CN112891329A - Application of terpenoid in preparation of anti-influenza virus medicine - Google Patents
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Abstract
The invention relates to the field of pharmaceutical chemistry, and particularly discloses application of a terpenoid in preparation of an anti-influenza virus medicament. The terpenoid has a structure shown in a general formula I. The inventor conducts activity screening on terpenoid compounds with the structure shown in the general formula I, and discovers that the terpenoid compounds with the structure shown in the general formula I have excellent anti-influenza virus activity for the first time; among the compounds, cyperenoic acid and other compounds have very remarkable inhibitory effect on influenza viruses. The screening of in vitro and in vivo anti-influenza virus experiments shows that cyperenoic acid has an inhibiting effect on the influenza A H1N1 virus which is equivalent to or even stronger than that of oseltamivir phosphate serving as a positive control medicament.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to application of terpenoid in preparing anti-influenza virus medicines.
Background
Influenza viruses are a major threat to human health. Respiratory diseases caused by influenza viruses are called influenza (flu), and have the characteristics of wide epidemic range, strong infectivity, high morbidity and the like. Influenza as a viral infectious disease not only seriously threatens the health of people, but also brings heavy burden to the nation and the society, and how to effectively prevent and treat influenza, especially highly pathogenic influenza, becomes an important subject which is urgently researched and solved before medicinal workers in various countries around the world. Because of influenza virus antigen variation, the conventional vaccine cannot effectively prevent outbreak and epidemic of influenza at present, so that the research on anti-influenza virus medicaments has important significance in influenza treatment.
The terpenoid with the structure shown in the general formula I is a compound separated from a traditional Chinese medicine, namely the chicken bone incense in the earlier stage by the inventor; through retrieval and analysis, the compounds are also separated from other natural plants and are known compounds; of course, the compounds have been reported to be synthesized by synthetic methods. However, terpenoids of the structure shown in formula I have not been reported to have an anti-influenza virus effect. "biological-guided isolation of anti-hepatitis B virus active tissue culture from the traditional Chinese medicine", "Structure of the tissue hydrophilic carbon cycle", "Sestissues from Rhizomes of Cyperus with cytoxic Activities on Human Cancer Cells in vitro", "Sestissues from the infection of Cyperus epithelial tissues", "New clinical reagent from the tissue of cell epithelial tissues of the tissue culture, compounds of the general classes of compounds from the microorganisms of the nutritional dichotomous Pax, Evaluation of the pharmaceutical immunological products and the synthetic antibodies AS potential immunological therapeutic agents, microbiological information of the genetic acid and genetic infection of the genetic acid derivatives AS 3.2028and the genetic acid and genetic activity of the microorganisms of the genetic acid and genetic acid derivatives AS 3.2028 are disclosed.
The above-mentioned reference also discloses that the compound has an anti-hepatitis B virus effect, but it does not disclose that the compound has an anti-influenza virus effect. In the field of medicinal chemistry, the predictability of the antiviral action of a medicament is low, and a certain compound has an inhibiting effect on a certain virus, but does not represent that the compound also has an inhibiting effect on other viruses. For example, the common anti-influenza virus drug oseltamivir phosphate only has an inhibitory effect on influenza viruses, and has no inhibitory effect or obvious inhibitory effect on other viruses. That is, the person skilled in the art cannot expect that the compound has an inhibitory effect on other viruses based on the effect of the compound disclosed in the above documents on the hepatitis b virus, and even cannot expect that the compound has a significant inhibitory effect on which virus.
Disclosure of Invention
The invention aims to solve the technical problem of providing an application of a terpenoid in preparing an anti-influenza virus medicament in order to overcome the defects of the development of anti-influenza virus medicaments in the prior art.
The technical problem to be solved by the invention is realized by the following technical scheme:
the application of terpenoid in the preparation of anti-influenza virus drugs, wherein the terpenoid has a structure shown as a general formula I:
wherein R1 is selected from hydrogen atom and C1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r2 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r3 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r4 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r5 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r6 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10。
Preferably, R1 is selected from hydrogen atom, C1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r2 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r3 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r4 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r5 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r6 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; and n is 0-5.
Further preferably, R1 is selected from the group consisting of hydrogen atom, C1～3Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-3;
r2 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r3 is selected from the group consisting of hydrogen atom, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r4 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r5 is selected from hydrogen atom, ═ O, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r6 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、 -(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; and n is 0-3.
Most preferably, R1 is selected from the group consisting of a hydrogen atom, methyl, -COOH, -COOCH3、CH2OCOCH3、-CHO、 -CH2OH、CONHC2H5、CONHC4H9Or CONHC6H4OCH3。
Most preferably, R2 is selected from the group consisting of hydrogen atom, ═ O, -OCOCH3or-OH. Most preferably, R3 is selected from a hydrogen atom, ═ O or-OH. Most preferably, R4 is selected from the group consisting of hydrogen atom, ═ O, -OCOCH3-OH or O-Glu. Most preferably, R5 is selected from a hydrogen atom, ═ O, or-OH. Most preferably, R6 is selected from the group consisting of hydrogen atom, ═ O, -OCOCH3-OH or OCH3。
Specifically, the terpenoid is selected from any one of compounds 1-41 in Table 1.
TABLE 1 terpenoids having the structure shown in general formula I
Preferably, the influenza virus is an influenza a virus and/or an influenza b virus.
Has the advantages that: the inventor of the invention conducts activity screening on terpenoid compounds with the structure shown in the general formula I, and finds that the terpenoid compounds with the structure shown in the general formula I all have excellent anti-influenza virus activity; the inhibition effect of the terpenoid with the structure shown in the general formula I on other viroids is not as remarkable as that of influenza viruses. The result is related to the structure of the terpenoid with the structure shown in the general formula I, and the terpenoid with the structure shown in the general formula I forms 4 annular structures, wherein 2 five-membered rings, 1 six-membered ring and 1 seven-membered ring are formed; the compounds having the parent nucleus structure all have excellent anti-influenza virus effects. However, the compound having the parent nucleus structure is not effective against other viruses. Further tests show that the compounds 1-6, 9, 12, 17, 20, 22, 31, 35, 39 and 40 in the compounds have EC on influenza A virus H1N150Has a value lower or significantly lower than the EC of oseltamivir phosphate50A value; this indicates that the inhibitory effect of these compounds on H1N1 influenza virus is greater than or even far greater than that of the positive control drug oseltamivir phosphate. These compounds have unexpected anti-influenza virus effects.
Drawings
FIG. 1 is a graph showing the change in body weight of mice.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to these examples in any way.
Experimental example 1 in vitro anti-influenza A Virus Activity test
Cytotoxicity experiments: 6X 104The MDCK cells/mL are paved in a 96-well plate, placed in an incubator at 37 ℃ overnight, then the diluted compound to be tested is added in a multiple ratio, the culture is continued for 48 hours, the old culture medium is discarded, a fresh culture medium containing 10 percent is added, the culture is continued for 0.5 to 2 hours, then the OD value is measured, and the half lethal concentration (CC) of the compound is calculated by Graphpad Prime 6.0 software50)。
Plaque reduction method: MDCK cells grown in six-well plates full in monolayers were infected with virus (-50 pfu/well) and incubated in an incubator at 37 ℃ for 1 hour, shaking every 15 minutes. The cells were washed twice with PBS, agarose containing compounds at different concentrations was added, and then cultured for 48 to 72 hours, and after the cells were fixed with paraformaldehyde for 15 minutes, they were stained with crystal violet, and then blotted. The concentration at which the number of plaques decreased by half after the treatment with the test compound was found to be the half inhibitory concentration (EC) of the compound50)。
The above method was used to test the CC of compounds 1-41 and positive control Oseltamivir phosphate (Oseltamivir phosphate) in Table 1 against A/PR/8/34H 1N1, A/FM/1/47H 1N1, A/chicken/Guangdong/1996H 9N2, and A/Hong Kong/498/97H 3N2 strains50And EC50The values, specific results are shown in Table 2.
TABLE 2 in vitro anti-influenza A Virus Activity test results
As shown in the results of in vitro anti-influenza virus activity tests in Table 2, the terpenoid compound with the structure shown in the general formula I has an inhibiting effect on influenza A H1N1, influenza A H3N2 and/or influenza A H9N 2. The result shows that the terpenoid compound with the structure shown in the general formula I can be used as a potential lead compound of anti-influenza virus medicines and used for preparing anti-influenza virus medicines.
Table 2 in vitro anti-influenza virus activity test results also show that the EC of the compounds 1-6, 9, 12, 17, 20, 22, 31, 35, 39 and 40 on influenza A H1N1 virus50Has a value lower or significantly lower than the EC of oseltamivir phosphate50A value; this indicates that the inhibitory effect of these compounds on H1N1 influenza virus is greater than or even far greater than that of the positive control drug oseltamivir phosphate. These compounds have unexpected anti-influenza virus effects.
Comparative example 1 in vitro anti-HSV and RSV Activity test of the terpenoid cyperenic acid having the Structure shown in general formula I
Screening anti-HSV activity: vero cells grown to 80% in 96-well plates, were aspirated off the old, cyperenoic acid diluted at a multiple of 100. mu.L/well in DMEM medium with 2% FBS was added, and 200TCID was added per well50Of HSV-1/HSV-2 virus solution, adding 100 μ L DMEM culture solution containing 2% FBS and 100 μ L virus solution into each well of virus control group, adding only 200 μ L DMEM culture solution containing 2% FBS into cell control group, setting 4 repeat wells in each group, placing at 37 deg.C, 5% CO2The cells were cultured in a cell incubator for 2-3 days, and the cytopathic condition was observed every day, and when the viral lesions reached more than 75%, i.e., complete lesions (+++), the cytopathic condition was recorded for each well, 0-25%: +; 25% -50%: + +; 50-75%: + + + +; 75-100%: ++++. The HSV-1 and HSV-2 are herpes simplex virus type I and herpes simplex virus type II respectively. As a result: half maximal inhibitory concentration (EC) of Cyperenoid acid on HSV-1 and HSV-250) All at 200. mu.M, complete inhibitory concentration (EC)100) All at 400. mu.M, half inhibitory concentration (CC)50)>800μM，SI>4。
Screening for anti-RSV activity: human laryngeal squamous carcinoma (HEp2) cells plated in 96-well plates were grown to 80%, old fluid was aspirated off, cyperenoic acid diluted at a doubling ratio in DMEM medium with 2% FBS at 100. mu.L/well was added, and then 200TCID was added per well50The RSV of (1), wherein 100. mu.L of DMEM culture solution containing 2% FBS and 100. mu.L of virus solution are added to each well of the virus control group, only 200. mu.L of DMEM culture solution containing 2% FBS is added to the cell control group, each group is provided with 4 repeat wells, and the cells are placed at 37 ℃ and 5% CO2The cells were cultured in a cell incubator for 2-3 days, and the cytopathic condition was observed every day, and when the viral lesions reached more than 75%, i.e., complete lesions (+++), the cytopathic condition was recorded for each well, 0-25%: +; 25% -50%: + +; 50-75%: + + + +; 75-100%: ++++. As a result: EC of cyperenoic acid on RSV50Is 150 μ M, CC50>200μM，SI>1.3。
The EC of cyperenoid acid on HSV can be seen from the comparative test50EC for RSV at 200. mu.M 50150 μ M, much higher than the EC of influenza A H1N1 virus50This indicates that cyperenoic acid does not significantly inhibit HSV and RSV viruses. This also indicates that the compounds having the parent nucleus structure of formula I do not have significant inhibitory effects on all viruses. The compound with the mother nucleus structure shown in the general formula I has obvious inhibition effect on which viruses, and the fieldThe skilled person is unforeseeable.
Example 2 in vivo anti-influenza Virus Activity assay
4-6 weeks old male mice were selected and randomly divided into 8 groups, 10 mice/group. Each mouse was infected with 50. mu.L of A/PR 8/34H 1N1 of 2LD50 by nasal drip, and two hours later, the drugs were administered in the following groups, respectively; continuous administration for 5 days; for testing the in vivo activity of cyperenoid acid and Oseltamivir phosphate (Oseltamivir). After the administration, the body weight and death of the mice were recorded daily and observed for 14 days. The results are shown in FIG. 1 and Table 2.
Ca (cyperenoid acid) test group administration and dose:
(1) gavage, 2 times/day: high dose group (80 mg/kg/day), medium dose group (40 mg/kg/day), low dose group (20 mg/kg/day); the high, medium and low dose components of cyperenoid acid administered by intragastric administration are respectively abbreviated as: CA (o.p.80mg/kg/day), CA (o.p.40mg/kg/day), and CA (o.p.20mg/kg/day).
(2) Intraperitoneal injection, 1 time per day: high dose group (40 mg/kg/day), medium dose group (20 mg/kg/day), low dose group (10 mg/kg/day); the high, medium and low dose components of cyperenoid acid administered by intraperitoneal injection are respectively abbreviated as follows: CA (i.p.80mg/kg/day), CA (i.p.40mg/kg/day), and CA (i.p.20mg/kg/day).
Oseltamivir test groups administration mode and dose:
gavage, 2 times/day: 20 mg/kg/day; the abbreviation is: oseltamivir (o.p.20mg/kg/day).
Administration and dose of virus control group:
gavage administration of solvent (28% Na)2CO3+42％NaHCO3+ 30% PEG300), 2 times/day; the abbreviation is: a vehicle.
As can be seen from the graph of the change curve of the body weight of the mouse in figure 1, the intraperitoneal injection administration mode of cyperenoid acid has better effect than the intragastric administration mode; mice in the cyperenoic acid (i.p.20mg/kg/day) and cyperenoic acid (i.p.10 mg/kg/day) groups showed weight loss at a magnitude better than/equivalent to the positive control drug oseltamivir, and both of them were able to protect infected mice well compared with the virus control group (vehicle).
As can be seen from the experiments in Table 3, the mortality rate of the mice in the virus control group reaches 80%, while the survival rates of the mice in the cyperenoic acid intraperitoneal injection group, the middle-low dose gastric lavage administration group and the oseltamivir control group reach 100%.
The in vivo anti-influenza virus activity test experiment shows that Cyperenoic acid also has anti-influenza virus activity in vivo which is equivalent to that of oseltamivir phosphate (oseltamivir), a positive control drug; particularly, cyperenoic acid has better/equivalent reduction amplitude on the weight of mice than the positive control drug oseltamivir phosphate group, which also indicates that cyperenoic acid has smaller in vivo side effect than the positive control drug oseltamivir phosphate. Therefore, cyperenoic acid can be used for preparing a medicament against influenza viruses.
TABLE 3 mouse survival test results
a
Mortality rate
b
A protection index.
Claims (10)
1. The application of the terpenoid in the preparation of anti-influenza virus drugs is characterized in that the terpenoid has a structure shown as a general formula I:
wherein R1 is selected from hydrogen atom and C1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r2 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r3 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r4 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r5 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-10;
r6 is selected from hydrogen atom (O, C)1～10Alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; and n is 0-10.
2. Use according to claim 1, wherein R1 is selected from hydrogen atom, C1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r2 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r3 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r4 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r5 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-5;
r6 is selected from hydrogen atom (O, C)1～5Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-O-glycosyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; and n is 0-5.
3. Use according to claim 2, wherein R1 is selected from hydrogen atom, C1～3Alkyl, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-CHO、-(CH2)n-CO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl, - (CH)2)n-CONH2、-(CH2)n-CONH-alkyl, - (CH)2)n-CONH-aryl or- (CH)2)n-CONH-substituted aryl; n is 0-3;
r2 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r3 is selected from the group consisting of hydrogen atom, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r4 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r5 is selected from hydrogen atom, ═ O, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; n is 0-3;
r6 is selected from hydrogen atom, ═ O, - (CH)2)n-COOH、-(CH2)n-COO-alkyl, - (CH)2)n-OH、-(CH2)n-O-alkyl or- (CH)2)n-an O-glycosyl group; and n is 0-3.
4. Use according to claim 3, wherein R1 is selected from the group consisting of a hydrogen atom, a methyl group, -COOH, -COOCH3、CH2OCOCH3、-CHO、-CH2OH、CONHC2H5、CONHC4H9Or CONHC6H4OCH3。
5. Use according to claim 3, wherein R2 is selected from the group consisting of hydrogen atom, ═ O, -OCOCH3or-OH.
6. Use according to claim 3, wherein R3 is selected from the group consisting of a hydrogen atom, ═ O and-OH.
7. Use according to claim 3, wherein R4 is selected from the group consisting of hydrogen atom, ═ O, -OCOCH3-OH or O-Glu; r5 is selected from a hydrogen atom, ═ O, or — OH; r6 is selected from hydrogen atom, ═ O, -OCOCH3-OH or OCH3。
8. Use according to claim 3, wherein R1 is selected from methyl, -COOH, -COOCH3、CH2OCOCH3、-CHO、-CH2OH、CONHC2H5、CONHC4H9Or CONHC6H4OCH3R2 is selected from hydrogen atoms, R3 is selected from hydrogen atoms, R4 is selected from hydrogen atoms,r5 is selected from hydrogen atoms and R6 is selected from hydrogen atoms; or the like, or, alternatively,
r1 is selected from methyl, -COOH, CH2OCOCH3、-CH2OH, R2 is selected from hydrogen atom, ═ O or-OH, R3 is selected from hydrogen atom, ═ O or-OH, R4 is selected from hydrogen atom, R5 is selected from hydrogen atom and R6 is selected from hydrogen atom; or the like, or, alternatively,
r1 is selected from methyl, R2 is selected from hydrogen atom, R3 is selected from hydrogen atom, R4 is selected from hydrogen atom, R5 is selected from hydrogen atom and R6 is selected from-OH.
9. The use according to claim 1, wherein the terpenoid is cyperenic acid.
10. The use according to claim 1, wherein the influenza virus is an influenza a virus and/or an influenza b virus.
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| US6063383A (en) * | 1999-01-28 | 2000-05-16 | Hsu; Wu-Ching | Pharmaceutical suppository composites for fever and influenza and method of producing the composites |
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