JP3229738B2 - Breast cancer therapeutic agent containing pyridazine derivative as active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for breast cancer containing a 3- (1H-imidazol-1-yl) pyridazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION The development of breast cancer is hormone, ie, estrogen dependent. Currently, the treatment of hormone-dependent breast cancer includes surgical therapy by mastectomy, surgical endocrine therapy to lower blood estrogen by ovariectomy, or medical endocrine therapy to lower blood estrogen by tumor drugs by drugs. I have. A representative drug for this therapy is tamoxifen, an estrogen receptor antagonist for tumor tissue, but treatment with this drug alone has been limited due to the occurrence of refractory disease during clinical use. Therefore, drugs with different mechanisms of action, that is, aromatase inhibitors that inhibit the enzyme that converts testosterone to estrogen and lower blood estrogen, have attracted attention (J. Med. Chem.,
34, 725, 1991).

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a therapeutic agent for breast cancer which has little effect on other steroid metabolizing enzyme systems and has a low toxicity aromatase inhibitory activity.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above-mentioned situation, and as a result, have been disclosed in
The present invention has been completed by finding that the 3- (1H-imidazol-1-yl) pyridazine derivative described in 39578 is suitable for the purpose.

That is, the present invention provides the following general formula (I)

[0006]

Embedded image

Wherein R ¹ is a hydrogen atom or a lower alkyl group, and R ² is a benzyl group or a naphthylmethyl group having or not having a substituent.
The present invention relates to a therapeutic agent for breast cancer containing a (1H-imidazol-1-yl) pyridazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] Specific examples of the pyridazine derivative of the present invention include the following derivatives.

[0009]

[Table 1]

The pharmaceutically acceptable acid addition salt of the pyridazine derivative of the present invention can be produced by using an acid having an acidity sufficient to form an acid addition salt with a weakly basic imidazole group. For example, examples of such an acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and maleic acid.

The pyridazine derivative of the formula (I) is disclosed in
It can be manufactured by a known method described in -139578.

[0012]

Embedded image (Wherein, R ¹ and R ² have the same meaning as described above)

The pharmaceutically acceptable salt of the pyridazine derivative of the present invention obtained as described above can be easily produced according to a conventional method.

The pyridazine derivative of the present invention has aromatase inhibitory activity and is effective for treating breast cancer. Therefore, when administered for the purpose of treating the above diseases, tablets, powders,
Orally as granules, capsules, syrups, etc.
In addition, it may be administered parenterally as an injection. At the time of formulation, it can be produced using a usual formulation carrier according to a conventional method in the technical field. That is, when producing an oral solid preparation, the excipient and the binder if necessary,
After adding disintegrant, lubricant, coloring agent, flavoring agent, etc.,
Tablets, coated preparations, granules, powders, capsules and the like are prepared according to a conventional method. Here, as the excipient, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like are used. Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl starch, and polyvinylpyrrolidone. As the lubricant, for example, silica, talc,
Magnesium stearate, polyethylene glycol,
Hardened vegetable oils and the like, as disintegrants, for example, starch, agar,
Gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and the like are used. As the flavoring agent, for example, cocoa powder, peppermint oil, dragon brain, cinnamon powder and the like are used. These tablets and granules may be sugar-coated, gelatin-coated or otherwise appropriately coated as necessary.
Also, when preparing an injection for parenteral administration,
If necessary, a pH adjusting agent, a buffer, a stabilizer, a solubilizing agent and the like may be added to the main drug to prepare a subcutaneous, intramuscular, or intravenous injection by a conventional method.

As described above, the pyridazine derivative of the present invention may be administered orally or parenterally. The dose varies depending on the severity of the symptoms and the age of the patient. 200 mg / kg, preferably 0.05-50 mg / kg
At a rate of 1 to several times a day.

[0016]

The present invention will be described more specifically with reference to the following Examples and Test Examples.

Example 1 Compound 1 and lactose were mixed and pulverized, lactose, crystalline cellulose, and magnesium stearate were added to the mixture, and the mixture was further uniformly mixed. / Tablet tablets. Compound 1 2.0 mg Lactose 65.0 mg Crystalline cellulose 32.0 mg Magnesium stearate 1.0 mg

Example 2 The following ingredients were mixed and pressed using a tableting machine to give 250 mg of the active ingredient.
mg / tablet were obtained. Compound 1 25.0 mg Microcrystalline cellulose 45.0 mg Lactose 158.0 mg Magnesium stearate 3.0 mg Hydroxypropylcellulose 8.0 mg Sodium carboxymethylcellulose 10.0 mg Talc 1.0 mg

Example 3 Compound 1 and lactose were mixed and pulverized, and this mixture was further mixed with lactose, corn starch and magnesium stearate.
This was filled into a No. 3 gelatin hard capsule at a rate of 200 mg per capsule to prepare a capsule. Compound 2 5.0 mg Lactose 32.0 mg Corn starch 61.0 mg Magnesium stearate 2.0 mg

Example 4 After thoroughly mixing the following compounds, adding a wetting liquid (30% ethanol), kneading, granulating with an extrusion granulator, immediately sizing with a marmellaizer, drying, The mixture was sieved to produce 12-42 mesh columnar granules. Composition in columnar granules 200 mg Compound 1 10.0 mg Lactose 69.0 mg Corn starch 50.0 mg Microcrystalline cellulose 49.0 mg Hydroxypropyl cellulose 2.0 mg Carboxymethyl cellulose 20.0 mg

Example 5 1 m of Compound 1 was added per ml.
An injection containing the following components containing g was prepared by a conventional method. Compound 2 10 mg Polyethylene glycol for injection 400 5 ml Sodium dihydrogen phosphate 4 mg Distilled water for injection is added to make a total volume of 10 ml.

Test Example 1 Aromatase Enzyme Inhibiting Activity Under ice cooling, a coenzyme (NADP ^{+ and} NADPH regeneration system) was added to bovine placenta microsomes, and then the substrate [1β- ³
The reaction was started by adding [H] -4-androstene-3,17-dione. The reaction is 95% O ₂ -5%
The mixture was incubated at 37 ° C. for 30 minutes under a stream of CO ₂ , followed by the method of Thompson et al. (J. Biol. Chem., 249, 5364-537).
2, 1974) with some modifications. The inhibitory effect is
After pre-incubating the test compound and the enzyme solution at 37 ° C. for 5 minutes, the reaction was measured by adding the NADPH regeneration system and the substrate to start the reaction. The measured value of the test compound was determined from the measured value of the control group to which only the solvent was added. Find the difference,
This was determined as a percentage of the measured value of the control group. Table 2 is 50%
The inhibitory concentration (IC ₅₀ ) was indicated.

[0023]

[Table 2]

Test Example 2 Inhibition of 11β, 18α-hydroxylase Under ice cooling, bovine adrenal mitochondrial coenzyme cocktail (NA
After adding DPH and calcium chloride), the substrate [4-
^The reaction was started by adding < ¹⁴ > C] -deoxycorticosterone. The reaction was incubated at 37 ° C. for 30 minutes, and the method of Sato et al. (Arch. Biochem. Biophyte.
s., 190, 307-314, 1978). The inhibitory effect was measured by pre-incubating the test compound and the enzyme solution at 37 ° C. for 5 minutes, and then starting the reaction by adding a NADPH regeneration system and a substrate. The difference between the measured values of the compounds was determined, and this was calculated as a percentage of the measured value of the control group. Table 3 shows the 50% inhibitory concentration (IC ₅₀ ).

[0025]

[Table 3]

Test Example 3 DMBA-Induced Rat Breast Cancer Model Shimkin et al. (Cancer Res., 29, 503-505 (1969))
It went according to. That is, 7,
12-dimethylbenz [a] anthracene (DMBA)
5 mg / 0.5 ml was orally administered once a week for 5 weeks (total amount
25 mg). 5 to 6 weeks after the final administration, the test compound was orally administered once a day for 28 days from the time when the minor axis of the breast cancer grew to about 1 cm. The major axis and minor axis of the tumor were measured every 7 days, and the tumor diameter (major axis × minor axis ² × 0.5 (mm ³ )) was calculated. The tumor increase rate was expressed as the rate of increase, with the start of administration as 100. Table 4 shows the results of the above test.

[0027]

[Table 4]

[Test Example 4] Acute toxicity test The present compound (1000 mg / kg) was suspended in a 0.5% sodium carboxymethylcellulose solution, and fasted for 24 hours to ddY male mice (5 weeks old, 5 mice per group). Oral administration and observation for 7 days after administration showed no death.

[0029]

According to the present invention, 3- (1H-imidazole-1)
The -yl) pyridazine derivatives and their pharmaceutically acceptable salts have little effect on other steroid metabolizing enzyme systems and are highly safe, so that they are useful as selective aromatase inhibitors for treating breast cancer. is there.

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Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I): Wherein R ¹ is a hydrogen atom or a lower alkyl group, and R ² is a benzyl group or a naphthylmethyl group having or not having a substituent. 3- (1H-imidazol-1-yl) pyridazine A therapeutic agent for breast cancer, comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.