JPH0137372B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to metastasis-inhibiting anticancer agents used in chemotherapy for cancer (hereinafter referred to as "cancer"). In general, treatment with anticancer drugs is considered the most preferable therapy because it causes less physical burden on patients as long as there are no side effects. However, the reality is that many of the conventional anticancer drugs have strong side effects in proportion to their anticancer effects, and they lack a decisive factor. Therefore, the development of anticancer drugs that have few side effects, are effective against all types of cancer, and can be safely administered is a pressing technical issue in this field. In addition, there are few known drugs that effectively inhibit cancer metastasis itself, and there is a strong desire for the development of anticancer drugs that effectively suppress cancer cell proliferation and cancer metastasis and invasion. come. The purpose of the present invention is to provide a newly regulated cancer drug that meets the above technical problems. That is, in order to achieve the above object, the present invention has synthesized various secondary amines having N-sulfonylcyclohexylamine as a functional group as a result of intensive research, and has synthesized various secondary amines having N-sulfonylcyclohexylamine as a functional group. The anticancer agent of the present invention was found to have a strong cancer growth suppressing effect and metastasis suppressing effect when administered to patients, and was completed. (In the formula, R is a hydroxyl group, a halogen, a lower alkyl group, a cyclohexyl group, or a cyclohexylamino group) or an acid addition salt thereof. It is characterized by containing as follows. The present invention will be explained in detail below. The secondary amine group used in the present invention which has N-sulfonylcyclohexylamine as a functional group and has an additional group attached to the amino group has the general structure shown in the above formula A (the additional group is R ). The additional groups in the compound represented by formula A above include hydrogen, oxygen, lower alkyl group, cyclohexyl group,
Hydrocarbons such as cyclohexylamino groups and halogen elements such as chlorine, fluorine, and bromine are used. The secondary amines shown in formula A above are:
It is synthesized by reacting commercially available aminocyclohexane with a commercially available halide of the group to be added, such as methanesulfonyl chloride, ethanesulfonyl chloride, difluoromethanesulfonyl chloride, etc., and converts it into an acid addition salt such as hydrochloride, and then converts it into an acid addition salt such as ether. It can be crystallized in organic solvents. The pharmaceutically acceptable acid addition salts of each compound represented by the above formula A used in the present invention include a wide variety of salts, such as inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; , propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, benbroic acid, methanesulfonic acid, and salicylic acid. can. When used as an anticancer agent of the present invention, the N-sulfonylcyclohexylamine derivative represented by the formula A and various pharmaceutically acceptable acid addition salts of these compounds are usually used as a pharmaceutical carrier. be administered in the form of a pharmaceutical composition. The carriers include fillers, extenders, binders, etc. that are commonly used to prepare drugs according to the usage form.
Examples include disintegrants, surfactants, lubricants, and excipients, which are appropriately selected depending on the dosage unit form of the anticancer agent. As for the dosage unit form of the anticancer drug, various forms can be selected depending on the therapeutic purpose, and representative examples include tablets, capsules, powders, suppositories, and injections (solutions, emulsions, and suspensions). agents, etc.). The content of N-sulfonylcyclohexylamine derivatives and their acid addition salts with various acids to be contained in the anticancer agent of the present invention is not particularly limited, but is usually about 1% to 90% (by weight) of the total composition. %), preferably about 5% to 40% (wt%). In addition, the anticancer agent of the present invention may contain known coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc. as necessary, and may also contain other compounds having pharmacological activity. You can also do that. The dose of the anticancer agent of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., but the amount of the N-sulfonylcyclohexylamine derivative and its acid addition salt is approximately 1 mg to 200 mg/Kg body weight per day. It is administered in one to several divided doses. Next, to describe the effects of the anticancer agent of the present invention, the N-sulfonylcyclohexylamine derivatives contained in the anticancer agent and various medically acceptable acid addition salts of these compounds are polyamine They share the unique property of significantly inhibiting spermidine synthetase, which synthesizes spermidine. By inhibiting intracellular spermidine synthesis, which increases as cells become cancerous,
The anticancer agent of the present invention is characterized by significantly suppressing the proliferation of cancer cells and inhibiting metastasis to other organs.
In addition, the anticancer drug exhibits the unique property that its action on normal tissue is very secretive, and almost no side effects are observed even when administered in large amounts. The results of the toxicity test for the anticancer agent of the present invention are as follows. That is, a male ICR line weighing approximately 26 g at 7 weeks of age and
N-methanesulfonylcyclohexylamine/hydrochloric acid, N-chlorosulfonylcyclohexylamine/hydrochloric acid, and N-octanesulfonylbutylamine/hydrochloric acid were administered to C57BL/6 mice.
Even if administered intraperitoneally at once at a dose of 300 mg/Kg of each body weight, there is no toxicity at all, and the above three drugs, such as N-methanesulfonylcyclohexylamine and hydrochloric acid, are administered in drinking water at a concentration of 1%. When dissolved and ingested freely, each animal drinks approximately 2 c.c. of the drug and ingests approximately 800 mg/Kg of the drug per day, but it has been found that it does not exhibit any toxicity or side effects. There is. Examples of formulations of the present invention and specific examples of pharmacological effects using the formulations will be described below. Example 1: Sulfonyldiamine-N,
Anticancer test of N'-cyclohexane/hydrochloric acid, two human leukemia cell lines K562 and Molt4B,
In RPMI1640 medium supplemented with 10% fetal bovine serum,
Start culturing at a cell concentration of 2.5×10 ⁵ cells/cc.
The K562 strain and the Molt4B strain were divided into a control group and a drug administration group, and the medium in the drug administration group was
0.5mM sulfonyldiamine-N,N'-cyclohexane/hydrochloric acid (SDC) is added from the first day of culture. Cell culture was performed at 37°C with 5% carbon dioxide gas and 95%
Perform in an air environment. The anticancer effect was determined by counting the number of viable (proliferating) cells every 24 hours for up to 5 days after the start of culture. The above results are as shown in Figure 1, and there is a significant difference in the number of cells in the drug administration group compared to the number of cells in the control group, indicating that the anticancer drug of the present invention has a significant anticancer effect. It's obvious. Example 2: Anticancer and antimetastatic test of N-methanesulfonylcyclohexylamine/hydrochloric acid, N-chlorosulfonylcyclohexylamine/hydrochloric acid, and sulfonyldiamine-N,N'-cyclohexane/hydrochloric acid, 10-week-old male BDF1 mice were tested. 1 group of 10 animals, 4
Divide into groups and transplant 1 x 10 ⁶ Lewis lung cancer cells subcutaneously into the left thigh. The control group mice received tap water, and the drug administration group mice received N-methanesulfonylcyclohexylamine/hydrochloric acid, N-
Chlorosulfonylcyclohexylamine/hydrochloric acid,
Each group of mice is given free access to 1% solutions of sulfonyldiamine-N,N'-cyclohexane and hydrochloric acid from the day before cancer cell transplantation. Anti-cancer and anti-metastatic effects will be determined after the start of the experiment.
At the 14th day, the weight of the tumor that had metastasized to the main body and the number of metastatic foci to both lungs were evaluated by comparing the mice in the drug administration group and the mice in the control group. The results are shown in the table below, and the growth inhibition rate in drug-administered mice was approximately 34% to 40%, and the metastasis inhibition rate was approximately 53%.
% to 66%, and the remarkable anticancer and antimetastasis pharmacological effects of the anticancer agent of the present invention are evident.

【table】

[Table] In the experiments of each of the above Examples, no side effects were observed due to the administration of the drug. In addition, a metastasis-inhibiting anticancer product containing "a derivative of N-sulfododecahydrodiphenyloamine or an acid salt thereof" as an active ingredient, which has a similar structure to the above-mentioned structure of the present invention and solves the same technical problem. Regarding the agent,
This is detailed in the specification of Japanese Patent Application No. 59-0158, No. 28 (Japanese Unexamined Patent Publication No. 158-114-1988) filed at the same time as the present invention. As described above, the present invention provides an excellent anticancer agent that has excellent anticancer and antimetastatic pharmacological effects and does not cause any side effects.

[Brief explanation of drawings]

FIG. 1: A drawing showing the effect of an anticancer drug in an example of the present invention.

Claims (1)

[Claims] 1 formula (In the formula, R is a hydroxyl group, a halogen, a lower alkyl group, a cyclohexyl group, or a cyclohexylamino group) or an acid addition salt thereof. A metastasis-inhibiting anticancer agent characterized by comprising: