CN103922966A - Formamide and isonitrile compounds serving as influenza A virus inhibitors and preparation and application thereof - Google Patents
Formamide and isonitrile compounds serving as influenza A virus inhibitors and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses formamide and isonitrile compounds serving as influenza A virus inhibitors and preparation and application thereof. The structural formulae of the formamide-isonitrile compounds serving as the influenza A virus inhibitors are shown as a formula I and a formula II described in the specification, wherein R is selected from alkyl, naphthenic group, aromatic group, heteroaromatics group, amino acid group and substitutive derivatives of all the groups; the substituent groups of the substitutive derivatives are alkyl, naphthenic group, aromatic group, heteroaromatics group and amino acid group. The formamide and isonitrile compounds are prepared from amine serving as a raw material by means of acylation, dehydration and the like. These formamide and isonitrile compounds and pharmaceutically-acceptable salts thereof can be used for preparing anti-influenza medicaments of which the activities are much higher than that of an existing anti-influenza medicament, namely, amantadine, and the drug tolerance generated by existing compounds can be overcome.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to methane amide and isonitrile compounds and preparation and application thereof as influenza A virus inhibitor.
Background technology
Influenza (hereinafter to be referred as influenza) is a kind of Acute respiratory infectious disease that is caused serious harm human society by influenza virus.Influenza virus can be caused 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 more than 2,000 ten thousand people's life.After this seasonal influenza H3N2 is constantly in human society outburst, and only the U.S. causes 3.6 ten thousand people's death every year, and 200,000 people are in hospital, cost more than $ 10 billion.The H5N1 subtype avian influenza of finding first in Hong Kong for 1997 can the direct infection mankind.2013, Global Raport people infect highly pathogenic H5N1 bird flu 622 examples, 2013, China has found again H7N9 type bird flu case first, although on May 1st, 2013, confirmed cases only have 127 examples, but China's aviculture whole industry in 2013 because the loss that bird flu reason is subject to up to hundred billion.
The medicine for the treatment of clinically influenza is at present respectively the amantadine (Amantadine) of listing in 1976 and the Rimantadine (rimantadine) of listing in 1994; Their viral target is M2 ionophorous protein.（Erik?De?Clercq.Nat?RevDrug?Discov.2006，5(12):1015-25）。The drug effect of Rimantadine oral preparations is stronger 4～6 times than amantadine.The major advantage of these two medicines is simple in structure, synthetic convenient, and oral administration biaavailability is high, therefore uses cheaply, is widely used 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 medicine has also brought its a kind of side effect, after oral absorption, by hemato encephalic barrier, causes the toxic side effect of central nervous system.Although pass by decades so far from the medicine listing of these two single skeletons, do not have the medicine appearance of any novel texture, the medicine overwhelming majority inhibitor in research, still using diamantane as skeleton, are therefore badly in need of finding the inhibitor of novel texture.The present invention develops novel resisiting influenza virus small molecules, provides a kind of scheme for solving the above-mentioned shortcoming of part.Improved antiviral small molecules has been avoided basic group amido, is adjusted into carbonylamino group and isonitrile, and these functional groups can to a certain degree be avoided 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, has part positive charge on nitrogen-atoms, carbon atom band portion negative charge.The special emphasis of research isonitrile is isonitrile to participate in multi-component reaction as raw material at present, and row are 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 suc 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 that containing one or more is selected from the aryl of the heteroatomss such as N, O, S as annular atoms, as pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyridazinyl etc.; " amino acid based " refers to amino acid except the skeleton deaminizing.
The above-mentioned Carbox amide pharmacy acceptable salt as influenza A virus inhibitor.Suitable sour example 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 obtaining 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 suc 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 that containing one or more is selected from the aryl of the heteroatomss such as N, O, S as annular atoms, as pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyridazinyl etc.; " amino acid based " refers to amino acid except the skeleton deaminizing.
The above-mentioned isonitrile compounds pharmacy acceptable salt as influenza A virus inhibitor.Suitable sour example 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 obtaining 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 prepare by method 1,2 or 3:
Wherein, method 1 comprises the steps: that amino acids amine solvent, in acetonitrile, adds excessive ammonium formiate, is heated to 60-90 DEG C, stirring and refluxing 8-24h, and reaction solution adds organic solvent extraction, dry, filters, and desolventizes and obtains Carbox amide.
Method 2 comprises the steps: that amine solvent, in excessive methyl-formiate, adds triethylamine, stirs 5-25 hour, and reaction solution organic solvent extraction is dry, filters, and steams to desolventize to obtain Carbox amide.
Method 3 comprises the steps: that diacetyl oxide and formic acid mix, and stirs 5-60min, joins in the amine of methylene dichloride dissolving, stir 4-8h, reaction solution is neutralized to after neutrality with sodium bicarbonate, adds organic solvent extraction, dry, to filter, steaming desolventizes and obtains Carbox amide.
Isonitrile compounds as influenza A virus inhibitor can prepare 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: to drip water in sodium hydroxide dissolves it, separately amine, chloroform, aryl triethyl ammonium chloride and methylene dichloride are mixed, after mixed solution is dropwise dripped to back flow reaction 10-15h in sodium hydroxide solution; After reaction, wash with frozen water, water layer dichloromethane extraction, dry filter revolves to steam 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 viral effect of killing, therefore, it is expected to exploitation 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; Can also comprise the above-mentioned Carbox amide as influenza A virus inhibitor or the pharmaceutically acceptable carrier of isonitrile compounds or vehicle.
Tool of the present invention has the following advantages and effect: the present invention is the newtype drug using methane amide and isonitrile compounds as resisiting influenza virus first, provides a kind of scheme for solving the above-mentioned shortcoming of part.The present invention has found activity is very good and toxicity is lower several methane amides 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 that existing compound is produced.The present invention has avoided basic group amido after transforming, and is adjusted into carbonylamino group and isonitrile, and these functional groups can to a certain degree be avoided above neural side effect.
Embodiment
Below by preparation example and embodiment, the invention will be further described.These embodiment are only for the present invention is described, but do not limit the present invention in any way, and under design prerequisite of the present invention, simple modifications of the present invention are all belonged to the scope of protection of 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, there is a small amount of white solid after slowly dissolving in a large amount of white solids, after 24h, reacts completely.Filter, by supernatant liquor vacuum concentrated by rotary evaporation, water, ethyl acetate extraction merge organic phase three times, with after anhydrous sodium sulfate drying, filter, and 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, there is a small amount of white solid after slowly dissolving in a large amount of white solids, after 24h, reacts completely.Filter, by supernatant liquor vacuum concentrated by rotary evaporation, water, ethyl acetate extraction merge organic phase three times, with after anhydrous sodium sulfate drying, filter, and 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, under room temperature, add triethylamine (1.8mL, 13mmol), within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, uses dichloromethane extraction three times, merges organic phase, then with saturated sodium chloride solution washing three times, with 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, under room temperature, add triethylamine (1.8mL, 13mmol), within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, uses dichloromethane extraction three times, merges organic phase, then with saturated sodium chloride solution washing three times, with 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, under room temperature, add triethylamine (1.8mL, 13mmol), within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, uses dichloromethane extraction three times, merges organic phase, then with saturated sodium chloride solution washing three times, with 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, under room temperature, add triethylamine (1.8mL, 13mmol), within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, uses dichloromethane extraction three times, merges organic phase, then with saturated sodium chloride solution washing three times, with 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 the phosphorus oxychloride solution (4.9g, 32mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and to adjust solution with dilute hydrochloric acid be neutral (can meta-alkalescence), merges organic phase after extract three times, anhydrous sodium sulfate drying, and 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, under room temperature, add triethylamine (1.8mL, 13mmol), within stirring at room temperature 5-25 hour, react completely, reaction solution vacuum concentrated by rotary evaporation, uses dichloromethane extraction three times, merges organic phase, then with saturated sodium chloride solution washing three times, with 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), in ice bath, dropwise add the phosphorus oxychloride solution (4.9g heavily steaming, 32mmol), solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains weak yellow liquid, productive rate 40%.
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) mix, stir 30min, join slowly in the amantadine (0.5g, 3.3mmol) of methylene dichloride dissolving stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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 the phosphorus oxychloride solution (0.25mL, 2.7mmol) heavily steaming, it is yellow that solution gradually becomes, and after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains faint yellow solid, productive rate 78%.
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) mix, stir 30min, add slowly in the tert-Octylamine (10.3g, 80mmol) of methylene dichloride dissolving stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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 the phosphorus oxychloride solution (0.6mL, 6.4mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains weak yellow liquid, productive rate 50%.
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-tert.-butylbenzene methane amide
Diacetyl oxide (44.0mL, 420mmol) and formic acid (20.3mL, 450mmol) mix, stir 30min, add slowly 2 of methylene dichloride dissolving, 6-dimethyl-4-tertiary butyl aniline (10.3g, 80mmol), stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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-tert.-butylbenzene methane amide (1g, 6.7mmol) be dissolved in dichloromethane solution (5mL), add triethylamine (4.7mL, 33mmol), in ice bath, dropwise add the phosphorus oxychloride solution (0.63mL, 6.7mmol) heavily steaming, it is yellow that solution gradually becomes, and after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains yellowish liquid, productive rate 48%.
1H?NMR(400MHz,CDCl3)δ7.02(s,2H),2.34(s,H6),1.21(s,9H).
Embodiment 11: to tertiary butyl hexamethylene alkanamine isonitrile
(1) preparation to tertiary butyl cyclohexane carboxamide
Diacetyl oxide (18.2mL, 192mmol) and formic acid (8.4mL, 224mmol) mix, stir 30min, add slowly methylene dichloride dissolve in tertiary butyl hexamethylene alkanamine (5.0g, 32mmol), stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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) preparation to tertiary butyl hexamethylene alkanamine isonitrile
Will be to tertiary butyl cyclohexane carboxamide (2.0g, 11mmol) be dissolved in dichloromethane solution (10mL), add triethylamine (7.6mL, 55mmol), in ice bath, dropwise add the phosphorus oxychloride solution (1.0mL heavily steaming, 11mmol), solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains yellowish liquid, productive rate 54%.
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) mix, stir 30min, add slowly in the 1-rimantadine (3.0g, 14mmol) of methylene dichloride dissolving stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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 the phosphorus oxychloride solution (0.6mL, 6mmol) heavily steaming, solution gradually becomes sorrel, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains yellow solid, productive rate 88%.
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) mix, stir 30min, (1R, the 2R that add slowly methylene dichloride to dissolve, 3R, 5S) in-3-pinane amine (1g, 6.5mmol), stirring at room temperature 8h, reaction solution is neutralized to after pH=7.0 with sodium bicarbonate, 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 the phosphorus oxychloride solution (0.5mL, 5mmol) heavily steaming, solution gradually becomes brown, after 12h, reacts completely.Shrend on the rocks adds dichloromethane extraction after going out, and merges organic phase after extracting three times, and anhydrous sodium sulfate drying filters final vacuum concentrated by rotary evaporation, separates with silicagel column, obtains brown color liquid, productive rate 53%.
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, 200mmol) add in bottle with two necks after being dissolved in 15.4mL water, by TERTIARY BUTYL AMINE (3.6g, 50mmol), chloroform (3.0g, 25mmol), benzyltriethylammoinium chloride (104.6mg, 25mmol) is dissolved in after 10mL dichloromethane solution, join in constant pressure funnel, dropwise join in bottle with two necks 60 DEG C of back flow reaction.After 12h, react completely, add frozen water cancellation, add after dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, filters final vacuum concentrated by rotary evaporation, obtains 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 experiment
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 when infection
-2dilution, i.e. 40～50pfu/ hole, is provided by virusology National Key Laboratory of Wuhan University.
(2) cell: mdck cell (source, Chinese Typical Representative culture collection center, mdck cell is the classical cell of influenza virus plaque experiment), 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 are made into the mother liquor of 10mg/mL with DMSO, is diluted to corresponding gradient with DMSO when use.
2. experimental technique
2.1 cytotoxicity experiments (MTT analytical method)
MTT analytical method is taking viable cell metabolite reductive agent MTT as basis.MTT full name is 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide; Chinese chemistry 3-(4,5-dimethyl-2-thiazole)-2 by name, 5-phenylbenzene bromination tetrazole; Commodity are called tetrazolium bromide.
The preparation of 5mg/mL MTT: take 0.5g MTT powder, be dissolved in 100mL phosphate buffered saline buffer (PBS) or without in phenol red medium, with 0.22 μ m membrane filtration degerming, 4 DEG C keep in Dark Place.MTT is preferably now with the current, and 4 DEG C 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: hydrochloric acid and 12.5mL isopropylcarbinol that 25g sodium laurylsulfonate (SDS), 250 μ L concentration are 11.6mo1/L, add deionized water and be settled to 250mL and obtain three formazan lysates, the mass percent that the mass percent of sodium laurylsulfonate in this lysate (SDS) is 10%, hydrochloric acid volumetric molar concentration is 0.012mo1/L, isopropylcarbinol is 5%.
This cytotoxicity experiment step is as follows successively:
(1) will after mdck cell strain digestion, be diluted to 2 × 10 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 is cultivated 4 hours, makes cell fully adherent;
(2) tested the compounds of this invention mother liquor (10mg/mL) is used to 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 is established three parallel holes.Control wells is established three parallel holes equally, and every hole adds 1 μ L DMSO.Separately positive control drug is done to same processing in contrast;
(3) cultivate after 48 hours, remove supernatant liquor, monolayer is rinsed three times with the phosphate buffered saline buffer (PBS) of sterilizing;
(4) every hole adds MTT and the fresh culture mixed solution (MTT final concentration 0.5mg/mL) of 100 μ L, hatches 4 hours at 37 DEG C, makes MTT be reduced to formazan;
(5) remove supernatant liquor, every hole adds 100 μ L tri-formazan lysates, hatches 4 hours for 37 DEG C, and Shi formazan is all dissolved;
(6), taking the absorbance value at 655nm place as background, measure absorbance value at 570nm place.
Complete after above-mentioned experiment, calculate cell mortality according to following formula:
Cell mortality (%)=[1-(adding compound cell OD value/control cells OD value)] × 100.
Half toxic concentration (the CC of the compounds of this invention, positive control drug
50) method of calculation be: taking compound concentration as X-coordinate, cell mortality is ordinate zou mapping, and compound concentration when then obtaining 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, grows to 100% when full until cell, with PBS washing 2 times, process virus and cell according to following different modes, 4 every group multiple holes: 1) positive control hole: positive control drug and virus are mixed to rear directly adding in cell; 2) virus infection contrast: viral suspension is added in cell; 3) cell contrast: hatch with DMEM and cell; 4) new compound is processed hole: after mixing in 300 μ L substratum by the compounds of this invention and virus, directly add in cell.Used medium, not containing serum, adds the pancreatin of final concentration 10 μ g/mL to promote to infect.The compounds of this invention is made into the mother liquor of 10mg/mL with DMSO, use DMSO gradient dilution when 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.Separately positive control drug is done to same processing in contrast.After 37 DEG C of infection 2h, abandon supernatant, with PBS washing 2 times, add mixed solution without phenol red DMEM substratum and 1% agarose (melt in advance and solidify avoiding in 37 DEG C of insulations), in this mixed solution, the volume ratio of DMEM and agarose is 1:1, then adds the pancreatin of final concentration 10 μ g/mL to promote to infect.The room temperature that faces up is placed 20-40min, is inverted in 37 DEG C, 5%CO after solidifying
2incubator is cultivated 2-4 days.In the time that plaque is large and clear, by 0.5% violet staining, 130 μ L/ holes, with the naked eye count plaque after lucifuge dyeing 6-8h, every hole counting 2 times, and while coming to the same thing, effectively, repeat count when different, until be designated as effectively when identical for twice for counting.The plaque number of every group is the mean value in 3 holes.
Complete after above-mentioned experiment, adopt following formula to calculate the compounds of this invention, the inhibiting rate of positive control drug to virus infection:
Inhibiting rate (%)=[the plaque number of (the plaque number of plaque number-Jia compound group of virus infection control group)/virus infection control group] × 100.
Half-inhibition concentration (the IC of the compounds of this invention, positive control drug
50) method of calculation be: taking compound concentration as X-coordinate, inhibiting rate is ordinate zou mapping, and compound concentration when obtaining 50% inhibiting rate, is exactly IC
50, SI is selectivity index, 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 inhibition virus activity, and isonitrile compounds shows good antiviral activity too.Show that compound of the present invention can be used 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, rectum formulation etc., the dosage of every day depends on the seriousness of disease, application method and compound itself.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (10)
1. as a Carbox amide for influenza A virus inhibitor, it is characterized in that: its structure is suc 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.
2. Carbox amide according to claim 1, is characterized in that: described alkyl is C1-C8 alkyl; Described cycloalkyl is C3-C8 cycloalkyl; Described aromatic base is carbocyclic aromatic; Described heteroaryl is to contain one or more to be selected from the aryl of heteroatoms as annular atoms; Described is amino acid based for amino acid is except the skeleton deaminizing.
3. the Carbox amide pharmacy acceptable salt described in a claim 1 or 2.
4. as an isonitrile compounds for influenza A virus inhibitor, it is characterized in that: its structure is suc as formula shown in II:
R-NC
Formula II
Wherein, R is identical with the R in claim 1 or 2.
5. an isonitrile compounds pharmacy acceptable salt claimed in claim 4.
6. the preparation method of the Carbox amide described in claim 1 or 2, is characterized in that for method 1,2 or 3;
Wherein, method 1 comprises the steps: that amino acids amine solvent, in acetonitrile, adds excessive ammonium formiate, is heated to 60-90 DEG C, stirring and refluxing 8-24h, and reaction solution adds organic solvent extraction, dry, filters, and desolventizes and obtains Carbox amide;
Method 2 comprises the steps: that amine solvent, in excessive methyl-formiate, adds triethylamine, stirs 5-25 hour, and reaction solution organic solvent extraction is dry, filters, and steams to desolventize to obtain Carbox amide;
Method 3 comprises the steps: that diacetyl oxide and formic acid mix, and stirs 5-60min, joins in the amine of methylene dichloride dissolving, stir 4-8h, reaction solution is neutralized to after neutrality with sodium bicarbonate, adds organic solvent extraction, dry, to filter, steaming desolventizes and obtains Carbox amide.
7. the preparation method of isonitrile compounds claimed in claim 4, is characterized in that for method 4 or 5;
Wherein, method 4 comprises the steps: the Carbox amide described in claim 1 or 2 to be dissolved in methylene dichloride, add triethylamine, under the condition of ice bath, add phosphorus oxychloride, after reacting completely, in reaction solution, add organic solvent extraction, dry, to filter, steaming desolventizes and obtains isonitrile compounds;
Method 5 comprises the steps: to drip water in sodium hydroxide dissolves it, separately amine, chloroform, aryl triethyl ammonium chloride and methylene dichloride are mixed, after mixed solution is dropwise dripped to back flow reaction 10-15h in sodium hydroxide solution; After reaction, wash with frozen water, water layer dichloromethane extraction, dry filter revolves to steam and obtains isonitrile compounds.
8. the application of the salt described in the Carbox amide described in claim 1 or 2, isonitrile compounds claimed in claim 4 or claim 3 or 5 in preparation Tamiflu.
9. for preventing and/or treating a medicine for influenza, it is characterized in that: comprise the salt described in Carbox amide, isonitrile compounds claimed in claim 4 or the claim 3 or 5 described in claim 1 or 2.
10. according to claim 9 for preventing and/or treating the medicine of influenza, it is characterized in that: also comprise Carbox amide or the pharmaceutically acceptable carrier of isonitrile compounds claimed in claim 4 or vehicle described in claim 1 or 2.
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| CN105708830A (en) * | 2016-03-28 | 2016-06-29 | 张雪燕 | Medicine composition resisting influenza virus A(H1N1) and application of medicine composition |
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| CN111116423A (en) * | 2019-12-30 | 2020-05-08 | 苏州百灵威超精细材料有限公司 | Process method for preparing tert-butyl isocyano |
| CN114644577A (en) * | 2020-12-18 | 2022-06-21 | 新发药业有限公司 | Environment-friendly preparation method of substituted isonitrile compound |
| WO2022126947A1 (en) * | 2020-12-18 | 2022-06-23 | 新发药业有限公司 | Environmentally friendly preparation method for substituted isonitrile compound |
| CN114644577B (en) * | 2020-12-18 | 2023-06-27 | 新发药业有限公司 | Environment-friendly preparation method of substituted isonitrile compound |
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