preparations were prepared according to the formulations shown in Table 5. That is, the prescription ingredients were weighed in a Glad granulator, and 100 ml of 50
% Fluidized bed granulation while gradually adding a% ethanol solution,
After drying with air blowing at 40 ° C. for 48 hours, the particles were sieved to obtain granules.

[0025]

[Table 5]

Examples 12 to 15 Preparation Examples Granule preparations were prepared according to the formulations shown in Table 6. That is, the prescription ingredients were weighed in a Glad granulator, and 100 ml of 50
% Fluidized bed granulation while gradually adding a% ethanol solution,
After drying with air blowing at 40 ° C. for 48 hours, the particles were sieved to obtain granules.

[0027]

[Table 6]

Examples 16 to 19 Preparation Examples Granule preparations were prepared according to the formulations shown in Table 7. That is, the prescription ingredients were weighed in a Glad granulator, and 100 ml of 50
% Fluidized bed granulation while gradually adding a% ethanol solution,
After drying with air blowing at 40 ° C. for 48 hours, the particles were sieved to obtain granules.

[0029]

[Table 7]

Examples 20 to 23 Formulation Examples Granule preparations were prepared according to the formulations shown in Table 8. That is, the prescription ingredients were weighed in a Glad granulator, and 100 ml of 50
% Fluidized bed granulation while gradually adding a% ethanol solution,
After drying with air blowing at 40 ° C. for 48 hours, the particles were sieved to obtain granules.

[0031]

[Table 8]

[0032]

INDUSTRIAL APPLICABILITY The resistance overcoming agent of the present invention is very useful for cancer chemotherapy and infectious disease chemotherapy because it has an excellent resistance overcoming action against resistant cancer and resistant pathogenic microorganisms.

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Claims (4)

[Claims] 1. An agent for overcoming resistance to a resistant cancer or a resistant pathogenic microorganism, which comprises a compound represented by the following general formula (I) and / or a physiologically acceptable salt thereof. Embedded image 2. The compound represented by the general formula (I) is 1-amino-4-dibenzosuberylpiperazine (structural formula 1),
1-Dibenzosuberonyl-4-piperonylideneaminopiperazine (Structural Formula 2), 1-dibenzosuberonyl-4-
The resistance overcoming agent according to claim 1, which is any one of benzylideneaminopiperazine (Structural formula 3) and 1-dibensosberyl-4- (2-pyridylmethyleneamino) piperazine (Structural formula 4). Embedded image Embedded image [Chemical 4] Embedded image 3. A pharmaceutical composition for treating or preventing an infectious disease caused by cancer or a pathogenic microorganism, which comprises the compound according to claim 1 or 2. 4. The pathogenic microorganism is staphylococcus, Escherichia coli,
The pharmaceutical composition according to claim 3, which is either a malaria parasite or a Rhischmania parasite.