CN107266499B - A kind of antiviral compound and preparation method thereof - Google Patents
A kind of antiviral compound and preparation method thereof Download PDFInfo
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- CN107266499B CN107266499B CN201710414543.1A CN201710414543A CN107266499B CN 107266499 B CN107266499 B CN 107266499B CN 201710414543 A CN201710414543 A CN 201710414543A CN 107266499 B CN107266499 B CN 107266499B
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- tenofovir
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention discloses a kind of antiviral compounds and preparation method thereof, it is that 1:1 is reacted and is prepared with glutathione that the antiviral compound is by phosphonate nucleotide analogues in molar ratio, it connects to form new compound using two active groups of sulfydryl or amino in the hydroxyl and glutathione in the phosphate group of phosphonate nucleotide analogues, while improving bioavilability, antiviral and liver protecting effect is played, there is good medicinal application prospect.
Description
Technical field
The invention belongs to pharmaceutical technology fields more particularly to a kind of antiviral compound and preparation method thereof.
Background technique
The beginning of the fifties in last century, the first discoveries such as Hitchings purine or miazines metabolic poison, which have, inhibits bacterium
The effect of nucleic acid synthesis, hereafter finds it with stronger antivirus action again.Purines nucleosides and miazines nucleosides medicine are main
It is resisting DNA virus, it is the thymidine kinase generated by virus, makes purines nucleosides and miazines nucleosides phosphotidic
Nucleoside triphosphate analog is formed, to inhibit the activity of viral DNA polymerase and reverse transcriptase, and and deoxycytidine
Competitiveness penetrates into the DNA chain of virus, terminates the extension and synthesis of DNA chain, is that the duplication of virus is suppressed and plays anti-DNA disease
Toxic action.
Tenofovir is a kind of novel nucleoside reverse transcriptase inhibitor.In vivo, a variety of viruses can be effective against, are used
In treatment disease of viral infection.Tenofovir structural formula are as follows:
Since tenofovir itself cannot be absorbed completely by gastrointestinal tract, it can not play a role, be replaced to improve in vivo
The bioavilability of Nuo Fuwei develops tenofovir by the method in two hydroxy positions of phosphate group at ester
Prodrug, one of which are tenofovir dipivoxils, its medicinal fumarate, and the specification for developing listing is 300mg/ piece, structure
Formula are as follows:
Another kind is the ester prodrug thereof that tenofovir Chinese mugwort drawing phenol amine (tenofovir, TAF) is tenofovir, is being faced
Bed test in, the medicine have been demonstrated be equivalent to tenofovir disoproxil fumarate (tenofovir disoproxil fumarate piece,
Viread, TDF) ten/dose when, just there is very high antiviral effect, while can reduce to renal function and bone side
The side effect in face.Currently, tenofovir Chinese mugwort draw phenol amine single preparations of ephedrine and tenofovir Chinese mugwort draw phenol amine compound preparation respectively at
In the U.S., China and European list marketing obtain the listing license for the treatment of AIDS and hepatitis B.Its structural formula is as follows:
The drug as tenofovir disoproxil fumarate, belong to be tenofovir prodrug, in vivo rapidly drop
Solution plays a role for tenofovir.
Also due to tenofovir Chinese mugwort draws phenol amine melting point compound itself low, poorly water-soluble is made into after preparation in vivo
Dissolubility and result of extraction are bad, thus develop at salt form be used for preparation, patent document CN1443189A and
CN1706855A reports its fumarate and patent document CN105085571A reports the form of hemifumarate, at present on
What is used in the compound preparation and single preparations of ephedrine in city is its hemifumarate.Its structural formula is as follows:
And CN105085571A reports a series of a series of shape including sulfuric acid, hydrochloric acid and tartaric acid and amino acid
At different salt form.
But the salt of quovis modo, tenofovir Chinese mugwort draws phenol amine as fumaric acid tenofovir in vivo, is all to belong to
In the prodrug of tenofovir, it is converted into tenofovir in vivo to play therapeutic effect.Clinical report replaces promise being used alone
When good fortune Wei class drug or the other anti-retroviral therapies of combination, once has and lactic acidosis and serious hepatomegaly occurs
With the report of steatosis, including there is lethal case, the long-term exposure to nucleosides may be risk factor.There is known hepatopathy
To pay special attention to when giving nucleoside analog in the patient of risk factor, however, in the patient of not known risk factor
Once there is case report.In clinical treatment, it is often necessary to monitor the transaminase situation of patient to decide whether to deactivate for promise
Good fortune Wei class drug therapy or the liver protecting class drug for using some assisted class.This increased in clinic the treatment of patient at
Sheet and Operative risk.In addition, once reported, when carrying out the treatment of HIV and HBV using tenofovir class antiviral drugs,
There is kidney function damage in patient, the case including acute renal failure and Fanconi syndrome (renal damage is with low-phosphorous acidaemia).
Glutathione (glutathione, r-glutamyl cysteingl+glycine, GSH) is a kind of containing γ-amide
The tripeptides of key and sulfydryl is made of glutamic acid, cysteine and glycine.It is present in almost each cell of body.Paddy
The sweet peptide of Guang can assist in keeping the function of normal immune system, and have antioxidation and integrate detoxication.Cysteine
On sulfydryl be its active group (therefore being often abbreviated as G-SH), is easily combined with some drugs etc., and with integrating detoxication, paddy
The sweet peptide of Guang is a kind of peptide of small molecule, is largely present in organism, especially in liver cell, there is protection liver plasma membrane, is promoted
The effect of liver enzyme activity, and play the role of removing toxic substances in conjunction with numerous toxic chemical substances.GSH is as a kind of intracellular important
Regulatory metabolites matter, is both the prothetic group of Triose phosphate dehydrogenase, and is the coenzyme of aldoketonutase and triose dehydrogenase, participates in
Internal tricarboxylic acid cycle and glycometabolism, and a variety of enzymes can be activated, such as sulfydryl (SH) enzyme-coenzyme, thus promote carbohydrate, fat and
Protein metabolism.GSH molecule feature is active sulfydryl (- SH), is most important function group, it is a variety of heavy to may participate in body
The biochemical reaction wanted, important enzyme protein sulfhydryl is not oxidized in protective, inactivation, guarantees that energetic supersession, cell utilize.Meanwhile
It in conjunction with intracorporal free radical, directly can make radical reduction at acidic materials, to accelerate the row of free radical by sulfydryl
It lets out, and wants the damage of internal organs to free radical resisting counterweight.Glutathione structural formula are as follows:
Summary of the invention
In view of the problems of the existing technology, it is high, Small side effects that the object of the present invention is to provide a kind of bioavilabilities
Antiviral compound and preparation method thereof.
To achieve the goals above, the invention adopts the following technical scheme:
A kind of antiviral compound, general structure are as follows:
Wherein, in formula
R1Selected from amino, alkyl amino, oxygroup, dialkyl amido；
R2Selected from amino, hydrogen；
R3Selected from hydrogen, cyclopropyl；Carbon atom number is the straight chained alkyl or branched alkyl, fluoromethyl, hydroxyl, hydroxyl first of 1-6
Base；
It is R is selected from hydrogen, carbon atom number is 1-7 straight chained alkyl or branched alkyl, alkenyl, alkynyl, benzyl, substituted or unsubstituted
Phenyl, contain the heteroatomic ester groups of O, S, N.
Preferably, the general structure of the antiviral compound are as follows:
It is further preferred that the general structure of the antiviral compound are as follows:
Preferably, the general structure of the antiviral compound are as follows:
It is further preferred that the general structure of the antiviral compound are as follows:
A kind of above-mentioned antiviral compound or above-mentioned anti-for in antiviral medicinal composition containing therapeutically effective amount
The pharmaceutical salts of virus compound, and contain one or more pharmaceutically acceptable excipient substances.
The preparation method of above-mentioned antiviral compound, the antiviral compound are by phosphonate nucleotide analogues and paddy
The sweet peptide of Guang is that 1:1 reaction is prepared in molar ratio.
Preferably, the phosphonate nucleotide analogues are tenofovir class drug.
It is further preferred that the nucleotide analog is tenofovir dipivoxil, tenofovir Chinese mugwort drawing phenol amine or one
Phenyl tenofovir.
Beneficial effects of the present invention:
A kind of novel antiviral is prepared by reacting phosphonate nucleotide analogues with glutathione in the present invention
Object is closed, two activity of sulfydryl or amino in the hydroxyl and glutathione in the phosphate group of phosphonate nucleotide analogues are utilized
Group connects to form new compound, and the dissolubility of obtained compound significantly improves, to improve the biology benefit of compound
Expenditure.It is similar can to generate phosphonate-nucleotide ester in vivo to antiviral compound of the invention other than bioavilability height
Object and glutathione and its degradation product amino acid to generate synergistic effect, while playing antiviral and liver protecting effect,
With good medicinal application prospect.
Tenofovir class drug (tenofovir dipivoxil, tenofovir Chinese mugwort draw phenol amine or a phenyl tenofovir) and paddy
The sweet peptide of Guang is at salt, by retaining a masking group of tenofovir class drug, ends than tenofovir and draws phenol amine or for promise good fortune
The dissolubility of Wei dipivoxil is high, and by utilizing HBV transgene mouse model evaluation comparison, the compound of the present invention ratio replaces promise good fortune
Wei Aila phenol amine, tenofovir dipivoxil or a phenyl tenofovir have preferable antivirus action, and can significantly reduce
Side effect.
Detailed description of the invention
Fig. 1 is the synthetic route chart of 3 compound of embodiment.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment 1
It draws phenol amine to be dissolved in the acetonitrile of 10ml the tenofovir Chinese mugwort of 9.52g, is heated to 50~50 DEG C, stirs, be added
The glutathione of 6.14g, the methanol of 2ml stir 30 minutes, cool to 0~5 DEG C, a large amount of solids are precipitated, and stir 1 at 0~5 DEG C
After hour, filtering obtains crude product；Crude product is washed with the nitrile of 15ml second, obtains the white solid of 12.3g, for containing for promise good fortune
The salt that Wei Aila phenol amine and glutathione molar ratio are 1:1, purity are 99.5% (HPLC, normalization).
Embodiment 2
The tenofovir dipivoxil of 10.38g is dissolved in the acetonitrile of 10ml, is heated to 50~50 DEG C, is stirred, is added
The glutathione of 6.14g, the methanol of 2ml stir 30 minutes, and dissolved clarification cools to 0-5 DEG C, and a large amount of solids are precipitated, stir at 0-5 DEG C
It mixes 1 hour, after filtering, obtains crude product；Crude product is washed with the acetonitrile of 15ml, obtains 12.8g white solid, is tenofovir
The salt that dipivoxil and glutathione molar ratio are 1:1, purity are 99.8% (HPLC, normalization).
Embodiment 3
At 25-30 DEG C, a phenyl tenofovir (synthesis of referenced patent CN1443189A preparation method) of 9g is added
Into the dichloromethane solvent of 90ml, the thionyl chloride of 9ml is added, is heated to 40 DEG C of back flow reactions 120 hours, reaction solution is molten
Clearly, the glutathione of 6g is added, reacts 6 hours, after fully reacting, 100m water is added, washes twice, dichloromethane layer is at 35 DEG C
Lower vacuum concentration, grease is obtained, is separated and (is washed with ethyl acetate: methanol=3:1 mixed liquor using silica gel chromatographic column
It is de-), it is collected into compound 1 and compound 2,99% or more HPLC purity respectively.The conjunction for the compound that the present embodiment is prepared
At route referring to attached drawing 1.
Embodiment 4
At 25-30 DEG C, a phenyl tenofovir of 9g is added in the toluene of 100ml, is heated to 70 DEG C, is added
The thionyl chloride of 9ml is stirred to react 80 hours, reaction solution dissolved clarification, and the glutathione of 63g is added, and is reacted 5 hours, fully reacting
Afterwards, 100m water is added, washes twice concentration removal toluene, obtains grease, separated using silicagel column (with ethyl acetate:
The elution of methanol=3:1 mixed liquor), respectively obtain 2 grease of compound 1 and compound, 99% or more HPLC purity.
Embodiment 5: the crystallization of compound 1
Embodiment 3 is synthesized obtained 1 grease 1.3g of compound to be added in the isopropanol of 20ml, 60 DEG C is heated to and stirs
It mixes 45 minutes, is down to room temperature, white solid is precipitated, filtering obtains the white solid 0.86g of compound 1, purity 99.4%.Change
The structural formula for closing object 1 is as follows:
Compound 1 is subjected to hydrogen nuclear magnetic resonance spectrum analysis, the chemical shift of nuclear magnetic resonance spectroscopy is as follows:
1HNMR (400MHZ, DMSO): δ: 8.18 (s, 1H), 8.11 (s, 1H), 7.32~7.26 (t, 2H), 7.28 (s,
2H), 7.15~5.56 (m, 4H), 4.88~4.76 (m, 1H), 4.56 (t, 1H), 3.98 (s, 2H), 3.83 (t, 1H), 2.98~
2.90 (m, 2H), 2.58~2.50 (m, 2H), 2.1 8~2.1 4 (m, 2H)；, 1.06~1.04 (d, 3H).
Embodiment 6: the crystallization of compound 2
Embodiment 3 is synthesized obtained 2 grease 1.5g of compound to be added in the isopropanol of 20ml, is heated to 60 DEG C,
Room temperature is down in heating 40 minutes, and white solid is precipitated, and filtering obtains the light yellow solid 0.97g of compound 2, purity
99.7%.
The structural formula of compound 2 is as follows:
Compound 2 is subjected to hydrogen nuclear magnetic resonance spectrum analysis, the chemical shift of nuclear magnetic resonance spectroscopy is as follows:
1HNMR (400MHZ, DMSO) δ: 8.38 (s, 1H), 8.15 (s, 1H), 7.36~7.26 (t, 2H) 7.28 (s, 2H),
7.35~5.76 (m, 4H) 4.88~4.76 (m, 1H), 4.56 (t, 1H), 4.08 (s, 2H), 3.83 (t, 1H), 2.98~2.90
(m, 2H), 2.59~2.52 (m, 2H), 2.1 9~2.1 5 (m, 2H)；, 1.08~1.06 (d, 3H).
Embodiment 7
The monomethyl phenyl tenofovir (synthesis of referenced patent CN1443189A preparation method) of 9.5g is added to
In the dichloromethane solvent of 90ml, the thionyl chloride of 9ml is added, is heated to 40 DEG C of back flow reactions 60 hours, reaction solution dissolved clarification adds
Enter the glutathione of 5.5g, react 6 hours, after fully reacting, 100m water is added, washes twice, dichloromethane layer is at 35 DEG C
Vacuum concentration, grease is obtained, is separated and (is washed with ethyl acetate: methanol=3:1 mixed liquor using silica gel chromatographic column
It is de-), it is collected into the analog of compound 1 and the analog of compound 2,98% or more HPLC purity respectively.Grease is according to reality
The crystallization of 5 method of example is applied, crystalline solid can be obtained.
Embodiment 8: zoopery evaluation
Utilize the compound 1 of HBV transgene mouse model evaluation embodiment 5 and the compound 2 of embodiment 6.HBV is taken to turn base
Because of mouse 20, it is randomly divided into four groups, every group 5.It is administered using gastric perfusion needle administration by gavage, blank group feeds physiological saline, compares
Group (tenofovir Chinese mugwort draws phenol amine group) feeds tenofovir Chinese mugwort and draws phenol amine, and experimental group 1 feeds compound 1, and experimental group 2 feeds chemical combination
Object 2.The dosage that feeds of every mouse is 20mg/kg, 1 time a day, after continuous filling 21 days, is discontinued one week, takes a blood sample 1 time within every 7 days.Benefit
Serum HBV DNA result is detected with PCR.After 21 days, all mice serum HBVDNA of experimental group 1, experimental group 2 and control group
Electrophoresis band disappears, and blank group does not change but.It is discontinued after 1 week, detects in serum HBV DNA control mice group and experimental group again
Serum HBV DNA electrophoresis band occurs again.Continuous gavage takes each group mouse blood sample to experimental animal again after 8 weeks, is detected, and logarithm
According to statistical analysis is carried out, test result is indicated using average ± standard deviation, serum creatinine (Scr), the urea nitrogen of each group
(BUN), Urinary Albumin Excretion, fractional excretion of filtrated sodium (FENa), endogenous creatinine clearance rate (Ccr) and nitric oxide (NO) for 24 hours,
As shown in table 1.
The results of animal of table 1 the compounds of this invention 1 and compound 2
From upper table result it can be seen that compound 1 and compound 2 have antivirus action；Furthermore blank group and experimental group
1, experimental group 2, renal function indices do not have significant change, and the decline of control group kidney local function is more obvious, the results show that
The compound of the present invention is in addition to playing same antivirus action with tenofovir, additionally it is possible to effectively reduce tenofovir to kidney
The damage of function.Wherein compound 1 is better than compound 2 in terms of protecting renal function.
Claims (9)
1. a kind of antiviral compound, which is characterized in that the general structure of the compound are as follows:
Wherein, in formula
R1 is selected from amino, alkyl amino, oxygroup, dialkyl amido；
R2 is selected from amino, hydrogen；
R3 is selected from hydrogen, cyclopropyl；Carbon atom number is the straight chained alkyl or branched alkyl, fluoromethyl, hydroxyl, methylol of 1-6；
The straight chained alkyl or branched alkyl, alkenyl, alkynyl, benzyl, substituted or unsubstituted benzene that R is selected from hydrogen, carbon atom number is 1-7
Base contains the heteroatomic ester groups of O, S, N.
2. antiviral compound according to claim 1, which is characterized in that the general structure of the compound are as follows:
3. antiviral compound according to claim 2, which is characterized in that the structural formula of the compound are as follows:
4. antiviral compound according to claim 1, which is characterized in that the general structure of the compound are as follows:
5. antiviral compound according to claim 4, which is characterized in that the structural formula of the compound are as follows:
6. one kind is used for antiviral medicinal composition, which is characterized in that contain therapeutically effective amount in described pharmaceutical composition
Compound or pharmaceutically acceptable salt thereof of any of claims 1-5, and contain one or more pharmaceutically acceptable drugs
Auxiliary material.
7. the preparation method of antiviral compound according to any one of claims 1-5, which is characterized in that described disease-resistant
It is that 1:1 is reacted and is prepared with glutathione that cytotoxic compound is by phosphonate nucleotide analogues in molar ratio.
8. preparation method according to claim 7, which is characterized in that the phosphonate nucleotide analogues are tenofovir
Class drug.
9. preparation method according to claim 8, which is characterized in that the phosphonate nucleotide analogues are tenofovir
Dipivoxil, tenofovir Chinese mugwort draw phenol amine or a phenyl tenofovir.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2013167743A1 (en) * | 2012-05-11 | 2013-11-14 | Akron Molecules Gmbh | Use of compounds for the treatment of pain |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
| CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
| CN106565785A (en) * | 2016-11-09 | 2017-04-19 | 周雨恬 | Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012154698A2 (en) * | 2011-05-06 | 2012-11-15 | Mckenna Charles E | Method to improve antiviral activity of nucleotide analogue drugs |
| US20140288025A1 (en) * | 2013-03-13 | 2014-09-25 | Catabasis Pharmaceuticals, Inc. | Fatty acid antiviral conjugates and their uses |
-
2017
- 2017-06-05 CN CN201710414543.1A patent/CN107266499B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2013167743A1 (en) * | 2012-05-11 | 2013-11-14 | Akron Molecules Gmbh | Use of compounds for the treatment of pain |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
| CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
| CN106565785A (en) * | 2016-11-09 | 2017-04-19 | 周雨恬 | Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound |
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