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Phosphoryl-containing compounds and application thereof

A compound and acyl technology, applied in the field of preparation of phosphoryl-containing compounds, can solve the problems of high liver and heart toxicity and low bioavailability of abiraterone

Active Publication Date: 2019-06-14
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the bioavailability of abiraterone is low, and it is highly toxic to the liver and heart. Therefore, it is of great significance to seek steroidal anticancer drugs with better activity, lower dosage and safer

Method used

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  • Phosphoryl-containing compounds and application thereof
  • Phosphoryl-containing compounds and application thereof
  • Phosphoryl-containing compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] The synthesis of embodiment 1 compound I-1

[0149] Synthesized from 1 mmol of compound II-1 and 1.6 mmol of phosphorus oxychloride according to method B to obtain the title compound I-1 with a yield of 70%.

[0150] 1H NMR (500MHz, CDCl3), δ: 8.62(s, 1H, Py2-H), 8.45(d, J=5.5Hz, 1H, Py6-H), 7.66(d, J=10Hz, 1H, Py4-H ),7.65~7.53(m,4H),7.21~7.25(m,1H,Py5-H),6.00(s,1H,16-H),5.40(d,J=6Hz,1H,6-H), 3.51~3.58(m,1H),3.90(s,2H),3.66~3.42(m,1H,3α-H),2.62~2.59(m,2H),2.30~2.27(m,2H),2.20~2.13 (m,4H),2.11~2.06(m,2H),1.93~1.90(m,1H),1.89~1.77(m,3H),1.64~1.40(m,4H),1.07(s,3H,18- CH 3 ),1.05(s,3H,19-CH 3 ),0.94(d,J=5Hz,3H),0.87(d,J=10Hz,3H).

Embodiment 2

[0151] The synthesis of embodiment 2 compound I-2

[0152] Synthesized from 1 mmol of compound II-2 and 1.6 mmol of III-2 according to general method A to obtain the title target compound I-2 with a yield of 72%.

[0153] 1H NMR (500MHz, CDCl3), δ: 8.62(s, 1H, Py2-H), 8.42(d, J=5.5Hz, 1H, Py6-H), 7.74(d, J=9.5Hz, 1H, Py4- H), 7.18~7.14(m,1H,Py5-H),6.00(s,1H,16-H),5.40(d,J=6.5Hz,1H,6-H),5.18~5.01(m,2H ),4.66~4.61(m,1H,3α-H),3.88(s,2H),3.50(s,6H),3.47(d,J=4.5Hz,1H),2.59~2.27(m,2H), 2.26~2.19(m,2H),2.13~2.09(m,1H),1.94~1.91(m,2H),1.90~1.87(m,1H),1.86~1.62(m,4H),1.61~1.52(m ,4H),1.05(s,3H,18-CH 3 ),1.00(s,3H,19-CH 3 ),0.94(d,J=5.5Hz,3H),0.94~0.87(m,2H),0.87(d,J=9.5Hz,3H).

Embodiment 3

[0154] The synthesis of embodiment 3 compound Ⅰ-4

[0155] Synthesized from 1 mmol of compound II-4 and 1.6 mmol of phosphorus oxychloride according to method B to obtain the title compound I-4 with a yield of 65%.

[0156] 1H NMR (500MHz, CDCl3), δ: 7.84(s, 1H, 2'-H), 7.70~7.60(m, 2H, Ar-H), 7.26~7.22(m, 1H, Ar-H), 7.11~ 7.07(m,1H,Ar-H),5.84(s,1H,16-H),5.19(d,J=5.5Hz,1H,6-H),4.66~4.59(m,1H,3α-H) ,3.88(s,2H),3.52(s,6H),3.47(d,J=5Hz,1H),2.32~2.24(m,2H),2.13~2.11(m,1H),1.99~1.96(m, 2H),1.95~1.55(m,4H),1.78~1.57(m,2H),1.67~1.60(m,2H),1.60~1.57(m,3H),1.21~1.19(m,1H)1.05,1.11 ~1.05(m,3H),1.05(s,3H,18-CH 3 ),1.00(s,3H,19-CH 3 ),0.94(d,J=5Hz,3H),0.87(d,J=10Hz,3H).

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Abstract

The present invention relates to a series of phosphoryl-containing steroidal compounds, a preparation method and an application thereof, in particular to the compounds as a formula I, an isomer, pharmaceutically acceptable salts or chemically protected forms thereof, the preparation method thereof, and the application of the compounds in preparation of a medicine for treating cancer-related diseases. The compounds of the present invention have the good activity for inhibiting malignant tumors such as melanoma and prostate cancer.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a series of phosphoryl-containing compounds, their preparation methods and uses. Background technique [0002] Steroids widely exist in animals and plants, have various biological activities, and are widely used. With the development of biological and chemical technology, steroid drugs have been widely used in the treatment of rheumatism, cardiovascular, collagen diseases, lymphatic leukemia, tumors, endocrine disorders and other diseases, especially malignant tumors related to sex hormones. Steroid drugs often have a better effect. For example, abiraterone, a CYP17 inhibitor, is clinically used in combination with prednisone to treat prostate cancer patients who have previously received paclitaxel chemotherapy and then have a tendency to metastasize, which can significantly improve the quality of life of patients and prolong their survival. However, the bioavailability of abiraterone i...

Claims

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Application Information

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IPC IPC(8): C07K5/083C07K5/065C07K5/062C07J43/00A61K38/05A61K38/06A61K31/675A61P35/00
CPCY02P20/55
Inventor 冯娟马兰刘守信李立娟黄净魏茜茜
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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