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Tricyclic diterpene-2-methylpyrimidine analogues, preparation method and application thereof

A technology of methyl pyrimidine and tricyclic diterpene is applied in the field of tricyclic diterpene and 2-methylpyrimidine analogs and their preparation, and can solve the problems of low serum testosterone level, decreased sperm count, azoospermia and the like

Active Publication Date: 2020-07-03
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Existing therapy for LOH is mainly exogenous supplementation of testosterone. The goal of this therapy is to restore testosterone to normal physiological levels and reverse the symptoms of hypogonadism. However, current clinical trials have not fully confirmed that the treatment of low testosterone can improve the related symptoms of LOH. In addition, , the latest research shows that polycythemia may occur during the treatment of LOH with exogenous testosterone supplementation, which may increase the risk of stroke, heart disease and prostate tumors, and also inhibit luteinizing hormone (LH), thereby further reducing The ability of Leydig cells to synthesize testosterone in the patient's testis, the concentration of testosterone in the testis is reduced, and the number of sperm is reduced, causing low serum testosterone levels Azoospermia

Method used

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  • Tricyclic diterpene-2-methylpyrimidine analogues, preparation method and application thereof
  • Tricyclic diterpene-2-methylpyrimidine analogues, preparation method and application thereof
  • Tricyclic diterpene-2-methylpyrimidine analogues, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] The preparation of embodiment 1 compound 9

[0265]

[0266] Compound 4 (10 g, 36.5 mmol) was dissolved in 100 mL of anhydrous THF, IBX (12.3 g, 43.8 mmol) was added, DMSO (50 mL) was added, and the reaction was carried out at 40° C. for 12 h. After the reaction is complete, add 200 mL of water to the system, add EA (50 mL) to stir, pad diatomaceous earth for suction filtration, wash the filter residue repeatedly with EA until no product remains, separate the filtrate, combine the EA phases, and wash with 1M sodium hydroxide solution. Anhydrous Na 2 SO 4 Drying and distillation under reduced pressure gave crude product 6 as a white solid, which was purified by column chromatography with PE:EA=5:1 to give pure compound 6 (8.9 g white solid, yield 90%).

[0267] Compound 6 (8.9g, 32.7mmol) was dissolved in 80mL of ethyl formate, placed in an ice-salt bath, sodium hydride (7.8g, 327.0mmol) was slowly added, a huge amount of heat was released, slowly added dropwise, vi...

Embodiment 2

[0270] The preparation of embodiment 2 compound 10-1-10-8

[0271]

[0272] Compound 9 (2g, 6.211mmol) was dissolved in anhydrous DCM. After cooling the system to 0°C, anhydrous aluminum chloride (2.5g, 18.634mmol) was added, and then the corresponding acid chloride (12.422mmol) was added dropwise. After the dropwise addition, the reaction was continued at 0° C. for 2 hours, and the TLC raw material was completely reacted. Slowly add ice water to quench (huge exotherm, slow dropwise, vigorous stirring). After liquid separation, the aqueous phase was extracted with DCM several times, and the organic phases were combined, washed with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, the crude product was obtained by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=10:1→5:1) to obtain compound 10-1-10-8 (white solid, 70-88%).

[0273] Compound 10-1, white solid, yield 70%. 1 H NMR (400MHz, Chloroform-d) δ8.39(s...

Embodiment 3

[0281] The preparation of embodiment 3 compound 11

[0282]

[0283]Compound 9 (258mg, 0.8mmol) was dissolved in dichloromethane (30mL), then liquid bromine (25mg, 0.4mmol) and p-toluenesulfonic acid (0.4mL, 8mmol) were added under ice-cooling, and the reaction was carried out under nitrogen protection for 2 hours. TLC detects that the reaction is complete, the reaction solution is poured into 100 ml of water, extracted with ethyl acetate (3 × 15mL), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried in vacuo, and subjected to silica gel column chromatography (PE: EA=5:1) to obtain compound 11 (white solid, 244 mg, yield 76%). 1 HNMR (400MHz, CDCl 3 )δ8.39(s,1H),7.29(s,1H),6.89(s,1H),3.93(s,3H),3.15(d,J=15.5Hz,1H),2.94–2.73(m,3H ),2.71(s,3H),2.01–1.94(m,1H),1.88–1.82(m,1H),1.80–1.72(m,1H),1.37(s,3H),1.34(s,3H), 1.15(s,3H). 13 C NMR (101MHz, CDCl 3 )δ172.10,166.07,157.62,154.19,146.27,133.41,129.53,123.40,109.46...

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Abstract

The invention discloses tricyclic diterpene-2-methylpyrimidine analogues represented by formulas (X) and (I)-(IV), and a preparation method thereof, wherein a target product is prepared through IBX oxidation, Aldol condensation, substitution, cyclization, haloform reaction, hydrolysis, condensation and other reactions. The invention also provides an application of the tricyclic diterpene-2-methylpyrimidine analogue in resisting late onset hypogonadism (LOH). The invention also relates to a new mechanism, namely an autophagy mechanism, of the tricyclic diterpene-2-methylpyrimidine analogue in LOH treatment so as to provide a beneficial reference for research in resisting late onset hypogonadism, wherein the good application prospect is achieved.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a tricyclic diterpene 2-methylpyrimidine analogue and its preparation method and application. Background technique [0002] Late-onset hypogonadism (LOH) is an age-related clinical syndrome in which testosterone levels decline in patients, causing a series of conditions that lead to reduced quality of life, such as decreased libido, fatigue, depressed mood, and erectile dysfunction And so on, it will cause multiple organ dysfunction at the same time. The incidence of LOH in men gradually increased with age. With the intensification of global aging, various aging-related diseases have attracted increasing attention, and LOH has also become a research hotspot in recent years. A recent epidemiological survey conducted in a community in my country found that about 9.1% of middle-aged and elderly men had low serum testosterone levels ...

Claims

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Application Information

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IPC IPC(8): C07D239/70C07D417/12C07D413/12C07D401/12A61P15/08A61P15/10
CPCA61P15/08A61P15/10C07D239/70C07D401/12C07D413/12C07D417/12
Inventor 仇文卫易正芳汤杰刘明耀白捷王李婷谢佳邢雅婧
Owner EAST CHINA NORMAL UNIVERSITY
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