WO2009110416A1

WO2009110416A1 - Concomitant drug

Info

Publication number: WO2009110416A1
Application number: PCT/JP2009/053833
Authority: WO
Inventors: 義一大田; 慎二 ▲高▼木; 正宏矢口
Original assignee: 武田薬品工業株式会社
Priority date: 2008-03-03
Filing date: 2009-03-02
Publication date: 2009-09-11
Also published as: TW200940546A; UY31683A; AR070735A1

Abstract

Disclosed is a pharmaceutical agent that is obtained by combining an HER2 inhibitor and either a hormonal therapeutic agent or an anti-cancer agent. Specifically, the pharmaceutical agent consists of a combination of (1) an HER2 inhibitor represented by formula (I) (in formula I, R¹ represents a hydrogen atom; R² represents a C_1-6 alkyl group substituted with a group indicated by a C_1-4 alkyl that may be -NR⁶-CO-(CH₂)n-SO₂-halogenated (therein n is an integer from 1 to 4, R⁶ is a hydrogen atom or an C_1-4 alkyl group, and -(CH₂)_n- can be substituted with a C_1-4 alkyl); R³ represents a hydrogen atom or a C_1-6 alkyl group; R⁴ represents a halogen atom or a C_1-6 alkyl group; R⁵ represents a halogen atom or a C_1-6 alkyl group; and X represents a hydrogen atom or a halogen atom; however, N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidine-5-yl)ethyl] -2-(methylsulfonyl)acetoamide, is excluded) or a salt or prodrug thereof, and (2) a hormonal therapeutic agent or an anti-cancer agent.

Description

Concomitant medication

The present invention is (1) a formula having HER2 inhibitory action:

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof and (2) a hormonal therapeutic agent or an anticancer agent.
The present invention also relates to a thymidine synthase production inhibitor comprising the compound represented by the formula (I) or a salt thereof or a prodrug thereof.

(Background of the Invention)
Patent Document 1 describes a HER2 inhibitor having a pyrrolopyrimidine skeleton or a pyrazolopyrimidine skeleton.
Patent Document 2 discloses a formula that is a HER2 inhibitor:

The use of a compound represented by the above and trastuzumab in combination for breast cancer treatment is described.
International Publication No. 2005/010451 Pamphlet International Publication No. 2005/120512 Pamphlet

The present invention is useful as an agent for preventing or treating cancer (1):

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) (hereinafter sometimes abbreviated as compound (I)) or a salt or prodrug thereof and (2) a hormonal therapeutic agent or an anticancer agent A thymidine synthase production inhibitor (hereinafter, referred to as a concomitant agent of the present invention) and a compound represented by the formula (I) or a salt or prodrug thereof It is an object of the present invention to provide a thymidine synthase production inhibitor of the present invention.

As a result of intensive studies, the present inventors have found that the formula (1):

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt thereof or a prodrug thereof, and (2) a hormonal therapeutic agent or an anticancer agent in combination for use as a single agent or in other combinations As a result of further investigation, it was found that the compound represented by the above formula (I) exhibits a significant anticancer activity than a pharmaceutical agent, and exhibits a thymidine synthase production inhibitory activity. . That is, the present invention
[1] Formula (1):

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof;
(2) a pharmaceutical comprising a combination of a hormone therapy agent or an anticancer agent;
[2] The medicament according to [1] above, wherein X is a hydrogen atom;
[3] R ¹ is a hydrogen atom,
R ² is
—NR ^6a —CO—CR ⁷ R ⁸ —SO ₂ —C _1-4 alkyl (R ^6a is a hydrogen atom or a methyl group, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a methyl group) A C _1-6 alkyl group substituted with a group represented by:
R ³ is a hydrogen atom,
The medicament according to the above [2], wherein R ⁴ is a chlorine atom or a methyl group, and R ⁵ is a fluorine atom, a chlorine atom or a methyl group;
[4] The medicament according to [3] above, wherein R ⁷ and R ⁸ are methyl groups;
[5] (1) N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl 2-methyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[6] (1) N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl ] -2- (ethylsulfonyl) acetamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[7] (1) N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl -N, 2-dimethyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[8] (1) N- [2- (4-{[3-Chloro-4- (3-methylphenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl ] -2- (methylsulfonyl) acetamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[9] (1) N- [2- (4-{[3-Chloro-4- (3-fluorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl ] -2- (methylsulfonyl) acetamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[10] (1) N- [2- (4-{[4- (3-Chlorophenoxy) -3-methylphenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl 2-methyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to [1] above, which is combined with a hormone therapy agent or an anticancer agent;
[11] The medicament according to [1] above, wherein the anticancer agent is a HER2 antibody, EGFR antibody, EGFR inhibitor, VEGFR inhibitor or chemotherapeutic agent;
[12] The medicament according to [1] above, wherein the anticancer agent is trastuzumab, cetuximab, erlotinib, gefitinib or paclitaxel;
[13] The medicament according to [1] above, wherein the hormone therapy agent is an ER down regulator;
[14] The medicament according to [1] above, wherein the hormone therapy agent is fulvestrant;
[15] The medicament according to [1] above, which is a preventive or therapeutic agent for cancer;
[16] The medicament according to [15] above, wherein the cancer is breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer, colon cancer, small intestine cancer, esophageal cancer or stomach cancer;
[17] For mammals, formula (1):

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Ile) ethyl] -2- (methylsulfonyl) acetamide)) or a salt thereof or a prodrug thereof, and (2) an effective amount of a hormonal therapeutic agent or an anticancer agent, Or treatment method;
[18] Formula (1) for producing a preventive or therapeutic agent for cancer:

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof; and (2) use of a hormonal therapeutic agent or an anticancer agent;
[19] Formula

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof, a thymidine synthase production inhibitor;
[20] For mammals, the formula:

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt thereof or a prodrug thereof, and a method for inhibiting thymidine synthase production comprising administering an effective amount thereof;
[21] A formula for producing a thymidine synthase production inhibitor:

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof;
The present invention is described in detail below.

(1) Formula:

[Wherein R ¹ represents a hydrogen atom,
R ² is
—NR ⁶ —CO— (CH ₂ ) _n —SO ₂ —optionally halogenated C _1-4 alkyl (n is an integer of 1 to 4; R ⁶ is a hydrogen atom or a C _1-4 alkyl group; A C _1-6 alkyl group substituted with a group represented by the _formula : — (CH ₂ ) _n — may be substituted with C _1-4 alkyl),
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁴ represents a halogen atom or a C _1-6 alkyl group,
R ⁵ represents a halogen atom or a C _1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Ill) ethyl] -2- (methylsulfonyl) acetamide)) or a salt thereof or a prodrug thereof, and (2) a hormonal therapeutic agent or an anticancer agent are used in combination as a single agent or other combination drugs More significant effects are recognized, and it is useful as a safe preventive or therapeutic agent for cancer.
In addition, the hormonal therapeutic agent may increase the HER family molecule and enhance the stimulation of the HER family molecule, thereby reducing the effect. On the other hand, the compound (I) has an action of blocking the HER signal. Therefore, in particular, a pharmaceutical comprising a combination of (1) compound (I), which is a HER2 inhibitor, and (2) a hormonal therapeutic agent, prevents the increase in HER family molecules compared to the case of using a hormonal therapeutic agent alone. Drugs with different mechanisms can be used in combination.
Furthermore, the compound represented by the formula (I) or a salt thereof or a prodrug thereof has a thymidine synthase production inhibitory action, so that it is useful as a single agent active ingredient for the safe prevention or treatment of cancer. is there.

It is a figure which shows the combined use effect of a compound A and cetuximab. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is 100%. (■; Compound A alone (μM), ◆; cetuximab alone (μg / mL), ▲; Compound A + cetuximab) It is a figure which shows the combined use effect of a compound A and erlotinib. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is 100%. (■; Compound A alone, ◆; erlotinib alone, ▲; Compound A + erlotinib) It is a figure which shows the combined use effect of compound A and trastuzumab. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is 100%. (◆; Compound A alone (μM), ■; Trastuzumab alone (μg / mL), ▲; Compound A + Trastuzumab) The figure which shows the effect by combined use of the compound A and trastuzumab with respect to the tumor growth of HER2 high expression human breast cancer cell line BT-474 is shown. (●; control group, ■; compound A, ♦; trastuzumab, □; compound A + trastuzumab) It is a figure which shows the average value of TS gene expression level when compound A is added to human breast cancer cell line BT-474 which is HER2 high expression cell. The vertical axis shows the relative value of TS gene expression level. It is a figure which shows that A431 * cell proliferation is inhibited more strongly by combined use with the compound A and AZD6474 compared with each time alone. Cell growth inhibition assay was performed using CellTiter-Glo Luminescent Cell Viability assay kit. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is defined as 100%. (◆; Compound A alone (μM), ■; AZD6474 alone (μM), ▲; Compound A + AZD6474) It is a figure which shows that SK-BR-3 sputum cell proliferation is inhibited more strongly by combined use of compound A and BEZ235 compared with each time alone. Cell growth inhibition assay was performed using CellTiter-Glo Luminescent Cell Viability assay kit. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is defined as 100%. (◆; Compound A alone (μM), ■; BEZ235 alone (μM), ▲; Compound A + BEZ235) It is a figure which shows that 併用 Calu-3 Ａ cell proliferation is inhibited more strongly by combined use of compound A and PD0325901 compared with each time alone. Cell growth inhibition assay was performed using CellTiter-Glo Luminescent Cell Viability assay kit. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is defined as 100%. (◆; Compound A alone (μM), ■; PD0325901 alone (μM), ▲; Compound A + PD0325901) It is a figure which shows that the combined use of Compound A and rapamycin inhibits BT-474 sputum cell proliferation more strongly than when each compound is used alone. Cell growth inhibition assay was performed using CellTiter-Glo Luminescent Cell Viability assay kit. The horizontal axis indicates the concentration of each drug, and the vertical axis indicates the number of cells (%) when the group to which no drug is added is defined as 100%. (◆; Compound A alone (μM), ■; Rapamycin alone (μM), ▲; Compound A + rapamycin)

(Detailed description of the invention)
Below, each term used by compound (I) is demonstrated.

Unless otherwise specified, in this specification, examples of the “halogen atom” (and “halogen” in a substituent) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present specification, unless otherwise specified, the term “C _1-6 alkyl” means straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. It is done.

In the present specification, unless otherwise specified, “C _1-4 alkyl” means straight or branched alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl and tert-butyl.

Hereinafter, preferred groups of each substituent of the compound (I) will be described in detail.

R ² is preferably a C _1-6 alkyl group (particularly an ethyl group) substituted with a group represented by the formula “—NR ^6a —CO—CR ⁷ R ⁸ —SO ₂ —C _1-4 alkyl”. .

In the formula, R ^6a is a hydrogen atom or a methyl group, and R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a methyl group. R ⁷ and R ⁸ are preferably a methyl group.

R ³ is preferably a hydrogen atom.

The “halogen atom” represented by R ⁴ is preferably a chlorine atom. The “C _1-6 alkyl group” represented by R ⁴ is preferably a methyl group. R ⁴ is preferably a chlorine atom or a methyl group.

The “halogen atom” represented by R ⁵ is preferably a fluorine atom or a chlorine atom. Further, the “C _1-6 alkyl group” represented by R ⁵ is preferably a methyl group. R ⁵ is preferably a fluorine atom, a chlorine atom or a methyl group.

The “halogen atom” represented by X is preferably a fluorine atom. X is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.

As a preferred embodiment of compound (I),
R ¹ is a hydrogen atom,
R ² is
—NR ^6a —CO—CR ⁷ R ⁸ —SO ₂ —C _1-4 alkyl (wherein R ^6a is a hydrogen atom or a methyl group, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a methyl group) A C _1-6 alkyl group (particularly an ethyl group) substituted with a group represented by
R ³ is a hydrogen atom,
R ⁴ is a chlorine atom or a methyl group,
R ⁵ is a fluorine atom, a chlorine atom or a methyl group,
X is a hydrogen atom or a fluorine atom (preferably a hydrogen atom),
Compounds.

As a more preferred embodiment of the compound (I),
R ¹ is a hydrogen atom,
R ² is
Substituted with a group represented by —NR ^6a —CO—CR ⁷ R ⁸ —SO ₂ —C _1-4 alkyl (wherein R ^6a represents a hydrogen atom or a methyl group, and R ⁷ and R ⁸ represent a methyl group) A C _1-6 alkyl group (especially an ethyl group),
R ³ is a hydrogen atom,
R ⁴ is a chlorine atom or a methyl group,
R ⁵ is a fluorine atom, a chlorine atom or a methyl group,
X is a hydrogen atom or a fluorine atom (preferably a hydrogen atom),
Compounds.

As compound (I), particularly preferably,
N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2-methyl- 2- (methylsulfonyl) propanamide,
N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2- (ethyl Sulfonyl) acetamide,
N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -N, 2- Dimethyl-2- (methylsulfonyl) propanamide,
N- [2- (4-{[3-Chloro-4- (3-methylphenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2- (methyl Sulfonyl) acetamide,
N- [2- (4-{[3-Chloro-4- (3-fluorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2- (methyl Sulfonyl) acetamide, and N- [2- (4-{[4- (3-chlorophenoxy) -3-methylphenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2-methyl-2- (methylsulfonyl) propanamide,
Is mentioned.

Compound (I) and a salt thereof can be produced according to the method described in International Publication No. 2007/064045.

When compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are encompassed in compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. The crystal can be produced by crystallization by applying a crystallization method known per se.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
Compounds labeled with isotopes (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also encompassed in compound (I).

Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with organic base include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethane [tris (hydroxymethyl) methylamine], t-butylamine. , Salts with cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.

Of these, pharmaceutically acceptable salts are preferred, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid And salts with organic acids such as citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. In particular, a salt with p-toluenesulfonic acid is preferred.
A prodrug of compound (I) or a salt thereof is a compound that is converted into compound (I) or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc. It refers to a compound that changes to compound (I) or a salt thereof, or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I) or a salt thereof. As a prodrug of the compound (I) or a salt thereof, a compound in which the amino of the compound (I) or a salt thereof is acylated, alkylated or phosphorylated (eg, the amino of the compound (I) or a salt thereof is eicosanoylated, Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butyl And the like are used. These compounds can be produced from compound (I) or a salt thereof by a method known per se.
The prodrug of compound (I) or a salt thereof is compound (I) or a compound thereof under physiological conditions as described in Hirokawa Shoten, 1990, “Pharmaceutical Development”, Volume 7, Molecular Design, pages 163 to 198. It may change into a salt.
Hereinafter, Compound (I) or a salt thereof or a prodrug thereof is abbreviated as Compound (I).

In the present specification, examples of the `` hormone therapeutic agent '' include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, azoprisnil, Allylestrenol, gestrinone, nomegestrol, tadenane, mepaltricine, raloxifene, oloxifene, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate), ER down regulators (eg fulvestrant ( Faslodex (trademark), etc.), human menopausal gonadotropin, follicle stimulating hormone, pill preparation, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonist ( , Goserelin acetate, buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane, etc.), Antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, dutasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibition Drugs (eg, abiraterone, etc.), retinoids and drugs that delay the metabolism of retinoids (eg, riarozole, etc.) are used, among them LH-RH agonists (eg, goserelin acetate) Buserelin, leuprorelin etc.), ER down regulator (for example fulvestrant (Faslodex (TM)) and the like) are preferable.

In the present specification, examples of the “anticancer agent” include a chemotherapeutic agent, an immunotherapeutic agent, a cell growth factor, and a drug that inhibits the action of its receptor.

Examples of the “chemotherapeutic agent” include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like.
Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide, Roh statins scan Chima Lamar, adozelesin, system scan Chin, Bizereshin or the like is used.
Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritorexime, idoxyuridine, mitoxifridin Ambamustine, pemetrexed disodium salt (Alimta (trademark)) and the like are used.
Examples of the “anticancer antibiotic” include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)), acrarubicin hydrochloride , Pirarubicin hydrochloride, epirubicin hydrochloride, neocalcinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like.
Examples of the “plant-derived anticancer agent” include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel (Taxol ™), docetaxel, vinorelbine and the like.

Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, coryne Bacterium parvum, levamisole, polysaccharide K, procodazole and the like are used.

The “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less. In this peptide, a factor that exerts an action at a low concentration by binding to a receptor is used. Specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity as that of [e.g. (2) Insulin or a substance having substantially the same activity (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast) growth factor) or a substance having substantially the same activity (eg, acid) FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.], (4) other cell growth factors [eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (never grow growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), etc.
The “cell growth factor receptor” may be any receptor that has the ability to bind to the cell growth factor, and specifically includes an EGF receptor, a haregulin receptor (HER2). Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, and the like.
Examples of the “drug that inhibits the action of cell growth factor” include HER2 antibody (such as trastuzumab (Herceptin (trademark))), imatinib mesylate, ZD1839 or EGFR antibody (cetuximab (Erbitux (trademark), etc.)) , Antibodies against VEGF (eg, bevacizumab (Avastin ™)), VEGFR antibody, VEGFR inhibitor, EGFR inhibitor (erlotinib (Tarceva ™), gefitinib (Iressa ™), etc.) Is mentioned.

In addition to the above drugs, mTOR inhibitors (temsirolimus, rapamycin, AZD8055, RAD001, CCI-779, Ap23573 / MK8669, etc.), Akt inhibitors, PI3 kinase inhibitors (PI-103:

, Compounds described in International Publication WO2005 / 011686, SF-1126, XL-147, BGT226, GDC-0941, etc.), PI3 kinase / mTOR inhibitors (BEZ235, XL-765, etc.), c-Met inhibitors (PF-2341066) :

, Compounds described in US Patent Application Publication US2004 / 0198750, compounds described in US Patent Application Publication US2007 / 0197537, ARQ-197, JNJ-38877605, SGX-523, etc.), VEGFR / c-Met inhibitor (XL -880, XL-187, MGCD-265, etc.), VEGR (RET) / EGFR inhibitor (AZD6474, etc.), MEK inhibitor (PD0325901, etc.), L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury Hematoporphyrin sodium, topoisomerase I inhibitor (eg, irinotecan hydrochloride (topotecin (trademark), campto (trademark)), topotecan, etc.), topoisomerase II inhibitor (eg, sobuzoxane, etc.), differentiation inducer (eg, retinoid, vitamin) D), angiogenesis inhibitors (eg, thalidomide, SU11248, etc.), α-blockers (eg, tamsulosin hydrochloride, naphthopidyl, urapidil, alfuzosin, terra) Syn, prazosin, silodosin, etc.), serine / threonine kinase inhibitors, endothelin receptor antagonists (eg, atrasentan, etc.), proteasome inhibitors (eg, bortezomib, etc.), Hsp90 inhibitors (eg, 17-AAG, etc.) Spironolactone, minoxidil, 11α-hydroxyprogesterone, bone resorption inhibitor / metastasis inhibitor (eg, zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid) and the like can also be used.

Among the above, hormone therapy agents or anticancer agents (hereinafter abbreviated as concomitant drugs) include ER down regulators (for example, fulvestrant (Faslodex ™)), HER2 antibodies (trastuzumab (Herceptin ™)) ), EGFR antibody (cetuximab (Erbitux (trademark) etc.), EGFR inhibitor (erlotinib (Tarceva (trademark), gefitinib (Iressa (trademark)) etc.), VEGFR inhibitor or chemotherapeutic agent (Paclitaxel (Taxol (trademark) etc.) is preferable.
In particular, fulvestrant (Faslodex ™), trastuzumab (Herceptin ™), cetuximab (Erbitux ™), erlotinib (Tarceva ™), gefitinib (Iressa ™) )), Paclitaxel (Taxol ™) and the like are preferred.
Also, preferable examples include doxorubicin hydrochloride (Adriacin (trademark)), irinotecan hydrochloride (topotecin (trademark), campto (trademark)), 5FU, docetaxel or methotrexate.

The combination agent of the present invention is not limited to the combination of two agents, and three or more agents may be used in combination.

In the combined use of Compound (I) and a concomitant drug, the timing of administration of Compound (I) and the concomitant drug is not limited, and Compound (I) and the concomitant drug may be administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration mode of compound (I) and the concomitant drug is not particularly limited, as long as compound (I) and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating compound (I) and a concomitant drug, and (2) separate preparation of compound (I) and concomitant drug. Simultaneous administration of the two preparations obtained by the same route by the same route of administration, (3) with a time difference in the same route of administration of the two formulations obtained by separately formulating the compound (I) and the concomitant drug (4) Simultaneous administration of two kinds of preparations obtained by separately formulating Compound (I) and a concomitant drug by different administration routes, (5) Preparation of Compound (I) and a concomitant drug separately Administration of the two types of preparations obtained by the preparation at different time intervals in different administration routes (for example, administration in the order of Compound (I) → concomitant drug or administration in the reverse order) and the like are used.

The combination agent of the present invention is a therapeutic agent that suppresses the growth of cancers expressing HER2 and / or EGFR kinase, and prevents the transition of hormone-dependent and hormone-dependent cancers to hormone-independent cancers It is also useful as a preventive agent. In addition, it has low toxicity (eg acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), high water solubility, stability, pharmacokinetics (absorbability, distribution) , Metabolism, excretion, etc.), and is also useful as a medicine because of its excellent medicinal effects.
That is, the concomitant drug of the present invention can be used for various cancers (among others, breast cancer (for example, invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer, etc.), prostate cancer (for example, hormone-dependent prostate cancer, hormone). Independent prostate cancer, etc.), pancreatic cancer (eg, pancreatic duct cancer, etc.), stomach cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant) Mesothelioma), colon cancer (eg, gastrointestinal stromal tumor), rectal cancer (eg, gastrointestinal stromal tumor), colorectal cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, digestion) Ductal stromal tumors), small intestine cancer (eg, non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (eg, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, etc.) ), Salivary gland cancer, brain tumor (eg pineal astrocyte tumor, ciliary cell) Cell tumor, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (eg, primary liver cancer, extrahepatic cholangiocarcinoma), kidney cancer (eg, renal cell carcinoma, renal pelvis and urine) Transitional cell carcinoma of the duct), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (eg epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor, etc.) , Bladder cancer, urethral cancer, skin cancer (eg, intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (eg, medullary thyroid cancer), Parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (eg, osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma, etc.), angiofibroma, retinal sarcoma, penile cancer, testicular cancer, childhood solid cancer (For example, Wilms tumor, childhood kidney tumor, etc.), Kaposi's sarcoma, Disarcoma, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia (eg, acute myeloid leukemia, acute lymphoblastic leukemia, etc.), atherosclerosis, angiogenesis Diseases caused by abnormal cell proliferation, such as angiogenesis associated with growth of solid tumors and sarcomas, angiogenesis associated with tumor metastasis, and angiogenesis associated with diabetic retinopathy, etc., viral diseases (such as HIV infection) It can be used as a safe preventive or therapeutic agent for.
Tyrosine kinase dependent diseases further include cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity. Therefore, the combination agent of the present invention can also be used as a preventive or therapeutic agent for cardiovascular diseases such as restenosis.
The combination agent of the present invention is useful as an anticancer agent for prevention or treatment of cancer, particularly breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer, colon cancer, small intestine cancer, esophageal cancer and gastric cancer.
The concomitant drug of the present invention has low toxicity and is used as a pharmaceutical as it is or mixed with a pharmaceutically acceptable carrier known per se, for example, to mammals (eg, human, horse, cow, dog, cat, rat, mouse, Rabbit, pig, monkey, etc.) can be used as a pharmaceutical composition.
The concomitant drug of the present invention is prepared by mixing a compound (I) or (and) the above concomitant drug with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet, film coating). Including tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) It can be safely administered. The injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials, such as excipients and lubricants in solid preparations. , Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.

Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

The compounding ratio of the compound (I) and the concomitant drug in the combination drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of compound (I) in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
The same content may be used when compound (I) and the concomitant drug are formulated separately.

These preparations can be produced by a method known per se generally used in the preparation process.
For example, the compound (I) or the concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose. , Dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), buffers (eg, , Phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose etc.), pH regulators (eg, hydrochloric acid, hydroxylated) Sodium), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, para Methyl xybenzoate, propyl paraoxybenzoate, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol) Etc.) in aqueous injections, or in olive oil, sesame oil, cottonseed oil, corn oil and other vegetable oils, or in solubilizing agents such as propylene glycol, and then molded into oily injections to make injections Can do.

In order to obtain a preparation for oral administration, according to a method known per se, compound (I) or a concomitant drug is used, for example, an excipient (eg, lactose, sucrose, starch, corn starch, etc.), a disintegrant (eg, starch, calcium carbonate). Etc.), binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, gelatin, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) Then, if necessary, it can be coated by a method known per se for the purpose of taste masking, enteric property or persistence, to obtain a preparation for oral administration. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) (Made in Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengara, titanium dioxide, etc.) are used. Examples of the sugar coating include sucrose, talc, gum arabic, pigments (eg, bengara, titanium dioxide, etc.), polishes (eg, beeswax, etc.), and the like. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
For example, to make a suppository, the compound (I) or the concomitant drug can be converted into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the above composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
Examples of the sustained-release preparation include sustained-release microcapsules.
In order to obtain a sustained-release type microcapsule, a method known per se can be employed.
Compound (I) is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
The concomitant drug can be in the above-mentioned dosage form depending on the type of drug.

The dose of the concomitant drug of the present invention varies depending on the type of compound (I), age, body weight, symptom, dosage form, administration method, administration period, etc., for example, usually per patient (adult, body weight about 60 kg) per person The compound (I) and the concomitant drug are each in the range of about 0.1 mg to about 500 mg, preferably in the range of about 1 mg to about 100 mg for oral administration, and about 0.01 mg to about 100 mg for parenteral administration. A range can be selected, more preferably from about 0.1 mg to about 10 mg. These dosages can be administered in 1 to 3 divided doses per day. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually in the range of about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg parenterally per kg body weight of the mammal, for example, by oral administration. For administration, it can be selected from the range of about 0.0001 mg to about 400 mg, more preferably from the range of about 0.001 mg to about 200 mg. These dosages are usually administered in 1 to 3 divided doses per day.

When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I) may be administered, or compound (I) is administered first. Thereafter, the concomitant drug may be administered. When administered at a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably The method includes administering Compound (I) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When compound (I) is administered first, the concomitant drug is administered within 1 minute to 1 day after administration of compound (I), preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
As a preferable administration method, for example, about 0.001 to 200 mg / kg body weight of a concomitant drug formed into a preparation for parenteral administration was injected intravenously or intramuscularly, and after about 15 minutes, it was formed into a preparation for oral administration. Compound (I) is orally administered at a daily dose of about 0.005 to 100 mg / kg body weight.

In addition, since the compound (I) of the present invention has a thymidine synthase production inhibitory action, it can be used as a single agent active ingredient, as a therapeutic agent that suppresses the growth of cancer, and for hormone-dependent and hormone-dependent cancers. It is useful as a prophylactic agent that prevents the transition to hormone-independent cancer. The compound (I) of the present invention has low toxicity (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), high water solubility, stability, It is also useful as a medicine because it is excellent in pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.) and in terms of drug efficacy.
That is, the compound (I) of the present invention can be used as an active ingredient of a single agent as well as various cancers (especially breast cancer (for example, invasive breast cancer, non-invasive breast cancer, inflammatory breast cancer, etc.), prostate cancer) (Eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), pancreatic cancer (eg, pancreatic duct cancer, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (eg, Non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc., colon cancer (eg, gastrointestinal stromal tumor), rectal cancer (eg, gastrointestinal stromal tumor), colon cancer (eg, familial colon) Cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor, etc.), small intestine cancer (eg, non-Hodgkin lymphoma, gastrointestinal stromal tumor, etc.), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (eg, nasopharynx) Cancer, oropharyngeal cancer, hypopharyngeal cancer, etc.), salivary gland cancer, brain tumor (eg Pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannomas, liver cancer (eg primary liver cancer, extrahepatic cholangiocarcinoma, etc.), Kidney cancer (eg renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (eg epithelial ovarian cancer, extragonadal germ cell tumor, ovary Germ cell tumor, ovarian low grade tumor, etc.), bladder cancer, urethral cancer, skin cancer (eg, intraocular (eye) melanoma, Merkel cell carcinoma, etc.), hemangioma, malignant lymphoma, malignant melanoma, Thyroid cancer (eg, medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (eg, osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma, etc.), angiofibroma, Retinal sarcoma, penile cancer, testicular tumor, pediatric solid cancer (eg Wilms tumor, pediatric kidney tumor), Disarcoma, Kaposi sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia (eg, acute myeloid leukemia, acute lymphoblastic leukemia, etc.), atheroma Atherosclerosis, angiogenesis (eg, angiogenesis with growth of solid tumors and sarcomas, angiogenesis with tumor metastasis, angiogenesis with diabetic retinopathy, etc.), viral diseases (HIV infection, etc.), etc. It can be used as a safe preventive or therapeutic agent for diseases caused by abnormal cell proliferation.

The thymidine synthase production inhibitor containing the compound (I) of the present invention has low toxicity, and is used as it is as a medicine or mixed with a pharmaceutically acceptable carrier known per se as a mammal (eg, human, horse, etc.). Bovine, dog, cat, rat, mouse, rabbit, pig, monkey, etc.).
The thymidine synthase production inhibitor of the present invention is prepared, for example, by mixing compound (I) with a pharmacologically acceptable carrier according to a method known per se, including pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets). ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained release, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) can do. The injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
Examples of the pharmacologically acceptable carrier that may be used for the production of the thymidine synthase production inhibitor of the present invention include the pharmacologically acceptable carrier that may be used for the production of the combination agent of the present invention. The same thing is mentioned.

The content of compound (I) in the thymidine synthase production inhibitor of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50%, based on the whole preparation. % By weight, more preferably about 0.5 to 20% by weight.

These preparations can be produced by a method known per se generally used in the preparation process, and examples thereof include the same methods as those described above for the concomitant drug of the present invention.
Compound (I) is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.

The dosage of the thymidine synthase production inhibitor of the present invention varies depending on the type, age, weight, symptom, dosage form, administration method, administration period, etc. of compound (I). Per person, usually as compound (I), in the range of about 0.1 mg to about 500 mg, preferably in the range of about 1 mg to about 100 mg for oral administration, and about 0.01 mg to about 100 mg for parenteral administration. A range can be selected, more preferably from about 0.1 mg to about 10 mg. These dosages can be administered in 1 to 3 divided doses per day. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.

The production method and use method of the present invention will be described in the following examples and test examples, but the present invention is not limited thereto. Other aspects that fall within the spirit and scope of the invention as defined by the claims are also encompassed by the invention. The compound A in Examples and Test Examples is N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d]. ] Pyrimidin-5-yl) ethyl] -2-methyl-2- (methylsulfonyl) propanamide means p-toluenesulfonate.

Example 1
(1) Compound A 8.0g
(2) Lactose 60.0g
(3) Cornstarch 35.0g
(4) Gelatin 3.0g
(5) Magnesium stearate 2.0 g
After granulating a mixture of Compound A (8.0 g), lactose (60.0 g) and corn starch (35.0 g) with a 10% by weight aqueous gelatin solution (30 mL, 3.0 g as gelatin) through a 1 mm mesh sieve. , Dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Example 2
After dissolving 50 mg of trastuzumab in 50 mL of JP distilled water for injection, JP distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 3
After dissolving 50 mg of cetuximab in 50 mL of JP injection distilled water, JP injection distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 4
(1) Compound A 8.0g
(2) Erlotinib 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
Using a mixture of Compound A (8.0 g), erlotinib (8.0 g), lactose (60.0 g) and corn starch (35.0 g) in a 10 wt% gelatin aqueous solution (30 mL, 3.0 g as gelatin), 1 mm mesh And then dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Example 5
(1) Compound A 8.0g
(2) Gefitinib 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
Using a mixture of Compound A (8.0 g), gefitinib (8.0 g), lactose (60.0 g) and corn starch (35.0 g) in a 10 wt% gelatin aqueous solution (30 mL, 3.0 g as gelatin), 1 mm mesh And then dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Example 6
Dissolve 50 mg of paclitaxel in 50 mL of JP injection distilled water, and then add JP injection distilled water to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 7
(1) Compound A 8.0g
(2) Fulvestrant 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
A mixture of Compound A (8.0 g), fulvestrant (8.0 g), lactose (60.0 g) and corn starch (35.0 g) was used with a 10 wt% gelatin aqueous solution (30 mL, 3.0 g as gelatin), After granulating through a 1 mm mesh sieve, it is dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Example 8
After dissolving 50 mg of doxorubicin hydrochloride in 50 mL of distilled water for injection, JP injection distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 9
After dissolving 50 mg of irinotecan hydrochloride in 50 mL of JP injection distilled water, JP injection distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 10
(1) Compound A 8.0g
(2) 5FU 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
Using a mixture of Compound A (8.0 g), 5FU (8.0 g), lactose (60.0 g) and corn starch (35.0 g) in a 10% by weight gelatin aqueous solution (30 mL, 3.0 g as gelatin), 1 mm mesh And then dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Example 11
After dissolving 50 mg of docetaxel in 50 mL of JP injection distilled water, JP injection distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

Example 12
(1) Compound A 8.0g
(2) Methotrexate 8.0g
(3) Lactose 60.0g
(4) Corn starch 35.0g
(5) Gelatin 3.0g
(6) Magnesium stearate 2.0 g
Using a mixture of Compound A (8.0 g), methotrexate (8.0 g), lactose (60.0 g) and corn starch (35.0 g) in a 10 wt% gelatin aqueous solution (30 mL, 3.0 g as gelatin), 1 mm mesh And then dried at 40 ° C. and sieved again. The resulting granules are mixed with magnesium stearate (2.0 g) and compressed. The resulting center tablet is coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain 1000 coated tablets.

Test example 1
Combined effect of Compound A and cetuximab (in vitro)
Human epidermoid carcinoma cell line A431 cells were seeded in a 96-well plate at 2000 cells / 100 μL / well. The next day, Compound A alone, cetuximab alone or Compound A and cetuximab were mixed and added in serial dilutions. After adding the compound, it was left in a CO ₂ incubator for 5 days. 50 μL of 25% glutaraldehyde solution (Wako) was added to 200 μL of the medium, and allowed to stand at room temperature for 15 minutes. Thereafter, the plate was washed once with PBS, 200 μL of PBS was added, 25 μL of 50% trichloroacetic acid was added, and the mixture was allowed to stand at 4 ° C. for 1 hour or longer. The plate was washed 5 times with tap water, and excess water was removed by tapping on a Kim towel. 50 μL of 0.4% (w / v) Sulforhodamine B (SRB, Sigma) -containing 1% (v / v) acetic acid solution was added to each well, and 15 minutes later, 1% acetic acid solution (v / v) was plated 3 times. Was washed. After the plate was thoroughly dried, 10 mM Tris solution was added, and the mixture was well stirred with a plate shaker, and the absorbance at 550 nm was measured (CORONA ELRCTRIC, MTP-450). Calculations were made assuming that the control with no drug added was 100% (FIG. 1). The combined use of Compound A and cetuximab showed a strong cell growth inhibitory effect compared to the case of each alone.

Test example 2
Combined effect of compound A and erlotinib (in vitro)
Human lung cancer cell line Calu-3 cells were seeded in a 96-well plate at 5000 cells / 50 μL / well. The next day, compound A alone, erlotinib alone or compound A and erlotinib were mixed and added in serial dilutions. After adding the compound, it was left in a CO ₂ incubator for 5 days. 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added to 100 μL of the medium and stirred well. Luminescence intensity was measured with ARVO light (Perkin Elmer). The luminescence intensity in the control to which no drug was added was calculated as 100% (FIG. 2). By using Compound A and erlotinib in combination, the cell growth inhibitory action was stronger than when each compound was used alone.

Test example 3
Combined effect of Compound A and trastuzumab (in vitro)
Human breast cancer cell line BT-474 cells were seeded in a 96-well plate at 6000 cells / 50 μL / well. The next day, compound A alone, trastuzumab alone or compound A and trastuzumab were mixed and added in serial dilutions. After adding the compound, it was left in a CO ₂ incubator for 5 days. 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added to 100 μL of the medium and stirred well. Luminescence intensity was measured with ARVO light (Perkin Elmer). Calculations were made assuming that the control with no drug added was 100% (FIG. 3). The combined use of Compound A and trastuzumab showed a stronger cell growth inhibitory effect than when each compound was used alone.

Test example 4
Combined effect of Compound A and trastuzumab (in vivo)
Trypsinized human breast cancer cell line BT-474 (ATCC (American Type Culture Collection) catalog No.HTB-20, Lasfargues EY, In Vitro 15: 723-729 (1979)), a HER2 highly expressing cell that has been subcultured The suspension was treated and suspended in RPMI-1640 medium (GibcoInvitrogen) containing 10% fetal bovine serum (GibcoInvitrogen). The cell density of this cell suspension was measured with a cell counter Sysmex CDA500, and the cell density was adjusted to 1 × 10 ⁸ cells / mL using the above-mentioned medium. This was further diluted with the same amount of Matrigel (Basement Membrane Matrix, phenol-red free, Cat. No. 40234C, Becton Dickinson) to obtain a cell suspension for transplantation of nude mice (5 × 10 ⁷ cells / mL). Nude mice for transplantation were BALB / cAJcl-nu / nu, female, 5-week-old mice purchased from CLEA Japan. After arrival, the cells were acclimatized for 1 week, and the cells were transplanted at a concentration of 1 × 10 ⁷ cells / 200 μL into the abdomen subcutaneously of a 6-week-old mouse. At the time of transplantation, estradiol propionate (Ova hormone Depot 5mg Asuka Pharmaceutical) was injected intramuscularly at a dose of 50 μL in the right hind paw. Furthermore, one week after transplantation, estradiol propionate was similarly injected intramuscularly into the left hind paw at a dose of 50 μL. Tumor volume was measured over time from 2 weeks after transplantation, and an individual with a tumor volume of 200 to 300 mm ³ was used.
Compound A was prepared in 0.5% aqueous methylcellulose solution to a concentration of 13.06 mg / mL, and the above-mentioned Compound A suspension was orally administered at a liquid volume of 10 mL / kg. Compound A was administered twice a day in the morning and afternoon (the administration interval was set to be 7 hours or longer), and was administered continuously for 14 days. Trastuzumab (Genentech, Inc. Catalog No. NDC 50242-134-68) was prepared by diluting a stock solution of 21 mg / mL to 1 mg / mL with physiological saline and intraperitoneally at a volume of 10 mL / kg. Administered. Trastuzumab was administered four times, twice a week. The tumor volume was measured over time every 2 to 3 days, and the final tumor volume was measured on the day after the end of the 14-day administration to determine the combined effect.
Compound A showed a synergistic effect with trastuzumab on HER2-highly expressing BT-474 breast cancer tumors (FIG. 4).

Test Example 5
Measurement of TS (thymidine) expression level by addition of compound A Human breast cancer cell line BT-474 (ATCC (American Type Culture Collection) catalog No. HTB-20, Lasfargues EY, In Vitro 15: 723-729 (1979)) was trypsinized and suspended in RPMI-1640 medium (GibcoInvitrogen) containing 10% fetal bovine serum (GibcoInvitrogen). The cell density of this cell suspension was measured with a cell counter Sysmex CDA500, and the cell density was adjusted to 5 × 10 ⁴ cells / mL using the above-mentioned medium. 2 mL of this was dispensed into each well of a 6-well multi-well culture plate (Corning) and cultured overnight at 37 ° C. and 5% CO ₂ . Compound A was added to the culture plate at 100 nmol / L. Two days after compound addition, each total RNA was extracted with RNA easy Mini kit (QIAGEN) and converted into cDNA using TaqMan Reverse Transcription Reagent (Applied Biosystems). Using this cDNA as a template, the TS expression level was examined using TaqMan Gene Expression Assays (Applied Biosystems). Detected with GeneAmp7700 (Applied Biosystems) and GAPDH as internal standard

(See Applied Biosystems) (FIG. 5). By adding 100 nmol / L of compound A, the TS expression level was significantly reduced.

Test Example 6
Combined effect of Compound A and AZD6474 (A431 in vitro)
Human epidermoid carcinoma cell line A431 cells were seeded in a 96-well plate at 2000 cells / 50 μL / well. The next day, Compound A alone, AZD6474 alone or Compound A and AZD6474 were mixed and added in serial dilution. After adding the compound, it was left in a CO ₂ incubator for 5 days. 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added to 100 μL of medium and mixed on a plate shaker for about 5 minutes at room temperature. Thereafter, the plate was left at room temperature for about 10 minutes, and luminescence was measured with ARVO-Light (Perkin Elmer). The amount of wells containing only the medium was calculated as the background, and the control with no drug added was calculated as 100% (FIG. 6). By using Compound A and AZD6474 in combination, the cell growth inhibitory action was stronger than when each compound was used alone.

Test Example 7
Combined effect of Compound A and BEZ235 (SK-BR-3 in vitro)
Human breast cancer cell line SK-BR-3 cells were seeded in a 96-well plate at 2000 cells / 50 μL / well. Two days later, Compound A alone, BEZ235 alone or Compound A and BEZ235 were mixed and serially diluted. After the compound was added, it was left in a CO ₂ incubator for 4 days. To 100 μL of the medium, 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added and stirred well. Luminescence intensity was measured with ARVO-light (Perkin Elmer). The luminescence intensity in the control with no drug added was calculated as 100% (FIG. 7). By using Compound A and BEZ235 in combination, the cell growth inhibitory action was stronger than when each compound was used alone.

Test Example 8
Combined effect of Compound A and PD0325901 (Calu-3 in vitro)
Human lung cancer cell line Calu-3 cells were seeded in a 96-well plate at 5000 cells / 50 μL / well. The next day, Compound A alone, PD0325901 alone or Compound A and PD0325901 were mixed and serially diluted. After adding the compound, it was left in a CO ₂ incubator for 5 days. To 100 μL of the medium, 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added and stirred well. Luminescence intensity was measured with ARVO light (Perkin Elmer). The luminescence intensity in the control to which no drug was added was calculated as 100% (FIG. 8). By using Compound A and PD0325901 in combination, the cell growth inhibitory action was stronger than when each compound was used alone.

Test Example 9
Combined effect of Compound A and rapamycin (BT-474 in vitro)
Human breast cancer cell line BT-474 cells were seeded in a 96-well plate at 6000 cells / 50 μL / well. The next day, compound A alone, rapamycin alone or compound A and rapamycin were mixed and added in serial dilutions. After adding the compound, it was left in a CO ₂ incubator for 5 days. To 100 μL of the medium, 100 μL of CellTiter-Glo Luminescent Cell Viability assay reagent (Promega, G7571) was added and stirred well. Luminescence intensity was measured with ARVO light (Perkin Elmer). The amount of wells containing only the medium was calculated as the background, and the control with no drug added was calculated as 100% (FIG. 9). The combined use of Compound A and rapamycin showed a stronger cell growth inhibitory effect than when each compound was used alone.

This application is based on Japanese Patent Application No. 2008-052715 filed in Japan, the contents of which are incorporated in full herein.

Claims

(1) Formula:

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof;
(2) A pharmaceutical comprising a combination of a hormone therapy agent or an anticancer agent.
The medicine according to claim 1, wherein X is a hydrogen atom.
R 1 is a hydrogen atom,
R 2 is
—NR 6a —CO—CR 7 R 8 —SO 2 —C 1-4 alkyl (R 6a is a hydrogen atom or a methyl group, R 7 and R 8 are the same or different and each represents a hydrogen atom or a methyl group) A C 1-6 alkyl group substituted with a group represented by:
R 3 is a hydrogen atom,
The pharmaceutical according to claim 2, wherein R 4 is a chlorine atom or a methyl group, and R 5 is a fluorine atom, a chlorine atom or a methyl group.
The pharmaceutical according to claim 3, wherein R 7 and R 8 are methyl groups.
(1) N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2 -Methyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
(1) N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2 -(Ethylsulfonyl) acetamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
(1) N- [2- (4-{[3-Chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -N , 2-dimethyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
(1) N- [2- (4-{[3-Chloro-4- (3-methylphenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2 -(Methylsulfonyl) acetamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
(1) N- [2- (4-{[3-Chloro-4- (3-fluorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2 -(Methylsulfonyl) acetamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
(1) N- [2- (4-{[4- (3-Chlorophenoxy) -3-methylphenyl] amino} -5H-pyrrolo [3,2-d] pyrimidin-5-yl) ethyl] -2 -Methyl-2- (methylsulfonyl) propanamide;
(2) The medicament according to claim 1, which is a combination of a hormone therapy agent or an anticancer agent.
The medicament according to claim 1, wherein the anticancer agent is a HER2 antibody, an EGFR antibody, an EGFR inhibitor, a VEGFR inhibitor or a chemotherapeutic agent.
The medicament according to claim 1, wherein the anticancer agent is trastuzumab, cetuximab, erlotinib, gefitinib or paclitaxel.
The medicament according to claim 1, wherein the hormone therapy agent is an ER down regulator.
The medicine according to claim 1, wherein the hormone therapy agent is fulvestrant.
The medicament according to claim 1, which is a preventive or therapeutic agent for cancer.
The medicament according to claim 15, wherein the cancer is breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer, colon cancer, small intestine cancer, esophageal cancer or stomach cancer.
For mammals, formula (1):

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Ile) ethyl] -2- (methylsulfonyl) acetamide)) or a salt thereof or a prodrug thereof, and (2) an effective amount of a hormonal therapeutic agent or an anticancer agent, Or treatment method.
Formula (1) for producing a preventive or therapeutic agent for cancer:

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt thereof or a prodrug thereof, and (2) use of a hormone therapeutic agent or an anticancer agent.
formula:

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide), or a salt or prodrug thereof, a thymidine synthase production inhibitor.
For mammals, the formula:

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt thereof or a prodrug thereof, and a method for inhibiting thymidine synthase production, which comprises administering an effective amount thereof.
Formula for the production of thymidine synthase production inhibitor:

[Wherein R 1 represents a hydrogen atom,
R 2 is
—NR 6 —CO— (CH 2 ) n —SO 2 —optionally halogenated C 1-4 alkyl (n is an integer of 1 to 4; R 6 is a hydrogen atom or a C 1-4 alkyl group; A C 1-6 alkyl group substituted with a group represented by the formula : — (CH 2 ) n — may be substituted with C 1-4 alkyl),
R 3 represents a hydrogen atom or a C 1-6 alkyl group,
R 4 represents a halogen atom or a C 1-6 alkyl group,
R 5 represents a halogen atom or a C 1-6 alkyl group,
X represents a hydrogen atom or a halogen atom. Embedded image wherein N- [2- (4-{[3-chloro-4- (3-chlorophenoxy) phenyl] amino} -5H-pyrrolo [3,2-d] pyrimidine-5- Yl) ethyl] -2- (methylsulfonyl) acetamide) or a salt or prodrug thereof.