JP5794873B2 - Antitumor agent - Google Patents

Description

  The present invention relates to an antitumor agent comprising a combination of a compound having a kinase inhibitory action and everolimus. More specifically, the present invention relates to an antitumor agent comprising a combination of a compound having a multi-tyrosine kinase inhibitory action and a compound having a mammalian rapamycin target protein (mTOR) inhibitory action.

［式中、Ｒ^１はＣ_１−６アルキル基またはＣ_３−８シクロアルキル基を意味し、Ｒ^２は水素原子またはＣ_１−６アルコキシ基を意味し、Ｒ^３は水素原子またはハロゲン原子を意味する。］

[Wherein, R ¹ represents a C _1-6 alkyl group or a C _3-8 cycloalkyl group, R ² represents a hydrogen atom or a C _1-6 alkoxy group, and R ³ represents a hydrogen atom or a halogen atom. means. ]

  The compound represented by the formula (I) has an angiogenesis inhibitory action (Patent Document 1) and an inhibitory action on tyrosine kinases (Non-Patent Document 1 to Non-Patent Document 5) reported to be involved in tumor malignancy. (Patent Literature 2 to Patent Literature 5) and the like, and are known as therapeutic agents for various tumors such as thyroid cancer, lung cancer, melanoma, endometrial cancer, gastric cancer, bladder cancer and the like.

  On the other hand, the compound represented by the formula (II) is a rapamycin derivative known as a macrolide antibiotic. This compound is called everolimus (42-O- (2-hydroxyethyl) -rapamycin) and can be used as an antitumor agent (Patent Document 6, Non-Patent Document 6) or an autoimmune disease therapeutic agent (Patent Document 7). It has been reported.

  In general, anti-tumor agents are often not effective for all patients when used alone. Thus, attempts have been made to improve the treatment rate by using a plurality of antitumor agents in combination (Patent Documents 8-10).

International Publication No. 2002/032872 International Publication No. 2004/080462 International Publication No. 2007/015569 International Publication No. 2007/136103 International Publication No. 2008/026748 International Publication No. 2002/066019 International Publication No. 1994/09010 International Publication No. 2009/140549 US Patent Application Publication No. 2004-259834 US Pat. No. 6,217,866

American Journal of Pathology, 157, 1091-1095, 2000. Cancer Research, 52, 3498-3502, 1992. Current Cancer Drug Targets, 6, 65-75, 2006. Nature Reviews, Cancer, 10, 116-129, 2010. Clinical Cancer Research, 15, 7119-7123, 2009. Oncology, 77 (Suppl. 1), 122-131, 2009.

  However, the therapeutic effect of the combination of antitumor agents reported so far is not sufficient, and further development of a combination therapy of new antitumor agents is awaited.

  In view of such a situation, as a result of intensive studies, the present inventors unexpectedly exceeded the expectation by administering the compounds represented by formula (I) and formula (II) to a tumor patient in combination. The present invention was completed by finding that it exhibits an excellent antitumor effect.

［式中、Ｒ^１はＣ_１−６アルキル基またはＣ_３−８シクロアルキル基を意味する。Ｒ^２は水素原子またはＣ_１−６アルコキシ基を意味する。Ｒ^３は水素原子またはハロゲン原子を意味する。］
および式（ＩＩ）で表されるエベロリムス

を併用する抗腫瘍剤。
［２］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩および上記式（ＩＩ）で表されるエベロリムスを同時にまたは別々に投与する抗腫瘍剤。
［３］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩および上記式（ＩＩ）で表されるエベロリムスを含む抗腫瘍剤。
［４］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩と併用することによる腫瘍治療のための上記式（ＩＩ）で表されるエベロリムス。
［５］ 上記式（ＩＩ）で表されるエベロリムスと併用することによる腫瘍治療のための上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩。
［６］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩および上記式（ＩＩ）で表されるエベロリムスを併用する腫瘍の治療方法。
［７］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩、上記式（ＩＩ）で表されるエベロリムスおよび賦形剤を含む医薬組成物。
［８］ 上記式（Ｉ）で表される化合物またはその薬理学的に許容される塩および賦形剤を含む医薬組成物と上記式（ＩＩ）で表されるエベロリムスおよび賦形剤を含む医薬組成物とを含むキット。 That is, the present invention provides the following [1] to [8].
[1] A compound represented by formula (I) or a pharmacologically acceptable salt thereof

[Wherein, R ¹ represents a C _1-6 alkyl group or a C _3-8 cycloalkyl group. R ² represents a hydrogen atom or a C _1-6 alkoxy group. R ³ means a hydrogen atom or a halogen atom. ]
And everolimus represented by the formula (II)

An antitumor agent.
[2] An antitumor agent in which the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof and everolimus represented by the above formula (II) are administered simultaneously or separately.
[3] An antitumor agent comprising a compound represented by the above formula (I) or a pharmacologically acceptable salt thereof and everolimus represented by the above formula (II).
[4] Everolimus represented by the above formula (II) for tumor treatment by using in combination with the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof.
[5] A compound represented by the above formula (I) or a pharmacologically acceptable salt thereof for treating a tumor by using in combination with everolimus represented by the above formula (II).
[6] A method for treating a tumor, comprising combining a compound represented by the above formula (I) or a pharmacologically acceptable salt thereof and everolimus represented by the above formula (II).
[7] A pharmaceutical composition comprising a compound represented by the above formula (I) or a pharmacologically acceptable salt thereof, everolimus represented by the above formula (II) and an excipient.
[8] A pharmaceutical composition comprising a compound represented by the above formula (I) or a pharmacologically acceptable salt thereof and an excipient, and a medicine comprising everolimus and an excipient represented by the above formula (II) A kit comprising the composition.

４−［３−クロロ−４−（メチルアミノカルボニル）アミノフェノキシ］−７−メトキシ−６−キノリンカルボキサミド

４−［３−クロロ−４−（エチルアミノカルボニル）アミノフェノキシ］−７−メトキシ−６−キノリンカルボキサミド

Ｎ６−メトキシ−４−（３−クロロ−４−｛［（シクロプロピルアミノ）カルボニル）アミノ］フェノキシ｝−７−メトキシ−６−キノリンカルボキサミド

および
Ｎ６−メトキシ−４−（３−クロロ−４−｛［（エチルアミノ）カルボニル］アミノ｝フェノキシ）−７−メトキシ−６−キノリンカルボキサミド

からなる群から選択される１種以上の化合物であり、
より好ましくは、
４−［３−クロロ−４−（シクロプロピルアミノカルボニル）アミノフェノキシ］−７−メトキシ−６−キノリンカルボキシアミド

である（以下、化合物Ａと表記することがある）。 The compound represented by the above formula (I) is preferably
4- [3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

4- [3-Chloro-4- (methylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

4- [3-Chloro-4- (ethylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

N6-methoxy-4- (3-chloro-4-{[(cyclopropylamino) carbonyl) amino] phenoxy} -7-methoxy-6-quinolinecarboxamide

And N6-methoxy-4- (3-chloro-4-{[(ethylamino) carbonyl] amino} phenoxy) -7-methoxy-6-quinolinecarboxamide

One or more compounds selected from the group consisting of:
More preferably,
4- [3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

(Hereinafter sometimes referred to as Compound A).

  The present invention provides an antitumor agent comprising a combination of a compound having multi-tyrosine kinase inhibitory action and everolimus. Such an antitumor agent exhibits a remarkable antitumor effect as compared with the case of being used alone, and also exhibits an antitumor effect against various cancer types.

It is a graph which shows the combined effect of the compound A and everolimus in the model animal which transplanted the human renal cell carcinoma cell line (Caki-1).

  The compound represented by formula (I) or a pharmacologically acceptable salt thereof according to the present invention can be produced by the method described in Patent Document 1. Further, everolimus represented by the formula (II) according to the present invention can be produced by the method described in Patent Document 7.

  Examples of the pharmacologically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, and a salt with an acidic or basic amino acid.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid. And salt.

  Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferable examples of the salt with organic base include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.

  Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.

  Particularly preferred pharmacologically acceptable salts are salts with organic acids.

  The antitumor agent of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders, capsules or liquids, jellies, syrups and the like.

  The antitumor agent of the present invention may be administered parenterally in the form of injections, suppositories, ointments, cataplasms, and the like.

  The dose of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, pharmaceutical preparation. Depending on the type, etc., it can be selected as appropriate. Usually, when orally administered to an adult (body weight 60 kg), it is 1 to 600 mg, preferably 5 to 400 mg, more preferably 5 to 200 mg per day. This can be administered in 1 to 3 divided doses per day.

  The dosage of everolimus represented by the formula (II) can be appropriately selected as described above. Usually, when orally administered to an adult (body weight 60 kg), it is 1 to 50 mg per day, preferably 1 to 20 mg, more preferably 5 to 10 mg. This can be administered in 1 to 3 divided doses per day.

  When preparing an oral solid preparation, an excipient is added to the main drug, that is, the compound represented by the formula (I) or a pharmacologically acceptable salt thereof and everolimus represented by the formula (II). After adding a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc., it can be made into tablets, granules, fine granules, powders, capsules and the like by conventional methods.

  Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like. Examples of the binder include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like. Examples of the lubricant include magnesium stearate, talc, and silica. Examples of the colorant include titanium oxide, iron sesquioxide, yellow iron sesquioxide, cochineal, carmine, and riboflavin. Examples of flavoring agents include cocoa powder, ascorbic acid, tartaric acid, mint oil, borneol, and cinnamon powder. These tablets and granules may be coated as necessary.

  When preparing injections, add pH adjusters, buffers, suspending agents, solubilizers, stabilizers, tonicity agents, preservatives, etc. to the active ingredient as necessary. Subcutaneous, intramuscular injection, and intravenous infusion. At that time, if necessary, a freeze-dried product can be obtained by a conventional method.

  Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.

  Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and glycerin fatty acid ester.

  Examples of the stabilizer include sodium sulfite and sodium metasulfite. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

  The antitumor agent of the present invention comprises a compound represented by the formula (I) or a pharmacologically acceptable salt thereof and everolimus represented by the formula (II), which are separately or both simultaneously or separately. May be administered. Moreover, it is good also as what is called a kit formulation by putting two formulations in one package. Furthermore, both compounds may be contained in one preparation.

  The type of tumor to be treated with the antitumor agent of the present invention is not particularly limited. For example, fibroma, lipoma, myxoma, chondroma, osteoma, hemangioma, lymphoma, myeloma, melanoma, Myoma, neuroma, glioma, schwannomas, sarcoma, osteosarcoma, muscle species, fibrosarcoma, papilloma, adenoma, cyst, brain tumor, cervical cancer, esophageal cancer, tongue cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, Small intestine cancer such as duodenum, jejunum, ileum, colon cancer such as colon, cecum, rectum, etc., bladder cancer, kidney cancer, liver cancer, gallbladder cancer, prostate cancer, uterine cancer, ovarian cancer, thyroid cancer, pharyngeal cancer, etc., and These mixed tumors can be mentioned.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1 Tumor Growth Inhibitory Effect by Combined Use of Compound A and Everolimus on Human Renal Cell Carcinoma Cell Line (Caki-1) Nude mice of 5 cases in each group (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River Japan Co., Ltd.) Was used to evaluate the anti-tumor effect when compound A, everolimus or both compounds were administered. A human-derived renal cell carcinoma cell line Caki-1 (ATCC) was suspended in a medium (RPMI-1640, Wako Pure Chemical Industries, Ltd.) to a concentration of 2 × 10 ⁸ cells / mL. The same volume of Matrigel ^™ matrix (Nippon Becton Dickinson Co., Ltd.) was added to the suspension and mixed thoroughly. 0.1 mL of the mixture was transplanted into the left flank subcutaneous part of each mouse.
Forty-eight days after transplantation, the major axis and minor axis of the tumor were measured with an electronic digital caliper (Digimatic ^TM Caliper, Mitutoyo Corporation). The mice were divided into groups so that the average values of the tumor volumes in each group were almost equal. The tumor volume was calculated according to the following formula.
Tumor volume = major axis (mm) × minor axis (mm) × minor axis (mm) / 2

Compound A was dissolved in purified water to a concentration of 1 mg / mL. Further, everolimus is suspended in a mixed solution of DMSO, Tween 80 and glucose (3.5: 6.5: 90 (V / V / V), hereinafter referred to as a solvent) so as to have a concentration of 3 mg / mL. did.
Each group of mice was orally administered Compound A solution and solvent, Everolimus suspension and purified water, or Compound A solution and Everolimus suspension, 10 mL / kg once a day for 15 days. The doses of Compound A and everolimus were 10 mg / kg and 30 mg / kg, respectively. In the control group, 10 mL / kg of purified water and a solvent were administered.

  The tumor volume of each mouse was measured on days 4, 7, 11 and 14 after the start of administration. The ratio of the tumor volume on each measurement day to the tumor volume on the administration start day was calculated as a specific tumor volume (hereinafter referred to as RTV). The results are shown in Table 1 and FIG.

Claims (2)

4- [3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

Or a preparation containing a pharmacologically acceptable salt thereof;
Everolimus represented by formula (II)

A therapeutic agent for renal cell cancer , wherein a preparation comprising 4- [3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide

Or a pharmacologically acceptable salt thereof
Everolimus, which is represented by your and formula (II)

Renal cell cancer therapeutic agent comprising in a single formulation.

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