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Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

A compound and halogen technology, applied in organic chemistry, pharmaceutical formulation, drug combination, etc., can solve the problems of short overall survival, short PSA progression-free survival, low PSA response rate, etc.

Pending Publication Date: 2021-11-19
蒙特利诺治疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recent work (Antonarakis, E.S. et al., New Engl. J. Med. 2014 37, 1028-1038) showed that patients treated with enzalutamide and abiraterone with an AR splice variant (labeled AR-V7) Has a lower PSA response rate, shorter PSA progression-free survival, and shorter overall survival

Method used

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  • Bi-functional compounds and methods for targeted ubiquitination of androgen receptor
  • Bi-functional compounds and methods for targeted ubiquitination of androgen receptor
  • Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0174] By using 2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E) (0.02 g, 0.056 mmol) in dry DMF (1.0 mL) , 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (M)( 0.024g, 0.056mmol), DIPEA (0.03mL, 0.224mmol) and HATU (0.027g, 0.70mmol) for general method III through SiO 2 After purification by flash column chromatography (DCM / MeOH, 99:1-96:4), followed by further purification by HPLC (Agilent Technologies 1200; column, Eclipse XDB-C18 4.6x150 mm (5 μm); flow rate, 1.0 mL / min; DAD 190-650nm; isocratic eluent, ACN / H 2 (070:30) afforded the title compound as a yellow solid (0.016 g, 50% yield). 1 H NMR (400MHz, CDCl 3 ):δ8.14(s,1H),7.64-7.55(m,1H),7.55-7.45(m,1H),7.11(d,J=7.1Hz,1H),7.04(s,1H),7.04- 6.97(m,1H),6.93(s,1H),6.90(d,J=8.6Hz,1H),6.25(s,1H),5.02-4.86(m,1H),4.60(s,2H),3.97 -3.76(m,4H),3.64-3.48(m,4H),3.34(q,J=6.8Hz,2H),3.28(q,J=6.6Hz,2H),2.99-2.67(m,3H), 2.21-2.08(m,1H),1.81-1.31(m,12H); 13 C NMR (101MHz, CDC...

Embodiment 3

[0176] By using 2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E) (0.04 g, 0.086 mmol) in dry DMF (2.0 mL) , 4-((10-aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (N)( 0.04g, 0.086mmol), DIPEA (0.05mL, 0.44mmol) and HATU (0.041g, 0.107mmol) for general method III through SiO 2 Purification by flash column chromatography (DCM / acetone, 95:5-85:15) afforded the title compound as a yellow solid (0.026 g, 39% yield). 1 H NMR (400MHz, CDCl 3 ):δ8.16(s,1H),7.61(ddd,J=8.4,6.0,2.1Hz,1H),7.55-7.47(m,1H),7.10(d,J=7.1Hz,1H),7.06- 6.95(m,2H),6.94(s,1H),6.90(d,J=8.5Hz,1H),6.25(t,J=5.6Hz,1H),4.93(dd,J=12.1,5.3Hz,1H ),4.59(s,2H),3.93-3.78(m,4H),3.59-3.50(m,4H),3.38-3.23(m,4H),2.97-2.69(m,3H),2.20-2.08(m ,1H),1.74-1.64(m,2H),1.59-1.48(m,2H),1.47-1.39(m,2H),1.37-1.29(m,10H); 13 C NMR (101MHz, CDCl 3 ): δ170.97, 170.79, 169.51, 168.32, 167.89, 167.65, 150.71(dd, J=251.9, 10.9Hz), 147.04, 146.51-146.34(m), 144.21(dd, J=247.4, 14.0Hz), 144....

Embodiment 5

[0180] By using 2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetic acid (E) (0.027 g, 0.076 mmol) in dry DMF (1.0 mL) , 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3- base) isoindoline-1,3-dione hydrochloride (P) (0.037g, 0.076mmol), DIPEA (0.053mL, 0.305mmol) and HATU (0.036g, 0.095mmol) for general method III, through SiO 2 After purification by flash column chromatography (DCM / MeOH, 98:2), the title compound was obtained as a yellow solid (0.041 g, 69% yield). 1 H NMR (400MHz, CDCl 3 ):δ8.31(s,1H),7.66(t,J=6.6Hz,1H),7.50(t,J=7.8Hz,1H),7.12(d,J=7.1Hz,1H),7.09-6.96 (m,3H),6.91(d,J=8.5Hz,1H),6.48(t,J=4.8Hz,1H),4.92(dd,J=5.3,11.9Hz,1H),4.56(s,2H) ,3.97-3.81(m,6H),3.81-3.22(m,18H),3.07-2.58(m,3H),2.16-2.06(m,1H); 13 C NMR (101MHz, CDCl 3 ): δ171.00, 170.63, 169.24, 168.30, 168.05, 167.58, 150.54 (dd, J = 11.4, 251.2 Hz), 146.79, 146.23-145.77 (m), 144.52 (d, J = 9.3 Hz), 144.29 (dd, J =13.9,247.2Hz),136.02,132.51,125.28,124.43,116....

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Abstract

The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and / or otherwise inhibited by the compounds as described herein.

Description

[0001] field of invention [0002] The present invention relates to therapeutic compounds and compositions and their methods for use in the treatment of various indications, including various cancers. In particular, the invention relates to therapies and methods of treating cancer, such as prostate cancer. [0003] Background of the invention [0004] Prostate cancer is the most commonly diagnosed malignancy in American men and the second leading cause of cancer death in men. A large number of studies have shown that the androgen receptor (AR) is not only the core of prostate carcinogenesis, but also the core of the disease's progression to castration-resistant state (Taplin, M.E. et al., J.Clin.Oncol.2003 21:2673-8 and Tilley, W.D. et al., Cancer Res. 1994 54:4096-4102). Therefore, effective inhibition of human AR remains one of the most effective therapeutic approaches for the treatment of advanced metastatic prostate cancer. [0005] Androgens are also known to play a rol...

Claims

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Application Information

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IPC IPC(8): C07D277/20C07D401/04C07D417/04
CPCC07D417/04C07D401/04C07D417/14C07D417/12A61P35/00A61P13/08A61P35/04A61K45/06
Inventor J·德桑蒂斯R·J·瓦兹
Owner 蒙特利诺治疗公司
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