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Sulfonamido-macrocycles as tie2 inhibitors

A technology of alkyl and hydroxyl, which is applied in the field of preparing sulfonylamino macrocycles, and can solve the problems of selective small dose tolerance and other issues

Inactive Publication Date: 2007-12-12
BAYER SCHERING PHARMA OY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This stems from the low selectivity of the substance and the issue of dose tolerance

Method used

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  • Sulfonamido-macrocycles as tie2 inhibitors
  • Sulfonamido-macrocycles as tie2 inhibitors
  • Sulfonamido-macrocycles as tie2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example A

[0100] The synthesis of halogenated macrocycle A is described in WO 2004 / 026881 A, exemplified herein as Preparation A for brominated macrocycle A, and Preparation B for iodinated macrocycle A.

[0101] Preparation A: 1 5 -Bromo-4-thia-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-phenheteronone-phane-4,4-dioxide preparation

[0102]

[0103] Method A

[0104] 200 mg (0.48 mmol) of 3-amino-N-[3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-benzenesulfonamide in acetonitrile / A water / 2-butanol (9.0ml / 1.0ml / 0.3ml) solution was added to a refluxing mixture of acetonitrile / water / 4 molar hydrochloric acid in dioxane (45ml / 5ml / 0.6ml). After another 3 hours at reflux, the oil bath was turned off and the reaction solution was stirred overnight at room temperature. The precipitate formed was filtered off, washed with water and dried in vacuo. 112 mg (0.31 mmol) of product are obtained. The filtrate was concentrated by evaporation in a rotary evaporator. The formed precipitate was w...

preparation example B

[0114] Preparation Example B: 1 5 -Iodo-4-thia-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-phenheteronone-phane-4,4-dioxide preparation

[0115]

[0116] Over 3 hours, 2.34 g (5.00 mmol) of 3-amino-N-[3-(5-iodo-2-chloro-pyrimidin-4-ylamino)-propyl]-benzenesulfonamide in acetonitrile was injected via a syringe pump A solution of water / 2-butanol (94 mL / 10.4 mL / 3.1 mL) was added to a refluxing mixture of acetonitrile / water / 4 molar hydrochloric acid in dioxane (470 mL / 52 mL / 6.2 mL). After another 3 hours at reflux, the heating of each oil bath was turned off and the reaction solution was stirred overnight at room temperature. The formed precipitate was filtered off, washed with acetonitrile and dried in vacuo to afford 1.71 g (79% yield) of the desired product.

[0117] 1 H-NMR (DMSO, 300MHz): 10.81 (s, 1H), 9.02 (s, 1H), 8.30-8.38 (m, 1H), 8.27 (s, 1H), 7.82 (t, 1H), 7.43-7.56 ( m, 2H), 7.29-7.40 (m, 1H), 3.38-3.52 (m, 2H), 3.21-3.36 (m, 2H), 1.72-1.90 (m, 2H).

[0118] ESI-...

preparation example 1 to 43

[0126] General Procedure 1 (GP1): Suzuki Coupling

[0127] (Typical range: 0.25mmol)

[0128] At room temperature, with the corresponding organoboron compound (1.25eq.), K 2 CO 3 (2.5 eq., either as a solid or as a 2M aqueous solution), and POPd (2.5-5 mol-%) were treated with a DMF (8 mL / mmol halide) solution of the corresponding macrocyclic halide. The stirred resulting mixture was placed in an oil bath preheated to 100°C. The progress of the reaction was monitored by TLC, in case the macrocyclic halide was not completely converted after 2 h, additional portions of POPd and organoboron compound were added, followed by further stirring at 100 °C. After cooling to room temperature, water was added and the resulting suspension was stirred for 30 min. The crude product is isolated by vacuum filtration, dried in vacuo, purified by column chromatography, then optionally triturated with methanol and / or subjected to preparative HPLC (e.g. YMC Pro C 18 RS 5μ, 150×20mm, 0.2% NH ...

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Abstract

The invention relates to sulfonamido-macrocycles according to the general Formula I and the salts thereof, to pharmaceutical compositions comprising the sulfonamido-macrocycles and to a method of preparing the sulfonamido-macrocycles as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with angiopoietin and therefore influence Tie2 signalling, wherein R<1>, R<2> and R<3> have the meaning as given in the specification and the claims.

Description

technical field [0001] The invention relates to a sulfonylamino macrocycle and its salt, a pharmaceutical composition comprising the sulfonylamino macrocycle, a method for preparing the sulfonylamino macrocycle and its application. Background technique [0002] To combat dysregulation of vascular growth in diseases such as cancer, different strategies have been developed. One possible strategy is to block angiogenesis in tumor tissue, as tumor angiogenesis is a prerequisite for the growth of solid tumors. [0003] In the development of the vasculature, angiogenesis is one of two fundamental processes besides angiogenesis. Angiogenesis refers to the neogenesis of vasculature during embryonic development, while angiogenesis describes the neogenesis of vasculature from the sprouting or differentiation of existing vasculature. Two receptors have been found expressed on endothelial cells: the VEGF-receptor (vascular endothelial growth factor) and the Tie-receptor, which are imp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/08A61K31/529A61P35/00
CPCC07D513/08A61P1/00A61P11/00A61P13/08A61P15/00A61P17/02A61P17/06A61P19/08A61P25/00A61P27/02A61P29/00A61P35/00A61P35/04A61P37/08A61P43/00A61P9/10A61P9/12
Inventor G·克特绍H·布里姆U·吕金M·舍费尔K·蒂劳赫W·施韦德M·胡泽曼A·胡特
Owner BAYER SCHERING PHARMA OY
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