CN105943547B - The pharmaceutical composition of Anti-HBV activity and its application - Google Patents
The pharmaceutical composition of Anti-HBV activity and its application Download PDFInfo
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- CN105943547B CN105943547B CN201610344035.6A CN201610344035A CN105943547B CN 105943547 B CN105943547 B CN 105943547B CN 201610344035 A CN201610344035 A CN 201610344035A CN 105943547 B CN105943547 B CN 105943547B
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- thymidine
- arabinofuranosidases
- glycosyl
- virus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
The invention provides the pharmaceutical composition comprising 1 (the fluorine β L arabinofuranosidases glycosyl of 2 deoxidation 2) thymidine and its application, for anti-hepatitis B virus.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, the present invention relates to comprising 1- (2- deoxidation -2- fluoro-betas-L- I
Primary furyl glycosyl) thymidine composition and its application.
Background technology
Nucleoside analog is antiviral at present（Including hepatitis type B virus, HBV）A kind of important candidate compound in medicine
Thing, it mainly plays curative effect by suppressing reverse transcriptase and/or the archaeal dna polymerase of virus.There are many nucleoside analogs because anti-
Virus effectiveness significantly patent medicine and popularization and application, compound but more because effect itself is not so good as into drug compound,
With into drug compound difference very little, also being given it up in structure.
However, the present inventor is in the studying for a long period of time of the medicine of anti-hepatitis B virus, it has unexpectedly been found that some quilts
The compound discarded is screened although the ability of the Anti-HBV activity of itself is weaker（But also it can not be used alone）, in a large proportion with into
Drug compound is used in mixed way the Anti-HBV activity efficiency for the composition that can make mixing not as being used alone into drug compound in itself, but few
Amount is used in mixed way the efficiency without reduction, the Anti-HBV activity that can possibly even increase.Therefore, inventor developed these
Nucleoside analog through being discarded, it is mainly used in and the connection of 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidine
Close and use, for Anti-HBV activity.
The content of the invention
The technical problem to be solved in the present invention is the medicinal application for providing new nucleoside analog, including is used for and 1-
(2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidine is used in combination, for Anti-HBV activity.In addition, the present invention also provides
Pharmaceutical composition comprising the nucleoside analog and 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidine etc..
Specifically, in a first aspect, the invention provides 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) chest
Gland pyrimidine and another or multiple compounds combine the application in the medicine of anti-hepatitis B virus is prepared, wherein, it is described another
One or more compounds are to be selected from one or more compounds such as the following group：
1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine；With,
1- (the bromo- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine.
It is preferred that in the application of the first aspect of the present invention, another or multiple compounds be 1- (the chloro- β of 2- deoxidations -2- -
L- arabinofuranosidases glycosyl) thymidine, i.e. the application of the first aspect of the present invention is that (2- deoxidation -2- fluoro-betas-L- is Arabic by 1-
Furyl glycosyl) thymidine and 1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine apply in combination.
Found through present invention research, it is another or multiple compounds（Always）Amount no more than 1- (2- deoxidation -2- fluoro-betas -
L- arabinofuranosidases glycosyl) thymidine amount.It is preferred that in the application of the first aspect of the present invention, (2- deoxidations -2- is fluoro- by 1-
β-L- arabinofuranosidases glycosyl) thymidine and another or multiple compounds mol ratios be 1000：1~1：1, be preferably
1000：5~20：1, more preferably 100：1~10：1.
It is preferred that in the application of the first aspect of the present invention, anti-hepatitis B virus is the DNA for reducing hepatitis type B virus
It is horizontal.The antiviral-mechanism of this and such nucleoside analog is consistent.
In second aspect, the invention provides the pharmaceutical composition of anti-hepatitis B virus, and it includes 1- (2- deoxidations -2-
Fluoro-beta-L- arabinofuranosidases glycosyl) thymidine and another or multiple compounds, wherein, another or multiple compounds are
One or more compounds selected from such as the following group：
1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine；With,
1- (the bromo- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine.
It is preferred that the pharmaceutical composition of the second aspect of the present invention is by 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl)
Thymidine and another or multiple compounds composition.
It is preferred that in the pharmaceutical composition of the second aspect of the present invention, 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranoses
Base) thymidine and another or multiple compounds mol ratios be 1000：1~1：1, preferably 1000：5~20：1, more preferably
For 100：1~10：1.
It is also preferred that in the pharmaceutical composition of the second aspect of the present invention, another or multiple compounds be 1- (2- deoxidations-
Chloro- β-L- arabinofuranosidases the glycosyls of 2-) thymidine.In the embodiment of the present invention, the 1- (chloro- β-L- of 2- deoxidations -2-
Arabinofuranosidase glycosyl) thymidine show it is more preferable than 1- (the bromo- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine
Itself Anti-HBV activity ability, and with 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidine form compound
When, Anti-HBV activity effect may also be more preferable.
In the third aspect, the invention provides the pharmaceutical preparation of anti-hepatitis B virus, and it includes the second party of the present invention
The pharmaceutical composition in face and pharmaceutically acceptable auxiliary material.Herein, pharmaceutically acceptable auxiliary material refers to nontoxic and not disturbed
Active constituents of medicine plays filler, stabilizer, diluent, adjuvant or other pharmaceutical adjuncts of curative effect.Those skilled in the art
Member can be according to therapeutic purposes, method of administration（Such as injection or oral）Need various formulations are made in pharmaceutical composition, preferably
Said composition is unit dosage form, such as freeze-dried, tablet, granule, capsule, pulvis, emulsion agent, injection or spray.
The pharmaceutical preparation of third aspect present invention is preferably ejection preparation（Such as freeze-dried or parenteral solution）Or oral formulations（Such as tablet）.
In another aspect, the invention provides 1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine
And/or 1- (the bromo- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine is in the medicine of anti-hepatitis B virus is prepared
Using, it is preferable that the invention provides 1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine to prepare anti-second
Application in the medicine of Hepatitis virus.
The application of this paper other side can be used alone or use in conjunction.It is preferred that in this paper application
（Application including first aspect）In, it is described（Prepare）Medicine is the pharmaceutical composition or the present invention of the second aspect of the present invention
The pharmaceutical preparation of the third aspect.
The beneficial effect that the present invention obtains includes turning waste into wealth the nucleoside analog being discarded, in some instances it may even be possible to reduces patent medicine
Compound A dosage, it is cost-effective, improve the efficiency of Anti-HBV activity.
In order to make it easy to understand, the present invention will be described in detail by specific embodiment below.Need to refer in particular to
Go out, the description that these descriptions are merely exemplary, and be not meant to limit the scope of the invention.Opinion according to this specification
State, many changes of the invention, change will be apparent from for one of ordinary skill in the art.
Embodiment
The present invention is further illustrated by the following examples.As do not specialized, technological means used is in embodiment
Conventional meanses, equipment and reagent well-known to those skilled in the art, some provide commercialization service, reference can be made to《It is organic
Synthesis》Deng handbook.
The synthesis of the 1- of embodiment 1 (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidine
1 2
2 3
3 4
Building-up process can entrust Guangxi Hui Baoyuan Pharmaceutical Co., Ltd to synthesize, specifically as shown in above flow：Will
The compound of formula 1（400mg, 0.86mmol）It is dissolved in anhydrous CH2Cl2In (10ml), the hydrogen bromide being dissolved in acetic acid is added（45% w/
V, 1.5ml）, and resulting solution is stirred at room temperature 17 hours, evaporation solvent and after being steamed altogether with toluene obtains the compound of formula 2.
Meanwhile by thymidine（215mg, 1.72mmol）In HMDS（25ml）In flow back under nitrogen protection 17 hours,
Homogeneous phase solution is obtained, solvent is boiled off and obtains the thymidine of silylation.
The compound of formula 2 is dissolved in dichloroethanes（50ml）In, the thymidine of silylation is added, and resulting solution is existed
Refluxed under nitrogen 3 days, water is added, then uses CHCl3Extraction.Organic layer with water, salt water washing and is used into MgSO successively4Dry.Steam
Hair solvent obtains crude product, and it is purified through TLC, uses 2%MeOH/CHCl3Expansion, obtains the compound of formula 3.
At room temperature by the compound of formula 3（145mg, 0.309mmol）Use NH3/CH3OH is handled 18 hours, evaporation solvent, warp
Prepare TLC（15% MeOH/CHCl3）Purifying, obtains the compound of formula 4.
The synthesis of the 1- of embodiment 2 (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine
5 6
6 7
7 8
Building-up process is essentially identical to the specific building-up process of embodiment 1 as shown in above flow, except that starting
Compound replaces with the compound of formula 5, and it is chlorine substitution.
The synthesis of the 1- of embodiment 3 (the bromo- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine
9 10
10 11
11 12
Building-up process is essentially identical to the specific building-up process of embodiment 1 as shown in above flow, except that starting
Compound replaces with the compound of formula 9, and it is bromine substitution.
The Anti-HBV effect of embodiment 4 is tested
The compound synthesized according to embodiment 1-3 individually or is in varing proportions mixed, determines them in vitro to B-mode
Hepatitis viruse（HBV）Influence.Specifically, will transfect HBV HepG 2.2.15 cells containing 10% hyclone most
Cultivated in low basal medium, fresh culture medium was changed once every 3 days.Culture changes fresh culture simultaneously to after collecting
The compound synthesized according to embodiment 1-3 and its mixture of different total concentrations are added, cultivates 3 days, then changes fresh training again
Support base and add previous medicine, be further cultured for 3 days.Then the virion in culture medium is collected with polyethylene glycol precipitation, split
The quantitative real-time fluorescence PCR method measure HBV of Xie Houyong amount of DNA, calculates the DNA level relative to the control group for being not added with any medicine
Each drug concentration when suppressing 50%（IC50）.
The Anti-HBV activity result of the test of table 1
The result of the test of the present inventor is as shown in table 1, effect having got well about than compound B and C of compound A Anti-HBV activity
More than an order of magnitude, it is shown that compound A more has prospect of the exploitation into Anti-HBV drugs than compound B and C；However, make us frightened
It is surprised, compound A and a small amount of compound B and C（Especially mol ratio is less than 1/10 compound B）Compound is formed, but base
Instinct plays the compound A of identical total amount effect, in some instances it may even be possible to improves inhibition, correspondingly saves compound A use
Amount, therefore also there is prospect of the exploitation into compound medicine.
Claims (4)
1.1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidines and the 1- (chloro- β-L- Arab furans of 2- deoxidations -2-
Mutter glycosyl) thymidine combines the application in the medicine of anti-hepatitis B virus is prepared,
(the chloro- β-L- of 2- deoxidations -2- are Arabic by wherein 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidines and 1-
Furyl glycosyl) thymidine mol ratio be 100：1~10：1.
2. the application described in claim 1, wherein anti-hepatitis B virus are to reduce the DNA level of hepatitis type B virus.
3. the pharmaceutical composition of anti-hepatitis B virus, it includes 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymus gland
Pyrimidine and 1- (the chloro- β-L- arabinofuranosidases glycosyls of 2- deoxidations -2-) thymidine；
(the chloro- β-L- of 2- deoxidations -2- are Arabic by wherein 1- (2- deoxidation -2- fluoro-beta-L- arabinofuranosidases glycosyl) thymidines and 1-
Furyl glycosyl) thymidine mol ratio be 100：1~10：1.
4. the pharmaceutical preparation of anti-hepatitis B virus, it includes pharmaceutical composition described in claim 3 and pharmaceutically acceptable
Auxiliary material.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610344035.6A CN105943547B (en) | 2016-05-23 | 2016-05-23 | The pharmaceutical composition of Anti-HBV activity and its application |
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|---|---|---|---|
| CN201610344035.6A CN105943547B (en) | 2016-05-23 | 2016-05-23 | The pharmaceutical composition of Anti-HBV activity and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1380303B1 (en) * | 1998-11-02 | 2008-09-17 | Gilead Sciences, Inc. | Combination therapy to treat hepatitis B virus |
| JP2006507255A (en) * | 2002-09-24 | 2006-03-02 | コローニス ファーマシューティカルズ インコーポレイテッド | 1,3,5-triazine for the treatment of viral diseases |
| KR100839322B1 (en) * | 2006-12-08 | 2008-06-17 | 부광약품 주식회사 | Improved preparation of Clevudine, a hepatitis V treatment drug |
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Address after: 100085, Haidian District Road, Beijing, No. 5, A District, four floor, A407, A408 room Applicant after: Beijing Hui Yuan biotechnology Limited by Share Ltd Address before: 100085, Haidian District Road, Beijing, No. 5, A District, four floor, A407, A408 room Applicant before: BEIJING HUIBAOYUAN BIOTECHNOLOGY CO., LTD. |
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