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Antitumor drugs and preparation method and application thereof

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

Pending Publication Date: 2019-10-01
李斌
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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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  • Antitumor drugs and preparation method and application thereof
  • Antitumor drugs and preparation method and application thereof
  • Antitumor drugs and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] 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

[0099] Embodiment 1 of the present invention is basically carried out with reference to the method of Embodiment 1 of CN104592105A.

[0100] Phase 1: Preparation of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride

[0101] 420 g of a solution (approximately 30% w / w) of 4-chloro-N-methylpyridine-2-carboxamide (prepared according to WO2006 / 034796) in toluene and 49 g of ethanol were added to the reaction flask. 67.5 g of acetyl chloride was 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 (210 g) and dried under reduced pressure (30° C., 80 mbar). In this way, 156.0 g (quantitative yield) of the product 4-chloro-N-methyl-pyridin...

Embodiment 2

[0122] Example 2: Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy Base}-N-methylpyridine-2-carboxamide (anhydrous)

[0123] 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}- N-picoline-2-carboxamide monohydrate was dried under reduced pressure at 90°C (21mbar) for 3 hours, then vacuumized, and then filled with a mixed gas of carbon dioxide and nitrogen at a volume ratio of 60:40 into the desiccator , sealed, and continue to keep the drier at this 90°C for 2 hours, then drop to room temperature at a cooling rate of 1°C / min, and then maintain it in the above-mentioned mixed atmosphere for 2 hours to obtain 4.67g of white crystalline solid as 4-{4 -[({[4-Chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)-amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide. The melting point of the product is 212.5-213.0° C., and the 1H-NMR and MS data are consistent with the anhydrous product obtained in S...

Embodiment 3

[0131] Example 3: Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy Base}-N-methylpyridine-2-carboxamide (anhydrous)

[0132] 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}- N-methylpyridine-2-carboxamide monohydrate was dried under reduced pressure (21mbar) at 90°C for 3 hours, then vacuumized, and then filled the desiccator with a mixed gas of carbon dioxide and nitrogen at a volume ratio of 55:45 , sealed, and continue to keep the drier at this 90°C for 2 hours, then drop to room temperature at a cooling rate of 1°C / min, and then maintain it in the above-mentioned mixed atmosphere for 2 hours to obtain 4.68g of white crystalline solid as 4-{4 -[({[4-Chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)-amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide. The melting point of the product is 211.8-212.6° C., and the 1H-NMR and MS data are consistent with the anhydrous product obtained in ...

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Abstract

The invention relates to antitumor drugs and a preparation method and application thereof, in particular to a compound shown as a following formula (I). The compound adopts Cu-Kalpha radiation and hasa typical powder X-ray diffraction pattern shown in a figure 1. The invention also provides a preparation method of the compound, a pharmaceutical composition comprising the compound and the application of the compound in preparation of the drugs for resisting tumors such as, but not limited to, colon cancer, lymphoma, sarcoma, leukemia, pancreatic cancer, breast cancer, prostate cancer, bone cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, skin cancer, stomach cancer, colorectal cancer, renal cell carcinoma, hepatocellular carcinoma and melanoma. The compound has excellent performance.

Description

technical field [0001] The present invention relates to the antineoplastic drug regorafenib, in particular to a new crystal of regorafenib, which can be used to treat abnormal VEGFR, PDGFR, raf, p38, and / or flt-3 kinase signaling Mediated diseases and disease symptoms, in view of the better properties of the new crystal form of the present invention, it can also be used to treat the above diseases. The invention also relates to a preparation method of the antitumor drug 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 dominan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81A61K31/44A61P35/00A61P35/02
CPCC07D213/81A61P35/00A61P35/02C07B2200/13
Inventor 李斌黄丽华张鹏李雅
Owner 李斌
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