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5-cyano-thienopyridines for the treatment of tumors

A technology of pyridine and cyano, which is applied in the field of new compounds for the treatment of kinase-induced diseases and the preparation of drugs, which can solve the problems of increasing tumor risk and accelerating tumor development, etc.

Inactive Publication Date: 2010-09-08
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, these anticancer treatments increase the risk and accelerate the development of tumors with enhanced growth and invasiveness

Method used

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  • 5-cyano-thienopyridines for the treatment of tumors
  • 5-cyano-thienopyridines for the treatment of tumors
  • 5-cyano-thienopyridines for the treatment of tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] for the preparation of which R 2 and R 3 A general reaction scheme for compounds of formula I each representing H:

[0267]

[0268] Preparation of 3,6-diamino-4-benzofuran-2-yl-5-cyanothieno[2,3-b]pyridine-2-carboxamide ("A1"):

[0269] 1.1 First, 2.685 g of malononitrile and 4.196 g of cyanothioacetamide were added to a solution of 6.0 g of benzofuran-2-carbaldehyde ("E1") in 200 mL of ethanol. Then 203.2 μL of piperidine was added and the resulting red-brown suspension was boiled at 90° C. for 3 hours and subsequently stirred at room temperature for 16 hours. The precipitated material (yellow and orange crystals) was separated, washed with ethanol and dichloromethane and dried to give 8.1530 g of 6-amino-4-benzofuran-2-yl-2-thio-1,2-dihydro A mixture of pyridine-3,5-dicarbonitrile and 2,6-diamino-4-benzofuran-2-yl-2H-thiopyran-3,5-dicarbonitrile (“1”), which may not be purified And react further.

[0270] 1.2 To a solution of 1.0 g of the mixture ("1") prepar...

Embodiment 2

[0302]

[0303] 3-amino-4-benzofuran-2-yl-5-cyano-6-[3-(4-methyl-piperazin-1-yl)propylamino]thieno[2,3-b] Preparation of pyridine-2-carboxamide ("A30"):

[0304] 2.1 Under an inert atmosphere, 8.14 g ("2") was added to a solution of 3.97 g copper(II) chloride and 4.96 mL isoamyl nitrite in 470 mL dry acetonitrile. The resulting suspension was heated to 65°C and stirred for 4 hours. The resulting red-brown solution was cooled to room temperature, transferred to 400 mL hydrochloric acid (20% by weight), and extracted 3 times with 100 mL each of ethyl acetate. The combined organic phases were concentrated and transferred to ice water. The resulting precipitate was isolated, washed with acetonitrile and water and dried to give 3.1326 g of 2-(4-benzofuran-2-yl-6-chloro-3,5-dicyanopyridin-2-ylsulfanyl) Acetamide ("3") sandy powder.

[0305] HPLC content: 95.8%

[0306] HPLC-MS: [M+H]369

[0307] 2.2 At room temperature, 200 mg of 2-(4-benzofuran-2-yl-6-chloro-3,5-dicyanopyr...

Embodiment 3

[0347] If steps 1.1 and 1.2 of Example 1 are carried out analogously using furan-2-carbaldehyde as "E1", 2-(6-amino-4-furan-2-yl-3,5-dicyano-pyridine- 2-ylsulfanyl)acetamide ("2a"). "2a" is subsequently reacted analogously to steps 2.1 to 2.3 of Example 2 using 3-pyrrolidin-1-ylpropylamine as "E2" in step 2.2. 3-amino-5-cyano-4-furan-2-yl-6-(3-pyrrolidin-1-ylpropylamino)thieno[2,3-b]pyridine-2-carboxamide "A51 ".

[0348]

[0349] HPLC-MS: [M+H]411

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Abstract

The invention relates to novel 5-cyano-thienopyridines of the formula (I) where R1, R2, and R3 have the meanings designated in Claim 1. Said 5-cyano-thienopyridines are inhibitors of TGF-beta receptor kinase and may be used, among other things, for the treatment of tumors.

Description

Background of the invention [0001] The object of the present invention was to discover new compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds in which inhibition, regulation and / or modulation of signal transduction by kinases, in particular TGF-beta receptor kinases, acts and uses of said compounds, the invention further relates to pharmaceutical compositions comprising these compounds And the use of these compounds in the treatment of kinase-induced diseases. [0003] Transforming growth factor beta is the prototype of the TGF-beta superfamily, a family of highly conserved pleiotropic growth factors that play important functions both during embryonic development and in adult organisms. In mammals, three isoforms of TGF-β have been identified (TGF-β1, 2 and 3), with TGF-β1 being the most common isoform (Kingsley (1994) Genes Dev 8:133-146) . TGF-β3, for example, ...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61P35/00A61P35/02
CPCC07D495/04A61P17/02A61P25/00A61P25/28A61P31/18A61P35/00A61P35/02A61P9/10
Inventor G·赫尔策曼U·格拉德勒H·格雷纳尔C·阿门特D·穆斯尔P·希勒茨
Owner MERCK PATENT GMBH
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