CN103087045B - A kind of benzimidazole-like heterocyclic compound, medical composition and its use - Google Patents
A kind of benzimidazole-like heterocyclic compound, medical composition and its use Download PDFInfo
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- CN103087045B CN103087045B CN201310011757.6A CN201310011757A CN103087045B CN 103087045 B CN103087045 B CN 103087045B CN 201310011757 A CN201310011757 A CN 201310011757A CN 103087045 B CN103087045 B CN 103087045B
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Abstract
The invention discloses benzimidazole-like heterocyclic compound or its pharmacy acceptable salt, ester or its pharmaceutical composition that a kind of molecular formula is (I); Wherein: R is halogen, alkyl, alkylamino radical, cycloalkanes amido, aryl amine, heterocycle amido, aryl, alkoxyl group, heterocyclic oxy group, aryloxy or heterocyclic radical; R
1it is the heterocyclic radical of 4 or 5; R
2for hydrogen or alkyl.Described pharmaceutical composition contains the benzimidazole-like heterocyclic compound of the present invention or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.The invention also discloses a kind of method preparing this benzimidazole-like heterocyclic compound, and this benzimidazole-like heterocyclic compound, its pharmacy acceptable salt, ester or the application of its pharmaceutical composition in the medicine for the preparation of anti-Coxsackie virus.
Description
Technical field
The present invention relates to a kind of benzimidazole-like heterocyclic compound, particularly relate to a kind of novel benzimidazoles heterogeneous ring compound and the medical composition and its use containing them.
Background technology
Benzimidazoles derivative is the compound that a class has broad-spectrum biological activity, and at occurring in nature, an integral part of vitamin B12 is exactly 5,6-bisbenzimidazole, and this discovery causes the interest of Many researchers to benzimidazoles compound.In research in our prior, find that a series of 2-pyridyl-1H-benzoglyoxaline-4-amides has good restraining effect (Chinese patent ZL200410084296.6 to cells of coxsackie B 3 virus, CN200810042790.4, CN201010000050.1).
The transmissible disease caused by enterovirus (enteroviruses) worldwide happens occasionally.Enterovirus genus Picornaviridae, comprise poliovirus (Polio viruses), Coxsackie virus (Cosxackie viruses), EHCO virus (Enteric cytopathogenic human orphan virus) and new enterovirus (New enteroviruses) etc., every viroid has various serotype, have more than 70 types at least, Various Tissues can be invaded, as nerve, cardiac muscle, muscle, skin and eye conjunctiva etc., cause a variety of communicable disease in the whole world.Picornavirus can invade Various Tissues system, causes diverse clinical manifestations.Clinical commonly have respiratory tract infection, herpangina, hot fash, hand foot mouth disease, infantile diarrhea, central nervous system syndromes, myocarditis and pericarditis, epidemic pleurodynia or myalgia, epidemic conjunctivitis, viral hepatitis and Other diseases.
Therefore, those skilled in the art is devoted to develop and a kind ofly synthesizes the less safer antiviral compound of toxicity.
Summary of the invention
Because the above-mentioned defect of prior art, technical problem to be solved by this invention is to provide a kind ofly synthesizes the little and novel benzimidazoles Heterocylic antiviral compounds of safety of toxicity.
For achieving the above object, the invention provides a kind of have benzimidazole-like heterocyclic compound of anti-Coxsackie virus and preparation method thereof, application.
From an aspect, the invention provides the benzimidazole-like heterocyclic compound shown in formula (I) that one has anti-Coxsackie virus (Cosxackie viruses)
Or its pharmacy acceptable salt;
Wherein: R is halogen, alkyl, alkylamino radical, cycloalkanes amido, aryl amine, heterocycle amido, aryl, alkoxyl group, heterocyclic oxy group, aryloxy, or heterocyclic radical; R
1it is the heterocyclic radical of 4 or 5; R
2for hydrogen, or alkyl.
In better embodiment of the present invention, R is fluorine, chlorine, bromine, iodine, C
1~ C
10alkyl, C
1~ C
10alkylamino radical, triatomic ring or tetra-atomic ring or five-ring or six-ring alkylamino radical, the anilino containing substituting group or unsubstituted, the triatomic ring containing oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or six-ring amido, the phenyl containing substituting group or unsubstituted, C
1~ C
10alkoxyl group, containing the triatomic ring of oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or hexa-atomic epoxy group(ing), containing the phenoxy group of substituting group or unsubstituted, containing any one in oxygen or the triatomic ring of nitrogen heteroatom or the group of tetra-atomic ring or five-ring or six-ring heterocycle oxygen composition;
R
1be 4 or 5 Wei oxadiazolyls, thiadiazolyl group, or triazol radical;
R
2for hydrogen, or C
1~ C
10alkyl.
In the present invention, described pharmaceutically acceptable salt refers to the salt prepared from pharmaceutically acceptable nontoxic alkali or acid, comprises mineral alkali or organic bases, and mineral acid or organic acid.It should be pointed out that molecular formula (I) or (II) compound comprise pharmacy acceptable salt.
In another better embodiment of the present invention, described pharmaceutically acceptable salt is molecular formula of the present invention is the compound of (I) or (II) and the hydrochlorate of mineral acid or organic acid adduction gained, any one or its combination in example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate; Or be that the compound of (I) or (II) adds the alkali salt with gained with mineral alkali or organic bases by molecular formula of the present invention, as any one in alkaline earth salt, organic amine salt or its combination.
In the preferred embodiments of the invention, described alkaline earth salt is selected from any one or its combination of magnesium salts or calcium salt.
In the preferred embodiments of the invention, described organic amine salt is selected from any one or its combination in alkylbenzyldimethylasaltsum saltsum, piperidinium salt, trialkyl amine salt, pyridinium salt, dimethylamine salt, diethylamine salt.
In the specific embodiment of the present invention, additionally provide a kind of benzimidazole-like heterocyclic compound shown in formula (II) with anti-Coxsackie virus
Its pharmacy acceptable salt, or its pharmaceutically acceptable ester;
Wherein: R is halogen, alkyl, alkylamino radical, cycloalkanes amido, aryl amine, heterocycle amido, aryl, alkoxyl group, heterocyclic oxy group, aryloxy or heterocyclic radical; R
1it is the heterocyclic radical of 4 or 5.
In better embodiment of the present invention, the R of the benzimidazole-like heterocyclic compound shown in formula (II)
1be 4 or 5 Wei oxadiazolyls, thiadiazolyl group or triazol radical.
In another better embodiment of the present invention, the benzimidazole-like heterocyclic compound of structure shown in formula (II) or the preferred example of its pharmacy acceptable salt as follows:
1) 2-(2 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
2) 2-(3 '-pyridyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
3) 2-(4 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
4) 2-(2 '-thienyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
5) the bromo-4-of 2-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
6) 2-(2 '-pyridyl)-5-[3 '-(2 '-pyridyl)-1,2,4-oxadiazoles-5 '-Ji]-1H-benzoglyoxaline;
7) 2-(3 '-pyridyl)-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
8) 2-(4 '-pyridyl)-5-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
9) the bromo-5-of 2-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
10) 2-oxyethyl group-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
11) 2-isopropylamine base-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-4 '-Ji)-1H-benzoglyoxaline;
12) 2-oxyethyl group-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline;
13) 2-isopropylamine base-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-4 '-Ji)-1H-benzoglyoxaline;
14) 2-(2 '-pyridyl)-4-(5 '-amino-1,3,4-thiazole-2 '-Ji)-1H-benzoglyoxaline;
15) 2-(2 '-pyridyl)-5-(5 '-amino-1,3,4-thiazole-2 '-Ji)-1H-benzoglyoxaline;
16) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
17) 2-(3 '-pyridyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
18) 2-(4 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
19) 2-(2 '-thienyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
20) the bromo-4-of 2-(5 '-methyl-1,3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
21) 2-(2 '-pyridyl)-5-[5 '-(2 '-pyridyl)-1,3,4-oxadiazoles-2 '-Ji]-1H-benzoglyoxaline;
22) 2-(3 '-pyridyl)-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
23) 2-(4 '-pyridyl)-5-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
24) the bromo-5-of 2-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
25) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
26) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
27) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
28) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-Ji)-1H-benzoglyoxaline;
29) 2-(2 '-pyridyl)-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
30) 2-(3 '-pyridyl)-4-(4 '-ethyl-5 '-p-methylphenyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
31) 2-(4 '-pyridyl)-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
32) 2-(2 '-pyridyl)-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
33) the bromo-4-of 2-(5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
34) 2-(2 '-pyridyl)-5-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
35) the bromo-5-of 2-(5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
36) the bromo-5-of 2-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
37) 2-oxyethyl group-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
38) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
39) 2-oxyethyl group-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
40) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
41) 2-oxyethyl group-4-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji-)-1H-benzoglyoxaline;
42) 2-(2 '-pyridyl)-4-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
43) 2-isopropylamine base-4-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
44) 2-(1 '-piperidyl)-4-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
45) 2-(2 '-pyridyl)-5-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
46) 2-isopropylamine base-5-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
47) 2-(1 '-morpholinyl)-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
48) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
49) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
50) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
51) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
52) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-Ji)-1H-benzoglyoxaline;
53) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-thiazole-2 '-Ji)-1H-benzoglyoxaline.
From other aspect, the invention provides one and prepare the benzimidazoles derivative of structure or the method for its pharmacy acceptable salt shown in formula as above (I), the method comprises the steps:
Step one, preparation 4-or 5-carboxylic acid benzoglyoxaline b1
3-or 4-carboxylic acid O-Phenylene Diamine and aldehyde compound condensation closed loop under organic oxidizing agent exists prepares 4-or 5-carboxylic acid benzoglyoxaline b1;
Wherein, organic oxidizing agent is preferably para benzoquinone or Meta-dinitrobenzene;
Or 3-or 4-carboxylic acid O-Phenylene Diamine and urea closed loop, then use phosphorus oxychloride or the halogenation of tribromo oxygen phosphorus, then replaces with R contain aminocompound or oxy-compound condensation to prepare 4-or 5-carboxylic acid benzoglyoxaline;
Wherein, X is halogen; R is halogen, alkyl, alkylamino radical, cycloalkanes amido, aryl amine, heterocycle amido, aryl, alkoxyl group, heterocyclic oxy group, aryloxy, or heterocyclic radical.
Step 2, preparation R
1the compound i replaced
Wherein, R
1it is the heterocyclic radical of 4 or 5;
In a preferred embodiment of the invention, R
1be 4 or 5 Wei oxadiazolyls, thiadiazolyl group, or triazol radical; Such as, R
1for being selected from the one in following molecular formula,
In another preferred implementation of the present invention, work as R
1when being 1,2, the 4-oxadiazolyl of 4 or 5, above-mentioned steps two is specific as follows:
1) 1,2,4-oxadiazole compounds is prepared
4-or the 5-carboxylic acid benzoglyoxaline using above-mentioned steps one to prepare and amidine compound closed loop prepare benzoglyoxaline 1,2,4-oxadiazole compound IA or IB;
Work as R
1when being 1,3, the 4-thiadiazolyl group of 4 or 5, above-mentioned steps two is specific as follows:
2) 1,3,4-thiadiazole compound is prepared
Obtained 4-or the 5-carboxylic acid benzoglyoxaline of step one and thiosemicarbazide closed loop is used to prepare 1,3,4-thiadiazole compound IC;
Work as R
1when being 1,3, the 4-oxadiazolyl of 4 or 5, above-mentioned steps two is specific as follows:
3) 1,3,4-oxadiazole compounds is prepared
After 4-or the 5-carboxylic acid benzoglyoxaline esterification obtained by step one, then itself and hydrazine hydrate are obtained by reacting hydrazide compound, and then prepare 1,3,4-oxadiazole compounds ID with carboxylic acid cpd closed loop;
Work as R
1when being the triazol radical of 4 or 5, above-mentioned steps two is specific as follows:
4) triazole compound IE is prepared
1,3, the 4-oxadiazole compounds obtained by step 3) and aminocompound react prepares triazole compound.
Step 3, preparation molecular formula are the benzimidazole-like heterocyclic compound of (I)
By step 1), 2), 3) or 4) prepare oxadiazolyl, thiadiazolyl group or triazole compound and haloalkane (R
2x) react, obtain the benzimidazole-like heterocyclic compound shown in formula (I);
Wherein, R
1it is the heterocyclic radical of 4 or 5; R
2for C
1~ C
10alkyl, X is halogen; Preferably R
2x is methyl iodide.
In the embodiment of preparation method of the present invention, R ' is halogen, haloalkyl, C
1~ C
10alkyl, C
1~ C
10alkylamino radical, aryl, aralkyl, C
1~ C
10alkylamino radical, triatomic ring or tetra-atomic ring or five-ring or six-ring alkylamino radical, C
1~ C
10one in alkoxyl group etc., such as fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, trifluoromethyl, phenyl, pyridyl, tolyl, 2-Propylamino, oxyethyl group, piperazinyl etc.; R " be haloalkyl, C
1~ C
10alkyl, aryl, C
1~ C
10one in alkylamino radical, H etc., such as trifluoromethyl, methyl, ethyl, phenyl, tolyl, pyridyl, amino or H etc.R " ' be C
1~ C
10alkyl or aryl, is preferably methyl, ethyl or phenyl etc.
On the other hand, present invention also offers a kind of pharmaceutical composition with anti-Coxsackie virus activity, described pharmaceutical composition contains the benzimidazole-like heterocyclic compound of the present invention or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
In the preferred embodiments of the invention, described pharmaceutical composition is applicable to (such as oral or rectal administration) in intestines, local or administered parenterally, such as, and oral, injection, implantation, external application, spraying, suction etc.
In the preferred embodiments of the invention, described combination of oral medication is selected from tablet (ordinary tablet, lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, vaginal tablet or vagina effervescence, slow releasing tablet, controlled release tablet, enteric coated tablet, oral dosage form etc.), capsule (hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.), pill (dripping pill, sugar-pill, piller), oral liquid (syrup, suspensoid, oral solution, oral suspensions, Orally taken emulsion, syrup, mixture, distillate medicinal water or medicinal tea), granule (mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.), any one in powder.
In the preferred embodiments of the invention, described injection comprises any one in injection liquid, injectable sterile powder or aseptic block (comprising the preparation such as the technique that adopts solvent crystallization, spray-drying process or freeze-drying), transfusion, concentrated solution for injection.
In the preferred embodiments of the invention, described external preparation is selected from any one in suppository, aerosol, powder inhalation, sprays, film, gelifying agent, patch, jelly, emplastrum, plaster, ointment, liniment, lotion, basting agent, solidifying paste.
In the preferred embodiments of the invention, preparation technique means well known in the art can be adopted to prepare the present composition.
In the preferred embodiments of the invention, described pharmaceutical composition is selected from inclusion preparation or dispersible preparation.
In the preferred embodiments of the invention, described pharmaceutically acceptable carrier is the usual excipients for the preparation of above-mentioned preparation well known to those skilled in the art or auxiliary material.Wherein, the vehicle that oral preparations or external preparation are conventional or auxiliary material comprise but are not limited only to weighting agent or thinner, lubricant or glidant or antitack agent, dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent etc.Tackiness agent, such as syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, cellulose and its derivates, gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Weighting agent, such as lactose, Icing Sugar, dextrin, starch and derivative thereof, cellulose and its derivates, inorganic calcium salt, sorbyl alcohol or glycine, preferred inorganic calcium salt is calcium sulfate, calcium phosphate, secondary calcium phosphate or precipitated calcium carbonate etc.; Lubricant, such as micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil or polyoxyethylene glycol etc.; Disintegrating agent, such as starch and derivative thereof, polyvinylpyrrolidone or Microcrystalline Cellulose etc.; Wetting agent, such as sodium lauryl sulphate, water or alcohol etc., preferred pharmaceutically acceptable carrier is cyclodextrin (alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin), Celldone102CG, Polyplasdone XL-10, talcum powder, Magnesium Stearate or ethanol etc.
Preferably, derivatived cellulose is Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose, HPMC.Preferred starch derivative is sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum.
In the preferred embodiments of the invention, the vehicle that described injection is conventional or auxiliary material comprise but are not limited only to: oxidation inhibitor, such as Sulfothiorine, S-WAT, sodium bisulfite, dibutyl benzoic acid or Sodium Pyrosulfite etc.; Fungistat, such as 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; PH adjusting agent, such as hydrochloric acid, Citric Acid, potassium hydroxide (sodium), Sodium Citrate, buffer reagent (as the buffer reagent that phosphoric acid dioxy sodium and Sodium phosphate dibasic form); Emulsifying agent, such as Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, such as tween-80, glycerine etc.
In the preferred embodiments of the invention, also activeconstituents can be prepared requirement with pharmaceutically acceptable slow controlled release carrier by it to be mixed, be prepared according to the method preparing sustained-release preparation well known in the art again, as added retarding agent dressing or making micropill again by after active principle microcapsules, as sustained release pellet or controlled release micro pill.Described slow controlled release carrier comprises but is not limited only to oilly mix agent, hydrophilic colloid or dressing retarding agent etc.; It is described that oil to mix agent be glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane, dimethyl siloxane; Described hydrophilic colloid is the derivatived celluloses such as Xylo-Mucine, hydroxypropylcellulose, Vltra tears, or PVP, gum arabic, tragcanth or carbopol etc.; Described dressing retarding agent is ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin etc.
In the preferred embodiments of the invention, according to required administering mode, pharmaceutically acceptable composition comprises any one or its combination of acceptable ester on acceptable salt on the structural compounds shown in the formula I of about 1-99 % by weight, compound 1-53 or its pharmacology or its pharmacology, and the pharmaceutically acceptable carrier that 1-99 % by weight is suitable.
In the preferred embodiments of the invention, any one or its combination of acceptable ester on acceptable salt or its pharmacology on structural compounds, compound 1-53 or its pharmacology shown in the formula I comprising about 5-75 % by weight in described pharmaceutical composition, surplus is pharmaceutically acceptable carrier.
In addition on the one hand, present invention also offers a kind of benzimidazole-like heterocyclic compound as above, its pharmacy acceptable salt, its pharmaceutically acceptable ester or the application of its pharmaceutical composition in the medicine for the preparation of anti-Coxsackie virus.
In better embodiment of the present invention, the medicine of described anti-Coxsackie virus is for preventing and treating any one or its combination in respiratory tract infection, herpangina, hot fash, hand foot mouth disease, infantile diarrhea, central nervous system syndromes, myocarditis, pericarditis, epidemic pleurodynia or myalgia, epidemic conjunctivitis, viral hepatitis, flu or Other diseases.
In another better embodiment of the present invention, dosage when Suo Shu oxadiazole compounds of the present invention or its pharmacy acceptable salt or its pharmaceutically acceptable ester or its pharmaceutical composition are used for anti-Coxsackie virus is about 10-500mg/ days, is preferably 20-300mg/ days.
In order to clearly state protection scope of the present invention, except as otherwise noted, the present invention defines as follows to following term:
" C of the present invention
1-C
10alkyl " comprise the straight or branched low alkyl group with 1-10 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl or hexyl etc.
" C of the present invention
1-C
10alkylamino radical " comprise the rudimentary carbon amido of the straight or branched with 1-10 carbon atom, such as methylamino, ethylamino-, Propylamino, 2-Propylamino, butylamine base, 2-butylamine base, 3-butylamine base, 2-methyl-2-butylamine base, amylamine base, tertiary amylamine base or hexylamine base etc.
" cycloalkanes amido " of the present invention refers to 4-unit, 5-is first, 6-is first or the first saturated or undersaturated carbocyclic ring amido of part of 7-; Such as cyclopropyl amino, ring butylamine base, cyclopentamine base, cyclohexylamino etc.
" C of the present invention
1-C
10alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, tertiary pentyloxy or hexyloxy etc.
" aryl " of the present invention comprises phenyl, naphthyl etc., and described aryl can have one or more (preferably 1-3) suitable substituting group, such as halogen, itrile group, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, list (or two or three) halo (C
1-C
10) alkyl etc.
" aryloxy " of the present invention comprises phenoxy group, naphthyloxy etc., and described aryloxy can have one or more (preferably 1-3) suitable substituting group, such as halogen, itrile group, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, list (or two or three) halo (C
1-C
10) alkyl etc.
" heterocyclic oxy group " of the present invention refers to the heteroatomic 5-unit's epoxy group(ing) or 6-unit epoxy group(ing) that comprise 1,2,3 or 4 such as nitrogen, oxygen or sulphur, and described heterocycle optionally can comprise the individual suitable substituting group of 1-4.Preferably, suitable substituting group is selected from halogen, itrile group, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, list (or two or three) halo (C
1-C
10) substituting group such as alkyl;
" heterocycle " of the present invention refers to 4-unit, 5-is first, 6-is first or the first saturated or undersaturated member ring systems of part of 7-, and described member ring systems contains 1-2 heteroatoms as the heteroatoms of nitrogen, oxygen and/or sulphur, such as piperidines, morpholine or piperazine.
Except as otherwise noted, when the present invention relates to the per-cent between liquid and liquid, described per-cent is volume/volume per-cent; When the present invention relates to the per-cent between liquid and solid, described per-cent is volume/weight per-cent; When the present invention relates to the per-cent between solid and liquid, described per-cent is weight/volume percent; All the other are weight/weight percent.
Be described further below with reference to the technique effect of accompanying drawing to design of the present invention, concrete structure and generation, to understand object of the present invention, characteristic sum effect fully.
Accompanying drawing explanation
Fig. 1 is the compounds of this invention 1
1hNMR schemes;
Fig. 2 is the compounds of this invention 10
1hNMR schemes;
Fig. 3 is the compounds of this invention 16
1hNMR schemes;
Fig. 4 is the compounds of this invention 32
1hNMR schemes.
Embodiment
Illustrate the present invention below with reference to embodiment, embodiments of the invention are only for illustration of technical scheme of the present invention, and non-limiting essence of the present invention and scope.
Embodiment 1
The preparation of 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (I1)
By 3g(19.8mmol) 2,3-diaminobenzoic acids join in round-bottomed flask, add 100mL1,4-dioxane dissolves, then adds 2.15g para benzoquinone (19.8mmol), under agitation adds 2.23g(20.9mmol) 2-pyridylaldehyde.Be warming up to backflow, keep 12 hours.TCL detection reaction to terminal, after cool to room temperature, suction filtration.Filter cake ethanol: the solution of ether=1:1 cleans 3 times.Oven dry obtains crude product, is further purified obtains target product Compound I 1 with column chromatography.Productive rate about 95%.
1H MNR(DMSO,400MHz)：7.34-7.38(t,1H,),7.56-7.59(m,1H),7.69-7.71(d,1H),7.87-7.89(d,1H),8.02-8.06(m,1H),8.45-8.47(d,1H),8.76-8.77(m,1H)。
Embodiment 2 ~ 10
Adopt different raw materials, with and the same method preparation table 1 of embodiment 1 in compound:
Table 1
Embodiment 11
The preparation of the bromo-1H-benzoglyoxaline of 2--4-carboxylic acid (II1)
2.4g(0.04mol) urea and 6.08g(0.04mol) 3,4-diaminobenzoic acids are added in 30mL toluene, temperature rising reflux 5 hours, and after reaction terminates, solvent is evaporated, obtains 6g product.
Compound 0.5g(2.8mmol by above-mentioned preparation) be added in 5mL tribromo oxygen phosphorus, be warmed up to 70 DEG C, keep being added in water after 3 hours, filter after neutralization and obtain the bromo-1H-benzoglyoxaline of target product 2--4-carboxylic acid (yield 70%).
1H MNR(DMSO,400MHz)：7.47-7.50(t,1H),8.04-8.13(d,2H)。
Embodiment 12
The preparation of 2-oxyethyl group-1H-benzoglyoxaline-4-carboxylic acid (II2)
Bromo-for 1.1mmol2-1H-benzoglyoxaline-4-carboxylic acid (Compound II per 1) be added in 10mL DMF, add 2.1mmol sodium ethylate, be warmed up to 80 DEG C of reactions 2 hours, cooling filtration washing can obtain the 2-oxyethyl group-1H-benzoglyoxaline-4-carboxylic acid of 65% yield.
1H MNR(DMSO,400MHz)：1.33-1.40(t,3H),3.98-4.02(m,2H),7.47-7.50(t,1H),8.04-8.13(d,2H)。
Embodiment 13 ~ 17
Adopt different material, and the same method of embodiment 10 can obtain the compound in table 2
Table 2
Embodiment 18
The preparation of 2-isopropylamine base-1H-benzoglyoxaline-4-carboxylic acid (III1)
The bromo-1H-benzoglyoxaline of the 1.1mmol2--4-carboxylic acid of preparation in example 10 is added (Compound II per 1) in 10mLDMF, add 2.2mmol Isopropylamine, be warmed up to 80 DEG C of reactions 2 hours, cooling filtration washing can obtain the 2-isopropylamine base-1H-benzoglyoxaline-4-carboxylic acid of 60% yield.
1H MNR(DMSO,400MHz)：1.05-1.08(d,6H),2.97-3.01(m,1H),4.01(s,1H),5.0(s,1H),7.44-7.51(m,2H),7.98-8.01(d,1H).
Embodiment 19 ~ 22
Adopt different material, with and the same method preparation table 3 of embodiment 18 in compound
Table 3
Embodiment 28 ~ 36
Adopt different material, with and the same method preparation table 4 of embodiment 18 in compound
Table 4
Embodiment 37
The preparation of 2-(2 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-Ji)-1H-benzoglyoxaline (1)
By 1g(4.18mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (Compound I 1) is dissolved in 20mL dimethyl formamide, then adds 1.60g(8.37mmol) N-(3-dimethylaminopropyl)-N`-ethyl-carbodiimide hydrochloride and 1.13g(8.37mmol) 1-hydroxybenzimidazole hydrate.Mixture is at room temperature stirred 1 hour.Add 0.31g(4.18mmol) N-hydroxyl acetamidine, and stirring at room temperature 24 hours.TCL detection reaction to terminal.This reactant is added in 40mL water and separates out.Filter, dry and obtain crude product.Column chromatography purification obtains compound 1.Productive rate about 70%.
1H MNR(DMSO,400MHz)：2.46(s,3H),7.41-7.48(m,1H),7.55-7.60(m,1H),7.81-7.83(d,1H),7.97-7.99(m,1H),8.03-8.07(t,1H),8.40-8.42(d,1H),8.76-8.77(d,1H)。
Embodiment 38 ~ 49
Adopt different material, with and the same method of embodiment 37 obtain compound in table 5
Table 5
Embodiment 50
The preparation of 4-(amino-1,3, the 4-thiazol-2-yl of 5-)-2-(2-pyridyl)-1H-benzoglyoxaline (14)
By 1g(4.18mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4 carboxylic acid (Compound I 1) and 0.56g thiosemicarbazide (5.02mmol) join 10mL POCl
3in solution.Be warming up to 80 DEG C of reactions 12 hours, after reaction terminates, join after reactant cool to room temperature in frozen water.Separate out solid, filter, saturated NaHCO first used by filter cake
3solution washing, then wash, the compound 14 of yield about 65% is obtained after filtration cakes torrefaction with column chromatography purification.
1H MNR(DMSO,400MHz)：7.55-7.57(t,1H),7.68-7.88(m,2H),7.99-8.04(t,1H),8.10-8.23(d,1H),8.34-8.36(d,1H),8.75-8.76(d,1H)。
Embodiment 51
The preparation of 5-(amino-1,3, the 4-thiazol-2-yl of 5-)-2-(2-pyridyl)-1H-benzoglyoxaline (15)
Adopt different material, with and the same method of embodiment 50 obtain 5-(5-amino-1,3,4-thiazol-2-yl)-2-(2-pyridyl)-1H-benzoglyoxaline (15).
1H NMR(DMSO,400MHz)δ:7.55-7.57(t,1H),7.68-7.88(m,2H),7.99-8.04(t,1H),8.10-8.23(d,1H),8.34-8.36(d,1H),8.75-8.76(d,1H).
Embodiment 52
The preparation of 4-(5-methyl isophthalic acid, 3,4-oxadiazoles-2-base)-2-(2-pyridyl)-1H-benzoglyoxaline (16)
By 3g(13.1mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid in 60mL methyl alcohol, add 3mL SOCl
2, reflux 4 hours.TCL detection reaction is to terminating, and decompression evaporates solvent.Saturated NaHCO
3solution adjusts pH value to weakly alkaline, and suction filtration, solid drying obtains 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylate methyl ester.
By 2.5g(9.7mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4/5 carboxylate methyl ester is dissolved in 50mL methyl alcohol, adds 2.43g(48.6mmol) hydrazine hydrate, be heated to backflow.To terminal, cool to room temperature, solid suction filtration, drying obtains 2-(2-pyridyl)-1H-benzoglyoxaline-4-hydrazides to TCL detection reaction.
By 2g(7.9mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4--hydrazides and 0.58g(7.9mmol) Glacial acetic acid joins 15mL POCl
3in solution.Be warming up to 80 DEG C of reactions 12 hours.After reaction terminates, slowly join after reactant cool to room temperature in frozen water.Separate out solid, filter, successively use saturated NaHCO
3solution and washing washing, obtain compound 16 with column chromatography purification after drying.
1H MNR(DMSO,400MHz)：2.65(s,3H),7.39-7.43(t,1H),7.54-7.57(m,1H),7.80-7.82(t,1H),7.84-7.86(d,1H),8.00-8.05(m,1H),8.36-8.38(d,1H),8.75-8.77(m,1H)。
Embodiment 53 ~ 64
Adopt different material, with and the same method preparation table 6 of embodiment 50 in compound
Table 6
Embodiment 65
The preparation of 4-(4 '-amino-5-methyl-4H-1,2,4-triazole-3-base)-2-(2-pyridyl)-1H-benzoglyoxaline (29)
By 1g(3.6mmol) 2-(2-pyridyl)-4-(5-methyl isophthalic acid, 3,4-oxadiazoles-2-base)-1H-benzoglyoxaline joins in 15mL hydrazine hydrate, back flow reaction 8 hours.Be added in 20mL cold water after cool to room temperature, filter, after washing, drying obtains crude product.Yield 50% target product is obtained with column chromatography purification.
1H NMR(DMSO,400MHz)δ:4.75(s,3H),7.35-7.39(t,1H),7.56-7.59(t,1H),7.70-7.72(d,1H),7.88-7.90(d,1H),8.03-8.07(m,1H),8.42-8.44(d,1H),8.76-8.77(d,1H)。
Embodiment 66 ~ 76
Adopt different material, with and the same method preparation table 7 of embodiment 65 in compound
Table 7
Embodiment 77
The preparation of 2-oxyethyl group-4-(5-Trifluoromethyl-1,2,4-oxadiazole-3-base)-1H-benzoglyoxaline (41)
By 2-oxyethyl group-4-cyano-benzimidazole 52g, oxammonium hydrochloride 47g joins in 500mL ethanol, reflux 4 hours, and thin-layer chromatography detects, 2-oxyethyl group-4-cyano-benzimidazole primitive reaction is complete, after distillation removing ethanol, add 500mL tetrahydrofuran (THF), slowly add trifluoroacetic anhydride 236g, reflux 4 hours, after cooling, filter, obtained target product.
1H MNR(DMSO,400MHz)：1.33-1.40(t,3H),3.98-4.10(m,2H),7.32-7.41(t,1H),7.48-7.53(d,1H),7.66-7.69(d,1H).
Embodiment 78 ~ 88
Adopt different material, with and the similar method of embodiment 77 obtain compound in table 8
Table 8
Embodiment 89
The preparation of 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-thiazole-2 '-Ji)-1H-benzoglyoxaline (53)
1g2-(2 '-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (4.18mmol) and 0.56g thiosemicarbazide (, 5.02mmol) are joined 10mL POCl
3in solution.Be warming up to 80 DEG C of reactions 12 hours.Be added in frozen water after cool to room temperature.After filtering, dry column chromatography purification obtains target product.
1H NMR(DMSO,400MHz)δ:2.65(s,3H),7.39-7.43(t,1H),7.54-7.57(m,1H),7.80-7.82(t,1H),7.84-7.86(d,1H),8.00-8.05(m,1H),8.36-8.38(d,1H),8.75-8.77(m,1H).
Embodiment 90
The anti-Cox_B of compound 1-53
6experimental result
The anti-Cox_B of the present embodiment experimental verification the compounds of this invention 1-53
6experimental result, adopts Pleconaril3-[3,5-dimethyl-4-[5-(3-methyl isophthalic acid, 2-oxazolyl) propoxy-] phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole to be positive control.Experimental technique: Vero cell kind 96 well culture plate, 24 hours postoperative infection Cox_B
3virus, adsorb 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 Cox_B when virus control group lesion degree (CPE) reaches 4+
6half-inhibition concentration (the IC of virus
50).Result shows compound of the present invention and has good anti-Cox_B
6virus performance.The results are shown in Table 9.
Table 9
Note: IC
50represent viral half-inhibition concentration.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that the ordinary skill of this area just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technician in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (8)
1. following compounds or its pharmacy acceptable salt:
1) 2-(2 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
2) 2-(3 '-pyridyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
3) 2-(4 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
4) 2-(2 '-thienyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
5) the bromo-4-of 2-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
6) 2-(2 '-pyridyl)-5-[3 '-(2 '-pyridyl)-1,2,4-oxadiazole-5 '-Ji]-1H-benzoglyoxaline;
7) 2-(3 '-pyridyl)-5-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
8) 2-(4 '-pyridyl)-5-(3 '-p-methylphenyl-1,2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
9) the bromo-5-of 2-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
10) 2-oxyethyl group-4-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
11) 2-isopropylamine base-4-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
12) 2-oxyethyl group-5-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
13) 2-isopropylamine base-5-(3 '-methyl isophthalic acid, 2,4-oxadiazole-5 '-Ji)-1H-benzoglyoxaline;
14) 2-(2 '-pyridyl)-4-(5 '-amido-1,3,4-thiadiazoles-2 '-Ji)-1H-benzoglyoxaline;
15) 2-(2 '-pyridyl)-5-(5 '-amido-1,3,4-thiadiazoles-2 '-Ji)-1H-benzoglyoxaline;
16) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
17) 2-(3 '-pyridyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
18) 2-(4 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
19) 2-(2 '-thienyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
20) the bromo-4-of 2-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
21) 2-(2 '-pyridyl)-5-[5 '-(2 '-pyridyl)-1,3,4-oxadiazole-2 '-Ji]-1H-benzoglyoxaline;
22) 2-(3 '-pyridyl)-5-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
23) 2-(4 '-pyridyl)-5-(5 '-p-methylphenyl-1,3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
24) the bromo-5-of 2-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
25) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
26) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
27) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
28) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 3,4-oxadiazole-2 '-Ji)-1H-benzoglyoxaline;
29) 2-(2 '-pyridyl)-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
30) 2-(3 '-pyridyl)-4-(4 '-ethyl-5 '-p-methylphenyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
31) 2-(4 '-pyridyl)-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
32) the bromo-4-of 2-(5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
33) 2-(2 '-pyridyl)-5-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
34) the bromo-5-of 2-(5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
35) the bromo-5-of 2-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
36) 2-oxyethyl group-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
37) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
38) 2-oxyethyl group-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
39) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-Ji)-1H-benzoglyoxaline;
40) 2-oxyethyl group-4-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji-)-1H-benzoglyoxaline;
41) 2-(2 '-pyridyl)-4-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
42) 2-isopropylamine base-4-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
43) 2-(1 '-piperidyl)-4-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
44) 2-(2 '-pyridyl)-5-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
45) 2-isopropylamine base-5-(5 '-Trifluoromethyl-1,2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
46) 2-(1 '-morpholinyl)-5-(5 '-methyl isophthalic acid, 2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
47) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
48) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
49) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
50) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 2,4-oxadiazole-3 '-Ji)-1H-benzoglyoxaline;
51) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-thiadiazoles-2 '-Ji)-1H-benzoglyoxaline.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein, any one or its that described pharmacy acceptable salt is selected from the hydrochlorate of described compound and mineral acid or organic acid adduction gained combine, or any one or its that are selected from the alkali salt of described compound and mineral alkali or organic bases adduction gained combine.
3. compound as claimed in claim 2 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is selected from any one or its combination in hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate.
4. compound as claimed in claim 2 or its pharmacy acceptable salt, wherein, described pharmacy acceptable salt is selected from any one or its combination in alkaline earth salt, organic amine salt.
5. compound as claimed in claim 4 or its pharmacy acceptable salt, wherein, described alkaline earth salt is selected from any one or its combination of magnesium salts or calcium salt.
6. compound as claimed in claim 4 or its pharmacy acceptable salt, wherein, described organic amine salt is selected from any one or its combination in alkylbenzyldimethylasaltsum saltsum, piperidinium salt, trialkyl amine salt, dimethylamine salt, diethylamine salt.
7. a pharmaceutical composition, containing, for example the compound according to any one of claim 1-6 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
8. the compound according to any one of claim 1-6, its pharmacy acceptable salt, or the application of pharmaceutical composition in the medicine for the preparation of anti-Coxsackie virus as claimed in claim 7.
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