CN108314684A - A kind of more base substituted purin analog derivatives and the preparation method and application thereof - Google Patents
A kind of more base substituted purin analog derivatives and the preparation method and application thereof Download PDFInfo
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- CN108314684A CN108314684A CN201810345592.9A CN201810345592A CN108314684A CN 108314684 A CN108314684 A CN 108314684A CN 201810345592 A CN201810345592 A CN 201810345592A CN 108314684 A CN108314684 A CN 108314684A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention provides a kind of more base substituted purin analog derivatives and the preparation method and application thereof, first pass through the more active acyl chlorides of thionyl chloride preparation property, reduce the generation of by-product, and by-product is only sulfur dioxide and hydrogen chloride, is gas, purification is convenient, further esterification is carried out by acyl chlorides and phenol again, be conducive to being smoothed out for reaction, reaction is thorough, greatly improves the yield of final product；In addition the site of action of more base substituted purin analog derivatives of the invention and mode are unique, with very high antiviral activity, especially Anti-HBV effect, it is suitble to the space requirement of drug special role target spot, with better biocompatibility, good therapeutic effect is all had to respiratory virus infection, virus hepatitis, polio, flu virus disease.
Description
Technical field
The present invention relates to field of medical technology, specifically, the present invention relates to a kind of more base substituted purin analog derivatives and
Preparation method and application.
Background technology
Disease of viral infection is the major class disease for seriously endangering human life and health.Hepatitis B (HBV) is B-mode
The main pathogens of hepatitis.Although current hepatitis B vaccine is successfully researched and developed and is widely popularized, hepatitis B is extremely strong because of its
Infectiousness and pathogenic, social harm is still very big.In addition, the implementation of interferon and nucleoside medicine is resistance of hepatitis B
One important breakthrough for the treatment of, but since the appearance of drug resistance and the toxicity problem of Long-term taking medicine significantly limit the therapy
Application, with new construction, new mechanism anti-hepatitis B medicine research and development it is very urgent.
Heterocyclic compound has extensive antiviral activity, they are usually female as the basic structure for constituting pharmacophore
Core to be suitble to the space requirement of drug special role target spot, or is produced as active substituent or the component part of ring system
Raw corresponding bioactivity.Why drug is because heterocycle is more fatty or aromatic compound is less susceptible in vivo dependent on heterocycle
Metabolic breakdown, and there is better biocompatibility.Benzimidazole ring is a kind of important heteroaromatic, and derivative has extensive
Bioactivity and clinical application.The present invention is based on the good Anti-HBV effects of benzimidazole analogues, utilize bioelectronics etc.
Isostere purine ring substituted benzimidazole ring, design have synthesized a series of substituted purin analog derivatives, have had no in the prior art such
Compound and its application.
Invention content
To achieve the above object, one object of the present invention is to provide a kind of more base substituted purin analog derivatives, described
The chemical structural formula of more base substituted purin analog derivatives is formula（A）It is shown,
Further, R, R1With R2For amino, nitro, hydroxyl, hydrogen, C1~C6Alkyl, C1~C6Alkoxy, benzyl, substituted benzyl；
Further, R3For C1~C6Alkyl, C1~C6Alkoxy, various substituted hexa-member heterocycles, various substituted five yuan it is miscellaneous
Ring, various substituted hexa-atomic and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five yuan it is miscellaneous
Ring, various substituted benzo five-membered heterocycles or various substituted benzo hexa-member heterocycles；
Further, R4For alkyl, naphthenic base, acyl group, alkyl acyl, sulfonyl, alkyl sulphonyl；
Further, X is chlorine atom, fluorine atom, bromine atom or iodine atom.
Further, the formula（A）Structure is selected from：
。
Another object of the present invention is to provide the formula（A）Synthetic route be：
。
Reaction step is：
（1）By formula（B）Compound and formula（C）Compound is added in reaction vessel, is added and is urged in the presence of organic solvent is with alkali
Agent, heating water bath are simultaneously stirred continuously, and TLC detection reactions are completed, production（D）Compound；
（2）Step（1）The formula of generation（D）Compound is in the presence of thionyl chloride by being heated to reflux production（E）Compound；
（3）Step（2）The formula of generation（E）Compound and formula（F）Compound is dissolved in dioxane, and the sodium hydroxide 50% is molten
It reacts in the presence of liquid, production（A）Compound；
Further, the step（1）In organic solvent be dichloromethane, the alkali be sodium carbonate, the catalyst be 1,
1 '-two (diphenylphosphino) ferrocene palladium bichloride.
Further, the step（1）Middle heating temperature is 80-100 DEG C.
Further esterification is carried out by acyl chlorides and phenol again by first preparing acyl chlorides in building-up process, is conducive to react
Be smoothed out.The compound that the present invention synthesizes has good chemism more so that these compounds, which have, well may be used
Expansion also provides good active group for their pharmacological activity.
The present invention is optimized reaction condition and reaction route from economic benefit, either the dosage of solvent,
The selection of the type and dosage or reaction temperature of reactant has all carried out condition optimizing, and the reaction route and condition of gained are
Route with Atom economy and the feature of environmental protection in the route that we select.
It is another object of the present invention to provide a kind of more base substituted purin analog derivative pharmaceutical compositions, including power
Profit requires the formula described in 1（A）And pharmaceutically acceptable carrier.
Further, the formula（A）As sole active agent.
Further, the pharmaceutically acceptable carrier is filler, adhesive, moisturizer, disintegrant, retarding solvent, profit
It is one or more in humectant or lubricant.
It is another object of the present invention to provide a kind of more base substituted purin analog derivative formulas（A）Disease is infected in virus
Application in terms of medicine, the disease are selected from respiratory virus infection, virus hepatitis, polio, influenza virus.
The present invention is not to formula（A）Or include formula（A）The method of application of pharmaceutical composition be particularly limited, it is representative
Method of application include（But it is not limited to）：Oral, intravenous injection, local administration.Solid dosage forms for oral medication includes
Capsule, tablet, pill, powder and granule.In these solid dosage forms, formula（Ⅰ）With at least one conventional inert excipients
（Or carrier）Mixing is mixed such as sodium citrate or Dicalcium Phosphate, or with following compositions：（a）Filler, such as starch, lactose, sugarcane
Sugar, glucose, mannitol and silicic acid；（b）Adhesive, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone
Ketone, sucrose and Arabic gum；（c）Moisturizer, such as glycerine；（d）Disintegrant, such as agar, calcium carbonate, potato starch or wood
Sweet potato starch, alginic acid, certain composition silicates, sodium carbonate；（e）Retarding solvent, such as paraffin；（f）Absorbsion accelerator, for example, it is quaternary ammoniated
Close object；（g）Wetting agent, such as cetanol and glycerin monostearate；（h）Adsorbent, such as kaolin；（i）Lubricant, such as
Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate.In capsule, tablet and pill, dosage form
It may include buffer.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable other medicines administering drug combinations.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Compared with prior art, the present invention having the advantages that：
1, the present invention first passes through the more active acyl chlorides of thionyl chloride preparation property, reduces the generation of by-product, and by-product
Only sulfur dioxide and hydrogen chloride are gas, and purification is convenient；Further esterification is carried out by acyl chlorides and phenol again, is had
Conducive to being smoothed out for reaction, reaction is thorough, greatly improves the yield of final product.
2, the site of action of oxazole ketones derivant of the present invention and mode are unique, have very high antiviral activity, especially
It is Anti-HBV effect, is suitble to the space requirement of drug special role target spot, there is better biocompatibility, to Respirovirus
Infection, virus hepatitis, polio, flu virus disease all have good therapeutic effect.
Specific implementation mode
Present invention is further elaborated in following combination specific embodiment, and embodiment only helps understand the present invention, but not
Present disclosure can be limited, any restrictions of the scope of the invention are should not be construed as.
Following structural formula of the present invention in above compound（A）Carry out specific implementation explanation, but be not limited to as
Lower structure formula（A）.
Specific synthetic route is as follows：
Embodiment 1
[2-[（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid（D）Synthesis.
Structural formula：
。
By (the chloro- 6- pyridines of 2-) purine -8- base formic acid（B）（5g, 1.8mol）With（2- nitro -4- hydroxyls）Pyrimidine -5- bases -
Trimethyl borate（C）（5.8g, 2.3mol）It is added in reaction vessel, in organic solvent dichloromethane（50ml）With sodium carbonate
（0.8g）In the presence of be added catalyst 1,1 '-two (diphenylphosphino) ferrocene palladium bichloride（0.32g）, heating water bath to 85 DEG C simultaneously
It being stirred continuously, TLC detection reactions are completed, generate [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases -
Formic acid（D）（9.69g 2.4mol）.
[2-[（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formyl chloride（E）Synthesis.
Structural formula：
。
By above-mentioned generation [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid（D）
（9.69g 2.4mol）In thionyl chloride（40ml）In the presence of through being heated to reflux generation [2- [（2- nitro -4- hydroxyl -5- bases）
Pyrimidine] -4- pyridines] purine -8- bases-formyl chloride（E）（9.28g 2.3mol）.
[2-[（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester
（A）Synthesis.
Structural formula：
。
By the formula of above-mentioned generation [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formyl chloride
（E）（9.28g 2.3mol）With 4- methyl -3- chlorophenols（F）（10g, 1.5mol）It is dissolved in dioxane（60ml）, 50%
Sodium hydroxide solution（20ml）In the presence of react, generate [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] it is fast
Purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester（A）（17.25g 3.1mol）, yield 96.87%.
There is no stringent restriction, this field skills with 50% sodium hydroxide solution for the dosage of organic solvent in the present embodiment
Art personnel can carry out suitable selection and be determined according to actual conditions, and dosage size is to facilitate reaction to carry out, herein not
It is being described in detail.
Embodiment 2-4
Change embodiment 1 in catalyst, it is other operation it is constant, repeat embodiment 1 operating procedure, obtain embodiment 2~
4, as a result it see the table below.
In conjunction with the embodiments 1 with embodiment 2~4, catalyst to the present invention synthesis have great influence, use 1,1 '-two
(diphenylphosphino) ferrocene palladium bichloride, which makees catalyst, has good catalytic effect, without using catalyst or using palladium as urging
Agent or using bis- (two-phenyl phosphino-s) ferrocene of 1,1'- as catalyst, ultimate yield for 10.58% or 60.12% or
48.77%, seriously affect [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- of 2-
Methyl）Phenyl ester（A）Yield.
Embodiment 5
Alkali in embodiment 1 is removed, other operations are constant, repeat the operating procedure of embodiment 1, obtain embodiment 5, as a result
It see the table below.
In conjunction with the embodiments 1 with embodiment 5, in the presence of alkali-free, it is final [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine]-
4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester（A）Yield greatly reduce, therefore alkali the present invention react
In play an important role.
Embodiment 6-11
Change the temperature of heating water bath in embodiment 1, other operations are constant, repeat the operating procedure of embodiment 1, implemented
Example 6-11, as a result see the table below.
1 and embodiment 6-11 in conjunction with the embodiments, changes the temperature of heating water bath, [2- [（2- nitro -4- hydroxyl -5- bases）It is phonetic
Pyridine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester（A）Yield change correspondingly.When temperature is higher and higher
When, [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester（A）'s
Yield is also higher and higher, but is not to tend to increase trend always, when temperature reaches 96 DEG C, [2- [（2- nitro -4- hydroxyls -
5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）Phenyl ester（A）Yield yield highest, when only
When more than 96 DEG C, [2- [（2- nitro -4- hydroxyl -5- bases）Pyrimidine] -4- pyridines] purine -8- bases-formic acid -（The chloro- 4- methyl of 2-）
Phenyl ester（A）Yield reduce.
The Anti-HBV effect of the more base substituted purin analog derivatives of the present invention and application
External Anti-HBV effect is carried out by cell strain to the more base substituted purin analog derivatives of the newly synthesized present invention to study, with
Lamivudine (3TC) is positive control medicine, and inhibiting HBsAg in vitro using ELISA method measurement target compound, (surface is anti-
It is former) and the activity secreted of HBeAg (core antigen)；The inhibition HBV DNA replication dnas that part of compounds is determined by PCR methods are lived
Property；The cytotoxicity that sample compound is detected using CCK-8 methods, to be screened to the Anti-HBV effect of sample compound.
Following table is more base substituted purin analog derivative anti-hepatitis virus primary dcreening operations activity.
Following table is the anti-HBsAg and HBeAg secretion activities of part of compounds.
Note：bIC50：The concentration of compound when 50%HBsAg or HBeAg being inhibited to secrete；cCC50：Inhibit 50% cell growth
When compound concentration；dSI：Select index, the ratio of CC50/IC50；eNA：It is inactive.
More base substituted purin analog derivatives of the present invention can be used as non-nucleoside HBV inhibitor and answer it can be seen from above
With.Specifically, can be used as HBV inhibitor is used to prepare anti-hepatitis B medicine.
A kind of more base substituted purin analog derivative pharmaceutical compositions, including the more base substituted purin analog derivatives of the present invention and medicine
Acceptable carrier on.The present invention provides the completely new more base substituted purin analog derivatives and preparation method thereof of structure, Anti-HBV activities
Active ingredients result and its application in preparing anti-hepatitis B medicine.It was proved that substituted purin class of the invention
Derivative can be used as HBV inhibitor and apply and have potential application.Specifically, being used to prepare as HBV inhibitor
Preventing respiratory viruses infection, virus hepatitis, polio, influenza virus.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.It is further to note that described in above-mentioned specific implementation mode
Each particular technique feature can be combined by any suitable means, in order to avoid not in the case of no contradiction
Necessary repetition, the present invention no longer separately illustrate various combinations of possible ways.In addition, a variety of different implementations of the present invention
Arbitrary combination can also be carried out between mode, as long as it does not violate the idea of the present invention, it is public equally to should be considered as institute of the invention
The content opened.
Claims (8)
1. a kind of more base substituted purin analog derivatives, it is characterised in that：The chemical constitution of more base substituted purin analog derivatives
Formula is formula（A）It is shown,
Wherein R, R1With R2For amino, nitro, hydroxyl, hydrogen, C1~C6Alkyl, C1~C6Alkoxy, benzyl, substituted benzyl；
R3For C1~C6Alkyl, C1~C6Alkoxy, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substitutions
Hexa-atomic and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, various substituted
Benzo five-membered heterocycle or various substituted benzo hexa-member heterocycles；
R4For alkyl, naphthenic base, acyl group, alkyl acyl, sulfonyl, alkyl sulphonyl；
Wherein X is chlorine atom, fluorine atom, bromine atom or iodine atom.
2. a kind of more base substituted purin analog derivatives according to claim 1, it is characterised in that：It is described
Formula（A）Synthetic route be：
。
Reaction step is：
（1）By formula（B）Compound and formula（C）Compound is added in reaction vessel, is added and is urged in the presence of organic solvent is with alkali
Agent, heating water bath are simultaneously stirred continuously, and TLC detection reactions are completed, production（D）Compound；
（2）Step（1）The formula of generation（D）Compound is in the presence of thionyl chloride by being heated to reflux production（E）Compound；
（3）Step（2）The formula of generation（E）Compound and formula（F）Compound is dissolved in dioxane, and the sodium hydroxide 50% is molten
It reacts in the presence of liquid, production（A）Compound.
3. a kind of more base substituted purin analog derivatives according to claim 1, it is characterised in that：The step（1）In
Organic solvent is dichloromethane, and the alkali is sodium carbonate, and the catalyst is 1,1 '-two (diphenylphosphino) ferrocene chlorination
Palladium.
4. a kind of more base substituted purin analog derivatives according to claim 1, it is characterised in that：The step（1）In plus
Hot temperature is 80-100 DEG C.
5. a kind of more base substituted purin analog derivative pharmaceutical compositions, it is characterised in that：Including formula described in claim 1（A）
And pharmaceutically acceptable carrier.
6. a kind of more base substituted purin analog derivative pharmaceutical compositions according to claim 5, it is characterised in that：The formula
（A）As sole active agent.
7. a kind of more base substituted purin analog derivative pharmaceutical compositions according to claim 5, it is characterised in that：The medicine
Acceptable carrier is one kind or more in filler, adhesive, moisturizer, disintegrant, retarding solvent, wetting agent or lubricant on
Kind.
8. a kind of more base substituted purin analog derivatives according to claim 1, it is characterised in that：The formula（A）In virus
Application in the drug aspect that catches, the disease are selected from respiratory virus infection, virus hepatitis, polio, influenza disease
Poison.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004047724A2 (en) * | 2002-05-16 | 2004-06-10 | Genelabs Technologies, Inc | Aryl and heteroaryl compounds as antibacterial and antifungal agents |
| WO2006124874A2 (en) * | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
| CN106008506A (en) * | 2016-06-27 | 2016-10-12 | 山东大学 | Substituted purine derivative and preparation method and application thereof |
-
2018
- 2018-04-18 CN CN201810345592.9A patent/CN108314684A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004047724A2 (en) * | 2002-05-16 | 2004-06-10 | Genelabs Technologies, Inc | Aryl and heteroaryl compounds as antibacterial and antifungal agents |
| WO2006124874A2 (en) * | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
| CN106008506A (en) * | 2016-06-27 | 2016-10-12 | 山东大学 | Substituted purine derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| CHIEN-HUANG WU ET AL.: "《Function-Oriented Development of CXCR4 Antagonists as Selective》", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20180724 |