JPH0543550A - New quinoline derivative and carcinostatic agent effect enhancer containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new quinoline derivative, having more powerful effect enhancing action on carcinostatic agents against resistant cancers and useful as a medicine with less side effects. CONSTITUTION:A compound expressed by formula I [A<1> is formula II, III or IV (R<1> and R<2> are H, halogen, alkyl, alkoxy, CF3, amino, cyano, nitro, OH, etc.; R<3> is heterocyclic ring (except pyridine ring); B<1> is heterocyclic ring bound to the adjacent ring; Y is CH2CH2 (except when R<2> is H); NHCO, NHCH2, SCH2 or S] or its salt, e.g. 5-[3-[4-(3-chloro-10,12-dihydro-5H-dibenzo[a, c]cycloheptan-5-yl) piperazin-1-yl]-2-hydroxypropoxy]quinoline. The compound expressed by formula I is obtained by reacting 5-(2,3-epoxypropoxy)quinoline with the corresponding amine derivative thermally or in the presence of a base.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel compound and an anticancer drug effect enhancer containing the same as an active ingredient.

[0002]

2. Description of the Related Art The number of patients with cancer is increasing year by year, and the death rate due to cancer is the highest in Japan, and there is a great interest in treating cancer socially.

Research and development of anticancer agents for the treatment of cancer have been actively conducted so far, and various kinds of anticancer agents are clinically used for the treatment of cancer. The effect is steadily improving year by year, but in many cases, it completely suppresses the growth of cancer,
Sufficient effects have not been obtained to maintain the survival of cancer patients for a long period of time. In addition, many attempts to enhance the effect of anticancer agents by combining a plurality of anticancer agents (multi-drug combination therapy) are now clinically made. However, even in this case, it is unsatisfactory as a chemotherapeutic method for cancer, and the development of a new cancer therapeutic agent from a new viewpoint is eagerly desired.

Under such circumstances, as one method, the development of a more potent anticancer agent, the development of a more selective delivery method of the anticancer agent to the target organ, and the like can be considered. Current,
Although these studies have been conducted all over the world, the difficulty is increasing. On the other hand, as another important method, there is a method of trying to enhance the effect of existing anticancer agents. In particular, the development of an agent that enhances the effect of existing anticancer agents on drug-resistant cancer, which is a clinically serious problem in cancer chemotherapy, is considered to be a very important new cancer treatment method.
The background of resistance to anticancer drugs in this clinical situation is not always simple. Clinical resistance can be roughly divided into two aspects. The first is when the cause is required for individual cancer patients, 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 has been elucidated at the molecular level, and treatment methods for it have been investigated. That is, recently, a gene responsible for multidrug resistance has been isolated, and this gene is a membrane protein or P-glycoprotein (p-glycoprotein) expressed in multidrug resistant cells.
oprotein) gene. The P-glycoprotein is presumed to be a protein having the function of extracellular elimination of an anticancer drug, and is considered to be a protein that plays a central role in the multidrug resistance mechanism. In addition, some common mechanisms have been suggested for cancers such as solid cancers where it is originally difficult for anticancer drugs to work.

That is, many anticancer drugs pass through the cell membrane and express their effects intracellularly, but in resistant cancer cells, the anticancer drug introduced by the action of this P-glycoprotein is excreted outside the cells, The drug concentration of is kept low. As a result, it is considered that the effect of the anticancer drug is not easily exhibited.

[0006] Therefore, the present inventors have found that, for example, a substance that suppresses the action of P-glycoprotein and inhibits the outflow of an anticancer agent from cancer cells has a potentiating effect on the anticancer agent and is particularly effective in overcoming resistance. , Considered to be effective as a new cancer chemotherapeutic agent.

[0007] In fact, Tsuruo et al. Reported that calcium antagonists such as verapamil block the outflow of anticancer agents from cancer cells, and therefore, in combination with in vitro and in vitro for resistant cancers.
Have found that it has an action of enhancing the effects of anticancer agents such as adriamycin and vincristine. But,
When these calcium antagonists are clinically used in cancer patients, side effects such as lowering of blood pressure and induction of arrhythmia appear, which poses a serious problem as a therapeutic agent for cancer. Therefore, there has been a demand for a drug that has a stronger effect of enhancing the effect of an anticancer drug against resistant cancer and has fewer side effects.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug having a stronger effect of enhancing the effect of an anticancer drug against resistant cancer and having fewer side effects.

[0009]

Means for Solving the Problems The inventors of the present invention have made diligent studies in view of the above viewpoints, and as a result, a specific compound has a strong antitumor effect-enhancing action against resistant cancer, and has low toxicity and low side effects. After finding out the matter, the present invention was completed. That is, the present invention has the general formula (I)

[0010]

[Chemical 5] (Where A ¹ is

[Chemical 6] Represents. Here, R ¹ and R ² are each independently 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, which can take all possible positions on the ring, R ³ represents a heterocycle (but not the pyridine ring), B ¹ represents a heterocycle fused to an adjacent ring. , Y represents —CH ₂ CH ₂ — (except when R ² is hydrogen), —NHCO—, —NHCH ₂ —, —SCH ₂ —, and —S—. ) And salts thereof (hereinafter referred to as the compound of the present invention), anticancer drug effect enhancers containing them as active ingredients, and methods for producing them.

The halogen atom mentioned here means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. The lower alkyl group means a methyl group, an ethyl group, a propyl group, a butyl group or the like. The lower alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like. The substituted amino group means a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a butylamino group and the like. The alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group or the like. The heterocycle means a thiophene ring, a furan ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring or the like. The heterocyclic ring condensed to the adjacent ring means a pyridine ring, a thiophene ring, a pyrazine ring, a furan ring and the like, and as A ¹ containing these,
4-aza-10,11-dihydro-5H-dibenzo [a, d] cycloheptane ring, 9,10-dihydro-4H-benzo [1,2] cycloheptane [4,5-b] thiophene ring, 1, 4-diaza-10,11-dihydro-
5H-dibenzo [a, d] cycloheptane ring, 9,10-dihydro-
4H-Benzo [1,2] cycloheptane [4,5-b] furan Ring etc. are formed.

Among the compounds represented by the general formula (I), the compounds represented by the following general formula (II) and salts thereof are preferable from the viewpoint of the strength of enhancing the effect of anticancer drug.

[Chemical 7] (In the formula, R ⁴ represents 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 or an alkoxycarbonyl group.) The compounds represented by the following general formula (III) and salts thereof are also preferable.

[Chemical 8] (In the formula, B ² represents a pyridine ring or a thiophene ring fused to adjacent rings.)

Next, as the compound represented by the general formula (I), 5- [3- {4- (3-chloro-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (3-bromo-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-fluoro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-methyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-ethyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-propyl-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {3-butyl-4- (10,11-dihydro-5H-dibenzo [a, d]
Cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-methylamino-5H-dibenzo [a, d] cycloheptane -5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-dimethylamino-5H-dibenzo [a, d] cycloheptane-5 -Yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-diethylamino-5H-dibenzo [a, d] cycloheptane-5-yl) Piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-propylamino-5H-dibenzo [a, d] cycloheptan-5-yl) piperazine- 1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-butylamino-5H-dibenzo [a, d] cycloheptan-5-yl) piperazine-1- Il} -2-hydroxypropo Xy] quinoline 5- [3- {4- (10,11-dihydro-3-methoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-ethoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-propoxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-butoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-methoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-ethoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-propoxycarbonyl-5
H-dibenzo [a, d] cycloheptane-5-yl) piperazine
-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-carboxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (1-chloro-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (1-bromo-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-fluoro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-methyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-ethyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-propyl-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-butyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-methylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy ] Quinoline 5- [3- {4- (10,11-dihydro-1-dimethylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-diethylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [ 3- {4- (10,11-Dihydro-1-propylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-Dihydro-1-butylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4 -(10,11-Dihydro-1-meth Shi -5H- dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-ethoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-propoxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-butoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-methoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-ethoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-propoxycarbonyl-5
H-dibenzo [a, d] cycloheptane-5-yl) piperazine
-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-carboxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (2-chloro-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-fluoro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-methyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-ethyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-methylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy ] Quinoline 5- [3- {4- (10,11-dihydro-2-dimethylamino-5H-dibenzo [a, d] cycloheptan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-methoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-ethoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-methoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-ethoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-carboxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (4-chloro-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-fluoro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-methyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-ethyl-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-methylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy ] Quinoline 5- [3- {4- (10,11-dihydro-4-dimethylamino-5H-dibenzo [a, d] cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-methoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-ethoxy-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-methoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-ethoxycarbonyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-carboxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-trifluoromethyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-trifluoromethyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-trifluoromethyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-trifluoromethyl-5H-
Dibenzo [a, d] cycloheptane-5-yl) piperazine-1
-Yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (1-cyano-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (2-cyano-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (3-cyano-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (4-cyano-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-nitro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-nitro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-nitro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-nitro-5H-dibenzo [a,
d] Cycloheptane-5-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-1-hydroxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-2-hydroxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-3-hydroxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-4-hydroxy-5H-dibenzo
[a, d] Cycloheptane-5-yl) piperazin-1-yl}-
2-Hydroxypropoxy] quinoline 5- [3- {4- (1-aza-10,11-dihydro-5H-dibenzo [a, d]
Cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (2-aza-10,11-dihydro-5H-dibenzo [a, d]
Cycloheptan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (3-aza-10,11-dihydro-5H-dibenzo [a, d]
Cycloheptane-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (4-aza-10,11-dihydro-5H-dibenzo [a, d]
Cycloheptan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (9,10-dihydro-4H-benzo [1,2] cyclohepta
[4,5-b] Thiophen-4-yl) piperazin-1-yl} -2-
Hydroxypropoxy] quinoline 5- [3- {4- (9,10-dihydro-4H-benzo [1,2] cyclohepta
[4,5-b] furan-4-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (1,2-diaza-10,11-dihydro-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (1,3-diaza-10,11-dihydro-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (2,4-diaza-10,11-dihydro-5H-dibenzo
[a, d] Cycloheptan-5-yl) piperazin-1-yl} -2
-Hydroxypropoxy] quinoline 5- [3- {4- (5,6-dihydro-dibenzo [b, f] azepine-11-
Il) Piperazine-1-yl} -2-hydroxypropoxy]
Quinoline 5- [3- {4- (5,6-dihydro-6-oxo-dibenzo [b, f] azepin-11-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (thioxanthen-9-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (10,11-dihydro-10-thio-5H-dibenzo [a, d ]
Cycloheptan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (2-thiophenyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (3-thiophenyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (2-furanyl) methyl) piperazine
-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (3-furanyl) methyl) piperazine
-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (2-pyrazinyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (Phenyl (3-pyrazinyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline 5- [3- {4- (phenyl (2-pyridazinyl) methyl) piperazin-1-yl} -2-hydroxypropoxy ] Quinoline 5- [3- {4- (phenyl (3-pyridazinyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline and the like.

Further, in the general formula (I), 5- {3- (piperazin-1-yl) 2-hydroxypropoxy} quinoline is mentioned as a structure for binding to A ¹ , but not only the quinoline ring but also It is considered that isoquinoline ring, quinoxaline ring, quinazoline ring and the like also exhibit similar effects. Further, not only 2-hydroxypropoxy group but also ethoxy group, propoxy group, butoxy group, N-methyl-ethylamino group, N-methyl-propylamino group and the like are considered to exert similar effects. Further, not only the piperazine ring but also a methylamino group, an ethylamino group, a propylamino group, a butylamino group and the like are considered to exert similar effects.

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, but the compound of the present invention is supposed to contain all of these.

Next, in the synthetic method of the present invention, 5- (2,3-epoxypropoxy) quinoline represented by the following formula and the corresponding amine derivative are reacted thermally or in the presence of a base to give a compound of the general formula of the present invention. The compound of (I) can be obtained.

[Chemical 9] Here, thermal means from room temperature to the boiling point of the solvent, and as the solvent, organic solvents such as alcohol, 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.

The effect of the compound of the present invention to enhance the effect of anticancer drug on resistant cancer is to enhance the uptake of the anticancer drug into human cells by using adriamycin resistant strain 2780AD of human ovarian cancer cells or adriamycin resistant strain K562 / ADM of human myeloid leukemia cells. The effect and the potentiating effect of the anticancer agent are proved. That is, the compounds of the present invention, which will be described in detail in Examples, exhibited remarkable anti-cancer agent uptake enhancing effect and anti-cancer agent action enhancing effect.

The antitumor agent to be used in combination with the compound of the present invention or a salt thereof is not particularly limited, but is preferably a non-metabolite anti-metabolite, such as anthracycline antibiotics such as adriamycin, daunomycin, acracinomycin A; Actinomycin antibiotics such as actinomycin C, actinomycin D; chromomycin antibiotics such as mithramycin, toyomycin; vinca alkaloids such as vincristine, vinplastin; maytansines; podophyllotoxin derivatives such as VP16-213. Homoharintonin; Angwydein; Bruceanthin; Neocarzinostatin; Anthramycin; Mitomycin C; Cisplatin derivative and the like.

The compound of the present invention and its salt can be administered either simultaneously with or before or after the administration of the carcinostatic agent, or in combination with or separately from the carcinostatic agent. That is,
The compound of the present invention and a salt thereof can be individually formulated into preparations according to various administration methods, and can be administered separately from various anticancer agents, but both are preliminarily blended, and these are used in various administration methods. It is also possible to administer the drug after it has been prepared into a similar formulation. The administration method naturally varies depending on the symptoms of the subject to be administered, the properties of the anticancer drug, etc., but 1 to 1000 mg per day for an adult is divided into one or several times, and tablets, granules, powders, suspensions, capsules, syrups are given. Orally administered drug such as drug, or injection,
It can be administered as a parenteral administration agent such as a suppository and isotonic solution for infusion.

For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid or the like is used as the adsorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as the excipient. In the case of an injection, an aqueous solution of the compound or a suspension aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, etc., and an emulsion using a surfactant such as HCO-60, etc. used. In addition, the administration method of the anticancer drug is
Various administration methods selected for each anticancer agent can be used as they are.

[0021]

EFFECT OF THE INVENTION The compound of the present invention strongly inhibits the efflux of anticancer agents from cancer cells, has low toxicity, and has very few side effects such as blood pressure reduction.

Therefore, the compound of the present invention is effective against cancer cells having low sensitivity to anticancer agents and cancer cells that have acquired resistance to the anticancer agents, and can provide a new therapeutic method for the currently stalled cancer chemotherapy. Is.

[0023]

EXAMPLES The present invention will be shown below with reference to examples, but the present invention is not limited thereto. Example 1 5- [3- {4- (4-aza-10,11-dihydro-5H-dibenzo [a, d]
Cycloheptan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline a) 4-aza-10,11-dihydro-5H-dibenzo [a, d] cycloheptane-5-ol It was dissolved in 20 ml of methylene and 1.1 g of thionyl chloride was added dropwise. Then, after heating under reflux for 10 minutes, the solvent was concentrated under reduced pressure to obtain an oily substance as a residue.
Next, 20 ml of methylene chloride and 6.0 g of anhydrous piperazine were added, and the mixture was heated under reflux for 2 hours. After cooling, 100 ml of water was added and the mixture was extracted with 150 ml of methylene chloride. The extract was dried, concentrated, and purified with a silica gel column (CHCl ₃ : MeOH = 10: 1) to give N- (4-
1.68 g of aza-10,11-dihydro-5H-dibenzo [a, d] cycloheptan-5-yl) piperazine was obtained. NMR δ ppm (CDCl ₃ ): 2.2 to 2.5 (m, 8H), 2.7 to 2.9 (m, 2
H), 3.91 ~ 3.98 (m, 1H), 4.1 ~ 4.17 (m, 1H), 4.369 (s, 1
H), 7.0 to 7.4 (m, 6H), 8.31 (d, 1H) b) 0.3 g of the amine compound synthesized above and 5- (2,3-
0.15 g of epoxypropoxy) quinoline was dissolved in 5 ml of isopropanol and heated under reflux for 3.5 hours. Next, the solvent was distilled off under reduced pressure, and the residue was filtered through a silica gel column (CHCl ₃ : MeOH).
= 20: 1) to obtain 0.38 g of the title compound. _{NMR δppm (CDCl 3): 2.2} ~2.9 (m, 12H), 3.86~3.93
(m, 1H), 4.07 to 4.26 (m, 4H), 4.59 (s, 1H), 6.85 (d, 1H),
7.09 ~ 7.42 (m, 7H), 7.59 (t, 1H), 7.68 (d, 1H), 8.32 (d, 1
H), 8.55 (d, 1H), 8.88 (dd, 1H) IR νcm ^-1 (KBr): 3423, 2930, 1618, 1590, 1450, 12
68, 1143, 1098, 1004, 800

Example 2 5- [3- {4- (3-chloro-10,11-dihydro-5H-dibenzo [a,
d] Cycloheptan-5-yl) piperazine} -2-hydroxypropoxy] quinoline a) 3-Chloro-10,11-dihydro-5H-dibenzo [a, d] cycloheptane-5 according to Example 1- (a). -All 208 mg
Was reacted with thionyl chloride and anhydrous piperazine to obtain 219 mg of N- (3-chloro-10,11-dihydro-5H-dibenzo [a, d] cycloheptan-5-yl) piperazine. NMR δ ppm (CDCl ₃ ): 2.13 to 2.35 (m, 4H), 2.70 to 3.10
(m, 6H), 3.80-4.20 (m, 3H), 6.97-7.16 (m, 7H) b) The amine compound 219 mg obtained above was reacted according to Example 1- (b) to give the title compound 284
mg was obtained. NMR δ ppm (CDCl ₃ ): 2.31 to 2.80 (m, 12H), 3.90 to 4.02
(m, 3H), 4.15 (m, 3H), 6.86 ~ 7.71 (m, 11H), 8.56 (d, 1H),
8.90 (q, 1H) IR νcm ^-1 (CHCl ₃ ): 3423, 2934, 2809, 1589, 1407,
1267, 1097, 798

Example 3 5- [3- {4- (5,6-dihydro-6-oxo-dibenzo [b, f] azepin-11-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline N- (5,6-dihydro-6-oxo-dibenzo [b, f] azepine
-11-yl) piperazine with 1.5 g of Example 1- (b)
The reaction was performed according to the above procedure to obtain 1.13 g of the title compound. NMR δ ppm (DMSO-d ₆ ): 2.49 (s, 10H), 3.95 ~ 4.20 (m, 2
H), 4.90 (s, 1H), 6.93 ~ 7.72 (m, 12H), 8.59 (d, 1H), 8.8
5 (d, 1H), 10.24 (s, 1H)

Example 4 5- [3- {4- (phenyl- (2-thiophenyl) methyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline N- {phenyl- (2-thiophenyl) methyl} piperazine 2.4
The reaction was carried out according to Example 1- (b) using 0 g,
2.48 g of the title compound was obtained. NMR δ ppm (CDCl ₃ ): 2.52 to 2.94 (m, 10H), 3.45 to 3.51
(m, 1H), 4.10 ~ 4.25 (m, 3H), 4.63 (s, 1H), 6.85 ~ 6.92
(m, 3H), 7.20 ~ 7.73 (m, 8H), 8.56 (d, 1H), 8.90 (q, 1H) IR νcm ^-1 (KBr): 3246, 2806, 1618, 1590, 1452, 14
12, 1269

Test Example 1 Effect of enhancing anti-cancer drug uptake into drug-resistant cancer cells Adriamycin-resistant strain 2 of human ovarian cancer cell A2780
780AD (AM Rogan et al., Science, Volume 224, 994-996)
Page, 1984) containing 5% fetal bovine serum RPMI-164
1 × 10 ⁶ cells / ml were suspended in 0 culture medium, 1 ml of the cancer cell suspension was seeded per well on a 24-well multiwell culture plate having a diameter of 16 cm, and cultured at 37 ° C. in 5% CO ₂ . .. After 24 hours, the culture solution was added with 20 nM ³ H-vincristine (1 × 10 ⁴ dpm / pmo).
l) RP containing 5% fetal bovine serum and 10 mM Hepes buffer
The medium was replaced with 0.5 ml of MI-1640 culture solution. After dissolving in DMSO, the test compound diluted with physiological phosphate buffer was added
Add μl (concentration in reaction solution is 1.0 or 10.0 μg / ml), 5
After continuing the culture for 2 hours at 37 ° C. in% CO ₂ , the cells were washed with chilled physiological phosphate buffer. Add 0.5 ml of 0.2N NaO
Add H, transfer to vial and heat bath at 56 ° C for 30-60 minutes,
The cells were lysed. Acid Aquasol 2 (4 ml) was added, and the amount of ³ H-vincristine incorporated into cells was measured by a liquid scintillation counter.

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

[0029]

[Table 1]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] November 21, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 1

[Correction method] Change

[Correction content]

[Chemical 1] (Where A ¹ is

[Chemical 2] Represents. Here, R ¹ and R ² are each independently 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, which can take all possible positions on the ring, R ³ represents a heterocycle (but not the pyridine ring), B ¹ represents a heterocycle fused to an adjacent ring. , Y is -CH ₂ CH ₂ - (. except if the proviso R ² is hydrogen), - NHCO -, - NHCH 2 -, - SCH 2 -, represents a -S-. )

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 2

[Correction method] Change

[Correction content]

[Chemical 3] (In the formula, R ⁴ represents 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 or an alkoxycarbonyl group.)

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 3

[Correction method] Change

[Correction content]

[Chemical 4] (In the formula, B ² represents a pyridine ring or a thiophene ring fused to adjacent rings.)

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 4

[Correction method] Change

[Correction content]

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction content]

[0010]

[Chemical 5] (Where A ¹ is

[Chemical 6] Represents. Here, R ¹ and R ² are each independently 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, which can take all possible positions on the ring, R ³ represents a heterocycle (but not the pyridine ring), B ¹ represents a heterocycle fused to an adjacent ring. , Y -CH ₂ CH ₂ is -, (except when R ² is hydrogen.) - NHCO -, - NHCH 2 -, -SCH 2 -, - represent S-. ) Or a salt thereof (hereinafter referred to as the compound of the present invention), an anticancer drug effect enhancer containing them as an active ingredient, and a method for producing them.

[Procedure Amendment 6]

[Document name to be amended] Statement

[Correction target item name] 0012

[Correction method] Change

[Correction content]

Among the compounds represented by the general formula (I), the compound represented by the following general formula (II) or a salt thereof is preferable from the viewpoint of the strength of enhancing the effect of anticancer drug.

[Chemical 7] (In the formula, R ⁴ represents 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 or an alkoxycarbonyl group.) Similarly, a compound represented by the following general formula (III) or a salt thereof is also preferable.

[Chemical 8] (In the formula, B ² represents a pyridine ring or a thiophene ring fused to adjacent rings.)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 401/12 8829-4C 405/12 8829-4C 409/12 8829-4C 471/04 121 8415- 4C 487/04 150 7019-4C 491/048 7019-4C 495/04 108 7329-4C 111 7329-4C 116 7329-4C // (A61K 31/71 31:47) 7252-4C (A61K 31/71 31: 55) 7252-4C (A61K 31/71 31:50) 7252-4C (C07D 401/12 215: 00 7019-4C 223: 00) 6701-4C (C07D 401/12 215: 00 7019-4C 221: 00) 6701-4C (C07D 401/12 215: 00 7019-4C 241: 00) 6701-4C (C07D 405/12 215: 00 7019-4C 307: 00) 7729-4C (C07D 409/12 215: 00 7019-4C 333: 00) 7729-4C (72) Inventor Tsuneji Suzuki 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Kengo Otsuka 1144, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor, Risa Yano, 1900, 1900, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Wakao Sato 1900, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Takashi Tsuru 4828-15 Tsukahara, Minamiashigara City, Kanagawa Prefecture

Claims (8)

[Claims] 1. A compound represented by the general formula (I) and a salt thereof. [Chemical 1] (A ^{1 in the} formula is Represents. Here, R ¹ and R ² are each independently 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, which can take all possible positions on the ring, R ³ represents a heterocycle (but not the pyridine ring), B ¹ represents a heterocycle fused to an adjacent ring. , Y represents —CH ₂ CH ₂ — (except when R ² is hydrogen), —NHCO—, —NHCH ₂ —, —SCH ₂ —, and —S—. ) 2. A compound represented by the following general formula (II):
And the salts thereof. [Chemical 3] (In the formula, R ⁴ represents 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 or an alkoxycarbonyl group.) 3. A compound represented by the following general formula (III):
And the salts thereof. [Chemical 4] (In the formula, B ² represents a pyridine ring or a thiophene ring fused to adjacent rings.) 4. An anticancer agent effect enhancer comprising the compound represented by the general formula (I) according to claim 1 or a salt thereof as an active ingredient. 5. The effect enhancer according to claim 4, wherein the anticancer drug is a nonmetabolite. 6. The effect enhancer according to claim 5, wherein the non-metabolite is vincristine, adriamycin, or etoposide. 7. The anticancer drug effect enhancer is an oral administration agent of tablets, granules, powders, suspensions, emulsifiers, capsules or syrups, injections, suppositories, isotonic solutions for infusion.
The anticancer agent effect potentiator according to. 8. A method for synthesizing a compound of general formula (I) by reacting 5- (2,3-epoxypropoxy) quinoline with a corresponding amine derivative thermally or in the presence of a base.