CN106957290A - A kind of fragrant Carbox amide and its application in anti-influenza A virus medicament is prepared - Google Patents
A kind of fragrant Carbox amide and its application in anti-influenza A virus medicament is prepared Download PDFInfo
- Publication number
- CN106957290A CN106957290A CN201710147143.9A CN201710147143A CN106957290A CN 106957290 A CN106957290 A CN 106957290A CN 201710147143 A CN201710147143 A CN 201710147143A CN 106957290 A CN106957290 A CN 106957290A
- Authority
- CN
- China
- Prior art keywords
- formamides
- ethyl
- sulfenyl
- fragrant
- influenza
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses a kind of fragrant Carbox amide and its application in anti-influenza A virus medicament is prepared, belong to pharmaceutical technology field.Specifically with heteroaromatic carboxylic acid and 2（Benzylthio）1-ethanamine derivatives are raw material, and a series of fragrant Carbox amides are prepared for by acid amides reaction.The fragrant Carbox amide and its pharmaceutically acceptable salt, can effectively suppress the activity of influenza A virus, and relatively low to the toxicity of cell, show application prospect of such compound in anti-influenza A virus medicament is prepared.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of fragrant Carbox amide and its is preparing anti-influenza A
Application in virus drugs.
Background technology
Influenza (hereinafter referred to as influenza) is the serious upper respiratory disease as caused by influenza virus.Influenza virus energy
The different kind organisms such as people, pig, horse, dog and birds are caused to produce influenza.Influenza virus is RNA virus, belongs to orthomyxoviridae family.According to
Influenza virus can be divided into three hypotypes by nucleoprotein and stromatin：A type, B-mode and the third type.Influenza A virus
(Influenza A virus, IAV) again can be according to haemocyte lectin (Hemagglutinin, HA) and neuraminidase
The antigenic specificity of (Neuraminidase, NA) both surface glycoproteins, is divided into a variety of hypotypes, example by influenza A virus
Such as H1N1, H2N2, H5N1 hypotype.Hispanic H1N1 influenzas have seized the life of more than 2,000 ten thousand people within 1918,2005
H5N1 influenzas result in up to a hundred people's death, and the death rate is up to 60%.2013, China was found that H7N9 cases first；According to state
Prevention and control of diseases office of Jia Wei planning commissions report, the number of in January, 2017 death because of infection bird flu H7N9 is 79 people.In addition
Annual bird flu (H5N1, H7N9 etc.) makes China's poultry industry suffer huge economic loss.
Currently, the medicine of clinical treatment influenza mainly has two major classes：M2 inhibitors of ion channels, by preventing intracellular disease
The acidifying of poison and then the de-hulling process for suppressing virus, have amantadine and rimantadine by the FDA medicines ratified；Neuraminic acid
Glycosides enzyme inhibitor, by suppressing progeny virus from the release process of host cell and then reaching the effect of resisiting influenza virus, by FDA
The medicine of approval has Oseltamivir and zanamivir.
In recent years, M2 inhibitors of ion channels and the strain of neuraminidase inhibitor medicament-resistant mutation is frequently occurred so that grinding
The anti-influenza virus medicament of hair new structure skeleton or novel targets is particularly important.
The content of the invention
It is an object of the invention to provide the fragrant Carbox amide shown in a class formula I or its pharmacology or physiologically may be used
The salt of receiving,
Wherein,
R1For H, 4-F, 4-Cl, 4-Br, 4-CN, 4-CF3、4-CH3、4-OCH3、2-NO2、3-NO2、4-NO2Or 3-Cl；
R2For
X is C or S；N is 0 or 3.
Preferably, the invention provides compound as shown in table 1 below：
The present invention has found that above-mentioned fragrant Carbox amide can be used by external anti-influenza A virus activity experiment
In preparing anti-influenza A virus medicament.
It is highly preferred that especially following compounds：
N- (2- (benzylthio) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((3- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides,
N- (2- ((4- luorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- bromobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
2,5- dimethyl-N -s (2- ((4- nitrobenzyls) sulfenyl) ethyl) thiophene -3- formamides,
N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides,
Dimethyl furan -3- the formamides of N- benzyls 2,5.
The present invention also provides the preparation method of the fragrant Carbox amide represented by structure above.
The aromatic heterocycle carboxylic acid derivates with R are obtained by reacting synthesis shown in following formula i.Concrete operation step can be：
Calcium hypochlorite (3.1g, 21.71mmol) is dissolved in 6mL warm water, then will dissolved with potassium carbonate (2.6g,
18.82mmol) it is slowly dropped to the 3mL of potassium hydroxide (727.5mg, the 30.39mmol) aqueous solution warmed in above-mentioned solution,
And it is sufficiently agitated until that semi-solid gel becomes liquid.Suspension, which filters and rinses solid with 10mL, obtains filtrate, and filtrate is added
Then heat be slowly added dropwise 3- acetyl group -2,5- dimethyl furan (5d) (1g, 7.237mmol), finish while stirring to 55 DEG C,
Reaction temperature is maintained at 60-70 DEG C.React after 1 hour, TLC monitoring reactions, reaction finishes addition sodium sulfite and removed
The hypochlorous acid of amount, cools down solution and is acidified, (3 × 30mL), saturated aqueous common salt and anhydrous sodium sulfate is then extracted with ethyl acetate
Dry, column chromatography for separation obtains raw material of 2, the 5- dimethyl -3- furans sour (6d) as reaction iv after concentration.Other virtues with R
The preparation method of fragrant heterocyclic carboxylic acid derivatives is ibid.
1- (bromomethyl) -2- nitrobenzene (2a) and 1- (bromomethyl) -3- nitros are obtained by reacting synthesis shown in following formula ii
Benzene (2b).Concrete operation step can be：
Under condition of ice bath, by PBr3(494.8mg, 1.828mmol) is slowly dropped to (2- nitrobenzophenones) methanol or (3-
Nitrobenzophenone) methanol (400mg, 2.612mmol) diethyl ether solution in, then ice bath stir 2 to 4 hours.TLC monitorings are anti-
Should, reaction is finished, and is gone out with 10mL water quenchings and is reacted and be extracted with ethyl acetate (3 × 30mL), saturated aqueous common salt and anhydrous sodium sulfate
Dry, column chromatography for separation obtains 1- (bromomethyl) -2- nitrobenzene (2a) or 1- (bromomethyl) -3- nitrobenzene (2b) conduct after concentration
React iii raw material.
Band R is obtained by reacting synthesis shown in following formula iii12- (benzylthio) 1-ethanamine derivatives.Concrete operation step can
Think：
Lithium hydroxide (105.4mg, 4.40mmol) is dissolved in 3mL water, 9mL ethanol is then added, above-mentioned solution is added dropwise
Into the round-bottomed flask for the 25mL for filling Mercaptamine (200mg, 1.76mmol), be eventually adding benzyl chloride (234.2mg,
1.85mmol), 35 DEG C of oil bath stirring 40min.TLC monitoring reactions, reaction is finished, concentration of reaction solution, and then ethyl acetate is extracted
Column chromatography for separation obtains 2- (benzylthio) ethamine (2i) work after (3 × 30mL), saturated aqueous common salt and anhydrous sodium sulfate drying, concentration
To react iv raw material.Other bands R12- (benzylthio) 1-ethanamine derivatives preparation method ibid.
By synthesis, the aromatic heterocycle carboxylic acid derivates with R are obtained, the band R of 1.05 equivalents is then taken12- (benzylthio)
1-ethanamine derivatives, HOBT and EDCI are passed through argon gas in 5mL round-bottomed flask, are eventually adding 3mL DMF room temperature reactions and stay overnight,
TLC monitoring reactions, after reaction completely, column chromatography for separation is target compound.Reaction equation is as shown in following iv formulas.
Wherein,
R1For H, 4-F, 4-Cl, 4-Br, 4-CN, 4-CF3、4-CH3、4-OCH3、2-NO2、3-NO2、4-NO2Or 3-Cl；
R2For
X is C or S；N is 0 or 3.
Specific operation process can be as follows：
The carboxylic acid derivates and 0.42mmol (1.05eq.) for taking 0.4mmol to react i react iii band R12- (benzyl sulphur
Base) 1-ethanamine derivatives and HOBT (0.4mmol) and EDCI (0.4mmol) be added to the 5mL single necked round bottom flask containing magneton
In, argon gas is passed through, being eventually adding 3mL DMF dissolves it, is stirred overnight at room temperature, TLC monitoring reactions are carried out, raw material fundamental reaction
After completely, column chromatography for separation obtains pure fragrant Carbox amide.
Another object of the present invention is to provide a kind of Pharmaceutical composition of anti-influenza A virus, includes above-mentioned fragrant formyl
Aminated compounds or its pharmacology or physiologically acceptable salt are constituted with pharmaceutically acceptable carrier or excipient.
Fragrant Carbox amide of the present invention, can effectively suppress the activity of influenza A virus, it is to thin
The small toxicity of born of the same parents, available for the medicine for preparing anti-influenza A virus.
Embodiment
By described further below it will be further appreciated that the features and advantages of the invention.The embodiment provided is only pair
The explanation of the inventive method, without limiting remaining content that the present invention is disclosed in any way.
【Embodiment 1】：The preparation of N- (2- (benzylthio) ethyl) -2,5- dimethyl furan -3- formamides (YYS1)
Take 2,5- dimethyl -3- furans sour (56mg, 0.4mmol), 2- (benzylthio) second -1- amine (70.3mg,
0.42mmol), HOBT (54mg, 0.4mmol) and EDCI (76.7mg, 0.4mmol), is added to the 5mL single port circle containing magneton
In the flask of bottom, argon gas is passed through, being eventually adding 3mL DMF dissolves it, is stirred overnight at room temperature, TLC monitoring reactions are carried out, raw material base
After this reaction completely, column chromatography for separation obtains pure target compound YYS-1, and product is colourless liquid, and yield is 78%.1H
NMR(400MHz,CDCl3) δ 7.32-7.27 (m, 4H), 7.26-7.20 (m, 1H), 6.19 (s, 1H), 6.00 (d, J=0.7Hz,
1H), 3.72 (s, 2H), 3.49 (dd, J=12.5,6.2Hz, 2H), 2.62 (t, J=6.4Hz, 2H), 2.52 (s, 3H), 2.22
(s,3H).13C NMR(100MHz,CDCl3)δ164.19,155.09,149.92,138.09,128.86,128.62,127.17,
115.95,104.14,37.75,35.76,31.22,13.51,13.30.HRMS(ESI)calcd for C16H19NO2S[M+H]+
290.1215,found 290.1208.
【Embodiment 2】：N- (2- ((3- chlorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS2)
Prepare
Preparation method such as embodiment 1, product is colourless liquid, and yield is 39%.1H NMR(400MHz,CDCl3)δ7.33
(s, 1H), 7.26-7.15 (m, 3H), 6.11 (s, 1H), 5.99 (s, 1H), 3.69 (s, 2H), 3.51 (q, J=6.2Hz, 2H),
(s, the 3H) of 2.64 (t, J=6.4Hz, 2H), 2.53 (d, J=2.8Hz, 3H), 2.2413C NMR(100MHz,CDCl3)δ
164.24,155.25,150.02,140.22,134.41,129.84,128.90,127.39,127.03,115.80,104.01,
37.73,35.30,31.33,13.51,13.29.HRMS(ESI)calcd for C16H18ClNO2S[M+H]+324.0825,
found 324.0818.
【Embodiment 3】：N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS3)
Prepare
Preparation method such as embodiment 1, product is colourless liquid, and yield is 11%.1H NMR(400MHz,CDCl3)δ7.31–
7.21 (m, 4H), 6.07 (s, 1H), 5.98 (d, J=0.5Hz, 1H), 3.69 (s, 2H), 3.51 (dd, J=12.4,6.3Hz,
2H), (s, the 3H) of 2.62 (t, J=6.4Hz, 2H), 2.53 (s, 3H), 2.2413C NMR(100MHz,CDCl3)δ164.19,
155.22,150.04,136.60,132.93,130.20,128.76,115.79,103.98,37.72,35.09,31.19,
13.51,13.31.HRMS(ESI)calcd for C16H18ClNO2S[M+H]+324.0825,found 324.0818.
【Embodiment 4】：N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS4)
Preparation
Preparation method such as embodiment 1, product is colourless liquid, and yield is 56%.1H NMR(400MHz,CDCl3)δ7.66–
7.55 (m, 2H), 7.45 (d, J=8.4Hz, 2H), 6.12 (s, 1H), 5.99 (s, 1H), 3.77 (s, 2H), 3.52 (q, J=
6.5Hz, 2H), 2.62 (t, J=6.6Hz, 2H), 2.53 (s, 3H), 2.24 (s, 3H)13C NMR(100MHz,CDCl3)δ
164.24,155.29,150.07,143.90,132.40,129.65,118.75,115.73,110.91,103.94,37.89,
35.54,31.28,13.50,13.30.HRMS(ESI)calcd for C17H18N2O2S[M+H]+315.1167,found
315.1160.
【Embodiment 5】：N- (2- ((3- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS5)
Preparation
Preparation method such as embodiment 1, product is white solid, and yield is 47%, and fusing point is 113-115 DEG C.1H NMR
(400MHz,CDCl3) δ 8.21 (d, J=1.5Hz, 1H), 8.09 (d, J=8.2Hz, 1H), 7.67 (d, J=7.5Hz, 1H),
7.56-7.43 (m, 1H), 6.28-6.13 (m, 1H), 6.01 (s, 1H), 3.83 (s, 2H), 3.54 (q, J=6.2Hz, 2H),
(s, the 3H) of 2.65 (t, J=6.4Hz, 2H), 2.53 (s, 3H), 2.2313C NMR(100MHz,CDCl3)δ164.27,155.31,
150.06,148.33,140.49,135.07,129.53,123.70,122.22,115.71,103.95,37.96,35.23,
31.38,13.48,13.26.HRMS(ESI)calcd for C16H18N2O4S[M+H]+335.1066,found 335.1057.
【Embodiment 6】：N- (2- ((4- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS6)
Preparation
Preparation method such as embodiment 1, product is white solid, and yield is 19%, and fusing point is 105-106 DEG C.1H NMR
(400MHz,CDCl3) δ 8.19-8.15 (m, 2H), 7.51 (d, J=8.7Hz, 2H), 6.72 (d, J=0.8Hz, 1H), 6.10
(s, 1H), 3.82 (s, 2H), 3.55 (q, J=6.4Hz, 2H), 2.65 (t, J=6.5Hz, 2H), 2.63 (s, 3H), 2.39 (s,
3H).13C NMR(100MHz,CDCl3)δ164.60,147.03,145.95,142.80,136.18,131.01,129.74,
123.99,123.88,38.02,35.24,31.34,15.03,14.87.HRMS(ESI)calcd for C16H18N2O4S[M+H
]+335.1066,found335.1058.
【Embodiment 7】：N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides (YYS7)
Prepare
Preparation method such as embodiment 1, product is colourless liquid, and yield is 29%.1H NMR(400MHz,CDCl3)δ7.35–
7.14 (m, 4H), 6.72 (d, J=0.9Hz, 1H), 6.15 (s, 1H), 3.69 (s, 2H), 3.52 (dd, J=12.5,6.1Hz,
2H),2.66–2.60(m,5H),2.39(s,3H).13C NMR(100,CDCl3)δ164.62,142.59,136.59,136.04,
132.95,131.22,130.21,128.77,124.15,37.90,35.06,31.17,15.04,14.85.HRMS(ESI)
calcd for C16H18ClNOS2[M+H]+340.0597,found 340.0590.
【Embodiment 8】：N- (2- ((4- luorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS8)
Prepare
Preparation method such as embodiment 1, product is yellow solid, and yield is 21%, and fusing point is 79-80 DEG C.1H NMR
(400MHz,CDCl3) δ 7.35-7.22 (m, 2H), 7.02-6.95 (m, 2H), 6.73 (d, J=0.9Hz, 1H), 6.18 (s,
1H), (s, the 3H) of 3.71 (s, 2H), 3.53 (dd, J=12.5,6.1Hz, 2H), 2.68-2.60 (m, 5H), 2.3813C NMR
(100MHz,CDCl3)δ164.61,142.57,136.03,133.77,133.74,131.23,130.44,130.36,
124.15,115.59,115.38,37.88,34.98,31.16,15.02,14.84.HRMS(ESI)calcd for
C16H18FNO2S[M+H]+308.1121,found 308.1115.
【Embodiment 9】：N- (2- ((4- bromobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides (YYS9)
Prepare
Preparation method such as embodiment 1, product is colourless liquid, and yield is 37%.1H NMR(400MHz,CDCl3)δ7.47–
7.37 (m, 2H), 7.24-7.14 (m, 2H), 6.06 (s, 1H), 5.98 (d, J=0.6Hz, 1H), 3.67 (s, 2H), 3.51 (dd,
J=12.5,6.2Hz, 2H), 2.62 (t, J=6.5Hz, 2H), 2.53 (s, 3H), 2.24 (s, 3H)13C NMR(100MHz,
CDCl3)δ164.20,155.19,150.02,137.15,131.70,130.56,121.00,115.82,104.01,77.44,
77.12,76.80,37.77,35.15,31.19,13.51,13.31.HRMS(ESI)calcd for C16H18BrNO2S[M+H]+
370.0299,found 370.0291.
【Embodiment 10】：2,5- dimethyl-N -s (2- ((4- (trifluoromethyl) benzyl) sulfenyl) ethyl) furans -3- formamides
(YYS10) preparation
Preparation method such as embodiment 1, product is white solid, and yield is 36%, and fusing point is 62-63 DEG C.1H NMR
(400MHz,CDCl3) δ 7.57 (d, J=8.1Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 6.06 (s, 1H), 5.98 (s, 1H),
(s, the 3H) of 3.77 (s, 2H), 3.53 (q, J=6.3Hz, 2H), 2.63 (t, J=6.5Hz, 2H), 2.53 (s, 3H), 2.2413C
NMR(100MHz,CDCl3)δ164.22,155.27,150.07,142.28,129.19,125.58,125.54,115.76,
103.93,37.75,35.30,31.27,13.48,13.25.HRMS(ESI)calcd for C17H18F3NO2S[M+H]+
358.1089,found 358.1082.
【Embodiment 11】：2,5- dimethyl-N -s (2- ((4- methyl-benzyls) sulfenyl) ethyl) furans -3- formamides
(YYS11) preparation
Preparation method such as embodiment 1, product is colourless liquid, and yield is 61%.1H NMR(400MHz,CDCl3)δ7.20
(d, J=8.0Hz, 2H), 7.11 (d, J=7.8Hz, 2H), 6.12 (s, 1H), 5.99 (s, 1H), 3.69 (s, 2H), 3.49 (dd,
J=12.4,6.0Hz, 2H), 2.62 (t, J=6.4Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H), 2.24 (s, 3H)13C N
MR(100MHz,CDCl3)δ164.16,155.10,149.94,136.84,134.94,129.32,128.74,115.92,
104.10,37.64,35.42,31.18,21.12,13.50,13.31.HRMS(ESI)calcd for C17H21NO2S[M+H]+
304.1371,found304.1364.
【Embodiment 12】：N- (2- ((4- methoxy-benzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides
(YYS12) preparation
Preparation method such as embodiment 1, product is white solid, and yield is 49%, and fusing point is 79-81 DEG C.1H NMR
(400MHz,CDCl3)δ7.26–7.15(m,2H),6.89–6.74(m,2H),6.23(s,1H),6.00(s,1H),3.77(s,
3H), 3.68 (s, 2H), 3.49 (q, J=6.2Hz, 2H), 2.61 (t, J=6.4Hz, 2H), 2.52 (s, 3H), 2.22 (s, 3H)
.13C NMR(100MHz,CDCl3)δ164.22,158.67,155.08,149.90,129.99,129.93,115.95,
113.97,104.14,55.24,37.81,35.13,31.07,13.49,13.27.HRMS(ESI)calcd for C17H21NO3S
[M+H]+320.1320,found320.1311.
【Embodiment 13】：2,5- dimethyl-N -s (2- ((2- nitrobenzyls) sulfenyl) ethyl) furans -3- formamides
(YYS13) preparation
Preparation method such as embodiment 1, product is yellow liquid, and yield is 67%.1H NMR(400MHz,CDCl3)δ7.97
(dd, J=8.1,1.2Hz, 1H), 7.56 (m, 1H), 7.50-7.37 (m, 2H), 6.19 (s, 1H), 6.04 (d, J=0.7Hz,
1H), 4.10 (s, 2H), 3.52 (q, J=6.2Hz, 2H), 2.68 (t, J=6.4Hz, 2H), 2.53 (d, J=3.0Hz, 3H),
2.24(s,3H).13C NMR(100MHz,CDCl3)δ164.21,155.19,150.00,148.60,133.83,133.24,
132.12,128.44,125.49,115.81,104.07,37.84,33.20,32.03,13.50,13.30.HRMS(ESI)
calcd for C16H18N2O4S[M+H]+335.1066,found 335.1058.
【Embodiment 14】：The preparation of N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) furans -3- formamides (YYS14)
Preparation method such as embodiment 1, product is white solid, and yield is 60%, and fusing point is 126-128 DEG C.1H NMR
(400MHz,CDCl3)δ7.93(s,1H),7.43(s,1H),7.32–7.22(m,4H),6.61(s,1H),6.39(s,1H),
(t, J=6.5Hz, the 2H) of 3.69 (s, 2H), 3.53 (q, J=6.3Hz, 2H), 2.6213C NMR(100MHz,CDCl3)δ
162.72,144.84,143.85,136.55,132.97,130.20,128.79,122.38,108.25,38.03,35.13,
31.00.HRMS(ESI)calcd for C14H14ClNO2S[M+H]+296.0512,found 296.0505.
【Embodiment 15】：The preparation of N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) furans -2- formamides (YYS15)
Preparation method such as embodiment 1, product is white solid, and yield is 34%, and fusing point is 91-93 DEG C.1H NMR
(400MHz,CDCl3) δ 7.45 (dd, J=1.7,0.8Hz, 1H), 7.31-7.24 (m, 4H), 7.11 (dd, J=3.5,0.8Hz,
1H), 6.70 (s, 1H), 6.50 (dd, J=3.5,1.8Hz, 1H), 3.72 (s, 2H), 3.57 (q, J=6.4Hz, 2H), 2.64
(t, J=6.5Hz, 2H)13C NMR(100MHz,CDCl3)δ158.41,147.76,144.02,136.55,132.95,
130.22,128.77,114.40,112.22,37.75,35.17,31.02.HRMS(ESI)calcd for C14H14ClNO2S[M
+H]+296.0512,found 296.0505.
【Embodiment 16】：The system of N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -5- methylfuran -2- formamides (YYS16)
It is standby
Preparation method such as embodiment 1, product is yellow liquid, and yield is 55%.1H NMR(400MHz,CDCl3)δ7.45
(dd, J=1.7,0.8Hz, 1H), 7.27 (s, 4H), 7.11 (dd, J=3.5,0.8Hz, 1H), 6.70 (s, 1H), 6.50 (dd, J
=3.5,1.8Hz, 1H), 3.72 (s, 2H), 3.57 (q, J=6.4Hz, 2H), 2.64 (t, J=6.5Hz, 2H)13C NMR
(100MHz,CDCl3)δ158.69,154.70,146.04,136.59,132.90,130.23,128.74,115.79,
108.64,37.81,35.16,31.05,13.88.HRMS(ESI)calcd for C15H16ClNO2S[M+H]+310.0669,
found 310.0662.
【Embodiment 17】：The system of N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2- methylthiazol -4- formamides (YYS17)
It is standby
Preparation method such as embodiment 1, product is white solid, and yield is 61%, and fusing point is 190-191 DEG C.1H NMR
(400MHz,DMSO-d6) δ 8.74 (t, J=5.6Hz, 1H), 8.17 (s, 1H), 7.43-7.32 (m, 4H), 3.78 (s, 2H),
3.44–3.37(m,2H),2.66(s,3H),2.58–2.53(m,2H).13C NMR(100MHz,DMSO-d6)δ169.50,
159.84,142.63,137.71,134.82,131.35,130.67,128.31,38.67,33.91,29.89,19.12.HRMS
(ESI)calcd for C15H17ClN2OS2[M+H]+341.0549,found 341.0542.
【Embodiment 18】：The preparation of N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2- methyl benzamides (YYS18)
Preparation method such as embodiment 1, product is white solid, and yield is 21%, and fusing point is 104-105 DEG C.1H NMR
(400MHz,CDCl3) δ 7.36-7.28 (m, 2H), 7.25 (d, J=5.5Hz, 4H), 7.19 (m, 2H), 6.22 (s, 1H), 3.70
(s, 2H), 3.54 (dd, J=12.6,6.2Hz, 2H), 2.63 (t, J=6.4Hz, 2H), 2.41 (s, 3H)13C NMR
(100MHz,CDCl3)δ170.21,136.59,136.17,136.06,132.95,131.05,130.25,129.99,
128.78,126.76,125.77,38.11,35.04,31.10,19.85.HRMS(ESI)calcd for C17H18ClNOS[M+
H]+320.0876,found320.0867.
【Embodiment 19】：2,5- dimethyl-N -s (2- ((4- nitrobenzyls) sulfenyl) ethyl) thiophene -3- formamides
(YYS19) preparation
Preparation method such as embodiment 1, product is yellow solid, and yield is 67%, and fusing point is 103-106 DEG C.1H NMR
(400MHz,CDCl3) δ 8.21-8.13 (m, 2H), 7.50 (d, J=8.7Hz, 2H), 6.04 (s, 1H), 5.97 (s, 1H), 3.81
(s, 2H), 3.53 (q, J=6.4Hz, 2H), 2.64 (t, J=6.6Hz, 2H), 2.53 (s, 3H), 2.24 (s, 3H)13C NMR
(100MHz,CDCl3)δ164.15,155.33,150.12,147.04,145.98,129.71,123.86,115.68,
103.85,37.90,35.32,31.42,13.47,13.26.HRMS(ESI)calcd for C16H18N2O3S2[M+H]+
351.0837,found 351.0830.
【Embodiment 20】：N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides
(YYS20) preparation
Preparation method such as embodiment 1, product is colourless liquid, and yield is 64%.1H NMR(400MHz,CDCl3)δ7.60
(m, 2H), 7.45 (d, J=8.2Hz, 2H), 6.05 (s, 1H), 5.98 (s, 1H), 3.77 (s, 2H), 3.52 (q, J=6.4Hz,
2H), (s, the 3H) of 2.62 (t, J=6.6Hz, 2H), 2.53 (s, 3H), 2.2513C NMR(100MHz,CDCl3)δ164.17,
155.29,150.08,143.85,132.39,129.63,118.69,115.74,110.99,103.89,37.87,35.57,
31.35,13.47,13.27.HRMS(ESI)calcd for C17H18N2OS2[M+H]+331.0939,found 331.0932.
【Embodiment 21】：The preparation of 2,5- dimethyl-N -s (4- phenyl butyls) furans -3- formamides (YYS21)
Preparation method such as embodiment 1, product is colourless liquid, and yield is 51%.1H NMR(400MHz,CDCl3)δ7.33–
7.24 (m, 2H), 7.19 (m, 3H), 6.70 (d, J=0.9Hz, 1H), 5.77 (s, 1H), 3.39 (dd, J=12.9,6.9Hz,
2H),2.67–2.61(m,5H),2.37(s,3H),1.76–1.55(m,4H).13C NMR(100MHz,CDCl3)δ164.73,
142.13,135.96,131.60,128.44,128.37,125.85,124.09,39.41,35.52,29.35,28.79,
15.03,14.78.HRMS(ESI)calcd for C17H21NO2[M+H]+272.1651,found 272.1642
【Embodiment 22】：The preparation of the dimethyl furan -3- formamides (YYS22) of N- benzyls 2,5
Preparation method such as embodiment 1, product is white solid, and yield is 59%, and fusing point is 109-112 DEG C.1H NMR
(400MHz,CDCl3) δ 7.34-7.18 (m, 5H), 6.29 (s, 1H), 6.02 (s, 1H), 4.50 (d, J=5.8Hz, 2H), 2.52
(s,3H),2.20(s,3H).13C NMR(100MHz,CDCl3)δ164.25,155.38,149.89,138.65,128.64,
127.71,127.35,115.87,104.15,43.22,13.52,13.28.HRMS(ESI)calcd for C14H15NO2[M+H
]+30.1181,found 230.1175.
The target compound YYS1-22 of the inventive method of table 1 synthesis chemical constitution
【Experimental example 23】：Fragrant Carbox amide pharmacological evaluation
(1) fragrant Carbox amide CTA：
The Thiazolyl blue of yellow, abbreviation MTT can pass through cell membrane and enter intracellular, the amber dehydrogenation in living cells mitochondria
Enzyme can make the needle-like Formazan for the bluish violet that exogenous MTT is reduced to be insoluble in water crystallize and be deposited in cell, crystal
Can be dissolved by 20% (quality specific volume) SDS, its absorbance value is determined at 575nm wavelength with enzyme-linked immunosorbent assay instrument, can between
It is reversed to reflect cell quantity.
During experiment, by mdck cell with every hole 2 × 104Density reach in 96 orifice plates, 37 DEG C culture 24 hours after, inhale
Culture medium is walked, the cell culture medium containing various concentration gradient compounds is added to each hole.After 24 hours, 5mg/ is added per hole
ML MTT solution, CO of the cell plates at 37 DEG C24h is cultivated in incubator.Then hydrotropy liquid is added to haemolysis cell, at 37 DEG C
Hatch 3h, ELIASA determines the OD values under 575nm wavelength.The inhibiting rate (%) of compound=[1- (E-N)/(P-N)] × 100,
Wherein " E " represents the OD values of administration group, and " P " represents the OD values of non-administered group, and " N " represents blank group OD values.The half of compound
Inhibition concentration (CC50) it is used as the index of the Compound Cytotoxicity.
(2) the external anti-H5N1 activity of fragrant Carbox amide：
Reduce analysis to assess the antiviral activity of compound by virus plaques number.Be paved with 6 orifice plates of mdck cell by
Base containing Virus culture is removed according to 70PFU/ holes access influenza virus (H5N1), after 40 minutes and is added and contains certain concentration medicine to be measured
The culture medium of thing, culture medium contains final concentration of 0.001%DEAE-dextran, 2ug/ml TPCK-trypsin and 0.5%
agarose.In 37 DEG C of 5%CO2Under the conditions of culture 48-72 hours after, fix cell with 3% formalin, use 0.5% knot
Crystalviolet is dyed to cell and calculates virus plaques number.EC50Refer to that certain drug effectively suppresses virus and produces plaque number to right
According to the concentration needed for the 50% of hole.
The present invention is compareed with amantadine, and 22 compounds to synthesis carry out cytotoxicity and anti-influenza A virus
H5N1 activity is checked, and calculates the selectivity index SI of compound, the results are shown in Table 2.
The anti-H5N1 activity of target compound YYS1-22 and the result of cytotoxicity that the present invention of table 2 is synthesized
| Compounds | EC50(μM) | CC50(μM) | SI(CC50/IC50) |
| YYS 1 | 7.716±2.909 | 115.173±30.201 | 14.9 |
| YYS 2 | 54.545±16.440 | 53.514±13.247 | 0.9 |
| YYS 3 | 8.541±3.153 | 51.476±10.561 | 6.0 |
| YYS 4 | 5.302±1.450 | >100 | >18.9 |
| YYS 5 | 9.970±2.548 | 109.662±27.423 | 11.0 |
| YYS 6 | 1.247±0.335 | >100 | >80.2 |
| YYS 7 | 1.639±0.400 | 68.638±23.978 | 41.9 |
| YYS 8 | 13.771±5.095 | 86.766±15.225 | 6.3 |
| YYS 9 | 15.113±4.749 | 94.029±19.713 | 6.2 |
| YYS 10 | 44.763±11.696 | 113.069±15.837 | 2.5 |
| YYS 11 | 27.460±8.477 | >100 | >3.6 |
| YYS 12 | 34.431±10.804 | >100 | >2.9 |
| YYS 13 | NA | 91.749±21.621 | - |
| YYS 14 | 56.342±15.866 | >100 | >1.8 |
| YYS 15 | 31.550±9.281 | 68.192±21.097 | 2.2 |
| YYS 16 | 60.243±17.001 | 50.418±10.361 | 0.8 |
| YYS 17 | NA | >100 | - |
| YYS 18 | 35.429±12.115 | 78.724±24.168 | 2.2 |
| YYS 19 | 2.519±0.763 | >100 | >48.3 |
| YYS 20 | 1.338±0.318 | >100 | >93.0 |
| YYS 21 | NA | 104.400±19.494 | - |
| YYS 22 | 25.148±8.928 | 81.429±16.879 | 3.2 |
| Amantadine | 0.551±0.161 | >100 | >181.5 |
It is above-mentioned test result indicate that：Most of compound of synthesis all has anti-H5N1 activity, such as compound very well
YYS1(EC50=7.716 ± 2.909 μM, SI=14.9), (EC of YYS 450=5.302 ± 1.450 μM, SI>18.9)、YYS 5
(EC50=9.970 ± 2.548 μM, SI=11.0), (EC of YYS 650=1.247 ± 0.335 μM, SI>80.2)、YYS 7(EC50
=1.639 ± 0.400 μM, SI=41.9), (EC of YYS 1950=2.519 ± 0.763 μM, SI>48.3)、YYS 20(EC50=
1.338 ± 0.318 μM, SI=93.0) etc., especially compound YYS 6 and YYS 20 are shown close to sub-micromolar level
Bioactivity.
Claims (5)
1. a kind of fragrant Carbox amide or its pharmacology or physiologically acceptable salt as shown in formula I,
Wherein,
R1For H, 4-F, 4-Cl, 4-Br, 4-CN, 4-CF3、4-CH3、4-OCH3、2-NO2、3-
NO2、4-NO2Or 3-Cl；
R2For
X is C or S；N is 0 or 3.
2. fragrant Carbox amide according to claim 1 or its pharmacology or physiologically acceptable salt, its feature
It is that described compound is as follows compound respectively：
3. fragrant Carbox amide according to claim 2 or its pharmacology or physiologically acceptable salt, its feature
It is that described compound is as follows compound respectively：
N- (2- (benzylthio) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((3- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- nitrobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- chlorobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides,
N- (2- ((4- luorobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
N- (2- ((4- bromobenzyls) sulfenyl) ethyl) -2,5- dimethyl furan -3- formamides,
2,5- dimethyl-N -s (2- ((4- nitrobenzyls) sulfenyl) ethyl) thiophene -3- formamides,
N- (2- ((4- cyanobenzyls) sulfenyl) ethyl) -2,5- thioxene -3- formamides,
Dimethyl furan -3- the formamides of N- benzyls 2,5.
4. according to one of the claim 1-3 fragrant Carbox amides or its pharmacology or physiologically acceptable salt in system
Application in the medicine of standby anti-influenza A virus.
5. a kind of Pharmaceutical composition of anti-influenza A virus, includes the fragrant benzamide type described in one of claim 1-3
Compound or its pharmacology or physiologically acceptable salt are constituted with pharmaceutically acceptable carrier or excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710147143.9A CN106957290B (en) | 2017-03-13 | 2017-03-13 | A kind of fragrance and its is preparing the application in anti-influenza A virus medicament at Carbox amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710147143.9A CN106957290B (en) | 2017-03-13 | 2017-03-13 | A kind of fragrance and its is preparing the application in anti-influenza A virus medicament at Carbox amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106957290A true CN106957290A (en) | 2017-07-18 |
| CN106957290B CN106957290B (en) | 2019-04-09 |
Family
ID=59470254
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710147143.9A Expired - Fee Related CN106957290B (en) | 2017-03-13 | 2017-03-13 | A kind of fragrance and its is preparing the application in anti-influenza A virus medicament at Carbox amide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106957290B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303087A (en) * | 2020-04-07 | 2020-06-19 | 自然资源部第三海洋研究所 | Furanone compound and preparation method and application thereof |
| CN114989085A (en) * | 2022-05-23 | 2022-09-02 | 安徽医科大学 | Aryl lactam ring compound, pharmaceutical composition and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10114765A (en) * | 1996-10-15 | 1998-05-06 | Sankyo Co Ltd | Furan compound |
| CN104447625A (en) * | 2013-09-16 | 2015-03-25 | 中国科学院广州生物医药与健康研究院 | Benzamide compound or pharmaceutically acceptable salt thereof, and applications of benzamide compound or pharmaceutically acceptable salt thereof |
-
2017
- 2017-03-13 CN CN201710147143.9A patent/CN106957290B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10114765A (en) * | 1996-10-15 | 1998-05-06 | Sankyo Co Ltd | Furan compound |
| CN104447625A (en) * | 2013-09-16 | 2015-03-25 | 中国科学院广州生物医药与健康研究院 | Benzamide compound or pharmaceutically acceptable salt thereof, and applications of benzamide compound or pharmaceutically acceptable salt thereof |
Non-Patent Citations (5)
| Title |
|---|
| REGISTRY: "RN号为 260789-18-2", 《STN》 * |
| REGISTRY: "RN号为1043301-42-3", 《STN》 * |
| REGISTRY: "RN号为1061065-43-7", 《STN》 * |
| REGISTRY: "RN号为425680-46-2", 《STN》 * |
| REGISTRY: "RN号为691849-99-7", 《STN》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303087A (en) * | 2020-04-07 | 2020-06-19 | 自然资源部第三海洋研究所 | Furanone compound and preparation method and application thereof |
| CN111303087B (en) * | 2020-04-07 | 2021-08-10 | 自然资源部第三海洋研究所 | Furanone compound and preparation method and application thereof |
| CN114989085A (en) * | 2022-05-23 | 2022-09-02 | 安徽医科大学 | Aryl lactam ring compound, pharmaceutical composition and application thereof |
| CN114989085B (en) * | 2022-05-23 | 2023-11-24 | 安徽医科大学 | Aryl lactam ring compound, pharmaceutical composition and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106957290B (en) | 2019-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10226439B2 (en) | Small molecule inhibitors of STAT3 with anti-tumor activity | |
| AU2008315651B2 (en) | Histone deacetylase inhibitors | |
| CA2695071A1 (en) | The use of benzamide derivatives for the treatment of cns disorders | |
| US20110212943A1 (en) | Novel bridged cyclic compounds as histone deacetylase inhibitors | |
| JP7031002B2 (en) | Crystal form, salt type and method for producing the pyridinoimidazole compound | |
| RU2382029C2 (en) | Novel cyclohexane derivatives | |
| IE72090B1 (en) | Aromatic compounds pharmaceutical compositions containing them and their use in therapy | |
| SE408794B (en) | PROCEDURE FOR THE PREPARATION OF NEW (PHENOXY OR NAPTHYLOXY) PROPANOLAMINE DERIVATIVES WITH PHARMACOLOGICAL PROPERTIES | |
| JP2013507369A (en) | Modulator of G protein coupled receptor 88 | |
| US11773057B2 (en) | Naphthalenesulfonamide compound, preparation method, and application | |
| CN107880040A (en) | A kind of tetrahydro-b-carboline analog derivative and preparation method thereof and purposes | |
| CN106957290B (en) | A kind of fragrance and its is preparing the application in anti-influenza A virus medicament at Carbox amide | |
| Yu et al. | Synthesis and structure-activity relationship study of arylsulfonamides as novel potent H5N1 inhibitors | |
| US10273218B2 (en) | BCL-3 inhibitors | |
| CN111848463B (en) | Camphor sulfanilamide oxime ether compound and preparation method and application thereof | |
| CN108299255A (en) | Histone deacetylase 8 selective depressant and its preparation method and application | |
| CN102603553B (en) | Compound with collaborative antifungal effect and application thereof in pharmaceuticals | |
| Cao et al. | Leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Part II | |
| IE63299B1 (en) | Use of Gamma amino butyric acid autoreceptor agonists for the manufacture of medicaments | |
| CA2787860C (en) | Substituted 2-imidazolidones and analogs and their use against cancer | |
| CN110483425B (en) | Acyl thiourea compound, preparation method thereof and application of acyl thiourea compound in resisting influenza A virus | |
| CN108164503B (en) | A kind of heteroaromatic and the disubstituted benzenesulfonamides of alkyl side chain and its preparing the application in anti-influenza A virus medicament | |
| CN108129454B (en) | A kind of benzenesulfonamides and its preparing the application in anti-influenza A virus medicament | |
| CN108101804A (en) | The Oseltamivir derivative and its medical usage of carboxyl modified | |
| TW201605769A (en) | Substituted naphthalene compounds as calcium sensing receptor modulators |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190409 Termination date: 20210313 |