CN114702376A

CN114702376A - Cedrol derivative, preparation method and application thereof

Info

Publication number: CN114702376A
Application number: CN202210401909.2A
Authority: CN
Inventors: 刘吉开; 汪钢强; 陈贺平; 吴滨; 李正辉; 冯涛
Original assignee: South Central University for Nationalities
Current assignee: South Central Minzu University
Priority date: 2020-12-14
Filing date: 2020-12-14
Publication date: 2022-07-05
Also published as: CN112592252B; CN114890882B; CN114890882A; CN114716327A; CN112592252A

Abstract

The invention relates to the technical field of synthetic drugs, and particularly relates to cedrol derivatives, and a preparation method and application thereof. The cedrol derivative has the following structural formula:

Description

Cedrol derivative, preparation method and application thereof

The application case is a divisional application, the application date of a parent application is 12 months and 14 days 2020, the application number is CN202011475888.6, and the name is 'cedrol derivative, and a preparation method and application thereof'.

Technical Field

The invention relates to the technical field of synthetic drugs, and particularly relates to cedrol derivatives, and a preparation method and application thereof.

Background

Cedrol (cedrol), also known as cedrol, is a sesquiterpene alcohol which has a pleasant and persistent cedar aroma, is widely used in costustoot, spicy and oriental type essences, is also widely used as a fragrance enhancer for disinfectants and sanitary products and a fragrance fixative for essence, and is also an intermediate for synthesizing other fragrances. The research shows that cedrol has obvious inhibiting effect on colibacillus, staphylococcus aureus, bacillus subtilis, salmonella typhi and other bacteria. The cedrol has the pharmacological activity of resisting spasm, relieving pain, resisting inflammation, resisting cancer, resisting virus, resisting free radical oxidation, etc. In addition, cedrol accelerates the growth of skin fibroblasts in a dose-dependent manner and increases the production of collagen type I proteins and elastin. In addition, the inhalation of cedrol in healthy people can increase parasympathetic nerve excitation, reduce sympathetic nerve excitation, act on cardiovascular system, and reduce blood pressure. Cedrol also has termite resistance.

Influenza (flu) is an acute respiratory infectious disease caused by influenza virus, is mainly spread by air droplets, and has the characteristics of sudden outbreak, rapid spread and wide spread. Influenza pandemics worldwide occurred 3 times in the 20 th century, causing the death of tens of millions of people. Even today, influenza still threatens human life and health, and the seasonal influenza worldwide causes 300 to 500 ten thousand severe cases and 29 to 65 ten thousand death cases each year according to the estimation of the World Health Organization (WHO). The influenza virus includes human influenza virus and animal influenza virus, the human influenza virus is divided into A (A), B (B) and C (C)3 types, and is a pathogen of influenza, wherein the A type influenza virus is easy to have antigenic variation and causes a worldwide influenza pandemic for many times. At present, the prevention and treatment of influenza mainly adopt the prevention of vaccination and the development of antiviral drugs and the prevention and treatment of the influenza are repeated. Although vaccination can prevent infection with homoinfluenza viruses, it is desirable to start production just before influenza infection occurs. Accurate prediction of the upcoming influenza strains remains a serious challenge and influenza vaccines are regenerated every year due to antigenic shift and drift of influenza virus, which all pose great difficulties in vaccine production.

In view of the great threat of influenza, the research and development of antiviral drugs aiming at influenza become a research hotspot all the time, and the design of drugs based on structures, such as the neuraminidase inhibitors oseltamivir, peramivir and the like, has great success. However, with the variation of influenza virus, existing anti-influenza drugs face a severe drug resistance situation, and therefore, the development of novel anti-influenza drugs is urgently needed.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The invention aims to provide cedrol derivatives, a preparation method and application thereof. The embodiment of the invention provides a series of novel cedrol derivatives, which have good antagonistic action on viruses, particularly influenza viruses, so that the application range of cedrol and derivatives thereof is expanded, and the types of cedrol derivatives are expanded.

The invention is realized by the following steps:

in a first aspect, the present invention provides a cedrol derivative having the following structural formula:

in a second aspect, the present invention provides a method for preparing cedrol derivatives according to the foregoing embodiments, which includes performing a chemical reaction using cedrol as a raw material to obtain cedrol derivatives.

In a third aspect, the present invention provides a use of cedrol derivatives according to the previous embodiments in the preparation of an antiviral medicament.

The invention has the following beneficial effects: the cedrol derivative provided by the embodiment of the invention has good therapeutic action on viruses, particularly influenza viruses, and can be used for preparing and treating diseases caused by the viruses, so that the application range of the cedrol derivative is expanded, and the variety of the cedrol derivative is also expanded.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The embodiment of the invention provides a cedrol derivative which has the following structural formula:

the embodiment of the invention also provides application of the cedrol derivative in preparing antiviral drugs, and particularly, the viruses are influenza viruses.

It should be noted that: adopted by the embodiment of the invention¹H-and¹³C-NMR was determined by Bruker AVANCE III-600, DRX-500 or AM-400 with internal standard TMS, where¹H NMR was measured at 400MHz, 500MHz and 600MHz,¹³c NMR measurements at 100MHz, 125MHz and 150 MHz; mass spectra HREI-MS and EI-MS are measured by a Finnigan-MAT 90 mass spectrometer; HRESI-MS and ESI-MS were measured by an API QSTAR Pulsar i mass spectrometer; rotating the evaporator: buchi R-200, R-201; DLSB5110 model low temperature reaction coolant circulation pump, IKA RCT basic (safety control type) heating magnetic stirrer.

Column chromatography material: silica gel (80-100 meshes and 200-300 meshes) for column chromatography and preformed GF₂₅₄TLC plates are all produced by Qingdao ocean factories; sephadex LH-20 is a product of Amersham Biosciences, Sweden; chromatorex C-18(40-75 μm) is a product of Fuji Silysia chemical company, Japan. HPLC: agilent 1100, Zorbax SB-C18 column, 5 μm, 4.6mm × 150 mm; Prep-HPLC: agilent 1200, Zorbox SB-C18 column,5 μm, 9.4 mm. times.150 mm. The color development method is to observe fluorescence at 254 and 365nm under fluorescent lamp, I₂Steam color development, heating color development after 10% sulfuric acid vanillin treatment.

Other reagents were obtained from Sigma Aldrich, J & K carbofuran, Beijing InonoKay or Annaiji reagent company, and were all commercially available analytical or chemical pure reagents, and the anhydrous reagents used in the experimental part of the present invention (e.g., anhydrous THF, DCM, Toluene, DMF, etc.) were prepared according to the standard procedures for anhydrous solvents.

The features and properties of the present invention are described in further detail below with reference to examples.

Example 1

This example provides a cedrol derivative (numbered compound 2) named: (3R,3aS,7S,8aS) -3,6,8, 8-tetramethyl-2, 3,4,7,8,8 a-hexahydro-1H-3 a, 7-cedrane, the structural formula of which is shown aS follows:

this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of cedrol (numbered as compound 1) and 0.1mmol of p-toluenesulfonic acid into a reaction vessel, then adding 2mL of acetonitrile, reacting at 50 ℃ for 0.5 hour, after the reaction is finished, adding water or saturated salt solution into the reaction solution, washing and quenching the reaction, then extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 96%.

Characterization data for compound 2 are as follows: colorless oil, 96%,¹H NMR(600MHz,CDCl₃)δ5.23-5.22(m,1H),2.19-2.15(m,1H),1.86-1.57(m,11H),1.40-1.34(m,3H),1.02(s,3H),0.95(s,3H),0.85(d,3H,J＝7.3Hz)；¹³C NMR(150MHz,CDCl₃)δ140.59,119.21,58.92,54.80,53.85,48.17,41.45,40.65,38.81,36.06,27.67,25.61,24.79,15.45。

example 2

This example provides a cedrol derivative (compound No. 3) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-ol, which has the following structural formula:

this example provides a process for the preparation of cedrol derivatives: 0.1mmol of the compound 2 prepared in example 1 was added to a reaction vessel, dissolved in 2mL of THF, and 0.5mmol of BH was added₃After 4H of DMS reaction, 1eq of NaOH and H are then added₂O₂After the reaction is finished for 3 hours, adding water or saturated salt solution into the reaction solution after the reaction is finished, washing and quenching the reaction, then extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and recrystallizing the crude product to obtain the target product with the yield of 81%.

Characterization data for compound 3 are as follows: white salt, 81%, m.p.143-145 ℃.¹H NMR(600MHz,CDCl₃)δ3.79-3.78(m,1H),1.99-1.95(m,1H),1.85-1.83(m,1H),1.75-1.71(m,3H),1.62-1.48(m,5H),1.40-1.24(m,3H),1.20-1.18(m,2H),1.16(d,3H,J＝7.4Hz),1.13(s,3H),0.94(s,3H),0.85(d,3H,J＝6.8Hz)；¹³C NMR(150MHz,CDCl₃)δ72.16,57.28,54.11,53.92,45.87,45.27,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。

Example 3

This example provides a cedrol derivative (numbered compound 4) named: (3R,3aR,6S,7S,8aS) -5- (difluoromethoxy) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane, which has the following structural formula:

this example provides a process for the preparation of the cedrol derivatives: to a reaction vessel was added 0.1mmol of compound 3 provided in example 2 dissolved in 2mL of dichloromethane: to water (1:1), 3.8mmol of TMSCF was added₂Br and 7.6mmol KHF₂Reacting for 2 hours at room temperature, after the reaction is finished, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of about 72 percent.

Characterization of Compound 4The data are as follows: white salt, 72%, m.p.135-136 ℃.¹H NMR(600MHz,CDCl₃)δ6.39-6.13(m,1H),4.26-4.21(m,1H),1.99-1.96(m,1H),1.85-1.82(m,1H),1.75-1.70(m,2H),1.68-1.66(m,2H),1.62-1.57(m,2H),1.52-1.49(m,2H),1.22-1.18(m,2H),1.15(d,3H,J＝6.9Hz),1.12(s,3H),0.94(s,3H),0.85(d,3H,J＝6.9Hz)；¹³C NMR(150MHz,CDCl₃)δ117.11,115.40,113.69,72.14,57.28,54.11,53.92,45.88,45.26,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。

Example 4

This example provides a cedrol derivative (compound 5, No.), named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethylhexahydro-1H-3 a, 7-cedrane-5 (4H) -one, the formula of which is aS follows:

this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of compound 3 into a reaction vessel, dissolving in 2mL of dichloromethane, adding 0.11mmol of PCC, reacting for 3h at room temperature, after the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of about 84%.

Characterization data for compound 5 are as follows: colorless oil, 84%,¹H NMR(600MHz,CDCl₃)δ2.67-2.65(m,1H),2.35(d,1H,J＝1.6.2Hz),2.22-2.18(m,1H),1.89-1.83(m,3H),1.73-1.66(m,2H),1.63-1.56(m,2H),1.44-1.27(m,2H),1.12(d,3H,J＝7.5Hz),0.97(s,3H),0.95(s,3H),0.83(d,3H,J＝6.9Hz)；¹³C NMR(150MHz,CDCl₃)δ215.92,57.46,54.63,54.17,48.75,45.89,41.73,40.57,36.55,35.74,25.96,25.87,24.72,17.18,14.34.HR-EI-MS(positive)m/z 221.18999[M+H]⁺(calcd for C₁₅H₂₅O 221.18272)。

example 5

This example provides a cedrol derivative (numbered compound 6) named: (2aR,3R,5aS,7R) -3,6,6,7 a-tetramethyloctahydro-2H-2 a, 7-cedrane [5,6-b ]]Ethylene oxide, having the formula:

this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of the compound 2 prepared in the embodiment 2 into a reaction vessel, dissolving in 2mL of acetic anhydride, adding 0.12mmol of sodium percarbonate, placing into an ultrasonic reactor, reacting for 8 hours at room temperature, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution, extracting with an organic solvent, drying, distilling under reduced pressure, concentrating to remove the solvent, and separating the crude product by column chromatography to obtain a target product with the yield of 93%.

Characterization data for compound 6 are as follows: colorless oil, 93%,¹H NMR(600MHz,CDCl₃)δ3.00(d,1H,J＝4.6Hz),1.94-1.76(m,4H),1.68-1.56(m,5H),1.42-1.40(m,4H),1.30-1.23(m,2H),1.18(s,3H),0.99(s,3H),0.80(d,3H,J＝6.9Hz)；¹³C NMR(150MHz,CDCl₃)δ61.10,60.94,58.37,53.66,52.03,43.08,41.50,36.78,35.92,35.82,30.12,27.51,25.02,23.74,15.58.HR-EI-MS(positive)m/z 221.18999[M+H]⁺(calcd for C₁₅H₂₅O 221.18272)。

example 6

This example provides a cedrol derivative (No. compound 7) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-yl 2,2, 2-trifluoroacetate of the formula:

this example provides a process for the preparation of the cedrol derivatives: this example provides the same preparation of cedrol derivatives as provided in example 3, except that the starting material, TMSCF₂Br and KHF₂Replacement with trifluoroacetic anhydride and Et₃N。

Characterization data for compound 7 are as follows: white salt, 86%, m.p.125-127 ℃.¹H NMR(600MHz,CDCl₃)δ5.25-5.21(m,1H),2.09-2.06(m,1H),1.99-1.96(m,1H),1.88-1.72(m,5H),1.58-1.55(m,1H),1.43-1.38(m,2H),1.33-1.26(m,2H),1.19(s,3H),1.07(d,3H,J＝7.0Hz),0.98(s,3H),0.86(d,3H,J＝7.6Hz)；¹³C NMR(150MHz,CDCl₃)δ157.63,157.35,157.08,117.53,115.63,113.74,111.84,81.31,58.21,55.08,54.86,46.43,43.90,42.49,41.77,39.13,36.73,28.72,28.03,25.79,17.35,15.50。

Example 7

This example provides a cedrol derivative (No. compound 8) named: (3R,3aR,6S,7S,8aS) -5-allyl-3, 6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-ol, having the formula:

this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of the compound 5 prepared in the example 4 into a reaction container, dissolving the compound in 2mL of anhydrous THF, adding 0.12mmol of allyl bromide test reagent at 0 ℃, reacting for 12h at room temperature after the addition is finished, and adding saturated NH into the reaction solution after the reaction is finished₄And (3) washing and quenching the reaction by using a Cl solution or a saturated salt solution, then extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by using column chromatography to obtain the target product with the yield of about 73%.

Characterization data for compound 8 are as follows: colorless oil, 73%,¹H NMR(600MHz,CDCl₃)δ5.89-5.82(m,1H),5.15-5.08(m,2H),2.48-2.45(m,1H),2.35-2.31(m,1H),2.10-2.07(m,1H),1.83-1.76(m,3H),1.70-1.59(m,2H),1.62-1.59(m,2H),1.51-1.49(m,1H),1.41-1.35(m,2H),1.29(s,3H),1.27-1.25(m,1H),1.13(d,3H,J＝7.6Hz),0.93(s,3H),0.81(d,3H,J＝6.9Hz)；¹³C NMR(150MHz,CDCl₃)δ133.32,117.72,72.14,54.65,53.02,51.59,48.27,46.21,45.88,45.02,42.99,40.94,34.39,28.12,27.19,24.09,14.57,13.81。

example 8

This example provides a cedrol derivative (compound No. 9) named: (3R,3aR,6S,7S, E) -3,6,8, 8-tetramethylhexahydro-1H-3 a, 7-cedrane-5 (4H) -ketoxime, which has the following structural formula:

this example provides a process for the preparation of cedrol derivatives: adding 0.1mmol of compound 5 into a reaction container, dissolving in 2mL of ethanol, adding 0.12mmol of hydroxylamine hydrochloride, adjusting the pH value to be neutral by using 30% NaOH solution, reacting for 12 hours at room temperature after the addition is finished, adding water or saturated salt solution into the reaction solution after the reaction is finished, washing and quenching the reaction, extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain a target product with the yield of about 56%.

Characterization data for compound 9 are as follows: white salt, 56%, m.p.101-103 ℃.¹H NMR(600MHz,CDCl₃)δ9.37-9.31(m,1H),3.18-3.15(m,1H),2.54-2.52(m,1H),1.89-1.86(m,2H),1.80-1.75(m,3H),1.63-1.60(m,1H),1.54-1.48(m,2H),1.37-1.33(m,2H),1.29(d,3H,J＝7.0Hz),1.11(s,3H),0.93(d,6H,J＝7.0Hz)；¹³C NMR(150MHz,CDCl₃)δ161.86,59.89,56.14,54.65,46.56,43.97,43.76,42.21,37.25,34.34,28.40,27.94,25.76,16.64,15.55.HR-EI-MS(positive)m/z 236.20084[M+H]⁺(calcd for C₁₅H₂₆ON 236.19361)。

Example 9

This example provides a cedrol derivative (numbered compound 10) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-amine, which has the following structural formula:

this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of compound 9 into a reaction vessel, dissolving in 2mL of anhydrous THF, adding 0.1mmol of lithium aluminum hydride, heating and refluxing for 12h, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution, extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 70%.

Characterization data for compound 10 are as follows: white salt, 70%, m.p.129-130 ℃.¹H NMR(600MHz,CDCl₃)δ2.09-2.08(m,1H),1.81-1.71(m,4H),1.67-1.65(m,1H),1.59-1.56(m,3H),1.39(s,3H),1.38-1.36(m,1H),1.27-1.25(m,3H),1.20(s,3H),0.97(s,3H),0.93-0.91(m,1H),0.76(d,3H,J＝7.3Hz)；¹³C NMR(150MHz,CDCl₃)δ60.72,52.97,52.12,43.64,41.64,40.05,37.14,36.72,36.16,35.71,30.56,27.65,26.59,24.90,15.52.HR-EI-MS(positive)m/z 220.20576[M+H]⁺(calcd for C₁₅H₂₆N 220.21435)。

Example 10

This example provides a cedrol derivative (compound No. 11) named: (3R,3aR,6S,7S,8aS) -N,3,6,8, 8-pentamethyl octahydro-1H-3 a, 7-cedrane-5-amine, the formula of which is aS follows:

this example provides a process for the preparation of the cedrol derivatives: to a reaction vessel was added 0.1mmol of Compound 10 dissolved in 2mL MeOH and 0.12mmol of CH added₃I and 1.5mmol Na₂CO₃After the reaction is finished, the solvent is removed by reduced pressure distillation and concentration, and the crude product is separated by column chromatography to obtain the target product with the yield of 83 percent.

Characterization data for compound 11 are as follows: colorless oil, 83%,¹H NMR(600MHz,CDCl₃)δ2.28(s,3H),1.96-1.93(m,1H),1.83-1.70(m,3H),1.64-1.51(m,4H),1.40-1.36(m,1H),1.30(s,3H),1.28-1.23(m,3H),1.22(s,3H),1.18-1.14(m,1H),0.97(s,3H),0.77(d,3H,J＝7.0Hz)；¹³C NMR(150MHz,CDCl₃)δ60.94,54.81,51.79,45.21,43.74,41.65,39.75,36.42,36.40,35.65,30.71,27.90,24.87,16.09,15.56.HR-EI-MS(positive)m/z 234.22147[M+H]⁺(calcd for C₁₆H₂₈N 234.23000)。

example 11

This example provides a cedrol derivative (numbered compound 12) named: (3R,3aR,6S,7S,8aS) -5- (4-chlorophenyl) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-ol, which has the following structural formula:

this example provides a process for the preparation of the cedrol derivatives: the synthesis method was the same as the preparation method of example 7 except that the propylene bromide grignard reagent was replaced with p-chlorobenzene grignard reagent.

Characterization data for compound 12 are as follows: colorless oil, 51%,¹H NMR(600MHz,CDCl₃)δ7.19(d,2H,J＝8.6Hz),6.77(d,2H,J＝8.6Hz),5.15(brs,1H),2.79-2.76(m,1H),2.45-2.42(m,1H),2.24-2.21(m,1H),1.94-1.86(m,3H),1.71-1.55(m,8H),1.46(s,3H),1.43-1.39(m,1H),1.33-1.28(m,2H),1.01(s,3H),1.00(s,3H),0.86(d,3H,J＝7.0Hz)；¹³C NMR(150MHz,CDCl₃)δ154.22,129.49,125.54,116.65,61.44,58.64,55.44,48.66,41.32,40.95,38.92,37.01,29.00,28.78,25.66,24.09,15.61.HR-EI-MS(positive)m/z 331.18500[M+H]⁺(calcd for C₂₁H₂₈OCl 331.19069)。

example 12

This example provides a cedrol derivative (compound No. 13) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-formyl, the formula of which is aS follows:

this example provides a process for the preparation of the cedrol derivatives: this synthesis is identical to the preparation of example 3, except that oxalyl chloride is used.

Characterization data for compound 13 are as follows: colorless oil, 87%,¹H NMR(600MHz,CDCl₃)δ8.11(s,1H),5.20-5.15(m,1H),2.04-2.00(m,1H),1.87-1.68(m,7H),1.59-1.52(m,2H),1.40-1.37(m,1H),1.33-1.22(m,4H),1.18(s,3H),1.05(d,3H,J＝7.5Hz),0.96(s,3H),0.84(d,3H,J＝7.5Hz)；¹³C NMR(150MHz,CDCl₃)δ160.19,74.78,57.13,54.06,53.73,45.60,42.87,41.62,40.78,38.84,35.73,27.75,26.99,24.74,16.57,14.46。

example 13

This example provides a cedrol derivative (numbered compound 14) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-yl 4-methylbenzenesulfonate having the following structural formula:

this example provides a process for the preparation of the cedrol derivatives: the synthesis method is the same as the preparation method of example 3 except that p-toluenesulfonic anhydride is used.

Characterization data for compound 14 are as follows: white salt, 87%, m.p.74-76 ℃.¹H NMR(600MHz,CDCl₃)δ7.82-7.80(m,2H),7.33-7.32(m,2H),4.70-4.65(m,1H),2.43(s,3H),1.96-1.92(m,1H),1.83-1.79(m,2H),1.71-1.61(m,4H),1.52-1.48(m,1H),1.43-1.33(m,2H),1.25-1.22(m,1H),1.17-1.15(m,1H),1.06(s,3H),0.91(s,3H),0.85(d,3H,J＝7.5Hz),0.75(d,3H,J＝7.5Hz)；¹³C NMR(150MHz,CDCl₃)δ143.37,133.66,128.59,126.78,84.67,57.11,54.22,53.86,45.23,42.75,42.00,40.60,40.07,35.59,27.64,26.96,24.70,20.60,16.45,14.36。

Example 14

This example provides a cedrol derivative (compound No. 15) named: (3R,3aR,7R,8aS) -6-hydroxy-3, 6,8, 8-tetramethylhexahydro-1H-3 a, 7-cedrane-5 (4H) -one, the formula of which is aS follows:

this example provides a process for the preparation of the cedrol derivatives: to a reaction vessel was added 0.1mmol of compound 5 prepared in example 4 dissolved in 2mL of anhydrous DMSO: CH (CH)₃And (2) adding 0.1mmol of potassium tert-butoxide into OH (10:1), reacting at room temperature for 5h, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution to react, extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product, wherein the yield of the compound is 80%.

Characterization data for compound 15 are as follows: colorless oil, 80%,¹H NMR(600MHz,CDCl₃)δ2.78-2.75(m,1H),2.44-2.42(m,1H),2.23-2.20(m,1H),1.93-1.88(m,3H),1.70-1.66(m,5H),1.45(s,3H),1.32-1.29(m,3H),1.01(s,3H),0.99(s,3H),0.86(d,3H,J＝7.3Hz)；¹³C NMR(150MHz,CDCl₃)δ210.45,60.41,57.60,54.39,47.61,40.30,39.91,37.91,35.99,27.96,27.77,24.63,23.05,14.59.HR-EI-MS(positive)m/z 237.18481[M+H]⁺(calcd for C₁₅H₂₅O₂ 237.17763)。

examples of the experiments

The virus strain: the influenza virus strain H1N1 PR8 was expanded and stored in this laboratory.

Cell model: dog kidney cell line MDCK, passage preservation in this laboratory. The culture conditions are as follows: DMEM + 10% fetal bovine serum, 37 ℃ and 5% CO₂。

The samples were tested for their toxic effects on cells using the CellTiter-GloTM (Promega) kit.

Principle of cytotoxicity test: the CellTiter-Glo kit detects the number of viable cells in culture by quantitative determination of ATP. ATP may be produced by the respiration of metabolically active cells and other life processes, the stable glow-type signal generated by the luciferase being used in the kit, the luciferase requiring the involvement of ATP in the light-emitting process. When CellTiter-Glo reagent is added into cell culture medium to measure luminous value, the light signal is in direct proportion to ATP amount in the system, and ATP amount is in positive correlation with the number of living cells, so that the light signal value can reflect the number of living cells.

Cytotoxicity test procedure: and inoculating the MDCK cells into a 96-well cell culture plate, and keeping the cells for later use after the cells are attached to the wall. Compounds 1-15 were serially diluted 3-fold in 8-fold gradient with DMEM medium from 2-fold the highest assay concentration, respectively. Adding the compound and appropriate amount of culture medium into cells, and adding CO at 37 deg.C₂Culturing in an incubator. After adding drugs and culturing for 24h, observing cytopathic effect (CPE) caused by the drugs under a microscope, and adding CellTiter-Glo to detect the cell survival rate. The toxicity of a drug to a cell is expressed as the activity of the cell.

Calculating the formula: cell activity (%) ═ drug group value/cell control group mean value 100.

Experimental principle of antiviral activity: the experiment measures the level of influenza virus protein expression to detect the level of virus replication. The expression level of structural proteins of influenza viruses is directly proportional to the replication of the virus; the experiment adopts a high-sensitivity reagent to detect the expression of the influenza virus protein, and the expression is reflected by the change of the fluorescence intensity.

And (3) antiviral activity detection: MDCK cells were seeded in 96-well cell culture plates and cultured overnight at 37 ℃ for use. The corresponding compound and H1N1 virus solution were added simultaneously to MDCK cells. Culturing in a 37 deg.C cell culture box for 24 hr, and collecting culture supernatant for detection.

The experiment was performed with blank control wells (normal cells), virus control wells (no drug added after virus infection), and positive drug control wells (ribavirin added after infection).

Inhibition (%) > 100- (sample well number-blank number)/(virus control number-blank number) × 100.

The results are shown in the following table.

According to the table, the cedrol derivative provided by the embodiment of the invention has a good antiviral effect, and can be used for preparing antiviral medicines.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A cedrol derivative is characterized by being represented by the following structural formula:

2. the method for preparing cedrol derivatives according to claim 1, comprising the steps of:

adding 0.1mmol of cedrol and 0.1mmol of p-toluenesulfonic acid into a reaction vessel, then adding 2mL of acetonitrile, reacting for 0.5 hour at 50 ℃, after the reaction is finished, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain a compound 2;

adding 0.1mmol of compound 2 into a reaction vessel, dissolving in 2mL of THF, adding 0.5mmol of BH₃After 4H of DMS reaction, 1eq of NaOH and H are then added₂O₂After reacting for 3 hours, after the reaction is finished, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and recrystallizing the crude product to obtain a compound 3;

adding 0.1mmol of compound 3 into a reaction vessel, dissolving in 2mL of dichloromethane, adding 0.11mmol of PCC, reacting for 3h at room temperature, after the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and separating the crude product by column chromatography to obtain a compound 5;

to the reaction vessel was added 0.1mmol of compound 5 dissolved in 2mL of anhydrous DMSO: CH (CH)₃And (2) adding 0.1mmol of potassium tert-butoxide into OH (10:1), reacting at room temperature for 5h, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution for reaction, extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the cedrol derivative.

3. Use of cedrol derivative as claimed in claim 1 in the preparation of antiviral medicament; the virus is influenza virus.

4. The use as claimed in claim 3, wherein the cedrol derivative is present in the medicament in an amount of 0.1 to 99% by mass.

5. The use as claimed in claim 4, wherein the cedrol derivative is present in the medicament in an amount of 0.5 to 90% by mass.