JP3474940B2 - Drug resistance overcomer - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug resistance overcoming agent and a pharmaceutical composition containing the same for treating cancer or preventing or treating microbial infection.

[0002]

2. Description of the Related Art Cancer is currently one of the major threats to humankind due to the large number of sufferers and low cure rate, and thus high mortality rate. A number of anti-cancer agents have been developed and marketed since the importance of cancer treatment was recognized. However, at the time of development, drug-resistant strains appeared as the use frequency of anticancer drugs with high potency increased, and their potency was reduced. Originally, since the difference between drug efficacy and toxicity is small, anticancer drugs often have a fatal effect on the treatment of the cancer even if a small amount of resistance is acquired. Therefore, various compounds have been repeatedly screened using the drug resistance overcoming effect as an index, and it has been revealed that calcium antagonists such as diphenylpiperazine derivatives and dihydropyridine derivatives have such resistance overcoming effect. However, since these compounds have a strong calcium antagonistic effect, it was impossible to administer them until the drug resistance conquering effect was developed.

On the other hand, with respect to infectious diseases caused by microorganisms, drug resistance has been a serious problem as in cancer. That is, most of the pathogenic microorganisms such as MRSA (methicillin-resistant Staphylococcus aureus), which is notorious for hospital-acquired infection in recent years, resistant Escherichia coli, resistant spirochete, resistant malaria, resistant leishmania, and large and small resistant strains appeared, and chemotherapy. Is throwing a big shadow on. For such diseases, there are currently no good treatments to the extent that development of new chemotherapeutic agents is desired. Further, as a drug that overcomes the drug resistance of such drug-resistant pathogenic microorganisms, calcium antagonists like cancer, divensveronylpiperazines, and diphenylacetylpiperazines have been found to have such effects, but side effects, It was hard to say that it was sufficiently satisfactory in terms of stability and effect. In particular, the present inventors have found a strain in MRSA that cannot sufficiently exert the resistance overcoming effect of these drugs. It can be said at present that there is a strong demand for effective agents for overcoming these resistances.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and overcomes the drug resistance of cancer or pathogenic microorganisms that have a low calcium antagonistic activity and have acquired resistance to chemotherapeutic agents. Another object of the present invention is to provide a novel drug resistance overcoming agent that improves the therapeutic effect of a chemotherapeutic agent.

[0005]

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted diligent studies on diphenylpiperazines, with indicators of a decrease in calcium antagonism and an improvement in drug resistance overcoming as indicators. The inventors have found that the compound represented by the general formula (I) has such an action and completed the invention.

[0006]

[Chemical 8]

That is, the present invention relates to the compound represented by the general formula (I) and physiologically acceptable salts thereof.

Further, the present invention relates to a drug resistance overcoming agent comprising a compound represented by the general formula (I) and / or a salt thereof.

The present invention also relates to a pharmaceutical composition containing the agent for overcoming drug resistance, for anti-cancer or for treating microbial infection.

The present invention will be described in detail below. (1) Compound of the present invention The compound of the present invention is represented by the general formula (I).
Here, X and Y in the general formula each independently represent a hydrogen atom or a halogen atom, and among these, a preferred one is a hydrogen atom, a chlorine atom or a fluorine atom, and a more preferred one is a hydrogen atom. When chlorine or fluorine atom is introduced, the medicinal effect does not change and the action is sustained, but the possibility of developing Parkinson's disease increases, so in order to prevent microbial infectious diseases in a short period, hydrogen atom is used. Although more preferable, a hydrogen atom is preferable for general purposes. or,
n is an integer of 1 to 4, and 1 is the most preferable. This is because when n is 1, the calcium antagonistic action is the smallest. Specific examples of the compounds represented by the general formula (I) of the present invention include the following compounds. That is, 1- (2,2-diphenylethylcarbonyl) -4- [3- (7-chloroquinolin-1-yloxy) -2-hydroxypropyl] piperazine (Compound 1, Chemical formula 9), 1- (2,2 -Diphenylethylcarbonyl) -4- [2-hydroxy-3- (quinoline-5-
Iloxy) propyl] piperazine (Compound 2, Chemical formula 1
0), 1- (2,2-diphenylethylcarbonyl)-
4- [2-hydroxy-3- (3-methylphenyloxy) propyl] piperazine (Compound 3, Chemical formula 11), 1-
(2,2-diphenylethylcarbonyl) -4- [2-
Hydroxy-3- (3-methoxyphenyloxy) propyl] piperazine (Compound 4, Chemical formula 12), 1- (2,2
-Diphenylethylcarbonyl) -4- [2-hydroxy-3- (3-nitrophenyloxy) propyl] piperazine (Compound 5, Chemical formula 13), 1- (2,2-diphenylethylcarbonyl) -4- [2- Hydroxy-3-
(4-Nitrophenyloxy) propyl] piperazine (Compound 6, Chemical formula 14), 1- [2,2-bis (4-fluorophenyl) ethylcarbonyl] -4- [3- (7-
Chloroquinolin-1-yloxy) -2-hydroxypropyl] piperazine (Compound 7, Chemical formula 15), 1- [2-
(4-Chlorophenyl) -2-phenylethylcarbonyl)]-4- [2-hydroxy-3- (4-nitrophenyloxy) propyl] piperazine (Compound 8, Chemical Formula 1
6). All of these compounds are new compounds. These compounds can be synthesized from commercially available raw materials according to the reaction formula (II) shown below. That is, the halide of 1 is reacted with piperazine to form a compound of 1. Separately, the compound of (1) is reacted with epihalogenohydrin with sodium hydride to form an epoxy compound. When and are condensed by a ring-opening condensation reaction of epoxy, the target compound of the general formula (I) is obtained. The compound represented by the general formula (I) can be purified by a usual method such as silica gel column chromatography or recrystallization. or,
These salts are easily obtained by reacting with a corresponding acid in a polar solvent. The type of salt is not particularly limited as long as it is physiologically acceptable, and examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as citric acid, oxalic acid and acetic acid. it can. All of these have excellent safety because they have little calcium antagonism, and have excellent resistance overcoming effects in chemotherapy of drug-resistant cancer or drug-resistant pathogenic microorganisms, and thus can be used as resistance overcoming agents. Here, the resistant pathogenic microorganism referred to in the present invention means a microorganism that has acquired resistance to a drug such as an antibiotic among the commonly referred to pathogenic microorganisms, and specifically, MRSA. (Methicillin-resistant Staphylococcus aureus), resistant Escherichia coli, penicillin-resistant spirochete, chloroquine-resistant malaria, resistant rheumania, and the like. The compound of the present invention has an action of lowering the resistance of these resistant pathogenic microorganisms, and when administered to an affected person together with a conventional drug against these microorganisms, the antipathogenic microbial effect of a therapeutic agent which has been ineffective until now is restored. And can cure illnesses that were untreatable. The present compound can also be used as an effect enhancer for an infection preventive agent such as fancidal.

[0011]

[Chemical 9]

[0012]

[Chemical 10]

[0013]

[Chemical 11]

[0014]

[Chemical 12]

[0015]

[Chemical 13]

[0016]

[Chemical 14]

[0017]

[Chemical 15]

[0018]

[Chemical 16]

[0019]

[Chemical 17]

(2) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention comprises the compound represented by the above general formula (I) and / or a salt thereof and optional components for pharmaceutical preparation. As an optional component, an excipient, a bulking agent, a binder,
Examples thereof include disintegrants, colorants, lubricants, flavoring agents, coating agents, sugar coating agents, stabilizers, pH adjusters, emulsifying dispersants and isotonic agents. Furthermore, an anti-cancer agent or an anti-pathogenic microbial agent may be used as an optional component. The pharmaceutical composition of the present invention can be formulated by an ordinary method using one or more selected from the compounds represented by the general formula (I) and salts thereof and optional components. The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include granules, powders, tablets, capsules, solutions, and injections. Among these, examples of the administration route of the injection include intravenous administration, intraarterial administration, portal vein administration, subcutaneous administration, intraperitoneal administration, intralesional direct administration and the like. Administration by infusion is also possible. In addition, oral administration may be performed as a sustained release preparation. When the pharmaceutical composition of the present invention is used for treating drug-resistant cancer or drug-resistant microbial infection, the preferred dosage is symptom, age, body type, physical condition,
It varies depending on the sex etc., but it is 10 to 2000 mg by oral administration and 5 to 500 m by injection per adult per day.
It is suitable to administer g once or divided into several times.

[0021]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 Synthesis of Compound 1 25 g of 3,3-diphenylpropionyl chloride, 25 g of piperazine, 0.1 g of potassium iodide, benzene 1
00 ml was heated under reflux for 6 hours, washed 3 times with 100 ml of water, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluting solvent chloroform: methanol = 100: 0).
→ 1: 1) to obtain 165.0 g of 1- (2,2-diphenylcarbonyl) piperazine. Separately, 1.2 g of 7-chloro-4-hydroxyquinoline was dissolved in dimethylformamide (DMF), and then sodium hydride 0.3
g, and 2.8 g of epibromhydrin was added dropwise thereto, and the mixture was stirred with heating at 90 ° C. for 3 hours, the solvent was distilled off under reduced pressure, 300 ml of chloroform was added for extraction, and 200 m of water was added.
Wash 3 times with 1 times, concentrate under reduced pressure, and perform silica gel column chromatography (eluting solvent chloroform: methanol = 10).
The product was purified by 0: 0 → 7: 3) to obtain 0.89 g of 7-chloro-4-glycidylquinoline. 0.89 g of this 7-chloro-4-glycidylquinoline and 1 g of 1- (2,2-diphenylcarbonyl) piperazine were added to methanol 1
It was dissolved in 00 ml and stirred at room temperature for 3 days. The reaction product was concentrated under reduced pressure and subjected to silica gel column chromatography (eluting solvent chloroform: methanol = 100: 0 → 3: 4).
After purification in 1.6 g, 1.6 g of the title compound was obtained. NMR (CDCl ₃ , δppm) 2.12-2.71 (m, 7H), 3.06 (d, 2H), 3.30-3.45 (m, 2H), 3.4
8-3.72 (m, 2H), 4.15-4.33 (m, 3H), 4.67 (t, 1H), 6.73 (d,
1H), 7.14-7.34 (m, 10H), 7.45 (d, 1H), 8.02-8.16 (m, 2
H), 8.72 (d, 1H) 1500 mg of the compound obtained as described above was added to 3 ml of ethyl acetate.
220 mg of fumaric acid and 100 ml of ethyl acetate
What was dissolved by heating in ml was added, and the mixture was concentrated under reduced pressure and the precipitated crystals were collected by filtration to obtain 560 mg of a salt of compound 1. NMR (DMSO, δppm) 2.35-2.65 (m, 7H), 3.22 (d, 2H), 3.40-3.66 (m, 4H), 4.20
-4.42 (m, 3H), 4.06 (t, 1H), 6.73 (s, 3H), 7.17 (d, 1H),
7.20-7.47 (m, 10H), 7.72 (dd, 2H), 8.12 (d, 1H), 8.39 (d,
1H), 8.86 (dd, 1H)

Example 2 Synthesis of Compound 2 In the same manner as in Example 1, 1 g of 1- (2,2-diphenylcarbonyl) piperazine was reacted with 1 g of 5-hydroxyquinoline and 2 g of epibromohydrin. 6 g of 5
-Glycidyloxyquinoline was reacted and purified to obtain 1.1 g of the title compound. NMR (CDCl ₃ , δppm) 2.12-2.65 (m, 7H), 3.06 (d, 2H), 3.33-3.42 (m, 2H), 3.52
-3.65 (m, 2H), 4.10-4.27 (m, 3H), 4.67 (t, 1H), 6.87 (d, 1
H), 7.13-7.32 (m, 10H), 7.39 (dd, 1H), 7.59 (t, 1H), 7.7
1 (d, 1H), 8.56 (dd, 1H), 8.90 (dd, 1H) 500 mg of this compound 2 was taken, dissolved in 3 ml of ethyl acetate, and dissolved in 100 ml of ethyl acetate 220
Fumaric acid (mg) was added, and the resulting crystals were collected by filtration to obtain 420 mg of the fumaric acid salt of compound 2. NMR (DMSO, δppm) 2.35-2.65 (m, 7H), 3.22 (d, 2H), 3.40-3.66 (m, 4H), 4.20
-4.42 (m, 3H), 4.06 (t, 1H), 6.73 (s, 3H), 7.17 (d, 1H),
7.20-7.47 (m, 10H), 7.72 (dd, 2H), 8.12 (d, 1H), 8.39 (d,
1H), 8.86 (dd, 1H)

Example 3 Synthesis of Compound 3 In the same manner as in Example 1, 3.75 g of 1-glycidyloxy-3-methylbenzene was obtained from 4 g of m-cresol and 14.5 g of epibromhydrin. 1g of this and Example 1
In the same manner as above, 1 g of 1- (2,2-diphenylcarbonyl) piperazine and 100 ml of methanol were used as a solvent, and the mixture was reacted at room temperature for 3 days, concentrated and purified to obtain 1.2 g of the title compound. NMR (CDCl ₃ , δppm) 2.12-2.60 (m, 10H), 3.06 (d, 2H), 3.31-3.41 (m, 2H), 3.5
2-3.63 (m, 2H), 3.95 (m, 2H), 4.01-4.13 (m, 1H), 4.67 (t,
1H), 6.66-6.82 (m, 3H), 7.13-7.35 (m, 11H) In the same manner as in Examples 1 and 2, 488 mg of a fumarate of Compound 3 was obtained from 500 mg of Compound 3 and 130 mg of fumaric acid. NMR (DMSO, δppm) 2.36-2.74 (m, 10H), 3.26 (d, 2H), 3.44-3.73 (m, 4H), 3.9
5-4.16 (m, 3H), 4.64 (t, 1H), 6.79 (s, 2H), 6.83-6.93 (m,
3H), 7.26-7.60 (m, 11H)

Example 4 Synthesis of Compound 4 In the same manner as in Examples 1 to 3, 3.9 g of 1-glycidyloxy-3-methoxybenzene was obtained from 5 g of m-methoxyphenol and 16 g of epibromohydrin. 1g of this compound
And 1 g of 1- (2,2-diphenylcarbonyl) piperazine obtained in the same manner as in Example 1 and 100 ml of methanol
Was used as a solvent and reacted at room temperature for 3 days, concentrated and purified to obtain 1.4 g of the title compound. NMR (CDCl ₃ , δppm) 2.08-2.58 (m, 7H), 3.04 (d, 2H), 2.28-3.36 (m, 2H), 3.50
-3.63 (m, 2H), 3.79 (s, 3H), 3.94 (d, 2H), 4.00-4.13 (m, 1
H), 6.45-6.56 (m, 3H), 7.14-7.32 (m, 11H) 412 mg of the fumarate salt of compound 4 from 500 mg of compound 4 and 120 mg of fumaric acid in the same manner as in Examples 1, 2 and 3.
Obtained. NMR (DMSO, δppm) 2.38-2.60 (m, 4H), 3.26 (d, 2H), 3.45-3.67 (m, 4H), 3.88
(s, 3H), 3.94-4.16 (m, 3H), 4.63 (t, 1H), 6.62-6.70 (m, 3
H), 6.78 (s, 2H), 7.26-7.60 (m, 11H)

Example 5 Synthesis of Compound 5 In the same manner as in Examples 1 to 4, 3.5 g of 1-glycidyloxy-3-nitrobenzene was obtained from 5 g of m-nitotophenol and 16 g of epibromohydrin. Using 1 g of this compound and 1 g of 1- (2,2-diphenylcarbonyl) piperazine obtained in the same manner as in Example 1 and 100 ml of methanol as a solvent, they were reacted at room temperature for 3 days, concentrated and purified to give 1.1 g of the title compound. Obtained. NMR (CDCl ₃ , δppm) 2.12-2.58 (m, 7H), 3.07 (d, 2H), 3.27-3.44 (m, 2H), 3.48
-3.70 (m, 2H), 3.96-4.16 (m, 3H), 4.67 (t, 1H), 7.15-7.3
6 (m, 11H), 7.44 (t, 1H), 7.76 (t, 1H), 7.85 (dd, 1H) Similar to Examples 1, 2, 3 and 4, 500 mg of compound 5 and 120 mg of fumaric acid were used to give compound 5 423 of fumarate
mg was obtained. NMR (DMSO, δppm) 3.09 (d, 2H), 3.25-3.52 (m, 5H), 3.90-4.14 (m, 3H), 4.20
-4.45 (7H), 6.61 (s, 2H), 7.71-7.46 (m, 11H), 7.58 (t, 1
H), 7.72 (dd, 1H), 7.80 (dd, 1H)

Example 6 Synthesis of Compound 6 In the same manner as in Examples 1 to 5, 3.5 g of 1-glycidyloxy-4-nitrobenzene was obtained from 5 g of p-nitotophenol and 16 g of epibromohydrin. 1 g of this compound, 1 g of 1- (2,2-diphenylcarbonyl) piperazine obtained in the same manner as in Example 1 and 100 ml of methanol were used as a solvent, reacted at room temperature for 3 days, concentrated and purified to give 1.5 g of the title compound. Obtained. NMR (CDCl ₃ , δppm) 2.12-2.63 (m, 7H), 3.05 (d, 2H), 3.30-3.45 (m, 2H), 3.48
-3.68 (m, 2H), 4.00-4.14 (m, 3H), 4.65 (s, 1H), 6.96 (d, 2
H), 7.14-7.32 (m, 10H), 8.18 (d, 2H) In the same manner as in Examples 1, 2, 3 and 4, 500 mg of compound 5 and 120 mg of fumaric acid were used to prepare 423 of the fumarate of compound 5.
mg was obtained. NMR (DMSO, δppm) 2.34-2.60 (m, 7H), 3.26 (d, 2H), 3.47-3.69 (m, 4H), 4.12
-4.36 (m, 3H), 4.65 (t, 1H), 6.75 (s, 2H), 7.24-7.53 (m, 1
2H), 8.32-8.41 (m, 2H)

Example 7 Acute toxicity of the compounds of the present invention Using ICR mice (male, 5 weeks old, weight 25-35 g), the acute toxicity of the compounds 1-6 of the present invention was investigated. That is, Compounds 1-5 were dispersed in 0.1% CMC physiological saline containing 0.1% polyoxyethylene hydrogenated castor oil at a concentration of 0.01 g / ml in 5 animals per group to give 1000
It was orally administered at a dose of mg / Kg. The life or death of the animals was determined 7 days after the administration, but no death was observed. From this, it can be seen that the compound of the present invention has an LD ₅₀ of 1000 mg / Kg or more and is excellent in safety.

Example 8 Calcium Antagonism The calcium antagonism was examined using the thoracic aorta of male Wistar rats (body weight 300-350 g). That is, after exsanguination of the rat, the thoracic aorta was excised, and the width was 3 to 4
A ring specimen of mm was prepared. Sample is mixed gas (95%
Oxygen + 5% carbon dioxide gas) was suspended in a Magnus tube filled with Krebs-Henseleit solution at 37 ° C, and a change in tension was isometrically recorded by applying a load of 2 g. Calcium antagonism is a concentration-dependent contraction of potassium chloride (10-6
The negative logarithm (IC ₅₀ ) of the molar concentration of the test substance that suppresses the maximum contraction of 0 mmol) by 50% is shown in Table 1. From this, it is understood that all of the compounds of the present invention have a value of 6 or less, and the calcium antagonistic action is extremely weak.

[0030]

[Table 1]

Example 9 Overcoming Resistance to Resistant Cancer Using the cultured cancer cells AUXB1 derived from Chinese hamster and its resistant cell CH ^R C5, the effect of overcoming resistance to mitomycin was examined. That is, 10% FC
A cell dispersion liquid having a concentration of 2 × 10 ⁴ cells / ml was prepared in α-MEM medium containing S, 100 μl of each was dispersed in a 96-well plate, and cultured at 37 ° C. for 1 day. As an anti-cancer agent, mitomycin has a final concentration of 10 ⁻³ to 10 ^−11.
It was adjusted to a molar concentration and 50 μl was added. Furthermore, the compound of the present invention or verapamil as a positive control was diluted to prepare a final concentration of 3 × 10 ⁻⁶ mol,
50 μl was added. After culturing at 37 ° C. for 3 days, 10 μl of MTT reagent (5 mg / ml) dissolved in PBS was added,
It was left at 37 ° C. for 4 hours. The culture solution was removed, 100 μl of dimethyl sulfoxide was added and mixed, and the absorbance at 570 nm was measured to determine the survival rate. Based on this value, the 50% viable concentration of cells was determined. Half survival concentration of mitomycin for CH ^R C5 was divided by overcoming resistance value at half survival concentration of mitomycin against AUBX1. The results are shown in Table 2. From this table, it is clear that the drug for overcoming resistance of the present invention has an action of reducing drug resistance of resistant cancer.

[0032]

[Table 2]

Example 9 Action on MRSA Various antibiotics in the presence or absence of the compound of the present invention were used using Staphylococcus aureus experimentally methicillin-resistant and methicillin-resistant strains clinically isolated. The MIC of the material was measured. The test bacterium was inoculated into a broth for susceptibility measurement, precultured at 37 ° C. for 24 hours, and then a bacterium solution prepared so that the number of bacteria was 10 ⁶ / ml was inoculated into a modified Mueller-Hinton medium. DM of the compound of the present invention
It was dissolved in 1 ml of SO, adjusted to a final concentration of 100 μg, and added to the medium. Only 10% DMSO was used as a negative control. Various antibiotics were prepared at the highest concentration (as the final concentration), and the concentration at which the growth of the bacteria was completely inhibited was defined as MIC. Judgment is 42 ℃ 2 after inoculation
It was performed after culturing for 4 hours. The maximum concentrations of various antibiotics were as follows. Methicillin: 800 μg / ml, Cefmetazole: 100 μg / ml, Fosfomycin 40
0 μg / ml, ciproxacin: 100 μg / ml, norfloxacin: 400 μg / ml. The control was a negative control without drug administration, and 1-dibenzosuberyl-4- [3- (7-chloroquinolin-4-yloxy)-, which has been known to date as a potent drug for overcoming tolerance. 2-Hydroxypropyl] piperazine (Compound A) 100 μg / ml, 1-diphenylacetyl-4-
[3- (quinolin-4-yloxy) -2-hydroxypropyl] piperazine (Compound B) 100 μg / ml was used. The results are shown in Tables 3 and 4. From this, it is clear that the compound of the present invention exhibits an excellent action of overcoming resistance against MRSA for which conventional drug resistance overcoming agents are difficult to act.

[0034]

[Table 3]

[0035]

[Table 4]

INDUSTRIAL APPLICABILITY The compound of the present invention has an extremely weak calcium antagonistic action, and therefore is highly safe and has an excellent resistance overcoming action, and is therefore extremely useful for treating cancer and treating diseases caused by pathogenic microorganisms.

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 35/00 A61P 35/00 43/00 121 43/00 121 C07D 215/22 C07D 215/22 295/18 295/18 A ( 56) References JP-A-6-211664 (JP, A) JP-A-6-199669 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 215/20 C07D 215/22 C07D 295/18 A61K 31/495 A61K 31/496 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A compound represented by the general formula (I) and a physiologically acceptable salt thereof. [Chemical 1] 2. The compound according to claim 1, wherein n is 1 and X and Y are hydrogen atoms in the general formula (I), and a physiologically acceptable salt thereof. 3. The compound according to claim 1 and a physiologically acceptable salt thereof, wherein the compound represented by the general formula (1) is any of the following compounds. 1- (2,2-diphenylethylcarbonyl) -4- [3- (7-chloroquinolin-4-yloxy) -2-hydroxypropyl] piperazine (Compound 1, Chemical formula 2), 1- (2,2-diphenyl Ethylcarbonyl) -4- [2-hydroxy-3- (quinolin-5-yloxy) propyl] piperazine (Compound 2, Chemical formula 3), 1- (2,2-diphenylethylcarbonyl) -4- [2-hydroxy- 3- (3-Methylphenyloxy) propyl] piperazine (Compound 3, Chemical formula 4), 1- (2,2-diphenylethylcarbonyl)-
4- [2-hydroxy-3- (3-methoxyphenyloxy) propyl] piperazine (Compound 4, Chemical formula 5), 1-
(2,2-diphenylethylcarbonyl) -4- [2-
Hydroxy-3- (3-nitrophenyloxy) propyl] piperazine (Compound 5, Chemical formula 6), 1- (2,2-diphenylethylcarbonyl) -4- [2-hydroxy-
3- (4-nitrophenyloxy) propyl] piperazine (Compound 6, Chemical formula 7) [Chemical 3] [Chemical 4] [Chemical 5] [Chemical 6] [Chemical 7] 4. A drug resistance overcoming agent comprising the compound according to claim 1 and / or a physiologically acceptable salt. 5. A pharmaceutical composition for treating cancer, which comprises one or more agents for overcoming drug resistance according to claim 4. 6. A pharmaceutical composition for preventing or treating microbial infection, which comprises one or more agents for overcoming the drug resistance according to claim 4. 7. The pharmaceutical composition according to claim 6, wherein the microbial infection is caused by Staphylococcus aureus, malaria parasite, trypanosomes, Escherichia coli or spirochete.