CN102206172B - Substituted diaryl compound and preparation method and antiviral application thereof - Google Patents

Substituted diaryl compound and preparation method and antiviral application thereof Download PDF

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CN102206172B
CN102206172B CN201010275476.8A CN201010275476A CN102206172B CN 102206172 B CN102206172 B CN 102206172B CN 201010275476 A CN201010275476 A CN 201010275476A CN 102206172 B CN102206172 B CN 102206172B
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formyl
amine
anisole
benzene
amino
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CN102206172A (en
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蒋建东
李卓荣
李艳萍
李玉环
彭宗根
郝兰虎
仲兆金
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Institute of Medicinal Biotechnology of CAMS
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Abstract

The invention provides substituted diaryl compounds as shown in general formula (I) or their pharmaceutically acceptable salts, and also provides a preparation method; a class of novel broad-spectrum antiviral compounds and pharmaceutical salts targeting cytokines are screened and obtained through studies on structure-activity relationship and action mechanism of active compounds; the compounds not only have significant broad-spectrum antiviral activity, but also have the advantages of low toxicity and good pharmaceutical properties.

Description

One group replaces bi-aromatic compounds and preparation method thereof and antiviral application
Technical field
The present invention relates to one group and replace bi-aromatic compounds, also relate to the preparation method of described compound, and at broad-spectrum antiviral, the application especially in hepatitis virus resisting, preventing respiratory viruses and enterovirus and AIDS virus resisting.
Background technology
At present, the antiviral applied clinically, its action target spot is viral protein, and mechanism of action is the intrusion of copying of suppression virus or blocking virus.Virus is " target of movement ", relies on constantly variation to escape drug attack.Be that the medicine of target spot all causes virus variation and resistance with viral protein, become global problem.Equally, 6 medicines of the treatment hepatitis B of current clinical application, except Interferon, rabbit, its structure type is nucleoside analog, and action target spot is viral protein DNA polymerase, can produce serious resistance problems, cause Endodontic failure after long-term prescription.Multiple medicines combined utilization (drug cocktail therapy (treatment)) can reduce patient's virus load greatly, slows down resistance and occurs, but finally or unavoidably resistance occurs; New listing kind has some superiority on overriding resistance strain, but along with the prolongation of Clinical practice time, resistance still cannot be avoided.Therefore, tackling viral resistance is the current major subjects that will solve.In addition, the virus disease that some RNA viruses (as Coxsackie virus, influenza virus and EV71 virus etc.) cause still lacks effective clinical treatment medicine, therefore, current urgent need develops some convenient, effective and that side effect is less new drugs, to supplement the treatment use of existing antiviral.
So far still go on the market without new anti-virus medicine after approval Interferon, rabbit in 1998 and ribavirin combination application for the treatment of hepatitis C, and Interferon, rabbit and ribavirin combination application for the treatment of limited efficiency, there is nearly half patient nonreply after combination therapy, a lot of patient can not tolerate the side effect of this conjoint therapy simultaneously, as anaemia, fatigue, dysthymia disorders etc., and there is very high recurrence rate.Therefore, some convenient, effective and that side effect is less new drugs of exploitation are badly in need of at present, to supplement existing treatment plan.
Along with deepening continuously of virusology and RESEARCH ON CELL-BIOLOGY, lot of research shows, in the lengthy procedure of organic evolution, host cell generally forms the defense system for Different Kinds of Pathogens virus, and virus also can form specific Antagonizing, realize the inhibiting escape of host cell.Between virus and host cell, interdependence and mutual the antagonism relationship, particularly virus replication relevant cell factor have become the direction in forward position the most in current Medical Biology basic and applied research in the world and field with the fastest developing speed.
Contriver is in broad-spectrum antiviral medicament screening study, find and confirm to replace bi-aromatic compounds that there is the activity that wide spectrum suppresses virus, especially suppress the effect of hepatitis B and hepatitis c viral replication, suppression Respirovirus and enterovirus and AIDS virus resisting.The action target spot of invention compound may be different from existing antiviral, and the latter's multiaction is in viral enzyme, and compound of the present invention may be then play broad-spectrum disease resistance toxic action based on novel cell mechanism.Compound of the present invention and effect thereof, up to now there are no the report of domestic and international pertinent literature.Development is the Novel antivirus compound of target spot for cytokine, is expected to make a breakthrough, thus provides more effective New-type wide-spectrum antiviral for clinical for solution virus drug resistance problem.
Summary of the invention
Main purpose of the present invention is, by replacing the structure effect research of bi-aromatic compounds to one group, and the study on mechanism of active compound, broad-spectrum disease resistance cytotoxic compound and the pharmaceutical salts thereof of what screening acquisition one class was new with cytokine is target spot, this compounds not only has significant broad anti-viral activity, also there is low toxicity, the advantages such as pharmaceutical properties is good.
In order to achieve the above object, the present invention adopts following technical scheme:
The invention provides one group and replace bi-aromatic compounds or its pharmaceutical salts, there is structure shown in following general formula (I):
Wherein:
X represent-C (O)-,-CH 2c (O)-,-OCH 2c (O)-,-S (O)-,-S (O) 2-,-C (OH) (R 10)-or-CH (R 10)-, Y represents-O-,-S-,-CH (R 11)-,-N (R 12)-or singly-bound; Described R 10, R 11represent hydrogen, alkyl, aralkyl, aryloxyalkyl group or fragrant sulfanyl, R 12represent hydrogen, alkyl, halo alkyl, acyl group, hydroxy alkylene, hydrocarbyl amino, alkylsulfonyl.
Wherein, when X represent-C (O)-,-CH 2c (O)-,-OCH 2c (O)-time, Y represents-O-,-CH (R 11)-,-N (R 12)-or singly-bound; When X represent-S (O)-,-S (O) 2in-time, Y represents-O-or-N (R 12)-; When X represents-C (OH) (R 10)-time, Y represents-CH (R 11)-or singly-bound; When X represents-CH (R 10)-time, Y represents-O-,-S-or-N (R 12)-.
Or, when X represent-C (O)-,-CH 2c (O)-,-OCH 2c (O)-,-S (O) 2-,-C (OH) (R 10)-or-CH (R 10)-, Y represents-N (R 12)-,-O-,-S-,-CH (R 11)-or singly-bound.
In present pre-ferred embodiments, X represents-C (O)-or-S (O) 2-, Y represents-O-or-NH-.
W 1, W 2, W 3, W 4, W 5respectively represent independently carbon atom, nitrogen-atoms, Sauerstoffatom or a sulphur atom, and have at least 4 to exist in any molecule simultaneously, and at least 1 represents carbon atom; When W represents heteroatoms, there is not substituting group in this position;
Described W 1, W 2, W 3, W 4and W 5with R 3, R 4or R 5form substituted or unsubstituted phenyl ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, furan nucleus or pyrrole ring, more preferably phenyl ring, pyrimidine ring, thiazole ring or furan nucleus;
Work as R 1, R 2, R 3, R 4, R 5to can be the same or different when independently existing separately, represent hydrogen, alkyl, halo alkyl, hydroxy alkylene, halogen, nitro, cyano group, acyl group, carboxyl, sulfonic group, phosphate, aryl, heteroaryl, C (O) OR respectively 13, CONR 13r 14, S (O) 2nR 13r 14, SR 13, OR 14or NR 13r 14, described R 13, R 14represent respectively hydrogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl, heteroaryl, alkylsulfonyl, acyl group, or
Wherein, preferably, R 1, R 2, R 3, R 4, R 5represent hydrogen, alkyl, halo alkyl, halogen, nitro, aryl, CONR respectively 13r 14, S (O) 2nR 13r 14, SR 13, OR 14or NR 13r 14, described R 13, R 14represent hydrogen respectively, aryl that aryl that alkyl, aryl, benzsulfamide replace, para toluene sulfonamide replace, acyl group or alkylsulfonyl, hydrogen, alkyl, halo alkyl, halogen, nitro,-oxyl or NR 13r 14, described R 13, R 14represent hydrogen, alkyl or acyl group respectively;
In present pre-ferred embodiments, preferred, described R 1, R 2, R 3, R 4, R 5represent hydrogen, alkyl, nitro, aryl, SR respectively 13, OR 14or NR 13r 14, described R 13, R 14represent hydrogen, alkyl, aryl, acyl group or alkylsulfonyl respectively;
Or, R 3and R 4or R 4and R 5can be interconnected, formation five yuan or hexa-atomic aromatic shape structure M are condensed with parent nucleus, its constitutional features is such as formula shown in (IIa and IIb), allow containing 0-3 heteroatoms in the skeleton of M, and the position allowed on chemical theory may be connected with one or more identical or different substituent R 15, in addition, heteroatoms represents nitrogen, oxygen or sulphur;
Preferred described M and parent nucleus form substituted or unsubstituted benzothiazole, cumarone, indoles, quinoline or naphthyridines etc., described R jointly 15represent halogen, amino, nitro, C1-C6 alkyl, C1-C6 alkoxyl group or sulfonamido;
Z 1, Z 2, Z 3, Z 4, Z 5respectively represent independently carbon atom or a nitrogen-atoms, and have at least 4 to exist in any molecule simultaneously, and at least one represents carbon atom; When Z represents nitrogen-atoms, there is not substituting group in this position;
Described Z 1, Z 2, Z 3, Z 4and Z 5with R 6, R 7, R 8and R 9form substituted or unsubstituted phenyl ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, furan nucleus, pyrrole ring, imidazole ring or triazole ring, more preferably phenyl ring, pyridine ring, pyrimidine ring, thiazole ring or triazole ring; Described R 6, R 7, R 8and R 9to can be the same or different when independently existing separately, represent hydrogen respectively, aryl, heteroaryl, CONR that aryl that alkyl, halo alkyl, hydroxy alkylene, halogen, nitro, amino, hydrocarbylamino, hydroxyl, cyano group,-oxyl, acyl group, amido, ester group, carboxyl, sulfonic group, phosphate, aryl, benzsulfamide replace, para toluene sulfonamide replace 16r 17, S (O) 2nR 16r 17, SR 16, OR 17or NR 16r 17deng;
Described R 16, R 17represent hydrogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl, heteroaryl, alkylsulfonyl, acyl group respectively, in addition, R 16with R 17also aza-cyclic structure can be connected into;
In addition, R 6and R 7, R 7and R 8or R 8and R 9all may be interconnected to form thick with parent nucleus and the fragrance five yuan of structure as shown in IIIa, IIIb and IIIc or six-membered cyclic structure N, allow containing 0-3 heteroatoms in the skeleton of N, and the position allowed on chemical theory may be connected with one or more identical or different substituent R 15, in addition, heteroatoms represents nitrogen, oxygen or sulphur
Preferred N and parent nucleus form substituted or unsubstituted benzothiazole, cumarone, indoles, purine, quinoline or naphthyridines etc. jointly, described R 15represent hydrogen, alkyl,-oxyl, halogen, oxo, acyl group, amido, sulfonamido replace;
Wherein, preferred described Z 1, Z 2, Z 3, Z 4and Z 5with R 6, R 7, R 8and R 9form substituted or unsubstituted phenyl ring, pyrimidine ring or pyridine ring, described R 6, R 7, R 8and R 9represent hydrogen, alkyl, aryl, the aryl of benzsulfamide replacement, aryl, halo alkyl, halogen, the CONR of para toluene sulfonamide replacement respectively 16r 17, S (O) 2nR 16r 17, SR 16, OR 17or NR 16r 17, described R 16, R 17represent hydrogen, alkyl, aryl or alkylsulfonyl respectively.
More than described in definition:
" alkyl " can refer to the alkyl or cycloalkyl of carbonatoms at the straight or branched of 1-8, such as, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl etc. or its corresponding cycloalkyl.Be more preferably the low alkyl group of C1-C6.
" aryl " refers to aromatic moiety and can be substituted or not be substituted; aromatic hydrocarbons is selected from phenyl, naphthyl, xenyl, tetralyl, phenanthryl, fluorenyl, acenaphthenyl or phenanthrylene etc., and described replacement refers to halogen, alkyl, hydroxyl, nitro, amino, acyl group,-oxyl, the CONH of unit or multidigit 2, CONH (alkyl), CON (alkyl) 2, trifluoromethyl, trifluoromethoxy, sulfonic group, SO 2nH 2, SO 2nH (alkyl), SO 2n (alkyl) 2, SO 2n (cyclic hydrocarbon radical), ester group, itrile group, oxygen aryl, sulphur aryl or alkylaryl etc.; Preferred aryl substituent comprises: alkyl, halogen, nitro, amino, CONH 2,-oxyl, trifluoromethyl, SO 2nH (alkyl), itrile group, oxygen aryl, sulphur aryl or alkylaryl;
" heteroaryl " can refer to substituted or unsubstituted aromatic heterocyclic ring systems (monocycle or dicyclo), wherein fragrant heterocyclic moiety is for being selected from N, O or S heteroatomic five yuan or six-ring containing 1-4, and include but not limited to: as furans, thiophene, indoles, oxazole, thiazole, imidazoles, pyridine, pyrimidine, pyrazine, pyrroles, pyrazoles, 1,2, mono-cyclic aromatic systems such as 4-triazole or condense the Bicyclic system formed, as thionaphthene, cumarone, benzoglyoxaline and quinazoline etc. by benzene, pyridine, pyrimidine or pyridazine and other five yuan or hexa-member heterocycle; Described replacement refers to halogen, alkyl, hydroxyl, nitro, amino, acyl group,-oxyl, the CONH of unit or multidigit 2, CONH (alkyl), CON (alkyl) 2, trifluoromethyl, trifluoromethoxy, sulfonic group, SO 2nH 2, SO 2nH (alkyl), SO 2n (alkyl) 2, SO 2n (cyclic hydrocarbon radical), ester group, itrile group, oxygen aryl, sulphur aryl or alkylaryl etc.; Preferred aryl substituent comprises: alkyl, halogen, nitro, amino, CONH 2,-oxyl, trifluoromethyl, SO 2nH (alkyl), itrile group, oxygen aryl, sulphur aryl or alkylaryl;
"-oxyl " can be the alkoxyl group of carbonatoms at 1-8, such as, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc.Be more preferably the lower alkoxy of C1-C6.
" acyl group " can be have the hydrocarbon substituted acyl of 1-8 carbon or aryl-acyl or heteroaroyl; such as formyl radical, ethanoyl, sec.-propyl acyl group, n-propyl acyl group, allyl group acyl group, cyclopropyl acyl, normal-butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group, n-pentyl acyl group, isopentyl acyl group, n-hexyl acyl group, isohexyl acyl group, phenylacyl, tolyl acyl group, 2-pyridine acyl etc., can also be halo alkyl substituted acyl.Be more preferably low alkyl group substituted acyl or the halo alkyl substituted acyl of C1-C6.
" ester group " can be hydrocarbon ester appended (alkylacyloxy) or the aryl ester group with 1-8 carbon, such as methanoyl, acetoxyl group, sec.-propyl acyloxy, n-propyl acyloxy, allyl group acyloxy, cyclopropyl acyloxy, normal-butyl acyloxy, isobutyl-acyloxy, sec-butyl acyloxy, tertiary butyl acyloxy, n-pentyl acyloxy, isopentyl acyloxy, n-hexyl acyloxy, isohexyl acyloxy, phenyl acyloxy, tolyl acyloxy etc.Be more preferably the low alkyl group ester appended (alkylacyloxy) of C1-C6.
" amido " can be that the hydrocarbon with 1-8 carbon replaces amido or acrylamido, such as methylamido, ethylamido, sec.-propyl amido, n-propyl amido, allyl group amido, cyclopropyl amido, normal-butyl amido, isobutyl-amido, sec-butyl amido, t-butylamido, n-pentyl amido, isopentyl amido, n-hexyl amido, isohexyl amido, phenyl amido, tolyl amido etc.The low alkyl group being more preferably C1-C6 replaces amido.
" halo " or " halogen " can be fluorine, chlorine, bromine or iodine.
" alkylsulfonyl " can be hydrocarbon substituted sulphonyl or the aryl sulfonyl with 1-8 carbon, such as methyl sulphonyl, ethylsulfonyl, isopropelsulfonyl, n-propyl alkylsulfonyl, allyl group alkylsulfonyl, Cyclopropylsulfonyl, normal-butyl alkylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert. butylsulfonyl, n-pentyl alkylsulfonyl, isopentyl alkylsulfonyl, n-hexyl alkylsulfonyl, isohexyl alkylsulfonyl, phenyl sulfonyl, tolylsulfonyl-base etc.In better embodiment of the present invention, be preferably substituted phenyl sulfonyl base, described replacement is the alkyl of unit or multidigit, amino, nitro, halogen, hydroxyl replaced.
In the substituting group of replacement bi-aromatic compounds of the present invention or its pharmaceutical salts structural formula, the alkyl in described halo alkyl, carbonyl alkyl, hydroxy alkylene, hydrocarbyl amino is the alkyl of C1-C6.
Pharmaceutical salts of the present invention also comprises itself and the sour product that salt-forming reaction occurs according to the replacement bi-aromatic compounds of above-mentioned definition general formula (I), and namely its pharmacy acceptable salt, comprises inorganic acid salt, example hydrochloric acid salt, hydrobromate or vitriol etc.; Organic acid salt, as acetate, lactic acid salt, succinate, fumarate, maleate, Citrate trianion, benzoate, mesylate or paratolunitrile salt etc.
The preferred representative compound of the present invention comprises following compound, wherein:
(A) there is structure shown in following general formula (IV):
Wherein: X represent-C (O)-,-S (O) 2-,-S (O)-,-CH (OH)-or-CH 2-, Y represents-O-,-CH 2-,-N (R 12)-; Described R 12represent hydrogen, the phenyl sulfonyl of replacement or the phenylacyl of replacement, described replacement is the C1-C6 alkyl of unit or multidigit, C1-C6 alkoxyl group, amino, nitro, C1-C6 alkyl amido replaced;
R 2for amino, nitro, C1-C6 alkyl acyloxy or NR 13r 14, described R 13, R 14represent respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halo C1-C6 alkyl acyl,
R 3for hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group ,-S (O) 2nH 2or phenyl-S-;
R 6, R 7, R 8and R 9to can be the same or different when independently existing separately, represent hydrogen respectively, aryl, halo C1-C6 alkyl or methylthio group that aryl that halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxyl group, benzsulfamide replace, para toluene sulfonamide replace, or R 7with R 8common composition-O-CH 2-CH 2-O-.
The preferred compound of the present invention comprises those compounds of (A), wherein:
(B) X represent-C (O)-,-S (O) 2-,-S (O)-, Y represents-O-or-NH-;
R 2for amino, nitro or NR 13r 14, described R 13, R 14represent hydrogen, C1-C6 alkyl acyl, trifluoroacetyl group respectively;
R 3for hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;
R 6, R 7, R 8and R 9represent H, halogen or C1-C6 alkoxyl group independently of one another.
The preferred compound of the present invention comprises those compounds of (B), wherein:
(C) X represent-C (O)-,-S (O) 2-, Y represents-O-or-NH-;
R 2for amino, nitro or NR 13r 14, described R 13for R during hydrogen 14for propionyl or trifluoroacetyl group, or R 13and R 14be propionyl;
R 3for methyl or methoxy;
R 6, R 7, R 8and R 9represent H, halogen or methoxyl group independently of one another.
In present pre-ferred embodiments, the part of compounds in general formula (IV) especially has the activity of anti HIV-1 virus, wherein
(D) X representative-C (O)-, Y represents-O-or-NH-;
R 2for amino or NHR 14, described R 14for propionyl or trifluoroacetyl group;
R 3for methoxyl group;
R 6, R 7, R 8and R 9represent H, halogen or methoxyl group independently of one another.
Or the preferred compound of the present invention comprises following compound, wherein
(E) there is structure shown in following logical formula V:
Wherein: X represent-C (O)-,-S (O) 2-,-S (O)-, Y represents-N (R 12)-; Described R 12represent the phenylacyl of hydrogen or replacement, described replacement is the nitro of unit or multidigit, C1-C6 alkoxyl group, C1-C6 alkyl amido replaced;
R 2for amino, nitro or NHR 13, described R 13represent C1-C6 alkyl acyl or halo C1-C6 alkyl acyl;
R 3for hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Q1 is selected from
The preferred compound of the present invention comprises those compounds of (E), wherein:
X represent-C (O)-,-S (O) 2-, Y representative-NH-;
R 2for NO 2;
R 3for C1-C6 alkyl;
Q1 is
Or the preferred compound of the present invention comprises following compound, wherein
(G) there is structure shown in following general formula (VI):
Wherein: X represent-C (O)-,-S (O) 2-or-S (O)-, Y representative-NH-
R 6, R 7, R 8and R 9to can be the same or different when independently existing separately, represent hydrogen respectively, aryl, C1-C6 alkoxyl group that aryl that halogen, benzsulfamide replace, para toluene sulfonamide replace, preferred chlorine or methoxyl group;
Q2 is selected from substituted or unsubstituted pyridyl or thienyl, described replacement by nitro or methylthio group monosubstituted.
Or the preferred compound of the present invention comprises following compound, wherein
(H) there is structure shown in following general formula (VII):
Wherein, X represent-C (O)-,-S (O) 2-or-S (O)-, Y representative-NH-;
Q1 and Q2 is selected from substituted or unsubstituted pyridyl, pyrimidyl, thienyl or benzofuryl respectively, described replacement by halogen or aminoacyl replace.
The present invention also provides the preparation method of described replacement bi-aromatic compounds or its pharmaceutical salts, can determine initiator and reactant according to the structure design of X, Y in object compound, specifically can carry out according to Lung biopsy:
Method one: the X of formula (I) compound be-C (O)-,-CH 2c (O)-or-OCH 2c (O)-, Y is-O-,-N (R 12)-time, adopt following route methods to synthesize: by A and condensing agent (e.g., I-hydroxybenzotriazole, HOBT; N, N '-DIC, DIC etc.) be dissolved in polar aprotic solvent (as: DMF) by suitable proportion mixing, add B after stirring 0.5-5h, react under room temperature, separation and purification obtains product
Wherein, X=-C (O)-,-CH 2c (O)-or-OCH 2c (O)-; Y=-O-or-N (R 12)-; The definition of other substituting group is the same;
Method two: the X of formula (I) compound be-C (O)-,-CH 2c (O)-,-OCH 2c (O)-,-S (O) 2-or-S (O)-time, Y is-O-,-N (R 12)-time, also can adopt and synthesize with the following method: by the suitable halide reagent of A (as, thionyl chloride, phosphorus pentachloride etc.) be converted into acyl chlorides, under the condition making acid binding agent with alkali (e.g., triethylamine), in the polar aprotic solution of B, gained acyl chlorides is slowly added under low temperature, finish, reply room temperature to reacting completely, separation and purification obtains target compound;
Wherein, X=-C (O)-,-CH 2c (O)-,-OCH 2c (O)-,-S (O) 2-or-S (O)-; Y=-O-or-N (R 12)-; The definition of other substituting group is the same;
Method three: the X of formula (I) compound is-C (OH) (R 10)-, Y is-CH (R 11)-or singly-bound time, adopt and synthesize with the following method: the halohydrocarbon containing (mixing) aryl is made Grignard reagent or direct metal organic base (as, butyllithium etc.) catalysis under, react with aryl ketones (aldehyde) and generate 2-diaryl alcohol class target compound;
Method four: the X of formula (I) compound be-C (O)-, Y is-CH (R 11)-or singly-bound time, the synthetic method of employing is: diaryl secondary alcohol class target compound is generated diaryl ketone class target compound through peroxychromic acid oxidation;
Method five: the X of formula (I) compound is-CH (R 10)-, Y is-O-,-N (R 12)-or-S-time, adopt and synthesize with the following method: A is generated halides, in polar aprotic solvent (e.g., methylene dichloride) by halogen (as bromine) generation reaction, target compound is obtained with B condensation under alkalescence (e.g., Anhydrous potassium carbonate) condition;
Wherein, Y=O, N (R 12) or S; G represents chlorine, bromine or iodine; The definition of other substituting group is the same.
The present invention on the other hand additionally provides a kind of anti-viral pharmaceutical compositions, and it comprises the above-mentioned replacement bi-aromatic compounds for the treatment of significant quantity or its pharmaceutical salts is activeconstituents, and containing one or more pharmaceutically acceptable pharmaceutical excipients.Pharmaceutical composition provided by the invention can be the various form of administration prepared according to the conventional production process of pharmaceutical field, such as, make activeconstituents mix with one or more carriers, be then made into required formulation.Such as the mixture of compound itself or itself and pharmaceutically useful vehicle, thinner etc. can be prepared into combination of oral medication with the form of tablet, capsule, granule, powder or syrup with the form oral administration of tablet, capsule, granule, powder or syrup or with the form non-oral administration of injection by the mixture of compound itself or itself and pharmaceutically acceptable vehicle, thinner etc., or be prepared into parenteral pharmaceutical composition with the form of injection.
It is the activeconstituents of 0.1%-99.5% that pharmaceutical composition of the present invention preferably contains weight ratio, and most preferably containing weight ratio is the activeconstituents of 0.5%-99.5%.
Above-mentioned preparation is prepared by conventional pharmaceutical method.The example of available medicinal adjuvant comprises vehicle, and (such as carbohydrate derivative is as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative is as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose is as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative is as Neusilin US2; Phosphate derivative is as calcium phosphate; Carbonate derivative is as calcium carbonate; Sulfate-derivatives is as calcium sulfate etc.); Tackiness agent (such as gelatin, polyvinylpyrrolidone and polyoxyethylene glycol); Disintegrating agent (such as derivatived cellulose is as Xylo-Mucine, polyvinylpyrrolidone); Lubricant (such as talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.); Correctives (such as conventional sweeting agent, acidic flavoring agent and spices etc.); Thinner and injection liquid are with solvent (such as water, ethanol and glycerine etc.).
Present invention also offers described one group and replace bi-aromatic compounds or its pharmaceutical salts and the application of described anti-viral pharmaceutical compositions in broad-spectrum antiviral field, especially the application in treatment hepatitis B and hepatitis c virus infection, comprises the combined utilization of antiviral chemotherapeutics with other.
Present invention also offers the pharmacodynamic experiment research of described compound.Adopt HepG2.2.15 cell cultures, measure the toxicity of compound on intracellular by CPE method, measure compound to the restraining effect of hbv replication by qPCR method; Adopt Huh7.5 cell cultures, by the toxicity of MTT Determination Staining compound on intracellular, measure compound to the restraining effect of HCV infection by qRT-PCR method.Measurement result is in table 2.
The present invention also adopts MT-4P24 antigen method, determines the Anti-HIV-1 Active of invention compound, the results are shown in Table 3.The compounds of this invention is also inhibited to HIV.
Present invention also offers described one group and replace the application in treatment Respirovirus and enterovirus infection of bi-aromatic compounds or its pharmaceutical salts and described anti-viral pharmaceutical compositions, comprise the combined utilization of antiviral chemotherapeutics with other.
Present invention also offers the pharmacodynamic experiment research of described compound.Employing mdck cell is cultivated, and measure the toxicity of compound on intracellular and the restraining effect of compound infected by influenza by CPE method, measurement result is in table 4; Employing Vero cell cultures, measures the toxicity of compound on intracellular by CPE method and compound is viral to EV71 and the restraining effect of Coxsackie virus, and measurement result is in table 4.
Above result of study preliminary identification the compounds of this invention or its pharmaceutical salts are suppressing in hepatitis virus and HIV, are suppressing the effect in Respirovirus and enterovirus.Because its broad-spectrum disease resistance toxic action is based on novel cell mechanism, possibility advantages such as not easily producing resistance after having treatment, have potential combination therapy effect with other antiviral, security is better, for the Application and Development of this product as broad-spectrum antiviral medicament is laid a good foundation.
Embodiment
Following examples can help those skilled in the art to understand the present invention further, but do not limit the present invention in any way.
< embodiment 1>the synthesis of (3-propionamido-4-anisole) formyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (1)
In the flask of 25ml; by 3-amino-4-methoxyl phenylformic acid (1.0g; after 6mmol) being dissolved in dry THF (tetrahydrofuran (THF)); add triethylamine (1.2ml, 12mmol) and obtain yellow transparent solution, nitrogen protection; stir; drip propionyl chloride (0.78ml, 9mmol) wherein under ice-water bath condition, dropwise rear clear-cutting forestland room temperature reaction.Filtering reacting liquid, after filtrate evaporate to dryness, upper silicagel column is separated and obtains 3-propionamido-4-methoxybenzoic acid 1.3g (yield 67%).
By above-mentioned product 100mg (0.45mmol) under ice-water bath condition with HOBT 136mg (0.6mmol), DIC0.1ml (0.8mmol) is blended in dry DMF, N 2protection, add 3,4,5-trimethoxy-aniline 72mg (mmol) after stirring 30min, clear-cutting forestland is to stirred overnight at room temperature.Evaporated under reduced pressure reaction solution, filters after residue with ethyl acetate dissolves, and adopts silicagel column to be separated and obtain compound 1 120mg (yield 68%) after filtrate evaporate to dryness, 1h NMR data are in table 1.
< embodiment 2>the synthesis of (3-propionamido-4-anisole) formyl (4 '-chlorinated benzene) amine (2)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and p-Chlorobenzoic acid amide for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 2, yield 23%, 1h NMR data are in table 1.
< embodiment 3>the synthesis of (3-trifluoroacetamido-4-anisole) formyl (4 '-chlorinated benzene) amine (4)
With 3-amino-4-methoxyl phenylformic acid, trifluoroacetic anhydride and p-Chlorobenzoic acid amide for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 4, yield 26%, 1h NMR data are in table 1.
< embodiment 4>the synthesis of (3-amino-4-methoxyl benzene) formyl (3 ', 4 ', 5 '-trimethoxy benzene) amine (5)
With 3-amino-4-methoxyl phenylformic acid, (BOC) 2o and 3,4,5-trimethoxy-aniline are starting raw material, and according to embodiment 1 similar approach, synthesis obtains compound 5, yield 18%, 1h NMR data are in table 1.
< embodiment 5>the synthesis of (3-propionamido-4-anisole) formylaniline (6)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 6, yield 34%, 1h NMR data are in table 1.
< embodiment 6>the synthesis of (3-propionamido-4-first hydrogen base benzene) formyl-(4 '-methylbenzene) amine (7)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and open-chain crown ether for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 7, yield 32%, 1h NMR data are in table 1.
< embodiment 7>the synthesis of (3-propionamido-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine (8)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and p-trifluoromethylaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 8, yield 38%, 1h NMR data are in table 1.
< embodiment 8>the synthesis of (3-propionamido-4-anisole) formyl-(2 '-chlorinated benzene) amine (9)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 2-chloroaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 9, yield 32%, 1h NMR data are in table 1.
< embodiment 9>the synthesis of (3-propionamido-4-anisole) formyl (4 '-fluorobenzene) amine (10)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and para-fluoroaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 10, yield 35%, 1h NMR data are in table 1.
< embodiment 10>the synthesis of (3-propionamido-4-anisole) formyl (4 '-bromobenzene) amine (11)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and para-bromoaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 11, yield 16%, 1h NMR data are in table 1.
< embodiment 11>the synthesis of (3-propionamido-4-anisole) formyl-(3 '-chlorinated benzene) amine (12)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 3-chloroaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 12, yield 31%, 1h NMR data are in table 1.
< embodiment 12>the synthesis of (3-propionamido-4-anisole) formyl-(2 ', 4 '-dichlorobenzene) amine (13)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 2,4 dichloro aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 13, yield 30%, 1h NMR data are in table 1.
< embodiment 13>the synthesis of (3-(N-Cbz-valyl) amino-4-methoxyl benzene) formylaniline (16)
With 3-amino-4-methoxyl phenylformic acid, (BOC) 2o, aniline and N-Cbz-α-amino-isovaleric acid are starting raw material, and according to embodiment 1 similar approach, synthesis obtains compound 16, yield 30%, 1h NMR data are in table 1.
< embodiment 14>the synthesis of (3-valyl amino-4-methoxyl benzene) formylaniline (18)
With 16 for starting raw material, hydrogenation deprotection, synthesis obtains compound 18, yield 90%, 1h NMR data are in table 1.
< embodiment 15>the synthesis of (3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formylaniline (22)
With 3-amino-4-methoxyl phenylformic acid, 2-bromo propionyl chloro and aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 22, yield 37%, 1h NMR data are in table 1.
< embodiment 16>the synthesis of (3-(2 '-chlorine propionyl) amino-4-methoxyl benzene) formylaniline (23)
With 3-amino-4-methoxyl phenylformic acid, 2-chlorpromazine chloride and aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 23, yield 35%, 1h NMR data are in table 1.
< embodiment 17>(3-trifluoroacetamido-4-anisole) formyl-4 ' synthesis of-5-trifluoromethylaniline (24)
With 3-amino-4-methoxyl phenylformic acid, trifluoroacetic anhydride and p-trifluoromethylaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 24, yield 30%, 1h NMR data are in table 1.
< embodiment 18>the synthesis of (3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formyl-(4 '-trifluoromethylbenzene) amine (25)
With 3-amino-4-methoxyl phenylformic acid, 2-bromo propionyl chloro and p-trifluoromethylaniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 25, yield 30%, 1h NMR data are in table 1.
< embodiment 19>the synthesis of (3-propionamido-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (34)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 3,4,5-trimethoxy-aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 34, yield 21%, 1h NMR data are in table 1.
< embodiment 20>the synthesis of (3-propionamido-4-anisole) formyl-(4 '-anisole) amine (35)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 4-anisidine for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 35, yield 25%, 1h NMR data are in table 1.
< embodiment 21>the synthesis of (3-trifluoroacetamido-4-anisole) formyl (3 ', 4 ', 5 '-trimethoxy) amine (36)
With 3-amino-4-methoxyl phenylformic acid, trifluoroacetic anhydride and 3,4,5-trimethoxy-aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 36, yield 27%, 1h NMR data are in table 1.
< embodiment 22>the synthesis of (3-propionamido-4-anisole) methanoyl-(4 '-methoxyl group) benzene (39)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 4-methoxyphenol for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 39, yield 25%, 1h NMR data are in table 1.
< embodiment 23>the synthesis of (3-amino-4-methoxyl benzene) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (40)
With 3-amino-4-methoxyl phenylformic acid, (BOC) 2o and 3,4,5-trimethoxy phenol are starting raw material, and according to embodiment 1 similar approach, synthesis obtains compound 40, yield 21%, 1h NMR data are in table 1.
< embodiment 24>the synthesis of (3-trifluoroacetyl group-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (41)
With 3-amino-4-methoxyl phenylformic acid, trifluoroacetic anhydride and 3,4,5-trimethoxy phenol for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 41, yield 24%, 1h NMR data are in table 1.
< embodiment 25>the synthesis of (3-trifluoroacetyl group-4-anisole) methanoyl-(4 '-methoxyl group) benzene (42)
With 3-amino-4-methoxyl phenylformic acid, trifluoroacetic anhydride and 4-methoxyphenol for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 42, yield 24%, 1h NMR data are in table 1.
< embodiment 26>the synthesis of (3-propionamido-4-anisole) formyl-(3 '-methylthio phenyl) amine (45)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 3-methylthio group aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 45, yield 21%, 1h NMR data are in table 1.
< embodiment 27>the synthesis of (3-propionamido-4-anisole) formyl-(3 ', 4 '-ethylenedioxy base benzene) amine (46)
With 3-amino-4-methoxyl phenylformic acid, propionyl chloride and 3,4-ethylenedioxy aniline for starting raw material, according to embodiment 1 similar approach, synthesis obtains compound 46, yield 26%, 1h NMR data are in table 1.
< embodiment 28>the synthesis of 3-amino-4-methoxyl benzanilide (67)
With 3-amino-4-methoxyl phenylformic acid, (BOC) 2o and aniline are starting raw material, and according to embodiment 1 similar approach, synthesis obtains compound 67, yield 29%, 1h NMR data are in table 1.
< embodiment 29>the synthesis of (3-propionamido-4-anisole) sulphonyl (4 '-chlorinated benzene) amine (33)
3-nitro-4-methoxy benzenesulfonic acid (5.0g, 21mmol) is dissolved in SOCl 2in, reflux 3 hours, normal pressure steams except thionyl chloride, obtains benzene sulfonyl chloride crude product;
Get p-Chlorobenzoic acid amide (1.0g again, 7.8mmol) be dissolved in methylene dichloride, add triethylamine (2ml, 20mmol), under ice-water bath condition, add crude product benzene sulfonyl chloride (3.5g) wherein gradually, finish and stir clear-cutting forestland room temperature after half an hour, be stirred to and react completely, reaction solution silica gel adsorption, column chromatography for separation product obtains 3-nitro substituent 1.6 grams.
Be dissolved in methyl alcohol by above-mentioned nitro-compound (0.5g), add 10%Pd/C, middle pressure hydro-reduction, after 5 hours, raw material disappears, and filter, filtrate evaporate to dryness obtains 3-amino substituents 0.42g; This 3-amino substituents, in methylene dichloride, under making the condition of acid-binding agent, carries out acidylate with propionyl chloride and obtains target compound 330.47g at triethylamine.
< embodiment 30>the synthesis of (3-bis-propionamido-4-anisole) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (3)
With 3-nitro-4-methoxy benzenesulfonic acid, thionyl chloride, 3,4,5-trimethoxy-anilines and propionyl chloride for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 3, 1h NMR data are in table 1.
< embodiment 31>(3-nitro-4-methyl benzene) sulphonyl-3 ' synthesis of-(2 '-chloro-5 '-picoline) amine (14)
With 3-nitro-4-methyl Phenylsulfonic acid and the chloro-3-amino of 2--5-picoline for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 14, 1h NMR data are in table 1.
< embodiment 32>(3-nitro-4-methyl benzene) sulphonyl oxygen-4 ' synthesis of-anisole (15)
With 3-nitro-4-methyl Phenylsulfonic acid and 4-methoxyphenol for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 15, 1h NMR data are in table 1.
< embodiment 33>(3-propionamido-4-methylbenzene) sulphonyl oxygen-4 ' synthesis of-anisole (17)
With 3-nitro-4-methyl Phenylsulfonic acid and 4-methoxyphenol, propionyl chloride is starting raw material, and according to embodiment 29 similar approach, synthesis obtains compound 17, 1h NMR data are in table 1.
< embodiment 34>(3-nitro-4-methyl benzene) sulphonyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (19)
With amino-4, the 6-dimethoxy-pyridines of 3-nitro-4-methyl Phenylsulfonic acid and 2-for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 19, 1h NMR data are in table 1.
< embodiment 35>(3-amino-4-methylbenzene) sulphonyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (20) is with compound 19 for raw material, and palladium carbon makees catalyzer, and hydro-reduction obtains 20, 1h NMR data are in table 1.
< embodiment 36>(3-propionamido-4-methylbenzene) sulphonyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (21)
With compound 20 for raw material, obtain 21 by propionyl chloride acidylate, 1h NMR data are in table 1.
< embodiment 37>the synthesis of (3-nitro-4-methyl benzene) sulphonyl-(3 '-methylthio phenyl) amine (43)
With 3-nitro-4-methyl Phenylsulfonic acid and 3-methylthio group aniline for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 43, 1h NMR data are in table 1.
< embodiment 38>the synthesis of (3-nitro-4-methyl benzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (47)
With 3-nitro-4-methyl Phenylsulfonic acid, 3,4,5-trimethoxy-anilines for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 47, 1h NMR data are in table 1.
< embodiment 39>the synthesis of (3-amino-4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (48)
With 47 for starting raw material, make catalyzer with palladium carbon, hydrogenation synthesis obtains compound 48, 1h NMR data are in table 1.
< embodiment 40>the synthesis of (3-propionamido-4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (49)
With 48 and propionyl chloride for starting raw material, according to the process for acylating in embodiment 29, synthesis obtain compound 49, 1h NMR data are in table 1.
< embodiment 41>the synthesis of (3-methylamino--4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (50)
With 48 and methyl iodide for starting raw material, take triethylamine as acid binding agent, by halogenating reaction synthesis obtain compound 50, 1h NMR data are in table 1.
< embodiment 42>the synthesis of (3-acetylaminohydroxyphenylarsonic acid 4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (51)
With 48 and Acetyl Chloride 98Min. for starting raw material, according to the process for acylating in embodiment 29, synthesis obtain compound 51, 1h NMR data are in table 1.
< embodiment 43>the synthesis of (3-nitro-4-methyl benzene) sulphonyl (4 '-chlorinated benzene) amine (54)
With 3-nitro-4-methyl Phenylsulfonic acid, p-Chlorobenzoic acid amide for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 54, 1h NMR data are in table 1.
< embodiment 44>the synthesis of (3-N, N '-propionamido-4-methylbenzene) sulphonyl (4 '-chlorinated benzene) amine (57)
With 54 and propionyl chloride for starting raw material, according to the similar reduction of embodiment 29 and process for acylating, synthesis obtain compound 57, 1h NMR data are in table 1.
< embodiment 45>the synthesis of (3-nitro-4-methyl benzene) sulphonyl 3 '-triazole amine (58)
With 3-nitro-4-methyl Phenylsulfonic acid, the amino triazole of 3-for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 58, 1h NMR data are in table 1.
< embodiment 46>n, N ' synthesis of-(3-nitro-4-methyl benzene) sulphonyl-(4 '-chlorinated benzene) amine (62)
With 3-nitro-4-methyl Phenylsulfonic acid and p-Chlorobenzoic acid amide for starting raw material, according to embodiment 29 similar approach, time in second step reaction when excessive three times of SULPHURYL CHLORIDE, synthesis obtains compound 62, 1h NMR data are in table 1.
< embodiment 47>n, N ' synthesis of-(3-nitro-4-methyl benzene) sulphonyl-(3 '-methylthio phenyl) amine (63)
With 3-nitro-4-methyl Phenylsulfonic acid and 3-methylthio group aniline for starting raw material, according to embodiment 46 similar approach, synthesis obtains compound 63, 1h NMR data are in table 1.
< embodiment 48>(3-propionamido-4-anisole) formyl-4 ' synthesis of-aminopyrimidine (52)
3-nitro-4-methoxybenzoic acid (5.0g, 25mmol) is dissolved in SOCl 2in, reflux 3 hours, normal pressure steams except thionyl chloride, obtains Benzoyl chloride crude product;
Get 4-aminopyrimidine (1.0g again, 10mmol) be dissolved in methylene dichloride, add triethylamine-milliliter, under ice-water bath condition, add crude product Benzoyl chloride 3.8g wherein gradually, finish and stir clear-cutting forestland room temperature after half an hour, be stirred to and react completely, reaction solution silica gel adsorption, column chromatography for separation product obtains 3-nitro substituent 2.2 grams.
Be dissolved in methyl alcohol by above-mentioned nitro-compound (0.5g), add 10%Pd/C, middle pressure hydro-reduction, after 5 hours, raw material disappears, and filter, filtrate evaporate to dryness obtains 3-amino substituents 0.43g; This 3-amino substituents, in methylene dichloride, under making the condition of acid-binding agent, carries out acidylate with propionyl chloride at triethylamine, and reaction solution uses column chromatography and obtains target compound 520.51g.
< embodiment 49>(3-propionamido-4-anisole) formyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (26)
With 28 for starting raw material, obtain compound 26 by the propionating synthesis of the method for embodiment 48, 1h NMR data are in table 1.
< embodiment 50>(3-nitro-4-anisole) formyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (27)
With amino-4,6 dimethoxypyridins of 3-nitro-4-methoxybenzoic acid and 2-for starting raw material, obtain compound 27 by the method synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 51>(3-amino-4-methoxyl benzene) formyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (28)
With 27 for starting raw material, obtain compound 28 by the hydro-reduction method synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 52>(3-(2 "-bromo propionyl) amino-4-methoxyl benzene) formyl-2 ' synthesis of-(4 ', 6 '-dimethoxypyridin) amine (29)
With 28 for starting raw material, obtain compound 29 by the method acidylate synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 53>the synthesis of (3-nitro-4-anisole) formyl-(4 '-oil of mirbane) amine (30)
With 3-nitro-4-methoxybenzoic acid and p-Nitroaniline for starting raw material, obtain compound 30 by the method synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 54>the synthesis of (3-amino-4-methoxyl benzene) formyl-(4 '-amino-benzene) amine (31)
With 30 for starting raw material, obtain compound 31 by the method for hydrogenation synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 55>the synthesis of (3-propionamido-4-anisole) formyl-(4 '-amino-benzene) amine (32)
With 31 for starting raw material, obtain compound 32 by the process for acylating synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 56>the synthesis of (3-nitro-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine (37)
With 3-nitro-4-methoxybenzoic acid and p-trifluoromethylaniline for starting raw material, obtain compound 37 by the method synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 57>(3-nitro-4-anisole) formyl-2 '-the synthesis of (4 '-itrile group pyridine) amine (38)
With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine for starting raw material, obtain compound 38 by the method synthesis of embodiment 48, 1h NMR data are in table 1.
< embodiment 58>the synthesis of N, N '-(3-nitro-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (44)
With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine for starting raw material, easily synthesize when the acyl chlorides add-on prepared exceedes the triplication of assorted arylamine and obtain compound 44, 1h NMR data are in table 1.
< embodiment 59>(3-nitro-4-anisole) formyl-4 ' synthesis of-PYRIMITHAMINE (53)
With 3-nitro-4-methoxybenzoic acid and 4-aminopyrimidine for starting raw material, according to embodiment 48 similar approach, synthesis obtains compound 53, 1h NMR data are in table 1.
< embodiment 60>(3-propionamido-4-anisole) formyl-2 '-the synthesis of (4 '-itrile group pyridine) amine (55)
With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine for starting raw material, according to embodiment 48 similar approach, synthesis obtains compound 55, 1h NMR data are in table 1.
< embodiment 61>the synthesis of N, N '-(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (56)
With 44 for starting raw material, obtain compound 56 through hydro-reduction and acidylate synthesis, 1h NMR data are in table 1.
< embodiment 62>1-(3 '-nitro-4 '-methoxyl group) phenyl-2-(3 ", 4 ", 5 " and-trimethoxy) synthesis of phenylethyl alcohol (61)
By 200mg magnesium silk as in 15ml anhydrous tetrahydrofuran solution, be warming up to 65 degree, drip tetrahydrofuran solution and the micro iodine of 5 bromobenzyls (0.5ml) wherein, continue after causing to drip bromobenzyl, drip to finish and keep that micro-temperature 5 of boiling is little consumes in a large number up to magnesium silk, then drip 1g 3-nitro-4 methoxy-acetophenone tetrahydrofuran solution, reflux 8 hours, add 25% ammonium chloride solution termination reaction, column chromatography for separation obtains target compound 61 1h NMR data in table 1, (yield 20%).
< embodiment 63>the synthesis of (3-nitro-4-anisole) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (59)
In the acetone soln of 200mg compound 61, slowly drip 20% chromic acid solution 10ml under condition of ice bath, drip a complete room temperature reaction and spend the night, next day reaction solution water and extraction into ethyl acetate, after organic layer is concentrated, upper prop is separated and obtains target compound 59, 1h NMR data in table 1, (yield 31%).
< embodiment 64>the synthesis of (3-amino-4-methoxyl benzene) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (60)
Be dissolved in methyl alcohol by above-mentioned nitro-compound 59 (0.1g), add 10%Pd/C, middle pressure hydro-reduction, after 5 hours, raw material disappears, and filter, filtrate evaporate to dryness obtains 3-amino substituents 600.062g; 1h NMR data are in table 1.
< embodiment 65>the synthesis of (3-nitro-4-anisole) methylene amino-(3 ', 4 ', 5 '-trimethoxy) benzene (64)
By 3-nitro-4-methoxy toluene (5g, 30mmol) be dissolved in tetracol phenixin, add NBS wherein, add a small amount of sulphur, be heated to backflow, after 8 hours, return to room temperature, reaction solution evaporated under reduced pressure, residue from dichloromethane dissolves rear water, dilute hydrochloric acid solution, water washs successively, steams to desolventize to obtain crude product 3-nitro-4-methoxyl group toluene bromide after organic over anhydrous dried over sodium sulfate;
Get 3,4,5-trimethoxy-aniline (0.4g, 2.4mmol) be dissolved in methylene dichloride, add triethylamine 0.25ml, under ice-water bath condition, slowly adding above-mentioned crude product toluene bromide is wherein about 1.0g, and finish recovery stirred overnight at room temperature, next day, reaction solution used water successively, dilute acid soln, dilute alkaline soln, washing, organic layer drying afterwards concentrated upper silicagel column separation obtains sterling (3-nitro-4-anisole) methylene amino-3 ', 4 ', 5 '-trimethoxy-benzene 640.42g (yield: 55%); 1h NMR data are in table 1.
< embodiment 66>(3-amino-4-methoxyl benzene) methylene amino-3 ', the synthesis of 4 ', 5 '-trimethoxy-benzene (65)
Be dissolved in methyl alcohol by above-mentioned nitro-compound 64 (0.15g), add 10%Pd/C, middle pressure hydro-reduction, after 5 hours, raw material disappears, and filter, filtrate evaporate to dryness obtains 3-amino substituents 650.10g (yield: 73%); 1h NMR data are in table 1.
< embodiment 67>(3-propionamido-4-anisole) methylene amino-3 ', the synthesis of 4 ', 5 '-trimethoxy-benzene (66)
This 3-amino substituents 65, in methylene dichloride, under making the condition of acid-binding agent, carries out the separation of acidylate rear pillar with propionyl chloride and obtains target compound 66 0.10g (yield: 85%) at triethylamine. 1h NMR data are in table 1.
< embodiment 68>the synthesis of (3-propionamido-4-anisole) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (68)
3-amino substituents 60 is dissolved in methylene dichloride, make the condition of acid-binding agent at triethylamine under, carries out acidylate with propionyl chloride and be separated with post obtaining target compound 68 0.065g, 1h NMR data are in table 1.
The synthesis of < embodiment 69>N, N '-tolysulfonyl-(4,4 '-biphenyl two) amine (69)
With 4,4 '-benzidine and Tosyl chloride for raw material, according to the method that embodiment 29 second step is similar, synthesis obtains compound 69, 1h NMR data are in table 1.
The synthesis of < embodiment 70> bis-(N, N '-two tolysulfonyl)-(4,4 '-biphenyl two) amine (70)
With 4,4 '-benzidine and Tosyl chloride for raw material, according to the method that embodiment 29 second step is similar, while synthesis obtains compound 69, obtain compound 70, 1h NMR data are in table 1.
< embodiment 71>the synthesis of 2-oil of mirbane oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (71)
With p-nitrophenyl sulfonic acid and piperidines for starting raw material, obtain p-nitrophenyl sulphonyl piperylhydrazine according to the synthesis of embodiment 29 similar approach; Sulfanilyl-piperylhydrazine is obtained again with the reduction of the method for catalytic hydrogenation similar in embodiment 48; Finally with p-nitrophenyl fluoroacetic acid and sulfanilyl-piperylhydrazine for raw material, obtain compound 71 according to method similar in embodiment 48 synthesis, 1h NMR data are in table 1.
< embodiment 72>the synthesis of 2-amino-benzene oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (72)
With compound 71 for starting raw material, obtain compound 72 according to the method reduction of the similar catalytic hydrogenation of embodiment 48, 1h NMR data are in table 1.
< embodiment 73>the synthesis of 2-acetyl amino phenyl oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (73)
With compound 72 and Acetyl Chloride 98Min. for starting raw material, the process for acylating reduction similar according to embodiment 48 obtains compound 73, 1h NMR data are in table 1.
< embodiment 74>the synthesis of 4-sulfonamido benzoyl-(4 '-chlorobenzene) amine (74)
With to sulfonyl-benzoic acid and p-Chlorobenzoic acid amide for starting raw material, according to the method for condensing that embodiment 1 is similar, synthesis obtains compound 74, 1h NMR data are in table 1.
< embodiment 75>the synthesis of 4-thiophenyl benzoyl-(4 '-chlorobenzene) amine (75)
With to thiophenyl phenylformic acid and p-Chlorobenzoic acid amide for starting raw material, according to the method for condensing that embodiment 1 is similar, synthesis obtains compound 75, 1h NMR data are in table 1.
< embodiment 76>the synthesis of 6-chloronicotinoyl-(-4 '-pyrimidine) amine (76)
With 6-chloronicotinoyl chloride and 4-aminopyrimidine for starting raw material, according to the method that embodiment 48 is similar, synthesis obtains compound 76, 1h NMR data are in table 1.
< embodiment 77>the synthesis of 2-methylthio group nicotinoyl-(-3 ', 4 ', 5 '-trimethoxy-benzene) ester (77)
With 2-methylthio group nicotinoyl chlorine and 3,4,5-trimethoxy phenol for starting raw material, according to the method that embodiment 48 is similar, synthesis obtains compound 77, 1h NMR data are in table 1.
< embodiment 78>the synthesis of (3 '-methyl benzothiophene-2-base) acetyl-(4 "-chlorinated benzene) amine (78)
With 2-(3-methyl) thionaphthene acetic acid and p-Chlorobenzoic acid amide for starting raw material, according to the method that embodiment 48 is similar, synthesis obtains compound 78, 1h NMR data are in table 1.
< embodiment 79>5-chloro-benzofuran-2-formyl- (4'-formamido group thiophene) synthesis of-2-amine (79)
With the chloro-cumarone of 2-carboxyl-5-and 2-amino-4-formamido group thiophene for starting raw material, according to the method that embodiment 48 is similar, synthesis obtains compound 79, 1h NMR data are in table 1.
< embodiment 80>5-nitrothiophene-2-formyl- (4'-chlorinated benzene) synthesis of amine (80)
With 2-carboxyl-5-nitrothiophene and p-Chlorobenzoic acid amide for starting raw material, according to the method that embodiment 48 is similar, synthesis obtains compound 80, 1h NMR data are in table 1.
< embodiment 81>3-propionyloxy-4-methoxybenzoyl- (3', 4', 5 '-trimethoxy-benzene) synthesis of amine (81)
With 3-hydroxyl-4-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxy-aniline are starting raw material, and according to the method that embodiment 1 is similar, synthesis obtains compound 81, 1h NMR data are in table 1.
< embodiment 82>the synthesis of 3-nitro-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (84)
With 3-nitro-phenylsulfinyl chlorine, 3,4,5-trimethoxy-anilines for starting raw material, according to embodiment 29 similar approach, synthesis obtains compound 84, 1h NMR data are in table 1.
< embodiment 83>the synthesis of 3-amino-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (83)
With 84 for starting raw material, according to the method for reducing that embodiment 29 is similar, synthesis obtains compound 83, 1h NMR data are in table 1.
< embodiment 84>the synthesis of 3-propionamido-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (82)
With 83 and propionyl chloride for starting raw material, according to the process for acylating that embodiment 29 is similar, synthesis obtain compound 82, 1h NMR data are in table 1.
< embodiment 85>(3-amino-4-methoxyl benzene) formyl-4 ' synthesis of-PYRIMITHAMINE (85)
With (3-nitro-4-anisole) formyl-4 '-PYRIMITHAMINE for raw material, by embodiment 48 hydro-reduction method synthesis obtain compound 85, 1h NMR data are in table 1.
As indefiniteness example, replacement bi-aromatic compounds of the present invention can be selected from following particular compound:
Table 1 invention compound
< embodiment 85>, suppress HBV activity experiment
After HepG2.2.15 Tissue Culture Flask covers with cell, through digestion, be mixed with every milliliter of 200,000 cells, inoculate 96 well culture plates, every hole 100 μ l, 37 DEG C of 5%CO 2cultivate 24 hours, cell is tested after growing up to individual layer.After the compounds of this invention sample nutrient solution is mixed with different concns, add 96 porocyte culture plates, 37 DEG C of 5%CO 2cultivate, cell cultures was observed, with cytopathy (CPE) for cytotoxicity index to the 3rd day with inverted microscope.Record cytopathy, destroying completely is 4; 75% is 3; 50% is 2; 25% is 1; Anosisly become 0.Poisonous concentration (the TC of half is calculated by Reed-Muench method 50) and maximal non-toxic concentration (TC 0).Plate inner cell a small amount of DNA rapid extraction test kit extracts DNA in cell, add primer, by the level (HVB Ct value) of DNA in qPCR test kit and iQ5 quantitative PCR apparatus detection by quantitative cell and the level (GAPDH Ct value) of cell internal reference gene GAPDH.By following formulae discovery inhibition percentage.Suppress percentage %=1/2^ ((HBV Ct cell controls-HBV Ct medicine group)/(GAPDH Ct cell controls-GAPDHCt medicine group) × 100%, with Reed-Muench method calculation of half inhibitory concentration (IC 50).
Result lists table 2 in.
< embodiment 86>, suppress HCV determination of activity experiment
Compound is to the toxicity of Huh7.5 cell: 1 × 10 5/ mL Huh7.5 cell inoculates 100 μ L in 96 porocyte culture plates, in 37 DEG C, 5%CO 2after cultivating 6hrs in the incubator under saturated humidity condition, add the compounds of this invention liquid and the positive control drug (alpha-interferon) of different concns respectively, after continuing to cultivate 96hrs, every hole adds the MTT of 10 μ L 5mg/mL, continues cultivation 4 hours, after DMSO cracking, microplate reader measures OD 570nm value, compared with cell controls group OD value, calculate the toxicity inhibition rate of every concentration versus cell, calculate the poisonous concentration of the half of medicine to cell by Reed-Muench method.
Compound is anti-HCV activity in cell cultures: 1 × 10 5/ mL Huh7.5 cell inoculates 100 μ L in 96 porocyte culture plates, in 37 DEG C, 5%CO 2after cultivating 6hrs in the incubator under saturated humidity condition, while infecting Huh7.5 cell with the virus liquid containing restructuring full genome HCV virion, add the compounds of this invention liquid or the positive control drug of different concns respectively, after continuing to cultivate 96hrs, extract total serum IgE in cell respectively, the content of HCV RNA in cell is measured with single stage method quantitative RT-PCR, compared with virus control group rna level, calculate the inhibiting rate of every concentration to HCV, calculate the medium effective concentration of Drug inhibition HCV effect by Reed-Muench method.Result is see table 2.
Table 2 invention compound is to the inhibit activities of HBV and HCV
< embodiment 87>, suppression HIV-1 determination of activity experiment
In 96 porocytes are cultivated, add the compounds of this invention liquid and the positive control liquid of 8 different weaker concns, each extent of dilution repeats 2 holes, if cell controls; Again by 2 × 10 5cell/ml 100 μ l is inoculated in pastille 96 porocyte culture plate.Put 37 DEG C, 5%CO 2cultivate with in saturated humidity incubator, every day observation of cell pathology.By the operation steps that HIV-1P24 antigenic reagent box provides, 4th day (96 hours) cells and supernatant HIV-1P24 antigenic content after mensuration dosing, calculate the inhibit activities of drug on viral, the compounds of this invention initial concentration is 1 μ g/ml, and measurement result is see table 3.The concentration of contrast medicine AZT is 0.15ng/ml, its measurement result IC 50< 0.0005 μM.
The HIV (human immunodeficiency virus)-resistant activity of table 3 invention compound
NO. X Y R 2 R 3 R 6 R 7 R 8 R 9 IC 50(μM)
1 CO NH COCH 2CH 3 OCH 3 H OCH 3 OCH 3 OCH 3 0.058
5 CO NH H OCH 3 H OCH 3 OCH 3 OCH 3 0.073
36 CO NH COCF 3 OCH 3 H OCH 3 OCH 3 OCH 3 ＜0.032
35 CO NH COCH 2CH 3 OCH 3 H H OCH 3 H 0.053
2 CO NH COCH 2CH 3 OCH 3 H H Cl H 0.041
67 CO NH H OCH 3 H H H H ＜0.0566
34 CO O COCH 2CH 3 OCH 3 H OCH 3 OCH 3 OCH 3 0.077
40 CO O H OCH 3 H OCH 3 OCH 3 OCH 3 0.166
41 CO O COCF 3 OCH 3 H OCH 3 OCH 3 OCH 3 0.128
39 CO O COCH 2CH 3 OCH 3 H H OCH 3 H 0.091
< embodiment 88>, anti-EV71 virus and COxsackie (Coxaskies) virus activity measure
Vero cell kind 96 well culture plate, 24 hours postoperative infection virus (EV71 virus, COxsackie A16, B3 or B6 virus) about 100TCID 50adsorb 2 hours, abandon virus liquid, add the maintenance medium of the compounds of this invention sample containing different concns and positive control drug ribavirin (RBV), establish the virus control of not dosing and the cell controls of virus-free infection simultaneously, each group of cytopathy degree (CPE) is observed, with Reed-Muench method difference calculation sample to the half-inhibition concentration (IC of virus when virus control group lesion degree (CPE) reaches 4+ 50), contrast medicine RBV is to the IC of three strain Coxsackie viruss 50be 412.26 μ g/ml, the compounds of this invention result lists table 4 in.
< embodiment 89>, anti-influenza virus activity measure
Mdck cell inoculates 96 well culture plates, puts 5%CO 2, cultivate 24 hours for 37 DEG C.Mdck cell adds influenza virus (A/H1N1, A/H3N2 or B/13/79 type) about 100TCID 50, 37 DEG C of absorption hypsokinesis in 2 hours is prevented or cure a disease venom, adds the maintenance medium of different dilution the compounds of this invention or positive control drug ribavirin respectively.Establish the virus control of not dosing and the cell controls of virus-free infection simultaneously, each group of cytopathy degree (CPE) (about 36 hours) is observed in 37 DEG C of cultivations when virus control group lesion degree (CPE) reaches 4+, calculates each sample resisiting influenza virus half-inhibition concentration (IC 50), the IC of contrast medicine RBV infected by influenza A/H1N1, A/H3N2 or B/13/79 type 50be respectively 1.43,1.71 and 5.75 μ g/ml, the compounds of this invention result is see table 4.
Table 4 invention compound is to the inhibit activities of many strain virus
* ND represents undetermined.
As can be seen from Table 4,49 compounds are wherein had to have inhibit activities at least 3 strains; There are 55 compounds to have inhibit activities at least each 1 strain in above-mentioned two large viroids simultaneously; 34 compounds are had to demonstrate vitro inhibition activity at least 1 strain virus in above 4 strain gi tract viruses; 54 compounds are had to have inhibit activities at least 1 influenzae strain virus.This compounds visible generally has antiviral activity.

Claims (12)

1. replacement bi-aromatic compounds or its pharmaceutical salts with structure shown in following logical formula IV are preparing the application in broad-spectrum antiviral medicament, and described virus is hepatitis B virus, hepatitis C virus, Respirovirus or enterovirus:
Wherein: X representative-C (O)-, Y represents-N (R 12)-; Described R 12represent hydrogen, the phenyl sulfonyl of replacement or the phenylacyl of replacement, described replacement is the C1-C6 alkyl of unit or multidigit, C1-C6 alkoxyl group, amino, nitro, C1-C6 alkyl amido replaced;
R 2for NR 13r 14, described R 13, R 14represent respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halo C1-C6 alkyl acyl, or
R 3for methoxyl group;
R 6, R 7, R 8and R 9to can be the same or different when independently existing separately, represent hydrogen respectively, aryl, halo C1-C6 alkyl or phenyl-S-that aryl that halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxyl group, benzsulfamide replace, para toluene sulfonamide replace, or R 7with R 8common composition-O-CH 2-CH 2-O-.
2. apply as claimed in claim 1, wherein:
X represent-C (O)-, Y representative-NH-;
R 2for NR 13r 14, described R 13, R 14represent hydrogen, C1-C6 alkyl acyl, trifluoroacetyl group respectively;
R 3for methoxyl group;
R 6, R 7, R 8and R 9represent H, halogen or C1-C6 alkoxyl group independently of one another.
3. apply as claimed in claim 2, wherein:
X represent-C (O)-, Y representative-NH-;
R 2for NR 13r 14, described R 13for R during hydrogen 14for propionyl or trifluoroacetyl group, or R 13and R 14be propionyl;
R 3for methoxyl group;
R 6, R 7, R 8and R 9represent H, halogen or methoxyl group independently of one another.
4. apply as claimed in claim 1, described compound is
(3-propionamido-4-anisole) formyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine
(3-propionamido-4-anisole) formyl-(4 '-chlorinated benzene) amine
(3-trifluoroacetamido-4-anisole) formyl-(4 '-chlorinated benzene) amine
(3-amino-4-methoxyl benzene) formyl-(3 ', 4 ', 5 '-trimethoxy benzene) amine
(3-propionamido-4-anisole) formylaniline
(3-propionamido-4-anisole) formyl-(4 '-methylbenzene) amine
(3-propionamido-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine
(3-propionamido-4-anisole) formyl-(2 '-chlorinated benzene) amine
(3-propionamido-4-anisole) formyl-(4 '-fluorobenzene) amine
(3-propionamido-4-anisole) formyl-(4 '-bromobenzene) amine
(3-propionamido-4-anisole) formyl-(3 '-chlorinated benzene) amine
(3-propionamido-4-anisole) formyl-(2 ', 4 '-dichlorobenzene) amine
(3-(N-Cbz-valyl) amino-4-methoxyl benzene) formylaniline
(3-valyl amino-4-methoxyl benzene) formylaniline
(3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formylaniline
(3-(2 '-chlorine propionyl) amino-4-methoxyl benzene) formylaniline
(3-trifluoroacetamido-4-anisole) formyl-4 '-5-trifluoromethylaniline
(3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formyl-(4 '-trifluoromethylbenzene) amine
(3-propionamido-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene
(3-propionamido-4-anisole) formyl-(4 '-anisole) amine
(3-trifluoroacetamido-4-anisole) formyl-(3 ', 4 ', 5 '-trimethoxy) amine
(3-propionamido-4-anisole) formyl-(3 '-methylthio phenyl) amine
(3-propionamido-4-anisole) formyl-(3 ', 4 '-ethylenedioxy base benzene) amine
3-amino-4-methoxyl benzanilide
(3-propionamido-4-anisole) formyl-4 '-aminopyrimidine
(3-propionamido-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine
(3-amino-4-methoxyl benzene) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine
(3-(2 "-bromo propionyl) amino-4-methoxyl benzene) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine
(3-amino-4-methoxyl benzene) formyl-(4 '-amino-benzene) amine
(3-propionamido-4-anisole) formyl-(4 '-amino-benzene) amine
N, N '-(3-nitro-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine
(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine
N, N '-(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine
3-propionyloxy-4-methoxybenzoyl-(3 ', 4 ', 5 '-trimethoxy) aniline
(3-amino-4-methoxyl benzene) formyl-4 '-PYRIMITHAMINE.
5. the application as described in any one of claim 1-4, described pharmaceutical salts refers to that described replacement bi-aromatic compounds, with acid, the product of salt-forming reaction occurs, and comprises inorganic acid salt and organic acid salt.
6. apply as claimed in claim 5, described inorganic acid salt is hydrochloride, hydrobromate or vitriol; Organic acid salt is acetate, lactic acid salt, succinate, fumarate, maleate, Citrate trianion, benzoate, mesylate or paratolunitrile salt.
7. apply as claimed in claim 1, described Respirovirus refers to influenza virus.
8. apply as claimed in claim 7, described influenza virus comprises first, second, the third three type influenza virus and avian influenza virus.
9. apply as claimed in claim 1, described enterovirus refers to Coxsackie virus.
10. apply as claimed in claim 9, described Coxsackie virus comprises coxsackie virus A 16-type, Coxsackie virus type B3 and Coxsackie B virus 6 type.
11. apply as claimed in claim 1, and described enterovirus refers to new enterovirus.
12. apply as claimed in claim 11, and described new enterovirus is EV71 virus.
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