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Bifunctional compound, and preparation method and application thereof

A bifunctional compound and solvate technology, which is applied in the field of bifunctional compounds and their preparation, can solve the problems of drug resistance in patients

Active Publication Date: 2021-09-14
SUZHOU KINTOR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the development of effective targeted therapies, most patients develop drug resistance and the disease continues to progress

Method used

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  • Bifunctional compound, and preparation method and application thereof
  • Bifunctional compound, and preparation method and application thereof
  • Bifunctional compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0520]

[0521] 1-1 (2g, 10mmol), TMSCN (3g, 30mmol), ZnCl 2 (136mg, 1mmol) was added to 50ml of acetone in turn, reacted at room temperature for 1h, after the reaction, washed with 100ml of water, extracted with 100ml of EA, washed with 50ml of saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.3g of product 1-2, yield 88%, the product was used directly in the next step without purification.

[0522]

[0523] Add 1-2 (2.3 g, 8.8 mmol), 1-3 (4.3 g, 17.6 mmol) to 10 ml of DMF in turn, and react at room temperature overnight. After the reaction, add 20 ml of methanol, 20 ml of 6NHCl, and react at 90°C for 1 h. Washed with 50ml of water, extracted with 50ml of EA, washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, spin-dried on the upper chromatography column PE:EA=5:1-2:1 to obtain 400 mg of product 1-4 with a yield of 9.2%.

[0524]

[0525] 1-4 (300 mg, 0.6 mmol), 1-5 (112 mg, 0.6 mmol), HATU (456 mg, 1.2 mmol), tr...

Embodiment A2

[0534]

[0535] LCMS([M+H] + ):820.2

[0536] 1 HNMR(400MHz, DMSO-d6)δ11.11(s,1H),8.53(d,J=2.4Hz,1H),8.33–8.23(m,2H),7.87(t,J=5.6Hz,1H), 7.82(dd,J=8.3,2.5Hz,1H),7.59–7.52(m,1H),7.45(t,J=9.8Hz,1H),7.11(d,J=8.6Hz,1H),7.01(d , J=7.0Hz, 1H), 6.58(t, J=5.9Hz, 1H), 5.05(dd, J=12.8, 5.4Hz, 1H), 3.31(s, 2H), 3.09(dd, J=12.4, 6.3Hz, 2H), 2.96–2.70 (m, 4H), 2.62–2.53 (m, 2H), 2.15 (t, J=7.4Hz, 2H), 2.10–1.90 (m, 4H), 1.53 (s, 6H) ),1.47(d,J=7.3Hz,2H).

Embodiment A3

[0538]

[0539] LCMS([M+H] + ):854.2

[0540] 1 HNMR(400MHz, DMSO-d6)δ11.13(s,1H),8.54(t,J=5.4Hz,1H),8.30–8.22(m,2H),8.02(t,J=5.7Hz,1H), 7.81(dd,J=8.4,7.4Hz,1H),7.75(t,J=8.0Hz,1H),7.52(dd,J=10.6,1.8Hz,1H),7.49(d,J=7.2Hz,1H) ),7.37(m,2H),5.12(dd,J=12.9,5.4Hz,1H),4.78(s,2H),3.27(d,J=5.5Hz,2H),3.19(d,J=5.7Hz ,2H),2.95–2.83(m,1H),2.63–2.51(m,2H),2.06–1.96(m,1H),1.55(d,J=1.7Hz,6H),1.52(m,4H).

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Abstract

The invention relates to a bifunctional compound, and a preparation method and application thereof. The bifunctional compound comprises: a binding moiety which binds to E3 ubiquitin ligase; a target protein binding moiety that binds to an androgen receptor; and a linking moiety linking the E3 ubiquitin ligase binding moiety and the target protein binding moiety. The bifunctional compound locates an androgen receptor adjacent to the ubiquitin ligase to achieve degradation or inhibition of the androgen receptor.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a bifunctional compound and a preparation method and use thereof, wherein the bifunctional compound comprises a binding part bound to E3 ubiquitin ligase; a target protein binding part bound to androgen receptor; and E3 ubiquitin ligase binding part; A linking moiety that connects the ubiquitin ligase-binding moiety and the target protein-binding moiety. The bifunctional compounds of the present application locate androgen receptors adjacent to ubiquitin ligases to achieve degradation or inhibition of androgen receptors. Background technique [0002] The androgen receptor (AR) belongs to the nuclear hormone receptor family that is activated by androgen. In the absence of androgens, AR is bound by heat shock protein 90 (Hsp90) in the cytosol. When androgen binds AR, its conformation changes to release AR from Hsp90 and expose the nuclear localization signal (NLS). The latter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07K5/02C07K5/062A61P17/10A61P17/14A61P17/00A61P11/06A61P35/00A61P3/10A61P9/00A61P9/12A61P1/00A61P25/28A61P3/04A61P15/08A61P27/02A61P21/00A61P7/00A61P25/00A61P35/02A61K38/05A61K38/06A61K31/454A61K31/496A61K31/4545
CPCC07D401/14C07K5/06034C07K5/06165C07K5/02A61P17/10A61P17/14A61P17/00A61P11/06A61P35/00A61P3/10A61P9/00A61P9/12A61P1/00A61P25/28A61P3/04A61P15/08A61P27/02A61P21/00A61P7/00A61P25/00A61P35/02A61K47/55C07D417/14C07D409/14C07D413/14A61K47/545
Inventor 童友之
Owner SUZHOU KINTOR PHARMA
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