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Deuterated palbociclib derivative and preparation method and application thereof

A derivative and deuterium technology, which is applied in the field of pharmaceutical compounds, can solve the problems of high cost, poor compound stability, and low deuterium rate, and achieve the effects of solving instability, improving curative effect, increasing solubility and dissolution rate

Active Publication Date: 2017-07-21
TYK MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Studies have found that the compound shown in formula (VII) has poor stability, and the deuterium and hydrogen on the methyl group in the deuterated acetyl group are easily exchanged, resulting in a low deuterated rate. In addition, the cost of deuterated two methyl groups is relatively high

Method used

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  • Deuterated palbociclib derivative and preparation method and application thereof
  • Deuterated palbociclib derivative and preparation method and application thereof
  • Deuterated palbociclib derivative and preparation method and application thereof

Examples

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Effect test

Embodiment 1

[0049] The present embodiment prepares the Palbociclib derivative shown in formula (V), and its synthetic route is as follows:

[0050]

[0051] The present embodiment prepares the Palbociclib derivative shown in formula (V), comprises the following steps:

[0052] 1) Synthesis of the compound shown in formula (IV): Take 36g of compound A and add it to 250ml of tetrahydrofuran, and cool the system to 0°C; under nitrogen protection, slowly add 240mL of tetrahydrofuran solution of isopropylmagnesium chloride (1M), dropwise After the addition was complete, the system was warmed up to room temperature and continued to react for 1 h; then 35 g of compound B was added, and the reaction was continued overnight, and saturated NH 4 Cl solution quenched the reaction, extracted three times with ethyl acetate, combined the organic phases, dried and concentrated to obtain the compound shown in 44g formula (IV);

[0053] The nuclear magnetic information of compound shown in formula (IV)...

Embodiment 2

[0058] This embodiment prepares the deuterated Palbociclib derivative shown in formula (VI), and its synthetic route is as follows:

[0059]

[0060] The preparation of deuterated Palbociclib derivatives shown in formula (VI) in this embodiment comprises the following steps:

[0061] 1) prepare the Palbociclib derivative shown in formula (IV) according to the method of Example 1;

[0062] 2) prepare the Palbociclib derivative shown in formula (V) according to the method of Example 1;

[0063] 3) Under nitrogen protection, take 450mg of the compound shown in formula (V), 240mg of vinyl n-butyl ether, 10mg of Pd(OAc) 2 , 50 mg of dppf, and 160 mg of DIEPA were added to 20 mL of n-BuOH, and the system was heated to 95° C. for 20 h; after the reaction, the system was concentrated and purified by column chromatography to obtain 290 mg of the compound represented by formula (VI).

[0064] The nuclear magnetic resonance information of compound shown in formula (VI) is: 1 H NMR ...

Embodiment 3

[0066] The present embodiment prepares the deuterated Palbociclib derivative shown in formula (II), and its structural formula is as follows:

[0067]

[0068] The preparation method of the deuterated Palbociclib derivative shown in formula (II) comprises the following steps: take 300 mg of the compound shown in formula (VI) prepared in Example 2, add it to 20 mL of dichloromethane, add about 1 mL of concentrated hydrochloric acid dropwise at room temperature, Stir overnight at room temperature, the system precipitates a viscous yellow solid, add saturated NaHCO 3solution, adjusted until the system was weakly alkaline, the system was extracted with dichloromethane, the organic phase was dried, and concentrated to obtain 210 mg of the deuterated Palbociclib derivative shown in formula (II);

[0069] The nuclear magnetic resonance information of the deuterated Palbociclib derivative shown in formula (II) is: 1 H NMR (400MHz, CDCl 3 ): δ8.82(s,1H),8.21(s,1H),8.17-8.15(d,1H,J...

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Abstract

The invention belongs to the technical field of pharmaceutical compounds and particularly relates to a deuterated palbociclib derivative and preparation method and application thereof; the deuterated palbociclib derivative has a structure shown as in formula (I); by selectively deuterating active metabolic sites of palbociclib, the metabolic nature of a pharmaceutical is improved, and the therapeutic effect, safety and durability of the pharmaceutical are improved accordingly; through the synthesis of the deuterated palbociclib derivative, a novel compound is provided for synthesizing a novel antitumor pharmaceutical; this compound is applicable to the inhibitor pharmaceutical aspect to inhibit cyclin dependent kinase 4 and / or 6, and the aspect of pharmaceuticals for treating breast cancer, ovarian cancer, liver cancer or acute lymphoblastic leukemia.

Description

technical field [0001] The invention belongs to the technical field of medical compounds, and in particular relates to deuterated Palbociclib derivatives, preparation methods and applications thereof. Background technique [0002] Currently, many drugs are limited in their widespread use due to poor absorption, distribution, metabolism, or excretion (ADME) properties. At the same time, this is also the main reason for the failure of drug clinical development. Although the application of formulation technology and prodrug technology can improve the ADME properties of drugs to some extent, these methods cannot fundamentally change the ADME properties of drugs. For example, the problem of fast metabolism. Due to the fast metabolism, the drug will be metabolized by the body before it enters the body. Even if the activity is high, it will not have a therapeutic effect. If you want to achieve therapeutic effect, you need to increase the dosage to increase blood drug concentratio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07B59/00A61P35/00A61P35/02
CPCC07B59/002C07B2200/05C07D471/04Y02P20/55
Inventor 吴豫生牛成山耿阳郑茂林梁阿朋孟庆国杨挺王国辉霍云峰郭瑞云李敬亚邹大鹏
Owner TYK MEDICINES INC
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