JP3474941B2 - 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 drugs that overcome the drug resistance of such drug-resistant pathogenic microorganisms, calcium antagonists, dibenzosuberane derivatives, diphenylacetylpiperazine derivatives, and the like have been found to have such effects, as in cancer.
It was hard to say that it was sufficient in terms of side effects, stability, and effects. In particular, MRSA has been found to have strains that cannot overcome resistance with these compounds, and the development of new resistance overcoming agents has been desired.

[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 10]

That is, the present invention provides 1- (3,3-diphenylpropyl) -4- [2-hydroxy-3- (quinolin-5-yloxy) propyl] piperazine (compound 1,
1), 1- (3,3-diphenylpropyl) -4-
[3- (7-chloroquinolin-4-yloxy) -2-
Hydroxypropyl] piperazine (Compound 2, Chemical formula 2),
1- (3,3-diphenylpropyl) -4- [2-hydroxy-3- (3-methylphenyloxy) propyl]
Piperazine (Compound 4, Chemical Formula 3), 1- (3,3-diphenylpropyl) -4- [2-hydroxy-3- (3-methoxyphenyloxy) propyl] piperazine (Compound 5, Chemical Formula 4), 1- ( 3,3-diphenylpropyl) -4
-[2-hydroxy-3- (3-nitrophenyloxy) propyl] piperazine (Compound 6, Chemical formula 5), 1-
(3,3-Diphenylpropyl) -4- [2-hydroxy-3- (4-nitrophenyloxy) propyl] piperazine (Compound 7, Chemical formula 6), 4- [3- (3-Dimethylaminophenyloxy)- 2-hydroxypropyl]-
1- (3,3-diphenylpropyl) piperazine (Compound 8, Chemical Formula 7), and physiologically acceptable salts thereof.

Furthermore, the present invention relates to a drug resistance overcoming agent comprising the above compound and / or a physiologically acceptable salt.

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,
Of the substituents that may have, an alkyl group having 1 to 4 carbon atoms,
Of the alkyloxy groups, the number of carbon atoms is most preferably 1. The substituent R ₁ is not particularly limited as long as it is an aromatic compound, but a nitrogen-containing compound is preferable, and one having a quinoline skeleton is preferable. Specific examples of the compounds represented by the general formula (I) of the present invention include the following compounds. That is, 1-
(3,3-Diphenylpropyl) -4- [2-hydroxy-3- (quinolin-5-yloxy) propyl] piperazine (Compound 1, Chemical formula 11), 1- (3,3-diphenylpropyl) -4- [ 3- (7-chloroquinoline-4-
Iloxy) -2-hydroxypropyl] piperazine (Compound 2, Chemical formula 12), 1- (3,3-diphenylpropyl) -4- (2-hydroxy-3-phenyloxypropyl) piperazine (Compound 3, Chemical formula 13), 1- (3
3-diphenylpropyl) -4- [2-hydroxy-3
-(3-Methylphenyloxy) propyl] piperazine (Compound 4, Chemical formula 14), 1- (3,3-diphenylpropyl) -4- [2-hydroxy-3- (3-methoxyphenyloxy) propyl] piperazine ( Compound 5, Chemical 1
5), 1- (3,3-diphenylpropyl) -4- [2
-Hydroxy-3- (3-nitrophenyloxy) propyl] piperazine (Compound 6, Chemical formula 16), 1- (3,3
-Diphenylpropyl) -4- [2-hydroxy-3-
(4-Nitrophenyloxy) propyl] piperazine (Compound 7, Chemical formula 17), 4- [3- (3-Dimethylaminophenyloxy) -2-hydroxypropyl] -1-
(3,3-Diphenylpropyl) piperazine (Compound 8, Chemical formula 18), 1- [3,3-bis (4-fluorophenyl) propyl] -4- [3- (7-chloroquinoline-
4-yloxy) -2-hydroxypropyl] piperazine (Compound 9, Chemical formula 19), 1- [3- (4-chlorophenyl) -3-phenylpropyl] -4- [3- (7-chloroquinolin-1-yloxy ) -2-Hydroxypropyl] piperazine (Compound 10, Chemical formula 20). 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. Further, these salts can be 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 resistance pathogenic microorganisms referred to in the present invention, among the commonly referred to pathogenic microorganisms, means a microorganism that has acquired resistance to a drug such as an antibiotic, and specifically, Examples include 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 reducing the resistance of these resistant pathogenic microorganisms,
When administered to affected individuals in combination with conventional agents against these microorganisms, the previously ineffective anti-pathogenic microbial action of therapeutic agents may be restored and illnesses that could not be treated may be treated. The present compound can also be used as an effect enhancer for an infection preventive agent such as fancidal.

[0011]

[Chemical 10]

[0012]

[Chemical 11]

[0013]

[Chemical 12]

[0014]

[Chemical 13]

[0015]

[Chemical 14]

[0016]

[Chemical 15]

[0017]

[Chemical 16]

[0018]

[Chemical 17]

[0019]

[Chemical 18]

[0020]

[Chemical 19]

[0021]

[Chemical 20]

[0023]

[Chemical 21]

(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 to treat drug-resistant cancer or drug-resistant microbial infection, the preferred dose varies depending on symptoms, age, body type, physical condition, sex, etc. 10 to 2000m by oral administration
It is suitable to administer 5 to 500 mg by injection once or several times by injection.

[0026]

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 10 g of 1-hydroxycarbonyl-2,2-diphenylethane and 2 g of lithium aluminum hydride were TH
After reduction in F, the excess lithium aluminum hydride was treated with methanol to remove the solvent, and then extracted with 200 ml of isopropanol and distilled under reduced pressure to obtain crude 3,3-diphenylpropanol. While cooling with ice, 5 ml of thionyl chloride was allowed to act, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent; benzene: ethyl acetate = 1: 1) to obtain 6 g of 3,3-diphenylpropyl chloride. 1g of chloride,
4 g of piperazine, 0.1 g of potassium iodide and 1 benzene
00 ml was added, the mixture was heated under reflux for 5 hours, washed twice with 50 ml of water, the solvent was removed, and recrystallized from ethanol to give 1-
1.1 g of (3,3-diphenylpropyl) piperazine
Obtained. On the other hand, 7-chloro-4-hydroxyquinoline 6.
2 g was dissolved in methanol, and 1.5 g of sodium hydroxide was added and dissolved therein. Furthermore, 14.2 g of epibromohydrin was added thereto, and the mixture was heated under reflux for 5 hours. This was concentrated under reduced pressure, extracted and separated with 200 ml of chloroform and 200 ml of water, and the chloroform layer was taken out and concentrated under reduced pressure.
Purification by silica gel column chromatography (eluting solvent: chloroform: methanol = 100: 0 → 50: 50) gave 2.1 g of 7-chloro-4- (2-epoxy) propylquinoline. 1 g of 1- (3,3-diphenylpropyl) piperazine and 1 g of 7-chloro-4- (2-epoxypropyloxy) quinoline were added to 25 ml of methanol.
The mixture was stirred at room temperature for 4 days, and the solvent was removed, followed by purification by silica gel column chromatography (elution solvent; chloroform: methanol = 100: 0 → 7: 3).
g of the title compound was obtained. NMR (CDCl ₃ , δppm) 2.20-2.82 (m, 15H), 4.00 (t, 1H), 4.16-4.30 (m, 3H), 6.7
3 (d, 1H), 7.13-7.37 (m, 10H), 7.45 (d, 1H), 8.03 (s, 1
H), 8.14 (d, 1H), 8.72 (d, 1H) 300 mg of the above compound 1 was dissolved in 20 ml of ethyl acetate, 200 mg of maleic acid was dissolved in 20 ml of ethyl acetate and 5 ml of ethanol, and the precipitate was collected by filtration. Recrystallized from ethanol, maleic acid salt of compound 1 380mg
Obtained. NMR (DMSO, δppm) 2.24-3.70 (m, 15H), 3.94-4.33 (m, 4H), 6.17 (s, 6H), 7.0
7 (d, 1H), 7.13-7.42 (m, 10H), 7.62 (dd, 1H), 8.01 (d, 1
H), 8.29 (d, 1H), 8.79 (dd, 1H)

Example 2 Synthesis of Compound 2 1.5 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and 5-hydroxyquinoline and epibromohydrin in the same manner as in Example 1 More Derived 5- (2-epoxypropyloxy) quinoline
React with 1 g in 20 ml of methanol and purify 2.8
g of the title compound was obtained. NMR (CDCl ₃ , δppm) 2.24-2.75 (m, 15H), 3.95-4.02 (m, 1H), 4.13-4.28 (m, 3)
H), 6.87 (d, 1H), 7.12-7.30 (m, 10H), 7.31-7.39 (m, 1
H), 7.59 (t, 1H), 7.70 (d, 1H), 8.58 (dd, 1H), 8.89 (dd, 1
H) From 300 mg of compound 2 and 200 mg of maleic acid, 315 mg of the maleic acid salt of compound 2 was obtained in the same manner as in Example 1. NMR (DMSO, δppm) 2.22-3.72 (m, 14H), 3.93-4.34 (m, 4H), 6.17 (s, 6H), 7.0
5 (d, 1H), 7.15-7.42 (m, 11H), 7.50-7.72 (m, 3H), 8.67
(d, 1H), 8.91 (dd, 1H)

Example 3 Synthesis of Compound 3 1.1 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and 0.6 g of glycidyl phenyl ether were reacted and purified in 20 ml of methanol. 1.1 g of the title compound was obtained. NMR (CDCl ₃ , δppm) 2.17-2.70 (m, 15H), 3.94-4.00 (m, 3H), 4.02-4.13 (m, 1)
H), 6.89-7.00 (m, 3H), 7.12-7.31 (m, 12H) From 300 mg of compound 3 and 200 mg of maleic acid, 322 mg of the maleic acid salt of compound 3 was obtained in the same manner as in Example 1. NMR (DMSO, δppm) 2.24-3.70 (m, 15H), 3.84-4.16 (m, 4H), 6.14 (s, 4H), 6.9
0-7.01 (m, 3H), 7.15-7.39 (m, 12H)

Example 4 Synthesis of Compound 4 1.1 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and m-cresol and epibromohydrin in the same manner as in Example 1 Induced 1-
0.6 g of (2-epoxypropyloxy) -3-methylbenzene was reacted and purified in 20 ml of methanol, and 1
g of the title compound was obtained. NMR (CDCl ₃ , δppm) 2.20-2.79 (m, 15H), 3.94-4.13 (m, 4H), 6.67-6.80 (m, 3)
H), 7.12-7.33 (m, 11H) 300 mg of compound 4 and 160 m
g maleic acid, using diethyl ether as a solvent,
By the same method as in Example 1, 298 mg of the maleic acid salt of compound 4 was obtained. NMR (DMSO, δppm) 2.25 (s, 3H), 2.26-3.50 (m, 15H), 3.83-4.15 (m, 4H), 6.1
6 (s, 4H), 6.70-6.77 (m, 3H), 7.10-7.39 (m, 11H)

Example 5 Synthesis of Compound 5 1.4 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and m-methoxyphenol and epibromohydrin in the same manner as in Example 1 1 g of 1- (2-epoxypropyloxy) -3-methoxybenzene derived from the above was reacted and purified in 20 ml of methanol to obtain 1.2 g of the title compound. NMR (CDCl ₃ , δppm) 2.20-2.78 (m, 15H), 3.94-4.14 (m, 4H), 4.78 (s, 3H), 6.4
8-6.54 (m, 3H), 7.12-7.32 (m, 11H) From 400 mg of compound 5 and 200 mg of maleic acid,
387 mg of a maleic acid salt of compound 5 was obtained by the same method as in Example 1 using diethyl ether as a solvent. NMR (DMSO, δppm) 2.22-3.60 (m, 15H), 3.72 (s, 3H), 3.85-4.14 (m, 4H), 6.1
4 (s, 4H), 6.47-6.54 (m, 3H), 7.15-7.37 (m, 11H)

Example 6 Synthesis of Compound 6 1 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and m-in the same manner as in Example 1
Derived from nitrophenol and epibromohydrin 1
0.8 g of-(2-epoxypropyloxy) -3-nitrobenzene was reacted and purified in 20 ml of methanol to obtain 1.1 g of the title compound. NMR (CDCl ₃ , δppm) 2.19-2.82 (m, 15H), 3.96-4.18 (m, 4H), 7.13-7.33 (m, 11)
H), 7.43 (t, 1H), 7.75-7.90 (m, 2H) From 300 mg of compound 6 and 160 mg of maleic acid,
327 mg of the maleic acid salt of compound 6 was obtained in the same manner as in Example 1 using diethyl ether as a solvent. NMR (DMSO, δppm) 2.25-3.70 (m, 15H), 3.72 (s, 3H), 3.96-4.13 (m, 4H), 6.1
4 (s, 4H), 7.14-7.43 (m, 11H), 7.59 (dd, 1H), 7.73 (dd, 1
H), 7.83 (dd, 1H)

Example 7 Synthesis of Compound 7 1 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and p-in the same manner as in Example 1
Derived from nitrophenol and epibromohydrin 1
0.8 g of-(2-epoxypropyloxy) -4-nitrobenzene was reacted and purified in 20 ml of methanol to obtain 1.2 g of the title compound. NMR (CDCl ₃ , δppm) 2.20-2.79 (m, 15H), 3.95-4.16 (m, 4H), 6.98 (d, 2H), 7.1
3-7.33 (m, 10H), 8.19 (d, 2H) From 350 mg of compound 7 and 170 mg of maleic acid,
407 mg of the maleic acid salt of compound 7 was obtained in the same manner as in Example 1 using diethyl ether as a solvent. NMR (DMSO, δppm) 2.24-3.75 (m, 15H), 3.96-4.16 (m, 4H), 6.13 (s, 4H), 7.1
3-7.42 (m, 12H), 8.20-8.24 (m, 2H)

Example 8 Synthesis of Compound 8 0.8 g of 1- (3,3-diphenylpropyl) piperazine synthesized as in Example 1 and m-dimethylaminophenol and epibromohydride in the same manner as in Example 1 0.6 g of 4-dimethylamino-1- (2-epoxypropyloxy) benzene derived from phosphorus was reacted and purified in 20 ml of methanol to obtain 0.8 g of the title compound. NMR (CDCl ₃ , δppm) 2.19-3.76 (m, 15H), 3.92 (s, 6H), 3.93-4.12 (m, 4H), 6.2
5-6.39 (m, 3H), 7.09-7.30 (m, 11H) From 320 mg of compound 8 and 250 mg of maleic acid,
By a method similar to that in Example 1, 360 mg of a maleate salt of compound 8 was obtained. NMR (DMSO, δppm) 2.20-3.60 (m, 21H), 3.86-4.09 (m, 4H), 6.13 (s, 4H), 6.1
9-6.35 (m, 3H), 7.06 (t, 1H), 7.16-7.35 (m, 10H)

Example 9 Acute toxicity of the compounds of the present invention The acute toxicity of the compounds 1-8 of the present invention was investigated using ICR mice (male, 5 weeks old, weight 25-35 g). 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 10 Calcium antagonism The calcium antagonism was examined using the thoracic aorta of male Wistar rats (body weight 300 to 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.

[0037]

[Table 1]

Example 11 Effect of 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.

[0039]

[Table 2]

Example 12 Action against 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 (fosmicin): 400 μg / ml, Norfloxacin:
200 μg / ml, ciproxacin: 100 μg / m
l. As a control, 1-diphenylacetyl-4- [3-
(Quinolin-4-yloxy) -2-hydroxypropyl] piperazine (Compound A), 1-dibenzosuberyl-
4- [3- (7-chloroquinolin-4-yloxy)-
2-Hydroxykipropyl] piperazine (Compound B) was used. The results are shown in Table 3. From this, it is clear that the compound of the present invention exhibits a resistance overcoming action against MRSA for which the conventional resistance overcoming agents are difficult to act.

[0041]

[Table 3]

[0042]

[Table 4]

[0043]

[Table 5]

[0044]

[Table 6]

[0045]

[Table 7]

[0046]

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.

─────────────────────────────────────────────────── ─── 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 215/22 295/08 295/08 A ( 56) References JP-A-3-101662 (JP, A) JP-A-4-501711 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 215/20 C07D 215/22 C07D 295/08 A61K 31/495 A61K 31/496 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. 1- (3,3-diphenylpropyl)-
4- [2-hydroxy-3- (quinolin-5-yloxy) propyl] piperazine (Compound 1, Chemical Formula 1), 1-
(3,3-Diphenylpropyl) -4- [3- (7-chloroquinolin-4-yloxy) -2-hydroxypropyl] piperazine (Compound 2, Chemical formula 2), 1- (3,3-
Diphenylpropyl) -4- [2-hydroxy-3-
(3-Methylphenyloxy) propyl] piperazine (Compound 4, Chemical Formula 3), 1- (3,3-diphenylpropyl) -4- [2-hydroxy-3- (3-methoxyphenyloxy) propyl] piperazine (Compound 5, Chemical formula 4), 1- (3,3-diphenylpropyl) -4- [2
-Hydroxy-3- (3-nitrophenyloxy) propyl] piperazine (Compound 6, Chemical formula 5), 1- (3,3-
Diphenylpropyl) -4- [2-hydroxy-3-
(4-Nitrophenyloxy) propyl] piperazine (Compound 7, Chemical formula 6), 4- [3- (3-Dimethylaminophenyloxy) -2-hydroxypropyl] -1-
(3,3-Diphenylpropyl) piperazine (Compound 8, Chemical Formula 7), and physiologically acceptable salts thereof. [Chemical 1] [Chemical 2] [Chemical 3] [Chemical 4] [Chemical 5] [Chemical 6] [Chemical 7] 2. A drug resistance overcoming agent comprising the compound according to claim 1 and / or a physiologically acceptable salt. 3. A pharmaceutical composition for treating cancer, which comprises one or more agents for overcoming the drug resistance according to claim 2. 4. A pharmaceutical composition for preventing or treating a microbial infection, which comprises at least one agent for overcoming the drug resistance according to claim 2. 5. The pharmaceutical composition according to claim 4, wherein the microbial infection is caused by Staphylococcus aureus, malaria parasite, trypanosomes, Escherichia coli or spirochete.