CN103922966B - As the methane amide of influenza A virus inhibitor and isonitrile compounds and preparation and application thereof - Google Patents
As the methane amide of influenza A virus inhibitor and isonitrile compounds and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of methane amide as influenza A virus inhibitor and isonitrile compounds and preparation and application thereof.As the methane amide of influenza A virus inhibitor and the structural formula of isonitrile compounds respectively such as formula shown in I and II, wherein R is selected from the substitutive derivative of alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based and above-mentioned group, and the substituting group of substitutive derivative is alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based.Methane amide of the present invention and isonitrile compounds are that raw material prepares respectively by the mode such as acidylate, dehydration with amine.These methane amides and isonitrile compounds and pharmacy acceptable salt thereof can be used for preparing Tamiflu, and its activity is expected to the resistance of the generation overcoming existing compound higher than existing Tamiflu amantadine far away.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to as the methane amide of influenza A virus inhibitor and isonitrile compounds and preparation and application thereof.
Background technology
Influenza (hereinafter referred to as influenza) is a kind of Acute respiratory infectious disease being caused serious harm human society by influenza virus.Influenza virus can cause people, and the different kind organisms such as dog, horse, pig and bird produce influenza.The spanish influenza H1N1 of the most serious 1918 has seized the life of more than 2,000 ten thousand people.After this seasonal influenza H3N2 is constantly in human society outburst, and only the U.S. causes 3.6 ten thousand people dead every year, and 200,000 people are in hospital, and take over 10,000,000,000 dollars.Within 1997, the H5N1 subtype avian influenza at Hong Kong Late Cambrian can the direct infection mankind.2013, Global Raport people infects highly pathogenic H5N1 bird flu 622 example, 2013, China is Late Cambrian H7N9 type bird flu case again, although on May 1st, 2013, confirmed cases only have 127 examples, but China's aviculture whole industries in 2013 are because the loss that is subject to of bird flu reason is up to hundred billion.
The medicine of current clinical treatment influenza is the amantadine (Amantadine) of listing in 1976 and the Rimantadine (rimantadine) of listing in 1994 respectively; Their viral targets is M2 ionophorous protein.（Erik De Clercq.Nat RevDrug Discov.2006，5(12):1015-25）。The drug effect of Rimantadine oral preparations is stronger than amantadine 4 ~ 6 times.The major advantage of these two medicines is that structure is simple, and synthesis is convenient, and oral administration biaavailability is high, therefore uses cheap, widely uses in early days, obviously alleviates the symptom of influenza A.
According to the structure of amantadine and Rimantadine, the antivirus inhibitor for ionic channel target spot that all reports are known is aminated compounds.The active group amido of diamantane amine drug also brings its a kind of side effect, by hemato encephalic barrier after oral absorption, causes the toxic side effect of central nervous system.Although pass by decades so far from the medicine listing of these two single skeletons, the medicine of any novel texture has not occurred, the medicine overwhelming majority inhibitor in research, still using diamantane as skeleton, is therefore badly in need of the inhibitor finding novel texture.The present invention develops novel resisiting influenza virus small molecules, for the shortcoming solving part above-mentioned provides a kind of scheme.Improved antiviral small molecules avoids basic group amido, is adjusted to carbonylamino group and isonitrile, and these functional groups to a certain degree can avoid above neural side effect.
Isonitrile (Isocyanide) is also referred to as isocyanides (Carbylamine), and the general formula of this type of organic compound is R-N ≡ C.Carbon-nitrogen connects with triple bond, and nitrogen-atoms has part positive charge, carbon atom band portion negative charge.The special emphasis of current research isonitrile is isonitrile to participate in multi-component reaction as raw material, arranges as Passerini reaction, ugi reaction etc.Antiviral activity research for isonitrile does not have bibliographical information.
Summary of the invention
The object of the present invention is to provide a kind of benzamide type as influenza A virus inhibitor and isonitrile compounds and preparation and application thereof.
Object of the present invention is achieved through the following technical solutions:
As a Carbox amide for influenza A virus inhibitor, its structure is such as formula shown in I:
Wherein, R is selected from alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based and the substitutive derivative of above-mentioned group, and the substituting group of described substitutive derivative is alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based.In term: " alkyl " refers to C1-C8 alkyl, comprise straight or branched alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group etc.; " cycloalkyl " refers to C3-C8 cycloalkyl, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group; " aromatic base " refers to carbocyclic aromatic, as phenyl, naphthyl, anthryl or phenanthryl etc.; " heteroaryl " refers to and is selected from the aryl of the heteroatomss such as N, O, S as annular atoms containing one or more, as pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyridazinyl etc.; " amino acid based " refers to amino acid except the skeleton deaminized.
The above-mentioned Carbox amide pharmacy acceptable salt as influenza A virus inhibitor.The example of suitable acid has hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, crosses chloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, to toluic acid sulfonic acid, tartrate, acetic acid, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid, Phenylsulfonic acid or naphthene sulfonic acid etc.The salt obtained from suitable alkali comprises the salt that basic metal obtains as magnesium or calcium, ammonium etc. as sodium or potassium, alkaline-earth metal.
As an isonitrile compounds for influenza A virus inhibitor, its structure is such as formula shown in II:
R-NC
Formula II
Wherein, R is selected from alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based and the substitutive derivative of above-mentioned group, and the substituting group of described substitutive derivative is alkyl, cycloalkyl, aromatic base, heteroaryl, amino acid based.In term: " alkyl " refers to C1-C8 alkyl, comprise straight or branched alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group etc.; " cycloalkyl " refers to C3-C8 cycloalkyl, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group; " aromatic base " refers to carbocyclic aromatic, as phenyl, naphthyl, anthryl or phenanthryl etc.; " heteroaryl " refers to and is selected from the aryl of the heteroatomss such as N, O, S as annular atoms containing one or more, as pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyridazinyl etc.; " amino acid based " refers to amino acid except the skeleton deaminized.
The above-mentioned isonitrile compounds pharmacy acceptable salt as influenza A virus inhibitor.The example of suitable acid has hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, crosses chloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, to toluic acid sulfonic acid, tartrate, acetic acid, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid, Phenylsulfonic acid or naphthene sulfonic acid etc.The salt obtained from suitable alkali comprises the salt that basic metal obtains as magnesium or calcium, ammonium etc. as sodium or potassium, alkaline-earth metal.
The building-up reactions formula of the compound shown in above-mentioned formula I or formula II is as follows:
Wherein, R-NH
2be preferably the one in compound shown in following structure:
Carbox amide as influenza A virus inhibitor can be prepared by method 1,2 or 3:
Wherein, method 1 comprises the steps: that amino acids amine solvent is in acetonitrile, and add excessive ammonium formiate, be heated to 60-90 DEG C, stirring and refluxing 8-24h, reaction solution adds organic solvent extraction, dry, filters, desolventizes and obtain Carbox amide.
Method 2 comprises the steps: that amine solvent is in excessive methyl-formiate, adds triethylamine, stirs 5-25 hour, reaction solution organic solvent extraction, dry, filters, and steams to desolventize to obtain Carbox amide.
Method 3 comprises the steps: diacetyl oxide and formic acid mixing, stirs 5-60min, joins in the amine of methylene dichloride dissolving, stir 4-8h, after reaction solution sodium bicarbonate is neutralized to neutrality, add organic solvent extraction, drying, filters, and steams to desolventize to obtain Carbox amide.
Isonitrile compounds as influenza A virus inhibitor can be prepared by method 4 or 5:
Wherein, method 4 comprises the steps: above-mentioned Carbox amide to be dissolved in methylene dichloride, adds triethylamine, under the condition of ice bath, add phosphorus oxychloride, after reacting completely, in reaction solution, add organic solvent extraction, dry, filter, steaming desolventizes and obtains isonitrile compounds.
Method 5 comprises the steps: that in sodium hydroxide, drip water makes it dissolve, separately by amine, chloroform, aryl triethyl ammonium chloride and methylene dichloride mix, after mixed solution is dropwise dripped back flow reaction 10-15h in sodium hydroxide solution; Wash with frozen water after reaction, water layer dichloromethane extraction, dry filter revolves steaming and obtains isonitrile compounds.
The above-mentioned Carbox amide as influenza A virus inhibitor or isonitrile compounds influenza A virus ionophorous protein capable of blocking, suppress copying of influenza A virus, reach the effect of killing virus, therefore, it is expected to develop becomes novel Tamiflu.
The above-mentioned Carbox amide as influenza A virus inhibitor or isonitrile compounds, or its pharmacy acceptable salt application in preparation Tamiflu separately.
For preventing and/or treating a medicine for influenza, comprise the above-mentioned Carbox amide as influenza A virus inhibitor or isonitrile compounds, or it pharmaceutically goes up acceptable salt separately; The above-mentioned Carbox amide as influenza A virus inhibitor or the pharmaceutically acceptable carrier of isonitrile compounds or vehicle can also be comprised.
Tool of the present invention has the following advantages and effect: the present invention first using methane amide and the isonitrile compounds newtype drug as resisiting influenza virus, for the shortcoming solving part above-mentioned provides a kind of scheme.Present invention finds active very good and several methane amide that toxicity is lower and carbomethoxyisopropyl isonitrate, active in existing positive control medicine amantadine (50 times), therapeutic index more satisfactory (suitable with amantadine).Compound of the present invention is expected to overcome the resistance produced existing compound.The present invention is by avoiding basic group amido after transformation, and be adjusted to carbonylamino group and isonitrile, these functional groups to a certain degree can avoid above neural side effect.
Embodiment
Below by preparation example and embodiment, the invention will be further described.These embodiments only for illustration of the present invention, but do not limit the present invention in any way, under concept thereof of the present invention, all belong to the scope of protection of present invention to simple modifications of the present invention.
Embodiment 1: phenylalanine methyl ester isonitrile
(1) preparation of phenylalanine methyl ester methane amide
In 150mL round-bottomed flask, add acetonitrile solution, phenylalanine (8g, 45mmol), ammonium formate (5.61g, 90mmol), in 90 DEG C of reflux, a large amount of white solid slowly dissolves a small amount of white solid of rear appearance, reacts completely after 24h.Filter, by supernatant liquor vacuum concentrated by rotary evaporation, merge organic phase three times with water, extraction into ethyl acetate, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation supernatant liquor, obtains sorrel liquid, productive rate 85%.
1H NMR(400MHz,CDCl
3)δ8.07(s,1H),7.26(ddd,J=12.3,7.7,4.4Hz,3H),7.13–7.09(m,2H),4.92(dd,J=13.5,6.4Hz,1H),3.70(s,3H),3.10(ddd,J=33.5,13.9,6.1Hz,2H),2.01(s,1H).
13C NMR(101MHz,CDCl
3)δ171.02,160.31,136.04,129.06,128.72,127.22,55.04,52.99.
(2) preparation of phenylalanine methyl ester isonitrile
Phenylalanine methyl ester methane amide (6.6g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains sorrel liquid, productive rate 60%.
1H NMR(400MHz,CDCl
3)δ7.38–7.30(m,3H),7.26(d,J=8.0Hz,2H),4.46(dd,J=8.3,4.9Hz,1H),3.80(s,3H),3.20(ddd,J=22.2,13.8,6.6Hz,2H).
13C NMR(101MHz,CDCl
3)δ166.59,161.02,134.36,129.28,128.84,127.87,58.05,53.40,38.94.
Embodiment 2: tryptophan methyl ester isonitrile
(1) preparation of tryptophan methyl ester methane amide
In 150mL round-bottomed flask, add acetonitrile solution, tryptophane (14g, 45mmol), ammonium formate (5.61g, 90mmol), in 90 DEG C of reflux, a large amount of white solid slowly dissolves a small amount of white solid of rear appearance, reacts completely after 24h.Filter, by supernatant liquor vacuum concentrated by rotary evaporation, merge organic phase three times with water, extraction into ethyl acetate, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation supernatant liquor, obtains brown liquid, productive rate 85%.
1H NMR(400MHz,CDCl
3)δ8.19(s,1H),8.10(d,J=7.8Hz,1H),7.48(d,J=7.6Hz,1H),7.40(s,1H),7.33–7.29(m,1H),7.26–7.21(m,1H),5.04-4.99(m,1H),3.71(s,3H),3.31-3.23(m,1H),1.67(s,3H).
13C NMR(101MHz,CDCl
3)δ171.67,160.92,149.54,135.24,130.36,124.57,124.15,122.60,118.78,115.27,114.72,83.80,60.36,51.10,28.13,27.33.
(2) preparation of tryptophan methyl ester isonitrile
Tryptophan methyl ester methane amide (10.5g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains sorrel liquid, productive rate 62%.
1H NMR(400MHz,CDCl
3)δ8.16(d,J=7.9Hz,1H),7.59(s,1H),7.50(d,J=7.7Hz,1H),7.37–7.31(m,1H),7.28(s,1H),4.57(dd,J=8.1,4.9Hz,1H),3.79(s,3H),3.43-3.26(m,2H),1.67(s,3H).
13C NMR(101MHz,CDCl
3)δ166.68,160.97,149.45,135.46,129.50,124.96,124.80,122.73,118.36,115.52,113.27,83.99,60.40,56.65,29.11,28.18.
Embodiment 3:2-isocyano--2-methyl phenylacetate
(1) preparation of phenyl glycine methyl ester methane amide
Phenyl glycine methyl ester (1.4g, 8.5mmol), is dissolved in 6mL methyl-formiate, add triethylamine (1.8mL, 13mmol) under room temperature, within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, with dichloromethane extraction three times, merges organic phase, then three times are washed with saturated sodium chloride solution, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation, obtain weak yellow liquid, productive rate 43%.
1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.65–7.14(m,5H),5.56(d,J=7.5Hz,1H),3.64(s,3H).
13C NMR(101MHz,CDCl
3)δ171.05,160.73,136.03,129.00,128.66,127.26,55.08,52.89.
(2) preparation of 2-isocyano--2-methyl phenylacetate
Phenyl glycine methyl ester methane amide (5.6g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains sorrel liquid, productive rate 60%.
1H NMR(400MHz,CDCl
3)δ7.52–7.35(m,5H),5.39(s,1H),3.74(s,3H).
13C NMR(101MHz,CDCl
3)δ166.14,161.3,131.86,129.60,129.22,126.73,60.22,53.77.
Embodiment 4:2-isocyano--3 Methylbutanoic acid methyl esters
(1) preparation of valine methyl ester methane amide
Valine methyl ester (1g, 8.5mmol), is dissolved in 6mL methyl-formiate, add triethylamine (1.8mL, 13mmol) under room temperature, within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, with dichloromethane extraction three times, merges organic phase, then three times are washed with saturated sodium chloride solution, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation, obtain weak yellow liquid, productive rate 46%.
1H NMR(400MHz,DMSO-d6)δ8.48(d,J=8.2Hz,1H),4.28(dd,J=8.5,5.8Hz,1H),3.64(d,J=2.7Hz,3H),2.16-1.98(m,1H),0.87(dd,J=6.8,2.1Hz,6H).
(2) 2-isocyano--3 Methylbutanoic acid methyl esters preparation
Valine methyl ester methane amide (6.6g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains sorrel liquid, productive rate 53%.
1H NMR(400MHz,CDCl3)δ4.21(d,J=4.2Hz,1H),3.83(s,3H),1.11(d,J=6.8Hz,3H),1.01(d,J=6.7Hz,3H).13C NMR(101MHz,CDCl3)δ171.11,164.51,60.33,53.31,43.35,20.97.
Embodiment 5: glycine methyl ester isonitrile
(1) preparation of glycine methyl ester methane amide
Glycine methyl ester (0.75g, 8.5mmol), is dissolved in 6mL methyl-formiate, add triethylamine (1.8mL, 13mmol) under room temperature, within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, with dichloromethane extraction three times, merges organic phase, then three times are washed with saturated sodium chloride solution, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation, obtain weak yellow liquid, productive rate 86%.
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),3.90(d,J=6.1Hz,3H),3.64(s,2H).
(2) preparation of glycine methyl ester isonitrile
Glycine methyl ester methane amide (3.2g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains sorrel liquid, productive rate 40%.
1H NMR(400MHz,CDCl
3)δ4.26(d,J=15.6Hz,1H),3.84(s,3H).
13C NMR(101MHz,CDCl
3)δ171.11,164.51,53.31,43.35.
Embodiment 6: methyl butyl isonitrile
(1) preparation of methyl butyl methane amide
Methyl butyl (1.00g, 8.5mmol), is dissolved in 6mL methyl-formiate, add triethylamine (1.8mL, 13mmol) under room temperature, within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, with dichloromethane extraction three times, merges organic phase, then three times are washed with saturated sodium chloride solution, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation, obtain weak yellow liquid, productive rate 55%.
1H NMR(400MHz,CDCl
3)δ7.75(d,J=90.2Hz,1H),7.34(s,1H),3.28(d,J=102.5Hz,3H),3.11–2.69(m,2H),2.26–1.77(m,2H),1.75–1.20(m,2H).
13C NMR(101MHz,CDCl
3)δ173.02,164.89,161.80,50.89,36.66,30.52,25.80,24.15.
(2) preparation of methyl butyl isonitrile
Methyl butyl methane amide (4.0g, 32mmol) is dissolved in dichloromethane solution (50mL), adds triethylamine (9.61g, 96mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (4.9g, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and adjusts solution to be neutral (can meta-alkalescence) with dilute hydrochloric acid, and merge organic phase, anhydrous sodium sulfate drying after extract three times, filtration final vacuum concentrated by rotary evaporation, obtains yellow liquid, productive rate 45%.
1H NMR(400MHz,CDCl
3)δ3.64(s,3H),3.47–3.40(m,2H),2.45(t,J=7.1Hz,1H),2.05–1.83(m,1H).
13C NMR(101MHz,CDCl
3)δ172.60,110.00,51.86,40.86,40.79,40.73,30.16,24.26.
Embodiment 7: o-methyl benzoic acid methyl ester isonitrile
(1) preparation of methyl o-aminobenzoate methane amide
Methyl o-aminobenzoate (1.3g, 8.5mmol), is dissolved in 6mL methyl-formiate, add triethylamine (1.8mL, 13mmol) under room temperature, within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, with dichloromethane extraction three times, merges organic phase, then three times are washed with saturated sodium chloride solution, after anhydrous sodium sulfate drying, filter, vacuum concentrated by rotary evaporation, obtain weak yellow liquid, productive rate 67%.
1H NMR(400MHz,DMSO)δ10.72(s,1H),8.52(s,1H),7.86(d,J=7.6Hz,1H),7.54(t,J=7.4Hz,2H),7.11(t,J=7.6Hz,1H),3.83(s,3H).
(2) preparation of o-toluic acid isonitrile
By methyl o-aminobenzoate methane amide (5.7g, 32mmol) be dissolved in dichloromethane solution (20mL), add triethylamine (9.61g, 96mmol), heavy steamed phosphorus oxychloride solution (4.9g is dropwise added in ice bath, 32mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains weak yellow liquid, productive rate 40% with silicagel column.
1H NMR(400MHz,CDCl3)δ8.02–7.90(m,1H),7.58–7.51(m,1H),7.48–7.40(m,2H),3.93(s,3H).
Embodiment 8: amantadine isonitrile
(1) preparation of amantadine methane amide
Diacetyl oxide (2.8mL, 10mmol) and formic acid (1.1mL, 12mmol) mixing, stir 30min, join in the amantadine (0.5g, 3.3mmol) of methylene dichloride dissolving slowly, stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, add organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain faint yellow solid, productive rate 86%.
1H NMR(400MHz,DMSO)δ7.82(d,J=1.8Hz,1H),2.01(d,J=11.3Hz,6H),1.91(s,6H),1.75(d,J=1.7Hz,3H).
13C NMR(101MHz,DMSO)δ161.73,160.01,50.47,49.49,43.22,41.03,40.64–40.20,40.09,39.78,39.28,39.27–38.55,35.96,35.48,28.72.
(2) preparation of amantadine isonitrile
Amantadine methane amide (450mg, 2.7mmol) is dissolved in dichloromethane solution (2mL), adds triethylamine (2mL, 13mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (0.25mL, 2.7mmol), solution gradually becomes yellow, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains faint yellow solid, productive rate 78% with silicagel column.
1H NMR(400MHz,CDCl
3)δ2.09(s,3H),2.02(s,6H),1.68(d,J=14.3Hz,6H).
13C NMR(101MHz,CDCl
3)δ43.53,35.47,28.68.
Embodiment 9: tert-Octylamine isonitrile
(1) preparation of tertiary pungent methane amide
Diacetyl oxide (44.0mL, 420mmol) and formic acid (20.3mL, 450mmol) mixing, stir 30min, add in the tert-Octylamine (10.3g, 80mmol) of methylene dichloride dissolving slowly, stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, add organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain weak yellow liquid, productive rate 93%.
1H NMR(400MHz,DMSO)δ7.88(d,J=2.0Hz,1H),7.55(s,1H),1.63(q,J=7.5Hz,2H),1.48(q,J=7.4Hz,1H),1.24–1.17(m,9H),0.86–0.70(m,6H).
(2) preparation of tert-Octylamine isonitrile
Tertiary pungent methane amide (1.0g, 6.4mmol) is dissolved in dichloromethane solution (20mL), adds triethylamine (4.4mL, 30mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (0.6mL, 6.4mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains weak yellow liquid, productive rate 50% with silicagel column.
1H NMR(400MHz,DMSO)δ1.60–1.57(m,2H),1.45–1.41(m,6H),1.04(s,9H).
Embodiment 10:2,6-dimethyl-4-tertiary butyl aniline isonitrile
The preparation of (1) 2,6-dimethyl-4-t-butylbenzamide
Diacetyl oxide (44.0mL, 420mmol) and formic acid (20.3mL, 450mmol) mixing, stir 30min, add 2, the 6-dimethyl-4-tertiary butyl aniline (10.3g that methylene dichloride dissolves slowly, 80mmol), stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, adds organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain faint yellow solid, productive rate 93%.
1H NMR(400MHz,CDCl3)δ8.33(d,J=1.0Hz,1H),8.07(d,J=11.9Hz,1H),7.13(s,2H),2.30(s,6H),1.31(s,9H).
The preparation of (2) 2,6-dimethyl-4-tertiary butyl aniline isonitrile
By 2,6-dimethyl-4-t-butylbenzamide (1g, 6.7mmol) be dissolved in dichloromethane solution (5mL), add triethylamine (4.7mL, 33mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (0.63mL, 6.7mmol), solution gradually becomes yellow, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains yellowish liquid, productive rate 48% with silicagel column.
1H NMR(400MHz,CDCl3)δ7.02(s,2H),2.34(s,H6),1.21(s,9H).
Embodiment 11: to t-butylcyclohexyl alkanamine isonitrile
(1) to the preparation of t-butylcyclohexane methane amide
Diacetyl oxide (18.2mL, 192mmol) and formic acid (8.4mL, 224mmol) mixing, stir 30min, add slowly methylene dichloride dissolve in t-butylcyclohexyl alkanamine (5.0g, 32mmol), stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, add organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain faint yellow solid, productive rate 98%.
1H NMR(400MHz,CDCl
3)δ8.12–7.97(m,1H),5.24(s,1H),1.99–1.69(m,4H),1.58(d,J=11.9Hz,1H),1.45(dd,J=18.6,8.2Hz,1H),1.15–0.95(m,4H),0.78(d,J=5.7Hz,9H).
(2) to the preparation of t-butylcyclohexyl alkanamine isonitrile
Will to t-butylcyclohexane methane amide (2.0g, 11mmol) be dissolved in dichloromethane solution (10mL), add triethylamine (7.6mL, 55mmol), heavy steamed phosphorus oxychloride solution (1.0mL is dropwise added in ice bath, 11mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains yellowish liquid, productive rate 54% with silicagel column.
1H NMR(400MHz,CDCl
3)δ3.89(s,1H),3.39–3.22(m,1H),2.20(d,J=12.4Hz,2H),1.99(d,J=10.9Hz,2H),1.80(d,J=10.4Hz,2H),1.66(d,J=10.7Hz,2H),0.86(s,9H).
Embodiment 12:1-rimantadine isonitrile
(1) preparation of 1-rimantadine methane amide
Diacetyl oxide (8.0mL, 84mmol) and formic acid (3.7mL, 98mmol) mixing, stir 30min, add in the 1-rimantadine (3.0g, 14mmol) of methylene dichloride dissolving slowly, stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, add organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain white solid, productive rate 77%.
1H NMR(400MHz,CDCl
3)δ8.09(dd,J=87.5,6.6Hz,1H),3.96–3.60(m,1H),1.99(d,J=3.5Hz,3H),1.70(d,J=11.8Hz,3H),1.64–1.53(m,6H),1.44(ddd,J=26.5,12.0,2.0Hz,3H),1.13(d,J=6.9Hz,1H),1.05(d,J=6.9Hz,2H).
(2) preparation of 1-rimantadine isonitrile
1-rimantadine methane amide (1.5g, 6mmol) is dissolved in dichloromethane solution (3mL), adds triethylamine (4.3mL, 30mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (0.6mL, 6mmol), solution gradually becomes sorrel, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains yellow solid, productive rate 88% with silicagel column.
1H NMR(400MHz,CDCl
3)3.25–3.16(m,1H),2.02(s,3H),1.70(d,J=12.3Hz,4H),1.61(d,J=11.3Hz,5H),1.54–1.48(m,3H),1.27–1.20(m,3H).
Embodiment 13:(1R, 2R, 3R, 5S)-3-pinane amine isonitrile
(1) preparation of (1R, 2R, 3R, 5S)-3-pinane methane amide
Diacetyl oxide (3.9mL, 36mmol) and formic acid (1.7mL, 42mmol) mixing, stir 30min, add (1R, 2R that methylene dichloride dissolves slowly, 3R, 5S) in-3-pinane amine (1g, 6.5mmol), stirring at room temperature 8h, after reaction solution sodium bicarbonate is neutralized to pH=7.0, adds organic solvent extraction, dry, filter, remove solvent under reduced pressure and obtain white solid, productive rate 96%.
1H NMR(400MHz,CDCl
3)δ8.21–7.99(m,1H),4.29(dddd,J=43.2,15.9,9.2,6.8Hz,1H),2.71–2.55(m,1H),2.47–2.28(m,1H),1.91–1.65(m,3H),1.53(ddd,J=14.1,6.2,2.3Hz,1H),1.21(t,J=4.3Hz,3H),1.13–1.01(m,6H).
(2) preparation of (1R, 2R, 3R, 5S)-3-pinane amine isonitrile
By (1R, 2R, 3R, 5S)-3-pinane methane amide (1.0g, 5mmol) is dissolved in dichloromethane solution 3mL, add triethylamine (3.8mL, 25mmol), in ice bath, dropwise add heavy steamed phosphorus oxychloride solution (0.5mL, 5mmol), solution gradually becomes brown, reacts completely after 12h.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase, anhydrous sodium sulfate drying after extracting three times, filters final vacuum concentrated by rotary evaporation, is separated, obtains brown color liquid, productive rate 53% with silicagel column.
1H NMR(400MHz,CDCl
3)δ3.86–3.75(m,1H),2.62–2.52(m,1H),2.47–2.39(m,1H),2.30(dd,J=6.1,3.3Hz,1H),2.12–2.01(m,1H),1.97(dt,J=5.9,4.4Hz,1H),1.86–1.80(m,1H),1.25–1.16(m,7H),1.05(dt,J=10.0,6.3Hz,2H),0.89(s,3H).
Embodiment 14: TERTIARY BUTYL AMINE isonitrile
By sodium hydroxide (16.6g, add after 200mmol) being dissolved in 15.4mL water in bottle with two necks, by TERTIARY BUTYL AMINE (3.6g, 50mmol), chloroform (3.0g, 25mmol), after benzyltriethylammoinium chloride (104.6mg, 25mmol) is dissolved in 10mL dichloromethane solution, join in constant pressure funnel, dropwise join in bottle with two necks, 60 DEG C of back flow reaction.React completely after 12h, add frozen water cancellation, after adding dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, filter final vacuum concentrated by rotary evaporation, obtain yellow liquid, productive rate 30%.
1H NMR(400MHz,CDCl
3)δ1.42–1.35(m,9H).
13C NMR(101MHz,CDCl
3)δ152.88,53.49,30.68.
Embodiment 15
Anti-avian influenza virus is tested
1. experiment material
(1) virus: H
5n
1strain is A/VietNam/1194/2004, and recording that it tires early stage is 4 × 10
9pfu/mL, presses 10 with substratum during infection
-2dilution, i.e. 40 ~ 50pfu/ hole, is provided by virusology National Key Laboratory of Wuhan University.
(2) cell: mdck cell (China typical culture collection center is originated, and mdck cell is the classical cell of influenza virus plaque assay), virusology National Key Laboratory of Wuhan University provides.
(3) positive control drug: amantadine, virusology National Key Laboratory of Wuhan University provides.
(4) sample preparation: amantadine and the compounds of this invention DMSO are made into the mother liquor of 10mg/mL, is diluted to corresponding gradient with DMSO during use.
2. experimental technique
2.1 cytotoxicity experiments (MTT analytical method)
MTT analytical method is based on living cells metabolize thing reductive agent MTT.MTT full name is 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide; Chinese chemistry 3-(4,5-dimethyl-2-thiazole)-2,5-phenylbenzene bromination tetrazoles by name; Commodity are called tetrazolium bromide.
The preparation of 5mg/mL MTT: take 0.5g MTT powder, is dissolved in 100mL phosphate buffered saline buffer (PBS) or without in phenol red medium, degerming with 0.22 μm of membrane filtration, 4 DEG C keep in Dark Place.MTT is preferably now with the current, and 4 DEG C to keep in Dark Place in two weeks effectively.Or in-20 DEG C of Long-term Cryopreservations, be distributed into tubule, avoid multigelation.
The preparation of three formazan lysates: 25g sodium laurylsulfonate (SDS), 250 μ L concentration are hydrochloric acid and the 12.5mL isopropylcarbinol of 11.6mo1/L, add deionized water to be settled to 250mL and namely to obtain three formazan lysates, in this lysate, the mass percent of sodium laurylsulfonate (SDS) is 10%, hydrochloric acid volumetric molar concentration is 0.012mo1/L, the mass percent of isopropylcarbinol is 5%.
This cytotoxicity experiment step is as follows successively:
(1) 2 × 10 are diluted to after mdck cell strain digestion with DMEM perfect medium
5individual/mL, spreads into 96 orifice plates, and 100 μ L/ holes, put 37 DEG C, 5%CO
2cell culture incubator cultivates 4 hours, makes cell fully adherent;
(2) tested the compounds of this invention mother liquor (10mg/mL) is used DMSO gradient dilution, final concentration is respectively 33.33 μ g/mL, 6.66 μ g/mL, 3.33 μ g/mL, 0.33 μ g/mL and 0.03 μ g/mL, adds in 96 hole versions, every hole 1 μ L.Each concentration establishes three parallel holes.Control wells establishes three parallel holes equally, and every hole adds 1 μ L DMSO.Another being done by positive control drug processes in contrast equally;
(3) cultivate after 48 hours, remove supernatant liquor, the phosphate buffered saline buffer (PBS) of monolayer sterilizing rinses three times;
(4) every hole adds MTT and the fresh culture mixed solution (MTT final concentration 0.5mg/mL) of 100 μ L, hatches 4 hours, make MTT be reduced to formazan at 37 DEG C;
(5) remove supernatant liquor, every hole adds 100 μ L tri-formazan lysates, and hatch 4 hours for 37 DEG C, Shi formazan is all dissolved;
(6) with the absorbance value at 655nm place for background, 570nm place measure absorbance value.
After completing above-mentioned experiment, according to following formulae discovery cell mortality:
Cell mortality (%)=[1-(adding Compound cellular OD value/compared with control cells OD value)] × 100.
Half toxic concentration (the CC of the compounds of this invention, positive control drug
50) method of calculation be: take compound concentration as X-coordinate, cell mortality be ordinate zou mapping, then obtaining compound concentration when 50% mortality ratio, is exactly CC
50, calculation result is as shown in table 1.
2.2 anti-H
5n
1activity experiment
Mdck cell is incubated in 24 orifice plates, until cell grow to 100% full time, wash 2 times with PBS, according to following different modes process virus and cell, often organize 4 multiple holes: 1) Positive control wells: directly add in cell after positive control drug and virus being mixed; 2) virus-infected controls: viral suspension is added in cell; 3) cell controls: with DMEM and cell incubation; 4) new compound disposal hole: directly add in cell after mixing in 300 μ L substratum by the compounds of this invention and virus.Used medium is not containing serum, and the pancreatin adding final concentration 10 μ g/mL promotes to infect.The compounds of this invention DMSO is made into the mother liquor of 10mg/mL, uses DMSO gradient dilution during use, and the compounds of this invention final concentration is respectively 33.33 μ g/mL, 6.66 μ g/mL, 3.33 μ g/mL, 0.33 μ g/mL and 0.03 μ g/mL, and every hole adds 1 μ L.Another being done by positive control drug processes in contrast equally.Supernatant is abandoned after 37 DEG C of infection 2h, 2 times are washed with PBS, add the mixed solution (melt in advance and be incubated to avoid solidifying in 37 DEG C) without phenol red DMEM substratum and 1% agarose, in this mixed solution, the volume ratio of DMEM and agarose is 1:1, then the pancreatin adding final concentration 10 μ g/mL promotes to infect.The room temperature that faces up places 20-40min, is inverted in 37 DEG C, 5%CO after to be solidified
22-4 days cultivated by incubator.When plaque is large and clear, by the violet staining of 0.5%, 130 μ L/ holes, with the naked eye count plaque after lucifuge dyeing 6-8h, every hole counts 2 times, and when coming to the same thing, counting is effectively, repeat count time different, until twice identical time be designated as effectively.The plaque number often organized is the mean value in 3 holes.
After completing above-mentioned experiment, adopt following formulae discovery the compounds of this invention, positive control drug to the inhibiting rate of virus infection:
Inhibiting rate (%)=[the plaque number of (the plaque number of the plaque number-Jia compound group of virus-infected controls group)/virus-infected controls group] × 100.
Half-inhibition concentration (the IC of the compounds of this invention, positive control drug
50) method of calculation be: take compound concentration as X-coordinate, inhibiting rate be ordinate zou mapping, obtaining compound concentration when 50% inhibiting rate, is exactly IC
50, SI is selectivity index, and its value is CC
50/ IC
50, calculation result is in table 1.
The anti-influenza virus activity of the representative methane amide of table 1. and isonitrile
As shown in table 1, compared with positive amantadine medicine, the most Carbox amide of the present invention shows good suppression virus activity, and isonitrile compounds shows good antiviral activity too.Show that compound of the present invention can as the activeconstituents of Tamiflu, with pharmaceutically acceptable solid support material or mixing diluents, as unit agent administration.Suitable unit agent comprises: oral dosage form, injection type, rectal dosage form etc., and the dose-dependant of every day is in the seriousness of disease, application method and compound itself.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (11)
1. as a Carbox amide for influenza A virus inhibitor, it is characterized in that: its structure is such as formula shown in I:
Wherein, R is
2. a Carbox amide pharmacy acceptable salt according to claim 1.
3. as an isonitrile compounds for influenza A virus inhibitor, it is characterized in that: its structure is such as formula shown in II:
R-NC
Formula II
Wherein, R is identical with the R in claim 1.
4. an isonitrile compounds pharmacy acceptable salt according to claim 3.
5. the preparation method of Carbox amide according to claim 1, is characterized in that for method 3;
Method 3 comprises the steps: diacetyl oxide and formic acid mixing, stir 5-60min, join (1R, 2R that methylene dichloride dissolves, 3R, 5S) in-3-pinane amine, stir 4-8h, after reaction solution sodium bicarbonate is neutralized to neutrality, add organic solvent extraction, drying, filters, and steams to desolventize to obtain Carbox amide.
6. the preparation method of isonitrile compounds according to claim 3, it is characterized in that comprising the steps: Carbox amide according to claim 1 to be dissolved in methylene dichloride, add triethylamine, phosphorus oxychloride is added under the condition of ice bath, in reaction solution, organic solvent extraction is added after reacting completely, drying, filters, and steams to desolventize to obtain isonitrile compounds.
7. a Carbox amide is at the anti-H of preparation
5n
1application in the medicine of the influenza that virus causes, is characterized in that: described Carbox amide is
8. the application of Carbox amide pharmacy acceptable salt in the medicine preparing the influenza that anti-H5N1 virus causes, is characterized in that: described Carbox amide is with described in claim 7.
9. an isonitrile compounds is at the anti-H of preparation
5n
1application in the medicine of the influenza that virus causes, is characterized in that: described isonitrile compounds is
10. an isonitrile compounds pharmacy acceptable salt is at the anti-H of preparation
5n
1application in the medicine of the influenza that virus causes, is characterized in that: described isonitrile compounds is with described in claim 9.
11. 1 kinds for preventing and/or treating H
5n
1the medicine of the influenza that virus causes, is characterized in that: comprise Carbox amide according to claim 7, isonitrile compounds according to claim 9 or the salt described in claim 8 or 10.
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| Isoselenocyanates derived from amino acid esters: an expedient synthesis and application to the assembly of sele-noureidopeptidomimetics, unsymmetrical Selenoureas and selenohydantoins;Hosahalli P. Hemantha et al.;《J. Pept. Sci.》;20100916;644–651 * |
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