CN109810063A - A kind of novel resisiting influenza virus " twin medicine ", preparation method and the usage - Google Patents
A kind of novel resisiting influenza virus " twin medicine ", preparation method and the usage Download PDFInfo
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- CN109810063A CN109810063A CN201711168544.9A CN201711168544A CN109810063A CN 109810063 A CN109810063 A CN 109810063A CN 201711168544 A CN201711168544 A CN 201711168544A CN 109810063 A CN109810063 A CN 109810063A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention belongs to pharmaceutical chemistry and the field of chemical synthesis, and in particular to a kind of resisiting influenza virus " twin medicine " preparation method and the usage, the compound have structure shown in logical formula (I).Antiviral twin medicine in the present invention is that influenza virus neuraminidase inhibitor is put together from polymerase inhibitors by different linking groups, can be used for the prevention and treatment of influenza infection.
Description
Technical field
The invention belongs to pharmaceutical chemistry and the field of chemical synthesis, and in particular to a kind of novel resisiting influenza virus " twin medicine " and its
Preparation method and purposes.
Background technique
Influenza virus is the RNA virus of a kind of highly infective, highly pathogenic and high mutation ability, is seriously affected for a long time
The life and health of the mankind.Since there is historical record in last century, a lot of flu outbreaks are had occurred in the whole world, popular every time
All cause the massive loss of life and property loss.According to the statistics of the World Health Organization, even if between non-epizootic modeling, influenza is every year still
Ten thousand people of 25-50 can be caused dead in the world.H5 and H7 is two kinds of highly pathogenic avian influenza virus, wherein H5N1 hypotype
Started to infect the mankind early in 1997, lethality is up to 60%.There is whole world people for the first time in March, 2013, Chinese Shanghai and Anhui
Class infects H7N9 avian influenza virus case, and virus infection still uninterruptedly occurs at present, the death rate nearly 30%.
The antigenicity of influenza virus easily changes, and existing vaccine can not effectively prevent new virus, therefore
Antiviral drugs is still the most important means for the treatment of of influenza.The activated centre of neuraminidase (NA) is all well-conserved, can urge
Change the glycosidic bond between cracking sialic acid and glycoprotein, promotes the release of newly-generated virus, be that anti-influenza virus medicament designs
Important target spot.Zanamivir and oseltamivir was listed in 1999, in addition two kinds of drug peramivir and
Laninamivir is also in some country's listings.NA inhibitor curative effect with higher and good safety and tolerance, are anti-
The choice drug of influenza.However, worrying be, the drug resistant Strain of NA inhibitor continuously emerges in recent years.
Favipiravir is that a kind of novel influenza RNA polymerase of Japan Toyama chemical pharmaceutical company's exploitation inhibits
Agent in Japan's listing, is infected caused by influenza virus, the entitled fluoro- 3- hydroxypyrazine-of 6- of chemistry for 2014 for treating
2- formamide.In the same year, during West Africa Ebola virus is popular, favipiravir is authorized as a kind of emergency drug and is used for
The treatment of virus infection person.
Influenza, especially severe influenza can cause multiple complications, seriously threaten the life of patient, therefore clinically still compel
It is essential and wants efficient Tamiflu.
To enhance drug effect, reducing side effect or improving pharmacokinetic property, frequently with twin medicine strategy by two guideizations
It closes object or drug to be covalently keyed, be conjugated into recruit.It can phase at the chemical structure and mechanism of action of two molecules of twin medicine
Together can also be different, covalent attachment is also varied.Currently, twin medicine is in the existing preferable application in the fields such as anti-inflammatory, antitumor.
Summary of the invention
Goal of the invention
In order to solve deficiency in the prior art, it is an object of the present invention to provide the twin medicines indicated by leading to formula (I)
Close object, pharmaceutically acceptable inorganic or organic salt, crystalline hydrate and solvate.
It is a further object to provide the preparation methods of above-mentioned logical formula (I) compound.
It is a further object to provide a kind of pharmaceutical compositions, and it includes the logical formula (I) chemical combination of therapeutically effective amount
The mixture of one or more of object, its pharmaceutically acceptable inorganic or organic salt, crystalline hydrate and solvate.
It is also another object of the present invention to provide above-mentioned logical formula (I) compound, its is pharmaceutically acceptable inorganic or organic
The application of salt, crystalline hydrate and solvate in the drug of preparation treatment or flu-prevention virus infection.
Technical solution
The present invention relates to such as logical formula (I) compound represented, pharmaceutically acceptable inorganic or organic salt, crystalline hydrates
Object and solvate:
Wherein X is H or halogen；R is H or CH2R ', R ' it is that substituted or unsubstituted aryl, substituted or unsubstituted virtue are miscellaneous
Base；Substituent group on the aryl or heterocyclic base is selected from one or more of fluorine, chlorine, bromine, methoxyl group, hydroxyl, phenyl；N is
1,2 or 3.
Preferably, X is H or F；R is H or substituted aryl, and the substituent group on the aryl is selected from fluorine, chlorine, bromine, methoxy
One or more of base, hydroxyl, phenyl；N is 1.
It is highly preferred that logical formula (I) compound of the invention is in following compounds:
The present invention also provides the preparation method of logical formula (I) compound and its intermediate, the preparation method can be by such as
Lower method one or method two carry out, and starting material used in the present invention is commercially available or according to analogue compounds known synthesis side
Method preparation:
Method one: being raw material with compound 1, reacts to obtain chemical combination with chloromethyl chlorosulfonic acid ester in a solvent in the presence of a base
Object 2；Reaction obtains compound 4 in a solvent in the presence of a base for compound 2 and pyrazinone derivatives 3；Compound 4 is in trifluoroacetic acid
In the presence of in a solvent deprotection base obtain -1 compound of Formulas I, as shown in reaction equation 1:
Reaction equation 1:
Method two: condensating reductive reaction occurs in a solvent in the presence of sodium cyanoborohydride for -1 compound of Formulas I and R ' CHO
- 2 compound of Formulas I is obtained, as shown in reaction equation 2:
Reaction equation 2:
Wherein, X is H or halogen；R ' is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic base；The aryl
Or the substituent group on heterocyclic base is selected from one or more of fluorine, chlorine, bromine, methoxyl group, hydroxyl, phenyl.
In above-mentioned steps a and step b, the alkali be selected from inorganic base or organic base, the inorganic base be selected from sodium hydroxide,
Potassium hydroxide, cesium hydroxide, barium hydroxide, hydrofining, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, saleratus, sodium bicarbonate,
In potassium carbonate, sodium carbonate and calcium carbonate, the organic base is selected from pyridine, triethylamine, diisopropylethylamine, n,N-Dimethylaniline
And in N, N- lutidines.Step a can be carried out in the presence of a catalyst, and the catalyst is selected from tetrabutyl Ammonium hydrogen sulfate, four
Butylammonium bromide, tetrabutylammonium iodide and benzyltriethylammoinium chloride.
Step a, the reaction dissolvent of b, c are selected from water, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, methanol, second
One of alcohol, acetonitrile, toluene, acetone, dioxane and chloroform are a variety of.The reaction dissolvent of step d be selected from methanol, ethyl alcohol,
The lower alcohols such as isopropanol or lower alcohol-water mixed solvent.
The reaction temperature of step a~c is room temperature~150 DEG C, and the reaction time is unlimited.
Heretofore described " pharmaceutically acceptable inorganic or organic salt " is the compound and such as salt that logical formula (I) indicates
The salt that the inorganic acids such as acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid are formed, with such as formic acid, acetic acid, propionic acid, grass
The salt that the organic acids such as acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric acid, methanesulfonic acid, citric acid are formed, or and hydrogen
Sodium, potassium, calcium or the ammonia salt that the alkali such as sodium oxide molybdena, potassium hydroxide, calcium hydroxide or ammonium hydroxide are formed." pharmaceutically acceptable salt " also wraps
Their solvate is included, the example of solvate has, hydrate, alcohol adduct etc..
The present invention also provides logical formula (I) compound represented according to the present invention and its pharmaceutically acceptable salts, knot
The application of brilliant hydrate and solvate in the drug for preparing resisiting influenza virus.Preferably, the influenza virus is A type, second
At least one of type and influenza virus C.
The present invention also provides a kind of for treating and/or the method for flu-prevention virus infection, this method include to people
Or compound, its pharmaceutically acceptable salt, crystalline hydrate and solvent that the logical formula (I) of animal application aforementioned present invention indicates
Close the mixture of one or more of object.
The present invention also provides a kind of pharmaceutical composition, it includes the above-mentioned logical formula (I) compound represented of therapeutically effective amount,
One or more of its pharmaceutically acceptable salt, crystalline hydrate and solvate mixture, and optional pharmaceutically acceptable load
Body.Described pharmaceutical composition can be used for treating or flu-prevention virus infection.
The present invention also provides a kind of methods for preparing described pharmaceutical composition, including by chemical combination shown in above-mentioned logical formula (I)
The mixture and pharmaceutical acceptable carrier of one or more of object, its pharmaceutically acceptable salt, crystalline hydrate and solvate
Mixing.
Beneficial effect
The compounds of this invention has the advantages that structure novel, has significant anti-influenza virus activity.
Specific embodiment
Illustrate embodiment of the present invention by the following example.It should be appreciated, however, that embodiment of the present invention is unrestricted
Specific detail in the following example, because other variations are to ordinary skill people in view of the disclosure
Member is known and obvious.
Preparation example 1:
The synthesis of compound 2
React 1 reference literature of starting material (Med Chem Res, 2013,22:3485-3496) synthesis.Compound 1
(540mg, 1.4mmol), sodium bicarbonate (590mg, 7mmol, 5eq) and tetrabutyl Ammonium hydrogen sulfate (47mg, 0.14mmol,
It 0.1eq) is added sequentially to the in the mixed solvent of methylene chloride (20mL) and water (10mL), is stirred at room temperature, is slowly added to chloromethyl
Chlorosulfonic acid ester (1.5eq), fully reacting after 3 hours.Methylene chloride (20mL) is added into reaction solution, separates organic layer, does
It is dry, be concentrated to give grease 2,575mg, yield 95%, HPLC purity is 98%.1H NMR(CDCl3, 400Hz): δ 6.90 (s,
1H), 6.05 (d, 1H, J=8.8Hz), 5.77-5.83 (m, 2H), 5.20 (d, 1H, J=9.2Hz), 3.98-4.14 (m, 2H),
3.78-3.88 (m, 1H), 3.33-3.41 (m, 1H), 2.79 (dd, 1H, J=17.6,5.2Hz), 2.33 (dd, 1H, J=
17.6,10.0 Hz), 2.00 (s, 3H), 1.47-1.57 (m, 4H), 1.44 (s, 9H), 0.83-0.94 (m, 6H).
Embodiment 1:
The synthesis of compound 4a (X=F)
Compound 2 (216mg, 0.5mmol) and Favipiravir 3a (78.5mg, 0.5mmol, 1eq) are dissolved in N, N- dimethyl
In formamide (6mL), under ice bath, triethylamine (177mg, 1.75mmol, 3.5eq) is added and is stirred at room temperature after 30 minutes.Overnight
Afterwards, water (20mL) is added into reaction solution, ethyl acetate extraction is distilled water washing, is concentrated after organic layer is dry.Column chromatography for separation
Obtain white solid 3a, 166 mg, yield 60%, HPLC purity 99%.H-NMR(CDCl3, 400Hz): δ 8.19 (d, 1H, J=
8.4Hz), 7.41 (s, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 6.25-6.28 (m, 3H), 5.28 (d, 1H, J=9.2Hz),
3.96-4.07 (m, 2H), 3.73-3.81 (m, 1H), 3.28-3.38 (m, 1H), 2.72 (dd, 1H, J=17.6,5.2Hz),
2.27 (dd, 1H, J=17.6,10.0Hz), 1.97 (s, 3H), 1.44-1.55 (m, 4H), 1.41 (s, 9H), 0.80-0.90
(m, 6H), ESI-MS m/z:554.1 [M+H]+。
The synthesis of compound I-1a (X=F)
Compound 4a (276mg, 0.5mmol) is added in methylene chloride (2mL), is added trifluoroacetic acid (0.5mL), room temperature
Stirring.After 3 hours, solvent is evaporated off, ether is added, insoluble matter is precipitated, filtering obtains white solid 241mg after vacuum drying, be three
Fluoroacetate, yield 85%, HPLC purity 97.5%.H-NMR(D2O, 400Hz): δ 8.28 (d, 1H, J=8.0Hz), 6.82
(s, 1H), 6.23 (d, 1H, J=6.0Hz), 6.17 (d, 1H, J=6.0Hz), 4.21-4.25 (m, 1H), 3.95 (dd, 1H, J
=12.0,8.8Hz), 3.46-3.54 (m, 1H), 3.39-3.45 (m, 1H), 2.86 (dd, 1H, J=17.6,6.0Hz),
2.39-2.48 (m, 1H), 1.99 (s, 3H), 1.32-1.48 (s, 4H), 0.69-0.76 (m, 6H).ESI-MS m/z:454.4
[M+H]+。
Embodiment 2:
The synthesis of compound 4b (X=H)
Referring to the synthetic method of embodiment 1, compound 2 (216mg, 0.5mmol) and 2- hydroxyl-pyrazine -3- formamide 3b
(70mg, 0.5mmol, 1eq) reaction, obtains white solid 4b, 90mg, yield 34%, HPLC purity 99%.H-NMR(DMSO-
d6, 400Hz): δ 8.39 (d, 1H), 8.37 (d, 1H), 7.96 (s, 1H), 7.80 (d, 1H, J=8.8Hz), 6.67 (s, 1H),
6.62 (d, 1H, J=9.2Hz), 6.14-6.19 (m, 2H), 4.04-4.11 (m, 1H), 3.65-3.74 (m, 1H), 3.51-
3.62 (m, 1H), 3.34-3.40 (m, 1H), 2.45 (dd, 1H, J=18.0,5.2Hz), 2.20-2.31 (m, 1H), 1.77 (s,
3H), 1.29-1.47 (m, 12H), 0.71-0.83 (m, 6H), ESI-MS m/z:536.3 [M+H]+。
The synthesis of compound I-1b (X=H)
Referring to the synthetic method of embodiment 1, compound 4b (107mg, 0.2mmol) is deprotected to obtain white solid 99mg, is
Trifluoroacetate, yield 90%, HPLC purity 98%.H-NMR(CD3OD, 400Hz): δ 8.35-8.44 (m, 2H), 6.92 (s,
1H), 6.30-6.35 (m, 2H), 4.19-4.26 (m, 1H), 3.96 (dd, 1H, J=11.2,8.4Hz), 3.48-3.56 (m,
1H), 3.39-3.45 (m, 1H), 2.93 (dd, 1H, J=17.6,5.6Hz), 2.40-2.51 (m, 1H), 2.04 (s, 3H),
1.44-1.60 (m, 4H), 0.82-0.94 (m, 6H).ESI-MS m/z:436.3[M+H]+。
Embodiment 3:
The synthesis of compound I-2a
Compound I-1a (30mg, 0.053mmol) and to phenyl benzaldehyde (12.5mg, 0.069mmol, 1.3eq) be added
It in dehydrated alcohol (2mL), is stirred at room temperature, is added sodium cyanoborohydride (10mg, 0.16mmol, 3eq), has been reacted after 2 hours
Entirely.Column chromatography for separation obtains white solid 33mg, yield 56%, HPLC purity 98.7%.H-NMR(CD3OD, 400Hz): δ 8.34
(d, 1H, J=8.4Hz), 7.58-7.66 (m, 4H), 7.41-7.49 (m, 4H), 7.35 (t, 1H, J=7.2Hz), 6.87 (s,
1H), 6.27-6.32 (m, 2H), 3.97-4.14 (m, 3H), 3.90 (d, 1H, J=13.2Hz), 3.36-3.43 (m, 1H),
3.04-3.15 (m, 1H), 2.92 (dd, 1H, J=17.6,5.6Hz), 2.32-2.45 (m, 1H), 2.03 (s, 3H), 1.42-
1.61 (m, 4H), 0.79-0.94 (m, 6H).ESI-MS m/z:620.3[M+H]+。
Embodiment 4:
The synthesis of compound I-2b
Reference compound I-2a synthetic method, compound I-1a (30mg, 0.053mmol), benzaldehyde (11.2mg,
0.1mmol, 2eq) and sodium cyanoborohydride (10mg, 0.16mmol, 3eq) reaction, column chromatography for separation obtains white solid 13mg, receives
Rate 45%, HPLC purity 98.5%.H-NMR (CD3OD, 400Hz): δ 8.34 (d, 1H, J=8.4Hz), 7.27-7.42 (m,
5H), 6.86 (s, 1H), 6.26-6.32 (m, 2H), 4.08-4.11 (m, 1H), 3.94-4.00 (m, 2H), 3.80-3.84 (m,
1H), 3.36-3.42 (m, 1H), 3.01-3.08 (m, 1H), 2.87 (dd, 1H, J=17.6,5.6Hz), 2.29-2.38 (m,
1H), 2.01 (s, 3H), 1.44-1.56 (m, 4H), 0.81-0.93 (m, 6H).ESI-MS m/z:544.1[M+H]+。
Embodiment 5:
The synthesis of compound I-2c
Reference compound I-2a synthetic method, compound I-1a (30mg, 0.053mmol), 2,3- dimethoxy benzaldehyde
The reaction of (17.6mg, 0.1mmol, 2eq) and sodium cyanoborohydride (10mg, 0.16mmol, 3eq), column chromatography for separation obtains white solid
Body 17.6mg, yield 55%, HPLC purity 98.5%. H-NMR(CD3OD, 400Hz): δ 8.35 (d, 1H, J=8.4Hz),
6.99-7.07 (m, 2H), 6.84-6.89 (m, 2H), 6.26-6.32 (m, 2H), 4.06-4.14 (m, 1H), 3.96 (d, 1H, J
=13.2Hz), 3.83-3.91 (m, 7H), 3.77-3.82 (m, 1H), 3.35-3.39 (m, 1H), 2.88-3.04 (m, 2H),
2.23-2.35 (m, 1H), 2.02 (s, 3H), 1.39-1.55 (m, 4H), 0.81-0.95 (m, 6H).ESI-MS m/z:604.5
[M+H]+。
Embodiment 6:
The synthesis of compound I-2d
Reference compound I-2a synthetic method, the fluoro- 4- bromobenzaldehyde of compound I-1a (30mg, 0.053mmol), 2-
The reaction of (21.4mg, 0.1mmol, 2eq) and sodium cyanoborohydride (10mg, 0.16mmol, 3eq), column chromatography for separation obtains white solid
Body 16.9mg, yield 50%, HPLC purity 99.0%. H-NMR(CD3OD, 400Hz): δ 8.34 (d, 1H, J=8.4Hz),
7.62 (dd, 1H, J=6.8,2.4Hz), 7.42-7.47 (m, 1H), 7.04 (t, 1H, J=9.2Hz), 6.85 (s, 1H),
6.26-6.32 (m, 2H), 4.06-4.14 (m, 1H), 3.80-3.94 (m, 3H), 3.53-3.41 (m, 1H), 2.80-2.96 (m,
2H), 2.20-2.32 (m, 1H), 1.42-1.58 (m, 4H), 0.80-0.96 (m, 6H).ESI-MS m/z:640.4[M+H]+。
Embodiment 7:
The synthesis of compound I-2e
Reference compound I-2a synthetic method, compound I-1a (30mg, 0.053mmol), furfural (10.2 mg,
0.1mmol, 2eq) and sodium cyanoborohydride (10mg, 0.16mmol, 3eq) reaction, column chromatography for separation obtains white solid 12.7mg,
Yield 45%, HPLC purity 98.8%.H-NMR (DMSO-d6, 400Hz): δ 8.47 (d, 1H, J=8.4Hz), 7.99 (s,
1H), 7.79-7.86 (m, 2H), 7.55 (s, 1H), 6.67 (s, 1H), 6.36 (s, 1H), 6.21 (s, 1H), 6.12-6.17 (m,
2H), 3.96-4.06 (m, 1H), 3.61-3.83 (m, 3H), 3.36-3.42 (m, 1H), 2.71-2.85 (m, 1H), 2.58-
2.68 (m, 1H), 1.98-2.14 (m, 1H), 1.29-1.49 (m, 4H), 0.66-0.92 (m, 6H).ESI-MS m/z:534.4
[M+H]+。
Only illustratively, the scope of the present invention is not limited thereto for above-mentioned example.To those skilled in the art
For to modify be it will be apparent that the present invention is only limited by attached rights require scope.
Claims (7)
1. a kind of by following general formula (I) compound represented, pharmaceutically acceptable salt, crystalline hydrate and solvate:
Wherein X is H or halogen；R is H or CH2R ', R ' it is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic base, institute
The substituent group stated on aryl or heterocyclic base is selected from one or more of fluorine, chlorine, bromine, methoxyl group, hydroxyl, phenyl；N be 1,2 or
3。
2. compound represented according to claim 1, pharmaceutically acceptable salt, crystalline hydrate and solvate are special
Sign is: X is H or F；R is H or substituted aryl, and the substituent group on the aryl is selected from fluorine, chlorine, bromine, methoxyl group, hydroxyl, benzene
One or more of base；N is 1.
3. compound as described in claim 1, pharmaceutically acceptable salt, crystalline hydrate and solvate, feature
It is, leads to formula (I) compound and be selected from following compound:
4. the preparation method of compound according to any one of claims 1 to 3, which is characterized in that by the following method one or
Method two carries out:
Method one: being raw material with compound 1, reacts to obtain compound 2 with chloromethyl chlorosulfonic acid ester in a solvent in the presence of a base；
Reaction obtains compound 4 in a solvent in the presence of a base for compound 2 and pyrazinone derivatives 3；Compound 4 exists in trifluoroacetic acid
Under in a solvent deprotection base obtain -1 compound of Formulas I, as shown in reaction equation 1:
Reaction equation 1:
Method two: -1 compound of Formulas I and R ' CHO occur condensating reductive in a solvent in the presence of sodium cyanoborohydride and react to obtain
- 2 compound of Formulas I, as shown in reaction equation 2:
Reaction equation 2:
Wherein, the definition of X and R ' is the same as claim 1.
5. compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, crystalline hydrate and solvent close
Purposes of the object in the drug for preparing resisiting influenza virus.
6. purposes according to claim 5, which is characterized in that the influenza virus is A type, B-mode and influenza C is sick
At least one of poison.
7. a kind of pharmaceutical composition, it is characterised in that being selected from comprising therapeutically effective amount is according to any one of claims 1 to 3
Compound, its pharmaceutically acceptable salt, crystalline hydrate and solvate and optional pharmaceutical acceptable carrier.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079785A (en) * | 2019-06-13 | 2020-12-15 | 中国科学院上海药物研究所 | Novel anti-influenza virus oseltamivir derivative, preparation method and application thereof |
| CN112079785B (en) * | 2019-06-13 | 2023-08-04 | 中国科学院上海药物研究所 | Novel anti-influenza virus oseltamivir derivative, and preparation method and application thereof |
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Application publication date: 20190528 |