CN113387864A - S-indole benzamide derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses an S-indole benzamide derivative and a preparation method and application thereof, relating 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 and a preparation method and application thereof.

Background

Indole is a perfume and an important raw material of medicines, and derivatives of the indole have various biological activities, including pharmacological actions of resisting tumors, bacteria, inflammation and viruses. In recent years, the synthesis of indole derivatives and the research on their biological activity have been the focus of research, especially on antiviral derivatives, but there are few drugs available on the market other than arbidol. The reported indole derivatives have insufficient antiviral activity, complex synthesis process and low yield, so that the indole derivatives are limited from being further developed into medicaments. 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 urgently at present.

Disclosure of Invention

Aiming at the technical problems, the invention provides an S-indole benzamide derivative, a preparation method and an application thereof.

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

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

the second technical scheme is as follows: a preparation method of S-indole benzamide derivatives is characterized in that indole is used as an initial raw material, and a target product is obtained through acylation reaction, reduction reaction, oxidation reaction, asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfenamide, hydrolysis reaction and acylation reaction.

The reaction route is as follows:

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

b: adding lithium aluminum hydride (THF) under the protection of nitrogen, and heating at 0 deg.C for 1h at 70 deg.C to react;

c: adding dimethyl sulfoxide (DMSO) and 2-iodoxybenzoic acid (IBX), and reacting for 90min under nitrogen atmosphere;

d: adding THF, indium powder, R) - (+) -tert-butyl sulfinamide and ethyl titanate, and reacting for 3h at 23 ℃ in a nitrogen atmosphere; then adding 3-bromopropylene, and reacting for 20 hours at the temperature of 60 ℃;

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

f: 4-Phenylbenzoyl chloride, triethylamine and dichloromethane were added and the reaction was carried out overnight.

Further, the acylation reaction steps are as follows: adding diethyl ether and oxalyl chloride into indole to generate yellow suspended substance, adding methanol to obtain mixture, filtering, and washing to obtain 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-butyl sulfinamide are as follows: under the protection of nitrogen, adding a reducing agent, ethyl titanate, acrylic acid, indium powder and (R) - (+) -tert-butyl sulfenamide into a product obtained by oxidation reaction for asymmetric synthesis reaction, after the reaction is finished, adding saturated saline solution into the obtained product, and performing suction filtration, washing, drying, concentrating and purifying to obtain colorless oily liquid.

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

Further, the acylation reaction step is as follows: 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 third technical scheme is as follows: an application of S-indole benzamide derivative in anti-influenza virus medicines.

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

the invention takes indole as an initial raw material, and obtains a target product through acylation reaction, reduction reaction, oxidation reaction, asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfinamide, hydrolysis reaction and acylation reaction. The method can obtain a new antiviral drug with development prospect, and has the advantages of high yield, relatively simple synthesis process and good antiviral activity.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description 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. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless defined otherwise, 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 herein 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 present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.

Example 1

Preparation of compound 1:

a reaction flask was charged with 7g (60mmol) of indole and 300mL of dry ether, and 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, 12mL of methanol was added dropwise thereto at 0 ℃ and stirred for 30min, and the resulting mixture was filtered and washed with ethyl glacial ether to obtain 10.93g of 1 as a yellow solid in a yield of 90%.

Preparation of compound 2:

in a three-necked flask, 47mL of lithium aluminum hydride (4.44g, 117mmol,2.5mol/L in THF) was injected under nitrogen, placed at 0 ℃ and 10.15g (50mmol) of yellow solid 1 was dissolved in 36mL of THF and added dropwise to the solution over a period of 1h, then heated to 70 ℃ to keep the reaction for 4h, the reaction was completed, the reaction was quenched by Fieser treatment, the resulting 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 with a yield of 80%.

Preparation of compound 3:

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

Preparation of compound 4:

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

Preparation of compound 5:

1.78g (5.8mmol) of colorless oily liquid 4, 16.1mL of methanol and 16.1mL of dioxane were charged into a reaction flask, and 6.01mL of anhydrous HCl (4mol/L dioxane solution) was added thereto to conduct reaction for 1 hour, which was completed. Concentrating, adding 20mL of water, and adding NaCO₃The 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 a reaction flask were added 0.20g (1.0mmol) of yellow solid 5, 7mL of dichloromethane, 0.48mL of triethylamine, 0.21g (1.2mmol) of 4-phenylbenzoyl chloride, reacted at room temperature overnight, added water, separated to give an organic layer, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and finally chromatographed over silica gel column [ eluent: purification of a ═ V (petroleum ether): V (ethyl acetate) ═ 4: 1] afforded 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 as a white solid in 71% yield and melting point (mp)196.1-196.5 ℃.

¹H NMR(600MHz,CDCl₃)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).

¹³C NMR(151MHz,CDCl₃)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 Performance test

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

(1) taking 60 BALB/c mice, each half of male and female, each weighing about 18-20g, each group containing 10 mice, randomly dividing into 6 groups, namely blank control group and 5 administration groups (the dosage of the administration group is 8000, 4000, 2000, 1000 and 500mg/kg body weight respectively). After 6 hours of fasting (free drinking water) before and after administration, the administration amount of each mouse is calculated according to the amount of each mouse, the total volume of each mouse is 0.4mL, and the mice are subjected to one-time intragastric administration by a metal intragastric lavage device. The control mice remained free to eat and drink water.

(2) As a result: by observation, no abnormal reaction is found in mice with the weight of 500mg/kg, and the skin, the stool, the breath, the activities of the four limbs, the behavior mode and the like are normal; in the 1000mg/kg body weight group, 1 mouse died in 48 hours, and the rest were normal; in the 2000mg/kg body weight group, 2 mice died in 48h, 3 mice died in 72h, and the rest were normal; 4 mice die in 48 hours and 3 mice die in 72 hours after 4000mg/kg body recombination, and the rest is normal; 6 of the 8000mg/kg body weight groups died within 24h, 3 mice died at 48h and 1 at 72h, with the results shown in Table 1.

TABLE 1 acute toxicity test results

Calculating according to test data to obtain LD of the medicine for mouse₅₀It was 2217.82mg/kg body weight, indicating that S-indole benzamide derivative 6i had little toxic or side effect.

Example 3

Test of drug efficacy

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

(1) half lethal dose LD of H1N1 influenza virus GX6 strain mouse₅₀Measurement of (2)

The experiment was divided into 7 groups of 8 female BALB/c mice each, at 6-8 weeks, 18-20g body weight, and the stable titer of 26 cytotoxic drug was diluted 10-fold to 10-fold in order from the original toxin^-5BALB/c mice were vaccinated. A control group was also set.

Before inoculation, dry ice is used for treatment, after mice are syncope, the mice are divided into groups according to different viruses by adopting a nose dropping method, and each mouse is given 50 mu L of virus. Body weight changes and death were recorded daily after receiving the virus, 14 days after recording and observation, according to Reed&LD calculated by Muench method₅₀。

Results half of mice lethal dose LD of H1N1 influenza virus GX6 strain₅₀Is 10^-3.58。

(2) Test of drug efficacy

Test grouping: 70 mice of BALB/c mouse species are selected, half of each mouse is male and female, each mouse weighs about 18-20g, and the mice are randomly divided into 10 groups. Group 1 was blank control; group 2 was a virus control group; the group 3 is a tamiflu administration group, and the concentration of the administered tamiflu is 75 mg/kg; groups 4, 5, 6, and 7 are administration groups, and the administration doses are 25, 50, 75, and 100mg/kg, respectively.

② mouse infection experiment: day 1 and 2, normal rearing, day 3 inoculation. Anaesthetizing with dry ice, after syncope of the mouse, adopting a nose dropping method, and assembling 50 mu L of physiological saline in a 1 st group; groups 2 to 7 were inoculated with H1N1 influenza virus GX6 strain at a concentration of 10LD per inoculation₅₀Mice were inoculated with 50. mu.L each.

③ administration: group 1 and 2 were not administered; on the 2 nd day after infection, the 3 rd group is orally fed with duffy, the administration concentration is 75mg/kg, 1 time per day, and the feeding is continuously carried out for 7 days; groups 4, 5, 6 and 7 were fed with synthetic compound 6i, each dosed orally 1 time a day for 7 days.

Recording: observing whether symptoms (including messy quilt, mental depression, crouching of the back and the back, etc.) appear, weighing, recording death, weight, body temperature, diet and mental status every day, and continuously observing for 14 days. And on the 4 th day after treatment, 3 mice per group were randomly selected for killing, and lung tissues were taken for virus detection.

Tissue virus detection: weighing the obtained lung tissue, adding normal saline according to the proportion of 20% emulsion, grinding completely by a grinder, centrifuging for 3min at the speed of 2000r/min, taking supernatant, and culturing virus by using cells.

(3) Results

Culturing the lung tissue viruses: influenza virus was isolated from lung tissue of mice in the virus control group, the 25mg/kg and the 50mg/kg administration groups, whereas lung tissue virus isolation was negative in all of the tamiflu administration group, the 75mg/kg and the 100mg/kg administration groups (see Table 2).

TABLE 2 mouse Lung tissue influenza Virus isolation results

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

② death of mice: all mice died by day 9 of the virus control group; 1 mouse died on day 7 and 10 in the 25mg/kg dose group; 1 mouse died on day 11 in the 50mg/kg dose group; mice survived in the control blank group, the 75mg/kg administration group, the 100mg/kg administration group, and the duffy administration group.

③ weight change: the average body weight of mice surviving in each test group was significantly different from that of the blank control group, but the body weight change of mice in the S-indole benzamide derivative 6i100mg/kg administration group and the duffy administration group of the present invention was not significantly different (see table 3).

TABLE 3 mouse weight Change

The results show that the derivative prepared by the invention has obvious therapeutic action on treating influenza virus, and the therapeutic effect is not different from that of a Tamiflu contrast group.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

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

。

2. a preparation method of S-indole benzamide derivative according to claim 1, characterized in that indole is used as a starting material, and a target product is obtained through acylation reaction, reduction reaction, oxidation reaction, asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfinamide, hydrolysis reaction and acylation reaction.

3. The method of claim 2, wherein the acylation reaction step is: adding diethyl ether and oxalyl chloride into indole to generate yellow suspended substance, adding methanol to obtain mixture, filtering, and washing to obtain yellow solid.

4. The method according to claim 2, wherein the reducing agent used in the reduction reaction process is lithium aluminum hydride.

5. The method according to claim 2, wherein the oxidizing agent used in the oxidation reaction process is 2-iodoxybenzoic acid.

6. The process according to claim 2, characterized in that the asymmetric synthesis reaction step of (R) - (+) -tert-butylsulfinamide is: under the protection of nitrogen, adding a reducing agent, ethyl titanate, acrylic acid, indium powder and (R) - (+) -tert-butyl sulfenamide into a product obtained by oxidation reaction for asymmetric synthesis reaction, after the reaction is finished, adding saturated saline solution into the obtained product, and performing suction filtration, washing, drying, concentrating and purifying to obtain colorless oily liquid.

7. The method according to claim 2, wherein the hydrolysis step is: adding dioxane, methanol and anhydrous hydrogen chloride into a product subjected to the asymmetric synthesis reaction of (R) - (+) -tert-butyl sulfenamide for hydrolysis reaction, and after the reaction is finished, concentrating, extracting, drying, concentrating and purifying the obtained product to obtain a yellow solid.

8. The method according to claim 2, wherein the acylation reaction step is: 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.

9. An S-indole benzamide derivative as claimed in claim 1 for use in a medicament against influenza virus.