CN112079785B - Novel anti-influenza virus oseltamivir derivative, and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and in particular relates to an oseltamivir derivative, a preparation method and application thereof, wherein the compound has a structure shown in a general formula (I). The oseltamivir derivative has remarkable anti-influenza virus activity, and can be used for preventing and treating influenza.

Description

A novel anti-influenza virus oseltamivir derivative, its preparation method and use

technical field

The invention belongs to the field of medicinal chemistry and chemical synthesis, and specifically relates to an oseltamivir derivative and its preparation method and application.

Background technique

Influenza is an acute respiratory infectious disease caused by a virus, which spreads rapidly and can cause serious complications, posing a great threat to human life and health. Influenza viruses mainly include three types: A, B, and C. Among them, type A influenza virus has the strongest pathogenicity and is easy to mutate. Historically, it has caused many influenza pandemics. According to the World Health Organization, during non-epidemic periods, influenza can still cause 250,000 to 500,000 deaths worldwide each year. Influenza virus has a wide range of hosts, and outbreaks occur every period of time, and its prevention and control has become a focus of global attention.

Because the antigenicity of influenza virus is easy to mutate, the timeliness of the vaccine is greatly reduced, so antiviral drugs have become the main means of influenza prevention and treatment. Neuraminidase is an important functional protein located on the surface of the anti-influenza virus. Its main function is to catalyze the binding between sialic acid on the cell surface and the hemagglutinin of the nascent virus particles, preventing the aggregation of virus particles on the cell surface , to promote the release of the virus. Among various influenza virus subtypes, the active center of neuraminidase is highly conserved, which also makes it a good anti-influenza virus target. At present, a variety of drugs that inhibit neuraminidase have been marketed, among which oseltamivir is the most widely used.

3-Hydroxypyrazine compounds have potential anti-influenza virus effects. Favipiravir is a new type of anti-influenza drug that can selectively inhibit influenza virus RNA polymerase and interfere with the expression of viral genetic material. In addition to anti-influenza activity, Favipiravir also has inhibitory activity against a variety of RNA viruses, and has the advantages of strong antiviral activity, low toxicity and side effects, and strong selectivity.

Formula 1 Structures of Oseltamivir and Favipiravir

Influenza virus is very easy to mutate, coupled with the widespread use of antiviral drugs in clinical practice, the problem of drug resistance of influenza virus has become increasingly prominent. Therefore, the development of new drugs with potent and high drug resistance barrier is the research focus in the field of anti-influenza virus.

Contents of the invention

purpose of invention

The main purpose of the present invention is to provide oseltamivir derivatives represented by general formula (I), their pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates; another purpose is to provide Synthetic method; Another object is to provide the application of this type of compound in medicine.

Technical solutions

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

Wherein X is oxygen or nitrogen; Y is hydrogen or halogen; R is H or CH ₂ R', R' is substituted or unsubstituted aryl, substituted or unsubstituted arylheteroyl; the aryl or arylheteroyl The substituents on are selected from one or more of fluorine, chlorine, bromine, methoxy, hydroxyl, and phenyl; n is 1, 2 or 3.

Preferably, X is H or F or Cl; 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 for the compound of general formula (I) and its intermediates. The preparation method can be carried out by the following method 1 or method 2. The starting materials used in the present invention are commercially purchased or according to the known synthesis of similar compounds Method preparation:

Method 1: 3-hydroxypyrazine derivative 1 reacts with compound 2 in a solvent in the presence of a base to obtain compound 3; compound 3 is deprotected in a solvent in the presence of trifluoroacetic acid to obtain a compound of formula I-1, as follows Show:

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

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

In the above steps a and b, the base is selected from inorganic bases or organic bases, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, potassium hydride, sodium hydride, sodium tert-butoxide , 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-dimethyl Aniline and N,N-lutidine.

The reaction solvent in steps a and b is selected from one or more of water, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, acetonitrile, toluene, acetone, dioxane and chloroform kind.

The reaction solvent in step c is selected from lower alcohols such as methanol, ethanol, and isopropanol, or lower alcohol-water mixed solvents.

The "pharmaceutically acceptable inorganic or organic salts" mentioned in the present invention are compounds represented by 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 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, or with sodium hydroxide, Sodium, potassium, calcium or ammonium salts formed from bases such as potassium hydroxide, calcium hydroxide or ammonia water. "Pharmaceutically acceptable salt" also includes their solvates. Examples of solvates include hydrates, alcoholates and the like.

The present invention also provides the application of the compound represented by the general formula (I) and its pharmaceutically acceptable salt, crystalline hydrate and solvate according to the present invention in the preparation of anti-influenza virus medicaments. Preferably, the influenza virus is at least one of influenza A, B and C viruses.

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

The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by the above general formula (I), its pharmaceutically acceptable salt, crystalline hydrate and solvate, or one or more mixtures thereof , and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition can be used for treating or preventing influenza virus infection.

Beneficial effect

The compound of the invention has a novel structure and significant anti-influenza virus activity, and can be used for developing anti-influenza virus drugs.

The anti-influenza virus activity of the oseltamivir derivative represented by the general formula (I) contained in the present invention is explained below.

The inhibitory effect of the compound on H5N1 and H5N2 subtype virus strains was determined by cytopathic effect inhibition assay, and the test results are shown in Table 1.

Table 1. Inhibitory activity of compounds against H5N1 and H5N2 influenza viruses

It can be seen from Table 1 that most of the compounds exhibit obvious anti-influenza virus effects. The inhibitory activity of compounds I-1a and I-2c on H5N2 and H5N1 subtypes is better than oseltamivir, and significantly better than favipiravir and ribavirin.

Detailed ways

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

Example 1:

Oseltamivir phosphate phosphate 2-1 (2g, 4.9mmol) and triethylamine (1mL) were dissolved in tetrahydrofuran (20mL), water (2mL) was added, and di-tert-butyl dicarbonate (Boc ₂ O, 1.6g, 7.34mmol), stirred overnight at room temperature. The reaction liquid was concentrated to obtain an oily substance, which was directly carried out to the next reaction without further purification.

Dissolve the oil in the previous step in methanol (10 mL), add 5M aqueous sodium hydroxide solution (7 mL), stir at room temperature for 2 h, and TCL shows that the reaction is complete. The reaction solution was concentrated, dilute hydrochloric acid was added dropwise until no solid precipitated, filtered, the filter cake was washed with water (20 mL×2), and dried to obtain 1.7 g of white solid 2-3 (the total yield of two steps was 91%). ¹ H NMR (400MHz, CDCl ₃ ): δ6.88(s,1H),6.44(s,1H),5.65 (d,J=9.0Hz,1H),4.11–3.99(m,2H),3.86–3.74 (m,1H),3.39–3.29(m,1H), 2.75(dd,J＝17.8,5.0Hz,1H),2.28(dd,J＝17.0,10.2Hz,1H),2.02(s,3H), 1.55–1.48(m,4H),1.44(s,9H),0.91(t,J＝6.5Hz,3H),0.88(t,J＝6.4Hz,3H). ESI-MS m/z:385.6[M +H] ⁺ .

Compound 2-3 (500mg, 1.3mmol), NaHCO ₃ (440mg, 4.76mmol), TBAHSO ₄ (45mg, 0.13mmol) were sequentially added to a mixture of dichloromethane and water (1:1, 10mL), and stirred for 30min , Chloromethyl chlorosulfonate (260 mg, 1.57 mmol) was added dropwise, stirred at room temperature for 5 h, TLC showed that the reaction was complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain compound 2 as an oil.

Example 2:

2-Hydroxy-pyrazine-3-carboxamide 1a (210 mg, 1.5 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol) were added to DMF (8 mL), stirred at room temperature for 10 min, and then added Compound 2 (560mg, 1.3mmol) and potassium iodide (220mg, 1.3mmol) were warmed up to 50°C and stirred overnight. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (50 mL×2), and the organic layer was dried and concentrated. Column chromatography isolated 90 mg of white solid 3a (13%).

Compound 3a (90 mg) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at room temperature for 2 h. After the reaction was complete, the solvent was distilled off, diethyl ether (2 mL) was added, a solid precipitated, and 85 mg of white solid I-1a (92%) was obtained by filtration. ¹ H NMR (400MHz, CD ₃ OD): δ8.44–8.35 (m,2H),6.92(s,1H),6.36–6.28(m,2H),4.28–4.18(m,1H),4.03–3.91 (m,1H),3.57–3.48(m,1H),3.46–3.38(m,1H),2.94(dd,J＝17.5,5.7Hz, 1H),2.54–2.38(m,1H),2.04(s ,3H),1.63–1.42(m,4H),1.02–0.80(m, 6H). ¹³ C NMR(100MHz,DMSO-d ₆ ):δ171.14,165.56,164.38,155.39,142.78, 140.59,139.13,138.03, 126.63,82.62,81.80,74.46,52.49,49.32,28.48,26.05, 25.55,23.61,9.76,9.33. ESI-MS m/z:436.5[M+H] ⁺ .

Example 3:

Referring to the synthetic method of compound Ⅰ-1a, compound 2 (560mg, 1.3mmol), favipiravir (250mg, 1.6mmol), N, N-diisopropylethylamine (0.5mL, 3mmol) and potassium iodide (220mg, 1.3mmol) to obtain the target compound I-1b (300mg, 48%). ¹ H NMR (500MHz,DMSO-d ₆ ):δ8.48(d,J＝8.3Hz,1H),8.17–7.97(m,4H),7.87(s,1H),6.71(s,1H),6.21 –6.11(m,2H),4.21-4.11(m,1H),3.83–3.71(m,1H),3.42–3.25(m,2H),2.74(dd,J＝17.4,5.5Hz,1H),2.41 –2.29(m,1H),1.87(s,3H),1.50–1.28(m,4H),0.82–0.70(m,6H).ESI-MS m/z:454.2[M+H] ⁺ .

Example 4:

Compound I-1a (30 mg, 0.055 mmol) and p-phenylbenzaldehyde (13 mg, 0.07 mmol) were added to absolute ethanol (2 mL), and sodium cyanoborohydride (10 mg, 0.16 mmol) was added. After the reaction was complete, the oil was separated by column chromatography. The oil was dissolved in dichloromethane (1.5mL), trifluoroacetic acid (1mL) was added dropwise, stirred at room temperature for 2h, the solvent was evaporated, diethyl ether (2mL) was added, solid precipitated out, filtered to obtain 15mg of off-white solid Ⅰ-2a ( 36%). ¹ H NMR (400MHz, CD ₃ OD): δ8.46 -8.32(m, 2H), 7.74(d, J=8.2Hz, 2H), 7.65(d, J=8.6Hz, 2H), 7.56(d, J＝8.2 Hz, 2H), 7.48(t, J＝7.5Hz, 2H), 7.39(t, J＝7.3Hz, 1H), 6.96(s, 1H), 6.41–6.31(m, 2H), 4.46( d,J=13.1Hz,1H),4.33(d,J=13.2Hz,1H),4.26–4.18(m,2H),3.67–3.59(m,1H),3.48–3.39(m,1H),3.09 (dd,J＝17.4,5.4Hz,1H), 2.81–2.68(m,1H),2.06(s,3H),1.66–1.43(m,4H),0.98–0.81(m,6H). ESI-MS m/z:602.6[M+H] ⁺ .

Example 5:

Referring to the synthetic method of Ⅰ-2a, compound Ⅰ-1a (30mg, 0.055mmol), 2-fluorobenzaldehyde (10mg, 0.08mmol) and sodium cyanoborohydride (10mg, 0.16mmol) were reacted to obtain 10 mg of white solid Ⅰ- 2b (26%). ¹ H NMR (400MHz, CD ₃ OD): δ8.41(s, 2H), 7.62-7.49(m, 2H), 7.35-7.22(m, 2H), 6.95(s, 1H), 6.40-6.31(m ,2H),4.49–4.36(m,2H),4.31–4.24(m,1H),4.23–4.14(m,1H),3.77–3.66(m,1H),3.47–3.39(m,1H),3.07 (dd,J＝17.3,5.6Hz,1H),2.81–2.68(m,1H),2.06(s,3H), 1.61–1.42(m,4H),0.97–0.80(m,6H).ESI-MS m/z:544.6[M+H] ⁺ .

Embodiment 6:

Referring to the synthetic method of Ⅰ-2a, compound Ⅰ-1a (30mg, 0.055mmol), 2-fluoro-5-chlorobenzaldehyde (12mg, 0.08mmol) and sodium cyanoborohydride (10mg, 0.16mmol) were reacted to obtain 15mg White solid I-2b (37%). ¹ H NMR (400MHz, CD ₃ OD): δ8.41(s, 2H), 7.60–7.50(m, 1H), 7.44(d, J＝8.1Hz, 1H), 7.28(t, J＝8.8Hz, 1H),6.96(s, 1H),6.40–6.30(m,2H),4.53(s,1H),4.31–4.25(m,1H),4.22–4.14(m,1H), 3.84–3.72(m, 1H),3.46–3.39(m,1H),3.06(dd,J＝17.3,5.6Hz,1H),2.88–2.75(m,1H),2.06(s,3H),1.60–1.43(m,4H) ,0.96–0.81(m,6H).ESI-MS m/z: 578.1[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 (4)

1. A compound or a pharmaceutically acceptable salt thereof selected from the following: 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of anti-influenza virus medicaments. 3. The use according to claim 2, characterized in that the influenza virus is at least one of influenza A, B and C viruses. 4. A pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound selected from claim 1 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.