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Glycolylurea and glycolythiourea compound with Ar (androgen receptor) and HDAC (histone deacetylase) double inhibition and application thereof
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A technology of thiohydantoin and thiohydantoin inhibition, which is applied in the field of hydantoin and thiohydantoin compounds, and can solve the problems of very limited improvement of AR inhibitory activity, lack of effect, weak antagonistic activity, etc.
Active Publication Date: 2019-05-24
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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The lack of activity of most antiandrogens against refractoryprostate cancer is partly due to their less antagonistic and more agonist activity when AR is overexpressed
Only enzalutamide and apalutamide, the second-generation AR antagonists, have been approved by the FDA for the treatment of patients with metastatic CRPC. Although it has better inhibitory activity than enzalutamide and reduces the probability of epileptic side effects, it still does not achieve the expected effect on patients with CRPC caused by mutant AR
[0007] At present, the research and development of non-steroidal AR antagonists are mostly structural modifications based on existing drugs to improve the inhibitory activity, selectivity, and pharmacokinetic properties of compounds, such as thiohydantoin derivatives Mainly modify the aromatic ring substituents, aromatic ring types and thiourea ring substituents of enzalutamide, but the improvement of AR inhibitory activity is very limited
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[0049] The synthesis method of compound (I) may include the following steps:
[0050]
Embodiment 1
[0051] Example 1 Preparation of Compound I-3
[0052]
[0053] Step A Synthesis of intermediate A3-1
[0054] Under the protection of nitrogen, the temperature was controlled at -10 to -5°C, and Intermediate 5 (2g, 4.3mmol), HATU (3.27g, 8.6mmol), DMF (20ml) and DIPEA (1.39g, 10.7mmol) were added and stirred for 20min. Add 4-aminobutyric acid methyl ester hydrochloride (0.70 g, 4.3 mmol) and stir for 1.5 h. Then add water, extract with dichloromethane, wash with water, wash with saturated brine, dry, concentrate, and obtain 2.18 g by column chromatography, with a yield of 90.1%. MS: 564.16 (M+1) + , 1 H-NMR(400MHz, DMSO-d 6 ), δ9.22(s, 1H), 8.76(s, 1H), 8.58(t, J=8Hz, 1H), 7.82(t, J=8Hz, 1H), 7.47(d, J=8Hz, 1H) , 7.39(d, J=8Hz, 1H), 3.61(s, 1H), 3.31(m, 1H), 2.61-2.69(m, 2H), 2.50(m, 2H), 2.36-2.44(m, 2H) , 1.91-2.05 (m, 1H), 1.75-1.96 (m, 2H), 1.52-1.66 (m, 1H)
[0060] The synthesis of compound I-1 was synthesized by a procedure similar to that described in Example 1, except that methyl 2-aminoacetate hydrochloride was substituted for methyl 4-aminobutyrate hydrochloride. MS:551.10(M+1) + , 1 H-NMR (400MHz, DMSO-d 6 ), δ10.35(s, 1H), 9.23(d, J=0Hz, 1H), 8.75(d, J=4Hz, 1H), 8.67(d, J=4Hz, 1H), 8.55(t, J= 8Hz, 1H), 7.81 (t, J = 8Hz, 1H), 7.46 (dd, J = 4Hz, 8Hz, 1H), 7.38 (dd, J = 0Hz, 8Hz, 1H), 4.09 (s, 2H), 2.60 -2.72 (m, 2H), 2.50 (m, 2H), 1.93-2.06 (m, 1H), 1.44-1.66 (m, 1H)
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Abstract
The invention discloses a glycolylurea and glycolythiourea compound with Ar (androgenreceptor) and HDAC (histone deacetylase) double inhibition, which has a structural formula shown in the description. A drug prepared via the compound herein can resistprostatecancer; a new direction is provided to study anti-prostatecancer drugs; the compound herein is significant to the development of anti-prostatecancer drugs.
Description
Technical field [0001] The invention belongs to the field of biomedicine, and relates to a hydantoin and thiohydantoin compound with dual inhibitory effects of AR and HDAC and its use. Background technique [0002] Prostate cancer (PCa) is one of the most common malignant tumors in men in Europe and the United States. According to the 2017 Tumor Data Annual Report of the United States, PCa is the most common malignant tumor in men in the United States, accounting for 19% of new tumors in American men. The mortality rate is also the second highest. In China, with the acceleration of the pace of life and the improvement of living standards, the incidence of PCa is not optimistic, and the mortality rate is also increasing year by year. In addition, due to the relatively lagging work of PCa screening in my country, most of the newly diagnosed patients are in the late stage. This cancer is a rapidly progressing malignant tumor that cannot be diagnosed and treated early. The average ...
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