Regorafenib and its preparation method

A compound and weight technology, applied in the preparation of regorafenib, in the field of regorafenib, can solve problems such as blindness and excessive blood vessel proliferation

Active Publication Date: 2017-01-18
HANGZHOU ZHUYANGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Overexpression of VEGF (such as under extreme hypoxic conditions) can cause angiogenesis in the eyeball, resulting in excessive blood vessel proliferation and eventually blindness

Method used

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  • Regorafenib and its preparation method
  • Regorafenib and its preparation method
  • Regorafenib and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}- Preparation of N-picoline-2-carboxamide, its hydrochloride and its monohydrate

[0217] Phase 1:

[0218] 4-Chloro-N-methyl-pyridine-2-carboxamide hydrochloride:

[0219] 420 g of a solution (approximately 30% w / w) of 4-chloro-N-methylpyridine-2-carboxamide (prepared according to WO2006 / 034796) in toluene and 48.8 g of ethanol were added to the reaction flask. 67.2 g of acetyl chloride were added with stirring to such an extent that the temperature of the reaction mixture did not exceed 30°C. After further stirring at room temperature for 1.5 h, the product was filtered off, washed with toluene (212 g) and dried under reduced pressure (30° C., 80 mbar). In this way, 156.3 g (quantitative yield) of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride were obtained. The melting point is 173.7-174.5°C.

[0220] 1 H-NMR (500MHz, DMSO-d 6 ): δ[ppm]=2.96(d, 3H), 7.79-...

Embodiment 2

[0269] Embodiment 2: the stability investigation of crude drug

[0270] Respectively compound the monohydrate of the compound of formula (I) of various purity and the anhydrate of the compound of formula (I) prepared in the above embodiment 1, its various stages, and each supplementary test example. Film-sealed packaging, placed in a 45°C incubator for 4 months for high-temperature treatment. Measure the purity and the relative content of the compound of formula (X) of each bulk drug at the time of 0 month and April, and compare the purity of each batch of samples and the change value of the relative content of the compound of formula (X) respectively, and use the purity change value and the relative content respectively The percent change in content characterizes this change. The calculation formula of the two parameters is as follows:

[0271] Purity change value = 0 month purity - 4 month purity

[0272] Percent change in relative content = [(relative content in April-...

Embodiment 3

[0275] Embodiment 3: Preparation of pharmaceutical composition in tablet form

[0276] Referring to the formulation and preparation method of steps a), b) and c) of Example 1 on page 19 of WO2014039677A1, use the compound of formula (I) monohydrate or the compound of formula (I) without The pharmaceutical raw material of water is the active ingredient, and coated tablets (each tablet containing 40 mg of the compound of formula (I)) are prepared.

[0277] The obtained tablets were respectively sealed and packaged with aluminum-plastic composite film, and placed in a 45°C incubator for 4 months for high-temperature treatment. With reference to the method in the above Example 2, measure the content of the compound of formula (I) and the compound of formula (X) relative to (in the compound of formula (I)) content of each tablet when 0 month and 4 months, and compare each tablet respectively The residual content of the compound of formula (I) and the change value of the relative...

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Abstract

The invention relates to Regorafenib and a manufacture method thereof and particularly relates to a compound shown in formula (I) or a pharmaceutical salt or a hydrate. The compound shown in formula (I) or the pharmaceutical salt or the hydrate can be used as a pharmaceutical bulk drug. The invention also relates to a method for preparing the compound shown in formula (I) or the pharmaceutical salt or the hydrate, and a pharmaceutical composition containing the compound shown in formula (I) or the pharmaceutical salt or the hydrate. The compound shown in formula (I) or the pharmaceutical salt or the hydrate can be used as a novel anti-tumour medicine for effectively treating the diseases mediated by abnormal VEGFR, PDGFR, raf, p38 and / or flt-3 kinase signal and the disease symptoms.

Description

technical field [0001] The present invention relates to a new antineoplastic drug, in particular to a regorafenib, which can be used to treat diseases and diseases mediated by abnormal VEGFR, PDGFR, raf, p38, and / or flt-3 kinase signaling symptom. The present invention also relates to the preparation method of the antitumor drug, especially regorafenib. Background technique [0002] Activation of the ras signaling pathway implies a cascade of events with profound effects on cell proliferation, differentiation and transformation. Raf kinase, a downstream effector of Ras, is a key transmitter of these signals from cell surface receptors to the nucleus. Inhibition of the effect of activated ras by inhibition of the raf kinase signaling pathway using an inactivating antibody to raf kinase or co-expression of dominant negative raf kinase or dominant negative MEK (a substrate of raf kinase) has been shown to result in transformed cells Return to normal growth phenotype. Kolch ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81A61K31/44A61P35/00A61P29/00A61P19/02A61P27/02A61P17/06A61P13/12A61P11/06A61P11/00A61P9/10A61P37/06A61P9/00A61P35/02A61P3/10A61P9/12A61P19/10A61P17/10A61P17/00A61P7/08A61P1/04A61P1/00A61P9/04A61P1/16
CPCC07D213/81
Inventor 李阅东唐建飞沈如杰何海珍马雯霞姚成娥张群赵福斌张婧
Owner HANGZHOU ZHUYANGXIN PHARMA
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