Protein degradation target compound, antitumor applications and intermediates thereof, and applications of intermediates

A technology of compound and small molecule compound, applied in the fields of antineoplastic drugs, active ingredients of heterocyclic compounds, organic chemistry, etc.

Active Publication Date: 2019-10-22
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there have been no reports and related studies that thalidomide, pomalidomide, and lenalidomide are covalently bound to linking units through carbon-sulfur bonds

Method used

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  • Protein degradation target compound, antitumor applications and intermediates thereof, and applications of intermediates
  • Protein degradation target compound, antitumor applications and intermediates thereof, and applications of intermediates
  • Protein degradation target compound, antitumor applications and intermediates thereof, and applications of intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0637] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. While the disclosure will be described in conjunction with specific embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments.

[0638] The following abbreviations are used throughout the specification and examples:

[0639] Boc tert-butoxycarbonyl

[0640] n-BuOH n-Butanol

[0641] Bipyridine

[0642] t BuOH tert-butanol

[0643] Con. Concentration

[0644] m-CPBA m-chloroperoxybenzoic acid

[0645] DME ethylene glycol dimethyl ether

[0646] DMF N,N-Dimethylformamide

[0647] DMSO dimethyl sulfoxide

[0648] DIPEA N,N-Diisopropylethylamine ...

preparation example 1

[0686] Intermediate Preparation Example 1: Preparation of 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)sulfanyl )ethoxy)acetic acid (SIAIS1204137):

[0687] Compound SIAIS1204137 was prepared according to the method of scheme 1 under appropriate conditions understandable in the art, except that tert-butyl acetate was used as linker The brominated substrate and the thiophenol substrate SIAIS151014 were used to obtain the target compound SIAIS1204137 (light yellow solid, 185 mg, yield 69%), 1 H NMR (500MHz, DMSO) δ11.12 (s, 1H), 7.83–7.73 (m, 2H), 7.64 (d, J = 6.6Hz, 1H), 5.12 (dd, J = 12.8, 5.4Hz, 1H) ,4.08(s,2H),3.77(t,J=6.4Hz,2H),3.14-3.07(m,2H),2.94–2.82(m,1H),2.66–2.55(m,2H),2.09-2.01 (m,1H).HRMS(ESI)m / z: calculated value C 17 h 17 N 2 o 7 S + [M+H] + ,393.0751; measured value, 393.0763.

preparation example 2

[0688] Intermediate Preparation Example 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl) Thio)ethoxy)ethoxy)acetic acid (SIAIS1204139):

[0689] Compound SIAIS1204139 was prepared according to the method described in Scheme 1 under appropriate conditions understood in the art, except that 2-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy ) tert-butyl acetate was used as the brominated substrate of the linker and the thiophenol substrate SIAIS151014 was used to obtain the target compound SIAIS1204139 (light yellow solid, 190 mg, yield 63%), 1 H NMR (500MHz, DMSO) δ11.12(s, 1H), 7.83-7.76(m, 2H), 7.63(dd, J=6.4, 1.3Hz, 1H), 5.12(dd, J=12.9, 5.4Hz, 1H), 4.02(s, 2H), 3.72(t, J=6.3Hz, 2H), 3.59(s, 4H), 3.39–3.30(m, 2H), 3.13-3.06(m, 1H), 2.64-2.52 (m,2H),2.09-2.02(m,1H).HRMS(ESI)m / z: calculated value C 19 h 21 BN 2 o 8 S + [M+H] + ,437.1013; measured value, 437.1032.

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PUM

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Abstract

The present invention relates to a compound represented by a formula (I), antitumor applications and intermediates thereof, and applications of the intermediates, wherein the intermediates are compounds represented by a formula (III) and a formula (IV), the compound represented by the formula (I) has degradation effects on specific target proteins, and mainly comprises three parts, the first partis small molecules binding protein (SMBP), the second part is a link unit (Linker), the third part ubiquitin ligase binding moiety (ULM) is a ligand with ubiquitination function, SMBP and LIN are covalently bound, and LIN is covalently bound to ULM. According to the present invention, a series of the designed and synthesized compounds of the present disclosure have wide pharmacological activities,have function of degradation of specific proteins and / or inhibition of activities, and can be used for related tumor treatment.

Description

technical field [0001] The present disclosure relates to a protein degradation targeting compound, its anti-tumor application, its intermediate and the application of the intermediate. Background technique [0002] PROTAD (Proteolysis Targeting Drug) is a ternary complex, the first part is composed of small molecule drugs or compounds that bind to specific proteins; the second part is composed of link units of different lengths; the third part is composed of pan- The composition of the E3 ligase ligands of the primed function. By designing PROTAD small molecule compounds, specific proteins can be targeted, and E3 ubiquitination ligase is recruited through E3 ligand, so that the target protein and E3 ligase are connected through PROTAD small molecules, and then E3 ligase makes the target protein be ubiquitinated. Under the action of the proteasome, the target protein is degraded by erythroxylation. [0003] The E3Cereblon (CRBN) / Cullin4A ubiquitination ligase ligand has a p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/06C07D471/04C07D401/14C07D401/04C07D405/14C07D417/14C07D495/14A61K31/519A61K31/506A61K31/496A61K31/4545A61K31/5025A61K31/502A61K31/53A61K31/5517A61K31/551A61K31/454A61K31/55A61P35/00
CPCC07D487/04C07D487/06C07D471/04C07D401/14C07D401/04C07D405/14C07D417/14C07D495/14A61P35/02C07D237/32A61K31/519A61K31/506A61K31/55A61K31/551A61P35/00A61K47/545A61K47/60A61K31/138A61K31/454A61K31/496A61K31/5025A61K31/5517A61K31/675A61K45/06
Inventor 杨小宝姜标孙仁红任超伟孙宁孔莹李岩陈金聚阴倩倩宋肖玲赵全菊仇星
Owner SHANGHAI TECH UNIV
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