CN102659783B - 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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CN102659783B
CN102659783B CN201210123512.8A CN201210123512A CN102659783B CN 102659783 B CN102659783 B CN 102659783B CN 201210123512 A CN201210123512 A CN 201210123512A CN 102659783 B CN102659783 B CN 102659783B
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compound
acid
general formula
kuh
seng
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CN102659783A (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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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 kuh-seng gadoleic acid derivative and its production and use
Technical field
The application relates to a kind of N-and replaces purposes in the medicine of the disease that kuh-seng gadoleic acid derivative, its preparation method, the pharmaceutical composition comprising described derivative, the method for disease using described derivatives for treatment CBV to cause and described derivative cause at preparation treatment CBV.
Background technology
Coxsackie virus is the papova separated poliomyelitic infant ight soil from New York, United States Coxsackie town in 1948 from clinical diagnosis.It belongs to Picornaviridae enterovirus genus.Pathogenic agent Coxsackie virus is divided into two classes according to its Biological characteristics: category-A and category-B.Adhere to dust gram virus and the poliovirus of enterovirus class separately, existing title " fine virus ".Coxsackie A disease poison infected children is common, and adult infects relatively less.The principal feature of clinical manifestation is acute febrile, fash.Meningoencephalitis is with Guillain-Barr é syndrome and acute viral myocardosis, and dominant and inapparent infection ratio reaches 1: 50-100.CBV infects and causes characteristic infectivity costalgia of chest and so-called Bornholm ' s disease, can merge meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia and pneumonia.The sophocarpine disclosing following formula in CN1303673A as preparing CBV myocarditis because of the purposes of medicine and method for making thereof, and discloses sophocarpine or the purposes of its pharmacologically acceptable salt in the medicine of preparation treatment diseases induced by coxsackie B virus in CN101416964A.
Specific medicine is not had at present, clinically mainly symptomatic treatment for Coxsackie virus.Therefore, find in recent years and develop the diseases induced medicine of the treatment CBV of novel type and be still a focus in drug research field.
Summary of the invention
The present inventor is by testing kuh-seng gadoleic acid derivative, find that a series of N-replaces kuh-seng gadoleic acid derivative and has obvious anti-CBV active, wherein with known marketed drug ribavirin (RBV) for positive control medicine, N-of the present invention replaces kuh-seng gadoleic acid derivative and demonstrates good selectivity (see table 1 herein).The anti-CBV activity of this compounds had not been appeared in the newspapers and had been led.The new texture type with anti-CBV activity will likely be found 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:
Wherein:
Substituent R: C 1-6alkyl, amino or aryl, wherein said amino is optionally by C 1-6alkyl list or two replaces, and described alkyl and aryl are optionally replaced by the individual group independently selected from lower group of 1-3: hydroxyl, halogen, nitro, cyano group, 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 in general formula I A is in the α position of carboxyl, and the position of double bond in 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.
3rd aspect of the present invention relates to the pharmaceutical composition comprising at least one general formula I A of the present invention or IB compound and one or more pharmaceutical carriers or vehicle.
4th aspect of the present invention relates to the purposes of the medicine of the disease that general formula I A of the present invention or IB compound cause at preparation treatment CBV.Especially, described CBV is cells of coxsackie B 3 virus.Described disease is characteristic infectivity costalgia of chest and so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, described disease is myocarditis, particularly viral myocarditis.
5th aspect of the present invention relates to general formula I A of the present invention or the IB compound of the medicine being used as the disease that treatment CBV causes.Especially, described CBV is cells of coxsackie B 3 virus.Described disease is characteristic infectivity costalgia of chest and so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, described disease is myocarditis, particularly viral myocarditis.
6th aspect of the present invention relates to the method for the treatment of the disease that CBV causes, and described method comprises the general formula I A of the present invention or IB compound that need the bacterium of this treatment.Especially, described CBV is cells of coxsackie B 3 virus.Described disease is characteristic infectivity costalgia of chest and so-called Bornholm ' s disease, meningoencephalitis, myocarditis, fever, Guillain-Ba-rr é syndrome, hepatitis, hemolytic anemia or pneumonia etc.Preferably, described disease is myocarditis, particularly viral myocarditis.
Substituting group defines
Term used herein " alkyl " refers to saturated straight or branched alkyl, has 1-6 carbon atom (i.e. C 1-6alkyl), preferably there is 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 " refers to group-NH 2.
Term used herein " aryl " means the unsaturated aromatic carbocyclyl groups of 5-14 the carbon atom with a monocycle or multiple fused rings.Described aryl preferably has 5-10,5-8 or 5-6 or 6 carbon atom.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, wherein R 1for hydrogen and alkyl as herein defined, assorted alkyl, cycloalkyl, 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 " refers to group-OH.
Term used herein " halogen " means fluorine, chlorine, bromine or iodine.Preferred halogen group is fluorine, chlorine or bromine, more preferably fluorine or chlorine.
Term used herein " nitro " refers to group-NO 2.
Term used herein " cyano group " refers to group-CN.
Term used herein " haloalkyl " means by halogen list defined herein or polysubstituted alkyl as herein defined.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, wherein R 2for alkyl as herein defined.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 alkoxyl group as herein defined.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, wherein R 3for hydrogen or alkyl or aryl as herein defined.The representative instance of " acyl group " includes but not limited to formyl radical, ethanoyl, benzoyl etc.
Term used herein " acyl amino " means group-NR 4c (O) R 5, wherein R 4and R 5be selected from hydrogen or alkyl or aryl as herein defined 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, in general formula I A or IB compound R be optionally by 1-3 independently selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6the aryl of the group replacement of alkoxyl group, cyano group and acyl amino, preferred phenyl.
According to the present invention one preferred embodiment, in general formula I A or IB compound, R is aryl, preferred phenyl, and double bond is E.
According to the present invention one preferred embodiment, in general formula I A or IB compound, R is by 1-3 C 1-6the aryl that alkyl replaces, preferred phenyl.More preferably, R is by 1 C 1-6the phenyl that alkyl replaces.
According to the present invention one preferred embodiment, in general formula I A or IB compound, R is by 1-3 halo C 1-6the aryl that alkyl replaces, preferred phenyl, and the position of double bond is in the β position of carboxyl.More preferably, R is that the phenyl and the position of double bond that are replaced by 1 trifluoromethyl are in the β position of carboxyl.
According to the present invention one preferred embodiment, in general formula I A or IB compound, R is the aryl replaced by 1-3 cyano group, preferred phenyl, and the position of double bond is in the β position of carboxyl.More preferably, R is that the phenyl and the position of double bond that are replaced by 1 cyano group are in the β position of carboxyl.
According to the present invention one preferred embodiment, in general formula I A or IB compound, R is the aryl replaced by 1-3 acyl amino, preferred phenyl, and the position of double bond is in the β position of carboxyl.More preferably, R is that the phenyl and the position of double bond that are replaced by 1 kharophen are in the β position of carboxyl.
General formula I A of the present invention or IB compound are by reaction scheme preparation below:
Wherein R as above to general formula I A of the present invention or IB compound define, PG is carboxyl-protecting group, is selected from benzyl, to nitrobenzyl, diphenyl-methyl, methyl, ethyl and the tertiary butyl, preferred diphenyl-methyl.
In superincumbent reaction scheme, the sophocarpine of general formula 1 (its source can see CN1303673A and CN101416964A) open loop under alkaline condition such as sodium hydroxide or potassium hydroxide aqueous solution exist first is made to obtain the mixture of general formula 2a compound and general formula 2b compound.Then can carry out protecting (see Greene with the carboxyl of method mutual-through type 2a compound as known in the art and general formula 2b compound; T.W.; Wuts; P.G, " Protective Groups in OrganicSynthesis ", the 3rd edition; John Wiley & Sons; New York:1999), such as use diphenyl diazomethane protection carboxyl, obtain the kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b.Kuh-seng olefin(e) acid and the sulfonylation agent such as RSO of the protection of general formula 3a and general formula 3b is made under existing at alkaline condition such as salt of wormwood 2cl (wherein R as mutual-through type IA above or IB compound define) reaction, the kuh-seng olefin(e) acid that the N-obtaining general formula 4a and general formula 4b replaces.The kuh-seng olefin(e) acid deprotection that then can replace with the N-of method mutual-through type 4a as known in the art and general formula 4b, such as, use meta-cresol, obtain the compound of general formula 5a and general formula 5b, and it is the mixture of α kuh-seng olefin(e) acid and β kuh-seng olefin(e) acid.Finally adopt such as methylene dichloride and methyl alcohol to be that moving phase mutual-through type 5a is separated with the compound of general formula 5b with method as known in the art such as flash column chromatography, obtain general formula I A of the present invention or IB compound.
Concrete general formula I A of the present invention or IB compound can adopt following exemplary reaction scheme to synthesize:
In above reaction scheme, the reaction conditions of each step is as shown in following a to e:
A:KOH/H 2o, backflow, ~ 8h;
B: diphenyl diazomethane, room temperature, ~ 12h;
C: benzene sulfonyl chloride, K 2cO 3, room temperature, 3-8h;
D: meta-cresol, 70-90 DEG C, ~ 8h;
E: rapid column chromatography, decompression silicagel column, moving phase is methylene dichloride: methyl alcohol 100:5.
Some examples of the compounds of this invention synthesized by the inventive method are listed in following table:
The compounds of this invention both can itself also can the form of its pharmacologically acceptable salt or solvate use.The pharmacologically acceptable salt of general formula I A or IB compound comprises and pharmaceutically acceptable mineral acid or organic acid, or the salt formed 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, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters 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. are formed.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, the salt that N-METHYL-ALPHA-L-GLUCOSAMINE and PROCAINE HCL, PHARMA GRADE etc. are formed.When relating to the compounds of this invention herein, comprise general formula I A or IB compound and pharmacologically acceptable salt thereof or solvate.
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 is by administrations such as such as oral or non-bowel.Pharmaceutical composition of the present invention can be prepared into various formulation by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension, granule or injection etc., through administrations such as such as oral or non-bowel.
It may be noted that the compounds of this invention using dosage and using method depend on factors in addition, comprise the age of patient, body weight, sex, natural health situation, nutritional status, the activity intensity of compound, Time of Administration, metabolic rate, the severity of illness and the subjective judgement of diagnosis and treatment doctor.Preferred using dosage is between 0.01-100mg/kg body weight/day.
Accompanying drawing explanation
Fig. 1: Fig. 1 is the X-ray single crystal diffraction figure of compound S C-87A.
Embodiment
N-replaces the synthesis 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 potassium hydroxide (KOH) 33.6g (0.6mol), reflux 9h, then room temperature reaction spends the night.By reaction solution under ice-water bath cooling, adjust pH 6-7 with 3N hydrochloric acid, be evaporated to dry.The solid of gained is added methyl alcohol fully dissolve, filter, filter cake methanol wash column, filtrate merges, and obtains the methanol solution of SC-1, is directly used in the next step:
The preparation of step 2. diphenyl diazomethane:
Get Benzophenonehydrazones 9.8g (0.05mol), add sherwood oil (30-60 DEG C) 120mL, add electrolytic manganese dioxide 13.05g (0.15mol) and to reflux 1h, suction filtration, filter cake petroleum ether, merging filtrate, is directly used in the next step.
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, stirring at room temperature, until purple is decorporated completely, about 12 hours, be concentrated into dry, add methylene dichloride and water stratification, dichloromethane layer anhydrous Na 2sO 4drying, obtains the dichloromethane solution of the phenylbenzene methyl esters of α and β kuh-seng olefin(e) acid, is directly used in the reaction that follow-up N-replaces the synthesis of α and β kuh-seng olefin(e) acid.
Step 4.N-replaces the preparation of the phenylbenzene methyl esters of α and β kuh-seng olefin(e) acid:
Get the half of the dichloromethane solution of the 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), drips SULPHURYL CHLORIDE 12.5mmol, stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, and obtaining solid is the phenylbenzene methyl esters that N-replaces 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, 80-90 DEG C of reaction about 8 hours, add methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, and obtaining solid is that N-replaces α and β kuh-seng olefin(e) acid mixture.
Step 6.N-replacement α kuh-seng olefin(e) acid is separated with β kuh-seng olefin(e) acid:
The N-of step 5 gained is replaced α and β kuh-seng olefin(e) acid mixture, with methylene dichloride and methyl alcohol (100: 5) for moving phase, carry out the separation of silica gel rapid column chromatography, obtain pure α kuh-seng olefin(e) acid and β kuh-seng olefin(e) acid respectively.
Embodiment
The following examples are used for further illustrating the present invention, but it does not mean that the present invention is only limitted to this.
The synthesis of embodiment 1.N-benzene sulfonyl kuh-seng olefin(e) acid (SC-16A) and (SC-16B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips benzene sulfonyl chloride 1.60mL (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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)。
The synthesis of embodiment 2.N-tolysulfonyl kuh-seng olefin(e) acid (SC-18A) and (SC-18B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips Tosyl chloride 2.38g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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)。
The synthesis of embodiment 3.N-methylsulfonyl kuh-seng olefin(e) acid (SC-25B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips Methanesulfonyl chloride 0.97mL (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, obtain faint yellow solid, soak with methyl alcohol, suction filtration obtains 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)。
The synthesis of embodiment 4.N-p-nitrophenyl sulphonyl kuh-seng olefin(e) acid (SC-81A):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips 4-Nitrobenzenesulfonyl chloride 2.77g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 4.0g white solid, adds meta-cresol 15mL, 80-90 DEG C of reaction 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, obtains faint yellow solid 2.0g, add methylene dichloride, suction filtration, obtain 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 the synthesis of anisole sulphonyl kuh-seng olefin(e) acid (SC-82A) and (SC-82B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips Methoxybenzenesulfonyl chloride 2.77g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 4.0g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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)。
The synthesis of embodiment 6.N-dimethylamino sulphonyl kuh-seng olefin(e) acid (SC-83A) and (SC-83B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips dimethylaminosulfonyl chloride 1.34mL (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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 to the synthesis of trifluoromethyl benzene sulfonyl kuh-seng olefin(e) acid (SC-84A):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips trifluoromethyl benzene sulfonyl chloride 3.05g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.3g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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 the synthesis of fluorobenzene sulphonyl kuh-seng olefin(e) acid (SC-85A) and (SC-85B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips fluorophenylsulfonyl chloride 2.43g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 4.2g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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 the synthesis of chlorobenzenesulfonyl kuh-seng olefin(e) acid (SC-86A) and (SC-86B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips parachloroben-zenesulfonyl chloride 2.64g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 4.2g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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 the synthesis of cyano group benzene sulfonyl kuh-seng olefin(e) acid (SC-87A) and (SC-87B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips cyanobenzenesulfonyl chloride 2.52g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.0g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, obtains white solid 1.5g.Crude product methylene dichloride and recrystallizing methanol, obtain SC-87a 0.6g, mother liquor concentrations, and purifying obtains compound S C-87B 0.5g.
SC-87A:X-ray single crystal diffraction figure is shown in Fig. 1; Single crystal data sees the following form A-F:
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)。
The synthesis of embodiment 11.N-2-chlorobenzenesulfonyl kuh-seng olefin(e) acid (SC-88A) and (SC-88B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips 2-chlorobenzene sulfonyl chloride 2.64g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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)。
The synthesis of cyano group benzene sulfonyl kuh-seng olefin(e) acid (SC-89A) and (SC-89B) between embodiment 12.N-:
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), cyanobenzenesulfonyl chloride 2.52g (12.5mmol) between dropping, stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.8g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, obtain white solid, rapid column chromatography, obtain 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)。
The synthesis of embodiment 13.N-acetparaminosalol benzene sulfonyl kuh-seng olefin(e) acid (SC-90A) and (SC-90B):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips p-acetaminobenzenesulfonyl chloride 2.92g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 4.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, obtain white solid, rapid column chromatography, obtain 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)。
The synthesis of embodiment 14.N-3-chlorobenzenesulfonyl kuh-seng olefin(e) acid (SC-91A):
K is added in the half of the dichloromethane solution of the kuh-seng olefin(e) acid phenylbenzene methyl esters of step 3 gained 2cO 33.45g (0.025mol), drips 3-chlorobenzene sulfonyl chloride 2.64g (12.5mmol), stirring at room temperature, until TLC detects, raw material point disappears, filtering inorganic salt, concentrated, rapid column chromatography, obtains 3.5g white solid, add meta-cresol 15mL, 80-90 DEG C is reacted 8 hours, adds methyl butyl ketone 50mL, with water extraction 3 times, water layer merges, concentrated, 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-Coxsackie B virus 3 type (COX-B3) screening active ingredients
Test philosophy: with Vero (African green monkey kidney) cell for virus host, measures general formula I A of the present invention or IB compound suppresses Coxsackie virus type B3 to cause 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 present invention 1-14 or IB compound before use DMSO are made into 100mg/ml mother liquor, 3 times of dilutions are remake 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), is produced by Hubei Ke Yi pharmaceutical factory.
4. testing method: Vero cell kind 96 well culture plate, 24 hours postoperative infection Coxsackie virus type B3s 10 -5adsorb 2 hours, abandon virus liquid, sample and positive control drug is added by above extent of dilution, establish cell control well and virus control wells simultaneously, each group of cytopathy degree (CPE) is observed, with Reed-Muench method difference calculation sample to the half-inhibition concentration (IC of Coxsackie virus type B3 when virus control group lesion degree (CPE) reaches 4+ 50), calculate SI value.
Following table 1 is some general formula Is A or IB compound resisting coxsackie virus B3 type (COX-B3) the screening active ingredients result of embodiment of the present 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 selectivity index (SI) of general formula I A of the present invention or IB compound anti-Coxsackie B virus 3 activity is apparently higher than contrast medicine ribavirin, particularly the SI value of compound S C-84A, SC-89B and SC-90A is 6.37,9.18 and 8.22 times of contrast medicine respectively.It is active that general formula I A of the present invention or IB compound have significant anti-Coxsackie B virus.
Test example 2
Interior animal experiment:
Virus: change of coxsackie b virus B3 type Nancy strain, goes down to posterity at weanling mice abdominal injection, strengthens virulence, after stable for virulence, receive and preserves.Adaptation of virus during experiment.
The male weanling mice of animal: Balb/C.
Positive control drug: Poly IC.
Virus virulence measures: mouse peritoneal injects 10 times of virus dilution, observes 2 weeks, calculates LD 50.
Drug toxicity measures: the general formula I A of Mouse oral or injection embodiment of the present invention 1-14 or IB compound, measure LD 0, LD 50.
The Coxsackie virus infection mice against viral test of pesticide effectiveness: weanling mice is through abdominal cavity infection 10-100LD 50virus, after infecting, different time gavage or abdominal cavity give general formula I A or the IB compound of embodiment of the present invention 1-14 to be measured, observation index:
Mortality ratio and on average living day: record death toll and dead day, calculate dead % and on average live day.Compare calculating Death prevention rate with virus control group, extending life rate, judges drug effect.
Serum viral load: after mouse infection administration, different time gets blood, separation of serum, Vero cell measures virus titer, calculates TCID 50.Comparing with virus control group, reducing a more than logarithm for there being suppression.
Serum lactic dehydrogenase (SLDH) (LDH) measures: after mouse infection administration, different time gets blood, measures LDH unit, compares with virus control group, takes statistics and learns process, judge 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 for virus host, measures general formula I A of the present invention or IB compound suppresses coxsackie virus A 16-type to cause 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 present invention 1-14 or IB compound before use DMSO are made into 100mg/ml mother liquor, 3 times of dilutions are remake 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), is produced by Hubei Ke Yi pharmaceutical factory.
4. testing method: Vero cell kind 96 well culture plate, 24 hours postoperative infection Coxsackie virus type B3s 10 -5adsorb 2 hours, abandon virus liquid, sample and positive control drug is added by above extent of dilution, establish cell control well and virus control wells simultaneously, each group of cytopathy degree (CPE) is observed, with Reed-Muench method difference calculation sample to the half-inhibition concentration (IC of coxsackie virus A 16-type when virus control group lesion degree (CPE) reaches 4+ 50), calculate SI value.
Following table 2 is some general formula Is A or IB compound resisting coxsackie virus A16 type (COX-A16) screening active ingredients result (the wherein TC of embodiment of the present invention 1-14 50be median lethal concentration, unit is μM; 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-Coxsackie B virus 6 type (COX-B6) screening active ingredients
Test philosophy: with Vero (African green monkey kidney) cell for virus host, measures general formula I A of the present invention or IB compound suppresses Coxsackie B virus 6 type to cause 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 present invention 1-14 or IB compound before use DMSO are made into 100mg/ml mother liquor, 3 times of dilutions are remake 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), is produced by Hubei Ke Yi pharmaceutical factory.
4. testing method: Vero cell kind 96 well culture plate, 24 hours postoperative infection Coxsackie B virus 6 types 10 -5adsorb 2 hours, abandon virus liquid, sample and positive control drug is added by above extent of dilution, establish cell control well and virus control wells simultaneously, each group of cytopathy degree (CPE) is observed, with Reed-Muench method difference calculation sample to the half-inhibition concentration (IC of Coxsackie B virus 6 type when virus control group lesion degree (CPE) reaches 4+ 50), calculate SI value.
Following table 3 is some general formula Is A or IB compound resisting coxsackie virus B6 type (COX-B6) the screening active ingredients result of embodiment of the present 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 (33)

1. the compound or pharmaceutically acceptable salt thereof of general formula I A:
Wherein,
R is C 1-6alkyl, amino or aryl, wherein said amino is optionally by C 1-6alkyl list or two replaces, and described aryl is optionally replaced by 1 group independently selected from lower group: halogen, cyano group, C 1-6alkyl, C 1-6alkoxyl group and C 1-6alkyl C (O) is amino; With
Position of double bond in general formula I A in the α position of carboxyl,
When wherein R is aryl, double bond is E,
Wherein said aryl is phenyl or naphthyl.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R be optionally by 1 independently selected from C 1-6alkyl, C 1-6alkoxyl group, cyano group and C 1-6the aryl of the group replacement that alkyl C (O) is amino.
3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R be optionally by 1 independently selected from C 1-6alkyl, C 1-6alkoxyl group, cyano group and C 1-6the phenyl of the group replacement that alkyl C (O) is amino.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is phenyl.
5. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is by 1 C 1-6the aryl that alkyl replaces.
6. the compound or pharmaceutically acceptable salt thereof of claim 5, wherein R is by 1 C 1-6the phenyl that alkyl replaces.
7. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
(E)-N-benzenesulfonyl α 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-is to MethOxybenzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-(N, N-dimethylamino-sulfonyl) α kuh-seng olefin(e) acid;
(E)-N-is to fluorophenylsulphonyl α kuh-seng olefin(e) acid;
(E)-N-is to chlorobenzenesulfonyl α kuh-seng olefin(e) acid;
(E)-N-is to cyanophenylsulfonyl α kuh-seng olefin(e) acid;
(E) cyanophenylsulfonyl α kuh-seng olefin(e) acid between-N-;
(E)-N-adjacent chlorobenzenesulfonyl α kuh-seng olefin(e) acid;
(E) chlorobenzenesulfonyl α kuh-seng olefin(e) acid between-N-; With
(E)-N-acetparaminosalol benzenesulfonyl α kuh-seng olefin(e) acid.
8. pharmaceutical composition, described pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of any one of at least one claim 1-7 and one or more pharmaceutically acceptable carrier or vehicle.
9. the preparation method of the compound of the general formula I A of claim 1, the method comprises the following steps:
A) the sophocarpine open loop of formula 1 is made,
Obtain the mixture of general formula 2a compound and general formula 2b compound;
B) carboxyl of mutual-through type 2a compound and general formula 2b compound is protected, and obtains α and the β kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b,
Wherein PG is carboxyl-protecting group;
C) α and the β kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b and sulfonylation agent is made to react, α and the β kuh-seng olefin(e) acid that the N-obtaining general formula 4a and general formula 4b replaces;
D) α and the β kuh-seng olefin(e) acid deprotection of the N-replacement of mutual-through type 4a and general formula 4b, obtains the compound of general formula 5a and general formula 5b;
E) mutual-through type 5a is separated with the compound of general formula 5b, obtains the compound of general formula I A,
Wherein R as described in the appended claim 1.
10. the compound or pharmaceutically acceptable salt thereof of any one of claim 1-7 treats the purposes in the medicine of the disease that CBV causes in preparation.
The purposes of 11. claims 10, wherein said disease is myocarditis.
The purposes of 12. claims 11, wherein said myocarditis is viral myocarditis.
The compound or pharmaceutically acceptable salt thereof of 13. general formula I B:
Wherein,
R is amino or aryl, and wherein said amino is optionally by C 1-6alkyl list or two replaces, and described aryl is optionally replaced by 1 group independently selected from lower group: halogen, nitro, cyano group, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group and C 1-6alkyl C (O) is amino; With
Position of double bond in general formula I B in the β position of carboxyl,
Wherein said aryl is phenyl or naphthyl.
The compound or pharmaceutically acceptable salt thereof of 14. claims 13, wherein R be optionally by 1 independently selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, cyano group and C 1-6the aryl of the group replacement that alkyl C (O) is amino.
The compound or pharmaceutically acceptable salt thereof of 15. claims 14, wherein R be optionally by 1 independently selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, cyano group and C 1-6the phenyl of the group replacement that alkyl C (O) is amino.
The compound or pharmaceutically acceptable salt thereof of 16. claims 13, wherein R is aryl, and double bond is E.
The compound or pharmaceutically acceptable salt thereof of 17. claims 16, wherein R is phenyl.
The compound or pharmaceutically acceptable salt thereof of 18. claims 13, wherein R is by 1 C 1-6the aryl that alkyl replaces.
The compound or pharmaceutically acceptable salt thereof of 19. claims 18, wherein R is by 1 C 1-6the phenyl that alkyl replaces.
The compound or pharmaceutically acceptable salt thereof of 20. claims 13, wherein R is by 1 halo C 1-6the aryl that alkyl replaces, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 21. claims 20, wherein R is by 1 halo C 1-6the phenyl that alkyl replaces, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 22. claims 20, wherein R is the phenyl replaced by 1 trifluoromethyl, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 23. claims 13, wherein R is the aryl replaced by 1 cyano group, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 24. claims 23, wherein R is the phenyl replaced by 1 cyano group, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 25. claims 13, wherein R is by 1 C 1-6the aryl that alkyl C (O) amino replaces, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 26. claims 25, wherein R is by 1 C 1-6the phenyl that alkyl C (O) amino replaces, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 27. claims 26, wherein R is the phenyl replaced by 1 kharophen, and position of double bond is in the β position of carboxyl.
The compound or pharmaceutically acceptable salt thereof of 28. claims 13, described compound is selected from:
(E)-N-benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-p-toluenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-p-nitrophenyl alkylsulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to MethOxybenzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-(N, N-dimethylamino-sulfonyl) β kuh-seng olefin(e) acid;
(E)-N-is to tnBuoromethyl-benzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to fluorophenylsulphonyl β kuh-seng olefin(e) acid;
(E)-N-is to chlorobenzenesulfonyl β kuh-seng olefin(e) acid;
(E)-N-is to cyanophenylsulfonyl β kuh-seng olefin(e) acid;
(E) cyanophenylsulfonyl β kuh-seng olefin(e) acid between-N-;
(E)-N-adjacent chlorobenzenesulfonyl β kuh-seng olefin(e) acid; With
(E)-N-acetparaminosalol benzenesulfonyl β kuh-seng olefin(e) acid.
29. pharmaceutical compositions, described pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of any one of at least one claim 13-28 and one or more pharmaceutically acceptable carrier or vehicle.
The preparation method of the compound of the general formula I B of 30. claims 13, the method comprises the following steps:
A) the sophocarpine open loop of formula 1 is made,
Obtain the mixture of general formula 2a compound and general formula 2b compound;
B) carboxyl of mutual-through type 2a compound and general formula 2b compound is protected, and obtains α and the β kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b,
Wherein PG is carboxyl-protecting group;
C) α and the β kuh-seng olefin(e) acid of the protection of general formula 3a and general formula 3b and sulfonylation agent is made to react, α and the β kuh-seng olefin(e) acid that the N-obtaining general formula 4a and general formula 4b replaces;
D) α and the β kuh-seng olefin(e) acid deprotection of the N-replacement of mutual-through type 4a and general formula 4b, obtains the compound of general formula 5a and general formula 5b;
E) mutual-through type 5a is separated with the compound of general formula 5b, obtains the compound of general formula I B,
Wherein R as claimed in claim 13.
The compound or pharmaceutically acceptable salt thereof of 31. any one of claim 13-28 treats the purposes in the medicine of the disease that CBV causes in preparation.
The purposes of 32. claims 31, wherein said disease is myocarditis.
The purposes of 33. claims 32, wherein said myocarditis is viral myocarditis.
CN201210123512.8A 2011-04-25 2012-04-25 N-substituted sophora flavescens olefine acid derivative as well as preparation method and application thereof Expired - Fee Related CN102659783B (en)

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