JPS60152417A - Enhancer for carcinostatic effect - Google Patents

Abstract

PURPOSE:The titled enhancer comprising a well-known quinazolinedione compound which is not found to have carcinostatic action in itself as an active ingredient. CONSTITUTION:A compound shown by the formula (R is H, or F) or its salt (e.g., inorganic salt such as hydrochloride, sulfate, organic salt such as tartrate, oxalate, etc.) as an active ingredient is blended with a carcinostatic agent (e.g., vincaalkaloid drug such as vincristine, vindesine, anthracycline drug such as adriamycin, daunomycin, etc., actinomycin drug, or chromomycin drug), to enhance carcinostatic effect. This enhancer can avoid advantageously improper excess administration, enhance carcinostatic action of the carcinostatic agent, and reduce manifestation of its side effects. It can be administered orally or parenterally, and a dose is preferably 30-100mg/person.day.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anticancer effect enhancer, and more particularly, to an anticancer effect enhancer containing a known quinazolinethion compound, which does not exhibit anticancer activity by itself, as an active ingredient.

More specifically, the present invention provides an anticancer effect enhancer comprising, as an active ingredient, a compound represented by the following formula (1), where R represents a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof. Regarding.

Various chemotherapeutic agents have been developed as anticancer agents and are in practical use. However, it is effective within cancer cells! !
l! It accumulates at high temperatures and is difficult to maintain its effective concentration satisfactorily. Furthermore, 1i! has low sensitivity to anticancer drugs! This is even more difficult in the case of i cells and anticancer drug-resistant cells. 1. Chemotherapy drugs for cancer generally have quite strong side effects, and unnecessarily administering large amounts and continuously can cause problems in terms of side effects. It would be desirable to develop a concomitant agent or adjuvant that can accumulate in cancer cells at an appropriate effective concentration that is not too excessive and can maintain that effective concentration for a satisfactory amount of time.

In the past, several proposals have been known that attempt to respond to such =m. For example, 1-(2-dialkylaminoalkyl)-3-(p-alkoxybenzyl)-1,
2-dihydroquinoxalin-2-one or its salt (JP-A-58-57317), 5-[(3,4-dimethoxyphenethyl)methylamino]-2,-(3,4-dimethoxyphenethyl) -2-7propyl nitrile salt (JP-A-58-83624), nicardipine [chemical name: 2,6-dimethyl-4-(3'-nitrophenyl)-], ]4-dihydropyridine -15-dicarboxylic acid-3-methyl ester-5-β-(A'-benzyl-6-methylamino)ethyl ester]
-152816) were proposed.

This time, the enhancer in these conventional proposals is a known compound 1-(3-[4-(2-phenylethyl)-modi<
tri (2-1p-fluorophenyl)ethyl) -
piperidine]propyl)-6-ethoxycarbonyl-5
．． 7-dimethyl-3-(o-tolylfluoromethylphenyl)-2,4(xH13B)-quinazolinedione or its pharmaceutically acceptable salts have remarkable effects as anticancer effect enhancers of anticancer drugs. It was observed that this was shown to be the case.

Fusion (1) The compound or its pharmaceutically acceptable salt accumulates the anticancer agent in cancer cells at an appropriate effective concentration that is not excessive, and maintains the effective concentration in the armpit to a satisfactory extent. It was found that this compound is noteworthy as an excellent anticancer effect enhancer that exhibits the ability to obtain cancer.

Therefore, an object of the present invention is to provide a new type of anticancer effect enhancer.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

The compound of formula (1) and its salts, which are the effective acid components of anticancer efficacy/enhancement c.11 of the present invention, are, for example, vasodilators,
It is known as a compound having effects as a flow-collapse improving agent, a hypotensive agent, or an anti-arteriosclerotic agent (see JP-A-57-206665). However, the action of the compound (1) and its salts as an anticancer effect enhancer has not been known at all. Examples of the salts ν1 of the compound of formula (1) above include inorganic acid salts such as hydrochloride, sulfur salt, and salt; An example of this is shoulder machine 6II salt.

The anticancer effect enhancer of the present invention exhibits an excellent anticancer effect enhancing effect when used in combination with an anticancer drug. can be enhanced, and the occurrence of side effects can be reduced.

There are no particular restrictions on the type of anticancer drug used, but
Particularly preferable examples include gold, an anticancer agent based on natural products and derivatives thereof. Specific examples of such anticancer drugs include vincristine,
Vinca alkaloids such as vindesine, vinblasting, etc.; for example, adriamycin, daunomycin,
Examples include anthracyclines such as aclacinomycin A, actinomycins such as actinomycin C1 and actinomycin D, and cronomycins such as mithramycin and toyomycin.

The anticancer effect enhancer of the present invention can be administered in combination with an anticancer drug in various ways.

For example, it can be administered at the same time as the anticancer drug, or it can be administered before or after the anticancer drug. When administering simultaneously, both may be administered in combination, or they may be administered separately.
Both can be prepared in advance in a dosage unit form and administered, or they can be made into separate dosage unit forms and administered simultaneously. Either oral administration or parenteral administration can be adopted.

In addition, the dosage form can be selected as appropriate, for example, powder,
Granules, fine granules, tablets, capsules, M cloudy agents, liquids,
It can be in oral or parenteral dosage forms such as suppositories, injections, and the like. For dispensing into such a strength dosage form, any pharmaceutically acceptable diluent or carrier known in the pharmaceutical field can be used. These preparations may contain the anticancer effect enhancer of the present invention in a suitable manner,
For example, about 1% to about 100%, preferably about 10% to about 1%
00% by weight of bean paste can be exemplified.

The company administering the anticancer effect enhancer of the present invention can be changed and selected as appropriate depending on the type of anticancer drug used, its known administration, and administration method, but for example, as a compound of formula (1) or a salt thereof, , 30 to about 100 for oral administration
A preferred example is the dosage per person/day.

The anticancer effect-enhancing agent of the present invention accumulates anticancer drugs in cancer cells at an appropriate effective concentration that is not too excessive, including cancer cells that are anticancer drug-resistant or have low sensitivity, and increases the effective concentration. It exhibits an action that can be maintained for a satisfactory period of time, thus making it possible to noticeably enhance the pharmacological effects of anticancer drugs, as well as to reduce the amount of administration of anticancer drugs and to reduce side effects.

Below, we will use the anticancer drug vincristine (VCR) as an example.
Inq+LLTO test and in
The qrivo test and its results are shown in Examples.

(in vitro):
- VCR-resistant murine leukemia P388 cells at 10'tel
ls/mt Each sample was treated with a dihydrochloride salt of a compound in which R was a fluorine atom, and the number of test cancer cells was counted after 72 hours of contact with the drug. Based on this measurement, the concentration of the anticancer drug VCH (I
C. value), and the anticancer drug enhancement effect was calculated according to the following formula. The results were as shown in Table 1 below.

IC3゜ Table-1 Table-1 Continued Example 2 V Test for enhancing the anticancer effect of the present agent in CR-resistant murine leukemia P388 tumor-bearing mice) (jn qri*)
o): - Each of the 5 test animals CDE and mice (♀) in group 1 was injected with VCR@4 murine leukemia P388 cells lXl.
After intraperitoneal transplantation of 0 @ cells and intraperitoneal injection of the drug shown in Example 1 for plO days from the next day, the number of survival days was determined based on the number of survival days of the test animals, and the treatment for the control group was performed. Rate (T/
C), the anticancer drug enhancement effect was calculated using the following formula (rli).The results are shown in Table 2 below.Q
Ta.

Anticancer drug enhancement effect (CH) = □ T/C when anticancer drug is administered alone x 100 Test example: Mouse leukemia P388 cells were treated with atriamycin (ADM) Anticancer drug enhancement effect on rigid mouse leukemia P388 cells> Mouse leukemia P388 cells or ADM-resistant mouse P3
The lateral muscle effect enhancing effect was examined using 88 cells according to the method of Test Example 1.

Table 2 Enhancement effect of anticancer drug in mouse leukemia P388 cells, %a Enhancement effect of anticancer drug in ADM-resistant mouse leukemia P388 cells

Claims (1)

[Claims] 1. An anticancer effect enhancer containing a compound represented by the following formula (1), where R represents a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof as an active ingredient. .