CN103087045A - Benzimidazole heterocyclic compound, pharmaceutical composition and application thereof - Google Patents

Benzimidazole heterocyclic compound, pharmaceutical composition and application thereof Download PDF

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CN103087045A
CN103087045A CN2013100117576A CN201310011757A CN103087045A CN 103087045 A CN103087045 A CN 103087045A CN 2013100117576 A CN2013100117576 A CN 2013100117576A CN 201310011757 A CN201310011757 A CN 201310011757A CN 103087045 A CN103087045 A CN 103087045A
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benzoglyoxaline
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CN103087045B (en
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罗先金
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Shanghai Jiaotong University
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Abstract

The invention discloses a benzimidazole heterocyclic compound with a molecular formula (I) or pharmaceutical acceptable salts, esters or pharmaceutical compositions, wherein R is halogen, alkyl, alkyamino, cyclic alkyamino, arylamine, heterocyclic amido, aryl, alkoxy, heterocyclicoxy, aryloxy or heterocyclic radical; R1 is 4-site or 5-site heterocyclic radical; and R2 is hydrogen or alkyl. The pharmaceutical composition contains an effective amount of benzimidazole heterocyclic compound for treatment or pharmaceutical acceptable salts and pharmaceutical acceptable carriers. The invention also discloses a method for preparing the benzimidazole heterocyclic compound, and application of the benzimidazole heterocyclic compound, the pharmaceutical acceptable salts, esters or pharmaceutical compositions in preparation of medicines for resisting Coxsackie viruses.

Description

A kind of benzimidazole-like heterocyclic compound, medical composition and its use
Technical field
The present invention relates to a kind of benzimidazole-like heterocyclic compound, the medical composition and its use that relates in particular to a kind of novel benzimidazoles heterogeneous ring compound and contain 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 has caused the interest of Many researchers to benzimidazoles compound.In research before us, found 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 that is caused by enterovirus (enteroviruses) worldwide happens occasionally.The 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, more than having 70 types at least, can invade Various Tissues, as nerve, cardiac muscle, muscle, skin and eye conjunctiva etc., cause a variety of communicable diseases in the whole world.Picornavirus can be invaded the Various Tissues system, causes the clinical manifestation variation.Clinical common 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 the less safer antiviral compound of a kind of synthetic toxicity.
Summary of the invention
Because the defects of prior art, technical problem to be solved by this invention is to provide the little and safe novel benzimidazoles Heterocylic antiviral compounds of a kind of synthetic toxicity.
For achieving the above object, the invention provides a kind of benzimidazole-like heterocyclic compound with anti-Coxsackie virus and preparation method thereof, application.
From an aspect, the invention provides the benzimidazole-like heterocyclic compound shown in a kind of formula (I) with anti-Coxsackie virus (Cosxackie viruses)
Figure BDA00002727479400021
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 4 or 5 s' heterocyclic radical; R 2Be 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 that contains substituting group or unsubstituted, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or six-ring amido, the phenyl that contains substituting group or unsubstituted, C 1～C 10Any in the group that alkoxyl group, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or hexa-atomic epoxy group(ing), the phenoxy group that contains substituting group or unsubstituted, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or six-ring heterocycle oxygen form;
R 1Be 4 or 5 Wei De oxadiazolyls, thiadiazolyl group, or triazol radical;
R 2Be hydrogen, or C 1～C 10Alkyl.
In the present invention, described pharmaceutically acceptable salt refers to comprise mineral alkali or organic bases from pharmaceutically acceptable nontoxic alkali or the sour salt for preparing, and mineral acid or organic acid.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 to be molecular formula of the present invention the be hydrochlorate of (I) or compound (II) and mineral acid or organic acid adduction gained, any 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; Perhaps add alkali salt with gained by molecular formula of the present invention for (I) or compound (II) and mineral alkali or organic bases, as any or its combination in alkaline earth salt, organic amine salt.
In the preferred embodiments of the invention, described alkaline earth salt is selected from any or its combination of magnesium salts or calcium salt.
In the preferred embodiments of the invention, described organic amine salt is selected from any or its combination in alkylbenzyldimethylasaltsum saltsum, piperidinium salt, trialkyl amine salt, pyridinium salt, dimethylamine salt, diethyl amine salt.
In the specific embodiment of the present invention, also provide the benzimidazole-like heterocyclic compound shown in a kind of formula (II) with anti-Coxsackie virus
Figure BDA00002727479400022
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 4 or 5 s' heterocyclic radical.
In better embodiment of the present invention, the R of the benzimidazole-like heterocyclic compound shown in formula (II) 1Be 4 or 5 Wei De oxadiazolyls, thiadiazolyl group or triazol radical.
In another better embodiment of the present invention, shown in formula (II), the preferred example of the benzimidazole-like heterocyclic compound of structure or its pharmacy acceptable salt is as follows:
1) 2-(2 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
2) 2-(3 '-pyridyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
3) 2-(4 '-pyridyl)-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
4) 2-(2 '-thienyl)-4-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
5) 2-bromo-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
6) 2-(2 '-pyridyl)-5-[3 '-(2 '-pyridyl)-1,2,4-oxadiazoles-5 '-yl]-the 1H-benzoglyoxaline;
7) 2-(3 '-pyridyl)-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
8) 2-(4 '-pyridyl)-5-(3 '-p-methylphenyl-1,2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
9) 2-bromo-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
10) 2-oxyethyl group-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
11) 2-isopropylamine base-4-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-4 '-yl)-1H-benzoglyoxaline;
12) 2-oxyethyl group-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline;
13) 2-isopropylamine base-5-(3 '-methyl isophthalic acid, 2,4-oxadiazoles-4 '-yl)-1H-benzoglyoxaline;
14) 2-(2 '-pyridyl)-4-(5 '-amino-1,3,4-thiazole-2 '-yl)-1H-benzoglyoxaline;
15) 2-(2 '-pyridyl)-5-(5 '-amino-1,3,4-thiazole-2 '-yl)-1H-benzoglyoxaline;
16) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
17) 2-(3 '-pyridyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
18) 2-(4 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
19) 2-(2 '-thienyl)-4-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
20) 2-bromo-4-(5 '-first-1,3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
21) 2-(2 '-pyridyl)-5-[5 '-(2 '-pyridyl)-1,3,4-oxadiazoles-2 '-yl]-the 1H-benzoglyoxaline;
22) 2-(3 '-pyridyl)-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
23) 2-(4 '-pyridyl)-5-(5 '-p-methylphenyl-1,3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
24) 2-bromo-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
25) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
26) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
27) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
28) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 3,4-oxadiazoles-2 '-yl)-1H-benzoglyoxaline;
29) 2-(2 '-pyridyl)-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
30) 2-(3 '-pyridyl)-4-(4 '-ethyl-5 '-p-methylphenyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
31) 2-(4 '-pyridyl)-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
32) 2-(2 '-pyridyl)-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
33) 2-bromo-4-(5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
34) 2-(2 '-pyridyl)-5-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
35) 2-bromo-5-(5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
36) 2-bromo-5-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
37) 2-oxyethyl group-4-(4 '-amino-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
38) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
39) 2-oxyethyl group-4-(4 '-phenyl-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-1H-benzoglyoxaline;
40) 2-isopropylamine base-4-(4 '-ethyl-5 '-methyl-4H-1,2,4-triazole-3 '-yl)-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 '-yl)-1H-benzoglyoxaline;
43) 2-isopropylamine base-4-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
44) 2-(1 '-piperidyl)-4-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
45) 2-(2 '-pyridyl)-5-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
46) 2-isopropylamine base-5-(5 '-Trifluoromethyl-1,2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
47) 2-(1 '-morpholinyl)-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
48) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
49) 2-oxyethyl group-4-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
50) 2-isopropylamine base-4-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
51) 2-oxyethyl group-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
52) 2-isopropylamine base-5-(5 '-methyl isophthalic acid, 2,4-oxadiazoles-3 '-yl)-1H-benzoglyoxaline;
53) 2-(2 '-pyridyl)-4-(5 '-methyl isophthalic acid, 3,4-thiazole-2 '-yl)-1H-benzoglyoxaline.
From other aspect, the invention provides a kind of benzimidazoles derivative of structure shown in formula as above (I) or method of its pharmacy acceptable salt of preparing, the method comprises the steps:
Step 1, 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;
Figure BDA00002727479400041
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 contain aminocompound or oxy-compound condensation with preparation 4-or 5-carboxylic acid benzoglyoxaline with R replaces;
Figure BDA00002727479400051
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 that replaces
Figure BDA00002727479400052
Wherein, R 1It is 4 or 5 s' heterocyclic radical;
In the preferred embodiment of the present invention, R 1Be 4 or 5 Wei De oxadiazolyls, thiadiazolyl group, or triazol radical; For example, R 1For being selected from a kind of in following molecular formula,
Figure BDA00002727479400053
In another preferred implementation of the present invention, work as R 1Be 4 or 5 s' 1,2, during the 4-oxadiazolyl, above-mentioned steps two is specific as follows:
1) preparation 1,2,4-oxadiazole compounds
The 4-of use above-mentioned steps one preparation or 5-carboxylic acid benzoglyoxaline and amidine compound closed loop prepare benzoglyoxaline 1,2,4-oxadiazole compound IA or IB;
Work as R 1Be 4 or 5 s' 1,3, during the 4-thiadiazolyl group, above-mentioned steps two is specific as follows:
2) preparation 1,3,4-thiadiazole compound
The 4-that the use step 1 makes or 5-carboxylic acid benzoglyoxaline and thiosemicarbazide closed loop prepare 1,3,4-thiadiazole compound IC;
Figure BDA00002727479400061
Work as R 1Be 4 or 5 s' 1,3, during the 4-oxadiazolyl, above-mentioned steps two is specific as follows:
3) preparation 1,3,4-oxadiazole compounds
After the 4-or the esterification of 5-carboxylic acid benzoglyoxaline that step 1 is made, then itself and hydrazine hydrate reaction are obtained hydrazide compound, and then prepare 1,3,4-oxadiazole compounds ID with the carboxylic acid cpd closed loop;
Figure BDA00002727479400062
Work as R 1When being 4 or 5 s' triazol radical, above-mentioned steps two is specific as follows:
4) preparation triazole compound IE
With step 3) make 1,3,4-oxadiazole compounds and aminocompound reaction preparation triazole compound.
Figure BDA00002727479400063
Step 3, preparation molecular formula are the benzimidazole-like heterocyclic compound of (I)
With step 1), 2), 3) or 4) preparation De oxadiazolyl, thiadiazolyl group or triazole compound and haloalkane (R 2X) reaction, obtain the benzimidazole-like heterocyclic compound shown in formula (I);
Figure BDA00002727479400064
Wherein, R 1It is 4 or 5 s' heterocyclic radical; R 2Be C 1～C 10Alkyl, X are halogen; R preferably 2X is methyl iodide.
In preparation method's of the present invention embodiment, 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 10A kind of 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 10A kind of 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, the present invention also provides a kind of pharmaceutical composition with anti-Coxsackie virus activity, and described pharmaceutical composition contains benzimidazole-like heterocyclic compound of the present invention or its pharmacy acceptable salt and the pharmaceutically acceptable carrier for the treatment of significant quantity.
In the preferred embodiments of the invention, described pharmaceutical composition is applicable to (for example oral or rectal administration) in intestines, part or administered parenterally, for example, 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 in powder.
In the preferred embodiments of the invention, described injection comprises any 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 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, can adopt preparation technique means well known in the art 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 commonly used 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, Mierocrystalline cellulose and derivative thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, 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 is such as starch and derivative, 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, vehicle or auxiliary material that described injection is commonly used comprise but are not limited only to: oxidation inhibitor, such as Sulfothiorine, S-WAT, sodium bisulfite, dibutyl benzoic acid or Sodium Pyrosulfite etc.; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; PH adjusting agent, for example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), Sodium Citrate, buffer reagent (as the buffer reagent of phosphoric acid dioxy sodium and Sodium phosphate dibasic composition); Emulsifying agent, for example 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 mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, be prepared according to the method for preparing sustained-release preparation well known in the art again, as add the retarding agent dressing or with making again micropill 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 oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing; 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 or its combination of acceptable ester on acceptable salt on structural compounds, compound 1-53 or its pharmacology shown in the formula I of about 1-99 % by weight or its pharmacology, and the suitable pharmaceutically acceptable carrier of 1-99 % by weight.
In the preferred embodiments of the invention, comprise shown in the formula I of about 5-75 % by weight any or its combination of acceptable ester on acceptable salt on structural compounds, compound 1-53 or its pharmacology or its pharmacology in described pharmaceutical composition, surplus is pharmaceutically acceptable carrier.
In addition on the one hand, the present invention also provides a kind of benzimidazole-like heterocyclic compound as above, its pharmacy acceptable salt, its pharmaceutically acceptable ester or its pharmaceutical composition for the preparation of the application in the medicine of anti-Coxsackie virus.
In better embodiment of the present invention, the medicine of described anti-Coxsackie virus is used for any or its combination of control 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 De 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 clearly to explain protection scope of the present invention, except as otherwise noted, the present invention carries out following defining 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 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, uncle's amylamine base or hexylamine base etc.
" cycloalkanes amido " of the present invention refers to that 4-is first, 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, uncle's 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, for example 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, for example 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 comprise heteroatomic 5-unit's epoxy group(ing) or the 6-unit epoxy group(ing) of 1,2,3 or 4 such as nitrogen, oxygen or sulphur, and described heterocycle can be chosen wantonly and comprises 1-4 suitable substituting group.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 that 4-is first, 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 the heteroatoms of 1-2 heteroatoms such as nitrogen, oxygen and/or sulphur, for example 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 fully purpose of the present invention, feature and effect.
Description of drawings
Fig. 1 is the compounds of this invention 1 1HNMR figure;
Fig. 2 is the compounds of this invention 10 1HNMR figure;
Fig. 3 is the compounds of this invention 16 1HNMR figure;
Fig. 4 is the compounds of this invention 32 1HNMR figure.
Embodiment
Illustrate the present invention below with reference to embodiment, embodiments of the invention only are used for technical scheme of the present invention is described, and non-limiting essence of the present invention and scope.
Embodiment 1
The preparation of 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (I1)
Figure BDA00002727479400101
With 3g(19.8mmol) 2, the 3-diaminobenzoic acid joins in round-bottomed flask, adds 100mL1, the dissolving of 4-dioxane, then add 2.15g para benzoquinone (19.8mmol), and under agitation add 2.23g(20.9mmol) the 2-pyridylaldehyde.Be warming up to backflow, kept 12 hours.The TCL detection reaction to terminal, after cool to room temperature, suction filtration.The solution of filter cake ethanol: ether=1:1 cleans 3 times.Oven dry obtains crude product, is further purified with column chromatography and obtains target product Compound I 1.Productive rate approximately 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:
Figure BDA00002727479400102
Table 1
Figure BDA00002727479400103
Figure BDA00002727479400111
Embodiment 11
The preparation of 2-bromo-1H-benzoglyoxaline-4-carboxylic acid (II1)
Figure BDA00002727479400112
2.4g(0.04mol) urea and 6.08g(0.04mol) 3, the 4-diaminobenzoic acid is added in 30mL toluene, temperature rising reflux 5 hours, and reaction after finishing is evaporated solvent, obtains the 6g product.
Compound 0.5g(2.8mmol with above-mentioned preparation) be added in 5mL tribromo oxygen phosphorus, be warmed up to 70 ℃, keep being added in water after 3 hours, filter after neutralization and obtain target product 2-bromo-1H-benzoglyoxaline-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)
Figure BDA00002727479400113
1.1mmol2-bromo-1H-benzoglyoxaline-4-carboxylic acid (Compound I I1) is added in 10mL DMF, adds the 2.1mmol sodium ethylate, be warmed up to 80 ℃ of reactions 2 hours, the cooling filtration washing can make the 2-oxyethyl group of 65% yield-1H-benzoglyoxaline-4-carboxylic acid.
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 make the compound in table 2
Figure BDA00002727479400121
Table 2
Embodiment 18
The preparation of 2-isopropylamine base-1H-benzoglyoxaline-4-carboxylic acid (III1)
The 1.1mmol2-bromo-1H-benzoglyoxaline-4-carboxylic acid of preparation in example 10 is added (Compound I I1) in 10mLDMF, add the 2.2mmol Isopropylamine, be warmed up to 80 ℃ of reactions 2 hours, the cooling filtration washing can make the 2-isopropylamine base of 60% yield-1H-benzoglyoxaline-4-carboxylic acid.
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
Figure BDA00002727479400132
Embodiment 28～36
Adopt different material, with and the same method preparation table 4 of embodiment 18 in compound
Table 4
Embodiment 37
2-(2 '-pyridyl)-4-(3 '-methyl isophthalic acid, the preparation of 2,4-oxadiazoles-5 '-yl)-1H-benzoglyoxaline (1)
With 1g(4.18mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (Compound I 1) is dissolved in the 20mL dimethyl formamide, then adds 1.60g(8.37mmol) N-(3-dimethylaminopropyl)-N`-ethyl-carbodiimide hydrochloride and 1.13g(8.37mmol) 1-hydroxy benzo imidazoles hydrate.Mixture was at room temperature stirred 1 hour.Add 0.31g(4.18mmol) the N-hydroxyl acetamidine, and stirring at room 24 hours.The TCL detection reaction to terminal.This reactant is added in 40mL water separates out.Filter, oven dry obtains crude product.Column chromatography purification obtains compound 1.Productive rate approximately 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, use and the same method of embodiment 37 make the compound in table 5
Figure BDA00002727479400151
Table 5
Figure BDA00002727479400152
Figure BDA00002727479400161
Embodiment 50
The preparation of 4-(5-amino-1,3,4-thiazol-2-yl)-2-(2-pyridyl)-1H-benzoglyoxaline (14)
Figure BDA00002727479400162
With 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 ℃ of reactions 12 hours, reaction will join in frozen water after the reactant cool to room temperature after finishing.Separate out solid, filter, filter cake is first used saturated NaHCO 3Solution washing, then washing obtain approximately 65% compound 14 of yield with column chromatography purification after filtration cakes torrefaction.
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-(5-amino-1,3,4-thiazol-2-yl)-2-(2-pyridyl)-1H-benzoglyoxaline (15)
Figure BDA00002727479400171
The employing different material is used and the same method of embodiment 50 makes 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-yl)-2-(2-pyridyl)-1H-benzoglyoxaline (16)
Figure BDA00002727479400172
With 3g(13.1mmol) 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid is dissolved in 60mL methyl alcohol, adds 3mL SOCl 2, reflux 4 hours.The TCL detection reaction is to finishing, reduce pressure to evaporate solvent.Saturated NaHCO 3Solution transfers pH value to weakly alkaline, and suction filtration, solid drying obtain 2-(2-pyridyl)-1H-benzoglyoxaline-4-carboxylate methyl ester.
With 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.The TCL detection reaction to terminal, cool to room temperature, the solid suction filtration, drying obtains 2-(2-pyridyl)-1H-benzoglyoxaline-4-hydrazides.
With 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 ℃ of reactions 12 hours.Reaction will slowly join in frozen water after the reactant cool to room temperature after finishing.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
Figure BDA00002727479400181
Table 6
Figure BDA00002727479400182
Figure BDA00002727479400191
Embodiment 65
The preparation of 4-(4 '-amino-5-methyl-4H-1,2,4-triazole-3-yl)-2-(2-pyridyl)-1H-benzoglyoxaline (29)
Figure BDA00002727479400192
With 1g(3.6mmol) 2-(2-pyridyl)-4-(5-methyl isophthalic acid, 3,4-oxadiazoles-2-yl)-1H-benzoglyoxaline joins in the 15mL hydrazine hydrate, back flow reaction 8 hours.Cool to room temperature is added to later in 20mL cold water, filters, and after washing, drying obtains crude product.Obtain yield 50% target product 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
Figure BDA00002727479400193
Table 7
Figure BDA00002727479400201
Embodiment 77
The preparation of 2-oxyethyl group-4-(5-Trifluoromethyl-1,2,4-oxadiazole-3-yl)-1H-benzoglyoxaline (41)
With 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 ethanol is removed in distillation, add the 500mL tetrahydrofuran (THF), slowly add trifluoroacetic anhydride 236g, reflux 4 hours, after cooling, filter, make 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, use and the similar method of embodiment 77 make the compound in table 8
Figure BDA00002727479400213
Table 8
Figure BDA00002727479400214
Figure BDA00002727479400221
Embodiment 89
2-(2 '-pyridyl)-4-(5 ' methyl isophthalic acid, preparations of 3,4-thiazole-2 '-yl)-1H-benzoglyoxaline (53)
Figure BDA00002727479400222
With 1g2-(2 '-pyridyl)-1H-benzoglyoxaline-4-carboxylic acid (4.18mmol) and 0.56g thiosemicarbazide (, 5.02mmol) join 10mL POCl 3In solution.Be warming up to 80 ℃ 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, the positive contrast of 4-oxadiazole.Experimental technique: Vero cell kind 96 well culture plates, 24 hours postoperative infection Cox_B 3Virus, adsorbed 2 hours, abandon virus liquid, add sample and positive control drug by above extent of dilution, establish simultaneously cell control well and virus control hole, observe the cytopathy degree (CPE) of respectively organizing until virus control group lesion degree (CPE) when reaching 4+, use Reed-Muench method difference calculation sample to Cox_B 6Half-inhibition concentration (the IC of virus 50).Result shows that compound of the present invention has anti-Cox_B preferably 6The virus performance.The results are shown in Table 9.
Table 9
Figure BDA00002727479400231
Annotate: IC 50Expression is to viral half-inhibition concentration.
More than describe preferred embodiment of the present invention in detail.The ordinary skill that should be appreciated that this area need not creative work and just can design according to the present invention make many modifications and variations.Therefore, all technician in the art all should be in the determined protection domain by 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 (10)

1. compound that molecular formula is (I)
Figure FDA00002727479300011
Its pharmacy acceptable salt, or its pharmaceutically acceptable ester;
Wherein: R is halogen, C 1～C 10Alkyl, C 1～C 10Alkylamino radical, cycloalkanes amido, aryl amine, heterocycle amido, aryl, C 1～C 10Alkoxyl group, heterocyclic oxy group, aryloxy, or heterocyclic radical;
R 1It is 4 or 5 s' heterocyclic radical;
R 2Be hydrogen or C 1～C 10Alkyl;
Described heterocycle refer to comprise 1-2 nitrogen, oxygen and/or sulphur heteroatomic 4-unit, 5-is first, 6-is first or the first saturated or undersaturated ring of part of 7-.
2. compound as claimed in claim 1, wherein:
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 that contains substituting group or unsubstituted, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or six-ring amido, the phenyl that contains substituting group or unsubstituted, C 1～C 10Any in the group that alkoxyl group, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or hexa-atomic epoxy group(ing), the phenoxy group that contains substituting group or unsubstituted, the triatomic ring that contains oxygen or nitrogen heteroatom or tetra-atomic ring or five-ring or six-ring heterocycle oxygen form;
R 1Be 4 or 5 Wei De oxadiazolyls, thiadiazolyl group, or triazol radical;
R 2Be hydrogen, or C 1～C 10Alkyl.
3. compound as claimed in claim 1 or 2, wherein, R 2Be hydrogen.
4. compound as claimed in claim 1, wherein, described pharmaceutically acceptable salt be the compound of (I) by described molecular formula with by any or its combination in the hydrochlorate of mineral acid or organic acid adduction gained, or add any or its combination in alkali salt with gained by mineral alkali or organic bases.
5. compound as claimed in claim 4, wherein, described pharmaceutically acceptable salt is the compound of (I) and any or its combination that is selected from hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate by described molecular formula.
6. compound as claimed in claim 4, wherein, described pharmaceutically acceptable salt is selected from any or its combination in alkaline earth salt, organic amine salt.
7. compound as claimed in claim 6, wherein, described alkaline earth salt is selected from any or its combination of magnesium salts or calcium salt.
8. compound as claimed in claim 6, wherein, described organic amine salt is selected from any or its combination in alkylbenzyldimethylasaltsum saltsum, piperidinium salt, trialkyl amine salt, pyridinium salt, dimethylamine salt, diethyl amine salt.
9. a pharmaceutical composition, contain just like compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of arbitrary described molecular formula in claim 1-8 for (I).
10. as arbitrary described compound, its pharmacy acceptable salt or ester in claim 1-8, or as claimed in claim 9 pharmaceutical composition for the preparation of the application in the medicine of the anti-Coxsackie virus of preparation.
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