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Deuterated cabozantinib derivative, preparation method and application thereof, and intermediate of deuterated cabozantinib derivative

A technology of drugs and compounds, applied in the field of deuterated cabozantinib derivatives, applications and their intermediates, and their preparation methods, can solve the problems of hair color changes, toxic reactions, etc., to increase concentration, increase half-life, reduce Effects of drug toxicity and other side effects

Active Publication Date: 2015-07-22
河南英诺唯医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the study also found that cabozantinib can cause significant toxic reactions, the most common (more than 25%) include: diarrhea, stomatitis, hand-foot syndrome, decreased weight and appetite, nausea, fatigue, oral pain, Changes in hair color, taste disturbance, high blood pressure, abdominal pain, and constipation

Method used

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  • Deuterated cabozantinib derivative, preparation method and application thereof, and intermediate of deuterated cabozantinib derivative
  • Deuterated cabozantinib derivative, preparation method and application thereof, and intermediate of deuterated cabozantinib derivative
  • Deuterated cabozantinib derivative, preparation method and application thereof, and intermediate of deuterated cabozantinib derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0135] Embodiment 1 Preparation of compounds with structures shown in formula II and malate thereof

[0136] Step 1: Preparation of a compound having a structure shown in formula XII

[0137] Weigh the compound (1.5 g, 6.7 mmol) having the structure shown in Formula XVIII and add it into a stuffy jar, then add 15 mL of acetic acid and 15 mL of 40% hydrobromic acid in sequence, and raise the temperature to 140° C. overnight (about 15 hours). LC-MS detected that there was no starting material, and at the same time, part of 6,7-dimethyloxy-4-bromoquinoline was generated. After directly evaporating the reaction liquid, add 25mL of water to make a slurry, then use a small amount of ammonia water to adjust the pH value to about 10, and make a slurry for 1 hour, then filter with suction to obtain a solid, use absolute ethanol (20mL) to azeotrope three times with water, and then use an oil pump Pump to constant weight. 1.3 g of white solid were obtained. Carry out LC-MS detection, ...

Embodiment 2

[0158] Example 2 Preparation of a compound having a structure shown in formula III and its malate

[0159] According to the preparation method provided in Step 1 to Step 6 in Example 1, the trideuteroiodomethane in Step 2 in Example 1 is replaced with dideuteriomethyl iodide, and the preparation is carried out to obtain a compound having the structure shown in formula III , named N-{4-[6,7-bis(dideuteriomethyl)oxy-4-quinolyl]oxyphenyl}-N-(4-fluorophenyl)-1,1-cyclo propanediformamide;

[0160]

[0161] According to the preparation method provided in Step 7 of Example 1, the malate salt of the compound having the structure shown in formula III was prepared.

Embodiment 3

[0162] Example 3 Preparation of a compound having a structure shown in formula IV and its malate

[0163] According to the preparation method provided in step 1 to step 6 in Example 1, the trideuteriodomethane in step 2 in Example 1 is replaced with deuteriodomethane for preparation, and the compound having the structure shown in formula IV is obtained, Named N-{4-[6,7-bis(deuteromethyl)oxy-4-quinolyl]oxyphenyl}-N-(4-fluorophenyl)-1,1-cyclopropane di Formamide;

[0164]

[0165] According to the preparation method provided in step 7 of Example 1, the malate salt of the compound having the structure shown in formula IV was prepared.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and discloses a deuterated cabozantinib derivative, a preparation method and an application thereof, and an intermediate of the deuterated cabozantinib derivative. The deuterated cabozantinib derivative is a compound represented by formula I and may be a pharmaceutically acceptable salt, a crystalline hydrate, a solvate, a prodrug, or a monocrystalline of polymorphic substance. The decomposition speed of the deuterated cabozantinib derivative in vivo is slow, so that the poor metabolism of the medicine is reduced; the half life of the medicine is prolonged; the blood concentration of the medicine is increased; and a better therapeutic effect is achieved. Furthermore, the dosage of the medicine is decreased while keeping the therapeutic effect, and the toxic and side effect of the medicine is further reduced.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a deuterated cabozantinib derivative, its preparation method, application and its intermediate. Background technique [0002] Cabozantinib, whose English name is Cabozantinib (XL184, BMS-907351), is a multi-target tyrosine kinase inhibitor developed by Exelixis Company of the United States. Its chemical name is: N-[4-[(6,7-di Methoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide (4-quinolinyl)oxy]phenyl]-N-(4 -fluorophenyl)-1,1-cyclopropanedicarboxamide), its CAS number is: 849217-68-1; molecular formula is C 28 h 24 FN 3 o 5 , with a molecular weight of 501.51 and the following structure: [0003] [0004] The main targets of cabozantinib are VEGFR2, c-Met and Ret. Vascular endothelial growth factor (VEGF, vascular endothelial growth factor) and its receptor VEGFR play an important role in tumor angiogenesis, tumor pro...

Claims

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Application Information

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IPC IPC(8): C07D215/233A61K31/47A61P35/00A61P35/02A61P35/04
CPCC07D215/233
Inventor 陈兴海彭伟奥玛·派克郑飞鸣傅勇
Owner 河南英诺唯医药科技有限公司
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