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A class of compounds that improve the sensitivity of pca drug-resistant cells to antagonists and their use

A technology of drug-resistant cells and compounds, applied in the field of medicine, can solve problems such as hot flashes in patients, and achieve the effect of improving sensitivity

Active Publication Date: 2021-09-07
LEADINGEN BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical phase III report shows that enzalutamide can prolong the survival of CPRC patients by 4.8 months, but some patients may experience adverse reactions such as hot flashes and high blood pressure

Method used

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  • A class of compounds that improve the sensitivity of pca drug-resistant cells to antagonists and their use
  • A class of compounds that improve the sensitivity of pca drug-resistant cells to antagonists and their use
  • A class of compounds that improve the sensitivity of pca drug-resistant cells to antagonists and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1, the synthesis of compound JT-21

[0052] The synthetic route of compound JT-21 is shown in the following formula:

[0053]

[0054] Experimental procedures and results of compound JT-21:

[0055] Step 1: Synthesis 2

[0056]

[0057] Compound 1 (2.24g, 10mmol, 1.0eq) was added into absolute ethanol (30mL), then 4-isopropylaniline (2.03g, 15mmol, 1.5eq) was added to the above solution, and reacted at 75°C for 20h. The reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small amount of ethanol and dried to obtain the target product (1.8 g, 51%, white solid).

[0058] 1 HNMR (400MHz, CDCl3): δ8.39(s, 1H), 7.60(d, J=8.4Hz, 2H), 7.27(d, J=8.6Hz, 2H), 7.19(br s, 1H), 4.37( q, J=7.1Hz, 2H), 3.04–2.86(m, 1H), 2.83(s, 3H), 1.42(t, J=7.1Hz, 3H), 1.29(d, J=6.9Hz, 6H).

[0059] LCMS: (M+H)+: 324.2.

[0060] Step 2: Synthesis 3

[0061]

[0062] Compound 2 (0.5g, 1.55mmol, 1.0eq) was dissolved in et...

Embodiment 2

[0071] Embodiment 2, the synthesis of compound JT-22

[0072] The synthetic route of compound JT-22 is shown in the following formula:

[0073]

[0074] Experimental procedures and results of compound JT-22:

[0075] Compound JT-21 (65mg, 0.2mmol, 1.0eq) was dissolved in methanol (2mL) and tetrahydrofuran (2mL), then lithium hydroxide (25mg, 0.6mmol, 3eq) aqueous solution (2mL) was added dropwise to the above solution, React overnight at room temperature. The organic phase was spin-off, the aqueous phase was extracted with ethyl acetate (2x5mL), then the pH of the aqueous phase was adjusted to 3 with 2N dilute hydrochloric acid, the precipitated solid was filtered, washed with a small amount of water and dried to obtain the target product (40mg, 67 %, white solid).

[0076] 1 HNMR(400MHz,DMSO-d6):δ13.14(br s,1H),12.43(s,1H),8.98(s,1H),8.04(d,J=1.8Hz,1H),7.72(dd,J =8.6,1.9Hz,1H),7.60(d,J=8.6Hz,1H),3.09–2.97(m,1H),2.85(s,3H),1.27(d,J=6.9Hz,6H).

[0077] LCMS: (M+H)+: ...

Embodiment 3

[0079] Embodiment 3, the synthesis of compound JT-38

[0080] The synthetic route of compound JT-38 is shown in the following formula:

[0081]

[0082] Experimental procedures and results of compound JT-38:

[0083] Step 1: Synthesis 2

[0084]

[0085]Compound 1 (300mg, 1mmol, 1eq) was dissolved in ethanol (10mL), concentrated sulfuric acid (1mL) was added thereto, and the reaction was refluxed for 60 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of ethanol, collected and dried to obtain the target compound 2 (300 mg, crude product, off-white solid).

[0086] 1 HNMR (400MHz, DMSO-d6): δ8.81(s, 1H), 8.37(br s, 1H), 8.11(br s, 1H), 7.93(d, J=1.9Hz, 1H), 7.75(dd, J=8.6,2.1Hz,1H),7.55(d,J=8.6Hz,1H),4.36(q,J=7.2,2H),3.13–2.99(m,1H),1.37(t,J=7.1Hz ,3H),1.26(d,J=6.9Hz,6H).

[0087] LCMS: (M+H)+: 327.1.

[0088] Step 2: Synthesis of JT-38

[0089]

[0090] Compound 2 (100mg, 0.31mmol, 1.0e...

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Abstract

The invention discloses a compound and its application for improving the sensitivity of PCa drug-resistant cells to antagonists; the structural formula of the compound is that when enzalutamide and the compound are co-cultured, the cell viability is obviously affected, suggesting that these compounds increase Sensitivity of drug-resistant prostate cancer cells to enzalutamide. Therefore, the compounds can be applied to prepare drugs for improving the sensitivity of prostate cancer drug-resistant cells to androgen receptor antagonists such as enzalutamide.

Description

technical field [0001] The invention belongs to the field of medical technology, and relates to a class of compounds and uses for improving the sensitivity of PCa drug-resistant cells to antagonists; in particular, a series of compounds and their effects in improving the resistance of prostate cancer drug-resistant cells to androgen receptor antagonists such as Enzalu Amine Sensitivity Uses. Background technique [0002] Prostate cancer (PCa) is a genitourinary system tumor that seriously threatens the life and health of middle-aged and elderly men. Its incidence rate ranks second among male tumors, second only to lung cancer. Usually prostate cancer patients are men aged 65 and over. In addition to advanced age factors, gene mutations and environmental factors may also cause prostate cancer, but the exact cause is still unclear. In my country, with the aging of the population, changes in lifestyles, the prolongation of the average life expectancy of men, and the improvemen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D495/04C07D491/052A61K31/4375A61K31/436A61K31/4365A61P35/00A61P15/00
CPCA61P15/00A61P35/00C07D471/04C07D491/052C07D495/04
Inventor 高维强朱鹤陈晓颀
Owner LEADINGEN BIOTECH INC