CN105943547A - Anti-HBV (hepatitis B virus) pharmaceutical composition and application thereof - Google Patents
Anti-HBV (hepatitis B virus) pharmaceutical composition and application thereof Download PDFInfo
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- CN105943547A CN105943547A CN201610344035.6A CN201610344035A CN105943547A CN 105943547 A CN105943547 A CN 105943547A CN 201610344035 A CN201610344035 A CN 201610344035A CN 105943547 A CN105943547 A CN 105943547A
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- Prior art keywords
- deoxidation
- thymus pyrimidine
- glycosyl
- virus
- hepatitis
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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
Abstract
The invention provides a pharmaceutical composition containing 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)thymine and application thereof, the composition being used to resist hepatitis B virus.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, the present invention relates to comprise 1-(2-deoxidation-2-fluoro-beta-L-I
Primary furyl glycosyl) compositions of thymus pyrimidine and application thereof.
Background technology
Nucleoside analog is the important candidate compound of class in current antiviral (including hepatitis B virus, HBV) medicine
Thing, it mainly plays curative effect by reverse transcriptase and/or the archaeal dna polymerase of suppression virus.There are many nucleoside analogs because of anti-
Virus effectiveness significantly and patent medicine popularization and application, compound but more is not so good as into drug compound due to effect own,
Even if structurally with to become drug compound difference the least, also being given it up.
But, the present inventor is in the studying for a long period of time of the medicine to anti-hepatitis B virus, it has unexpectedly been found that some quilt
Although the ability more weak (but the most not can not be used alone) of the Anti-HBV activity of compound itself that screening discards, in a large proportion with become
Drug compound is used in mixed way the Anti-HBV activity efficiency of the compositions that can make mixing and is not so good as to be used alone into drug compound itself, but few
Amount is used in mixed way without reducing, possibly even can increase the efficiency of Anti-HBV activity.Therefore, inventor developed these
Nucleoside analog through being discarded, is mainly used in the connection with 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine
Close and use, for Anti-HBV activity.
Summary of the invention
The technical problem to be solved in the present invention is to provide the medicinal application of new nucleoside analog, including for 1-
(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine is used in combination, for Anti-HBV activity.It addition, the present invention also provides for
Comprise this nucleoside analog and the pharmaceutical composition etc. of 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine.
Specifically, in first aspect, the invention provides 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) breast
Gland pyrimidine and another kind of or multiple compounds combine the application in the medicine preparing anti-hepatitis B virus, wherein, described separately
One or more compounds are one or more compounds selected from following group:
1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine；With,
1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine.
Preferably in the application of a first aspect of the present invention, another kind of or multiple compounds be 1-(the chloro-β of 2-deoxidation-2--
L-arabinofuranosidase glycosyl) application of thymus pyrimidine, i.e. a first aspect of the present invention is that (2-deoxidation-2-fluoro-beta-L-is Arabic for 1-
Furyl glycosyl) thymus pyrimidine and 1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine apply in combination.
Study discovery through the present invention, another kind of or multiple compounds (always) measure no more than 1-(2-deoxidation-2-fluoro-beta-
L-arabinofuranosidase glycosyl) amount of thymus pyrimidine.Preferably in the application of a first aspect of the present invention, (2-deoxidation-2-is fluoro-for 1-
β-L-arabinofuranosidase glycosyl) thymus pyrimidine and another kind of or multiple compounds mol ratio be 1000:1 ~ 1:1, it be preferably
1000:5 ~ 20:1, more preferably 100:1 ~ 10:1.
Preferably in the application of a first aspect of the present invention, anti-hepatitis B virus is the DNA reducing hepatitis B virus
Level.This is consistent with the antiviral-mechanism of this type of nucleoside analog.
In second aspect, the invention provides the pharmaceutical composition of anti-hepatitis B virus, it includes 1-(2-deoxidation-2-
Fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine and another kind of or multiple compounds, wherein, another kind of or multiple compounds is
One or more compounds selected from following group:
1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine；With,
1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine.
Preferably the pharmaceutical composition of a second aspect of the present invention is by 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl)
Thymus pyrimidine and another kind of or multiple compounds composition.
Preferably in the pharmaceutical composition of a second aspect of the present invention, 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosyl
Base) thymus pyrimidine and another kind of or multiple compounds mol ratio 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 a second aspect of the present invention, another kind of or multiple compounds be 1-(2-deoxidation-
2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine.In the detailed description of the invention of the present invention, 1-(2-deoxidation-2-chloro-β-L-
Arabinofuranosidase glycosyl) thymus pyrimidine shows more preferable than 1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine
The ability of self Anti-HBV activity, and forming compound recipe with 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine
Time, Anti-HBV activity effect is likely to more preferably.
In the third aspect, the invention provides the pharmaceutical preparation of anti-hepatitis B virus, it includes the second party of the present invention
The pharmaceutical composition in face and pharmaceutically acceptable adjuvant.In this article, pharmaceutically acceptable adjuvant refers to nontoxic and does not disturbs
Active constituents of medicine plays the filler of curative effect, stabilizer, diluent, adjuvant or other pharmaceutical adjuncts.Those skilled in the art
Member can according to therapeutic purposes, route of administration (such as injection or oral) need to make pharmaceutical composition various dosage form, preferably
Said composition is unit dosage form, such as lyophilized preparation, tablet, granule, capsule, powder, emulsion agent, injection or spray.
The pharmaceutical preparation of third aspect present invention is preferably ejection preparation (such as lyophilized preparation or injection) or oral formulations (such as tablet).
In yet another aspect, the invention provides 1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine
And/or 1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine is in the medicine preparing anti-hepatitis B virus
Application, it is preferable that the invention provides 1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine and preparing anti-second
Application in the medicine of Hepatitis virus.
Application in terms of another herein can be to be used alone, it is also possible to is use in conjunction.Preferably in application herein
In (including the application of first aspect), described (preparation) medicine is pharmaceutical composition or the present invention of a 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 reduce patent medicine
The consumption of compound A, cost-effective, improve the efficiency of Anti-HBV activity.
By specific embodiment, the present invention will be described in detail in order to make it easy to understand, following.Needs refer in particular to
Going out, these describe the description being merely exemplary, are not intended that limitation of the scope of the invention.Opinion according to this specification
Stating, many changes of the present invention, change will be apparent from for one of ordinary skill in the art.
Detailed description of the invention
Further illustrate the present invention by the following examples.As do not specialized, technological means used in embodiment is
Conventional means well-known to those skilled in the art, equipment and reagent, some provides commercialization service, can be found in " organic
Synthesis " etc. handbook.
The synthesis of embodiment 1 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine
1 2
2 3
3 4
Building-up process, as shown in above flow process, can entrust Guangxi Hui Baoyuan Pharmaceutical Co., Ltd to synthesize, specifically: by formula 1
Compound (400mg, 0.86mmol) is dissolved in anhydrous CH2Cl2(10ml) in, add be dissolved in acetic acid hydrogen bromide (45% w/v,
1.5ml), and gained solution is stirred at room temperature 17 hours, after evaporating solvent and steaming altogether with toluene, obtains formula 2 compound.
Meanwhile, by thymus pyrimidine (215mg, 1.72mmol) at HMDS(25ml) in reflux under nitrogen protection 17 hours,
Obtain homogeneous phase solution, boil off solvent and obtain the thymus pyrimidine of silylation.
Formula 2 compound is dissolved in dichloroethanes (50ml), adds the thymus pyrimidine of silylation, and gained solution is existed
Refluxed under nitrogen 3 days, adds water, then uses CHCl3Extraction.Organic layer is washed with water, saline successively and uses MgSO4It is dried.Steam
Send out solvent and obtain crude product, by it through TLC purification, use 2%MeOH/CHCl3Launch, obtain formula 3 compound.
At room temperature formula 3 compound (145mg, 0.309mmol) is used NH3/CH3OH processes 18 hours, evaporates solvent, warp
Preparation TLC(15% MeOH/CHCl3) purification, obtain formula 4 compound.
The synthesis of embodiment 2 1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine
5 6
6 7
7 8
Building-up process, as shown in above flow process, is essentially identical to the concrete building-up process of embodiment 1, except that initial chemical combination
Thing replaces with formula 5 compound, and it is that chlorine is substituted.
The synthesis of embodiment 3 1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine
9 10
10 11
11 12
Building-up process, as shown in above flow process, is essentially identical to the concrete building-up process of embodiment 1, except that initial chemical combination
Thing replaces with formula 9 compound, and it is that bromine is substituted.
Embodiment 4 Anti-HBV effect is tested
The compound synthesized according to embodiment 1-3 individually or is in varing proportions mixed, measures them external to hepatitis B
The impact of virus (HBV).Specifically, the HepG 2.2.15 cell of HBV will have been transfected at the minimum base containing 10% hyclone
Basal culture medium is cultivated, changed the freshest culture medium every 3 days.Cultivate to after collecting, change fresh culture and also add
The compound according to the synthesis of embodiment 1-3 of different total concentrations and mixture thereof, cultivate 3 days, change fresh culture the most again
And add previous medicine, it is further cultured for 3 days.Then the virion in culture medium is collected, after cracking with polyethylene glycol precipitation
Measure the amount of DNA of HBV by quantitative real-time fluorescence PCR method, calculate the DNA level suppression relative to the matched group being not added with any medicine
Each drug level (IC50) when 50%.
Table 1 Anti-HBV activity result of the test
The result of the test of the present inventor is as shown in table 1, and the effect of the Anti-HBV activity of compound A has got well about one than compound B's and C
More than the order of magnitude, it is shown that compound A more has the prospect developing into Anti-HBV drugs than compound B and C；But, surprising
It is, compound A and a small amount of compound B and the C(especially mol ratio compound B less than 1/10) composition compound recipe, basic energy
Play the effect of the compound A of identical total amount, in some instances it may even be possible to improve inhibition, the correspondingly usage amount of economized compound A, because of
This also has the prospect developing into compound medicine.
Claims (10)
1.1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine and another kind or multiple compounds are combined in system
Application in the medicine of standby anti-hepatitis B virus, wherein, described another kind or multiple compounds are the one selected from following group
Or multiple compounds:
1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine；With,
1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine.
2. the application described in claim 1, wherein 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine is with another
The mol ratio of one or more compounds is 1000:1 ~ 1:1, preferably 1000:5 ~ 20:1, more preferably 100:1 ~ 10:1.
3. the application described in claim 1, it is 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus pyrimidine and 1-
(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine is applied in combination.
4. the application described in claim 1, wherein anti-hepatitis B virus is the DNA level reducing hepatitis B virus.
5. the pharmaceutical composition of anti-hepatitis B virus, it includes 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus
Pyrimidine and another kind of or multiple compounds, wherein, another kind of or multiple compounds is one or more chemical combination selected from following group
Thing:
1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine；With,
1-(2-deoxidation-2-bromo-β-L-arabinofuranosidase glycosyl) thymus pyrimidine.
6. the pharmaceutical composition described in claim 5, wherein 1-(2-deoxidation-2-fluoro-beta-L-arabinofuranosidase glycosyl) thymus is phonetic
Pyridine and another kind of or multiple compounds mol ratio are 1000:1 ~ 1:1, preferably 1000:5 ~ 20:1, more preferably 100:1 ~
10:1.
7. the pharmaceutical composition described in claim 5, wherein another kind of or multiple compounds is 1-(2-deoxidation-2-chloro-β-L-Ah
Draw primary furyl glycosyl) thymus pyrimidine.
8. the pharmaceutical preparation of anti-hepatitis B virus, it arbitrary described pharmaceutical composition including claim 5 ~ 7 and pharmacy
Upper acceptable adjuvant.
9.1-(2-deoxidation-2-chloro-β-L-arabinofuranosidase glycosyl) thymus pyrimidine and/or 1-(2-deoxidation-2-bromo-β-L-I
Primary furyl glycosyl) thymus pyrimidine application in the medicine preparing anti-hepatitis B virus.
10. the application described in claim 9, wherein said medicine be claim 5 ~ 7 arbitrary described pharmaceutical composition or
Pharmaceutical preparation described in claim 8.
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| Application Number | Priority Date | Filing Date | Title |
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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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| CN201610344035.6A CN105943547B (en) | 2016-05-23 | 2016-05-23 | The pharmaceutical composition of Anti-HBV activity and its application |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329497A (en) * | 1998-11-02 | 2002-01-02 | 三角药物公司 | Cmbination therapy to treat hepatitis b virus |
| US20040127436A1 (en) * | 2002-09-24 | 2004-07-01 | Koronis Pharmaceuticals, Inc. | 1,3,5-Triazines for treatment of viral diseases |
| WO2008069451A1 (en) * | 2006-12-08 | 2008-06-12 | Bukwang Pharm Co., Ltd. | Improved process for the preparation of clevudine as anti-hbv agent |
-
2016
- 2016-05-23 CN CN201610344035.6A patent/CN105943547B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329497A (en) * | 1998-11-02 | 2002-01-02 | 三角药物公司 | Cmbination therapy to treat hepatitis b virus |
| US20040127436A1 (en) * | 2002-09-24 | 2004-07-01 | Koronis Pharmaceuticals, Inc. | 1,3,5-Triazines for treatment of viral diseases |
| WO2008069451A1 (en) * | 2006-12-08 | 2008-06-12 | Bukwang Pharm Co., Ltd. | Improved process for the preparation of clevudine as anti-hbv agent |
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| CN105943547B (en) | 2018-01-19 |
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