WO2020228463A1

WO2020228463A1 - Preparation method for and use of anti-leukemia selenium-substituted noscapine derivatives

Info

Publication number: WO2020228463A1
Application number: PCT/CN2020/084517
Authority: WO
Inventors: 王卫; 张永强; 阴倩倩; 刘传绪; 潘鹏
Original assignee: 华东理工大学; 上海科技大学
Priority date: 2019-05-10
Filing date: 2020-04-13
Publication date: 2020-11-19
Also published as: CN111909162B; CN111909162A

Abstract

The present invention relates to the field of medicine, and in particular, to a preparation method for anti-leukemia selenium-substituted noscapine derivatives and use thereof. The structure general formula of the selenium-substituted noscapine derivatives is as shown in general formula i or formula ii. The present invention synthesizes a series of 9-selenium noscapine derivatives by means of a semisynthesis method. The synthesis route is short, the experiment operation is simple, and the yield effect is good. The selenium-substituted noscapine derivatives obtained by the preparation method show excellent inhibitory activity for various leukemia cells, and can be used for preparing high-efficiency and low-toxicity leukemia therapeutic medicaments, (i), (ii). The R₁ or R₂ group is alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, ester alkyl, allyl, propargyl or cyano.

Description

Preparation method and application of anti-leukemia selenonate derivative

Technical field

The invention relates to the field of medicine, in particular to a preparation method and application of an anti-leukemia selenomatine derivative.

Background technique

Leukemia, also known as blood cancer, is a malignant proliferative disease of hematopoietic stem cells. The patient’s bone marrow hematopoietic system produces a large number of immature, non-working white blood cells, resulting in a reduction of normal platelets, red blood cells, and white blood cells. These undeveloped white blood cells are called leukemia cells. According to the degree of differentiation of leukemia cells and the length of the natural course, it can be divided into acute and chronic leukemia. According to the series of diseased cells, it is mainly divided into myeloid and lymphoid lines. There are four main types of common clinical disease, including acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). The survey shows that in our country, men rank sixth in mortality caused by leukemia and women rank eighth. This shows that leukemia is a serious threat to human health.

Chemotherapy drugs, as an effective way to treat leukemia, are widely used clinically. For example, vincristine for the treatment of various acute and chronic leukemias, cytarabine and methotrexate for the treatment of acute leukemias. However, the toxic and side effects of these drugs have seriously affected the quality of life of leukemia patients. In recent years, targeted drugs with low side effects have shown unique advantages in the treatment of leukemia. However, increasing drug resistance has become the bottleneck of its clinical application. Therefore, there is an urgent need to develop anti-leukemia drugs with high efficacy, low toxicity and high therapeutic index.

Summary of the invention

The invention discloses a selenonarcotin derivative that can be used as a leukemia therapeutic drug, and a preparation method and application thereof.

The design ideas are as follows:

Noscapine is a phthalide tetrahydroisoquinoline alkaloid isolated from opium poppy. It has a simple structure, rich natural content, and low price. It was first used clinically as an over-the-counter cough medicine and is safe and reliable. Can be administered orally. It was discovered in 1998 to show certain inhibitory activity against various solid tumors, such as lung cancer and colon cancer. At the same time, it can penetrate the blood-brain barrier for the treatment of brain glioma. Preliminary studies have shown that its mechanism of action is a tubulin inhibitor that combines with tubulin to interfere with the dynamic balance of microtubules, causing cells to stagnate in the G2/M phase of mitosis and apoptosis, resulting in anti-tumor effects. However, the application of such compounds in the treatment of leukemia is rarely reported.

As a trace element necessary for human body, selenium has very important physiological functions. Appropriate intake of trace selenium can effectively improve the body's antioxidant capacity and anti-cancer capacity, and enhance immune function. In recent years, many studies have shown that the introduction of selenium into anti-tumor compounds can play a synergistic effect and effectively improve the anti-tumor activity of lead compounds.

In view of this, this study synthesized a series of narcotine derivatives with 9 selenoses through a semi-synthetic method. These derivatives show excellent inhibitory activity on various leukemia cells and are expected to develop high-efficiency and low-toxic leukemia therapeutic drugs.

Specifically, the technical scheme of the present invention is as follows:

The first aspect of the present invention discloses a selenonarcotine derivative, the general structural formula of the selenonarcotine derivative is shown in general formula i or general formula ii:

The R ₁ or R ₂ group is alkyl, cycloalkyl, aryl, heteroaryl, oxyalkyl, ester alkyl, allyl, propargyl or cyano.

Preferably, the aryl group is phenyl, substituted phenyl, biphenyl, naphthyl or substituted naphthyl; and the heteroaryl group is pyridyl, substituted pyridyl, thienyl, substituted thiophene, furanyl, or substituted furan. Group, pyrrolyl, substituted pyrrolyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, benzothiazolyl, substituted benzothiazolyl, indolyl, substituted indolyl, benzene Aminoimidazolyl, substituted imidazolyl, benzoxazolyl, substituted benzoxazolyl, imidazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl or substituted thiazolyl;

The alkyl group is a C1-C6 alkyl group or a deuterated alkyl group;

The cycloalkyl group is a C1-C8 cycloalkyl group or a deuterated cycloalkyl group;

More preferably, the aryl group is a substituted phenyl group.

More preferably, the selenonarcotin derivative is the following compound:

The second aspect of the present invention discloses a method for preparing the above-mentioned selenonarcotin derivative. The general structural formula of the selenonarcotin derivative is shown in the general formula i, and includes the following steps:

Using the compound represented by the formula I as the substrate, the hydroxymethylation reaction, the chlorination reaction, the nucleophilic substitution reaction involving potassium selenocyanide, the in-situ reduction of selenol and the nucleophilic substitution reaction are carried out in sequence to obtain the structure The selenonarcotin derivative represented by the general formula i;

Using the compound represented by the formula I as the substrate, the bromination reaction, the amination reaction, the diazotization reaction, the nucleophilic substitution reaction involving potassium selenocyanide, the in-situ reduction of selenol and the nucleophilic substitution reaction are carried out in sequence, The selenonarcotin derivative with the general structural formula shown in general formula ii is obtained, or

Using the compound of formula I as the substrate, directly carry out free radical addition reaction with diselenide to obtain the selenonarcotine derivative with the general structural formula shown in general formula ii;

In a preferred embodiment of the present invention, a method for preparing selenonate derivatives is disclosed, which includes the following steps:

Specifically, the steps are as follows:

1) Compound I undergoes a methylolation reaction under the action of concentrated hydrochloric acid to obtain compound II with a yield of 98%. 2) Compound II is reacted with thionyl chloride at room temperature to obtain chlorinated product III with a yield of 100%.

3) Compound III and potassium selenocyanide undergo a nucleophilic substitution reaction to obtain compound IV (that is, compound S1) with a yield of 99%.

4) Compound IV (that is, compound S1) is reduced by sodium borohydride and continues to undergo nucleophilic substitution reaction with halogenated alkanes to obtain compound V (that is, compound S3-S22), with a yield of 40-72%.

5) Compound III can obtain 9-bronacomidine VI under the action of 48% hydrobromic acid and bromine water with a yield of 95%.

6) Compound VI undergoes amination reaction to obtain target product VII with a yield of 80%.

7) Compound VII undergoes diazotization reaction and nucleophilic substitution reaction participated by potassium selenocyanide to obtain the target product VIII with a yield of 50%.

8) After compound VIII is reduced by sodium borohydride, it continues to undergo nucleophilic substitution reaction with methyl iodide to obtain compound S24 with a yield of 68%.

9) After compound VIII is reduced by sodium borohydride, it continues to undergo nucleophilic substitution reaction with trifluoromethyltrimethylsilane to obtain compound S25 with a yield of 71%.

10) Compound I undergoes free radical addition reaction with diphenyl diselenide under the action of potassium persulfate to obtain compound S26 with a yield of 95%.

The third aspect of the present invention discloses the application of the above-mentioned selenonarcotin derivatives in the field of leukemia.

The fourth aspect of the present invention discloses a medicine for treating leukemia, which is characterized in that the active ingredient of the medicine is the selenonarcotin derivative according to claim 1.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily without exceeding the concept and protection scope of the present invention.

Compared with the prior art, the present invention has the following significant advantages and effects:

The present invention synthesizes a series of 9-seleno-selenium narcotine derivatives through a semi-synthetic method. The synthetic route is short, the experimental operation is simple, and the yield effect is good; the seleno- narcotine derivatives obtained by the preparation method The compound shows excellent inhibitory activity on various leukemia cells, and can be used to prepare high-efficiency and low-toxic leukemia therapeutic drugs.

Detailed ways

The technical solutions of the present invention will be described in detail below with reference to the drawings and embodiments, but the present invention is not limited to the scope of the embodiments.

In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification. The reagents and raw materials used in the present invention are all commercially available.

The selenonarcotin derivatives in the present invention are the following compounds:

In some preferred embodiments of the present invention, a method for preparing selenonarcotin derivatives is disclosed, and the design route includes the following steps:

The detailed description is as follows:

Example 1

1) Synthesis of compound II:

Weigh 1.8 g of Narcotine hydrochloride and dissolve it in 50 mL of concentrated hydrochloric acid, add 4 g of paraformaldehyde in batches at room temperature, and stir at 50°C for 2 hours. After the reaction, cool, add dropwise ammonia to adjust the pH to 10, extract with dichloromethane (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 1.9g of colorless oily liquid with a yield of 98% . ¹ H NMR (400MHz, CDCl ₃ ) δ 6.91 (d, J = 8.3 Hz, 1H), 6.14 (d, J = 8.2 Hz, 1H), 5.88 (s, 2H), 5.45 (d, J = 4.3 Hz ,1H),5.23(s,1H),4.56(s,2H),4.31(d,J=4.3Hz,1H),4.01(s,3H),3.92(s,3H),3.79(s,3H) , 2.70-2.54 (m, 2H), 2.46 (s, 3H), 2.39-2.27 (m, 1H), 1.90-1.86 (m, 1H).

2) Synthesis of compound Ⅲ:

Dissolve 1.62g of compound II in 20mL of dichloromethane, slowly add 0.5mL of thionyl chloride at 0°C. After the addition is complete, slowly warm to room temperature and stir for 2 hours. Add ammonia to adjust the pH to 10. Methane was extracted three times, the organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.7 g of the target product with a yield of 100%.

3) Synthesis of compound S1:

Weigh 1.38g compound III into 50mL acetonitrile, then add 0.86g KSeCN, stop the reaction after 5 minutes at 80°C, quickly cool to room temperature, dilute with water, extract three times with ethyl acetate, and wash the organic phase with saturated brine. It was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.6 g of the target product with a yield of 99%. ¹ H NMR(400MHz, CDCl ₃ )δ7.01(d,J=8.3Hz,1H), 6.20(d,J=8.2Hz,1H), 6.05-5.93(m,2H), 5.53(d,J= 4.2Hz, 1H), 4.41 (t, J = 8.6Hz, 2H), 4.18 (d, J = 11.4Hz, 1H), 4.09 (s, 3H), 4.04 (s, 3H), 3.86 (s, 3H) , 2.82-2.64 (m, 1H), 2.53 (d, J=7.0Hz, 3H), 2.52-2.37 (m, 2H), 1.90 (ddd, J=15.3, 8.0, 4.6Hz, 1H).

Example 2

Synthesis of compound S2:

Weigh 0.26g of compound IV into the reaction flask, add 5mL anhydrous tetrahydrofuran and 0.14g TMSCF _{3 at} 0°C, slowly add 0.1mL tetrabutylammonium fluoride solution in tetrahydrofuran (1mol/L), and then transfer to room temperature After the reaction was completed for 2 hours, it was diluted with water and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by silica gel column chromatography to obtain 0.20 g of target Product with a yield of 69%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.95 (d, J = 8.2 Hz, 1H), 6.04 (d, J = 8.2 Hz, 1H), 5.98 (d, J = 0.7 Hz, 2H), 5.50 (d ,J=4.2Hz,1H), 4.39(d,J=4.3Hz,1H), 4.27(d,J=11.6Hz,1H), 4.12(d,J=11.6Hz,1H),4.09(s,3H ), 4.02 (s, 3H), 3.86 (s, 3H), 2.76-2.64 (m, 1H), 2.53 (s, 3H), 2.51-2.32 (m, 2H), 1.88-1.73 (m, 1H).

Example 3

Synthesis of compound S3:

Weigh 0.11g compound IV and 0.015g sodium borohydride into the reaction flask at the same time, add 1mL of absolute ethanol under nitrogen protection, stir at room temperature for 30 minutes, add 0.035g of methyl iodide, continue the reaction at room temperature for 2 hours, after the reaction is complete, Dilute with water, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The resulting crude product is purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) , 0.071 g of the target product was obtained, and the yield was 68%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.89 (d, J = 8.3 Hz, 1H), 6.01 (d, J = 8.2 Hz, 1H), 5.88 (dd, J = 7.3, 1.3 Hz, 2H), 5.46 (d, J = 4.2 Hz, 1H), 4.34 (d, J = 4.2 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.79 (s, 3H), 3.66–3.58 (m, 3H), 2.65–2.55(m, 1H), 2.47(s, 4H), 2.33–2.25(m, 1H), 1.97(s, 3H), 1.76(ddd, J=13.5, 6.5, 3.1Hz, 1H) .

Example 4-9: The synthesis of compound S4-S9 is the same as that of S3.

Example 10

Synthesis of compound S10:

Weigh 0.11g of compound IV (that is, compound S1) and 0.015g of sodium borohydride into the reaction flask at the same time, add 5mL of absolute ethanol under nitrogen protection, stir at room temperature for 30 minutes, add 0.042g of bromomethylcyclopropane, at room temperature Continue the reaction for 2 hours. After the reaction is complete, it is diluted with water and extracted three times with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product is purified by silica gel column chromatography (ethyl acetate Ester: petroleum ether = 1:3) to obtain 0.078 g of the target product with a yield of 72%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.92 (d, J = 8.3 Hz, 1H), 6.02 (d, J = 7.2 Hz, 1H), 5.89 (dd, J = 7.6, 1.3 Hz, 2H), 5.47 (d,J=3.1Hz,1H), 4.35(d,J=4.0Hz,1H), 4.02(s,3H), 3.93(s,3H), 3.79(s,3H), 3.70(q,J= 11.7Hz, 2H), 2.61 (m, 1H), 2.53 (d, J = 7.2 Hz, 2H), 2.47 (s, 3H), 2.30 (m, 1H), 1.78 (m, 2H), 1.06-0.96 ( m,1H),0.59–0.48(m,2H),0.21–0.10(m,2H).

Example 11

Synthesis of compound S11:

Weigh 0.11 g of compound S1 and 0.015 g of sodium borohydride into the reaction flask at the same time, add 5 mL of absolute ethanol under nitrogen protection, stir at room temperature for 30 minutes, add 0.037 g of bromocyclopentane, and continue the reaction at room temperature for 2 hours. After completion, it was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 ), to obtain 0.078 g of the target product with a yield of 70%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.97 (d, J = 8.3 Hz, 1H), 6.04 (d, J = 8.1 Hz, 1H), 5.95 (dd, J = 6.7, 1.4 Hz, 2H), 5.52 (d,J=3.7Hz,1H),4.41(d,J=4.1Hz,1H),4.09(s,3H),4.01(s,3H),3.85(s,3H),3.78–3.64(m, 2H), 3.36–3.26(m,1H), 2.63(s,1H), 2.52(d,J=8.0Hz,4H), 2.35(t,J=7.7Hz,1H), 2.18–2.00(m,2H ),1.89–1.53(m,10H).LRMS(ESI)Calcd.for C ₂₈ H ₃₃ NO ₇ Se[(M+H) ⁺ ]576.1,found 576.1.

Example 12

Synthesis of compound S12:

Weigh 0.11g compound S1 and 0.015g sodium borohydride into the reaction flask at the same time, add 5mL absolute ethanol under nitrogen protection, stir at room temperature for 30min, add 0.044g bromocycloheptane, continue the reaction at room temperature for 2 hours, the reaction is complete Then, it was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) , Obtain 0.078 g of the target product with a yield of 42%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.97 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 5.96 (dd, J = 7.2, 1.4 Hz, 2H), 5.52 (d, J = 4.1 Hz, 1H), 4.40 (d, J = 4.2 Hz, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.85 (s, 3H), 3.70 (dd, J = 22.5, 11.6Hz, 2H), 3.19-3.09(m,1H), 2.68-2.59(m,1H), 2.53(s,4H), 2.40-2.29(m,1H), 2.19-2.07(m,2H) ,1.87–1.75(m,1H), 1.70(tdd,J=11.7,5.3,2.8Hz,4H), 1.55(dd,J=8.3,4.1Hz,3H), 1.53–1.39(m,3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 168.3, 152.1, 147.6, 146.5, 141.1, 139.2, 133.4, 130.8, 120.0, 118.5, 117.9, 117.8, 112.3, 100.8, 81.9, 63.3, 62.3, 60.9, 59.5, 56.8, 49.6, 46.3, 44.5, 41.7, 36.1, 36.1, 28.1,28.0, 26.9, 23.7, 16.7. LRMS (ESI) Calcd. for C ₃₀ H ₃₉ NO ₇ Se[(M+H) ⁺ ]604.2, found 604.2.

Example 13

Synthesis of compound S13:

Weigh 0.11g compound IV and 0.015g sodium borohydride into the reaction flask at the same time, add 5mL absolute ethanol under nitrogen protection, stir at room temperature for 30 minutes, add 0.043g benzyl bromide, continue the reaction at room temperature for 2 hours, after the reaction is complete , Diluted with water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3), Obtained 0.089 g of the target product with a yield of 75%. ¹ H NMR(400MHz,d ⁶ -DMSO)δ7.34–7.26(m,4H), 7.23–7.18(m,1H), 6.89(d,J=8.3Hz,1H), 6.03(d,J=8.2 Hz, 1H), 5.95 (dd, J = 10.6, 1.4 Hz, 2H), 5.51 (d, J = 4.1 Hz, 1H), 4.39 (d, J = 4.2 Hz, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.88 (dd, J = 23.2 Hz, 11.7 Hz, 2H), 3.79 (s, 3H), 3.70 (dd, J = 29.3, 11.7 Hz, 2H), 2.65–2.54 (m, 1H) ),2.52(s,3H),2.47–2.23(m,2H),1.71(ddd,J=15.5,8.7,4.5Hz,1H).LRMS(ESI)Calcd.for C ₃₀ H ₃₂ NO ₇ Se[( M+H) ⁺ ]598.1,found 598.1.

Example 14-22: The synthesis method of compound S14-S22 is the same as the synthesis method of S13.

Example 23

Synthesis of compound S23:

Weigh 0.28g compound IV into 10mL acetonitrile, then add 0.12g KSCN, react overnight at 80°C, cool to room temperature, dilute with water, extract three times with ethyl acetate (10mL×3), and wash the organic phase with saturated brine , Dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried, separated by column chromatography to obtain 0.21 g of the target product, with an isolated yield of 71%. ¹ H NMR(400MHz, CDCl ₃ )δ7.01(d,J=8.3Hz,1H), 6.20(d,J=8.2Hz,1H), 6.05-5.93(m,2H), 5.53(d,J= 4.2Hz, 1H), 4.41 (t, J = 8.6Hz, 2H), 4.18 (d, J = 11.4Hz, 1H), 4.09 (s, 3H), 4.04 (s, 3H), 3.86 (s, 3H) , 2.82–2.64(m,1H), 2.53(d,J=7.0Hz,3H), 2.52–2.37(m,2H), 1.93–1.87(m,1H).

Example 24

1) Synthesis of compound Ⅵ

Weigh 4.0 g of narcotin hydrochloride and dissolve it in 15 mL of HBr (48%) aqueous solution, stir vigorously, and slowly drop 50 mL of freshly prepared bromine water into the reaction system at room temperature until a yellow solid precipitates. After the addition is complete, react for 1 hour. After the reaction, adjust the pH to 10 with 25% ammonia water, extract with dichloromethane (50mL×3), wash with saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain 4.3g of white Solid, 90% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.02(d,J=8.3Hz,1H), 6.30(d,J=8.2Hz,1H), 6.02(s,2H), 5.50(d,J=4.5Hz ,1H), 4.34 (d, J = 4.6Hz, 1H), 4.10 (s, 3H), 3.98 (s, 3H), 3.88 (s, 3H), 2.67 (m, 2H), 2.54-2.41 (m, 4H), 1.96 (m, 1H).

2) Synthesis of compound Ⅶ

To a solution of 3 g of compound II in 20 mL of anhydrous DMSO was added 0.99 g of NaN ₃ , and then 0.87 g of Cu ₂ O and L-proline. After the addition, the reaction flask was placed at 100°C for 24 hours, and the reaction progress was monitored by TLC. After the reaction, the saturated ammonium chloride aqueous solution was quenched, and then extracted three times with dichloromethane, washed with water, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 2.1 g of yellow solid. The yield is 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.97 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 8.2 Hz, 1H), 5.94 (dd, J = 3.5, 1.4 Hz, 2H), 5.61 (d,J=4.0Hz,1H), 4.38(d,J=4.0Hz,1H), 4.08(s,3H), 3.88(s,3H), 3.85(s,3H), 3.30(s,2H) , 2.60–2.54(m,2H), 2.51(s,3H), 2.48–2.26(m,2H).

3) Synthesis of compound Ⅷ

Weigh 1.7g compound III into 50mL H ₂ O, slowly add 0.5mL concentrated hydrochloric acid dropwise to the reaction flask at 0°C, then add 0.28g sodium nitrite, and after stirring for 30min, adjust the pH to 6 with sodium acetate aqueous solution. Then 0.58g KSeCN was added, and the reaction was stirred at room temperature for 3h. After the reaction was almost complete, 50mL ethyl acetate was added, washed with saturated sodium carbonate aqueous solution and water successively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography. 1.0g white solid, yield 50%.

4) Synthesis of compound S24

Weigh 0.52g of compound Ⅷ and 76mg of sodium borohydride into the reaction flask at the same time, add 5mL of absolute ethanol under nitrogen protection, stir at room temperature for 30min, add 0.035g of methyl iodide, continue the reaction at room temperature for 2 hours, after the reaction is complete, add water to dilute , Extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by silica gel column chromatography to obtain 0.36 g of the target product with a yield of 68%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.93 (d, J = 8.2 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 6.01 (dd, J = 5.3, 1.2 Hz, 2H), 5.50 (d,J=4.2Hz,1H), 4.39(d,J=4.2Hz,1H), 4.10(s,3H),4.03(s,3H),3.86(s,3H),2.91-2.81(m, 1H), 2.78-2.65 (m, 1H), 2.55 (s, 3H), 2.36 (m, J=8.3 Hz, 1H), 2.22-2.13 (m, 3H), 1.88 (s, 1H).

Example 25

Synthesis of compound S25:

Weigh 0.26g compound Ⅷ into the reaction flask, add 5mL anhydrous THF and 0.14g TMSCF _{3 at} 0℃, slowly add 0.1mL tetrabutylammonium fluoride tetrahydrofuran solution (1mol/L), then transfer to room temperature for reaction After the reaction was completed for 2 hours, it was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by silica gel column chromatography to obtain 0.20 g of the target product. , The yield is 71%. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.91 (d, J = 8.2 Hz, 1H), 6.15-5.97 (m, 3H), 5.49 (d, J = 4.2 Hz, 1H), 4.41 (d, J = 4.2Hz, 1H), 4.11 (s, 3H), 4.09 (s, 3H), 3.85 (s, 3H), 2.94-2.77 (m, 1H), 2.75-2.64 (m, 1H), 2.54 (s, 3H) ), 2.40–2.26(m,1H),1.99–1.86(m,1H).

Example 26

Synthesis of compound S26:

Weigh 0.41g compound I into the reaction flask, add 0.088mL trifluoroacetic acid (TFA), 0.04g diphenyl diselenide and 0.11g K ₂ S ₂ O ₈ , and react at room temperature for 16 hours. After the reaction is complete, add water and stir. After 30 minutes, it was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.54 g of the target product with a yield of 95%. ¹ H NMR(400MHz, CDCl ₃ )δ7.32–7.17(m,7H), 6.68(d,J=8.3Hz,1H), 6.09(d,J=8.3Hz,1H),6.00(dd,J= 14.8, 1.2 Hz, 2H), 5.49 (d, J = 4.2 Hz, 1H), 4.40 (d, J = 4.2 Hz, 1H), 4.08 (d, J = 1.5 Hz, 6H), 3.80 (s, 3H) , 2.95–2.77(m,1H), 2.71–2.60(m,1H), 2.51(s,3H), 2.39–2.20(m,1H), 1.85(m,1H).

Example 27

In this example, it was found that the synthetic selenonarcotin derivatives have anti-leukemia activity, which was verified by pharmacological experiments. Specifically, the corresponding cell proliferation inhibitory activity analysis was carried out using the CCK-8 method. The experimental steps are as follows:

1. Sample preparation: use DMSO (purchased from Merck) to dissolve the S1-S26 synthesized in the above example and narcotin (Tichai (Shanghai) Chemical Industry Development Co., Ltd.) (as a negative control), and add PBS to make 1000mg /mL solution or uniform suspension, and then diluted with PBS containing DMSO;

2. Human leukemia cell line

JURKAT, U937, KAUSMI-1 (ATCC and Chinese Academy of Sciences Cell Bank);

3. Culture medium

RPMI 1640+10% FBS+ double antibody;

4. Other materials

Full-wavelength multifunctional microplate reader: Varioskan Flash model, Thermoscientific manufacturer, imported 96-well plate, etc.;

5. Experimental method: This experiment uses the CCK-8 method. Add 100 mL of a cell suspension of a human leukemia cell line with a concentration of 7-8×10 ³ cells/mL to each well of a 96-well plate, and place it in a 37°C, 5% CO ₂ incubator. After 24 hours of incubation, 100 mL of sample solution was added to each well, and three multiple wells were set up. 37°C, 5% CO ₂ acted for 48 hours. Then add 20 mL of CCK-8 solution to each well and place in the incubator for 2-4 hours. Then use a full-wavelength multifunctional microplate reader to measure the OD value at 450nm.

The results of in vitro leukemia cell inhibitory activity are shown in Table 1.

Table 1 Inhibition results of different compounds on the activity of leukemia cells in vitro

The results show that, compared with the negative control (narcotin), most of the selenonarcotin derivatives prepared in Examples 1-26 have a better inhibitory effect on leukemia cell lines, and compound S12 has the best effect .

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, etc. made without departing from the spirit and principle of the present invention Simplified, all should be equivalent replacement methods, and they are all included in the protection scope of the present invention.

Claims

A selenonarcotine derivative, characterized in that the general structural formula of the selenonarcotine derivative is shown in general formula i or general formula ii:

The R 1 or R 2 group is alkyl, cycloalkyl, aryl, heteroaryl, oxyalkyl, ester alkyl, allyl, propargyl or cyano.
The selenonarcotin derivative of claim 1, wherein the aryl group is a phenyl group, a substituted phenyl group, a biphenyl group, a naphthyl group, or a substituted naphthyl group; and the heteroaryl group is a pyridyl group , Substituted pyridyl, thienyl, substituted thiophene, furyl, substituted furyl, pyrrolyl, substituted pyrrolyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, benzothiazolyl, Substituted benzothiazolyl, indolyl, substituted indolyl, benzimidazolyl, substituted imidazolyl, benzoxazolyl, substituted benzoxazolyl, imidazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl Azolyl, thiazolyl or substituted thiazolyl;

The alkyl group is a C1-C6 alkyl group or a deuterated alkyl group;

The cycloalkyl group is a C1-C8 cycloalkyl group or a deuterated cycloalkyl group;
The selenonarcotin derivative of claim 2, wherein the aryl group is a substituted phenyl group.
The selenonarcotin derivative of claim 1, wherein the structure of the selenonarcotin derivative is shown in the following formula S1,
The selenonarcotin derivative of claim 1, wherein the structure of the selenonarcotine derivative is shown in the following formula VIII,
A method for preparing the selenonarcotin derivative of any one of claims 1 to 3, characterized in that it comprises the following steps:

With the compound of formula I as the substrate, the hydroxymethylation reaction, the chlorination reaction, the nucleophilic substitution reaction involving potassium selenocyanide, the in-situ reduction of selenol and the nucleophilic substitution reaction are carried out in sequence to obtain the structure The general formula is the selenonarcotine derivative represented by the general formula i;

Using the compound represented by the formula I as the substrate, the bromination reaction, the amination reaction, the diazotization reaction, the nucleophilic substitution reaction involving potassium selenocyanide, the in-situ reduction of selenol and the nucleophilic substitution reaction are carried out in sequence, The selenonarcotin derivative with the general structure formula shown in general formula ii is obtained, or

Using the compound of formula I as the substrate, directly carry out free radical addition reaction with diselenide to obtain the selenonarcotine derivative with the general structural formula shown in general formula ii;
A method for preparing the selenonarcotin derivative of claim 4, characterized in that it comprises the following steps:
A method for preparing the selenonarcotin derivative of claim 5, characterized in that it comprises the following steps:
The application of the selenonarcotin derivative according to any one of claims 1 to 3 in the field of leukemia.
A medicine for treating leukemia, characterized in that the active ingredient of the medicine is the selenonarcotin derivative according to claim 1.