JPH06271556A - Agent for recovering sensitivity to medicine - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an agent for recovering sensitivity of cancer exhibiting resistance to anticancer agents and pathogenic microorganism exhibiting resistance to antiphathogenic microbial agents to medicines. CONSTITUTION:A compound of formula I (X is O, S or imino; R<1> is H, alkyl, alkenyl, etc.; R<2> is formula II, etc.; R<3> to R<7> are H, halogen, alkyl, etc.) and its salt, e.g. 1-[4-(dibenzo[a,d]cycloheptan-1-yl)-1-piperazinyl]-3-phenoxypropane-2- ol. The compound of formula I is obtained by reacting 1-(dibenzo[a, b]cycloheptan-1-yl)-1-piperazine of formula III with epichlorhydrin of formula IV and sodium hydride in DMF to afford an epoxypropyl adduct of formula V and then reacting the epoxypropyl adduct of formula V with a compound of the formula R<2>XH in ethanol. The compound of formula I, etc., is useful in treatment for diseases remarkably endangering human lives, e.g. multiple drug cancer, multiple drug malaria and MRSA.

Description

Detailed Description of the Invention

[0001]

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

[0002]

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

On the other hand, with respect to infectious diseases caused by pathogenic microorganisms, the emergence and spread of resistant strains that have acquired resistance to antipathogenic agents have cast a great shadow on chemotherapy. For example, it is said that about 40% of malaria, which is estimated to have 100 million patients, is chloroquine-resistant malaria. Although these have been treated with novel malaria agents such as mefloquine, chloroquine-resistant strains also show cross-resistance to mefloquine and a sufficient therapeutic effect has not been obtained. Attempts to restore sensitivity are limited to calcium antagonists such as verapemil, which is far from practical use. In Japan, the emergence of MRSA (methicillin-resistant staphylococcus aureus), multidrug-resistant Escherichia coli, penicillin-resistant spirochetes, etc., which have recently been popular in newspapers, is because there is no definitive solution because only new antibiotics are awaited. 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 humanity not only in the treatment of cancer but also in the treatment of infectious diseases, and it restores the drug sensitivity of cancer or pathogenic microorganisms. Developing drugs is significant from an anthropological perspective in the sense that it provides a therapeutic tool for those diseases for which there is no cure.

[0005] Therefore, an object of the present invention is to provide a susceptibility-restoring agent for cancer and pathogenic microorganisms having resistance to anticancer agents and antipathogenic microorganism agents such as antibiotics and antimalarial agents.

[0006]

Means for Solving the Problems As a result of intensive studies in view of such circumstances, the present inventors have found that a specific piperazine derivative has a susceptibility to an anticancer drug of a cancer that has acquired resistance, and Staphylococcus aureus, Escherichia coli, The present invention has been completed by finding that it has an action of restoring the susceptibility of pathogenic microorganisms such as malaria parasite and spirochete to antibiotics and pathogenic microorganism agents such as antiprotozoal agents.

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

[0008]

[Chemical 2]

The property of the compound (1) of the present invention varies depending on the kind and number of substituents, and it is liquid, amorphous or crystalline. Although the solubility varies depending on the substituent, it generally tends to be soluble in an organic solvent such as dimethylsulfoxide, chloroform, methanol and the like, and less soluble in water.

Examples of the compound (1) of the present invention include the compounds shown below. (A) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -3-phenoxypropan-2-ol (b) 1- [4- (dibenzo [a, d] ] Cycloheptan-1-yl) -1-piperazinyl] -3- (3-methylphenoxy) propan-2-ol (c) 1- [4- (dibenzo [a, d] cycloheptan-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] cycloheptan-1-yl) -1-piperazinyl] -3- (4-quinolyl) oxypropan-2-ol (j) 1- [4- (dibenzo [a, d] cycloheptane- 1-yl) -1-piperazinyl] -3- (7-chloro-4-quinolyl) oxypropan-2-ol (k) 1- [4- (dibenzo [a, d] cycloheptan-1-yl)- 1-Piperazinyl] -3- (7-trifluoromethyl-4-quinolyl) oxypropan-2-ol (l) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl ] 3- (7-chloro-4-quinolyl) thiopropan-2-ol (m) 1- [4- (dibenzo [a, d] cycloheptan-1-yl) -1-piperazinyl] -3- (2-ethoxycarbonyl) -4-quinolyl) oxypropan-2-ol (n) 1- [4- (dibenzo [a, d] cycloheptan-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 methods shown in the following production methods 1 to 6.

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

[0013]

[Chemical 3]

Production Method 2 According to the following reaction scheme, compound (6) is reacted with epichlorohydrin (3) in ethanol to give a chlorohydroxypropyl adduct (7), which is prepared in the presence of alkali 1- (dibenzo [3] The compound (1a) of the present invention is obtained by reacting with a, d] cycloheptan-1-yl) piperazine (2).

[0015]

[Chemical 4]

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

[0017]

[Chemical 5]

Production Method 4 1- (Dibenzo [a, d] cyclohexane-1-yl) piperazine (2) is reacted with epichlorohydrin (3) according to the following reaction formula to form a chlorohydroxypropyl adduct (9), The present compound (1a) is obtained by reacting this with the compound (6) in the presence of an alkali.

[0019]

[Chemical 6]

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

[0021]

[Chemical 7]

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

[0023]

[Chemical 8]

[0024] Following the procedure 7 following reaction formula, the compound of the present invention is R ¹ = H ⁽¹
a) was dissolved in pyridine and the compound (16) was added to it at low temperature.
Was added dropwise and reacted at room temperature to give a compound of the present invention (1) in which R ¹ is an acyl group in the general formula (1).
b) is obtained.

[0025]

[Chemical 9]

[0026] Following the procedure 8 the following reaction formula, the compound of the present invention is R ¹ = H ⁽¹
a) was dissolved in pyridine and the compound (17) was added to it at low temperature.
Is added dropwise and reacted at room temperature to obtain the compound of the present invention (1c) in which R ¹ is an acyl group or an alkenyl group in the general formula (1).

[0027]

[Chemical 10]

[0028] Following the procedure 9 the following reaction formula, the compound of the present invention is R ¹ = H ⁽¹
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) by dissolving a) in N, N-dimethylformamide and reacting with compound (18) in the presence of an alkali. (1d) is obtained.

[0029]

[Chemical 11]

The compound (1) of the present invention thus obtained exhibits an excellent susceptibility-restoring action against drug-resistant strains of pathogenic microorganisms and cancer as shown in the Examples below, and is also highly safe. It is useful as a sensitizer for drug resistance.

When the compound (1) of the present invention is used as a drug for recovering susceptibility to drug resistance, its dose varies depending on the patient's age, weight, sex, administration method, physical condition, medical condition, etc. 10 to 2000 mg,
In the case of parenteral administration, 5-1000 mg is suitable.

The agent for recovering sensitivity to drug resistance of the present invention can be made into various dosage forms such as tablets, granules, powders, capsules, suspensions, injections and suppositories by a usual method. 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 Compound (1) Tablets, granules, powders, capsules and suppositories can be prepared by the method. 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 prepare an injection solution, or a powder for solubilization. Examples of the injection method include intravenous administration, intraarterial administration, portal vein administration, intraperitoneal administration, subcutaneous administration, and intralesional direct administration.

The anti-pathogenic microbial agent or anti-cancer agent used together with the sensitivity-restoring agent of the present invention is not particularly limited and may be any agent clinically used. Examples of the anti-cancer agent include adriamycin, mitomycin,
Cisplatin and the like are quinine as an anti-pathogenic microbial agent,
Antimalarial agents such as chloroquine, mefloquine and primaquine, and antibiotics such as penicillin, tetracycline, cephalosporin, chloramphenicol and the like can be mentioned.

Further, these anti-pathogenic microbial agents or anti-cancer agents can be incorporated in the preparation together with the compound (1) of the present invention.

[0035]

EXAMPLES The present invention will be described in more detail below 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]

[Chemical 12]

2.0 g of 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine and 2.0 g of glycidyl phenyl ether were dissolved in 100 ml of ethanol, and 24
After stirring for an hour, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent chloroform: methanol = 95: 5) to obtain 1.53 g of the title compound as white crystals. ¹ H-NMR δppm (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 value: 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]

[Chemical 13]

1.0 g of phenol was dissolved in 50 ml of ethanol, 5 ml of epichlorohydrin was added thereto, and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent, 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine 3.
0 g, potassium carbonate 1.5 g, potassium iodide 1.0 g
And 100 ml of toluene were added and the mixture was heated under reflux for 6 hours. After washing with water and evaporation of the solvent, the residue was purified by silica gel column chromatography (eluting 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]

[Chemical 14]

1 ml of thiophenol was dissolved in 50 ml of methanol, 1.5 g of potassium carbonate and 1.5 g of α-monochloroglycerol were added, and the mixture was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and silica gel column chromatography (eluting solvent chloroform: methanol = 3:
Purified in 1). Dissolve this in 50 ml pyridine,
What melt | dissolved 1.5 g of p-toluene sulfonyl chlorides in 50 ml of chloroform was dripped at it under ice cooling,
Stir at room temperature for 72 hours. Silica gel column chromatography (eluting solvent chloroform: methanol = 9:
Purified in 1), 50 ml of pyridine and 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine 2.
After stirring with 0 g at room temperature for 72 hours, the solvent was distilled off under reduced pressure,
Purification by silica gel column chromatography (eluting solvent chloroform: methanol = 9: 1) gave 1.46 g of the title compound as a colorless amorphous substance. ¹ H-NMR δppm (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]

[Chemical 15]

3.0 g of 1- (dibenzo [a, d] cycloheptan-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,
It was purified by silica gel column chromatography (elution solvent chloroform: methanol = 9: 1). This was dissolved in 50 ml of methanol and heated under reflux with 1.5 g of potassium carbonate and 1 ml of thiophenol for 6 hours. After evaporation of the solvent, silica gel column chromatography (elution solvent
Purification with chloroform: methanol = 9: 1) gave 2.04 g of the title compound as colorless amorphous.

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

[0049]

[Chemical 16]

7-Chloro-4-hydroxyquinoline 1.
8 g was dissolved in 50 ml of N, N-dimethylformamide,
0.4 g of sodium hydride (oily) was added. 10 ml of epichlorohydrin was added thereto, and the mixture was stirred for 24 hours, then the solvent was distilled off and purified by silica gel column chromatography (eluting solvent chloroform: methanol = 98: 2) to give 7-chloro-4- (2-epoxypropyl) quinoline. 0.6 g was obtained. This was dissolved in 100 ml of methanol, 0.85 g of 1- (dibenzo [a, d] cycloheptan-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 (eluting solvent chloroform: methanol = 9: 1), and recrystallized from isopropyl alcohol to obtain 0.47 g of the title compound. ¹ H-NMR δppm (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-
1-piperazinyl] -3- (7-chloro-4-)
Quinolyl) thiopropan-2-ol (compound (l))
Synthesis of:

[0052]

[Chemical 17]

3.0 g of 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine was added to 100 ml of N, N-.
It was dissolved in dimethylformamide, 0.4 g of sodium hydride was added thereto, 5 ml of epichlorohydrin was subsequently added, and the mixture was stirred at room temperature for 48 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 97: 3), added with 0.5 g of 7-chloro-4-mercaptoquinoline, dissolved in 100 ml of methanol and stirred at room temperature for 24 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluting solvent chloroform: methanol = 9: 1) and then recrystallized from ethanol to obtain 0.54 g of the title compound. ¹ H-NMR δppm (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]

[Chemical 18]

3.0 g of 1- (dibenzo [a, d] cycloheptan-1-yl) piperazine was dissolved in 100 ml of N, N-dimethylformamide, and potassium carbonate 1.
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 (eluting solvent chloroform: methanol = 3: 1). This was dissolved in 50 ml of pyridine and p- was added to it while cooling with ice.
A solution of 2.0 g of trienesulfonyl chloride dissolved in 50 ml of chloroform was added dropwise, and the mixture was stirred at room temperature for 24 hours. The mixture 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, 1.0 g of 4-hydroxyquinoline was added thereto, and the mixture was stirred at room temperature for 72 hours, then concentrated under reduced pressure and subjected to silica gel column chromatography (elution solvent chloroform: methanol = 9: 1).
The title compound (1.03 g) was obtained as a colorless amorphous. ¹ H-NMR δppm (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 spectrometry: 480 (M + H)

Example 8 Sensitivity-Restoring Action Against Multidrug-Resistant Cancer Using a cultured cancer cell AUXB1 derived from Chinese hamster and its multidrug-resistant cell CH ^R C5, a sensitizing action against mitomycin was assayed. 10%
A cell dispersion solution having a concentration of 2 × 10 ⁴ cells / ml was prepared with α-MEM medium containing FCS, 100 μl of the cell dispersion solution was dispensed into a 96 wells plate, and cultured at 37 ° C. for 1 day. As a carcinostatic agent, the final concentration of mitomycin is 10 ^-3 to 10 ^-11 M
Was adjusted to 50 μl and added. Furthermore, the compound of the present invention or verapamil as a positive control was diluted and adjusted to a final concentration of 3 × 10 ⁻⁶ M, and 50 μm
1 was added. After culturing at 37 ° C for 3 days, 10 μl of MTT reagent (5 mg / ml) dissolved in PBS was added and the mixture was incubated at 37 ° C for 4
Left for hours. The culture solution was removed, 100 μl of dimethyl sulfoxide was added and mixed well, the absorbance at 570 nm was measured to determine the survival rate, and the IC ₅₀ was calculated from this. 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. The results are shown in Table 1. As is clear from Table 1, all the compounds of the present invention showed a stronger sensitivity-restoring action than verapamil.

[0058]

[Table 1]

Example 9 Drug susceptibility recovery action against MRSA 2 experimental mutant strains that were experimentally methicillin-resistant to S. aureus, and methicillin-resistant Staphylococcus aureus clinical isolates 3 isolated from their parent strain and clinically The MR of the compound of the present invention was determined by measuring the MIC of various antibiotics in the presence and absence of the compound of the present invention.
The effect of recovering drug sensitivity to SA was examined. The test bacterium was inoculated into a broth for susceptibility measurement, precultured at 37 ° C. for 24 hours, and then a bacterium solution adjusted to have a bacterium number of 10 ⁶ / ml was inoculated into a modified Mueller Hinton medium. The compound of the present invention was dissolved in 1 ml of DMSO to give a final concentration of 100 μg.
/ Ml was added to the medium. Only 10% DMSO was used as a negative control. Prepare various antibiotics with the highest concentration (as final concentration)
Sequential adjustments were made by doubling the dilution, and the lowest concentration at which the growth of bacteria was completely inhibited was defined as MIC. Judgment is 42 ℃, 24 after inoculation
It was performed after culturing for a time. 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, fosfomycin: 400
μg / ml, norfloxacin: 400 μg / ml The results are shown in Tables 2-4. As is clear from Tables 2 to 4, all the compounds of the present invention significantly restored the drug sensitivity of MRSA.

[0060]

[Table 2]

[0061]

[Table 3]

[0062]

[Table 4]

Example 10 Sensitivity Restoring Effect on Chloroquine-Resistant Malaria Experimentally prepared chloroquine-resistant murine malaria (P
l. Chabaudi) and the method of Tanabe et al. (Ex
p. Parasitol. , 70 , 419-426, 1
990), the sensitivity recovery action of the compound of the present invention (1) against chloroquine-resistant malaria was examined. That is, I
After infecting CR mice by injecting 10 ⁸ malaria parasites through the tail vein, chloroquine and the compound (l) were dispersed in a 10% dimethylsulfoxide physiological saline solution and subcutaneously administered for 3 consecutive days from 3 days after the infection. . The dose was 3 mg / kg / day for chloroquine and 50 mg / kg / day for compound (1). The drug concentration was adjusted so that the total dose was 0.1 ml. A control group of chloroquine was injected with a 10% dimethyl sulfoxide physiological saline solution instead of the compound (1). In addition, a 10% dimethylsulfoxide physiological saline solution was administered instead of chloroquine to the control group of compound (l). In the experimental control group, 10% dimethylsulfoxide physiological saline solution was administered instead of chloroquine and compound (1). Blood was collected 24 hours after the end of drug administration, and the ratio of malaria-infected red blood cells to total red blood cells in the blood was determined. The results are shown in Table 5. 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]

INDUSTRIAL APPLICABILITY Since the agent for recovering susceptibility to drug resistance of the present invention exhibits an excellent sensitizing effect, it is extremely useful for the treatment of remarkably life-threatening diseases such as multidrug resistant cancer, multidrug resistant malaria and MRSA. , Is of great significance in the treatment of patients with these diseases, which may amount to hundreds of millions.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 31/50 7431-4C 31/505 7431-4C 31/53 7431-4C 31/645 7431-4C C07D 215/22 215/36 215/38 215/48 217/22 217/24 253/08 295/12 A (72) Inventor Makoto Kimura 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. (72) Inventor Katsumi Hasuda 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd.Pharmaceutical Research Laboratory (72) Inventor Takao Ito 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. ) Inventor Toyohiko Miki 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Masahiko Tsuchiya 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa -La Chemical Industry Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Shoichi Sakaguchi 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Takeuchi Tsutomu, Setagaya-ku, Tokyo 3-21- 6 (72) Inventor Kobayashi Regular 3-9-15 Tajiri Tajiri, Ichikawa City, Chiba Fuji Mansion 605

Claims (3)

[Claims] 1. A compound represented by the following general formula (1) and a salt thereof. [Chemical 1] 2. A drug susceptibility-restoring agent for drug-resistant cancer and drug-resistant pathogenic microorganisms, which comprises the compound (1) according to claim 1 or a salt thereof. 3. A medicine comprising the compound (1) according to claim 1 or a salt thereof and an anticancer agent or an antipathogenic microbial agent.