CN109745306A - 9,10- anthraquinone derivative, preparation method and application - Google Patents
9,10- anthraquinone derivative, preparation method and application Download PDFInfo
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Abstract
The invention discloses 9,10- of one kind anthraquinone derivative, preparation method and applications.The present invention provides a kind of 9,10- anthraquinone derivative or its pharmaceutically acceptable salt shown in formula I in preparation for treating and/or preventing the application in hepatitis C drug；Wherein, R R1Substituted C1~C4Alkyl；All R1It independently is-COOR1‑1、‑OH、‑CN、C1~C4Alkyl or C1~C4Alkoxy；All R1‑1It independently is C1~C4Alkyl.9,10- anthraquinone derivative provided by the invention shows preferable anti-HCV activity.
Description
Technical field
The present invention relates to 9,10- of one kind anthraquinone derivative, preparation method and applications.
Background technique
Hepatitis C is caused by Hepatitis C Virus (HCV) infects, mainly by blood/body fluid communication.According to world health group
Estimation is knitted, the whole world there are 1.7 hundred million people's HCV infections.In China, healthy population HCV-Ab IgG positive rate is 0.7%~3.1%, about 38,000,000
People.Due to many factors such as viral biology feature and host immune functions, immunity of organism is often difficult to effectively remove virus,
Causing about 50%~80%HCV the infected development is chronic hepatitis, wherein 20%~30% will develop into cirrhosis.Cirrhosis is suffered from
There is 1%~4% to develop into hepatocellular carcinoma in person every year.Since HCV is through blood born, has the characteristics that chronic, invisible, portion
Point HCV infection person would develop into chronic hepatitis, and serious person can even develop as cirrhosis, hepatic failure or liver cancer (" China's AIDS
Venereal disease ", 2017 (5): 461-462；" Journal of Jilin Medical College ", 2017,38 (2): 123-126).
Physcion (physcion) belongs to anthraquinone analog compound, is widely present in polygonaceae, pulse family, Labiatae, composite family, orchid
In section and rosaceous various plants perhaps.Physcion is to staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, streptococcus
There is inhibiting effect with 26 kinds of bacteriums such as shigella dysenteriaes；Physcion is highly active vegetable source bactericide, to powdery mildew, downy mildew
Disease, gray mold, anthracnose etc. have good control efficiency.(" Chinese traditional Chinese medicine academic periodical ", 2015 (4): 938-940).Patent
CN200810203112.1, which also discloses Physcion, certain inhibiting effect to hepatitis C virus, but action intensity is general,
Need further structure of modification to increase activity.
Summary of the invention
Technical problem to be solved by the invention is to provide 9,10- of one kind anthraquinone derivative, preparation method and applications.It should
9,10- anthraquinone derivatives show preferable anti-HCV activity.
The present invention provides a kind of 9,10- anthraquinone derivatives or its pharmaceutically acceptable salt shown in formula I to prepare
For treating and/or preventing the application in hepatitis C drug；
Wherein, R R1Substituted C1~C4The alkyl (R1Number can be one or more, and can be 1,2
It is a or 3；When there are multiple R1When, any two R1It is identical or different；" the C1~C4Alkyl " for example methyl, ethyl,
N-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl or ethyl；The R1Substituted C1~C4
Alkyl can be 2- hydroxyethyl, cyano methyl or ethoxycarbonylmethyl group)；
All R1It independently is-COOR1-1、-OH、-CN、C1~C4Alkyl (such as methyl, ethyl, n-propyl, isopropyl
Base, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl) or C1~C4Alkoxy (such as methoxyl group, ethyoxyl,
Positive propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy)；
The R1-1For C1~C4Alkyl (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or
Tert-butyl, in another example ethyl).
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
R is R1Substituted C1~C4Alkyl；All R1It independently is-OH or-CN.
The hepatitis C can be HCV2a type (such as caused by JFH1 Strain).
The present invention also provides the compound I to prepare the application in HCV inhibitor.The HCV such as HCV2a type
(such as caused by JFH1 Strain).
Invention further provides a kind of pharmaceutical composition, the pharmaceutical composition includes 9,10- anthracene as described above
Quinone derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.The pharmaceutical composition can be for for controlling
Treat and/or prevent the pharmaceutical composition of hepatitis C.
The present invention also provides a kind of 9,10- anthraquinone derivatives or its pharmaceutically acceptable salt as shown in Formula II:
Wherein, R ' is R2Substituted C1~C4The alkyl (R2Number can be one or more, and can be 1,2
It is a or 3；When there are multiple R2When, any two R2It is identical or different；" the C1~C4Alkyl " for example methyl, ethyl,
N-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl)；
All R2It independently is-COOR1-1Or-CN；
The R1-1For C1~C4Alkyl (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group
Or tert-butyl, in another example ethyl).
The R2Substituted C1~C4Alkyl can be cyano methyl or ethoxycarbonylmethyl group.
The present invention also provides a kind of preparation methods of above-mentioned Formula II compound comprising following step: in the presence of alkali
Under, compound 1 (rheum emodin) and compound 2 are subjected to substitution reaction, obtain the Formula II compound；
X is halogen.
The halogen can be fluorine, chlorine, bromine or iodine；It can also be chlorine or bromine.
The alkali can be conventional for such reaction of this field alkali, such as inorganic base (such as alkali carbonate, in another example
Potassium carbonate) and/or organic base (such as organic amine, in another example triethylamine).
The reaction condition of the substitution reaction can be the reaction condition of such reaction routine of this field, such as following reactions
Condition:
The substitution reaction can carry out in ketone or ether solvent.The ketones solvent can such be anti-for this field
Answer conventional ketones solvent, such as acetone；The ether solvent can be the ether solvent of such reaction routine of this field, such as
Tetrahydrofuran and/or dioxane.The Molar ratio of the ketone or ether solvent and the compound 1 can be ability
The conventional Molar ratio of such reaction of domain, such as 3mL/mmol.
In the substitution reaction, the molar ratio of the compound 2 and the compound 1 can for this field such
React conventional molar ratio, such as 2~3.
In the substitution reaction, the compound 2 such can be reacted with the molar ratio of the alkali for this field
Conventional molar ratio, such as 1~1.5.
The temperature of the substitution reaction can be conventional for such reaction of this field temperature, such as 0 DEG C~100 DEG C (such as
45 DEG C~50 DEG C).
The process of the substitution reaction can be used the routine monitoring method (such as TLC, HPLC or NMR) in this field into
Row monitoring, as reaction end when generally no longer being reacted using compound 1, the reaction time can be 5h~15h (such as 12h).
Term " pharmaceutically acceptable salt " is indicated by suitable non-toxic organic, inorganic acid, organic base or inorganic base
The salt formed with compound retains the bioactivity of compound.The organic acid can for this field it is conventional can be at salt
Various organic acids, such as methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, first
One of acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acids and salicylic acid or
It is a variety of.The inorganic acid can for this field it is conventional can be at the various inorganic acids of salt, such as one in hydrochloric acid, sulfuric acid and phosphoric acid
Kind is a variety of.The organic base can for this field it is conventional can be at the various organic bases of salt, such as pyridines, imidazoles, pyrrole
One of piperazine class, indoles, fast quinoline class, tertiary amines and phenyl amines are a variety of.The tertiary amines organic bases such as triethylamine
And/or n,N-diisopropylethylamine.The phenyl amines organic bases such as n,N-Dimethylaniline.The pyridines organic base
Such as one of pyridine, picoline, 4-dimethylaminopyridine and 2- methyl -5- ethylpyridine or a variety of.Described is inorganic
Alkali can for this field it is conventional can be at hydroxide, the alkali metal of the various inorganic bases of salt, such as alkali metal hydride, alkali metal
One of alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, saleratus and sodium bicarbonate or a variety of.It is described
Alkali metal hydride such as sodium hydride and/or hydrofining.The hydroxide of the alkali metal such as sodium hydroxide, hydroxide
One of potassium and lithium hydroxide are a variety of.The alkoxide of the alkali metal for example sodium methoxide, sodium ethoxide, potassium tert-butoxide and
One of sodium tert-butoxide is a variety of.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: 9,10- anthraquinone derivative provided by the invention shows preferable HCV-Ab IgG
Activity.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
It takes 5mmol rheum emodin to be dissolved in 15mL acetone, 10mmol potassium carbonate and 15mmol chloroacetonitrile is added, be warming up to 45 DEG C instead
It answers 12 hours, decompression steams solvent, adds 15mL water, then three times with the extraction of 15mL ethyl acetate, organic phase merges, 15mL washing one
Secondary, column chromatographs (PE/EA=4/1) and obtains compound 1, yield 59%.
1H NMR (500MHz, CDCl3) δ 12.29 (s, 1H), 11.99 (s, 1H), 7.65 (s, 1H), 7.41 (d, J=
2.5Hz, 1H), 7.11 (s, 1H), 6.79 (d, J=2.0Hz, 1H), 4.91 (s, 2H), 2.47 (s, 3H)；13C NMR (126MHz,
CDCl3) δ 191.1,181.4,164.9,162.7,162.6,149.1,135.8,132.9,124.8,121.6,113.8,
113.5,111.9,108.1,107.1,53.3,22.2；ESI-MS:m/z 310.2 [M+H]+；307.9[M-H]-。
Embodiment 2
Chloroacetonitrile is only replaced with bromoacetate, obtains compound 2, yield by reaction condition and operation with embodiment 1
45%.
1H NMR (500MHz, CDCl3) δ 12.27 (s, 1H), 12.05 (s, 1H), 7.62 (s, 1H), 7.37 (d, J=
2.5Hz, 1H), 7.09 (s, 1H), 6.68 (d, J=2.5Hz, 1H), 4.75 (s, 2H), 4.29 (q, J=2.0Hz, 2H), 2.45
(s, 3H), 1.32 (t, J=7.2Hz, 3H)；13C NMR (126MHz, CDCl3) δ 190.9,181.7,167.5,164.9,
164.5,162.6,148.7,135.4,133.1,124.6,121.4,113.6,111.0,107.9,107.8,65.2,61.8,
29.7,22.1,14.1；ESI-MS:m/z 355.0 [M-H]-。
The active testing of effect example compounds inhibition HCV virus strain
Purpose: antiviral effect of the detection compound to HCV2a type JFH1 virus.
Research technique: HCV infection stable cell line Huh7.5.1
Test grouping: drug-positive compares (interferon-' alpha ': Mo Rui (Shanghai) Biotechnology Co., Ltd), medicine group to be measured
Compound (0,0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM), negative control group.
Detection project and index: HCV rna content, NS3 gene expression.
Experimental program:
Cell: HCV permissive cell system Huh7.5.1 (Shanghai Sheng Ke institute cell bank), cell density are the 6 orifice plates (U.S.
Corning it) spreads into cell, 1 × 105/ hole；
Virus: JFH1 plants (genotype 2a, Wuhan institute of viruses, the Chinese Academy of Sciences), virus infection metering is 1mol；
Experiment flow:
1. being spread after counting according to experimental program to cell Huh7.5.1 into 6 orifice plates, cell is adherent overnight；
2. HCV virus (JFH1) is added according to infective dose, infection changed liquid after 6 hours, be added containing various concentration (0,
0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM) fresh culture of derivative, i.e., it is dilute continuous drug to be established with 2 times of dilutions
Release concentration.And the replacement of fresh culture containing corresponding concentration is carried out according to corresponding concentration daily, maintain drug concentration.Wherein drug is real
Testing negative control group is drug solvent (ddH2O), and positive control is interferon (PEG-IFN α, 500IU/mL, telavi
(VX950), 10 μM).
3. collecting sample after infecting concomitant drugs processing 72 hours, wherein supernatant uses TCID50Method detects venereal infection
Malicious particle titer, cellular component half detect viral genome copy number using real-time, and half uses western blot
Method detects virus nonstructural protein NS3 expression, and wherein GAPDH is as control.
Experimental result form: HCV rna content, NS3 gene expression, viral TCID50It is horizontal.
Table 1
Claims (10)
1. a kind of shown in formula I 9,10- anthraquinone derivative or its pharmaceutically acceptable salt are in preparation for treating and/or pre-
Application in anti-hepatitis C drug；
Wherein, R R1Substituted C1~C4Alkyl；
All R1It independently is-COOR1-1、-OH、-CN、C1~C4Alkyl or C1~C4Alkoxy；
All R1-1It independently is C1~C4Alkyl.
2. application as described in claim 1, which is characterized in that the R is R1" the C replaced1~C4Alkyl " in, it is described
" C1-C4Alkyl " is methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or the R1Number be one or more, as the R1Number be it is multiple when, any two R1It is identical
Or it is different；For example, it is described it is multiple be 2 or 3；
And/or as the R1For-COOR1-1When, the R1-1For methyl, ethyl, n-propyl, isopropyl, normal-butyl, Zhong Ding
Base, isobutyl group or tert-butyl；
And/or as the R1For C1~C4When alkyl, the C1~C4Alkyl is methyl, ethyl, n-propyl, isopropyl, just
Butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as the R1For C1~C4When alkoxy, the C1~C4Alkoxy is methoxyl group, ethyoxyl, positive third oxygen
Base, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy；
And/or the hepatitis C is HCV2a type.
3. application as described in claim 1, which is characterized in that the R1Substituted C1~C4Alkyl be 2- hydroxyethyl,
Cyano methyl or ethoxycarbonylmethyl group.
4. a kind of pharmaceutical composition, the pharmaceutical composition includes shown in Formulas I according to any one of claims 1 to 3
9,10- anthraquinone derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. 9,10- anthraquinone derivative shown in a kind of Formulas I according to any one of claims 1 to 3 is in preparation HCV inhibitor
In application, the HCV is, for example, HCV2a type.
6. a kind of 9,10- anthraquinone derivative or its pharmaceutically acceptable salt as shown in Formula II；
Wherein, R ' is R2Substituted C1~C4Alkyl；
All R2It independently is-COOR1-1Or-CN；
All R1-1For C1~C4Alkyl.
7. 9,10- anthraquinone derivative II as claimed in claim 6 or its pharmaceutically acceptable salt, which is characterized in that described
R ' be R2" the C replaced1~C4Alkyl " in, " the C1-C4Alkyl " is methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, sec-butyl, isobutyl group or tert-butyl；
And/or the R2Number be one or more, as the R2Number be it is multiple when, any two R2It is identical or
It is different；For example, it is described it is multiple be 2 or 3；
And/or as the R2For-COOR1-1When, the R1-1For methyl, ethyl, n-propyl, isopropyl, normal-butyl, Zhong Ding
Base, isobutyl group or tert-butyl.
8. 9,10- anthraquinone derivative II as claimed in claim 6 or its pharmaceutically acceptable salt, which is characterized in that described
R2Substituted C1~C4Alkyl be cyano methyl or ethoxycarbonylmethyl group.
9. a kind of preparation method of 9, the 10- anthraquinone derivative II as described in any one of claim 6~8, which is characterized in that
It includes the following steps: in the presence of base, and compound 1 and compound 2 are carried out substitution reaction, obtain the Formula II chemical combination
Object；
X is halogen.
10. preparation method as claimed in claim 9, which is characterized in that the halogen is fluorine, chlorine, bromine or iodine；The halogen
Element is, for example, chlorine or bromine；
And/or the alkali is alkali carbonate and/or organic amine；The alkali carbonate is, for example, potassium carbonate；Institute
The organic amine stated is, for example, triethylamine；
And/or the substitution reaction carries out in ketone or ether solvent；The ketones solvent is, for example, acetone；It is described
Ether solvent be, for example, tetrahydrofuran and/or dioxane；
And/or the molar ratio of the compound 2 and the compound 1 is 2~3；
And/or the molar ratio of the compound 2 and the alkali is 1~1.5；
And/or the temperature of the substitution reaction is 0 DEG C~100 DEG C；For example, 45 DEG C~50 DEG C.
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| CN114195630A (en) * | 2021-10-26 | 2022-03-18 | 湖南五江高科技材料有限公司 | Synthesis method of 9, 10-dialkoxy anthracene serving as photocuring initiator |
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| CN114195630A (en) * | 2021-10-26 | 2022-03-18 | 湖南五江高科技材料有限公司 | Synthesis method of 9, 10-dialkoxy anthracene serving as photocuring initiator |
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