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Amino steroid compound as well as preparation method and application thereof

A steroid compound and compound technology, applied in the field of chemistry, can solve the problems of loss of K-ras protein inhibitory effect and the inability of small molecule drugs to bind, and achieve the effect of promoting cancer cell death, tight binding and excellent inhibition.

Pending Publication Date: 2022-07-05
SHANGHAI STEROL PHARM TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the K-ras G12C mutation is curable, patients and doctors have to face another problem in actual treatment: cancer cells will develop drug resistance
The most important mechanism of drug resistance is K-ras protein allosteric, small molecule drugs cannot bind to the pocket region of the protein, and lose the inhibitory effect on K-ras protein

Method used

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  • Amino steroid compound as well as preparation method and application thereof
  • Amino steroid compound as well as preparation method and application thereof
  • Amino steroid compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] The compound having the following structure IV of Example 1 of the present application can be prepared by the following two process routes.

[0081]

[0082] Process route one:

[0083] (1.1) Dissolve quinolinic acid (10g, 57.7mmol) in 200ml of anhydrous DMF (N,N-dimethylformamide), add PyBOP (Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate, hexafluorophosphate) Benzotriazol-1-yl-oxytripyrrolidinophosphorus fluorophosphate, 36g, 69.2mmol) and HOBt (N-hydroxybenzotriazole, 1-hydroxybenzotriazole, 9.43g, 69.2mmol) were added after stirring for 5min Proline tert-butyrate, followed by DIPEA (N,N-diisopropylethylamine, 40 mL, 0.22 mol). The above solution was stirred at room temperature and reacted overnight for 12 h, then the reaction solution was poured into 1 L of water, extracted three times with ethyl acetate, dried over sodium sulfate, and evaporated to obtain N-(quinolinic acid-2-carboxylate)-L-pro Acid tert-butyrate (compound 9) 13.1 g.

...

Embodiment 2

[0100] The compound having the following structure V of Example 2 of the present application can be prepared through the following two process routes.

[0101]

[0102] Process route one:

(2.1)

[0103] Starting from compound (3) (2β-piperazinyl-3α-hydroxy-5α-steroid-17-one), this compound (3) is combined with 1-(quinoline-2-ester group by acylation reaction )-L-proline (compound 10) reaction into which a 1-(quinolin-2-yl-carbonyl)-L-proline moiety was introduced to yield compound D having the following structural formula

[0104]

[0105] (2.2) 313 mg of compound D, 447 mg of copper bromide and 20 ml of methanol were put into the reaction flask, and the temperature was raised to 80° C. for reflux reaction for 15 hours. The reaction solution was cooled to room temperature, water and dichloromethane were added, and the mixture was stirred for ten minutes to separate the layers. The organic phase was washed once with saturated brine, and concentrated to dryness under r...

Embodiment 3

[0112] The compound having the following structure VI of Example 3 of the present application can be prepared by the following procedure.

[0113]

[0114] The compound of structure VI above was prepared in the same manner as in Example 1, except that in step (1.6), trimethylsilyl acetylene was replaced with trimethylsilyl chloroacetylene, and since the halogen had been attached onto acetylene, so the halogenation process in step (1.8) is omitted here. Compound VI thus obtained was characterized as follows.

[0115] tested, 1 H NMR (400MHz, CDCl 3 )δ8.21(dd,J=12.3,8.6Hz,1H),8.13-7.92(m,2H),7.85-7.79(m,1H),7.72(m,1H),7.62-7.52(m,1H) ,5.86 and 5.11(m,1H),4.23–3.11(m,8H),2.77–2.58(m,2H),2.51–2.04(m,5H),2.01–0.98(m,22H),0.86(2s, 3H), 0.82 (2s, 3H), 0.76–0.64 (m, 1H).

[0116] Mass Spectrometry (MS, EI), C 40 H 51 ClN 4 O 4 , 687.1.

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PUM

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Abstract

The invention provides an amino steroid compound and a preparation method and application thereof, the amino steroid compound comprises at least one of chemical formulas shown as a formula I or a formula II, R1, R2, R3, R4 and R5 are independently selected from H, a halogen-containing group, a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C3-C10 cycloalkyl group, a C6-C10 aryl group or a C5-C10 heteroaryl group; at least one of R1 and R2 is a halogen-containing group; at least one of R3, R4 and R5 is a halogen-containing group.

Description

technical field [0001] The present application relates to the field of chemistry, in particular to an amino steroid compound and its preparation method and application. Background technique [0002] Kras (kirsten rat sarcoma viral oncogene) is a murine sarcoma virus oncogene. There are three genes in the ras gene family associated with human tumors, namely H-ras, K-ras and N-ras, which are located at 11, 12 and 12, respectively. on chromosome 1. K-ras is also known as the p21 gene because it encodes the 21kD ras protein. Among the ras genes, K-Ras is most closely related to human cancer. It is like a molecular switch: when normal, it can control and regulate the path of cell growth; once abnormal, It leads to continuous cell growth and prevents cells from self-apoptosis. It is involved in intracellular signal transmission. When the K-ras gene is mutated, the gene is permanently activated, and normal ras protein cannot be produced, resulting in disordered intracellular sign...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/00
CPCC07J43/003A61P35/00
Inventor 何群刘喜荣吴四清唐杰李龙袁飞鹏罗桂芳
Owner SHANGHAI STEROL PHARM TECH CO LTD
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