JP3345455B2 - Drug reversal agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for restoring susceptibility to a drug of a cancer resistant to an anticancer drug or a pathogenic microorganism resistant to an antipathogenic microbial agent, and a pharmaceutical containing the same.

[0002]

2. Description of the Related Art In recent years, cancer has become a leading cause of death along with cardiovascular diseases in a cultural society, and has become an important issue to be solved by society. In cancer treatment, chemotherapy with anticancer drugs such as adriamycin, mitomycin, and cisplatin has become an important treatment along with radiation therapy and surgery.However, the emergence of strains that are resistant to anticancer drugs has shown a therapeutic effect. Significantly inhibited. Attempts have been made to restore the sensitivity of these resistant cancers with calcium antagonists such as veraparmil, but this is not practical because the degree of sensitivity recovery is not sufficient, and the available dose is limited due to side effects. There are many.

On the other hand, with regard to infectious diseases caused by pathogenic microorganisms, the emergence and spread of resistant strains that have acquired resistance to antipathogenic microbial agents have cast a great influence on chemotherapy. For example, it is said that about 40% of malaria estimated to have 100 million patients is chloroquine-resistant malaria. These have been treated with a novel malaria drug such as mefloquine, but chloroquine-resistant strains also show cross-resistance to mefloquine, and a sufficient therapeutic effect has not been obtained. Attempts to restore sensitivity have been limited to calcium antagonists such as verapemil, which is far from practical. The emergence of MRSA (methicillin-resistant staphylococcus), multi-drug-resistant Escherichia coli, penicillin-resistant spirochetes, etc., which has recently been popular in newspapers in Japan, is awaiting the emergence of new antibiotics, and there is no definitive solution. It can be said to be a large dark cloud in infectious disease chemotherapy.

[0004]

As described above, the problem of drug-resistant strains is an important problem to be solved by human beings not only in the treatment of cancer but also in the treatment of infectious diseases, and restores drug sensitivity of cancer or pathogenic microorganisms. Developing a drug is significant from a human perspective in the sense that it provides a cure for these diseases for which there is no cure.

Accordingly, it is an object of the present invention to provide an agent for restoring susceptibility to cancer and pathogenic microorganisms, which has resistance to anticancer agents, antimicrobial agents such as antibiotics and antimalarial agents.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above situation, and as a result, have found that a specific piperazine derivative is susceptible to an anticancer agent of a cancer that has acquired resistance, and that Staphylococcus aureus, Escherichia coli, The present invention has been found to have an effect of restoring the susceptibility of pathogenic microorganisms such as malaria parasites and spirochetes to pathogenic microorganisms such as antibiotics and antiprotozoal agents, and completed the present invention.

That is, the present invention relates to a compound represented by the following general formula (1) and a salt thereof, and a drug-sensitizing agent and a medicine containing the compound.

[0008]

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The properties of the compound (1) of the present invention vary depending on the type and number of the substituents, and are in a liquid, amorphous or crystalline state. Although its solubility varies depending on the substituents, it generally tends to be easily soluble in organic solvents such as dimethyl sulfoxide, chloroform, methanol and the like and hardly soluble in water.

The compound (1) of the present invention includes, for example, the following compounds. (A) 1- [4- (dibenzo [a, d] cycloheptane-1-yl) -1-piperazinyl] -3-phenoxypropan-2-ol (b) 1- [4- (dibenzo [a, d ] Cycloheptane-1-yl) -1-piperazinyl] -3- (3-methylphenoxy) propan-2-ol (c) 1- [4- (dibenzo [a, d] cycloheptane-1-yl)- 1-piperazinyl] -3- (3-methoxyphenoxy) propan-2-ol (d) 1- [4- (dibenzo [a, d] cyclopeptan-1-yl) -1-piperazinyl] -3-anilinopropane -2-ol (e) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -3-phenylthiopropan-2-ol (f) 1- [4- ( Dibenzo [a, d] cyclo (Butan-1-yl) -1-piperazinyl] -3- (2-bromophenylthio) propan-2-ol (g) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1 -Piperazinyl] -2-methoxy-3
-Phenoxypropane (h) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -2-ethylcarbonyloxy-3-phenoxypropane (i) 1- [4- ( Dibenzo [a, d] cycloheptane-1-yl) -1-piperazinyl] -3- (2-allyl-4-methylphenoxy) propan-2-ol

The compound (1) of the present invention can be easily synthesized, for example, according to the following production methods 1 to 6.

Production method 1 According to the following reaction formula, 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine (2) is reacted with epichlorohydrin (3) and sodium hydride (4) in dimethylformamide. To give an epoxypropyl adduct (5), and then reacting the compound (6) in ethanol to obtain a compound (1a) of the general formula (1) in which R ¹ = H.

[0013]

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Production Method 2 According to the following reaction formula, epichlorohydrin (3) is reacted with compound (6) in ethanol to form a chlorohydroxypropyl adduct (7), which is converted to 1- (dibenzo [ a, d] cycloheptane-1-yl) piperazine (2) to give the compound (1a) of the present invention.

[0015]

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Production method 3 According to the following reaction formula, epichlorohydrin (3) and sodium hydride (4) are reacted with compound (6) to give an epoxypropyl adduct (8), which is converted to 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine (2) to give the compound of the present invention (1
a) is obtained.

[0017]

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Production method 4 According to the following reaction formula, 1- (dibenzo [a, d] cyclohexane-1-yl) piperazine (2) is reacted with epichlorohydrin (3) to give a chlorohydroxypropyl adduct (9). This is reacted with compound (6) in the presence of an alkali to obtain compound (1a) of the present invention.

[0019]

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Production method 5 According to the following reaction formula, α-monochloroglycerol (10) is reacted with 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine (2) in the presence of an alkali to add dihydroxypropyl. Compound (13) is obtained by reacting it with p-toluenesulfonyl chloride (12) at a low temperature in the presence of an alkali to form only the primary hydroxyl group, thereby obtaining compound (13). Then, this is reacted with the compound (6) in the presence of an alkali to obtain the compound (1a) of the present invention.

[0021]

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Production Method 6 According to the following reaction formula, the compound (6) is reacted with α-monochloroglycerol (10) to form a dihydroxypropyl adduct (14), and this is converted to p-toluenesulfonyl chloride in the presence of an alkali at a low temperature. Reaction with (12) to tosylate only the primary hydroxyl group to obtain monotosyl ester (15). This is then added in the presence of alkali 1-
The compound (1a) of the present invention can be obtained by reacting the compound with (dibenzo [a, d] cycloheptan-1-yl) piperazine (2).

[0023]

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Production Method 7 According to the following reaction formula, the compound of the present invention (1) wherein R ¹ = H
a) is dissolved in pyridine, and the compound (16) is added thereto at low temperature.
Is reacted dropwise at room temperature to give the compound of the present invention (1) in which R ¹ is an acyl group in the general formula (1).
b) is obtained.

[0025]

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Production method 8 According to the following reaction formula, the compound of the present invention (1) wherein R ¹ = H
a) is dissolved in pyridine, and the compound (17) is added thereto at low temperature.
Is added dropwise and reacted at room temperature to obtain the compound (1c) of the general formula (1) in which R ¹ is an acyl group or an alkenyl group.

[0027]

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[0028] Following the procedure 9 the following reaction formula, the compound of the present invention is R ¹ = H ⁽¹
a) is dissolved in N, N-dimethylformamide and reacted with compound (18) in the presence of an alkali, whereby the compound of the present invention wherein R ¹ is an alkyl group, an alkenyl group or an aryl group in the general formula (1) (1d) is obtained.

[0029]

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The compound (1) of the present invention thus obtained exhibits an excellent effect of restoring susceptibility to drug-resistant strains of pathogenic microorganisms and cancer and has high safety as shown in the Examples below. It is useful as an agent for restoring susceptibility to drug resistance.

When the compound (1) of the present invention is used as an agent for restoring susceptibility to drug resistance, its dosage varies depending on the age, weight, sex, administration method, physical condition, disease state, etc. of the patient. 10 to 2000 mg,
For parenteral administration, 5-1000 mg is appropriate.

The agent for restoring susceptibility to drug resistance of the present invention can be made into various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by usual methods. In the case of a solid preparation, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a bulking agent, a coating agent, a sugar coating agent and the like are added to the compound (1). Depending on the method, tablets, granules, powders, capsules, and suppositories can be prepared. In the case of an injection, the compound (1) of the present invention can be dissolved, dispersed or emulsified in an aqueous carrier such as physiological saline for injection to give an injection solution or a powder for business dissolution. Examples of the method of administering the injection include intravenous administration, intraarterial administration, intraportal administration, intraperitoneal administration, subcutaneous administration, and direct intralesional administration.

The antipathogenic microbial agent or anticancer agent used together with the sensitizing agent of the present invention is not particularly limited, and may be any clinically used one. Examples of the anticancer agent include adriamycin, mitomycin, and mitomycin.
Cisplatin and the like, quinine as an antipathogenic microbial agent,
Examples include antimalarial agents such as chloroquine, mefloquine and primaquine, and antibiotics such as penicillin, tetracycline, cephalosporin, and chloramphenicol.

Further, these antipathogenic microbial agents or anticancer agents can be incorporated in the preparation together with the compound (1) of the present invention.

[0035]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 1- [4- (dibenzo [a, d] cycloheptane-1-)
Synthesis of yl) -1-piperazinyl] -3-phenoxypropan-2-ol (compound (a)):

[0037]

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2.0 g of 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine and 2.0 g of glycidylphenyl ether were dissolved in 100 ml of ethanol,
After stirring for an hour, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 95: 5) to obtain 1.53 g of the title compound as white crystals. ¹ H-NMR δ ppm (CDCl ₃ ): 2.325-2.570 (m, 12H), 2.693-2.8
84 (m, 2H), 3.857-4.099 (m, 5H), 6.803-7.352 (m, 13H) Mass: 429 (M + 1) Elemental analysis: N 6.53% C 78.22% H 7.58%

Example 2 1- [4- (dibenzo [a, d] cycloheptane-1-)
Synthesis of yl) -1-piperazinyl] -3-phenoxypropan-2-ol (compound (a)):

[0040]

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1.0 g of phenol was dissolved in 50 ml of ethanol, and 5 ml of epichlorohydrin was added thereto, followed by stirring at room temperature for 24 hours. After evaporation of the solvent, 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine3.
0 g, potassium carbonate 1.5 g, potassium iodide 1.0 g
And 100 ml of toluene, and the mixture was heated under reflux for 6 hours. After washing with water and distilling off the solvent, the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 95: 5) and recrystallized from ethanol to give the title compound 2.6
0 g was obtained as white crystals.

Example 3 1- [4- (dibenzo [a, d] cycloheptane-1-)
Synthesis of yl) -1-piperazinyl] -3-phenylthiopropan-2-ol (compound (e)):

[0043]

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1 ml of thiophenol was dissolved in 50 ml of methanol, and 1.5 g of potassium carbonate and 1.5 g of α-monochloroglycerol were added thereto, followed by heating under reflux for 6 hours. The solvent was distilled off under reduced pressure, and silica gel column chromatography (elution solvent: chloroform: methanol = 3:
Purified in 1). This is dissolved in 50 ml of pyridine,
A solution prepared by dissolving 1.5 g of p-toluenesulfonyl chloride in 50 ml of chloroform was added dropwise thereto under ice-cooling.
Stirred at room temperature for 72 hours. Silica gel column chromatography (elution solvent: chloroform: methanol = 9:
Purified in 1), 50 ml of pyridine and 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine
After stirring at 0 g and room temperature for 72 hours, the solvent was distilled off under reduced pressure.
Purification by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1) gave 1.46 g of the title compound as a colorless amorphous. ¹ H-NMR δ ppm (CDCl ₃ ): 2.170-2.536 (m, 12H), 2.675-2.8
54 (m, 2H), 2.926-3.217 (m, 2H), 3.727-3.907 (m, 1H), 3.9
38-4.048 (m, 2H), 7.021-7.378 (m, 13H) Mass: 445 (M + H)

Example 4 1- [4- (dibenzo [a, d] cycloheptane-1-
Synthesis of yl) -1-piperazinyl] -3-phenylthiopropan-2-ol (compound (e)):

[0046]

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3.0 g of 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine was dissolved in 50 ml of methanol, 10 ml of epichlorohydrin was added thereto, and the mixture was stirred at room temperature for 24 hours. After the reaction, the reaction product was concentrated under reduced pressure,
Purification was performed by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1). This was dissolved in 50 ml of methanol, and heated under reflux for 6 hours together with 1.5 g of potassium carbonate and 1 ml of thiophenol. After evaporating the solvent, silica gel column chromatography (eluent
Purification with chloroform: methanol = 9: 1) gave 2.04 g of the title compound as a colorless amorphous.

Example 5 1- [4- (dibenzo [a, d] cycloheptane-1-
Yl) -1-piperazinyl] -3- (7-chloro-4-
Synthesis of quinolyl) oxypropan-2-ol (compound (j)):

[0049]

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7-Chloro-4-hydroxyquinoline
8 g was dissolved in 50 ml of N, N-dimethylformamide,
0.4 g of sodium hydride (oily) was added. To this was added 10 ml of epichlorohydrin, and after stirring for 24 hours, the solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 98: 2), and 7-chloro-4- (2-epoxypropyl) quinoline 0 was purified. 0.6 g was obtained. This was dissolved in 100 ml of methanol, 0.85 g of 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine was added, and the mixture was stirred at room temperature for 96 hours. The reaction product was concentrated under reduced pressure, purified by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1), and recrystallized from isopropyl alcohol to obtain 0.47 g of the title compound. ¹ H-NMR δ ppm (CDCl ₃ ): 2.30-2.70 (m, 11H), 2.75-2.86
(m, 2H), 3.91-4.08 (m, 3H), 4.12-4.26 (m, 3H), 6.74 (d, 1
H), 7.05-7.21 (m, 8H), 7.37-7.47 (dd, 1H), 8.01 (d, 1H),
8.15 (d, 1H), 8.71 (d, 1H) Mass: 514 (M + H) Elemental analysis: N 7.16% C 69.68% H 6.74%

Example 6 1- [4- (dibenzo [a, d] cycloheptane-1-)
Yl) -1-piperazinyl] -3- (7-chloro-4-
Quinolyl) thiopropan-2-ol (compound (l))
Synthesis of:

[0052]

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3.0 g of 1- (dibenzo [a, d] cycloheptane-1-yl) piperazine was added to 100 ml of N, N-
It was dissolved in dimethylformamide, and 0.4 g of sodium hydride was added thereto, followed by 5 ml of epichlorohydrin, and the mixture was stirred at room temperature for 48 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 97: 3), 0.5 g of 7-chloro-4-mercaptoquinoline was added, dissolved in 100 ml of methanol, and stirred at room temperature for 24 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1), and recrystallized from ethanol to obtain 0.54 g of the title compound. ¹ H-NMR δ ppm (DMSO): 2.12-2.51 (m, 8H), 2.62-2.81 (m, 2
H), 3.09-3.22 (m, 1H), 3.78-4.09 (m, 5H), 6.88-7.21 (m, 8
H), 7.55 (d, 1H), 7.62 (dd, 1H), 8.01 (d, 1H), 8.11 (d, 1
H), 8.71 (d, 1H) Mass: 530 (M + H) Elemental analysis: N 7.70% C 70.42% H 6.07%

Example 7 1- [4- (dibenzo [a, d] cycloheptane-1-
Synthesis of yl) -1-piperazinyl] -3- (4-quinolyl) oxypropan-2-ol (compound (i)):

[0055]

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3.0 g of 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine was dissolved in 100 ml of N, N-dimethylformamide, and potassium carbonate was added thereto.
5 g, 0.5 g of sodium iodide and 5 ml of α-monochloroglycerol were added, and the mixture was heated under reflux for 4 hours. The reaction product was concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent: chloroform: methanol = 3: 1). This was dissolved in 50 ml of pyridine, and p-
A solution of 2.0 g of triene sulfonyl chloride dissolved in 50 ml of chloroform was added dropwise, and the mixture was stirred at room temperature for 24 hours. It was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1). This was dissolved in 50 ml of pyridine, to which 1.0 g of 4-hydroxyquinoline was added, and the mixture was stirred at room temperature for 72 hours, then concentrated under reduced pressure, and silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1).
And 1.03 g of the title compound was obtained as a colorless amorphous. ¹ H-NMR δ ppm (CDCl ₃ ): 1.642 (bs, 6H), 2.340-2.669 (m, 6
H), 2.748-2.834 (m, 2H), 3.914-4.176 (m, 5H), 6.176 (d, 1
H), 7.025-7.200 (m, 8H), 7.303 (t, 1H), 7.466 (d, 1H), 7.
579-7.656 (m, 2H), 8.322 (d, 1H) Mass spec: 480 (M + H)

Example 8 Effect of Restoring Sensitivity to Multidrug-Resistant Cancer The effect of mitomycin on sensitivity to mitomycin was assayed using cultured cancer cells AUXB1 derived from Chinese hamster and its multidrug-resistant cell CH ^R C5. 10%
A cell dispersion solution having a concentration of 2 × 10 ⁴ cells / ml was prepared in an α-MEM medium containing FCS, and 100 μl of the solution was dispensed to a 96-wells plate and cultured at 37 ° C. for 1 day. Mitomycin is used as an anticancer drug at a final concentration of 10 ^-3 to 10 ^-11 M.
And adjusted to 50 μl. Furthermore, the compound of the present invention or verapamil as a positive control was diluted to adjust the final concentration to 3 × 10 ⁻⁶ M,
l was added. After culturing at 37 ° C. for 3 days, 10 μl of MTT reagent (5 mg / ml) dissolved in PBS was added.
Left for hours. The culture solution was removed, 100 μl of dimethyl sulfoxide was added, and the mixture was mixed well. The absorbance at 570 nm was measured to determine the survival rate, from which the IC ₅₀ was calculated. CH ^R
The value obtained by dividing an IC ₅₀ value of mitomycin for C5 with IC ₅₀ values of mitomycin for AUXB1 was used as an indicator of the strength of the sensitive healing. Table 1 shows the results. As is clear from Table 1, all of the compounds of the present invention showed a stronger sensitivity-recovering action than verapamil.

[0058]

[Table 1]

Example 9 Effect of Restoring Drug Sensitivity to MRSA Two experimental mutant strains that experimentally imparted methicillin resistance to Staphylococcus aureus, and its parent strain and a clinical isolate 3 of methicillin-resistant Staphylococcus aureus isolated from clinical practice By measuring the MIC of various antibiotics in the presence and absence of the compound of the present invention, the MR of the compound of the present invention was determined.
The effect of restoring drug sensitivity to SA was examined. The test bacterium was inoculated into a broth for sensitivity measurement, and after pre-cultivation at 37 ° C. for 24 hours, a bacterial solution adjusted so that the number of bacteria was 10 ⁶ cells / ml was inoculated into an improved Muller Hinton medium. The compound of the present invention is dissolved in 1 ml of DMSO, and the final concentration is 100 μg.
/ Ml and added to the medium. Only 10% DMSO was used as a negative control. Various antibiotics are prepared at the highest concentration (as the final concentration).
The MIC was determined as the MIC with the lowest concentration at which the growth of the bacteria was completely inhibited. Judgment is 24 ° C, 24 after inoculation
This was performed after culturing for an hour. The maximum concentrations of various antibiotics were as follows. Methicillin: 800 μg / ml, cefmetazole: 100
μg / ml, erythromycin: 400 μg / ml, kanamycin: 400 μg / ml, phosphomycin: 400
μg / ml, norfloxacin: 400 μg / ml The results are shown in Tables 2 to 4. As is clear from Tables 2 to 4, all of the compounds of the present invention significantly restored the drug sensitivity of MRSA.

[0060]

[Table 2]

[0061]

[Table 3]

[0062]

[Table 4]

Example 10 Restoring Sensitivity to Chloroquine-Resistant Malaria Experimentally produced chloroquine-resistant murine malaria (P
l. Using the method of Tanabe et al. (Ex.
p. Parasitol. , 70 , 419-426, 1
990), the effect of the compound (l) of the present invention on the recovery of chloroquine-resistant malaria sensitivity was examined. That is, I
After infection by injection of 10 ⁸ Plasmodium from the tail vein CR mice were subcutaneously administered dispersed chloroquine and the compound (l) in 10% dimethyl sulfoxide saline solution in succession than after 3 days 4 days . The dose was 3 mg / kg / day for chloroquine and 50 mg / kg / day for compound (l). The drug concentration was adjusted so that the total dose was 0.1 ml. The chloroquine control group was injected with a 10% dimethyl sulfoxide saline solution instead of compound (l). In addition, a 10% dimethylsulfoxide physiological saline solution was administered to the control group of compound (l) instead of chloroquine. To the experimental control group, a 10% dimethyl sulfoxide physiological saline solution was administered instead of chloroquine and compound (l). Blood was collected 24 hours after the end of drug administration, and the ratio of malaria-infected erythrocytes to total erythrocytes in the blood was determined. Table 5 shows the results. As is clear from this table, the compound of the present invention significantly restored the chloroquine sensitivity of the chloroquine-resistant malaria strain.

[0064]

[Table 5]

[0065]

EFFECTS OF THE INVENTION Since the agent for restoring susceptibility to drug resistance of the present invention exhibits an excellent effect of restoring susceptibility, it is extremely useful for treating life-threatening diseases such as multidrug-resistant cancer, multidrug-resistant malaria and MRSA. It is of great significance in treating patients with these diseases, which will reach hundreds of millions.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 31/04 A61P 31/04 33/06 33/06 35/00 35/00 43/00 121 43/00 121 C07D 215/22 C07D 215/22 215/36 215/36 215/38 215/38 215/48 215/48 217/22 217/22 217/24 217/24 253/08 253/08 295/12 295/12 A (72) Inventor Makoto Kimura 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture, Pharmaceutical Research Laboratories (72) Inventor Katsumi Hasada 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Pharmaceutical Research Laboratories (72) Inventor Takao Ito 560 Kashio-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratories (72) Inventor Toyohiko Miki 560 Kashio-cho, Kashio-cho, Totsuka-ku, Yokohama-shi Kanagawa Pref. Inventor Masahiko Tsuchiya God 560 Paula Kasei Kogyo Co., Ltd., Pharmaceutical Research Laboratory, Totsuka-ku, Yokohama, Japan (72) Inventor Shoichi Sakaguchi 560 Pola Kasei Kogyo Co., Ltd. Work 3-21-6 Okamoto, Setagaya-ku, Tokyo (72) Inventor Tadashi Kobayashi 3-9-15 Tajiri, Ichikawa-shi, Chiba Fuji Mansion 605 (56) References JP-A-3-101662 (JP, A) Kaihei 4-230376 (JP, A) Table 2 Hei 5-500979 (JP, A) WO 92/18131 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 295 / 08 C07D 295/12 C07D 215/22 C07D 215/36 C07D 215/38 C07D 215/48 C07D 217/22 C07D 217/24 C07D 253/08 A61K 31/495 A61K 31/50 A61K 31/505 A61K 31/53 A61P 31/04 A61P 33/06 A61P 35/00 A61P 43/00 121 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound represented by the following general formula (1) and a salt thereof. Embedded image 2. An agent for restoring drug sensitivity to multidrug-resistant cancer, methicillin-resistant Staphylococcus aureus or chloroquine-resistant malaria, comprising the compound represented by the general formula (1) according to claim 1.