CN109810063A - A novel anti-influenza virus "twin drug", its preparation method and use - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry and chemical synthesis, and in particular relates to a preparation method and use of an anti-influenza virus "twin drug", wherein the compound has the structure shown in general formula (I). The antiviral twin drug in the present invention is formed by combining an influenza virus neuraminidase inhibitor and a polymerase inhibitor through different linking groups, and can be used for the prevention and treatment of influenza virus infection.

Description

A novel anti-influenza virus "twin drug", its preparation method and use

technical field

The invention belongs to the field of medicinal chemistry and chemical synthesis, and in particular relates to a novel anti-influenza virus "twin drug" and a preparation method and application thereof.

Background technique

Influenza virus is an RNA virus with high infectivity, high pathogenicity and high mutation ability, which has seriously affected human life and health for a long time. Since records began in the last century, there have been many influenza pandemics around the world, each of which has resulted in a large number of deaths and property losses. According to the World Health Organization, even in non-epidemic periods, influenza still kills 250,000 to 500,000 people worldwide each year. H5 and H7 are two highly pathogenic avian influenza viruses. Among them, the H5N1 subtype began to infect humans as early as 1997, with a fatality rate as high as 60%. In March 2013, the world's first human cases of human infection with the H7N9 avian influenza virus occurred in Shanghai and Anhui, China, and the virus infection is still occurring continuously, with a mortality rate of nearly 30%.

The antigenicity of influenza virus is easily changed, and existing vaccines cannot effectively prevent new viruses. Therefore, antiviral drugs are still the most important means of influenza treatment. The active centers of neuraminidase (NA) are highly conserved, which can catalyze the cleavage of the glycosidic bond between sialic acid and glycoproteins and promote the release of newly generated viruses. It is an important target for the design of anti-influenza virus drugs. zanamivir and oseltamivir were launched in 1999, and two other drugs, peramivir and laninamivir, are also available in some countries. NA inhibitors have high efficacy, good safety and tolerability, and are the drugs of choice for anti-influenza. What is worrying, however, is that NA inhibitor-resistant virus strains have been emerging in recent years.

Favipiravir is a new type of influenza virus RNA polymerase inhibitor developed by Japan Toyama Chemical Pharmaceutical Co., Ltd. It was launched in Japan in 2014 for the treatment of infection caused by influenza virus. Its chemical name is 6-fluoro-3-hydroxypyrazine -2-Carboxamide. That same year, during the Ebola epidemic in West Africa, favipiravir was authorized as an emergency drug for the treatment of people infected with the virus.

Influenza, especially severe influenza, can cause a variety of complications and seriously threaten the lives of patients. Therefore, there is still an urgent need for efficient anti-influenza drugs in clinical practice.

In order to enhance drug efficacy, reduce side effects or improve pharmacokinetic properties, a twin-drug strategy is often used to link two lead compounds or drugs through covalent bonds to form new molecules. The chemical structure and mechanism of action of the two molecules of the twinned drug can be the same or different, and the covalent connection methods are also various. At present, twin drugs have been well used in the fields of anti-inflammatory and anti-tumor.

SUMMARY OF THE INVENTION

Purpose of invention

In order to solve the deficiencies in the prior art, an object of the present invention is to provide the geminal compound represented by the general formula (I), its pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates.

Another object of the present invention is to provide a method for preparing the compound of the general formula (I).

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I), its pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates of one or several mixtures.

Another object of the present invention is to provide the use of the compound of the general formula (I), its pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates in the preparation of medicines for treating or preventing influenza virus infection.

Technical solutions

The present invention relates to compounds represented by general formula (I), pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates thereof:

wherein X is H or halogen; R is H or CH ₂ R', and R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl hetero group; the substituents on the aryl or aryl hetero group are selected from One or more of fluorine, chlorine, bromine, methoxy, hydroxy, and phenyl; n is 1, 2 or 3.

Preferably, X is H or F; R is H or a substituted aryl group, and the substituents on the aryl group are selected from one or more of fluorine, chlorine, bromine, methoxy, hydroxyl, and phenyl; n is 1.

More preferably, the compound of general formula (I) of the present invention is selected from the following compounds:

The present invention also provides a preparation method of the compound of general formula (I) and its intermediates. The preparation method can be carried out by the following method one or two, and the starting materials used in the present invention are commercially purchased or according to known synthesis of similar compounds Method preparation:

Method 1: using compound 1 as a raw material, react with chloromethyl chlorosulfonate in a solvent in the presence of a base to obtain compound 2; compound 2 and pyrazinone derivative 3 react in a solvent in the presence of a base to obtain compound 4; Compound 4 is deprotected in a solvent in the presence of trifluoroacetic acid to obtain a compound of formula I-1, as shown in reaction formula 1:

Reaction 1:

Method 2: The compound of formula I-1 and R'CHO undergo a condensation reduction reaction in a solvent in the presence of sodium cyanoborohydride to obtain the compound of formula I-2, as shown in reaction formula 2:

Reaction 2:

Wherein, X is H or halogen; R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl hetero group; the substituent on the aryl or aryl hetero group is selected from fluorine, chlorine, bromine, methoxy One or more of group, hydroxyl and phenyl group.

In the above steps a and b, the base is selected from inorganic bases or organic bases, and the inorganic bases are selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, potassium hydride, sodium hydride, tert-butyl In sodium alkoxide, potassium tert-butoxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate and calcium carbonate, the organic base is selected from pyridine, triethylamine, diisopropylethylamine, N,N-diisopropylethylamine in methylaniline and N,N-lutidine. Step a can be carried out in the presence of a catalyst selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride.

The reaction solvent of steps a, b and c is selected from one of water, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, acetonitrile, toluene, acetone, dioxane and chloroform or variety. The reaction solvent in step d is selected from lower alcohols such as methanol, ethanol, and isopropanol, or a mixed solvent of lower alcohol and water.

The reaction temperature in steps a to c is room temperature to 150° C., and the reaction time is not limited.

The "pharmaceutically acceptable inorganic or organic salts" in the present invention are compounds represented by the general formula (I) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid. salts, salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric acid, methanesulfonic acid, citric acid, etc., or with sodium hydroxide, Sodium, potassium, calcium or ammonia salts formed from bases such as potassium hydroxide, calcium hydroxide or ammonia. "Pharmaceutically acceptable salts" also include their solvates, exemplified by hydrates, alcoholates, and the like.

The present invention also provides the use of the compound represented by the general formula (I) and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof in the preparation of anti-influenza virus drugs according to the present invention. Preferably, the influenza virus is at least one of influenza A, B and C influenza viruses.

The present invention also provides a method for treating and/or preventing influenza virus infection, the method comprising administering the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, a crystal thereof to a human or an animal One or more mixtures of hydrates and solvates.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above general formula (I), its pharmaceutically acceptable salts, crystalline hydrates and solvates of one or more mixtures , and an optional pharmaceutically acceptable carrier. The pharmaceutical composition can be used to treat or prevent influenza virus infection.

The present invention also provides a method for preparing the pharmaceutical composition, comprising adding one or more of the compound represented by the above general formula (I), its pharmaceutically acceptable salts, crystalline hydrates and solvates The mixture is mixed with a pharmaceutically acceptable carrier.

beneficial effect

The compounds of the present invention have the following beneficial effects: novel structure and significant anti-influenza virus activity.

Detailed ways

Embodiments of the invention are illustrated by the following examples. It is to be understood, however, that embodiments of the present invention are not limited to the specific details in the following examples, for other variations will be known and apparent to those of ordinary skill in the art in view of the present disclosure.

Preparation Example 1:

Synthesis of Compound 2

The reaction starting material 1 was synthesized with reference to the literature (Med Chem Res, 2013, 22: 3485-3496). Compound 1 (540 mg, 1.4 mmol), sodium bicarbonate (590 mg, 7 mmol, 5 eq) and tetrabutylamine hydrogen sulfate (47 mg, 0.14 mmol, 0.1 eq) were sequentially added to a mixture of dichloromethane (20 mL) and water (10 mL). In the mixed solvent, stirring at room temperature, chloromethyl chlorosulfonate (1.5eq) was slowly added, and the reaction was completed after 3 hours. Dichloromethane (20 mL) was added to the reaction solution, the organic layer was separated, dried and concentrated to obtain 2,575 mg of an oily product with a yield of 95% and HPLC purity of 98%. ¹ H NMR (CDCl ₃ , 400Hz): δ 6.90 (s, 1H), 6.05 (d, 1H, J=8.8Hz), 5.77-5.83 (m, 2H), 5.20 (d, 1H, J=9.2Hz) ), 3.98-4.14 (m, 2H), 3.78-3.88 (m, 1H), 3.33-3.41 (m, 1H), 2.79 (dd, 1H, J=17.6, 5.2Hz), 2.33 (dd, 1H, J = 17.6, 10.0 Hz), 2.00 (s, 3H), 1.47-1.57 (m, 4H), 1.44 (s, 9H), 0.83-0.94 (m, 6H).

Example 1:

Synthesis of compound 4a (X=F)

Compound 2 (216 mg, 0.5 mmol) and favipiravir 3a (78.5 mg, 0.5 mmol, 1 eq) were dissolved in N,N-dimethylformamide (6 mL), and under ice bath, triethylamine (177 mg, 1.75mmol, 3.5eq), after 30 minutes, stirred at room temperature. After overnight, water (20 mL) was added to the reaction solution, extracted with ethyl acetate, washed with distilled water, and the organic layer was dried and concentrated. The white solid 3a was isolated by column chromatography, 166 mg, the yield was 60%, and the HPLC purity was 99%. H-NMR (CDCl ₃ , 400Hz): δ 8.19 (d, 1H, J=8.4Hz), 7.41 (s, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 6.25-6.28 (m , 3H), 5.28 (d, 1H, J=9.2Hz), 3.96-4.07 (m, 2H), 3.73-3.81 (m, 1H), 3.28-3.38 (m, 1H), 2.72 (dd, 1H, J =17.6, 5.2Hz), 2.27(dd, 1H, J=17.6, 10.0Hz), 1.97(s, 3H), 1.44-1.55(m, 4H), 1.41(s, 9H), 0.80-0.90(m, 6H), ESI-MS m/z: 554.1 [M+H] ⁺ .

Synthesis of Compound I-1a (X=F)

Compound 4a (276 mg, 0.5 mmol) was added to dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature. After 3 hours, the solvent was evaporated, ether was added, insoluble matter was precipitated, filtered, and dried in vacuo to obtain 241 mg of white solid as trifluoroacetic acid salt, yield 85%, HPLC purity 97.5%. H-NMR (D ₂ O, 400Hz): δ 8.28 (d, 1H, J=8.0Hz), 6.82 (s, 1H), 6.23 (d, 1H, J=6.0Hz), 6.17 (d, 1H, J=6.0Hz), 4.21-4.25(m, 1H), 3.95(dd, 1H, J=12.0, 8.8Hz), 3.46-3.54(m, 1H), 3.39-3.45(m, 1H), 2.86(dd , 1H, J=17.6, 6.0Hz), 2.39-2.48 (m, 1H), 1.99 (s, 3H), 1.32-1.48 (s, 4H), 0.69-0.76 (m, 6H). ESI-MS m/z: 454.4 [M+H] ⁺ .

Example 2:

Synthesis of Compound 4b (X=H)

Referring to the synthesis method of Example 1, compound 2 (216 mg, 0.5 mmol) was reacted with 2-hydroxy-pyrazine-3-carboxamide 3b (70 mg, 0.5 mmol, 1 eq) to obtain white solid 4b, 90 mg, yield 34% , HPLC purity 99%. H-NMR (DMSO-d ₆ , 400Hz): δ 8.39(d, 1H), 8.37(d, 1H), 7.96(s, 1H), 7.80(d, 1H, J=8.8Hz), 6.67(s) , 1H), 6.62 (d, 1H, J=9.2Hz), 6.14-6.19 (m, 2H), 4.04-4.11 (m, 1H), 3.65-3.74 (m, 1H), 3.51-3.62 (m, 1H) ), 3.34-3.40(m, 1H), 2.45(dd, 1H, J=18.0, 5.2Hz), 2.20-2.31(m, 1H), 1.77(s, 3H), 1.29-1.47(m, 12H), 0.71-0.83 (m, 6H), ESI-MS m/z: 536.3 [M+H] ⁺ .

Synthesis of Compound I-1b (X=H)

Referring to the synthesis method of Example 1, compound 4b (107 mg, 0.2 mmol) was deprotected to obtain 99 mg of white solid as trifluoroacetic acid salt, the yield was 90%, and the HPLC purity was 98%. H-NMR (CD ₃ OD, 400Hz): δ 8.35-8.44 (m, 2H), 6.92 (s, 1H), 6.30-6.35 (m, 2H), 4.19-4.26 (m, 1H), 3.96 (dd , 1H, J=11.2, 8.4Hz), 3.48-3.56 (m, 1H), 3.39-3.45 (m, 1H), 2.93 (dd, 1H, J=17.6, 5.6Hz), 2.40-2.51 (m, 1H) ), 2.04 (s, 3H), 1.44-1.60 (m, 4H), 0.82-0.94 (m, 6H). ESI-MS m/z: 436.3 [M+H] ⁺ .

Example 3:

Synthesis of Compound I-2a

Compound I-1a (30 mg, 0.053 mmol) and p-phenylbenzaldehyde (12.5 mg, 0.069 mmol, 1.3 eq) were added to absolute ethanol (2 mL), stirred at room temperature, and sodium cyanoborohydride (10 mg, 0.16 mmol) was added. , 3eq), the reaction was complete after 2 hours. 33 mg of white solid was obtained by column chromatography, the yield was 56%, and the HPLC purity was 98.7%. H-NMR (CD ₃ OD, 400 Hz): δ 8.34 (d, 1H, J=8.4 Hz), 7.58-7.66 (m, 4H), 7.41-7.49 (m, 4H), 7.35 (t, 1H, J =7.2Hz), 6.87(s, 1H), 6.27-6.32(m, 2H), 3.97-4.14(m, 3H), 3.90(d, 1H, J=13.2Hz), 3.36-3.43(m, 1H) , 3.04-3.15(m, 1H), 2.92(dd, 1H, J=17.6, 5.6Hz), 2.32-2.45(m, 1H), 2.03(s, 3H), 1.42-1.61(m, 4H), 0.79 -0.94 (m, 6H). ESI-MS m/z: 620.3 [M+H] ⁺ .

Example 4:

Synthesis of Compound I-2b

Referring to the synthesis method of compound I-2a, compound I-1a (30 mg, 0.053 mmol), benzaldehyde (11.2 mg, 0.1 mmol, 2 eq) and sodium cyanoborohydride (10 mg, 0.16 mmol, 3 eq) were reacted and separated by column chromatography 13 mg of white solid was obtained, the yield was 45%, and the HPLC purity was 98.5%. H-NMR (CD ₃ OD, 400 Hz): δ 8.34 (d, 1H, J=8.4 Hz), 7.27-7.42 (m, 5H), 6.86 (s, 1H), 6.26-6.32 (m, 2H), 4.08-4.11(m, 1H), 3.94-4.00(m, 2H), 3.80-3.84(m, 1H), 3.36-3.42(m, 1H), 3.01-3.08(m, 1H), 2.87(dd, 1H) , J=17.6, 5.6Hz), 2.29-2.38 (m, 1H), 2.01 (s, 3H), 1.44-1.56 (m, 4H), 0.81-0.93 (m, 6H). ESI-MS m/z: 544.1 [M+H] ⁺ .

Example 5:

Synthesis of Compound I-2c

Referring to the synthesis method of compound I-2a, compound I-1a (30 mg, 0.053 mmol), 2,3-dimethoxybenzaldehyde (17.6 mg, 0.1 mmol, 2 eq) and sodium cyanoborohydride (10 mg, 0.16 mmol, 3eq) was reacted, and 17.6 mg of white solid was obtained by column chromatography, the yield was 55%, and the HPLC purity was 98.5%. H-NMR (CD ₃ OD, 400 Hz): δ 8.35 (d, 1H, J=8.4 Hz), 6.99-7.07 (m, 2H), 6.84-6.89 (m, 2H), 6.26-6.32 (m, 2H) ), 4.06-4.14 (m, 1H), 3.96 (d, 1H, J=13.2Hz), 3.83-3.91 (m, 7H), 3.77-3.82 (m, 1H), 3.35-3.39 (m, 1H), 2.88-3.04 (m, 2H), 2.23-2.35 (m, 1H), 2.02 (s, 3H), 1.39-1.55 (m, 4H), 0.81-0.95 (m, 6H). ESI-MS m/z: 604.5 [M+H] ⁺ .

Example 6:

Synthesis of Compound I-2d

Referring to the synthesis method of compound I-2a, compound I-1a (30mg, 0.053mmol), 2-fluoro-4-bromobenzaldehyde (21.4mg, 0.1mmol, 2eq) and sodium cyanoborohydride (10mg, 0.16mmol, 3eq) ) reaction and column chromatography to obtain 16.9 mg of white solid with a yield of 50% and a HPLC purity of 99.0%. H-NMR (CD ₃ OD, 400 Hz): δ 8.34 (d, 1H, J=8.4 Hz), 7.62 (dd, 1H, J=6.8, 2.4 Hz), 7.42-7.47 (m, 1H), 7.04 ( t, 1H, J=9.2Hz), 6.85 (s, 1H), 6.26-6.32 (m, 2H), 4.06-4.14 (m, 1H), 3.80-3.94 (m, 3H), 3.53-3.41 (m, 1H), 2.80-2.96 (m, 2H), 2.20-2.32 (m, 1H), 1.42-1.58 (m, 4H), 0.80-0.96 (m, 6H). ESI-MS m/z: 640.4 [M+H] ⁺ .

Example 7:

Synthesis of Compound I-2e

Referring to the synthesis method of compound I-2a, compound I-1a (30 mg, 0.053 mmol), furfural (10.2 mg, 0.1 mmol, 2 eq) and sodium cyanoborohydride (10 mg, 0.16 mmol, 3 eq) were reacted and separated by column chromatography to obtain The white solid was 12.7 mg, the yield was 45%, and the HPLC purity was 98.8%. H-NMR (DMSO-d ₆ , 400 Hz): δ 8.47 (d, 1H, J=8.4 Hz), 7.99 (s, 1H), 7.79-7.86 (m, 2H), 7.55 (s, 1H), 6.67 (s, 1H), 6.36 (s, 1H), 6.21 (s, 1H), 6.12-6.17 (m, 2H), 3.96-4.06 (m, 1H), 3.61-3.83 (m, 3H), 3.36-3.42 (m, 1H), 2.71-2.85 (m, 1H), 2.58-2.68 (m, 1H), 1.98-2.14 (m, 1H), 1.29-1.49 (m, 4H), 0.66-0.92 (m, 6H) . ESI-MS m/z: 534.4 [M+H] ⁺ .

The above examples are for illustrative purposes only, and the scope of the present invention is not limited thereto. Modifications will be apparent to those skilled in the art, and the invention is limited only by the scope of the appended claims.

Claims (7)

1. A class of compounds represented by the following general formula (I), pharmaceutically acceptable salts, crystalline hydrates and solvates thereof: wherein X is H or halogen; R is H or CH ₂ R', R' is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the substituents on the aryl or heteroaryl are selected from One or more of fluorine, chlorine, bromine, methoxy, hydroxy, and phenyl; n is 1, 2 or 3. 2. The compound according to claim 1, its pharmaceutically acceptable salt, crystalline hydrate and solvate, characterized in that: X is H or F; R is H or a substituted aryl group, and the aryl group The substituents on are selected from one or more of fluorine, chlorine, bromine, methoxy, hydroxyl and phenyl; n is 1. 3. The compound of claim 1, its pharmaceutically acceptable salts, crystalline hydrates and solvates, wherein the compound of general formula (I) is selected from the following compounds: 4. The preparation method of the compound according to any one of claims 1 to 3, characterized in that, it is carried out by the following method one or two: Method 1: using compound 1 as a raw material, react with chloromethyl chlorosulfonate in a solvent in the presence of a base to obtain compound 2; compound 2 and pyrazinone derivative 3 react in a solvent in the presence of a base to obtain compound 4; Compound 4 is deprotected in a solvent in the presence of trifluoroacetic acid to obtain a compound of formula I-1, as shown in reaction formula 1: Reaction 1: Method 2: The compound of formula I-1 and R'CHO undergo a condensation reduction reaction in a solvent in the presence of sodium cyanoborohydride to obtain the compound of formula I-2, as shown in reaction formula 2: Reaction 2: Wherein, the definitions of X and R' are the same as in claim 1. 5. Use of the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salts, crystalline hydrates and solvates in the preparation of anti-influenza virus medicaments. 6. The use according to claim 5, wherein the influenza virus is at least one of influenza A, B and C influenza viruses. 7. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound selected from any one of claims 1 to 3, its pharmaceutically acceptable salts, crystalline hydrates and solvates, and optionally pharmaceutically acceptable carrier.