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Fused heterocyclic compound

a heterocyclic compound and compound technology, applied in the field of pyrimidine compound, can solve the problems of poor prognostic factor, poor receptor expression, high expression and simultaneous expression of each of these receptors, and achieve the effect of superior tyrosine kinase inhibitory action, high drug satisfaction, and low toxicity

Inactive Publication Date: 2009-01-15
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]The present invention aims at providing a compound having a superior tyrosine kinase inhibitory action, which is low toxic and highly satisfactory as a pharmaceutical product.
[0063]According to the present invention, a fused pyrimidine compound having a superior tyrosine kinase inhibitory action, which is low toxic and highly satisfactory as a pharmaceutical product, a production method thereof and use thereof can be provided.
[0252]The compound obtained in each step can be used as a reaction mixture or as a crude product in the next reaction. In addition, the compound can be isolated from a reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization, distillation, chromatography and the like.
[0288]The compound (I) of the present invention, or a salt thereof or a prodrug thereof (hereinafter referred to as the compound of the present invention) possesses tyrosine kinase-inhibiting activity and can be used for the prophylaxis or treatment of treat tyrosine kinase-dependent diseases in mammals. Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity. Furthermore, the compound of the present invention specifically inhibits HER2 kinase and / or EGFR kinase and is therefore also useful as a therapeutic agent for suppressing the growth of HER2 and / or EGFR kinase-expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer. In addition, the compound is useful as a pharmaceutical agent because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like), high water solubility, and is superior in stability, pharmacokinetics (absorption, distribution, metabolism, excretion and the like) and efficacy expression.
[0292]The compound of the present invention shows low toxicity and can be used as a pharmaceutical agent as it is, or as a pharmaceutical composition in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like).
[0299]Although the compound of the present invention exhibits excellent anticancer action even when used as a simple agent, its effect can be enhanced by using it in combination with one or more of the concomitant drug(s) mentioned above (multi-agent co-administration).

Problems solved by technology

It is also known that high expression and simultaneous expression of each of these receptors are poor prognostic factors in various cancer patients.
Moreover, receptor expression and prognosis are correlated, and receptor expression is a poor prognostic factor in breast cancer, non-small cell lung cancer and the like.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Production of 2-[(2-chloro-4-nitrophehoxy)methyl]benzonitrile

[0320]To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.7 g), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration. The residue was washed with diisopropyl ether, and dried to give the title compound (5.04 g) as pale-yellow crystals.

[0321]1H-NMR (CDCl3) δ 5.44 (2H, s), 7.13 (1H, d, J=9.0 Hz), 7.51 (1H, dt, J=1.2, 7.2 Hz), 7.68-7.80 (3H, m), 8.19 (1H, dd, J=2.7, 9.0 Hz), 8.35 (1H, d, J=2.7 Hz).

reference example 2

Production of 2-[(4-amino-2-chlorophenoxy)methyl]benzonitrile

[0322]To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in ethanol / water (9:1, 40 mL) was added calcium chloride (90%, 427 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.6 g) was added at room temperature, and the mixture was stirred at 100° C. for 3 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:methylene chloride=2:1:1) to give the title compound (1.2 g) as a white solid.

[0323]1H-NMR (CDCl3) δ 3.53 (2H, br s), 5.23 (2H, s), 6.54 (1H, dd, J=2.7, 8.7 Hz), 6.76 (1H,...

reference example 3

Production of 2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile

[0324]The title compound (8.2 g) was obtained as a pale-yellow solid by the reaction in the same manner as in Reference Example 1 using 2-methyl-4-nitrophenol (5.0 g) and 2-(bromomethyl)benzonitrile (6.4 g).

[0325]1H-NMR (CDCl3) δ 2.37 (3H, s), 5.36 (2H, s), 6.97 (1H, d, J=8.4 Hz), 7.50 (1H, m), 7.65-7.69 (2H, m), 7.76 (1H, td, J=0.9, 7.5 Hz), 8.09-8.14 (2H, m).

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Abstract

The present invention relates to a compound represented by the formula:wherein W is C(R1) or N, each A is an optionally substituted aryl group or a heteroaryl group, X1 is —NR3—Y1—, —O—, —S—, —SO—, —SO2— or —CHR3— wherein R3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3 is optionally bonded to A to form an optionally substituted ring structure, R1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R2 is a hydrogen atom or optionally substituted group bonded via a carbon atom or a sulfur atom, or R1 and R2, or R2 and R3 are optionally bonded to form an optionally substituted ring structure, or a salt thereof, and a tyrosine kinase inhibitor or an agent for the prophylaxis or treatment of cancer, which contains this compound or a prodrug thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Division of application Ser. No. 10 / 592,812, filed Sep. 14, 2006, which is a U.S. National Stage of PCT / JP2005 / 010451, filed Jun. 1, 2005, which applications are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to a fused pyrimidine compound having a growth factor receptor tyrosine kinase inhibitory activity, which is useful for the prophylaxis or treatment of cancer, a production method thereof and use thereof.BACKGROUND ART[0003]The gene of cell growth factor and growth factor receptor is called a protooncogene and plays a key role in the pathology of human tumor. The epithelial cell growth factor receptor family (erbB) includes EGFR, HER2, HER3 and HER4, which are type I receptor type tyrosine kinases. These erbB family express in various cell groups, and are deeply involved in the control of the growth and differentiation of cells and the control of suppression of cell death (ap...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61K31/551A61P35/00A61P43/00C07D487/16
CPCC07D487/16C07D487/04A61P1/18A61P11/00A61P13/08A61P13/12A61P15/00A61P31/18A61P35/00A61P35/02A61P35/04A61P43/00A61P9/00A61P9/10A61K31/5377
Inventor ISHIKAWA, TOMOYASUTANIGUCHI, TAKAHIKOBANNO, HIROSHISETO, MASAKI
Owner TAKEDA PHARMA CO LTD
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