A swainsonine derivative, a preparation method thereof, a pharmaceutical composition and use thereof

Abstract

The present application belongs to the technical field of chemical medicine, and relates to a sophoridine derivative, a preparation method, a pharmaceutical composition and use thereof. The sophoridine derivative is a compound as shown in the structure of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is selected from S or O atom; R is selected from phenyl, substituted phenyl, naphthyl, pyridyl, acyl, C 1‑6 alkyl, C 1‑6 substituted alkyl, C 3‑6 cycloalkyl. The sophoridine derivative and the pharmaceutical composition thereof can be better used for the prevention or treatment of viral diseases.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and relates to a physostigmine derivative, its preparation method, pharmaceutical composition, and uses. Background Technology

[0002] The Chinese medicinal herb Sophora alopecuroides L., a plant belonging to the genus Sophora in the legume family, is the dried whole herb, root, and seeds. It is also known as bitter bean grass, bitter bean root, bitter licorice, and western bean root. This herb is cold in nature, bitter in taste, and toxic. It possesses properties of clearing heat and detoxifying, as well as antibacterial and anti-inflammatory effects.

[0003] Sophora flavescens mainly contains quinolone alkaloids, among which aloperine (ALO, structure as shown in formula (IⅠ)) is one of its representative alkaloids. Pharmacological studies have found that aloperine has antiviral, antitumor, anti-inflammatory, and antibacterial effects.

[0004]

[0005] Chinese patent application CN101209252A discloses the use of strychnine in the preparation of drugs for treating chronic hepatitis B; Chinese patent application CN106892920A discloses the use of strychnine 12-N-benzyl and aromatic acyl derivatives in the preparation of drugs for treating chronic hepatitis B, chronic hepatitis C, and influenza; Chinese patent application CN106822129A discloses the use of strychnine 12-N-benzenesulfonyl derivatives in the preparation of drugs for treating tumors. However, there is still a strong desire to discover strychnine derivatives with novel structural types, high antiviral activity, and good drug-like properties. Summary of the Invention

[0006] The primary objective of this invention is to provide a physostigmine derivative that can be better used for the prevention or treatment of viral diseases.

[0007] To achieve this objective, in a basic implementation scheme, the present invention provides a physostigmine derivative, wherein the physostigmine derivative is a compound with the structure shown in formula (Ⅰ) below, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0008]

[0009] in:

[0010] X is selected from S or O atoms;

[0011] R is selected from phenyl, substituted phenyl, naphthyl, pyridyl, acyl, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-6 Cycloalkyl.

[0012] In a preferred embodiment, the present invention provides a picrophylline derivative, wherein:

[0013] Each substituent on the benzene ring of the substituted phenyl group is independently selected from halogen, nitro, amino, acyl, cyano, meththio, halomethyl, halomethoxy, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino and phenyl substitutions can be mono- or poly-substituted;

[0014] The acyl group is selected from aromatic acyl or alkyl acyl;

[0015] The C mentioned 1-6 Each substituent of the substituted alkyl group is independently selected from alkenyl, halogen, methylthioyl, or phenyl, and the substitution is monosubstituted.

[0016] In a preferred embodiment, the present invention provides a picrophylline derivative, wherein the pharmaceutically acceptable salt is an inorganic or organic salt selected from hydrochloride, hydrobromide, sulfate, hydrogen sulfate, nitrate, phosphate, hydrogen phosphate, formate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, or p-toluenesulfonate.

[0017] In a preferred embodiment, the present invention provides a picrophylline derivative, wherein the picrophylline derivative is selected from one of the following compounds with the following structures:

[0018]

[0019]

[0020] The second objective of this invention is to provide a method for preparing the rutin derivative as described above, so as to better prepare the rutin derivative as described above, and to make the rutin derivative better used for the prevention or treatment of viral diseases.

[0021] To achieve this objective, in a basic embodiment, the present invention provides a method for preparing the physostigmine derivative as described above, wherein the preparation reaction formula of the method is as follows (physostigmine 12-amino group and isothiocyanate or isocyanate react in acetonitrile at room temperature to obtain the compound represented by general formula (I) of the present invention):

[0022]

[0023] A third object of the present invention is to provide a pharmaceutical composition of the stigmatine derivatives as described above, which is better suited for the prevention or treatment of viral diseases.

[0024] To achieve this objective, in a basic embodiment, the present invention provides a pharmaceutical composition of the as-described picolinine derivative, the pharmaceutical composition containing a preventive or therapeutically effective amount of the as-described picolinine derivative, and a suitable amount of pharmaceutically acceptable excipients.

[0025] In a preferred embodiment, the present invention provides a pharmaceutical composition of the physostigmine derivative as described above, wherein the pharmaceutical composition is a tablet, capsule, pill, injection, or eye drop.

[0026] In a preferred embodiment, the present invention provides a pharmaceutical composition of the picolinine derivative as described above, wherein the pharmaceutical composition is a controlled-release dosage form, a sustained-release dosage form, or a various particulate delivery system.

[0027] A fourth object of the present invention is to provide the use of the as-described stigmatine derivatives or the pharmaceutical compositions described above for the preparation of medicaments for the prevention or treatment of viral diseases, so as to enable better use for the prevention or treatment of viral diseases.

[0028] To achieve this objective, in a basic embodiment, the present invention provides the use of the as-described picolinine derivative or the as-described pharmaceutical composition for the preparation of a medicament for the prevention or treatment of viral diseases.

[0029] In a preferred embodiment, the present invention provides the use of the ascorbic acid derivatives or pharmaceutical compositions described above for the preparation of medicaments for the prevention or treatment of viral diseases, wherein the virus causing the viral disease is selected from one or more of influenza virus, HIV, hand-foot-mouth disease virus EV71 and CAV16, Coxsackievirus A16, and SARS-CoV-2.

[0030] The compounds of the present invention can be administered orally, for example, in the form of capsules, tablets, powders, granules, syrups, or similar dosage forms, or administered non-gastrointestinally via injection, ointment, suppositories, or similar dosage forms. These pharmaceutical preparations can be generated by conventional methods using adjuvants well known in the art, such as binders, excipients, stabilizers, disintegrants, flavoring agents, lubricants, etc. While the dosage varies depending on symptoms and the patient's age, the nature and severity of the disease or disorder, and the route and manner of administration, for oral administration in adult patients, the normal oral dose of the compounds of the present invention is 1 to 1000 mg daily, preferably 5 to 500 mg, as a single dose or in divided doses (e.g., twice or three times daily); for intravenous administration, a dose of 0.1 to 100 mg, preferably 0.5 to 50 mg, can be divided into one to three doses daily.

[0031] The beneficial effect of the present invention is that the physostigmine derivatives and pharmaceutical compositions thereof can be better used for the prevention or treatment of viral diseases.

[0032] The physostigmine derivatives of this invention introduce different substituent groups at the 12-nitrogen atom of physostigmine. Preliminary activity screening shows that these derivatives have improved antiviral activity and increased selectivity index compared to physostigmine, suggesting that these derivatives have good prospects for antiviral applications. Detailed Implementation

[0033] The following examples further illustrate specific embodiments of the present invention. The general synthetic methods for the compounds in Examples 1-33 are as follows:

[0034]

[0035] 1 mmol of picrophylline, 1.1 mmol of isothiocyanate or isocyanate (purchased from Beijing Innocare Technology Co., Ltd.) and 3 ml of acetonitrile were added to the reaction flask. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was analyzed by TLC, the acetonitrile was removed by concentration. The product was subjected to silica gel column chromatography (eluent: dichloromethane-methanol) to obtain the target compound. The target compound hydrochloride can be further obtained by salting with 2M 1,4-dioxane hydrogen chloride solution and then filtering.

[0036] Example 1: 12-N-(anilinethioformyl)matrine (ALO-1)

[0037]

[0038] ALO-1: White solid, mp 125-127℃, yield 75%. 1 H NMR(400MHz,DMSO-D6)δ8.97(s,1H),7.44–7.24(m,4H),7.12(s,1H),5.61(s,1H),3.70(s,1H) ),3.10(s,1H),2.82–2.57(m,4H),2.45–2.15(m,2H),2.07–1.19(m,12H),1.16–0.96(m,1H). 13 C NMR (101MHz, CDCl3) δ 181.40, 139.94, 135.83, 129.58, 128.74, 127.97, 127.34, 125.64, 125.46, 77.26, 64.28, 59.12, 54.11, 46.66, 44.80, 34.96, 28.16, 26.15, 24.96, 23.94, 23.49, 19.10. HRMS (ESI) m / z calculated values ​​C 22 H 30 ON3[M+H] +352.2383, measured value 352.2394.

[0039] Example 2: 12-N-(4-fluoroaniline thioformyl)matrine (ALO-3)

[0040]

[0041] ALO-3: white solid, mp 170-172℃, yield 85%. 1 H NMR (400MHz, CDCl3) δ7.36–7.22(m,2H),7.13–6.77(m,3H),5.64(d,J=5.4Hz,1H),4.96(s,1H),4.06–3.78(m,1H),3.14(dd,J=11.8,3.4Hz ,1H),2.89–2.70(m,2H),2.67–2.42(m,3H),2.29(t,J=11.2Hz,1H),2.16–1.57(m,10H),1.53–1.38(m,1H),1.11(dd,J=17.2,13.5Hz,2H). 13 C NMR (126MHz, CDCl3) δ 181.29, 161.55 (d, J = 245.7Hz), 135.80 (d, J = 3.8Hz), 135.69, 128.08, 128.00 (d, J = 3.8Hz), 127.98, 115.4 (d, J = 22.7Hz), 115.4 (d, J = 22.7Hz), 77.26, 58.99, 54.04, 46.52, 44.65, 34.87, 31.98, 28.09, 26.08, 24.87, 23.82, 23.39, 18.99. HRMS (ESI) m / z calculated values ​​C 22 H 29 N3FS[M+H] + 386.2061, measured value 386.2064.

[0042] Example 3: 12-N-(4-acrylonitrile-3-thioformyl)matrine (ALO-5)

[0043]

[0044] ALO-5: White solid, mp 90-92℃, yield 80%. 1H NMR (400MHz, DMSO-D6) δ7.67(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),5.58(d,J =4.9Hz,1H),3.32–3.23(m,4H),3.04(d,J=10.8Hz,1H),2.78–2.61(m,2H),2.5 6(d,J=10.8Hz,1H),2.49–2.43(m,4H),2.22(t,J=11.5Hz,1H),2.07–1.70(m,4 H),1.63–1.48(m,2H),1.42–1.32(m,1H),1.24–1.15(m,1H),1.10–0.94(m,2H). 13 C NMR (101MHz, CDCl3) δ 180.18, 144.09, 135.41, 133.65, 132.67, 128.40, 126.50, 123.77, 118.94, 107.50, 77.25, 64.66, 58.99, 54.12, 46.63, 45.06, 34.87, 28.05, 26.02, 24.90, 23.83, 23.53, 19.01. HRMS (ESI) m / z calculated values ​​C 23 H 29 N4S[M+H] + 393.2107, measured value 393.2098.

[0045] Example 4: 12-N-(4-methoxyaniline-thioformyl)matrine (ALO-7)

[0046]

[0047] ALO-7: White solid, mp 166-168℃, yield 88%. 1 H NMR (400MHz, CDCl3) δ7.25–7.19(m,2H),6.96(s,1H),6.90–6.85(m,2H),5.63(d,J=5.5Hz,1H),4.96(s,1H),3.90(s,1H),3.80(s,3H), 3.12(d,J=3.5Hz,1H),2.88–2.47(m,5H),2.28(t,J=11.2Hz,1H),2.21–1.56(m,10H),1.53–1.39(m,1H),1.11(dd,J=17.5,13.6Hz,2H). 13C NMR (126MHz, CDCl3) δ 181.66, 157.69, 135.91, 132.78, 127.98, 127.84, 126.99, 114.79, 113.92, 77.29, 59.06, 55.43, 54.07, 46.56, 44.67, 34.91, 32.03, 28.15, 26.11, 24.90, 23.89, 23.41, 19.05. HRMS (ESI) m / z calculated values ​​C 23 H 32 ON3S[M+H] + 398.2261, measured value 398.2254.

[0048] Example 5: 12-N-(4-nitroaniline-thioformyl)matrine (ALO-8)

[0049]

[0050] ALO-8: White solid, mp 170-172℃, yield 52%. 1 H NMR (500MHz, CDCl3) δ8.19(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),5.68(d,J=5.0Hz,1H),5.07(s,1H),4.01(s,1H),3.17(dd ,J=11.9,2.8Hz,1H),2.93–2.42(m,5H),2.33(t,J=11.7Hz,1H),2.21–1.58(m,11H),1.55–1.41(m,1H),1.13(t,J=15Hz,2H). 13 C NMR (101MHz, CDCl3) δ 179.99, 146.03, 143.57, 135.29, 128.43, 126.37, 124.39, 122.83, 77.23, 64.71, 58.96, 54.11, 46.61, 45.23, 34.83, 27.98, 25.97, 24.86, 23.80, 23.55, 18.98. HRMS (ESI) m / z calculated values ​​C 22 H 29 O2N4S[M+H] + 413.2006, measured value 413.2018.

[0051] Example 6: 12-N-(4-trifluoromethylanilinethioformyl)matrine (ALO-9)

[0052]

[0053] ALO-9: White solid, mp 174-176℃, yield 71%. 1 H NMR (500MHz, CDCl3) δ7.57(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,2H),7.08(s,1H),5.66(d,J=5.9Hz,1H),3.97(s,1H),3.16(dd,J=1 1.8,3.3Hz,1H),2.93–2.41(m,5H),2.31(t,J=11.7Hz,1H),2.20–1.63(m,11H),1.55–1.35(m,1H),1.12(dd,J=20.2,14.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ 180.60, 143.04, 135.51, 128.22, 126.67 (q, J = 33.3Hz), 126.4 (q, J = 4.0Hz), 124.22, 124.10 (q, J = 272.7Hz), 77.23, 64.48, 59.01, 54.09, 46.61, 44.90, 34.87, 28.05, 26.04, 24.89, 23.84, 23.50, 19.01. HRMS (ESI) m / z calculated values ​​C 23 H 29 N3F3S[M+H] + 436.2029, measured value 436.2037.

[0054] Example 7: 12-N-(4-chloroanilinethioformyl)matrine (ALO-11)

[0055]

[0056] ALO-11: White solid, mp 166-168℃, yield 65%. 1 H NMR (500MHz, CDCl3) δ7.38–7.21(m,4H),6.96(s,1H),5.65(d,J=4.7Hz,1H),3.94(s,1H),3.15(dd,J=11.7,2.7Hz,1H),2.85– 2.47(m,5H),2.30(t,J=11.7Hz,1H),2.19–1.62(m,10H),1.55–1.37(m,1H),1.37–1.22(m,1H),1.11(dd,J=21.2,13.9Hz,2H). 13C NMR (101MHz, CDCl3) δ 180.06, 146.08, 143.58, 135.36, 128.42, 126.40, 125.30, 124.41, 122.85, 77.26, 64.73, 58.99, 54.15, 46.64, 45.28, 34.84, 28.01, 25.97, 24.86, 23.83, 23.59, 19.01. HRMS (ESI) m / z calculated values ​​C 22 H 29 N3ClS[M+H] + 402.1765, measured value 402.1777.

[0057] Example 8: 12-N-(3,4,5-trimethoxyaniline-thioformyl)matrine (ALO-12)

[0058]

[0059] ALO-12: White solid, mp 158-160℃, yield 68%. 1 H NMR (400MHz, CDCl3) δ6.95(s,1H),6.58(s,2H),5.61(d,J=5.5Hz,1H),4.00–3.69(m,11H),3.13(dd,J=11.8,3.5H z,1H),2.84–2.37(m,5H),2.27(t,J=11.2Hz,1H),2.16–1.57(m,10H),1.47–1.39(m,1H),1.08(t,J=14.6Hz,2H). 13 C NMR (101MHz, CDCl3) δ 180.95, 153.02, 135.78, 135.66, 127.96, 103.40, 103.27, 77.29, 60.93, 59.10, 56.19, 54.09, 46.66, 44.68, 34.93, 32.06, 28.13, 26.11, 24.90, 23.94, 23.49, 19.09. HRMS (ESI) m / z calculated values ​​C 25 H 36 O3N3S[M+H] + 458.2472, measured value 458.2484.

[0060] Example 9: 12-N-(4-bromoaniline-thioformyl)matrine (ALO-13)

[0061]

[0062] ALO-13: White solid, mp 178-180℃, yield 63%. 1 H NMR (400MHz, CDCl3) δ7.45–7.39(m,2H),7.23–7.16(m,2H),6.97(s,1H),5.62(d,J=5.6Hz,1H),3.99–3.82(m,1H),3.12(dd,J =11.8,3.5Hz,1H),2.84–2.42(m,5H),2.27(t,J=11.4Hz,1H),2.21–1.58(m,11H),1.50–1.34(m,1H),1.09(t,J=15.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ 180.90, 138.99, 135.66, 132.78, 131.65, 128.09, 127.21, 127.16, 118.70, 77.27, 64.34, 59.05, 54.10, 46.60, 44.76, 34.91, 28.11, 26.10, 24.92, 23.88, 23.47, 19.05. HRMS (ESI) m / z calculated values ​​C 22 H 29 N3BrS[M+H] + 446.1260, measured value 446.1273.

[0063] Example 10: 12-N-(4-ethylanilinethioformyl)matrine (ALO-15)

[0064]

[0065] ALO-15: White solid, mp 138-140℃, yield 90%. 1H NMR (400MHz, CDCl3) δ7.23–7.19(m,2H),7.17–7.12(m,2H),6.97(s,1H),5.61(d,J=5.6Hz,1H) ,3.88(td,J=12.4,3.5Hz,1H),3.12(dd,J=11.8,3.5Hz,1H),2.82–2.69(m,2H),2.65–2.58(m, 4H),2.51(d,J=11.9Hz,1H),2.26(t,J=11.4Hz,1H),2.18–1.95(m,4H),1.94–1.75(m,4H),1.6 8(dd,J=18.8,6.3Hz,3H),1.52–1.34(m,1H),1.28–1.15(m,3H),1.09(dd,J=17.5,13.5Hz,2H). 13 CNMR (101MHz, CDCl3) δ 181.42, 141.77, 137.47, 135.90, 128.97, 128.12, 127.87, 125.74, 125.65, 77.28, 64.18, 59.12, 54.10, 46.63, 44.71, 34.95, 28.39, 28.17, 26.14, 24.94, 23.95, 23.48, 19.10, 15.43. HRMS (ESI) m / z calculated value C 24 H 34 N3S[M+H] + 396.2468, measured value 396.2482.

[0066] Example 11: 12-N-(3,4-dimethoxyaniline-thioformyl)matrine (ALO-16)

[0067]

[0068] ALO-16: White solid, mp 72-74℃, yield 88%. 1 H NMR (400MHz, CDCl3) δ7.02(s,1H),6.96(d,J=1.9Hz,1H),6.85–6.73(m,2H),5.63(d,J=5.6Hz,1H),3.87(d,J=2.9Hz,6H),3.15(dd,J=11 .8,3.4Hz,1H),2.87–2.40(m,5H),2.36–2.24(m,1H),2.20–1.54(m,10H),1.53–1.38(m,1H),1.32–1.20(m,2H),1.11(t,J=16.0Hz,2H). 13C NMR (126MHz, CDCl3) δ 181.41, 148.68, 147.20, 132.96, 127.85, 118.40, 111.17, 110.80, 110.66, 59.04, 55.99, 55.96, 54.06, 46.58, 34.89, 31.94, 29.72, 28.13, 27.22, 26.08, 24.86, 23.88, 23.40, 19.04. MS (ESI) m / z calculated value C 24 H 35 N3O2S[M+H] + 428.2, measured value 428.2

[0069] Example 12: 12-N-(4-trifluoromethoxyaniline thioformyl)matrine (ALO-17)

[0070]

[0071] ALO-17: White solid, mp 76-78℃, yield 78%. 1 H NMR (500MHz, CDCl3) δ7.40(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.00(s,1H),5.65(d,J=4.4Hz,1H),3.95(s,1H),3.15(d,J=11.5Hz,1H),2.89 –2.46(m,5H),2.31(t,J=11.5Hz,1H),2.22–1.97(m,3H),1.97–1.60(m,7 H),1.51–1.38(m,1H),1.34–1.21(m,1H),1.12(dd,J=20.5,12.4Hz,2H). 13 C NMR (126MHz, CDCl3) δ 180.91, 146.37, 138.39, 135.69, 128.12, 127.11, 126.72, 121.18, 119.43, 77.25, 64.29, 59.01, 54.08, 46.56, 44.63, 34.87, 31.92, 28.09, 26.06, 24.88, 23.84, 23.41, 19.01. HRMS (ESI) m / z calculated values ​​C 23 H 29 ON3F3S[M+H] + 452.1978, measured value 452.1967.

[0072] Example 13: 12-N-(4-Methylthioaniline-thioformyl)matrine (ALO-18)

[0073]

[0074] ALO-18: White solid, mp 152-154℃, yield 46%. 1 H NMR (500MHz, CDCl3) δ7.29–7.21(m,4H),6.97(s,1H),5.64(d,J=6.0Hz,1H),3.92(s,1H),3.15(dd,J=11.9,3.4Hz,1 H),2.90–2.44(m,8H),2.29(t,J=11.5Hz,1H),2.23–1.59(m,11H),1.53–1.37(m,1H),1.11(dd,J=22.0,13.6Hz,2H). 13 C NMR (101MHz, CDCl3) δ 181.15, 137.22, 135.77, 135.39, 127.93, 127.12, 127.04, 126.16, 126.06, 77.23, 64.23, 59.05, 54.07, 46.59, 44.72, 34.90, 28.11, 26.07, 24.89, 23.89, 23.44, 19.04, 16.27. HRMS (ESI) m / z calculated values ​​C 23 H 32 N3S2[M+H] + 414.2032, measured value 414.2044.

[0075] Example 14: 12-N-(3,4-methylenedioxyanilinethioformyl)matrine (ALO-11)

[0076]

[0077] ALO-11: White solid, mp 166-168℃, yield 65%. 1H NMR (400MHz, CDCl3) δ6.94–6.88(m,2H),6.87–6.72(m,1H),6.67(dd,J=8.2,2.0Hz, 1H),5.97(s,2H),5.63(d,J=5.8Hz,1H),3.90(s,1H),3.14(dd,J=11.8,3.5Hz,1H),2 .96–2.35(m,6H),2.28(t,J=11.4Hz,1H),2.22–2.04(m,2H),2.03–1.95(m,2H),1.9 2–1.79(m,3H),1.76–1.62(m,3H),1.51–1.40(m,1H),1.11(dd,J=17.4,13.4Hz,2H). 13 C NMR (126MHz, CDCl3) δ 181.61, 147.58, 145.81, 133.90, 127.88, 119.56, 108.70, 107.78, 101.47, 77.29, 64.05, 59.06, 54.06, 46.56, 44.63, 34.92, 32.02, 28.13, 26.11, 24.89, 23.89, 23.42, 19.05. HRMS (ESI) m / z calculated values ​​C 23 H 30 O2N3S[M+H] + 412.2053, measured value 412.2041.

[0078] Example 15: 12-N-(4-acetanilideformyl)matrine (ALO-14)

[0079]

[0080] ALO-14: White solid, mp 96-98℃, yield 42%. 1 H NMR (400MHz, CDCl3) δ8.14(d,J=9.2Hz,2H),7.58(d,J=8.9Hz,2H),6.72(s,1H),5.65(d,J=3.6Hz,1H),4.51(d,J=4.4Hz,1H) ,3.69(d,J=4.2Hz,2H),3.11(d,J=10.8Hz,1H),2.97–2.11(m,8H),2.07–1.53(m,10H),1.50–1.37(m,1H),1.32–1.02(m,2H). 13C NMR (126MHz, CDCl3) δ 151.77, 150.68, 145.75, 142.18, 136.11, 128.10, 126.04, 125.09, 123.94, 118.24, 77.24, 70.66, 59.19, 57.11, 54.27, 46.48, 44.72, 34.77, 28.22, 25.80, 24.60, 24.11, 23.98, 19.13. HRMS (ESI) m / z calculated values ​​C 24 H 32 ON3S[M+H] + 410.2261, measured value 410.2254.

[0081] Example 16: 12-N-(2-naphthylaminoformyl)matrine (ALO-33)

[0082]

[0083] ALO-33: White solid, mp 92-94℃, yield%. 1 H NMR (500MHz, CDCl3) δ7.91–7.74(m,3H),7.57–7.38(m,4H),7.22–7.14(m,1H),5.62(d,J=30.2Hz,1H),3.22(d,J=11.4Hz ,1H),2.87–2.64(m,4H),2.36–1.99(m,5H),1.94–1.66(m,6H),1.53–1.37(m,1H),1.30–1.08(m,4H),0.91–0.84(m,1H).

[0084] Example 17: 12-N-(3-pyridinylformyl)matrine (ALO-32)

[0085]

[0086] ALO-32: White solid, mp 96-98℃, yield%. 1H NMR (400MHz, CDCl3) δ8.48(s,1H),8.40(dd,J=4.7,1.3Hz,1H),8.00–7.91(m,1H),7.30–7.27(m,1H),5.67(d,J=5.2Hz,1H),3.99(s,1H),3.17(dd,J= 11.8,3.2Hz,1H),2.89–2.46(m,5H),2.40–2.26(m,1H),2.18–1.66(m,10H) ,1.49–1.42(m,1H),1.29–1.23(m,2H),1.13(s,1H),0.88(t,J=6.8Hz,1H).

[0087] Example 18: 12-N-(tert-butylaminoformyl)matrine hydrochloride (ALO-2)

[0088]

[0089] ALO-2: White solid, mp 274-276℃, yield 71%. HRMS (ESI) calculated m / z value C. 20 H 34 N3S[M+H] + 348.2468, measured value 348.2458.

[0090] Example 19: 12-N-(n-Butylaminoformyl)matrine hydrochloride (ALO-27)

[0091]

[0092] ALO-27: White solid, mp 62-64℃, yield 61%. HRMS (ESI) calculated m / z value C. 20 H 34 N3S[M+H] + 384.2468, measured value 384.2464.

[0093] Example 20: 12-N-(Benzylaminoformyl)matrine (ALO-4)

[0094]

[0095] ALO-4: white solid, mp 72-74℃, yield 83%. 1H NMR (400MHz, CDCl3) δ7.38–7.25(m,5H),5.60(d,J=5.1Hz,2H),4.96(dd,J= 14.5,4.8Hz,1H),4.83(dd,J=14.5,4.8Hz,1H),3.92–3.73(m,1H),3.16–3.0 1(m,1H),2.82–2.33(m,5H),2.25(t,J=11.4Hz,1H),2.14–1.93(m,3H),1.91 –1.55(m,7H),1.52–1.36(m,1H),1.33–1.22(m,1H),1.08(t,J=14.8Hz,2H). 13 C NMR (101MHz, CDCl3) δ 181.11, 138.46, 135.97, 128.78, 127.82, 127.75, 127.55, 77.38, 63.60, 59.07, 54.05, 50.13, 46.47, 34.88, 32.17, 28.17, 26.11, 24.84, 23.92, 23.39, 19.06. HRMS (ESI) m / z calculated values ​​C 23 H 32 N3S[M+H] + 382.2312, measured value 382.2315.

[0096] Example 21: 12-N-(Benzamidoformyl)matrine (ALO-6)

[0097]

[0098] ALO-6: White solid, mp 92-94℃, yield 65%. 1 H NMR (400MHz, DMSO-D6) δ10.61(s,1H),7.95(d,J=8.0Hz,2H),7.61(t,J=6.7Hz,1H),7.50(t,J=7.7 Hz,2H),5.69(s,1H),4.34–3.56(m,2H),3.08–2.66(m,1H),2.38–1.52(m,12H),1.53–0.97(m,7H). 13C NMR (126MHz, CDCl3) δ 181.06, 171.20, 138.36, 135.94, 128.81, 127.88, 127.61, 126.84, 77.27, 60.43, 58.46, 54.05, 46.45, 34.83, 29.72, 28.14, 26.10, 24.85, 23.91, 19.03, 18.47. HRMS (ESI) m / z calculated values ​​C 23 H 30 N3OS[M+H] + 396.2104, measured value 396.2104.

[0099] Example 22: 12-N-(allylaminoformyl)matrine (ALO-10)

[0100]

[0101] ALO-10: White solid, mp 74-76℃, yield 82%. 1 H NMR(500MHz, CDCl3)δ5.96(dq,J=10.8,5.6Hz,1H),5.61(d,J=4.4Hz,1H),5.39(s,1H),5.19(dd,J=19.6,13.8Hz,2H),4.45–4.27(m,2H),3.83 (s,1H),3.10(d,J=9.9Hz,1H),2.89–2.39(m,5H),2.25(t,J=10.9Hz,1H),2.15–1.54(m,11H),1.44(q,J=12.7Hz,1H),1.11(t,J=15.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ 181.11, 136.06, 134.55, 127.69, 116.71, 77.26, 63.56, 59.08, 54.05, 48.49, 46.47, 44.02, 34.89, 32.17, 28.15, 24.83, 23.91, 23.32, 19.04. HRMS (ESI) m / z calculated values ​​C 19 H 30 N3S[M+H] + 332.2155, measured value 332.2162.

[0102] Example 23: 12-N-(4-Toluidineformyl)matrine (ALO-19)

[0103]

[0104] ALO-19: White solid, mp 88-90℃, yield 36%. 1 H NMR (500MHz, CDCl3) δ7.28(d,J=8.2Hz,2H),7.07(d,J=8.2Hz,2H),6.26(s,1H),5.61( d,J=4.2Hz,1H),4.49(d,J=4.2Hz,1H),3.72(dd,J=12.9,6.0Hz,1H),3.55(dd,J=12.9, 6.0Hz,1H),3.07(dd,J=11.5,3.0Hz,1H),2.82–2.68(m,2H),2.57(d,J=11.1Hz,2H),2 .32–2.14(m,5H),1.99–1.65(m,9H),1.52–1.35(m,1H),1.10(dd,J=19.3,14.5Hz,2H). 13 C NMR (101MHz, CDCl3) δ 155.33, 136.78, 132.14, 129.32, 129.02, 127.52, 126.86, 124.59, 119.77, 77.27, 70.87, 59.45, 54.27, 46.62, 44.51, 34.96, 33.16, 28.36, 26.01, 24.76, 24.25, 20.75, 19.34. HRMS (ESI) m / z calculated values ​​C 23 H 32 ON3[M+H] + 366.2540, measured value 366.2547.

[0105] Example 24: 12-N-(4-trifluorotoluamide)matrine (ALO-20)

[0106]

[0107] ALO-20: White solid, mp 74-76℃, yield 60%. 1H NMR (500MHz, CDCl3) δ7.42(d,J=8.5Hz,2H),7.13(d,J=8.5Hz,2H),6.41(s,1H)5.64(d,J=4.8Hz,1H),4.49(d,J=4.6Hz,1H),3.81–3.39(m,2H),3.09( dd,J=11.7,3.4Hz,1H),2.89–2.49(m,4H),2.40–2.10(m,3H),2.05–1.77(m ,6H),1.74–1.63(m,2H),1.53–1.35(m,1H),1.13(dd,J=16.5,15.8Hz,2H). 13 C NMR (101MHz, CDCl3) δ 154.89, 144.20, 138.09, 127.78, 121.65, 121.35 (q, J = 38.4Hz), 121.82 (q, J = 255.5Hz), 120.54, 77.22, 59.46, 59.38, 54.23, 46.57, 40.34, 34.92, 33.10, 28.26, 25.98, 24.19, 24.15, 19.26. HRMS (ESI) m / z calculated values ​​C 23 H 29 ON3F3[M+H] + 420.2257, measured value 420.2295.

[0108] Example 25: 12-N-(4-methoxyanilineformyl)matrine (ALO-21)

[0109]

[0110] ALO-21: White solid, mp 74-76℃, yield 82%. 1 ¹H NMR (500MHz, CDCl₃) δ 7.25 (dd, J = 40.5, 8.6Hz, 2H), 6.85 (dd, J = 18.5, 8.7Hz, 2H), 6.18 (s, 1H), 5.62 (d, J = 5.1Hz, 1H), 4.48 (d, J = 3.8Hz, 1H), 3.78 (s, 3H), 3.75–3.45 (m, 2H), 3.08 (dd, J = 11.5, 3.2Hz, 1H), 2.83–2.53 (m, 4H), 2.37–2.07 (m, 3H), 1.96–1.64 (m, 8H), 1.52–1.35 (m, 1H), 1.11 (dd, J = 19.2, 14.9Hz, 2H). HRMS (ESI) m / z calculated value C 23 H 32O2N3[M+H] + 382.2489, measured value 382.2496.

[0111] Example 26: 12-N-(4-Nitrileanilinoformyl)matrine (ALO-22)

[0112]

[0113] ALO-22: White solid, mp 108-110℃, yield 62%. 1 H NMR (400MHz, CDCl3) δ7.60–7.49(m,5H),5.65(d,J=4.9Hz,1H),4.52(d,J=4.3Hz,1H),3.76–3.59(m,2H),3.11(dd,J=11.7,2. 9Hz,1H),2.91–2.67(m,1H),2.66–2.51(m,1H),2.41–2.24(m,1H),2.66–2.51(m,1H),2.05–1.63(m,11H),1.56–1.02(m,3H). 13 C NMR (101MHz, CDCl3) δ 154.28, 143.93, 135.65, 133.07, 127.95, 126.63, 119.41, 119.04, 118.94, 104.88, 77.28, 59.30, 54.25, 46.54, 40.60, 34.85, 32.92, 28.21, 25.89, 24.69, 24.20, 24.07, 19.21. HRMS (ESI) m / z calculated values ​​C 23 H 29 ON4[M+H] + 377.2336, measured value 377.2345.

[0114] Example 27: 12-N-(4-fluoroanilineformyl)matrine (ALO-23)

[0115]

[0116] ALO-23: White solid, mp 154-156℃, yield 61%. 1H NMR (400MHz, CDCl3) δ7.38–7.30(m,2H),7.04–6.74(m,2H),6.44(s,1H),5.62(d,J =5.5Hz,1H),4.49(d,J=5.5Hz,1H),3.72(dd,J=13.6,6.6Hz,1H),3.56(td,J=13.1, 5.4Hz,1H),3.07(dd,J=11.6,3.6Hz,1H),2.83–2.66(m,2H),2.57(t,J=10.8Hz,2H ),2.38–2.06(m,3H),2.04–1.57(m,8H),1.53–1.29(m,1H),1.11(t,J=15.4Hz,2H). 13 C NMR (101MHz, CDCl3) δ 159.84, 156.36 (d, J = 218.2Hz), 135.94, 135.37 (d, J = 2.0Hz), 127.70, 121.69 (d, J = 7.07Hz), 115.38 (d, J = 22.2Hz), 77.30, 59.44, 54.21, 46.62, 40.15, 34.99, 33.16, 28.28, 26.10, 24.82, 24.26, 24.20, 19.32. HRMS (ESI) m / z calculated values ​​C 22 H 29 ON3F[M+H] + 370.2289, measured value 370.2307.

[0117] Example 28: 12-N-(4-chloroanilineformyl)matrine (ALO-24)

[0118]

[0119] ALO-24: White solid, mp 86-88℃, yield 72%. 1H NMR(500MHz, CDCl3)δ7.35(d,J=8.7Hz,2H),7.23(d,J=8.7Hz,2H),6.31(s,1H),5 .63(d,J=4.5Hz,1H),4.48(d,J=4.3Hz,1H),3.80–3.46(m,2H),3.09(dd,J=11.6, 3.2Hz,1H),2.86–2.54(m,4H),2.35–2.25(m,2H),2.15(dd,J=19.8,10.9Hz,1H), 2.00–1.79(m,5H),1.76–1.62(m,3H),1.52–1.34(m,1H),1.11(t,J=15.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ 154.91, 137.99, 128.95, 128.78, 127.74, 127.55, 120.79, 77.25, 59.40, 54.26, 46.59, 40.38, 34.93, 33.08, 28.29, 25.98, 25.92, 24.76, 24.18, 19.28. HRMS (ESI) m / z calculated values ​​C 22 H 29 ON3Cl[M+H] + 386.1994, measured value 386.2003.

[0120] Example 29: 12-N-(4-nitroanilinoformyl)matrine (ALO-25)

[0121]

[0122] ALO-25: White solid, mp 202-204℃, yield 83%. 1 ¹H NMR (500MHz, CDCl₃) δ 7.19 (dd, J = 26.3, 8.1Hz, 2H), 7.02 (s, 1H), 6.86 (t, J = 9.0Hz, 2H), 5.63 (s, 1H), 3.99–3.84 (m, 1H), 3.47 (s, 1H), 3.14 (d, J = 11.5Hz, 1H), 2.87–2.45 (m, 5H), 2.36–1.96 (m, 5H), 1.95–1.80 (m, 3H), 1.75–1.58 (m, 3H), 1.53–1.34 (m, 1H), 1.11 (dd, J = 23.2, 13.2Hz, 2H). HRMS (ESI) m / z calculated value C 22 H 29 O3N4[M+H] +397.2234, measured value 397.2240.

[0123] Example 30: 12-N-(4-Methylthioanilineformyl)matrine (ALO-26)

[0124]

[0125] ALO-26: White solid, mp 78-80℃, yield 65%. 1 H NMR (400MHz, CDCl3) δ7.46(t,J=1.9Hz,1H),7.17(t,J=7.8Hz,1H),7.11(ddd,J=8.1,1 .8,1.0Hz,1H),6.90(ddd,J=8.1,1.8,1.0Hz,1H),6.33(s,1H),5.63(s,1H),4.51(s,1 H),3.87–3.50(m,2H),3.09(d,J=8.5Hz,1H),2.66–2.78(m,4H),2.48(s,3H),2.37–2. 09(m,3H),2.03–1.78(m,5H),1.75–1.59(m,3H),1.53–1.33(m,1H),1.21–1.01(m,2H). 13 C NMR (126MHz, CDCl3) δ 154.89, 139.93, 139.18, 135.92, 129.05, 127.77, 120.75, 117.12, 116.07, 77.26, 59.37, 54.22, 46.56, 40.18, 34.94, 33.20, 28.28, 26.11, 24.82, 24.22, 24.14, 19.27, 15.80. HRMS (ESI) m / z calculated values ​​C 23 H 32 ON3S[M+H] + 398.2261, measured value 398.2252.

[0126] Example 31: 12-N-(3-chloro-4-fluoroanilineformyl)matrine (ALO-28)

[0127]

[0128] ALO-28: White solid, mp 178-180℃, yield 67%. 1H NMR (400MHz, CDCl3) δ7.59 (dd, J=6.5, 2.6Hz, 1H), 7.24–7.15 (m, 1H), 7.03 (t, J=8.8Hz,1H),6.36(s,1H),5.68–5.59(m,1H),4.48(d,J=5.4Hz,1H),3.81–3. 46(m,2H),3.10(dd,J=11.7,3.4Hz,1H),2.92–2.50(m,4H),2.48–2.08(m,3H) ,2.06–1.78(m,5H),1.74–1.62(m,3H),1.54–1.38(m,1H),1.25–0.97(m,2H). 13 C NMR (101MHz, CDCl3) δ 155.08, 153.79 (d, J = 227.3Hz), 136.12 (d, J = 3.0Hz), 135.80, 127.80, 121.91, 120.75, 120.57, 119.41 (d, J = 6.1Hz), 77.28, 59.38, 54.23, 46.57, 40.24, 34.93, 33.09, 28.25, 26.03, 24.76, 24.21, 24.14, 19.26. HRMS (ESI) m / z calculated value r C 22 H 28 ON3ClF[M+H] + 404.1899, measured value 404.1919.

[0129] Example 32: 12-N-(4-isopropylanilineformyl)matrine (ALO-29)

[0130]

[0131] ALO-29: White solid, mp 176-178℃, yield 62%. 1 H NMR (400MHz, CDCl3) δ7.37–7.26(m,2H),7.18–6.99(m,2H),6.26(s,1H),5.60(d,J=5.0Hz,1H),4.48(d,J=5.1Hz,1H),3.8 2–3.42(m,2H),3.05(dd,J=11.7,3.7Hz,1H),2.94–2.43(m,5H),2.38–2.03(m,3H),2.00–1.37(m,11H),1.29–1.11(m,6H). 13C NMR (101MHz, CDCl3) δ 155.26, 143.34, 137.02, 136.12, 127.61, 126.71, 119.83, 77.27, 59.50, 59.46, 54.25, 46.65, 40.11, 35.02, 33.51, 33.24, 28.34, 26.15, 24.86, 24.28, 24.13, 19.37. HRMS (ESI) m / z calculated values ​​C 25 H 36 ON3[M+H] + 394.2853, measured value 394.2864.

[0132] Example 33: 12-N-(3-nitro-4-methylanilineformyl)matrine (ALO-30)

[0133]

[0134] ALO-30: White solid, mp 100-102℃, yield 82%. 1 H NMR (400MHz, CDCl3) δ7.99(d,J=2.3Hz,1H),7.69(dd,J=8.4,2.3Hz,1H),7.23(d,J=8.4Hz,1H),6.45(s,1H),5.69–5.59(m,1H),4.57–4.42(m,1H),3 .80–3.51(m,2H),3.10(dd,J=11.7,3.6Hz,1H),2.87–2.50(m,7H),2.37–2 .09(m,3H),2.04–1.65(m,8H),1.51–1.40(m,1H),1.11(t,J=14.5Hz,2H). 13 CNMR (101MHz, CDCl3) δ 154.69, 148.95, 138.44, 132.95, 127.91, 127.26, 124.27, 122.13, 115.25, 77.24, 59.47, 59.34, 54.24, 46.55, 34.90, 33.02, 28.24, 25.86, 24.72, 24.18, 24.10, 19.90, 19.23. HRMS (ESI) m / z calculated value C 23 H 31 O3N4[M+H] + 411.2391, measured value 411.2392.

[0135] Example 34: In vitro anti-influenza virus A / PR / 8 / 34 (H1N1) experiment

[0136] (I) Test Materials and Methods

[0137] 1. Virus strain: Influenza virus A / PR / 8 / 34 (H1N1), cultured and passaged in the allantoic cavity of chicken embryos (March 2018), stored at -80℃.

[0138] 2. Sample preparation: Before use, the sample is prepared into a stock solution with DMSO, and then diluted 3 times with culture medium, resulting in 8 dilutions.

[0139] 3. Positive control drugs: Ribavirin (RBV), Hubei Tianyao Pharmaceutical Co., Ltd. (batch number 31712252); Oseltamivir phosphate, repackaged by Roche Pharmaceuticals Shanghai Co., Ltd. (batch number SH0071).

[0140] 4. Test method: MDCK cells were seeded in 96-well culture plates and incubated at 37°C with 5% CO2. After 24 hours, the cells were infected with influenza virus. -5 After adsorption for 2 hours, the virus solution was discarded, and maintenance medium containing samples of different dilutions and positive control drugs was added. Cell control wells and virus control wells were also included. The cells were incubated at 37°C with 5% CO2. When the cytopathic effect (CPE) in the virus control group reached 4+, the cytopathic effect (CPE) in each group was observed, and the half-maximal toxic concentration (TC) of the sample to cells was calculated using the Reed-Muench method. 50 ) and half-maximal inhibitory concentration (IC50) against the virus 50 ).

[0141] (II) Test Results

[0142]

[0143]

[0144] Note:

[0145] TC 50 : Drug half-maximal toxic concentration; IC50 50 The half-maximal inhibitory concentration (MCC) of the drug against the virus.

[0146] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims and their equivalents, this invention is also intended to include these modifications and variations. The above embodiments or implementations are merely illustrative examples of this invention, and it can also be implemented in other specific ways or forms without departing from its gist or essential characteristics. Therefore, the described embodiments should be considered illustrative rather than limiting in any respect. The scope of this invention should be defined by the appended claims, and any changes equivalent to the intent and scope of the claims should also be included within the scope of this invention.

Claims

1. A matrine derivative or a pharmaceutically acceptable salt thereof for treating influenza virus infection, characterized in that, Selected from the following: 。 2. A pharmaceutical composition for treating influenza virus infection, characterized in that, The pharmaceutical composition comprises the picrophylline derivative of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical compositions include tablets, capsules, pills, injections, eye drops, sprays, and ointments.

4. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical composition is selected from controlled-release dosage forms, sustained-release dosage forms, and various microparticle delivery systems.

5. The use of the matrine derivative or a pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of an antiviral drug for influenza.

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