Novel aminopyridine derivatives having aurora a selective inhibitory action

a technology of aminopyridine and selective inhibitory action, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of difficult development of subtype-selective drugs, and achieve the effect of improving the activity of natural killer cells

Inactive Publication Date: 2010-01-21
IWASAWA YOSHIKAZU +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to novel aminopyridine derivatives that show excellent activity in inhibiting the action of Aurora A and cell growth. These compounds can be used alone or in combination with other antitumor agents to achieve a synergistic effect. The compounds can also be used orally, which is beneficial for treating cancers that have developed resistance to traditional antitumor agents. The invention solves the problem of creating new compounds that can overcome drug resistance and have a better safety profile."

Problems solved by technology

Meanwhile, with regard to the Aurora kinase inhibitor, development of subtype-selective drugs has been thought to be difficult in view of high homology among subtypes, protein structure analysis and the like; and although there have been known reports on drugs such as ZM447439 which inhibit both Aurora A and Aurora B at the same time [J.

Method used

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  • Novel aminopyridine derivatives having aurora a selective inhibitory action
  • Novel aminopyridine derivatives having aurora a selective inhibitory action
  • Novel aminopyridine derivatives having aurora a selective inhibitory action

Examples

Experimental program
Comparison scheme
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working examples

[0449]In a thin-layer chromatography of Examples and Referential Examples, Silica gel60F254 (Merck) was used as a plate and a UV detector was used as a detecting method. As silica gel for the column, Biotage FLASH column (SI, NH) was used. In a reversed phase preparative liquid chromatography, XBridge Prep C18 (Waters) was used as a column and a 0.1% aqueous trifluoroacetic acid solution and a 0.1% solution of trifluoroacetic acid in acetonitrile were used in a mobile phase. MS spectra were measured using Waters micromass ZQ2000 (ESI, ESCi). NMR spectra were measured using a spectrometer in the type of JEOL JNM-AL400 (400 MHz) or Varian MERCURY400 (400 MHz) and all δ values are represented in ppm. Melting points were measured under a 1° C. / min raise condition using a combination of Mettler Toledo FP82HT Hot Stage and NIKON Eclipse E600 POL.

[0450]Meanings of abbreviations are as follows.[0451]s: singlet[0452]d: doublet[0453]dd: double doublet[0454]t: triplet[0455]dt: double triplet[0...

example 1

Synthesis of trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)cyclohexanecarboxylic acid hydrochloride

[0468]

(1) Synthesis of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine

[0469]

[0470]To a solution of 10 g of (6-bromo-pyridin-2-yl)methanol in 50 ml of N,N-dimethylformamide were successively added 4 g of imidazole and 8.4 g of tert-butyldimethylsilyl chloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. After adding water to the reaction mixture, the mixture was extracted with n-hexane. The resulting hexane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil.

(2) Synthesis of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ylidene)pyridin-2-amine

[0471]

[0472]A mixture of 15.92 g of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine, 5.53 g of 2-amin...

example 2

Synthesis of trans-4-(3-chloro-2-fluorophenoxy)-1-(6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)cyclohexanecarboxylic acid

[0489]

[Method A]

[0490]To a 47.9 mg of trans-4-(3-chloro-2-fluorophenoxy)-1-(6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)cyclohexanecarboxylic acid hydrochloride as obtained in Example 1 were successively added 4 ml of water and 4 ml of ethanol, followed by stirring the reaction mixture at room temperature for 12 hours. The resulting precipitate was collected by filtration and washed with water to give the title compound as a colorless needle (mp: 202-222° C.).

[0491]1H-NMR (DMSO-d6) δ: 1.60-1.92 (8H, m), 2.98 (2H, s), 4.61 (1H, brs), 6.71 (1H, d, J=7.2 Hz), 6.90 (1H, d, J=8.2 Hz), 6.98 (1H, d, J=3.5 Hz), 7.10-7.22 (3H, m), 7.38 (1H, d, J=3.5 Hz), 7.60 (1H, t, J=7.6 Hz).

[0492]mass: 462,464 (M+1)+

[Method B]

[0493]To 460 mg of trans-4-(3-chloro-2-fluorophenoxy)-1-(6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)cyclohexanecarboxylic acid hydrochloride as obtained in Exa...

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Abstract

The present invention relates to a compound of formula I:wherein: R1 is a hydrogen atom, F, CN, etc.; R1′ is a hydrogen atom or lower alkyl which may be substituted; R2 is O, S, SO, SO2, etc.; R3 is a phenyl which may be substituted; X1, X2, and X3 each independently CH, N, etc. provided, however, that among X1, X2 and X3, the number of nitrogen is 0 or 1; W is the following residue:wherein: W1, W2, and W3 each independently CH, N, etc.,or a pharmaceutically acceptable salt or ester thereof.

Description

TECHNICAL FIELD[0001]The present invention relates to novel aminopyridine derivatives which are useful in the pharmaceutical field, and more particularly, to those which inhibit the growth of tumor cells based on an Aurora A selective inhibitory action and exhibit an antitumor effect, and also to an Aurora A selective inhibitor and an antitumor agent containing them.BACKGROUND ART[0002]Aurora kinase is a serine / threonine kinase involved in cell division. With regard to the Aurora kinase, three subtypes of A, B and C are known at present, and they have very high homology to each other. Aurora A participates in the maturation and distribution of centrosome or in the formation of spindle body. On the other hand, it is believed that Aurora B participates in the aggregation and pairing of chromosome, a spindle checkpoint and cytoplasm division [Nat. Rev. Mol. Cell. Biol., No. 4, pp. 842-854]. Also, it is believed that Aurora C acts similarly as a result of interaction with Aurora B [J. B...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/497C07D413/14A61K31/4439C07D417/14A61K31/506C07D403/04
CPCA61K45/06C07D401/12C07D417/12C07D413/14C07D403/12A61P35/00A61P35/02A61P43/00C07D241/22C07D241/20
InventorIWASAWA, YOSHIKAZUKATO, TETSUYAKAWANISHI, NOBUHIKOMASUTANI, KOUTAMITA, TAKASHINONOSHITA, KATSUMASAOHKUBO, MITSURU
OwnerIWASAWA YOSHIKAZU