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Thienopyrimidines

A technology of pyrimidine and thiophene, which is applied in the field of new compounds, can solve the problems of increased anticancer treatment and increased risk

Inactive Publication Date: 2011-04-13
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, these anticancer treatments increase the risk and promote the development of tumors with increased growth and invasion

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0232] Preparation of 5-amino-2-cyclopropyl-4-(5-methylfuran-2-yl)thieno[2,3-d]pyrimidine-6-carboxamide ("A1")

[0233] Synthetic flow diagram for the synthesis of "A1"

[0234]

[0235] 1.1 In a three-necked flask, 9.1 ml of 5-methyl-2-carboxyfurfuraldehyde ("E1") was dissolved in 70 ml of dichloromethane. Then 8 ml of methyl cyanoacetate and 45 g of alumina were added, and the mixture was stirred at room temperature for 2 h.

[0236] For work-up, the aluminum oxide was filtered off with suction. Flush it well with dichloromethane. The yellow solution was evaporated until only solids remained, yielding 15.3 g of methyl 2-cyano-3-(5-methylfuran-2-yl)acrylate.

[0237] HPLC-MS: [M+H]192

[0238] 1.2 In preparation, 460 mg of elemental sodium was dissolved in 8.0 ml of dry ethanol in a round bottom flask with a drying tube. 3.827 g of methyl 2-cyano-3-(5-methylfuran-2-yl)acrylate and 2.49 g of cyclopropylguanidine (“E2”) hydrochloride were then suspended in 35 ml of a 10...

Embodiment 2

[0268] Preparation of 5-amino-4-furan-2-yl-2-methylthiothieno[2,3-d]pyrimidine-6-carboxamide ("A8")

[0269] 2.1 Combine 13ml of furfural and 13.3ml of methyl cyanoacetate in a flask, add 60g of alumina, and the temperature rises to 53°C during the process. After adding 50 ml of dichloromethane, the reaction mixture was stirred at room temperature for 2 hours. For work-up, the aluminum oxide was filtered off and the filtrate was evaporated, yielding 23.3615 g of methyl 2-cyano-3-furan-2-ylacrylate ("E3").

[0270] HPLC content: 97.7%

[0271] HPLC-MS: [M+H]178

[0272] 2.2 In preparation, 1.3 g of elemental sodium was dissolved in 15 ml of ethanol. 5 g of methyl 2-cyano-3-furan-2-ylacrylate and 5.2 g of thiourea ("E4") were then suspended in 50 ml of butanol in a 250 ml round bottom flask and dissolved sodium ethoxide was added. The suspension was stirred at 110°C for 5.5 hours.

[0273] For work-up, the batch was cooled to room temperature, poured onto ice, adjusted to p...

Embodiment 3-37

[0291] Carrying out the operation of Example 1, but using furan-2-carbaldehyde as "E1" and guanidine as "E2" to give 2,5-diamino-4-furan-2-ylthieno[2,3-d] Pyrimidine-6-carboxamide ("A11") δ 8.0 (d, 1H), 7.3 (d, 1H), 7.2-6.8 (BR, 6H), 6.7 (m, 1H), 4.6 (d, 1H).

[0292]

[0293] Carry out the operation of Example 1, but use guanidine as "E2" to obtain 2,5-diamino-4-(5-methylfuran-2-yl)thieno[2,3-d]pyrimidine-6-methan Amide ("A11a") δ 7.2 (m, 3H), 7.0 (s, 2H), 6.9 (s, 2H), 6.4 (d, 1H), 2.4 (s, 3H).

[0294]

[0295] Carry out the operation of Example 1, but use benzofuran-2-carbaldehyde as "E1" and guanidine as "E2" to obtain 2,5-diamino-4-benzofuran-2-ylthieno[2, 3-d] pyrimidine-6-carboxamide ("A12") δ 7.8(dd, 2H), 7.7(s, 1H), 7.5(t, 1H), 7.4(t, 1H), 7.2(s, 2H ), 7.1(s, 2H), 7.0(s, 2H).

[0296]

[0297] Carrying out the procedure of Example 1 but using benzofuran-2-carbaldehyde as "E1" and pyridine-2-carboxamidine as "E2" gives 5-amino-4-benzofuran-2-yl-2- Pyridin-...

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Abstract

Novel thienopyrimidines of formula (I), in which R1, R2, and X have the meanings indicated in claim 1, are TGF-beta receptor kinase inhibitors and can be used for the treatment of tumors, among other things.

Description

Background of the invention [0001] The object of the present invention was to find new compounds having valuable properties, in particular compounds which can be used for the preparation of medicaments. [0002] The present invention relates to compounds and uses of compounds wherein kinases, in particular TGF-beta receptor kinases, play a role in the inhibition, regulation and / or regulation of signal transduction, to pharmaceutical compositions comprising these compounds and to the use of these compounds Use 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, which play important functions in embryonic development and adult organisms. In mammals, three isoforms of TGF-β have been identified (TGFβ1, 2 and 3), with TGF-β1 being the most common isoform (Kingsley (1994) Genes Dev 8:133-146). TGF-β3, for example, is expressed only in mesenchyma...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P31/00A61K31/519
CPCC07D495/04A61P17/02A61P25/28A61P31/00A61P31/18A61P35/00A61P35/02A61P35/04A61P43/00A61P9/10
Inventor G·赫尔策曼H·格雷纳尔C·阿门特F·岑克
Owner MERCK PATENT GMBH
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