JPH04235983A - Novel quinoline derivative and carcinostatic effect-enhancing agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To provide a novel quinoline derivative having a strong carcinostatic effect-enhancing activity against resistant cancers as a carcinostatic effect- enhancing agent, low toxicity and reduced adverse actions. CONSTITUTION:A compound of formula I [A is group of formula II or III (B is benzene ring or hetero ring condensed with the adjacent ring; R<2> is H, OH, etc.; R<3>, R<4> are substituted phenyl or hetero ring; R<5> is H, halogen, etc.; Y is NHCO, S, etc.); R<1> is R<2>, or R<1> and R<2> are bonded to each other to form a double bond] and a salt thereof, e.g. 5-[3-{4-(bis(2-chlorophenyl)methylene) piperidin-1-yl}-2hydroxypropoxy]quinoline. The compound is produced e.g. by reacting 5-(2,3-epoxypropoxy)quinoline with the corresponding amine derivative of formula V in the presence of a base such as pyridine in an organic solvent such as DMF.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a novel compound and an anticancer drug effect enhancer containing the same as an active ingredient.

0002

BACKGROUND OF THE INVENTION The number of cancer patients is increasing year by year, and the mortality rate due to cancer is the highest in Japan, and there is a high level of social interest in cancer treatment. Research and development of anticancer drugs for the treatment of cancer has been actively carried out, and various anticancer drugs are used clinically for the treatment of cancer. Although its effectiveness is steadily improving year by year, in many cases it is not always possible to achieve a satisfactory effect in completely suppressing cancer growth and maintaining the survival of cancer patients for a long period of time. In addition, many attempts are currently being made clinically to enhance the effects of anticancer drugs by combining multiple anticancer drugs (multidrug combination therapy). but,
This case is also unsatisfactory as a chemotherapy method for cancer, and there is a strong need for the development of new cancer therapeutics from a new perspective. Under these circumstances, one possible method would be to develop a more powerful anticancer drug or a method for more selectively transporting the anticancer drug to the target organ. These studies are currently being carried out all over the world, but the current situation is that they are becoming increasingly difficult.

On the other hand, another important method is to attempt to enhance the effects of existing anticancer drugs. In particular, the development of agents that enhance the effects of existing anticancer drugs against drug-resistant cancer, which is a serious clinical problem in cancer chemotherapy, is considered to be a very important new cancer treatment method. The background of clinical resistance to anticancer drugs is not necessarily simple.

[0004] Clinical resistance can be roughly divided into two aspects. The first is when the cause is sought in an individual cancer patient, and the second is when the cause is sought in the cancer cells themselves. In recent years, the mechanism of resistance in this second case is being elucidated at the molecular level, and treatment methods for this are also being investigated. In other words, a gene responsible for multidrug resistance has recently been isolated, and this gene is a membrane protein expressed in multidrug-resistant cells, P-glycoprotein (P-glycoprotein).
It was revealed that the gene is a gene of coprotein. P-glycoprotein is presumed to be a protein that has the function of excreting anticancer drugs from cells, and is considered to be a protein that plays a central role in the multidrug resistance mechanism. In addition, some mechanisms have been suggested to be common to cancers that are inherently difficult to respond to anticancer drugs, such as solid cancers. In other words, many anticancer drugs pass through the cell membrane and exert their effects within the cell, but in resistant cancer cells, the inflowing anticancer drug is excreted outside the cell by the action of this P-glycoprotein, and the drug concentration within the cancer cell decreases. is kept low. As a result, it is thought that the effects of anticancer drugs are less likely to be expressed.

[0005] Therefore, the present inventors believe that a substance that suppresses the action of P-glycoprotein and inhibits the outflow of anticancer drugs from cancer cells has the effect of enhancing the effect of anticancer drugs, and is particularly effective in overcoming resistance. We believe that it can be used as a new cancer chemotherapeutic agent.

In fact, Tsuruo et al. have shown that calcium antagonists such as verapamil block the outflow of anticancer drugs from cancer cells, and therefore, when used in combination with resistant cancers, can reduce the effects of anticancer drugs such as adriamycin and vincristine in vitro and in vivo. It has been found that it has a reinforcing effect. However, when these calcium antagonists are used clinically in cancer patients, side effects such as a decrease in blood pressure and induction of arrhythmia appear, which poses a major problem as a cancer treatment agent.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug that has a stronger effect of enhancing anticancer drug effects on resistant cancers and has fewer side effects.

[0008]

[Means for Solving the Problems] In view of the above points, the present inventors have made extensive studies and have found that a specific compound exhibits a strong effect of enhancing anticancer drug effects against resistant cancers, and has low toxicity and low side effects. The present invention was completed based on this discovery.

Specifically, the present invention provides compounds represented by the following general formula (1) and salts thereof, anticancer drug effect enhancers containing these as active ingredients,

0010

[C6] In the formula, A is

[0011]

Represents [Chemical 7]. B represents a benzene ring or a heterocycle fused to an adjacent ring. R1 and R2 each independently represent a hydrogen atom or a hydroxy group, or R1 and R2 combine to form a double bond. R3 and R4 each independently represent a substituted phenyl group or a heterocycle. R5
represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an amino group, a substituted amino group, a cyano group, a nitro group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, and all possible groups on the ring position can be taken. Y is -CH2CH2
- (except when R5 is hydrogen), -NHC
O-, -NHCH2-, -CH(OH)CH(OH
)-, -SCH2-, -S-. ) and 5-(2,3-epoxypropoxy)quinoline and the corresponding amine derivative are reacted thermally or in the presence of a base.

[0012] The substituted phenyl group mentioned here refers to a group substituted at the 2-, 3- or 4-position with a halogen atom, lower alkyl group, lower alkoxy group, substituted amino group, cyano group, hydroxy group, or carboxyl group. means phenyl group. The heterocycle means a pyridine ring, a thiophene ring, a pyran ring, a pyrrole ring, an imidazole ring, a pyrimidine ring, an isoquinoline ring, a quinoline ring, and the like. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, etc. The lower alkyl group means a methyl group, ethyl group, propyl group, butyl group, etc. The lower alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and the like. Moreover, the substituted amino group means a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a propylamino group, a butylamino group, and the like. Further, the alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, and the like.

[0013] As a preferable compound, the following general formula (2) is used.
- (4) Compounds can be mentioned.

[Chemical formula 8] (In the formula, R3 and R4 have the same meaning as in general formula (1).)

[0014]

embedded image (in the formula, R6 and R7 each independently represent a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an amino group, a substituted amino group, a cyano group,
It can take on all possible positions on the ring. )

0
015]

embedded image (In the formula, Y and R5 have the same meanings as in the general formula (1).) Specific examples of the compounds include the following compounds.

5-[3-{4-(bis(2-chlorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(
3-chlorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-
{4-(bis(4-chlorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(2-chlorophenyl)methylene)piperidin-1-yl} -2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(3-fluorophenyl)methylene)piperidin-1-yl}-2-
Hydroxypropoxy]quinoline, 995-[3-{4
-(bis(4-fluorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline,
5-[3-{4-(bis(2-bromophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(3-bromophenyl)methylene) piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-bromophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3
-{4-(bis(2-methylphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(3-methylphenyl))
methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-methylphenyl)methylene)piperidin-1-yl}-2
-hydroxypropoxy]quinoline, 5-[3-{4-
(bis(2-ethylphenyl)methylene)piperidine-
1-yl}-2-hydroxypropoxy]quinoline, 5
-[3-{4-(bis(3-ethylphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-ethylphenyl)methylene)piperidine -1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(
2-methoxyphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3
-{4-(bis(3-methoxyphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-methoxyphenyl)methylene)piperidine-1- yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4
-ethoxyphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-
{4-(bis(4-propoxyphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-butoxyphenyl)methylene)piperidin-1-yl }-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(2
-Methylaminophenyl)methylene)piperidine-1-
yl}-2-hydroxypropoxy]quinoline, 5-[
3-{4-(bis(3-methylaminophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-methylaminophenyl)methylene)piperidine -1-yl}-2
-hydroxypropoxy]quinoline, 5-[3-{4-
(bis(2-dimethylaminophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(3-dimethylaminophenyl)methylene)piperidin-1-yl} -2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-dimethylaminophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline,
5-[3-{4-(bis(4-diethylaminophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-
dipropylaminophenyl)methylene)piperidine-1
-yl}-2-hydroxypropoxy]quinoline, 5-
[3-{4-(bis(4-dibutylaminophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-methoxycarbonylphenyl)methylene) piperidine-1-
yl}-2-hydroxypropoxy]quinoline, 5-[
3-{4-(bis(4-ethoxycarbonylphenyl)
methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-propoxycarbonylphenyl)methylene)piperidine-
1-yl}-2-hydroxypropoxy]quinoline, 5
-[3-{4-(Hydroxy-bis(2-chlorophenyl)methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(hydroxy-bis(3-chlorophenyl)methyl) ) piperidine-1
-yl}-2-hydroxypropoxy]quinoline, 5-
[3-{4-(hydroxy-bis(4-chlorophenyl)methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(hydroxy-
Bis(2-fluorophenyl)methyl)piperidine-1-
yl}-2-hydroxypropoxy]quinoline, 5-[
3-{4-(hydroxy-bis(3-fluorophenyl)
methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(hydroxy-bis(4-fluorophenyl)methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3
-{4-(bis(4-cyanophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-nitrophenyl))
methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(bis(4-hydroxyphenyl)methylene)piperidin-1-yl}
-2-hydroxypropoxy]quinoline, 5-[3-{
4-(bis(4-carboxyphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(hydroxy-phenyl-(2
-pyridyl)methylene)piperidin-1-yl}-2-
Hydroxypropoxy]quinoline, 5-[3-{4-(
hydroxy-phenyl-(3-pyridyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(hydroxy-phenyl-(
4-pyridyl)methylene)piperidin-1-yl}-2
-hydroxypropoxy]quinoline, 5-[3-{4-
(phenyl-(2-pyridyl)methylene)piperidine-
1-yl}-2-hydroxypropoxy]quinoline, 5
-[3-{4-(phenyl-(3-pyridyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(phenyl-(4-pyridyl)methylene)piperidine -1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(phenyl-(2-thiophenyl)methylene)piperidine-1-
yl}-2-hydroxypropoxy]quinoline, 5-[
3-{4-(phenyl-(3-thiophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(phenyl-(2-pyranyl)methylene)piperidine-1 -yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(phenyl-(3-pyranyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline, and the like.

Examples of the salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid and sulfuric acid, or organic acids such as acetic acid, oxalic acid, maleic acid and tartaric acid. Further, since the compound of the present invention has an asymmetric carbon in its structure, optical isomers exist, and the compound of the present invention is assumed to contain all of these.

Furthermore, the structure bonded to the piperidine ring in general formula (1) is 5-{3-(piperazine-1
-yl)-2-hydroxypropoxy}quinoline, but it is thought that not only the quinoline ring but also the isoquinoline ring, quinoxaline ring, quinazoline ring, etc. can exhibit similar effects. Furthermore, not only 2-hydroxypropoxy group but also ethoxy group, propoxy group, butoxy group, N-methyl-ethylamino group, N-methyl-propylamino group, etc. are thought to exhibit similar effects. Furthermore, not only the piperazine ring but also methylamino groups, ethylamino groups, propylamino groups, butylamino groups, etc. are thought to exhibit similar effects.

The method for synthesizing the compound of the present invention is as follows:
For example, as shown below, the compound of general formula (1) can be obtained by reacting 5-(2,3-epoxypropoxy)quinoline with a corresponding amine derivative thermally or in the presence of a base.

[0020]

embedded image Here, thermal means from room temperature to the boiling point of the solvent used. As the solvent, alcohols such as methyl alcohol and ethyl alcohol, and organic solvents such as acetone, chloroform, methylene chloride, and dimethylformamide are used.

Examples of the base include inorganic bases such as potassium carbonate, sodium hydroxide and sodium carbonate, and organic bases such as triethylamine, pyridine and diazabicycloundecene.

[0022] The anticancer drug effect enhancing effect of the compound of the present invention on resistant cancer can be achieved by enhancing the uptake of the anticancer drug into the cells using the adriamycin-resistant human ovarian cancer cell line 2780AD or the adriamycin-resistant line K562/ADM of human myeloid leukemia cells. This is evidenced by its effectiveness and the effect of enhancing the action of anticancer drugs. That is, as will be described in detail in the Examples, the compounds of the present invention all exhibited significant anticancer drug uptake enhancement effects and anticancer drug action enhancement effects.

[0023]Although there are no particular restrictions on the anticancer agent to be used in combination with the compound of the present invention or its salt, preferred examples include anthracycline antibiotics, which are non-antimetabolites;
For example, adriamycin, daunomycin, aclacinomycin A; actinomycin antibiotics, such as actinomycin C, actinomycin D; chromomycin antibiotics, such as mithramycin, toyomycin; vinca alkaloids, such as vincristine, vinblastine, maytansines; podophyllotoxy derivatives , such as VP16-213; homoharitonin; anguwidein; bruceantin; neocarzinostatin; anthramycin; mitomycin C; cisplatin derivatives and the like.

[0024] The compound of the present invention and its salts can be administered simultaneously with, before or after the anticancer drug, or administered separately. That is,
The compound of the present invention and its salts can be administered alone as a drug according to various administration methods, or can be administered separately with various anticancer drugs. It can also be administered after being made into a preparation according to the law. The administration method varies depending on the symptoms of the subject, the properties of the anticancer drug, etc., but the dosage is 1 to 1,000 per day for adults.
Divide mg into one or several doses, tablets, granules, powders,
It can be administered orally, such as suspensions, capsules, and syrups, or parenterally, such as injections, suppositories, and isotonic solutions for infusion.

For example, when preparing tablets, crystalline cellulose, light anhydrous silicic acid, etc. are used as adsorbents, and corn starch, lactose, calcium phosphate, magnesium stearate, etc. are used as excipients. In addition, when preparing an injection, the compound may be prepared as an aqueous solution, a suspension aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, etc., or an emulsion using a surfactant such as HCO-60. used. In addition, as for the administration method of the anticancer drug, various administration methods selected for each anticancer drug can be used as they are.

[0026]

EFFECTS OF THE INVENTION The compounds of the present invention strongly inhibit the outflow of anticancer drugs from cancer cells, have low toxicity, and have very few side effects such as lowering of blood pressure.

Therefore, the compound of the present invention is effective against cancer cells that are less sensitive to anticancer drugs and cancer cells that have acquired resistance to anticancer drugs, and may provide a new treatment method for cancer chemotherapy, which is currently at a dead end. It is.

[0028]

[Examples] The present invention will be illustrated below with examples, but the present invention is not limited thereto. Example 1 5-[3-{4-(hydroxy-bis(4-chlorophenyl)methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) 4-{hydroxy-bis(4-chlorophenyl)methyl} 4.0 g of -N-methylpiperidine and 4.7 g of potassium carbonate were suspended in 60 ml of 1,1,2-trichloroethane, and 7.2 g of 2,2,2-trichloroethylchloroformic acid was added and the mixture was heated under reflux for 13 hours. The reaction solution was cooled, methanol was added, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel (CH2Cl2) to give 4-{hydroxy-bis(4-chlorophenyl)methyl}-N-(2,
4.9 g of 2,2-trichloroethoxycarbonyl piperidine was obtained. NMR δppm (CDCl3): 1.3-1.7
(m, 4H), 2.13 (s, 1H), 2.5~2
．． 6 (m, 1H), 2.8 ~ 3.0 (m, 2H)
, 4.2 ~ 4.4 (m, 2H) , 4.6 ~ 4.8
(dd, 2H), 7.2-7.5 (m, 8H)
b) Piperidine derivative synthesized as above 2.0
g was dissolved in 20 ml of THF, and 4.0 g of zinc powder was added. Then, 4 ml of 1M ammonium chloride aqueous solution was added and stirred for 8 hours. After filtering off insoluble materials, the filtrate was concentrated under reduced pressure. The residue was dissolved in 30 ml of isopropanol and 5-
1.0 g of (2,3-epoxypropoxy)quinoline and 1 ml of triethylamine were added and heated at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (CHC
13:MeOH=20:1) to obtain the title compound.
0.5g was obtained. NMR δppm (CDCl3): 1.4-1.6
(m, 4H), 1.7 to 2.8 (br, 1H),
2.0-2.1 (m, 1H), 2.3-2.5 (m
, 3H), 2.5-2.7 (m, 2H), 2.9
~3.0 (m, 1H), 3.1 ~ 3.2 (m, 1
H), 4.1 to 4.3 (m, 3H), 6.8 to 6.
9 (m, 1H), 7.2 to 7.5 (m, 9H),
7.5-7.8 (m, 2H), 8.5-8.6 (
m, 1H), 8.9-9.0 (m, 1H) IR νcm-1 (KBr): 3422, 2942
, 1619, 1589, 1489, 1470,
1404, 1318, 1267, 1204,
1171, 1146, 1094, 1013, 97
5, 890, 797, 737, 535, 505

Example 2 5-[3-{4-(bis(4-chlorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline Hydroxy compound obtained according to Example 1
400 mg was dissolved in 2 ml of trifluoroacetic acid and stirred at room temperature overnight. Ice water was added, neutralized with an aqueous potassium carbonate solution, extracted with ethyl acetate, and dried. The solvent was distilled off under reduced pressure to obtain 330 mg of the title compound. NMR δppm (CDCl3): 1.7-2.1
(br, 1H), 2.3 to 2.8 (m, 10H),
4.1-4.3 (m, 3H), 6.8-7.1 (m
,5H), 7.2-7.4(m,5H), 7.6
~7.8 (m, 2H), 8.5 ~ 8.6 (m, 1H
), 8.9 ~ 9.0 ((m, 1H) IRνcm-1 (KBr): 2943, 1619,
1589, 1489, 1470, 1406,
1317, 1267, 1204, 1170, 1
144, 1092, 1015, 823, 797
, 740,529,511

Example 3 5-[3-{4-(bis(4-methoxyphenyl)methylene)piperidin-1-yl}-2-hydroxy-propoxy]quinoline a) 4-{bis(4-methoxyphenyl) 4-(bis(4-methoxyphenyl)methylene)-N-(2,2,2-trichloroethoxycarbonyl ) 8 g of piperidine was obtained. NMR δppm (CDCl3): 2.35-2.4
5 (m, 4H), 3.55-3.65 (m, 4H),
3.83 (s, 6H), 4.76 (s, 2H), 6.
83 (d, 2H), 7.02 (d, 2H) b) Using 4.0 g of the piperidine compound synthesized above, the reaction was carried out according to Example 1-b) to obtain 0.6 g of the title compound. NMR δppm (CDCl3): 2.4-2.8
(m, 10H), 3.78 (s, 6H), 4.1~4
．． 3 (m, 3H), 6.8 - 6.9 (m, 5H)
, 7.0-7.1 (m, 4H) , 3.3-7.4
(m, 1H), 7.5-7.8 (m, 2H), 8.
5 ~ 8.6 (m, 1H), 8.9 ~ 9.0 (m, 1H)
H) IRνcm-1 (KBr): 3421, 29
34, 2834, 1606, 1589, 157
6, 1508, 1466, 1406, 1267
, 1243, 1203, 1172, 1144,
1097, 1033, 829, 798, 73
8, 616, 573

Example 4 5-[3-{4-(hydroxy-phenyl-(4-pyridyl)methyl)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) 4-{hydroxy-phenyl-(4 2.95 g of 4-{hydroxy-phenyl-(4-pyridyl)methyl}-N-(2,2,2- 1.35g of trichloroethoxycarbonyl)piperidine
Obtained. NMR δppm (CDCl3): 1.05 (d, 1
H), 1.5 to 1.7 (m, 4H), 2.55 to 2
．． 7 (m, 1H), 2.7-2.95 (m, 2H),
4.15-4.3 (m, 2H), 4.70 (s, 2H
), 6.10 (br, 1H), 7.15-7.40 (
m, 4H), 7.48 (d, 1H), 7.62 (d, 3
H), 8.48(d,1H)IRνcm-1(KBr)
:3455, 2866, 1691, 1431,
1235, 1143, 755, 706 b) 1.06 g of the piperidine derivative synthesized above was reacted according to Example 1-b) to obtain 0.59 g of the title compound. NMR δppm (CDCl3): 1.26 (s, 1
H), 1.50-2.10 (m, 5H), 2.25-2
．． 7 (m, 4H), 2.8-3.15 (m, 2H),
4.05-4.3 (m, 3H), 6.14 (s, 1H
), 6.86 (d, 1H), 7.1-7.75 (m,
1H), 8.48 (d, 1H), 8.58 (d, 1H)
, 8.99 (dd, 1H) IRνcm-1 (KBr)
:3374, 3061, 2940, 1618,
1589, 1575, 1267, 1094,
798,702

Example 5 5-[3-{4-(thioxanthene-9-ylidene)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) N-methyl-4-(thioxanthene-9-ylidene) 4-(thioxanthene-9-ylidene)-N
4.15 g of -(2,2,2-trichloroethoxycarbonyl)piperidine was obtained. NMR δppm (CDCl3): 2.55-2.7
8 (m, 4H), 3.05-3.25 (m, 2H), 3
．． 85-4.0 (m, 2H), 4.72 (d, 1H)
, 4.84 (d, 1H), 7.15-7.35 (m, 6
H), 7.50(d,2H)IRνcm-1(KBr)
:1713, 1455, 1423, 1222,
1130, 997, 770, 710 b) 4.5 g of the piperidine derivative synthesized above was reacted according to Example 1-b) to obtain 0.68 g of the title compound. NMR δppm (DMSO-d6): 2.60-2
．． 70 (m, 2H), 2.82-3.0 (m, 4H),
3.2-3.4 (m, 2H), 7.25-7.4 (
m, 4H), 7.43 (d, 2H), 7.56 (d,
2H), IR νcm-1 (KBr): 3443, 3207
, 3049, 2968, 2935, 1457,
1437, 1270, 1054, 982, 7
68, 747

Example 6 5-[3-{4-(phenyl-2-(thiophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) N-methyl-4-{phenyl-(2 Example 1-a using 2.0 g of -thiophenyl)methylene}piperidine
) to obtain 2.95 g of 4-{phenyl-(2-thiophenyl)methylene}-N-(2,2,2-trichloroethoxycarbonyl)piperidine. NMR δppm (CDCl3): 2.3-2.4
(m, 2H), 2.6 to 2.75 (m, 2H),
3.5-3.72 (m, 4H), 4.76 (s, 2H)
, 6.7-6.85 (m, 1H), 6.95-7.0
5 (m, 1H), 7.1-7.4 (m, 6H) b)
Using 0.6 g of the piperidine compound synthesized above, a reaction was carried out according to Example 1-b), and 0.2 g of the title compound was obtained.
I got 7g. NMR δppm (CDCl3): 2.3-2.9
(m, 10H), 4.05-4.35 (m, 3H),
6.79 (d, 1H), 6.88 (d, 1H), 6.
9 ~ 7.0 (m, 1H), 7.15 ~ 7.45 (m
, 8H), 7.59 (t, 1H), 7.70 (d, 1H
), 8.56-8.64 (m, 1H), 8.85-8.
95 (m, 1H)

Example 7 5-[3-{4-(bis(4-fluorophenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) 4-{bis(4-fluorophenyl)- Hydroxymethyl}-N-(p-toluenesulfonyl)piperidine
6.7 g and 3.5 g of phenol were mixed with 30 ml of a 48% HBr aqueous solution and heated under reflux for 2 hours. After cooling, the aqueous layer was separated, and ether was added to the residual oil for crystallization. The precipitated crystals were collected by filtration, and ether/ethanol = 50/3
3.64 g of 4-{bis(4-fluorophenyl)methylene}piperidine bromate was obtained. NMR δppm (DMSO-d6): 2.4-2
．． 5 (m, 4H), 3.1-3.2 (m, 4H)
, 7.1-7.2 (m, 8H) b) Add 1.82 g of the piperazine compound synthesized above to ethanol,
1.0 g of triethylamine was added dropwise. Furthermore, 5-(2,3-epoxypropoxy)quinoline
1.0g dissolved in 5ml of ethanol was added dropwise,
The mixture was heated under reflux for 3 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified using a silica gel column (CHCl3:MeOH).
=50:1) to obtain 1.66 g of the title compound. NMR δppm (CDCl3): 2.4-2.9
5 (m, 10H), 4.1 to 4.45 (m, 3H)
, 6.87 (d, 1H), 6.95-7.1 (m, 8H
), 7.3 ~ 7.45 (m, 1H), 7.5 ~ 7
．． 8 (m, 2H), 8.5-8.6 (m, 1H)
, 8.85-8.95 (m, 1H) IRνcm-1 (KBr): 3154, 1590,
1506, 1270, 1098, 838, 7
97

Example 8 5-[3-{4-(bis(4-methylphenyl)methylene)piperidin-1-yl}-2-hydroxypropoxy]quinoline a) 4-{bis(4-methylphenyl)methylene }-N
The reaction was carried out according to Example 7-a) using 6 g of -(p-toluenesulfonyl)piperidine, and 4-{bis(
4-methylphenyl)methylene}piperidine bromate
2.7g was obtained. NMR δppm (DMSO-d6): 2.28 (s
, 6H), 2.44 (t, 4H), 3.33 (s, 4H
), 6.96 (d, 4H), 7.12 (d, 4H), 8
．． 70(s,2H)IRνcm-1(KBr): 29
20, 2785, 2474, 1509, 142
4, 1004, 822, 786 b) Using 1.78 g of the piperazine compound synthesized above, the reaction was carried out according to Example 7-b) to obtain 1.03 g of the title compound. NMR δppm (CDCl3): 2.32 (s, 6
H), 2.4-2.95 (m, 10H), 4.10
~4.40 (m, 3H), 6.87 (d, 1H), 6.
99 (d, 4H), 7.08 (d, 4H), 7.35~
7.42 (m, 1H), 7.59 (t, 1H) IR
νcm-1 (KBr): 3424, 2920, 2
361, 1590, 1270, 1099, 79
5

Example 9 5-[3-{4-(10,11-dihydro-10,11
-dihydroxy-5H-dibenzo[a,d]cycloheptan-5-ylidene)piperidin-1-yl}-2
-hydroxylopoxy]quinoline, 5-[3-{4-(5H-dibenzo[a, d]cycloheptan-5-ylidene)piperidin-1-yl}-
1.8 g of 2-hydroxypropoxy]quinoline was suspended in toluene, and 1.0 g of osmium tetroxide was added. Then, 0.66 g of pyridine was added, and the mixture was stirred at room temperature for 8 days. 90ml of ethanol, 19g of Na2SO3 and 4ml of water
3 ml was added and heated to 70°C for 3 hours. Insoluble matter was then filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column to obtain 220 mg of the title compound. NMR δppm (DMSO-d6): 2.2-2
．． 8 (m, 10H), 4.0-4.3 (m, 3H)
, 4.8-5.2 (m, 4H), 6.9-7.2 (
m, 8H), 7.4-7.6((m, 4H), 8
．． 61 (d, 1H), 8.83 (d, 1H)

003
7] Test Example 1 Effect of enhancing anticancer drug uptake into drug-resistant cancer cells Adriamycin-resistant strain 2780AD of human ovarian cancer cell A2780 (A.M. Logan et al., Science
, Vol. 224, pp. 994-996, 1984) in RPMI-1640 medium containing 5% fetal bovine serum.
The cancer cell suspension was suspended at 106 cells/ml, and 1 ml of cancer cell suspension per well was seeded in a 24-well multi-well culture plate with a diameter of 16 cm, and cultured at 37° C. and 5% CO2. 24
After hours, the culture medium was treated with 20 nM H-vincristine (1x
10 dpm/pmol), 5% fetal bovine serum, 10 m
RPMI-1640 culture medium containing M Hepes buffer 0.
It was replaced with 5ml. After dissolving in DMSO, 5 μl of the test compound diluted with physiological phosphate buffer was added (concentration in the reaction solution was 1.0 or 10.0 μg/ml), and the mixture was incubated with 5% CO
2. After continuing to culture at 37°C for 2 hours, the cells were washed with cold physiological phosphate buffer. Add this to 0.5ml of 0
．． Add 2N NaOH, transfer to vial and incubate at 56°C for 30
Cells were lysed by warm bathing for ~60 minutes. 4 ml of Acid Aquasol 2 was added, and the amount of H-vincristine taken into the cells was measured using a liquid scintillation counter.

The effect was expressed as a percentage (%) of the amount of vincristine taken up by the drug-treated group, with the amount of vincristine taken up by the drug-untreated control group being taken as 100. The results are shown in Table 1.

[0039]

[Table 1]

Claims (1)

[Scope of Claims] [Claim 1] A compound represented by the following general formula (1) and a salt thereof. [Chemical 1] (In the formula, A represents [Chemical 2]. B represents a benzene ring or a heterocycle fused to an adjacent ring. R1 and R2 each independently represent a hydrogen atom, a hydroxy group, or R1 and R2 combine to form a double bond.R3 and R4 each independently represent a substituted phenyl group or a heterocycle.R
5 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an amino group, a substituted amino group, a cyano group, a nitro group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group; Can take all positions. Y is -CH2CH
2- (except when R5 is hydrogen), -NH
CO-, -NHCH2-, -CH(OH)CH(O
H)-, -SCH2-, -S-. ) [Claim 2] A compound represented by the following general formula (2) and a salt thereof [Claim 3] (In the formula, R3 and R4 have the same meanings as in the general formula (1).) [Claim 3] The following general formula A compound represented by (3) and a salt thereof. embedded image (in the formula, R6 and R7 each independently represent a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an amino group, a substituted amino group, a cyano group,
It can take on all possible positions on the ring. ) [Claim 4] A compound represented by the following general formula (4) and a salt thereof. [Claim 5] (In the formula, Y and R5 represent the same meanings as in general formula (1).) [Claim 5] General formula (1) described in claim 1
An anticancer drug effect enhancer comprising a compound represented by and a salt thereof as an active ingredient. [Claim 6]Claim 5, wherein the anticancer drug is a non-antimetabolite.
The anticancer effect enhancer described in . 7. The anticancer effect enhancer according to claim 6, wherein the non-antimetabolite is vincristine, adriamycin, or etoposide. 8. The anticancer drug effect enhancer is in the form of a tablet, granule, powder, suspension, emulsifier, capsule, or syrup for oral administration, injection, suppository, or isotonic solution for infusion. The anticancer drug effect enhancer described above. [Claim 9] 5-(2,3-epoxypropoxy)
A method for producing a compound of general formula (1), which comprises reacting quinoline and a corresponding amine derivative thermally or in the presence of a base.