CN113387864B - S-indole benzamide derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses an S-indole benzamide derivative, a preparation method and application thereof, and relates to the technical field of pharmacy. The structural formula of the derivative is

Description

S-indole benzamide derivative and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmacy, in particular to an S-indole benzamide derivative, a preparation method and application thereof.

Background

Indole itself is a perfume and is also an important pharmaceutical raw material, and its derivatives have various biological activities including pharmacological actions of anti-tumor, antibacterial, anti-inflammatory and antiviral. In recent years, the synthesis of indole derivatives and the research of their biological activity have become a research hotspot, particularly antiviral derivatives, but few drugs other than arbidol can be marketed. The reported indole derivatives have insufficient antiviral activity, complex synthesis process and low yield, and limit their further development into medicines. Therefore, the synthesis of new indole derivatives with good antiviral activity is becoming more and more important, and the synthesis process of the derivatives is also a technical problem which needs to be solved in the present stage.

Disclosure of Invention

Aiming at the technical problems, the invention provides an S-indole benzamide derivative, a preparation method and application thereof, wherein the S-indole benzamide derivative has high yield and good anti-influenza virus activity.

In order to achieve the technical purpose, the invention provides the following technical scheme:

the technical scheme is as follows: an S-indole benzamide derivative having the structure:

the second technical scheme is as follows: the preparation process of S-indole benzamide derivative includes the steps of acylation reaction, reduction reaction, oxidation reaction, asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfinamide, hydrolysis reaction and acylation reaction with indole as initial material.

The reaction route is as follows:

wherein a: 1) Adding dry diethyl ether and oxalyl chloride, and reacting at 0deg.C for 6 hr; 2) Adding methanol, and reacting for 30min at 0 ℃;

b: under the protection of nitrogen, adding lithium aluminum hydride (THF), and heating at the temperature of 70 ℃ for reaction for 1h;

c: dimethyl sulfoxide (DMSO) and 2-iodoxybenzoic acid (IBX) are added and reacted for 90min under nitrogen atmosphere;

d: adding THF, indium powder, R) - (+) -tert-butylsulfinamide and ethyl titanate, and reacting for 3h at 23 ℃ under nitrogen atmosphere; adding 3-bromopropene, and reacting at 60 ℃ for 20 hours;

e: adding dioxane according to the volume ratio of raw materials to dioxane of 1:1, adding anhydrous hydrogen chloride, and reacting for 1h;

f: 4-phenylbenzoyl chloride, triethylamine and dichloromethane were added and reacted overnight.

Further, the acylation reaction steps are as follows: diethyl ether and oxalyl chloride were added to indole to give a yellow suspension, which was then added with methanol to give a mixture, which was filtered and washed to give a yellow solid.

Further, the reducing agent used in the reduction reaction process is lithium aluminum hydride.

Further, the oxidant used in the oxidation reaction process is 2-iodoxybenzoic acid.

Further, the asymmetric synthesis reaction steps of the (R) - (+) -tert-butylsulfinamide are as follows: under the protection of nitrogen, adding a reducing agent, ethyl titanate, acrylic acid, indium powder and (R) - (+) -tert-butylsulfinamide into a product obtained through oxidation reaction for asymmetric synthesis reaction, and adding saturated saline into the obtained product after the reaction is finished, carrying out suction filtration, washing, drying, concentrating and purifying to obtain colorless oily liquid.

Further, the hydrolysis reaction steps are as follows: and adding dioxane, methanol and anhydrous hydrogen chloride into a product of the asymmetric synthesis reaction of the (R) - (+) -tert-butylsulfinamide to carry out hydrolysis reaction, and concentrating, extracting, drying, concentrating and purifying the obtained product after the reaction is finished to obtain a yellow solid.

Further, the acylation reaction comprises the following steps: in an organic solvent, triethylamine is used as an acid binding agent, a product obtained through hydrolysis reaction is used as a raw material, and the raw material reacts with 4-phenylbenzoyl chloride to obtain a target product.

The technical scheme is as follows: an application of S-indole benzamide derivative in anti-influenza virus medicine.

Compared with the prior art, the invention has the beneficial effects that:

indole is used as an initial raw material, and an objective product is obtained through an acylation reaction, a reduction reaction, an oxidation reaction, an asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfinamide, a hydrolysis reaction and an acylation reaction. The method can be used for preparing a new antiviral drug with development prospect, and has the advantages of higher yield, high yield, relatively simple synthesis process and good antiviral activity.

Detailed Description

Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples are exemplary only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.

Example 1

Preparation of Compound 1:

7g (60 mmol) of indole and 300mL of dry diethyl ether were added to a reaction flask, 16.1mL of oxalyl chloride was added dropwise to the reaction mixture at 0℃and reacted at room temperature for 6 hours to give a yellow suspension. Then, the mixture was left at 0℃to which 12mL of methanol was added dropwise, stirred for 30 minutes, and the obtained mixture was filtered and washed with glacial ethyl ether, whereby 10.93g of yellow solid 1 was obtained in a yield of 90%.

Preparation of compound 2:

in a three-necked flask, 47mL of lithium aluminum hydride (4.44 g,117mmol,2.5mol/L in THF) was injected under nitrogen protection, the flask was placed at 0℃and 10.15g (50 mmol) of yellow solid 1 was dissolved in 36mL of THF, the solution was added dropwise thereto for 1 hour, then heated to 70℃and kept for 4 hours, the reaction was completed, the reaction was quenched by Fieser treatment, the obtained suspension was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated brine, the organic layer was separated, concentrated, and finally purified by silica gel column chromatography to give 6.44g of white solid 2 in 80% yield.

Preparation of compound 3:

3.244g (20 mmol) of white solid 2, 6.144g (22 mmol) of 2-iodoxybenzoic acid (IBX) and 125mL of DMSO are taken, added into a reaction flask, and stirred at room temperature under nitrogen protection, the reaction is completed for 1.5h, 500mL of water is added to form a suspension, the suspension is filtered, the obtained filtrate is extracted with diethyl ether, the organic layers are combined, dried over anhydrous sodium sulfate and concentrated by reduction to obtain 2.339g of brown yellow oily liquid 3 with the yield of 73%.

Preparation of Compound 4:

2.9853g (26 mmol) of indium powder, 3.14g (26 mmol) of (R) - (+) -tert-butylsulfinamide were added to a reaction flask, and 2.339g of the brown yellow oily liquid 3 obtained above was dissolved in 60mL of THF under nitrogen protection, the solution was injected into the reaction flask, 9mL of ethyl titanate was further injected thereinto, stirring was carried out at room temperature for 3 hours, 6mL of 3-bromopropene was injected thereinto, heating to 60℃and reaction was carried out for 20 hours, and finally, cooling to room temperature, 20mL of saturated brine was added thereto, suction filtration was carried out, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated brine, the organic layer was separated, dried with anhydrous sodium sulfate, concentrated and finally purified by silica gel column chromatography to give 3.08g of colorless oily liquid 4 in 68% yield.

Preparation of compound 5:

1.78g (5.8 mmol) of colorless oily liquid 4, 16.1mL of methanol and 16.1mL of dioxane were taken, and the mixture was added to a reaction flask, followed by 6.01mL of anhydrous HCl (4 mol/L dioxane solution) and the reaction was completed for 1 hour. Concentrating, adding 20mL of water, and concentrating with NaCO ₃ The pH was adjusted to 9, extracted with ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and finally purified by silica gel column chromatography to give 1.05g of yellow solid 5 in 90% yield.

Preparation of Compound 6 i:

to the reaction flask was added 0.20g (1.0 mmol) of yellow solid 5,7mL of dichloromethane, 0.48mL of triethylamine, 0.21g (1.2 mmol) of 4-phenylbenzoyl chloride, reacted overnight at room temperature, water was added, the organic layer was obtained by separating the liquid, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and finally the mixture was purified by silica gel column chromatography [ eluent: purification of a=v (petroleum ether): V (ethyl acetate) =4:1 ] gave 0.274g S-tryptophan benzamide derivative 6i ((S) -N- (1- (1H-indol-3-yl) pent-4-en-2-yl) - [1,1' -biphenyl ] -4-carboxamide).

(S) -N- (1- (1H-indol-3-yl) pent-4-en-2-yl) - [1,1' -biphenyl ] -4-carboxamide is provided in the form of a white solid in 71% yield with a melting point (mp) of 196.1-196.5 ℃.

¹ H NMR(600MHz,CDCl ₃ )δ8.20(s,1H),7.75(td,J＝6.6,1.5Hz,3H),7.67–7.59(m,4H),7.48(dd,J＝8.4,6.9Hz,2H),7.43–7.38(m,2H),7.26–7.21(m,1H),7.19–7.13(m,1H),7.12(d,J＝2.3Hz,1H),6.14(d,J＝8.3Hz,1H),6.01–5.85(m,1H),5.22–5.13(m,2H),4.71–4.57(m,1H),3.27–3.06(m,2H),2.55–2.45(m,1H),2.44–2.30(m,1H).

¹³ C NMR(151MHz,CDCl ₃ )δ166.73,144.15,140.06,136.23,134.75,133.45,128.90,127.96,127.95,127.36,127.19,122.77,122.19,119.66,119.10,118.03,111.82,111.20,49.48,38.32,29.46.MS(ESI)m/z:381.1981[M+H] ⁺ .

Example 2

Safety test

The S-indole benzamide derivative 6i prepared in example 1 was used for acute toxicity test on mice, using the following procedure and effects:

(1) BALB/c mice were taken in 60 halves, each weighing about 18-20g, and 10 animals per group, and randomly divided into 6 groups, i.e., a blank group and 5 administration groups (administration groups were 8000, 4000, 2000, 1000 and 500mg/kg body weight, respectively). Fasted (free drinking water) 6 hours before and after administration, the administration amount of each test group is calculated according to the body weight of each mouse, and the total volume is 0.4mL, and the metal gastric lavage device is used for one-time gastric lavage administration. Control mice remained free to ingest and drink water.

(2) Results: the mice with the weight of 500mg/kg are observed to have no abnormal reaction, and the skin, stool, respiration, limb movement, behavior mode and the like are normal; 1 mouse in 1000mg/kg body weight group dies at 48 hours, and the rest are normal; 2 mice in 2000mg/kg weight group died at 48h, 3 at 72h, and the rest were normal; 4000mg/kg body recombination 4 mice died at 48h, 3 at 72h, the rest were normal; 8000mg/kg of body weight was reconstituted and 6 of them died within 24 hours, 3 of them died at 48 hours and 1 at 72 hours, and the results are shown in Table 1.

TABLE 1 acute toxicity test results

According to the calculation of the test data, the LD of the drug to the mice is obtained ₅₀ 2217.82mg/kg body weight, which indicates that the S-indole benzamide derivative 6i has little toxic or side effect.

Example 3

Test of efficacy

The S-indole benzamide derivative 6i prepared in example 1 was tested for inhibition of influenza virus using the following procedure and effects:

(1) Half-lethal-dose LD of mice of H1N1 influenza virus GX6 strain ₅₀ Is (are) determined by

The experiment was divided into 7 groups of 8 female BALB/c mice each, each group having a weight of 18-20g for 6-8 weeks , and the cytotoxicity of 26 stable titer was used as the original toxicity, which was diluted 10-fold to 10-fold in order from the original toxicity ^-5 And (3) inoculating the BALB/c mice. A control group was also set.

Treatment with dry ice before inoculation, and nasal drip method after syncope, each mouse is given 50 μl virus according to different virus groups. Daily record of body weight changes and death after toxin challenge, after 14 days of record observation, according to Reed&Muench method calculates LD ₅₀ 。

Results half lethal dose LD in mice of H1N1 influenza virus GX6 strain ₅₀ Is 10 ^-3.58 。

(2) Test of efficacy

(1) Test grouping: 70 BALB/c mice were selected and randomly divided into 10 groups, each having a weight of about 18-20 g. Group 1 is a blank control group; group 2 is a virus control group; group 3 is a tamiflu administration group, and the concentration of the administered tamiflu is 75mg/kg; groups 4, 5, 6, and 7 are dosing groups with doses of 25, 50, 75, and 100mg/kg, respectively.

(2) Mice infection experiments: day 1 and day 2, normal feeding, day 3, inoculation. Firstly, anaesthetizing with dry ice, and after the mice are syncoped, adopting a nasal drip method, wherein the 1 st group of the nasal drip comprises 50 mu L of physiological saline; group 2 to group 7, inoculating H1N1 influenza virus GX6 strain, each strain having a concentration of 10LD ₅₀ Mice were vaccinated with 50 μl each.

(3) Administration: groups 1 and 2 were not dosed; group 3 was orally fed with tamiflu at 75mg/kg at 1 time per day for 7 days after infection; groups 4, 5, 6 and 7 were filled with synthetic compound 6i, each orally at the prescribed dose, 1 time daily, for 7 consecutive days.

(4) Recording: the patients were observed for symptoms (including depression by Mao Lingluan, depression by mental depression, contracture by the back of the bow, etc.), weighed, and daily recorded for 14 days. And on day 4 after treatment, 3 mice were randomly sacrificed in each group and lung tissue was taken for virus detection.

(5) Tissue virus detection: the obtained lung tissue was weighed and added with physiological saline in a proportion of 20% emulsion, the whole was ground by a grinder, centrifuged at 2000r/min for 3min, and the supernatant was taken and cultured with cells.

(3) Results

(1) Results of lung tissue virus culture: the virus control group, 25mg/kg and 50mg/kg administration group were isolated from the mouse lung tissue, whereas the darifene administration group, 75mg/kg and 100mg/kg administration group were negative for the isolation of the mouse lung tissue virus (see Table 2).

TABLE 2 results of influenza Virus isolation in mouse lung tissue

The results show that S-indole benzamide derivative 6i of the administration groups of tamiflu, 75mg/kg and 100mg/kg has obvious effect of inhibiting proliferation of influenza virus in mice.

(2) Death of mice: all mice had died by day 9 in the virus control group; 1 mouse died on each of days 7 and 10 in the 25mg/kg dosing group; 1 mouse died on day 11 in the 50mg/kg dosing group; mice in the blank, 75mg/kg, 100mg/kg and Dafein groups survived.

(3) Weight change: the average body weight of the surviving mice in each test group was significantly different from that in the blank group, but the variation in body weight of the mice in the S-indolebenzamide derivative 6i100mg/kg administration group and the Dafei administration group was not significant (see Table 3).

TABLE 3 weight change in mice

The results show that the derivative prepared by the invention has obvious treatment effect on influenza virus, and the treatment effect is not different from that of a Dafei control group.

The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the particular embodiments disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Claims (3)

1. An S-indole benzamide derivative characterized by having the structure:

2. a process for preparing S-indole benzamide derivatives according to claim 1, wherein the target product is obtained by acylation, reduction, oxidation, (R) - (+) -tert-butylsulfonamide asymmetric synthesis, hydrolysis and acylation of indole;

the acylation reaction comprises the following steps: diethyl ether and oxalyl chloride are added into indole to generate yellow suspended matters, then methanol is added into the yellow suspended matters to obtain a mixture, and the mixture is filtered and washed to obtain yellow solid;

the reducing agent used in the reduction reaction process is lithium aluminum hydride;

the oxidant used in the oxidation reaction process is 2-iodoxybenzoic acid;

the asymmetric synthesis reaction steps of the (R) - (+) -tert-butylsulfinamide are as follows: under the protection of nitrogen, adding a reducing agent, ethyl titanate, acrylic acid, indium powder and (R) - (+) -tert-butyl sulfinamide into a product obtained through oxidation reaction to carry out asymmetric synthesis reaction, adding saturated saline into the obtained product after the reaction is finished, carrying out suction filtration, washing, drying, concentrating and purifying to obtain colorless oily liquid;

the hydrolysis reaction steps are as follows: adding dioxane, methanol and anhydrous hydrogen chloride into a product of an asymmetric synthesis reaction of (R) - (+) -tert-butylsulfinamide for hydrolysis reaction, concentrating the obtained product after the reaction is finished, extracting, drying, concentrating, and purifying to obtain yellow solid;

the acylation reaction comprises the following steps: in an organic solvent, triethylamine is used as an acid binding agent, a product obtained through hydrolysis reaction is used as a raw material, and the raw material reacts with 4-phenylbenzoyl chloride to obtain a target product.

3. Use of the S-indole benzamide derivative of claim 1 for the preparation of an anti-influenza virus medicament.