Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Derivatives, preparation method and application of deuterated palbociclib

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: 2018-03-23
TYK MEDICINES INC
View PDF5 Cites 1 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Derivatives, preparation method and application of deuterated palbociclib
  • Derivatives, preparation method and application of deuterated palbociclib
  • Derivatives, preparation method and application of deuterated palbociclib

Examples

Experimental program
Comparison scheme
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] The preparation of deuterated Palbociclib derivatives shown in formula (VI) in this embodiment comprises the following steps:

[0060] 1) prepare the Palbociclib derivative shown in formula (IV) according to the method of Example 1;

[0061] 2) prepare the Palbociclib derivative shown in formula (V) according to the method of Example 1;

[0062] 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).

[0063] The nuclear magnetic resonance information of compound shown in formula (VI) is: 1 H NMR (400MHz, C...

Embodiment 3

[0065] The present embodiment prepares the deuterated Palbociclib derivative shown in formula (II), and its structural formula is as follows:

[0066]

[0067] 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);

[0068] 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...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention falls within the technical field of pharmaceutical compounds, and in particular relates to a deuterated palbociclib derivative, a preparation method and the use thereof. The deuterated palbociclib derivative has a structure as shown in formula (I); by selectively deuterating active metabolic sites of palbociclib, the metabolic nature of a drug is improved, and the efficacy, safety and tolerance of the drug are improved accordingly. The synthesis of the deuterated palbociclib derivative provides a new type of compound for the synthesis of a new type anti-tumour drug; and such a compound can be used in the application of the inhibitor drug for inhibiting cyclin dependent kinases 4 and / or 6, and in the application of drugs for treating breast cancer, ovarian carcinoma, 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com