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Compound with androgen receptor degradation activity

A technology of compounds and substituents, applied in the field of new compounds and their ability to degrade androgen receptors, can solve problems such as the inability to prevent the development of prostate cancer

Pending Publication Date: 2019-10-11
SHANGHAI MEIZER PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the overexpression of AR in hormone refractory prostate cancer can convert the antagonist of antiandrogen into an agonist, which is an important reason why androgen deprivation therapy cannot prevent the development of prostate cancer in the later stage of treatment.

Method used

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  • Compound with androgen receptor degradation activity
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Examples

Experimental program
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preparation example Construction

[0145] Compound preparation

[0146] Preparation

[0147] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.

[0148] The following reaction schemes illustrate the preparation of compounds of the invention. Unless otherwise indicated, A, B, W, Y, Z, X, a, b, c, d, R in the reaction schemes and ensuing discussions 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 is as defined above; M1 is a leaving group or can be converted into a leaving group, such as halogen, sulfonate, alcohol, aldehyde, acid.

[0149] In general, compounds of formula I c...

Embodiment 1

[0188]

[0189] Synthesis of compound 3

[0190] Methyl 6-aminocaproate (1.45 g) and acetone cyanohydrin (0.85 g) were dissolved in methanol (20 ml), and stirred overnight at room temperature. The reaction solution was concentrated to obtain the crude intermediate 1. The crude intermediate 1 was completely dissolved in anhydrous tetrahydrofuran (20ml), 3-chloro-4-cyanobenzene isothiocyanate (2.00g) and triethylamine (2.02g) were added, and the reaction solution was refluxed for 2h. The reaction solution was concentrated, the residue was dissolved in water (20ml) and ethanol (20ml), hydrochloric acid (20ml) was added, refluxed for 1h, the reaction solution was cooled, the organic solvent was removed under reduced pressure, and the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate -9, extracted with ethyl acetate (20ml*3), the organic phases were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatograph...

Embodiment 2

[0196]

[0197] Synthesis of compound 6

[0198] Under nitrogen protection, 2-amino-isobutyric acid methyl ester (1.40g), 5-bromopyridine-2-carboxylic acid (2.02g) 1,8-diazabicycloundec-7-ene (3.04 g), cuprous iodide (381mg) was added to N,N-dimethylacetamide (50ml), and heated at 150°C for 4h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column to obtain compound 6 (613 mg). MS(ESI):239[M+H] + .

[0199] Synthesis of compound 7

[0200] Under the protection of nitrogen, compound 6 (610mg), 3-trifluoromethyl-4-cyanobenzene isothiocyanate (584mg) and triethylamine (517mg) were dissolved in anhydrous tetrahydrofuran (20ml), and reflux reaction 2h. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column to obtain compound 7 (835 mg). MS(ESI):435[M+H] + .

[0201] Synthesis of Compound 8

[0202] Compound 7 (434mg), 2-(2-(2-aminoethoxy)ethoxy)et...

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Abstract

The invention provides a compound with androgen receptor degradation activity and particularly provides a compound shown as a formula I. Definitions of each group are as shown in the specification. The compound has excellent AR (androgen receptor) degradation activity and can be used for preparing medicines for disease treatment.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a class of novel compounds and their application for degrading androgen receptor (AR). These compounds are capable of degrading AR and are useful as AR degrading agents for the treatment of prostate and breast cancer diseases. Background technique [0002] Prostate cancer is a common cancer, and some prostate cancer patients can be cured with surgery. However, about 30% of prostate cancer patients will relapse due to distant metastasis of cancer cells, forming advanced disease. Patients with such advanced disease can be treated with androgen deprivation therapy, that is: castration combined with antiandrogen drug therapy. Castration reduces circulating levels of androgens and androgen receptor (AR) activity. Antiandrogen therapy can competitively bind to androgens and block the function of the androgen receptor (AR). This therapy, although effective at first, can quickly fail and tran...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/454A61K31/4545A61P35/00
CPCA61P35/00C07D401/14
Inventor 舒永志
Owner SHANGHAI MEIZER PHARM CO LTD
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