CN102659783A - N-substituted sophora flavescens olefine acid derivative as well as preparation method and application thereof - Google Patents

N-substituted sophora flavescens olefine acid derivative as well as preparation method and application thereof Download PDF

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CN102659783A
CN102659783A CN2012101235128A CN201210123512A CN102659783A CN 102659783 A CN102659783 A CN 102659783A CN 2012101235128 A CN2012101235128 A CN 2012101235128A CN 201210123512 A CN201210123512 A CN 201210123512A CN 102659783 A CN102659783 A CN 102659783A
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acid
kuh
seng
olefin
compound
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CN102659783B (en
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蒋建东
宋丹青
高丽梅
李玉环
高荣梅
王辉强
杜娜娜
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Institute of Medicinal Biotechnology of CAMS
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Abstract

The invention relates to an N-substituted sophora flavescens olefine acid derivative represented by a general formula IA or IB, a preparation method thereof, a medicine composite containing the derivative, a method for utilizing the derivative to treat diseases caused by Coxsackie B viruses, and an application of the derivative to prepare a medicine for treating the diseases caused by the Coxsackie B viruses.

Description

N-replaces the kuh-seng gadoleic acid derivative
Technical field
The application relate to a kind of N-replace kuh-seng gadoleic acid derivative, its preparation method, comprise said verivate pharmaceutical composition, use the method and the purposes of said verivate in the medicine of the preparation treatment disease that CBV caused of the disease that said derivatives for treatment CBV caused.
Background technology
Coxsackie virus is to be a papova of separating the poliomyelitic infant ight soil from New York, United States Coxsackie town in 1948 from clinical diagnosis.It belongs to the Picornaviridae enterovirus genus.The pathogenic agent Coxsackie virus is divided into two types according to its biology characteristics: category-A and category-B.Adhere to the dust gram virus and the poliovirus of enterovirus class separately, existing claim " fine virus ".Coxsackie A disease poison infected children sees that the adult infects less relatively more.The principal feature of clinical manifestation is acute fever, fash.Meningoencephalitis is with Guillain-Barr é syndrome and acute viral myocardosis, and dominance and inapparent infection ratio reach 1: 50-100.CBV infects and causes that characteristic infectivity costalgia of chest is that so-called Bornholm ' s is sick, can merge meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia and pneumonia.The sophocarpine that discloses following formula among the CN1303673A is as purposes and the method for making thereof of preparation CBV property myocarditis because of medicine, and discloses sophocarpine or the purposes of its pharmacologically acceptable salt in the medicine of preparation treatment diseases induced by coxsackie B virus among the CN101416964A.
Not having the specific medicine to Coxsackie virus at present, mainly is symptomatic treatment clinically.Therefore, seek in recent years and develop novel type the treatment CBV diseases induced medicine be still a focus in the drug research field.
Summary of the invention
The inventor is through making an experiment to the kuh-seng gadoleic acid derivative; Found that a series of N-replace the kuh-seng gadoleic acid derivative and have tangible anti-CBV active; Wherein with the positive control drug of known marketed drug ribavirin (RBV), N-of the present invention replaces the kuh-seng gadoleic acid derivative and demonstrates good selectivity (referring to table 1 among this paper).The anti-CBV activity of this compounds had not been appeared in the newspapers and had been led.Might find to have the active new texture type of anti-CBV to the further investigation of this compounds.
Therefore, first aspect of the present invention relates to the compound or pharmaceutically acceptable salt thereof with following general formula I A or IB structure:
Figure BDA0000156886380000021
Wherein:
Substituent R: C 1-6Alkyl, amino or aryl, wherein said amino is randomly by C 1-6Alkyl list or two replaces, and described alkyl and aryl are randomly replaced by 1-3 group that is independently selected from down group: hydroxyl, halogen, nitro, cyanic acid, C 1-6Alkyl, halo C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, acyl group and acyl amino; With
Position of double bond among the general formula I A is in the α position of carboxyl, and the position of double bond among the general formula I B is in the β position of carboxyl.
Second aspect of the present invention relates to the preparation method of above-mentioned general formula I A or IB compound.
The 3rd aspect of the present invention relates to the pharmaceutical composition that comprises at least a general formula I A of the present invention or IB compound and one or more pharmaceutical carriers or vehicle.
The 4th aspect of the present invention relates to general formula I A of the present invention or the IB compound purposes at the medicine of the preparation treatment disease that CBV caused.Especially, said CBV is coxsackie B 3 viruses.Said disease is that characteristic infectivity costalgia of chest is so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, said disease is myocarditis, particularly viral myocarditis.
The 5th aspect of the present invention relates to general formula I A of the present invention or the IB compound as the medicine of the treatment disease that CBV caused.Especially, said CBV is coxsackie B 3 viruses.Said disease is that characteristic infectivity costalgia of chest is so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, said disease is myocarditis, particularly viral myocarditis.
The 6th aspect of the present invention relates to the method for treating the disease that CBV causes, and said method comprises general formula I A of the present invention or the IB compound that needs the patient treatment of this treatment significant quantity.Especially, said CBV is coxsackie B 3 viruses.Said disease is that characteristic infectivity costalgia of chest is so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, said disease is myocarditis, particularly viral myocarditis.
The substituting group definition
The term that uses among this paper " alkyl " is meant saturated straight or branched alkyl, and having 1-6 carbon atom (is C 1-6Alkyl), preferably has a 1-4 or 1-3 carbon atom.The representative instance of " alkyl " includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, 2-methyl amyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl etc.
Term used herein " amino " is meant group-NH 2
Term used herein " aryl " means the unsaturated aromatic carbocyclyl groups of 5-14 carbon atom with a monocycle or a plurality of fused rings.Said aryl preferably has 5-10,5-8 or 5-6 or 6 carbon atoms.The representative instance of " aryl " includes but not limited to phenyl, naphthyl and anthryl etc.
Term used herein " acyl group " means group-C (O) R 1, R wherein 1For hydrogen with like alkyl defined herein, assorted alkyl, naphthenic base, Heterocyclylalkyl or aryl.The representative instance of " acyl group " includes but not limited to formyl radical, ethanoyl, cyclohexyl-carbonyl, benzoyl-etc.
Term used herein " hydroxyl " is meant group-OH.
Term used herein " halogen " means fluorine, chlorine, bromine or iodine.Preferred halogen group is a fluorine, chlorine or bromine, more preferably fluorine or chlorine.
Term used herein " nitro " is meant group-NO 2
Term used herein " cyanic acid " is meant group-CN.
Term used herein " haloalkyl " means by halogen list defined herein or polysubstituted as alkyl defined herein.The representative instance of " haloalkyl " includes but not limited to-CF 3,-CHF 2,-CH 2CCl 3Deng.
Term used herein " alkoxyl group " means group-OR 2, R wherein 2For as alkyl defined herein.The representative instance of " alkoxyl group " includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl-butoxy etc.
Term used herein " halogenated alkoxy " means by halogen list defined herein or polysubstituted as alkoxyl group defined herein.The representative instance of " halogenated alkoxy " includes but not limited to-OCF 3,-OCHF 2,-OCH 2CCl 3Deng.
Term used herein " acyl group " means group-C (O) R 3, R wherein 3Be hydrogen or as alkyl or aryl defined herein.The representative instance of " acyl group " includes but not limited to formyl radical, ethanoyl, benzoyl-etc.
The term that uses among this paper " acyl amino " means group-NR 4C (O) R 5, R wherein 4And R 5Be selected from hydrogen or as alkyl or aryl defined herein independently of one another.The representative instance of " acyl amino " includes but not limited to formamido group, kharophen, benzamido-etc.
According to the present invention one preferred embodiment, R is for randomly being independently selected from C by 1-3 in general formula I A or the IB compound 1-6Alkyl, halo C 1-6Alkyl, C 1-6The substituted aryl of the group of alkoxyl group, cyanic acid and acyl amino, preferred phenyl.
According to the present invention one preferred embodiment R is an aryl in general formula I A or the IB compound, preferred phenyl, and two key is the E configuration.
According to the present invention one preferred embodiment, R is by 1-3 C in general formula I A or the IB compound 1-6The substituted aryl of alkyl, preferred phenyl.More preferably, R is by 1 C 1-6The substituted phenyl of alkyl.
According to the present invention one preferred embodiment, R is by 1-3 halo C in general formula I A or the IB compound 1-6The substituted aryl of alkyl, preferred phenyl, and the position of two keys is in the β position of carboxyl.More preferably, R is by the β position of the position of 1 substituted phenyl of trifluoromethyl and two keys at carboxyl.
According to the present invention one preferred embodiment R is by 1-3 the substituted aryl of cyanic acid in general formula I A or the IB compound, preferred phenyl, and the position of two keys is in the β position of carboxyl.More preferably, R is by the β position of the position of 1 substituted phenyl of cyanic acid and two keys at carboxyl.
According to the present invention one preferred embodiment R is by 1-3 the substituted aryl of acyl amino in general formula I A or the IB compound, preferred phenyl, and the position of two keys is in the β position of carboxyl.More preferably, R is by the β position of the position of 1 substituted phenyl of kharophen and two keys at carboxyl.
General formula I A of the present invention or IB compound can prepare through following reaction scheme:
Figure BDA0000156886380000051
Figure BDA0000156886380000061
Wherein R such as preceding text to general formula I A of the present invention or IB compound definition, PG is a carboxyl-protecting group, is selected from benzyl, to nitrobenzyl, diphenyl-methyl, methyl, ethyl and the tertiary butyl, preferred diphenyl-methyl.
In the superincumbent reaction scheme, the sophocarpine (its source can referring to CN1303673A and CN101416964A) that at first makes general formula 1 alkaline condition for example in the presence of sodium hydroxide or the potassium hydroxide aqueous solution open loop obtain the mixture of general formula 2a compound and general formula 2b compound.Can protect with the carboxyl of method mutual-through type 2a compound as known in the art and general formula 2b compound then (referring to Greene, T.W., Wuts; P.G, " Protective Groups in Organic Synthesis ", the 3rd edition; John Wiley & Sons; New York:1999), for example uses diphenyl diazomethane protection carboxyl, obtain the kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b.For example make kuh-seng olefin(e) acid and the sulfonylation agent RSO for example of the protection of general formula 3a and general formula 3b in the presence of the salt of wormwood at alkaline condition 2Cl (wherein R such as preceding text mutual-through type IA or IB compound definition) reaction, obtain the substituted kuh-seng olefin(e) acid of N-of general formula 4a and general formula 4b.Can use the substituted kuh-seng olefin(e) acid of the N-deprotection of method mutual-through type 4a as known in the art and general formula 4b then, for example use meta-cresol, obtain the compound of general formula 5a and general formula 5b, it is the mixture of α kuh-seng olefin(e) acid and β kuh-seng olefin(e) acid.Use at last method as known in the art for example flash column chromatography for example adopt that methylene dichloride separates with the compound of methyl alcohol as moving phase mutual-through type 5a and general formula 5b, obtain general formula I A of the present invention or IB compound.
Exemplary reaction scheme synthesized below concrete general formula I A of the present invention or IB compound can adopt:
Figure BDA0000156886380000071
Figure BDA0000156886380000081
In the above reaction scheme, the reaction conditions of each step is shown in following a to e:
A:KOH/H 2O refluxes～8h;
B: diphenyl diazomethane, room temperature ,～12h;
C: benzene sulfonyl chloride, K 2CO 3, room temperature, 3-8h;
D: meta-cresol, 70-90 ℃ ,～8h;
E: rapid column chromatography, the decompression silicagel column, moving phase is methylene dichloride: methyl alcohol 100:5.
Listed some instances in the following table through the inventive method synthetic The compounds of this invention:
Figure BDA0000156886380000082
Figure BDA0000156886380000091
The compounds of this invention both can itself also can its pharmacologically acceptable salt or solvate forms use.The pharmacologically acceptable salt of general formula I A or IB compound comprises and pharmaceutically acceptable mineral acid or organic acid, the salt that perhaps forms with pharmaceutically useful mineral alkali or organic bases.The example of suitable acid salt comprises and hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate; Propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, Hydrocerol A; Pounce on acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid; Toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, the salt that tannic acid etc. form.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethylolamine, quadrol, the salt that N-NMG and PROCAINE HCL, PHARMA GRADE etc. form.When relating to The compounds of this invention among this paper, comprise general formula I A or IB compound and pharmacologically acceptable salt or solvolyte.
According to the present invention, general formula I A of the present invention or IB compound can become pharmaceutical composition with conventional pharmaceutical carrier or vehicle group.This pharmaceutical composition can pass through administrations such as for example oral or non-enteron aisle.Pharmaceutical composition of the present invention can be prepared into various formulations by this area ordinary method, includes but not limited to tablet, capsule, and solution, suspension-s, granule or injection etc. are through administrations such as for example oral or non-enteron aisles.
It may be noted that in addition The compounds of this invention using dosage and method of use depend on many factors, comprise patient's age, body weight; Sex, natural health situation, nutritional status, the activity intensity of compound; Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's subjective judgement.Preferred using dosage is between the 0.01-100mg/kg body weight/day.
Description of drawings
Fig. 1: Fig. 1 is the X-ray single crystal diffraction figure of compound S C-87A.
Embodiment
N-replaces the synthetic of kuh-seng olefin(e) acid:
The preparation of the mixture (SC-1) of step 1. α and β kuh-seng olefin(e) acid:
Get sophocarpine 12.3g (0.05mol), add in the 300ml aqueous solution of Pottasium Hydroxide (KOH) 33.6g (0.6mol), reflux 9h, room temperature reaction spends the night then.With reaction solution down, transfer pH 6-7, be evaporated to dried with 3N hydrochloric acid in the ice-water bath cooling.The solid of gained is added methyl alcohol fully dissolve, filter, filter cake is washed with methyl alcohol, and filtrating merges, the methanol solution of SC-1, directly be used for step reaction down:
The preparation of step 2. diphenyl diazomethane:
Get Benzophenonehydrazones 9.8g (0.05mol), add sherwood oil (30-60 ℃) 120mL, add electrolytic manganese dioxide 13.05g (0.15mol) backflow 1h, suction filtration, filter cake is used petroleum ether, and merging filtrate directly is used for step reaction down.
The preparation of step 3. α and β kuh-seng olefin(e) acid phenylbenzene methyl esters:
The petroleum ether solution of diphenyl diazomethane is directly added in the methanol solution of SC-1, and stirring at room is decorporated until purple fully, and about 12 hours, be concentrated into driedly, add methylene dichloride and water stratification, dichloromethane layer is used anhydrous Na 2SO 4Drying obtains the dichloromethane solution of the phenylbenzene methyl esters of α and β kuh-seng olefin(e) acid, directly is used for the synthetic that follow-up N-replaces α and β kuh-seng olefin(e) acid and reacts.
Step 4.N-replaces the preparation of the phenylbenzene methyl esters of α and β kuh-seng olefin(e) acid:
Get dichloromethane solution half the of phenylbenzene methyl esters of α and the β kuh-seng olefin(e) acid of step 3 gained, add anhydrous K 2CO 33.45g (0.025mol), drip SULPHURYL CHLORIDE 12.5mmol, stirring at room detects until TLC, and raw material point disappears, and the filtering inorganic salt concentrate, rapid column chromatography, and obtaining solid is the phenylbenzene methyl esters that N-replaces the kuh-seng olefin(e) acid.
Step 5.N-replaces the preparation of α and β kuh-seng olefin(e) acid mixture:
In the solid of step 4 gained, add meta-cresol 15mL, about 8 hours of 80-90 ℃ of reaction adds methyl butyl ketone 50mL, and with water extraction 3 times, water layer merges, and concentrates, and obtaining solid is N-replacement α and β kuh-seng olefin(e) acid mixture.
Step 6.N-replaces separating of α kuh-seng olefin(e) acid and β kuh-seng olefin(e) acid:
The N-of step 5 gained is replaced α and β kuh-seng olefin(e) acid mixture, is moving phase with methylene dichloride and methyl alcohol (100: 5), carries out the silica gel rapid column chromatography and separates, and obtains pure α kuh-seng olefin(e) acid and β kuh-seng olefin(e) acid respectively.
Embodiment
Following embodiment is used to further specify the present invention, but it does not mean that the present invention only limits to this.
Embodiment 1.N-benzene sulfonyl kuh-seng olefin(e) acid (SC-16A) and (SC-16B) synthetic:
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip benzene sulfonyl chloride 1.60mL (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 1.6g.Rapid column chromatography obtains SC-16A 0.6g, SC-16B 0.8g.
SC-16A：
HRMS-ESI(M/Z)：C 21H 29N 2O 4S?405.1833(M+1)；406.1909(M+2)；407.1851(M+3)；
1H-NMR(CD 3OD，δppm)：7.73-7.75(2H，m)，7.50-7.59(3H，m)，5.42-5.45(2H，m)，3.79(1H，dd，J＝4.4，12.4Hz)，3.49-3.54(1H，m)，3.09(1H，t，J＝12.4Hz)，2.98(2H，t，J＝12.4Hz)，2.88-2.89(2H，m)，2.81(1H，s)，2.34-2.40(2H，m)，2.10-2.12(1H，m)，1.84-1.87(2H，m)，1.67-1.73(3H，m)，1.54-1.56(1H，m)，1.43-1.42(3H，m)。
SC-16B：
HRMS-ESI(M/Z)：C 21H 29N 2O 4S?405.1830(M+1)；406.1902(M+2)；407.1856(M+3)；
1H-NMR(D 2O，δppm)：7.95(2H，d，J＝7.6Hz)，7.67-7.80(3H，m)，6.52-6.59(1H，m)，5.57(1H，d，J＝15.6Hz)，3.96-3.99(1H，m)，3.59(2H，d，J＝8.4Hz)，3.54(1H，s)，3.44(2H，d，J＝12Hz)，3.00-3.05(2H，m)，2.44-2.50(2H，m)，2.20-2.23(2H，m)，1.86-1.97(8H，m)。
Embodiment 2.N-tolysulfonyl kuh-seng olefin(e) acid (SC-18A) and (SC-18B) synthetic:
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip Tosyl chloride 2.38g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.5g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 1.8g.Rapid column chromatography obtains SC-18A 0.7g, SC-18B 0.8g.
SC-18A：
HRMS-ESI(M/Z)：C 22H 31N 2O 4S?419.2006(M+1)；420.2083(M+2)；421.2011(M+3)；
1H-NMR(CD 3OD，δppm)：7.62(2H，d，J＝8Hz)，7.34(2H，d，J＝8Hz)，5.38-5.49(2H，m)，3.74(1H，dd，J＝4.4，12Hz)，3.43(1H，t，J＝9.6Hz)，2.91-3.05(5H，m)，2.76(1H，s)，2.33-2.39(5H，m)，2.07-2.10(1H，m)，1.80-1.88(2H，m)，1.34-1.71(8H，m)。
SC-18B：
HRMS-ESI(M/Z)：C 22H 31N 2O 4S?419.1984(M+1)；420.2060(M+2)；421.2011(M+3)；
1H-NMR(CD 3OD，δppm)：7.70(2H，d，J＝8Hz)，7.35(2H，d，J＝8Hz)，6.52-6.59(1H，m)，5.64(1H，d，J＝15.6Hz)，3.75(1H，s)，3.35-3.46(2H，m)，2.94-3.11(2H，m)，2.80(1H，s)，2.49-2.57(1H，m)，2.29-2.45(4H，m)，2.18(1H，s)，2.12(1H，s)，1.97(1H，s)，1.75-1.85(2H，m)，1.39-1.71(8H，m)。
Synthesizing of embodiment 3.N-methylsulfonyl kuh-seng olefin(e) acid (SC-25B):
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip Methanesulfonyl chloride 0.97mL (12.5mmol), stirring at room detects until TLC, and raw material point disappears; The filtering inorganic salt concentrate, and rapid column chromatography obtains the 3.5g white solid, add meta-cresol 15mL; 80-90 ℃ of reaction 8 hours adds methyl butyl ketone 50mL, with water extraction 3 times, and the water layer merging; Concentrate, obtain faint yellow solid, soak with methyl alcohol, suction filtration gets 1.8g white solid SC-25B.
SC-25B：
HRMS-ESI(M/Z)：C 16H 27N 2O 4S?343.1673(M+1)；
1H-NMR(D 2O，δppm)：6.99-7.06(1H，m)，6.09(1H，d，J＝15.6Hz)，3.98(1H，dd，J＝6.8，13.2Hz)，3.59-3.64(1H，m)，3.53(1H，s)，3.56-3.43(3H，m)，3.18(3H，s)，2.98-3.07(2H，m)，2.78-2.85(2H，m)，2.52(1H，s)，2.22(2H，d，J＝3.6Hz)，1.83-1.94(8H，m)。
Synthesizing of embodiment 4.N-p-nitrophenyl sulphonyl kuh-seng olefin(e) acid (SC-81A):
Figure BDA0000156886380000141
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip p-nitrophenyl SULPHURYL CHLORIDE 2.77g (12.5mmol), stirring at room detects until TLC, and raw material point disappears; The filtering inorganic salt concentrate, and rapid column chromatography obtains the 4.0g white solid, add meta-cresol 15mL; 80-90 ℃ of reaction 8 hours adds methyl butyl ketone 50mL, and with water extraction 3 times, water layer merges, and is concentrated; Obtain faint yellow solid 2.0g, add methylene dichloride, suction filtration obtains white solid SC-81A 1.35g.
SC-81A：
HRMS-ESI(M/Z)：C 21H 28N 3O 6S?450.1710(M+1)；451.1740(M+2)；452.1679(M+3)；
1H-NMR(CD 3OD，δppm)：8.36(2H，d，J＝8.8Hz)，7.99(2H，d，J＝8.8Hz)，5.44-5.47(2H，m)，3.76(1H，dd，J＝4.4，12Hz)，3.42-3.55(1H，m)，3.29-3.37(1H，m)，3.07-3.15(1H，m)，2.93(2H，d，J＝5.2Hz)，2.79(1H，J＝11.2Hz)，2.68-2.69(1H，m)，2.50-2.54(1H，m)，1.90-2.11(3H，m)，1.30-1.83(8H，m)。
Embodiment 5.N-is to anisole sulphonyl kuh-seng olefin(e) acid (SC-82A) and (SC-82B) synthetic:
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip anisole SULPHURYL CHLORIDE 2.77g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 4.0g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 2.0g.Rapid column chromatography obtains SC-82A 0.8g, SC-82B 0.9g.
SC-82A：
HRMS-ESI(M/Z)：C 22H 31N 2O 5S?435.1949(M+1)；436.2035(M+2)；437.1988(M+3)；
1H-NMR(CD 3OD，δppm)：7.65-7.69(2H，m)，7.02-7.06(2H，m)，5.38-5.53(2H，m)，3.83(3H，s)，3.73(1H，dd，J＝4.4，12Hz)，3.39-3.44(1H，m)，2.93-3.02(5H，m)，2.79(1H，m)，2.35-2.40(2H，m)，2.08-2.12(1H，m)，1.80-1.91(2H，m)，1.65-1.72(3H，m)，1.31-1.55(4H，m)。
SC-82B：
HRMS-ESI(M/Z)：C 22H 31N 2O 5S?435.1940(M+1)；
1H-NMR(CD 3OD，δppm)：7.74-7.77(2H，m)，7.05-7.08(2H，m)，6.54-6，61(1H，m)，5.67(1H，d，J＝15.2Hz)，3.84(3H，s)，3.65-3.77(1H，m)，3.30-3.46(2H，m)，3.08-3.16(2H，m)，2.44-2.59(3H，m)，2.26-2.33(1H，m)，2.17-2.22(1H，m)，1.99(1H，s)，1.40-1.86(9H，m)。
Embodiment 6.N-dimethylamino sulphonyl kuh-seng olefin(e) acid (SC-83A) and (SC-83B) synthetic:
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip dimethylamino SULPHURYL CHLORIDE 1.34mL (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.5g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 1.5g.Rapid column chromatography obtains SC-83A 0.6g, SC-83B 0.7g.
SC-83A：
HRMS-ESI(M/Z)：C 17H 30N 3O 4S?372.1951(M+1)373.1925(M+2)
1H-NMR(CD 3OD，δppm)：6.80(1H，dt，J＝6.8，15.6Hz)，5.87(1H，d，J＝15.6Hz)，3.83-3.89(1H，m)，3.40-3.46(2H，m)，3.11(2H，d，J＝11.6Hz)，2.87(1H，s)，2.71(3H，s)，2.65(3H，s)，2.60-2.63(2H，m)，2.43(2H，t，J＝12.4Hz)，2.17-2.19(2H，m)，1.89-1.92(1H，m)，1.47-1.79(7H，m)。
SC-83B：
HRMS-ESI(M/Z)：C 17H 3N 30O 4S?372.1942(M+1)373.1947(M+2)
1H-NMR(CD 3OD，δppm)：5.86-5.95(1H，m)，5.41-5.48(1H，m)，3.98(1H，t，J＝10.4Hz)，3.57(1H，dd，J＝4.4，13.2Hz)，3.42-3.47(1H，m)，3.33(1H，t，J＝12.8Hz)，3.11-3.22(2H，m)，2.95-3.10(2H，m)，2.69(3H，s)，2.65(3H，s)，2.46-2.56(1H，m)，2.18-2.23(1H，m)，2.00-2.20(2H，m)，1.95-1.90(1H，m)，1.40-1.85(7H，m)。
Embodiment 7.N-is synthetic to trifluoromethyl benzene sulfonyl kuh-seng olefin(e) acid (SC-84A):
Figure BDA0000156886380000171
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip trifluoromethyl benzene sulfonyl chloride 3.05g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.3g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 1.5g.Rapid column chromatography obtains SC-84A 0.5g.
SC-84A：
HRMS-ESI(M/Z)：C 22H 28N 2O 4F 3S?473.1715(M+1)；474.1768?(M+2)；
1H-NMR(CD 3OD，δppm)：7.95(2H，d，J＝8.4Hz)，7.85(2H，d，J＝8.4Hz)，5.47-5.49(2H，m)，3.79(1H，dd，J＝4.4，12Hz)，3.40-3.50(2H，m)，3.05(1H，t，J＝12Hz)，2.94(3H，s)，2.70(1H，s)，2.20-2.39(2H，m)，2.08-2.11(1H，m)，1.81-1.86(2H，m)，1.61-1.70(3H，m)，1.33-1.54(4H，m)。
Embodiment 8.N-is to fluorobenzene sulphonyl kuh-seng olefin(e) acid (SC-85A) and (SC-85B) synthetic:
Figure BDA0000156886380000181
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip fluorobenzene SULPHURYL CHLORIDE 2.43g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 4.2g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid.Rapid column chromatography obtains SC-85A 0.8g and SC-85B 0.8g.
SC-85A：
HRMS-ESI(M/Z)：C 21H 28N 2O 4FS?423.1746(M+1)
1H-NMR(CD 3OD，δppm)：7.80(2H，dd，J＝5.2，8Hz)，7.25(2H，t，J＝8.8Hz)，5.36-5.53(2H，m)，3.79(1H，d，J＝12Hz)，3.59-3.75(1H，m)，3.06-3.15(3H，m)，2.86-2.94(3H，m)，2.43(2H，s)，2.11-2.14(1H，m)，1.83-1.91(2H，m)，1.72(3H，s)，1.55-1.57(1H，m)，1.33-1.46(3H，m)。
SC-85B：
HRMS-ESI(M/Z)：C 21H 28N 2O 4FS?423.1758(M+1)；424.1789(M+2)；
1H-NMR(CD 3OD，δppm)：7.88(2H，dd，J＝3.2，4.8Hz)，7.24(2H，t，J＝8.8Hz)，6.51-6.58(1H，m)，5.67(1H，d，J＝15.6Hz)，3.84-3.92(1H，m)，3.40-3.56(2H，m)，3.08-3.27(2H，m)，2.91(1H，s)，2.41-2.61(4H，m)，2.06-2.21(2H，m)，1.41-1.95(8H，m)。
Embodiment 9.N-is to chlorobenzene sulphonyl kuh-seng olefin(e) acid (SC-86A) and (SC-86B) synthetic:
Figure BDA0000156886380000191
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip parachloroben-zenesulfonyl chloride 2.64g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 4.2g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid.Rapid column chromatography obtains SC-86A 0.7g and SC-86B 0.9g.
SC-86A：
HRMS-ESI(M/Z)：C 21H 28N 2O 4SCl?439.1449(M+1)；440.1441(M+2)；441.1429(M+3)；
1H-NMR(CD 3OD，δppm)：7.74(2H，d，J＝8Hz)，7.40(2H，d，J＝8Hz)，5.36-5.58(2H，m)，3.79(1H，dd，J＝4.4，12.4Hz)，3.67-3.72(1H，m)，3.05-3.25(3H，m)，2.96(1H，s)，2.84-2.85(2H，d，J＝4.4Hz)，2.42-2.46(2H，m)，2.11-2.14(1H，m)，1.82-1.92(2H，m)，1.73(3H，s)，1.55-1.57(1H，m)，1.32-1.46(3H，m)。
SC-86B：
HRMS-ESI(M/Z)：C 21H 28N 2O 4SCl?439.1444(M+1)；440.1498(M+2)；441.1436(M+3)；
1H-NMR(CD 3OD，δppm)：7.79(2H，d，J＝8.8Hz)，7.51(2H，d，J＝8.8Hz)，6.53-6.60(1H，m)，5.68(1H，d，J＝15.6Hz)，3.88-3.91(1H，m)，3.40-3.54(2H，m)，3.04-3.09(2H，m)，2.86(1H，s)，2.49-2.61(2H，m)，2.38-2.44(2H，m)，2.21(1H，s)，2.06-2.07(1H，m)，1.48-1.86(8H，m)。
Embodiment 10.N-is to cyanic acid benzene sulfonyl kuh-seng olefin(e) acid (SC-87A) and (SC-87B) synthetic:
Figure BDA0000156886380000201
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip cyanic acid benzene sulfonyl chloride 2.52g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.0g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid 1.5g.Bullion obtains SC-87a 0.6g with methylene dichloride and recrystallizing methanol, and mother liquor concentrates, and purifying obtains compound S C-87B 0.5g.
SC-87A:X-ray single crystal diffraction figure sees Fig. 1; The monocrystalline data A-F that sees the following form:
Figure BDA0000156886380000202
Figure BDA0000156886380000211
Figure BDA0000156886380000212
Figure BDA0000156886380000221
Figure BDA0000156886380000222
Figure BDA0000156886380000231
Figure BDA0000156886380000232
Figure BDA0000156886380000241
Figure BDA0000156886380000242
Figure BDA0000156886380000251
Figure BDA0000156886380000252
Figure BDA0000156886380000261
SC-87B：
HRMS-ESI(M/Z)：C 22H 28N 3O 4S?430.1785(M+1)431.1781(M+2)
1H-NMR(D 2O，δppm)：8.03-8.10(4H，m)，6.25-6.32(1H，m)，5.53(1H，d，J＝15.6Hz)，4.00(1H，dd，J＝6.8，12.8Hz)，3.63(2H，d，J＝8.4Hz)，3.56(1H，s)，3.44(2H，d，J＝12.5Hz)，3.37(1H，s)，3.00-3.06(2H，m)，2.51-2.52(1H，m)，2.39-2.47(1H，m)，2.27-2.28(1H，m)，2.17-2.23(1H，m)，1.79-2.00(7H，m)。
Embodiment 11.N-2-chlorobenzene sulphonyl kuh-seng olefin(e) acid (SC-88A) and (SC-88B) synthetic:
Figure BDA0000156886380000262
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip 2-chlorobenzene sulfonyl chloride 2.64g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.5g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid.Rapid column chromatography obtains SC-88A 0.7g and SC-88B 0.7g.
SC-88A：
HRMS-ESI(M/Z)：C 21H 28N 2O 4SCl?439.1441(M+1)；440.1482(M+2)；441.1398(M+3)；
1H-NMR(CD 3OD，δppm)：7.97-8.00(2H，m)，7.44-7.49(2H，m)，6.25(1H，dt，J＝6，15.6Hz)，5.44(1H，15.6Hz)，4.04(1H，dd，J＝5.6，14.8Hz)，3.82-3.88(1H，m)，3.61(1H，t，J＝3.2Hz)，3.39-3.51(3H，m)，2.97-3.04(2H，m)，2.53-2.60(3H，m)，2.35-2.38(1H，m)，1.75-1.98(5H，m)，1.67-1.69(3H，m)。
SC-88B：
HRMS-ESI(M/Z)：C 21H 28N 2O 4SCl?439.1446(M+1)；440.1487(M+2)；441.1414(M+3)；
1H-NMR(CD 3OD，δppm)：7.99(1H，dd，J＝1.6，8Hz)，7.90(1H，d，J＝8.4Hz)，7.47-7.49(2H，m)，5.53-5.60(1H，m)，5.20-5.26(1H，m)，4.08(1H，dd，J＝4.4，14Hz)，3.95(1H，t，J＝10.8Hz)，3.55(1H，s)，3.33-3.43(3H，m)，2.90-3.00(2H，m)，2.68-2.74(1H，m)，2.50-2.55(1H，m)，2.14-2.26(2H，m)，1.72-1.90(6H，m)，1.53-1.67(2H，m)。
Cyanic acid benzene sulfonyl kuh-seng olefin(e) acid (SC-89A) and (SC-89B) synthetic between embodiment 12.N-:
Figure BDA0000156886380000271
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), cyanic acid benzene sulfonyl chloride 2.52g (12.5mmol) between dropping, stirring at room detects until TLC, and raw material point disappears; The filtering inorganic salt concentrate, and rapid column chromatography obtains the 3.8g white solid, add meta-cresol 15mL; 80-90 ℃ of reaction 8 hours adds methyl butyl ketone 50mL, with water extraction 3 times, and the water layer merging; Concentrate, obtain white solid, rapid column chromatography obtains SC-89A 0.6g and SC-89B 0.8g.
SC-89A：
HRMS-ESI(M/Z)：C 22H 28N 3O 4S?430.1799(M+1)；
1H-NMR(CDCl 3，δppm)：8.03-8.09(2H，m)，7.77(1H，d，J＝7.6)，7.59(1H，t，J＝7.6Hz)，6.40(1H，d，J＝15.6Hz)，5.71(1H，d，J＝15.6Hz)，4.31(1H，s)，3.83-3.89(1H，m)，3.70-3.77(1H，m)，3.28-3.42(2H，m)，2.66-3.71(2H，m)，2.48-2.52(1H，m)，2.16-2.38(4H，m)，1.77-1.90(3H，m)，1.59-1.67(2H，m)，1.36-1.46(3H，m)。
SC-89B：
HRMS-ESI(M/Z)：C 22H 28N 3O 4S?430.1782(M+1)；
1H-NMR(CDCl 3，δppm)：8.01-8.07(2H，m)，7.78(1H，d，J＝8Hz)，7.61(1H，J＝8Hz)，5.40-5.56(2H，m)，4.11-4.16(1H，m)，3.50-3.91(2H，m)，3.42-3.49(1H，m)，3.18-3.42(1H，m)，2.58-2.91(3H，m)，2.19-2.39(4H，m)，1.42-2.06(8H，m)。
Embodiment 13.N-acetparaminosalol benzene sulfonyl kuh-seng olefin(e) acid (SC-90A) and (SC-90B) synthetic:
Figure BDA0000156886380000281
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip p-acetaminobenzenesulfonyl chloride 2.92g (12.5mmol), stirring at room detects until TLC, and raw material point disappears; The filtering inorganic salt concentrate, and rapid column chromatography obtains the 4.5g white solid, add meta-cresol 15mL; 80-90 ℃ of reaction 8 hours adds methyl butyl ketone 50mL, with water extraction 3 times, and the water layer merging; Concentrate, obtain white solid, rapid column chromatography obtains SC-90A 1.0g and SC-90B 1.1g.
SC-90A：
HRMS-ESI(M/Z)：C 23H 32N 3O 5S?462.2036(M+1)；463.2057(M+2)；
1H-NMR(CD 3OD，δppm)：7.71-7.74(2H，m)，7.66(2H，d，J＝8.8Hz)，5.48-5.55(1H，m)，5.34-5.40(1H，m)，3.78(1H，dd，J＝4.4，12.4Hz)，3.58(1H，t，J＝10Hz)，3.02-3.13(3H，m)，2.93(1H，s)，2.87(1H，d，J＝6.8Hz)，2.42-2.53(3H，m)，2.12(3H，s)，1.82-1.87(2H，m)，1.72(3H，s)，1.55-1.69(2H，m)，1.34-1.48(3H，m)。
SC-90B：
HRMS-ESI(M/Z)：C 23H 32N 3O 5S?462.2045(M+1)；463.2078(M+2)；
1H-NMR(CD 3OD，δppm)：7.63-7.87(4H，m)，6.56-6.63(1H，m)，5.72(1H，d，J＝15.2Hz)，3.74-3.81(1H，m)，3.37-3.43(1H，m)，2，74-3.14(4H，m)，2.49-2.60(1H，m)，2.26-2.52(3H，m)，2.18(3H，s)，1.35-1.83(10H，m)。
Synthesizing of embodiment 14.N-3-chlorobenzene sulphonyl kuh-seng olefin(e) acid (SC-91A):
Adding K in the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained half the 2CO 33.45g (0.025mol), drip 3-chlorobenzene sulfonyl chloride 2.64g (12.5mmol), stirring at room detects until TLC; Raw material point disappears, and the filtering inorganic salt concentrate rapid column chromatography; Obtain the 3.5g white solid, add meta-cresol 15mL, 80-90 ℃ was reacted 8 hours, added methyl butyl ketone 50mL; With water extraction 3 times, water layer merges, and concentrates, and obtains white solid.Rapid column chromatography obtains SC-91A 0.7g.
SC-91A：
HRMS-ESI(M/Z)：C 22H 30N 2O 3SCl?437.1651(M+1)438.1685(M+2)438.1628(M+3)
1H-NMR(CD 3OD，δppm)：7.83(1H，t，J＝3.2Hz)，7.75(1H，d，J＝7.6Hz)，7.48-7.59(2H，m)，6.61-6.69(1H，m)，5.70(1H，d，J＝15.2Hz)，3.77-3.81(1H，m)，3.44-3.49(1H，m)，3.32-3.38(1H，m)，2.84-2.84(2H，m)，2.57-2.64(1H，m)，2.53(1H，s)，2.41-2.48(1H，m)，2.16-2.21(2H，m)，2.10(1H，s)，1.91-1.92(1H，m)，1.66-1.77(2H，m)，1.37-1.64(6H，m)。
Test Example 1
Test event: anti-CB 3 types (COX-B3) screening active ingredients
Test philosophy: with Vero (African green monkey kidney) cell is virus host, measures general formula I A of the present invention or IB compound inhibition CB 3 types and causes Vero cytopathy degree.
Test material and method:
1. virus strain: COX-B3 is provided by ATCC.
2. the general formula I A of sample preparation: embodiment of the invention 1-14 or IB compound face with preceding DMSO and are made into the 100mg/ml mother liquor; Remake 3 times of dilutions after being diluted to 1mg/ml with nutrient solution during detection; Totally 8 dilution samples are respectively 1000,333.3,111.1,37.0,12.4,4.12,1.37,0.46 μ g/ml.
3. positive control drug: ribavirin (RBV), produce by benefit pharmaceutical factory of Hubei section.
4. testing method: Vero cell kind 96 well culture plates, 24 hours postoperative infection CB 3 types 10 -5Adsorbed 2 hours; Abandon viral liquid, add sample and positive control drug, establish cell control well and virus control hole simultaneously by above extent of dilution; Treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing when reaching 4+, with the Reed-Muench method respectively calculation sample to the half-inhibition concentration (IC of CB 3 types 50), calculate the SI value.
Following table 1 is some general formula I A or IB compound resisting coxsackie virus B3 type (COX-B3) the screening active ingredients result of embodiment of the invention 1-14:
Table 1: general formula I A of the present invention or IB compound resisting coxsackie virus B3 type
(COX-B3) screening active ingredients result
The anti-CB 3 active SI (SI) of general formula I A of the present invention or IB compound are apparently higher than contrast medicine ribavirin, particularly compound S C-84A, and the SI value of SC-89B and SC-90A is respectively 6.37,9.18 and 8.22 times of contrast medicine.It is active that general formula I A of the present invention or IB compound have significant anti-CB.
Test Example 2
Interior animal experiment:
Virus: change of coxsackie b virus B3 type Nancy strain, go down to posterity in the injection of ablactation mouse peritoneal, strengthen virulence, after stablizing for virulence, receive and preserve.Adaptation of virus during experiment.
The male ablactation of animal: Balb/C mouse.
Positive control drug: Poly IC.
Virus virulence is measured: 10 times of virus dilution of mouse peritoneal injection, observed for 2 weeks, and calculate LD 50
Drug toxicity is measured: general formula I A or the IB compound of the oral or injection embodiment of the invention 1-14 of mouse, measure LD 0, LD 50
The Coxsackie virus infection mouse anti virus test of pesticide effectiveness: the ablactation mouse is through abdominal cavity infection 10-100LD 50Virus, infect general formula I A or IB compound that back different time filling stomach or abdominal cavity give embodiment of the invention 1-14 to be measured, observation index:
Mortality ratio and average life day: the record death toll with dead day, calculate dead % and average life day.Relatively calculate dead protection ratio with the virus control group, prolong vital rates, judge drug effect.
The serum-virus carrying capacity: different time is got blood after the mouse infection administration, and separation of serum is measured virus titer on the Vero cell, calculates TCID 50Compare with the virus control group, it is above for inhibition is arranged to reduce a logarithm.
Serum lactic dehydrogenase (SLDH) (LDH) is measured: different time is got blood after the mouse infection administration, measures LDH unit, compares with the virus control group, takes statistics to learn and handles, and judges drug effect.
Test Example 3
Test event: anti-coxsackie virus A 16-type (COX-A16) screening active ingredients
Test philosophy: with Vero (African green monkey kidney) cell is virus host, measures general formula I A of the present invention or IB compound inhibition coxsackie virus A 16-type and causes Vero cytopathy degree.
Test material and method:
1. virus strain: COX-A16 is provided by ATCC.
2. the general formula I A of sample preparation: embodiment of the invention 1-14 or IB compound face with preceding DMSO and are made into the 100mg/ml mother liquor; Remake 3 times of dilutions after being diluted to 1mg/ml with nutrient solution during detection; Totally 8 dilution samples are respectively 1000,333.3,111.1,37.0,12.4,4.12,1.37,0.46 μ g/ml.
3. positive control drug: ribavirin (RBV), produce by benefit pharmaceutical factory of Hubei section.
4. testing method: Vero cell kind 96 well culture plates, 24 hours postoperative infection CB 3 types 10 -5Adsorbed 2 hours; Abandon viral liquid, add sample and positive control drug, establish cell control well and virus control hole simultaneously by above extent of dilution; Treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing when reaching 4+, with the Reed-Muench method respectively calculation sample to the half-inhibition concentration (IC of coxsackie virus A 16-type 50), calculate the SI value.
Following table 2 is some general formula I A or IB compound resisting coxsackie virus A16 type (COX-A16) screening active ingredients result (TC wherein of embodiment of the invention 1-14 50Be median lethal concentration, unit is μ M; SI=TC 50/ IC 50):
Table 2: general formula I A of the present invention or IB compound resisting coxsackie virus A16 type
(COX-A16) screening active ingredients result
Compound number TC 50(μM) IC 50(μM) SI
SC-84A 611.35±0 204.00±18.8 3.0
SC-85A ＞1184 264±24.0 4.5
SC-85B ＞1184 395±0 3.0
SC-86B ＞1141 335±19.6 3.4
SC-87B ＞1165 388±0 3.0
SC-89A ＞1165 342±20.0 3.4
SC-89B ＞1165 342±20.0 3.4
SC-90A ＞1084 306±35.8 3.6
RBV 8190±0.0 4095±0.0 2.0
Test Example 4
Test event: anti-CB 6 types (COX-B6) screening active ingredients
Test philosophy: with Vero (African green monkey kidney) cell is virus host, measures general formula I A of the present invention or IB compound inhibition CB 6 types and causes Vero cytopathy degree.
Test material and method:
1. virus strain: COX-B6 is provided by ATCC.
2. the general formula I A of sample preparation: embodiment of the invention 1-14 or IB compound face with preceding DMSO and are made into the 100mg/ml mother liquor; Remake 3 times of dilutions after being diluted to 1mg/ml with nutrient solution during detection; Totally 8 dilution samples are respectively 1000,333.3,111.1,37.0,12.4,4.12,1.37,0.46 μ g/ml.
3. positive control drug: ribavirin (RBV), produce by benefit pharmaceutical factory of Hubei section.
4. testing method: Vero cell kind 96 well culture plates, 24 hours postoperative infection CB 6 types 10 -5Adsorbed 2 hours; Abandon viral liquid, add sample and positive control drug, establish cell control well and virus control hole simultaneously by above extent of dilution; Treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing when reaching 4+, with the Reed-Muench method respectively calculation sample to the half-inhibition concentration (IC of CB 6 types 50), calculate the SI value.
Following table 3 is some general formula I A or IB compound resisting coxsackie virus B6 type (COX-B6) screening active ingredients results of embodiment of the invention 1-14:
Table 3: general formula I A of the present invention or IB compound resisting coxsackie virus B6 type
(COX-B6) screening active ingredients result
Compound number TC 50(μM) IC 50(μM) SI
SC-16A ＞1237 126±16.3 9.8
SC-16B ＞1237 101±8.8 12.2
SC-18A ＞1196 107±3.7 11.2
SC-18B 575±0 74±3.6 7.8
SC-81A ＞1113 88±3.5 12.6
SC-82A ＞1152 94±7.5 12.3
SC-82B ＞1152 74±7.7 15.6
SC-83A ＞1347 112±2.8 12.0
SC-83B ＞1347 117±10.5 11.5
SC-84A 611±0 30±0.3 20.4
SC-85A ＞1184 121±15.6 9.8
SC-85B ＞1184 96±6.2 12.3
SC-86A ＞1141 69±6.4 16.5
SC-86B ＞1141 76±4.2 15.0
SC-87A ＞1165 104±5.1 11.2
SC-87B ＞1165 120±13.9 9.7
SC-89A ＞1165 72±3.5 16.2
SC-89B ＞1165 70±6.6 16.6
SC-90B ＞1084 152±9.8 7.1
SC-91B ＞1141 79±6.2 13.7
SC-90A 251 12±2.1 20.9
RBV 8190 1688±23.4 4.85

Claims (14)

1. the compound or pharmaceutically acceptable salt thereof of general formula I A or IB:
Figure FDA0000156886370000011
Wherein,
R is C 1-6Alkyl, amino or aryl, wherein said amino is randomly by C 1-6Alkyl list or two replaces, and described alkyl and aryl are randomly replaced by 1-3 group that is independently selected from down group: hydroxyl, halogen, nitro, cyanic acid, C 1-6Alkyl, halo C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, acyl group and acyl amino; With
Position of double bond among the general formula I A is in the α position of carboxyl, and the position of double bond among the general formula I B is in the β position of carboxyl.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is for randomly being independently selected from C by 1-3 1-6Alkyl, halo C 1-6Alkyl, C 1-6The substituted aryl of the group of alkoxyl group, cyanic acid and acyl amino, preferred phenyl.
3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is an aryl, preferred phenyl, and two key is the E configuration.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is by 1-3 C 1-6The substituted aryl of alkyl, preferred phenyl; Preferably, R is by 1 C 1-6The substituted phenyl of alkyl.
5. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is by 1-3 halo C 1-6The substituted aryl of alkyl, preferred phenyl, and position of double bond is in the β position of carboxyl; Preferably, R is by 1 substituted phenyl of trifluoromethyl and the position of double bond β position at carboxyl.
6. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is by 1-3 the substituted aryl of cyanic acid, preferred phenyl, and position of double bond is in the β position of carboxyl; Preferably, R is by 1 substituted phenyl of cyanic acid and the position of double bond β position at carboxyl.
7. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is by 1-3 the substituted aryl of acyl amino, preferred phenyl, and position of double bond is in the β position of carboxyl; Preferably, R is by 1 substituted phenyl of kharophen and the position of double bond β position at carboxyl.
8. the compound or pharmaceutically acceptable salt thereof of claim 1, said compound is selected from:
(E)-N-benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-benzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-p-toluenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-p-toluenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-methylsulfonyl α kuh-seng olefin(e) acid;
(E)-N-p-nitrophenyl alkylsulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to anisole alkylsulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to anisole alkylsulfonyl α kuh-seng olefin(e) acid;
(E)-N-(N, N-dimethyl methyl acyl group) α kuh-seng olefin(e) acid;
(E)-N-(N, N-dimethyl methyl acyl group) β kuh-seng olefin(e) acid;
(E)-N-is to trifluoromethyl benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to fluorobenzene alkylsulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to fluorobenzene alkylsulfonyl α kuh-seng olefin(e) acid;
(E)-N-is to chlorobenzene alkylsulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to chlorobenzene alkylsulfonyl α kuh-seng olefin(e) acid;
(E)-N-is to cyanic acid benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to cyanic acid benzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-between cyanic acid benzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-between cyanic acid benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-the adjacent chlorobenzene alkylsulfonyl of N-α kuh-seng olefin(e) acid;
(E)-the adjacent chlorobenzene alkylsulfonyl of N-β kuh-seng olefin(e) acid;
(E)-N-m-chloro benzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-acetparaminosalol benzenesulfonyl β kuh-seng olefin(e) acid; With
(E)-N-acetparaminosalol benzenesulfonyl α kuh-seng olefin(e) acid.
9. pharmaceutical composition, said pharmaceutical composition comprise each compound or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or vehicle of at least a claim 1-8.
10. the preparation method of the compound of the general formula I A of claim 1 or IB, this method may further comprise the steps:
A) make the sophocarpine open loop of formula 1,
Figure FDA0000156886370000031
Obtain the mixture of general formula 2a compound and general formula 2b compound;
Figure FDA0000156886370000032
B) carboxyl of mutual-through type 2a compound and general formula 2b compound is protected, and obtains the α and the β kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b,
Figure FDA0000156886370000041
Wherein PG is a carboxyl-protecting group;
C) make α and β kuh-seng olefin(e) acid and the sulfonylation agent reaction of the protection of general formula 3a and general formula 3b, obtain substituted α of N-and the β kuh-seng olefin(e) acid of general formula 4a and general formula 4b;
D) the substituted α of N-of mutual-through type 4a and general formula 4b and β kuh-seng olefin(e) acid deprotection obtain the compound of general formula 5a and general formula 5b;
Figure FDA0000156886370000043
E) mutual-through type 5a separates with the compound of general formula 5b, obtains the compound of general formula I A or IB,
Figure FDA0000156886370000044
Wherein described in R such as the claim 1.
11. the method for the treatment disease that CBV caused, said method comprise each the compound or pharmaceutically acceptable salt thereof of at least a claim 1-8 that needs the patient treatment of this treatment significant quantity.
12. the method for claim 11, wherein said disease are myocarditis, particularly viral myocarditis.
13. each the purposes of compound or pharmaceutically acceptable salt thereof in the medicine of the preparation treatment disease that CBV caused of claim 1-8.
14. the purposes of claim 13, wherein said disease are myocarditis, particularly viral myocarditis.
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CN105218412A (en) * 2015-10-19 2016-01-06 哈尔滨工业大学 The method of the controlled modification of a kind of carbon material surface
CN106279167A (en) * 2015-06-02 2017-01-04 中国医学科学院医药生物技术研究所 Matrine compound derivant and its production and use
CN109422744A (en) * 2017-08-21 2019-03-05 南开大学 Matrine derivative and its synthesis and the application in terms of preventing and treating plant pest

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279167A (en) * 2015-06-02 2017-01-04 中国医学科学院医药生物技术研究所 Matrine compound derivant and its production and use
CN106279167B (en) * 2015-06-02 2018-11-13 中国医学科学院医药生物技术研究所 Matrine compound derivative and its preparation method and application
CN105218412A (en) * 2015-10-19 2016-01-06 哈尔滨工业大学 The method of the controlled modification of a kind of carbon material surface
CN105218412B (en) * 2015-10-19 2017-06-20 哈尔滨工业大学 A kind of method of the controllable modification of carbon material surface
CN109422744A (en) * 2017-08-21 2019-03-05 南开大学 Matrine derivative and its synthesis and the application in terms of preventing and treating plant pest
CN109422744B (en) * 2017-08-21 2021-03-30 南开大学 Matrine derivative, synthesis thereof and application thereof in prevention and treatment of plant diseases and insect pests

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