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Crizotinib prodrug, as well as preparation and application thereof

A pharmacy and compound technology, applied in the field of organic compound synthesis and medical application, can solve the problem of no pyridine ring amino modification and the like

Active Publication Date: 2013-10-30
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Crizotinib compound has been disclosed in CN1777427, CN101023064, but because the amino group on the pyridine ring is the active site (J.Med.Chem.54,6342-6363,2011), all do not have to pyridine in the prior art Amino groups on rings are reported to be modified

Method used

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  • Crizotinib prodrug, as well as preparation and application thereof
  • Crizotinib prodrug, as well as preparation and application thereof
  • Crizotinib prodrug, as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Preparation of N-acetyl-5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine

[0121]

[0122] The compound of this example was prepared by the acid chloride method. Dissolve 500mg of 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine in 15ml of dichloromethane and cool to 0°C After adding 1ml of triethylamine and continuing to stir for 5 minutes, after adding 1.1 equivalent of acetyl chloride dropwise, the temperature was raised to room temperature and reacted for 5 hours. Water was added to terminate the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography with ethyl acetate:petroleum ether=1:4 to obtain 400 mg of yellow-white solid with a yield of 72%.

[0123] 1 HNMR (500MHz, CDCl 3 )δ: 8.20(s, 1H), 7.69(d, 1H), 7.34(dd, 1H), 7.10(m, 1H), 6.86(d, 1H), 6.01(q, 1H), 2.47(s, 3H ), 1.84(d, 3H).

Embodiment 2

[0125] Preparation of N-acetyl-5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine

[0126]

[0127] The compound of this example was prepared by the acid anhydride method. Add 500mg of 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine into 10ml of acetic anhydride and heat to 50°C for reaction 2 hours. After the reaction, the reaction solution was concentrated to dryness, ethyl acetate and saturated aqueous sodium bicarbonate were added, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography with ethyl acetate:petroleum ether=1:4 to obtain 500 mg of a yellow-white solid with a yield of 90%.

Embodiment 3

[0129] N-acetyl-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-N-Boc-piperidinyl)- Preparation of 1H-pyrazol-4-yl]-2-pyridinamine

[0130]

[0131] According to the method of Example 1 or Example 2, N-acetyl-5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2 - Pyridinamine.

[0132] 300mg N-acetyl-5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-pyridinamine and 230mg 1-(4- N-Boc-piperidinyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (C) In 5ml of DMF, add 300mg of cesium carbonate in 1ml of aqueous solution, replace the air with nitrogen three times, add 20mg of Pd (PPh 3 ) 2 Cl 2 , and then replaced the air with nitrogen three times, and the reaction mixture was warmed to 75° C. and stirred for 12 hours. After the reaction, cool down to room temperature, add 20ml of ethyl acetate to dilute, filter with diatomaceous earth, wash with ethyl acetate, the combined ethyl acetate layer is concentrated after drying with anhydrous sod...

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Abstract

The invention relates to a crizotinib prodrug, as well as a preparation and an application thereof. The invention provides a compound showed as a general formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt, or a solvent compound or a hydrate of the compound, wherein X is O or CH2; m is 0 or 1; R1 and R2 are selected from the same or different groups, and are respectively independently hydrogen, halogen, nitryl, cyan, hydroxyl, amino saturated or unsaturated chain hydrocarbyl of C1-C6, and saturated or unsaturated cyclic hydrocarbyl of C1-C6; R1 and R2 also can exist in the same ring and form ternary-hexahydric ring together; the ternary-hexahydric ring can be substituted or un-substituted cyclic hydrocarbon, aromatic ring or hetero-aromatic ring; the substituent group on the ring can be selected from halogen, nitryl, cyan, hydroxyl, amino, C1-C6 alkyl and C1-C6 alkoxy; R3 is selected from hydrogen, substituted or un-substituted C1-C12 saturated or unsaturated alkyl, substituted or un-substituted phenyl or hetero-aryl, substituted or un-substituted alkyl acyloxy, substituted or un-substituted phosphorus acyloxy and substituted or un-substituted aryl acyloxy or hetero-aryl acyloxy; and the substituent groups are selected from halogen, nitryl, cyan, hydroxyl, amino, phenyl or hetero-aryl, C`-C6 alkyl, C1-C6 acyloxy, C1-C6 vinyl and C1-C6 alkynyl.

Description

technical field [0001] The invention relates to a prodrug of crizotinib and its preparation method and application. It belongs to the technical field of organic compound synthesis and medical application. Background technique [0002] Prodrug (Prodrug) refers to a class of compounds that are inactive or less active in vitro, and undergo one or more steps of enzyme and / or biotransformation of chemical species in vivo to release active substances and produce pharmacological effects. For bioreversible drugs. It is usually formed by connecting a biologically active drug molecule (original drug) with a non-toxic carrier (temporary transport group). According to the chemical structure, prodrugs can be divided into four categories: carrier-linked prodrugs, biological prodrugs, macromolecular prodrugs, and drug-antibody conjugates. [0003] Prodrug is a very useful drug design method, which is widely used in the design of various drug molecules. Many drugs are administered in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D213/75A61K31/4545A61P35/04A61P35/00A61P11/00
CPCY02P20/55
Inventor 吉民俞森王鹏杨玲蔡进顾红梅
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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