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Regorafenib and manufacture method thereof

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

Active Publication Date: 2015-05-06
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 manufacture method thereof
  • Regorafenib and manufacture method thereof
  • Regorafenib and manufacture method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0217] Phase 1:

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

[0219] 420 g of 4-chloro-N-methylpyridine-2-carboxamide (prepared according to WO2006 / 034796) in toluene (approximately 30% w / w) and 48.8 g of ethanol were added to the reaction flask. 67.2 g of acetyl chloride was added under stirring so that the temperature of the reaction mixture did not exceed 30°C. After further stirring for 1.5 h at room temperature, 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 was obtained. The melting point is 173.7-174.5°C.

[0220] 1 H-NMR(500MHz, DMSO-d 6 ): δ [ppm] = 2.96 (d, 3H), 7.79-7.97 (m, 1H), 8.13-8.26 (m, 1H), 8...

Embodiment 2

[0269] Example 2: Investigation of the stability of the bulk drug

[0270] Respectively, the various purity of the compound of formula (I) monohydrate and the compound of formula (I) anhydrate prepared in the above embodiment 1, its various stages, and each supplementary test example were prepared and composited Film sealed packaging, placed in a 45℃ thermostat for 4 months for high temperature treatment. Determine the purity and relative content of the compound of formula (X) of each drug substance at month 0 and April, and compare the purity of each batch of samples with the relative content of the compound of formula (X). The percentage 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] Percentage of relative content change=[(relative content in April-0 relative content in April)÷relative content in 0month]×100%

[0273] The results show that:

[0274] The...

Embodiment 3

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

[0276] With reference to the formula and preparation method of steps a), b), and c) of Example 1 on page 19 of WO2014039677A1, the compound of formula (I) monohydrate or compound of formula (I) prepared in Example 1 of the present invention is used respectively. The medicinal raw material of Aquatic is the active ingredient, and coated tablets are prepared (each tablet contains 40 mg of the compound of formula (I)).

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

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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 anti-tumor 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 signals symptom. The invention also relates to a preparation method of the anti-tumor drug, especially regorafenib. Background technique [0002] The activation of the ras signal transduction pathway implies a cascade of events that have profound effects on cell proliferation, differentiation, and transformation. Raf kinase, a downstream effector of Ras, is a key transmitter that transmits these signals from cell surface receptors to the nucleus. It has been shown that inhibition of the raf kinase signal pathway by co-expression of raf kinase or dominant negative raf kinase or dominant negative MEK (a substrate of raf kinase) inhibits the effect of activated ras, which results in transformed cells Return to a normal growth phenotype. Kolch et al. further ...

Claims

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Application Information

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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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