CN107162982A - Imidazole compounds with anticancer activity and derivatives thereof - Google Patents

Imidazole compounds with anticancer activity and derivatives thereof Download PDF

Info

Publication number
CN107162982A
CN107162982A CN201710468224.9A CN201710468224A CN107162982A CN 107162982 A CN107162982 A CN 107162982A CN 201710468224 A CN201710468224 A CN 201710468224A CN 107162982 A CN107162982 A CN 107162982A
Authority
CN
China
Prior art keywords
substituted
unsubstituted
cancer
compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710468224.9A
Other languages
Chinese (zh)
Other versions
CN107162982B (en
Inventor
曹华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huaji Pharmaceutical Technology Beijing Co ltd
Original Assignee
Guangdong Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong Pharmaceutical University filed Critical Guangdong Pharmaceutical University
Priority to CN201710468224.9A priority Critical patent/CN107162982B/en
Publication of CN107162982A publication Critical patent/CN107162982A/en
Application granted granted Critical
Publication of CN107162982B publication Critical patent/CN107162982B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to imidazole compounds with anticancer activity and derivatives thereof. It is represented by the following formula:

Description

One class has the glyoxaline compound and its derivative of active anticancer
Technical field
The present invention relates to imidazole class compound or its stereoisomer or its pharmaceutically acceptable salt or its is molten Agent compound.The invention further relates to the pharmaceutical composition containing at least one the compounds of this invention, it is used for treating cancer.
Background technology
Cancer is one of important diseases that current serious threatens human health, and its treatment and prevention causes extensive attention.Mesh Preceding treatment method has surgery excision, radiotherapy, chemotherapy etc., but still main based on chemotherapy.When Before be clinically used for treating cancer chemicals species it is more, such as platinum class, nitrogen mustards, triazole type, but most drug due to Toxicity is big, adverse reaction is more, bioavilability is low and is restricted its application.Therefore, the efficient, anticarcinogen of low toxicity is found Thing turns into one of current medical chemical field emphasis research topic.
Imidazole ring is histamine in organism, histidine generation bioactivity and the important group for playing physiological action.Imidazoles Ring is five yuan of fragrant azacyclo-s containing 2 nitrogen-atoms in structure, is also easy to produce a variety of non-covalent interactions, such as hydrogen bond and gold Belong to ion coordination and the π of π 2 interactions etc..The imidazole derivative constructed with the imidazole ring of this special construction has larger Development potentiality, is such as used for molecular recognition as artificial receptors, is used for bionic catalysis as artificial enzyme, has as medicine extensive Bioactivity, such as histamine receptor retarding agent, proton pump inhibitor, antiviral, anticancer.Shown extensively especially as cancer therapy drug Wealthy application prospect, in the last few years its research receives much concern and become increasingly active.The field has been achieved for many important achievements, its In have multiple glyoxaline compounds as cancer therapy drug be applied to clinic, such as CMNa, Arensm (fadrozole), Dacarbazine (dacarba-zine), Temozolomide etc..
In view of potential application of the imidazoles cancer therapy drug in treatment of cancer, and author has no that domestic and foreign literature is specially reported Imdazole derivatives, with reference to the research work in this laboratory, summarize imidazoles herein in the R＆D course in whole cancer therapy drug field Compound is as cancer therapy drug in radiosensitizer, farnesyl transferase inhibitor, cytochrome P 450 inhibitors, angiogenesis In terms of inhibitor, topoisomerase enzyme inhibitor, cycle plain dependent protein kinase inhibitor and tumor drug resistance reversal agent most Recent studies on and development progress.
The present invention relates to the new glyoxaline compound of a class, it can effectively suppress all kinds of cancers or tumour.
The content of the invention
The invention provides a kind of glyoxaline compound and its derivative with active anticancer.
It is used to treat various cancers or tumour, or its stereoisomer, tautomerism the present invention seeks to the compound Body, pharmaceutically acceptable salt, solvate or its prodrug.
Present invention provides prepare the compounds of this invention or its stereoisomer, dynamic isomer, be subjected on medicine Salt, the method and intermediate of solvate or its prodrug.
Present invention provides different including pharmaceutically acceptable carrier and at least one the compounds of this invention or its solid Structure body, dynamic isomer, pharmaceutically acceptable salt, the pharmaceutical composition of solvate or its prodrug.
Present invention provides treatment tumour or the method for cancer, including according to treatment needs, bestowing treatment to host has At least one the compounds of this invention of effect amount, or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt, solvation Thing or its prodrug.
Preferred embodiment is the various tumours for the treatment of or cancer.
Present invention provides the compound or its stereoisomer, dynamic isomer, medicine for treatment
Acceptable salt, solvate or its prodrug.
Present invention provides the compound or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt, molten Agent compound or its prodrug, the medicine for preparing treating cancer.
These and other features of the invention will be gone on to say in more detailed manner.
The invention provides selected from compound of formula I a general formula compound,
Or its stereoisomer or its pharmaceutically acceptable salt or its solvate, it is as follows：
Wherein
R1Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substitution or not Substituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10It is cycloalkyl, substituted or unsubstituted C6-10Aryl, containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or contain 1-4 and select The heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls from N, O and S；
R2Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substitution or not Substituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10It is cycloalkyl, substituted or unsubstituted C6-10Aryl, containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or contain 1-4 and select The heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls from N, O and S；
R3Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substitution or not Substituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10It is cycloalkyl, substituted or unsubstituted C6-10Aryl, containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or contain 1-4 and select The heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls from N, O and S；
R independences be selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substitution do not take The C in generation2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted C6-10 Aryl, containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or containing 1-4 it is selected from N, O With heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls in S.
Preferably, when wherein described substituted, refer to corresponding group by halogen, NH2、OH、C1-6Alkyl, C2-6Alkene Base, C2-6Alkynyl, C3-10Cycloalkyl, C6-10Aryl, contain in 1-4 5-10 unit's heteroaryls heteroatomic in N, O and S one It is individual or multiple replaced.
Preferably, the aryl is selected from phenyl, naphthyl, anthryl or phenanthryl.
Preferably, the heteroaryl is selected from indolinyl, benzothiazolyl, Pyrazolopyridine base, benzisothia oxazolyl, three Azoles and pyridine radicals, imidazopyridyl, benzoxazolyl, triazolo pyridyl, imidazopyridyl, pyrido-pyrazine base, quinoline Oxazoline base, pyrido-pyrazine base, Ben Bing oxadiazolyl, diazosulfide base, benzimidazolyl.
It is highly preferred that the compounds of this invention is selected from following particular compounds：
Present invention also offers a kind of preparation method of compound, it includes taking N- substituted amidines and substitution alkynes aldehyde as original Material, is prepared in oil bath pan reaction.It will be understood by those skilled in the art that when preparing particular compound, can basis Concrete condition selects starting compound.
The invention provides a kind of composition, it is characterised in that including the compound as shown in I or its stereoisomer, Or its pharmaceutically acceptable salt or its solvate, and pharmaceutically acceptable auxiliary agent, carrier or diluent.
Preferably, the composition can be prepared into various formulations, and its formulation is selected from plain piece, thin membrane coated tablet, sugar coated tablet, intestines Garment piece, dispersible tablet, capsule, granule, oral administration solution or oral administration mixed suspension.
Compound or its stereoisomer or its pharmaceutically acceptable salt or its solvate shown in the present invention are used In preparing tumour or cancer, the tumour or cancer are stomach cancer, adenocarcinoma of the uterine cervix, colon cancer, lung cancer, liver cancer, glioma, esophagus Cancer, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma, uterine cancer, osteocarcinoma, gallbladder cancer, lip Cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, hemangioma, lipoma, cervical carcinoma and first shape Gland cancer.
Present invention provides preparing the compounds of this invention, it is its stereoisomer, dynamic isomer, pharmaceutically acceptable The method and intermediate of salt, solvate or prodrug.
Present invention provides treatment tumour or cancer method (the present invention compound or its stereoisomer, mutually Tautomeric, pharmaceutically acceptable salt, solvate or prodrug are used to prepare the purposes for treating these disease medicaments), including According to treatment needs, at least one the compounds of this invention of therapeutically effective amount, or its stereoisomer, mutually variation are bestowed to host Structure body, pharmaceutically acceptable salt, solvate or its prodrug.
Present invention provides treatment disease method (the present invention compound or its stereoisomer, tautomerism Body, pharmaceutically acceptable salt, solvate or prodrug are used to prepare the purposes for treating these disease medicaments), including according to controlling The compound of formula I for needing that therapeutically effective amount is bestowed to patient is treated, wherein the disease is stomach cancer, adenocarcinoma of the uterine cervix, colon cancer, lung Cancer, liver cancer, glioma, cancer of the esophagus, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma, son Palace cancer, osteocarcinoma, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, hemangioma, Lipoma, cervical carcinoma and thyroid cancer.
Present invention provides the method for the treatment of disease, including the formula for needing that therapeutically effective amount is bestowed to patient according to treating I or its pharmaceutically acceptable salt, are used in combination with other therapeutic reagents.
Present invention provides the compound or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt, molten Agent compound or prodrug are used to treat.
In another embodiment, compound of formula I is selected from the combination or herein of example compound or example compound Other embodiments.
In another embodiment, present invention aims at including formula (I) compound and one or more activearms The pharmaceutical composition divided.
The term " alkyl " used herein is to include side chain and straight chain saturation alkane base with given number carbon atom.For example “C1-10Alkyl " (or alkylidene) purpose is C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl.In addition, such as " C1-6Alkane Base " represents the alkyl with 1 to 6 carbon atoms.Alkyl can be non-substituted or substitution, so that its one or more hydrogen atom quilt Other chemical group substitutions.The embodiment of alkyl includes but is not limited to methyl (Me), ethyl (Et), propyl group (such as n-propyl and different Propyl group), butyl (such as normal-butyl, isobutyl group, the tert-butyl group), amyl group (such as n-pentyl, isopentyl, neopentyl) and the like.
" alkenyl " is both to include the hydrocarbon of straight or branched structure, and appears in any point of safes in chain with one or more Carbon-to-carbon double bond.Such as " C2-6Alkenyl " (or alkenylene) purpose is to include C2, C3, C4, C5 and C6 alkenyl.The example bag of alkenyl Include but be not limited to vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- pentenyls, 3- pentenyls, 4- amylenes Base, 2- hexenyls, 3- hexenyls, 4- hexenyls, 5- hexenyls, 2- methyl -2- acrylic, 4- methyl-3-pentenyls and its class Like thing.
" alkynyl " is both to include the hydrocarbon of straight or branched structure, and appears in any point of safes in chain with one or more The key of carbon-to-carbon three.Such as " C2-6Alkynyl " (or alkynylene) purpose is to include C2, C3, C4, C5 and C6 alkynyl；Such as acetenyl, third Alkynyl, butynyl, pentynyl, hexin base and the like.
When mentioning substituted alkenyl, alkynyl, alkylidene, alkenylene or alkynylene, these groups are with as described above one to three The substituent of individual substitution alkyl.
The term " substituted " used herein refers to any one or more hydrogen atoms on specified atom or group Replaced with the specified group of selection, on condition that no more than the general chemical valence of specified atom.When substituent be oxygen or ketone (i.e.= O), then 2 hydrogen atoms on atom are substituted.Ketone substituent is not present in fragrant fragment.If without other explanations, substitution Base is named to division center.For example, it is to be understood that when (cycloalkyl) alkyl is possible substituent, the substituent to center The tie point of structure is in moieties.Ring double bond used herein is formed at two double bonds closed between annular atom (such as C=C, C=N or N=N).
The combination of substituent and/or variable is allowed, only when these combinations produce stable compound or useful synthesis Intermediate.Stable compound or rock-steady structure imply the compound with useful purity from reactant mixture separate when It is sufficiently stable, prepares form effective therapeutic reagent therewith.Preferably, the compound does not include N- halogens, S at present (O)2H or S (O) H bases.
Term " cycloalkyl " refers to cycloalkyl, including single-, double-or polycyclic system.C3-7 cycloalkyl purposes are to include C3, C4, C5, C6 and C7 cycloalkyl.Examples of cycloalkyl includes but is not limited to cyclopropyl, goes back butyl, cyclopenta, cyclohexyl, drop ice Chip base and the like." carbocyclic ring " used herein or " carbocyclic ring is remaining " refer to it is any stablize 3,4,5,6 or 7- unit monocycles or Bicyclic or 7,8,9,10,11,12 or 13- members pair or three rings, it can be saturation, unsaturated part, insatiable hunger and/or armaticity.This A little carbocyclic ring examples include but is not limited to cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, pentenyl, cyclohexyl, cyclohexenyl group, ring Heptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclo-octene base, cyclo-octadiene, [3.3.0] double-octane, [4.3.0] bicyclic nonyl Alkane, [4.4.0] bicyclic decane, [2.2.2] double-octane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthryl and tetrahydrochysene Naphthyl (tetralin).As described above, bridged ring is also contained in the definition of carbocyclic ring (such as [2.2.2] double-octane).If not other Illustrate, carbocyclic ring preferably is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and phenyl.When use term " carbocyclic ring ", it is therefore an objective to wrap Include " aryl ".There is bridged ring when one or more carbon atoms connect two non-carbon atoms that close on.It is preferred that bridge be one or two Carbon atom.Be pointed out that bridge always by it is monocyclic be converted into it is bicyclic.When ring is bridging, the substituent of ring is existed on bridge.
Term " aryl " refers to the monocyclic or Bicyclic alkyl for having 6 to 12 carbon atoms in loop section, such as phenyl And naphthyl, it can each be substituted.
Term " halogen " or " halogen " refer to chlorine, bromine, fluorine and iodine.
Term " haloalkyl " refers to the substitution alkyl with one or more halogenic substituents.Such as " haloalkyl " Including single, double and trifluoromethyl.
Term " heteroaryl " refers to replacing and non-substituted fragrant 5 or 6 unit monocycle group, 9- or 10- membered bicyclic groups, and 11 to 14 membered tricyclic groups, have at least one hetero atom (O, S or N) at least one ring, described excellent containing heteroatomic ring Choosing is with 1,2 or 3 hetero atoms in O, S and N.Each ring containing heteroatomic heteroaryl can contain one or two oxygen or Sulphur atom and/or by 1 to 4 nitrogen-atoms, on condition that heteroatomic sum is 4 or less in each ring, and each ring is with extremely A few carbon atom.Carbon atom can only be contained by completing bicyclic and three cyclic groups fused rings, it is possible to be saturation, fractional saturation or It is unsaturated.Nitrogen and sulphur atom can be optionally oxidized and nitrogen-atoms can be optionally quaternized.Bicyclic or three rings heteroaryls must be wrapped At least one full aromatic rings is included, the other fused rings of nitrogen can be armaticity or nonaromatic.Heteroaryl can be in any of any ring Connected using on nitrogen or carbon atom.When chemical valence allow, if other rings are cycloalkyl or heterocycle, its in addition optionally with =O (oxygen) replaces.
Exemplary monocyclic heteroaryl includes pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals, oxazolyl, isoxazolyls, thiophene Oxazolyl, thiadiazolyl group, furyl, thienyl, oxadiazolyls, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical and its class Like thing.
Exemplary bicyclic heteroaryl include indyl, benzothiazolyl, benzodioxole base, benzoxazolyl, Benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzo furan Mutter base, chromone base, cumarin base, benzopyranyl, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluorinated pyridine Base, dihydro-iso indolyl, tetrahydric quinoline group and the like.
If without other explanations, compound of the invention is interpreted as including free state and its salt.Term " salt " represent with Inorganic and/or organic bronsted lowry acids and bases bronsted lowry formation acid and/or basic salt.In addition, " salt may include amphion (inner salt) to term, such as work as Compound of formula I contains basic moiety such as amine or pyridine or imidazole ring, and acid fragment such as carboxylic acid.It is pharmaceutically acceptable (i.e. non- It is toxicity, physiologically acceptable) salt is preferred, such as acceptable metal and amine salt, its cationic do not have notable contribution The bioactivity of toxicity or salt.However, other salt can be useful, isolated or purified step is used such as in preparation process, because This is also contained in the scope of the invention.The salt of compound of formula I can be formed such as compound of formula I with a certain amount of acid or alkali, such as Amount, in medium such as wherein salt it is precipitable or its it is water-borne in, then carry out lyophilization.
Exemplary acid addition salt include acetate (such as formed with acetic acid or three halogen acetic acid, such as trifluoroacetic acid), oneself Diacid salt, alginates, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, borate, butyrate, Citrate, camphor hydrochlorate, camsilate, cipionate, double gluconates, lauryl sulfate, esilate, prolong Fumarate salt, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochloride (being formed with hydrochloric acid), hydrogen bromine Hydrochlorate (being formed with hydrobromic acid), hydriodate, 2- isethionates, lactate, maleate (being formed with maleic acid), first sulphur Hydrochlorate (being formed with methanesulfonic acid), 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, pectate, persulfate, 3- phenyl third Hydrochlorate, phosphate, picrate, Pivalate, propionate, salicylate, succinate, sulfate with sulfuric acid (as formed Those), sulfonate (as referenced herein those), tartrate, rhodanate, toluene fulfonate such as toluene fulfonate, 11 Hydrochlorate and the like.
Exemplary basic salts include ammonium salt, alkali metal salt such as sodium, lithium and sylvite；Alkali salt such as calcium and magnesium salts；Barium, zinc And aluminium salt；The salt (such as organic amine) formed with organic base such as trialkylamine such as triethylamine, procaine, dibenzylamine, N- benzyls-β- Phenyl ethylamine, 1- ephenamines, N, N '-bis- benzyls ethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexyl amine or similar medicine Acceptable amine and salt such as arginine, lysine and the like with amino acid on thing.Basic nitrogenous group can be with reagent season Ammoniumization such as elementary alkyl halide (such as methyl, ethyl, propyl group and butyl chloride, bromine and iodide), dialkyl sulfate (such as diformazan Base, diethyl, dibutyl and diamyl sulfate), long chain halide (such as decyl, dodecyl, myristyl and octadecyl Chlorine, bromine and iodide), aralkyl halide (such as benzyl and phenylethyl bromide) and other materials.It is preferred that salt include mono-salt Hydrochlorate, disulfate, mesylate, phosphate or nitrate.
Phrase " pharmaceutically acceptable " refers to those compounds, material, composition and/or formulation, in intact doctor Treat range of value in, be suitable for contacting with the tissue of human and animal, without extra toxicity, stimulation, allergic reaction or Other problems or complication, with the reasonable benefit/risk ratio matched.
" the pharmaceutically acceptable salt " used herein refers to the derivative of open compound, wherein paternal compound is With acid or the modification of its basic salt.The example of drug acceptable salt includes but is not limited to the inorganic or organic acid of alkali formula group such as amine Formula salt；With the alkali or organic salt of acidic groups such as carboxylic acid.Pharmaceutically acceptable salt includes traditional non-toxic salt or paternal lineization Compound formation quaternary ammonium salt, such as by non-toxic inorganic or organic acid.For example, these traditional non-toxic salts, which include those, is derived from nothing Machine acid such as hydrochloric acid, hydrobromic acid, thiosulfonic acid, sulfamic acid, phosphoric acid and nitric acid；With the salt prepared by organic acid such as acetic acid, propionic acid, amber Amber acid, hydroxyacetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, handkerchief not acid, maleic acid, hydroxyl horse Come sour, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- ethoxies benzoic acid, fumaric acid, toluenesulfonic acid, first Sulfonic acid, ethane disulfonic acid, oxalic acid and isethionic acid and the like.
The pharmaceutically acceptable salt of the present invention can pass through conventional chemical by the paternal compound containing alkali formula or acid fragment Method is synthesized.Normally, these salt can by these compounds free acid or alkali form and the suitable alkali or acid of stoichiometric proportion Prepared in water or organic solvent, or in its two kinds of mixtures；Normally, it is non-it is water-borne such as ether, it is ethyl acetate, ethanol, different Propyl alcohol or acetonitrile are preferred.
All stereoisomers of the compounds of this invention are considered, both with mixture or pure or substantially pure form. Stereoisomer may include the compound of the substituted optical isomer by one or more chiral atoms, and pass through limitation Rotate the optical isomer compound of one or more keys (atropisomer).The definition of the compounds of this invention includes being possible to Stereoisomer and its mixture.It especially includes racemic form and with especially active separating optical isomers.Pass through Physical method resolution of racemic form, for example, the crystallization of fractional crystallisation, separation or alloisomerism derivative or pass through chiral column color Spectrum separation.The salt that independent optical isomer is such as formed with optically active acid is obtained by racemic salt by conventional method, so After crystallize.
The prodrug and solvate of the compounds of this invention are also considered.Term " prodrug " represents compound, based on applying Acceptor is given, passes through metabolic or chemical method experience chemical reaction generation compound of formula I, and/or salt and/or its solvate. Before converting in vivo in any compound scope and spirit of the present invention to provide bioactive agents (i.e. compound of formula I) Medicine.For example, the compound containing carboxyl can form the physiology hydrolyzable ester as prodrug, by hydrolyzing production I in vivo Compound itself.The preferred oral administration of these prodrugs, under the influence of appearing in digestive ferment substantially due to the hydrolysis under the conditions of many. Usable parenteral is bestowed, and ester itself is active, in those examples, and hydrolysis is appeared in blood.The physiology of compound of formula I Learning hydrolysis ester example includes C1-6Alkyl benzyl, 4- methoxy-benzyls, indanyl, phthalyl, methoxy, C1-6Chain Alkanoyloxy-C1-6Alkyl such as acetyl-o-methyl, pivaloyloxymethyl or the third oxygen methyl, C1-6Alkyl oxy carbonyl oxygen-C1-6Alkyl, such as Methoxycarbonyl group-oxygen methyl or ethyoxyl carbonyl oxygen methyl, glycyl oxygen methyl, hydroxyphenylglycyl oxygen methyl, (5- methyl -2- oxygen -1, 3- Dioxol-4 -yls)-methyl and other well known physiology hydrolysis esters used, such as in penicillin and In cephalogensporin fields.These esters can be prepared by routine techniques well known in the prior art.Diversified forms Prodrug be well known in the prior art.
" pharmaceutically acceptable carrier " is generally referred to as what is generally received in this field, can transmit bioactive agents To animal, especially mammal.Acceptable carriers on compounding pharmaceutical, according to many well known to those of ordinary skill in the art Factor.These include the type and characteristic for the active agent being formulated without limitation；The acceptor bestowed containing reagent composition；Combination Thing bestows approach；Indicated with targeted therapy.Pharmaceutically acceptable carrier includes aqueous and nonaqueous liquid medium, and a variety of Solid-state and semisolid formulation.These carriers include many different components and additive, in addition to active agent, these additional sets Divide because many reasons are contained in formula, such as stability of active agent, adhesive, this is those of ordinary skill in the art Known.
Any suitable mode that formula I can treat symptom is bestowed, and is treated or is passed depending on site-specific The amount of drug delivery.The generally preferable skin related disease of topical administration, the systemic treatment of carcinous or carcinous preceding symptom, but other biographies The pattern of passing is also what is considered.Such as oral administration of Compound, such as with tablet, capsule, particle, powder or liquid including syrup Form of formulations；Part is such as with solution, suspension, gel or ointment；Sublingual administration；Cheek；Parenteral such as by it is subcutaneous, Intravenous injection, intramuscular injection or breastbone inner injection or perfusion art (such as sterilized water or non-aqueous solution or suspension)；Intranasal as logical Cross suction spraying；Partly such as with emulsion or ointment；Rectally such as with suppository form；Or liposome.It can bestow and contain The dosage unit formulations of excipient or diluent are subjected in non-toxic, medicine.The form of release can be discharged or delayed immediately Bestow the compound.The pharmaceutical composition that discharging or delay release immediately can be adapted to is obtained, the reality discharged in portion retards In example, equipment such as subcutaneous transplantation or osmotic pumps are used.
The exemplary composition of oral administration includes suspension, and it can contain such as the microcrystalline cellulose for transmitting, conduct The alginic acid or sodium alginate of suspending agent, the methylcellulose as viscosity intensifier and those sweet tastes well known in the prior art Agent or flavor enhancement；The tablet discharged immediately can contain such as microcrystalline cellulose, di(2-ethylhexyl)phosphate calcium salt, starch, magnesium stearate and/or lactose And/or other excipient, adhesive, swelling agent, disintegrant, diluent and lubricant it is as be known in the art those.This Invention compound can also bestow carry out oral delivery, such as pressing mold, compression or lyophilized tablet by sublingual and/or cheek.It is exemplary Composition may include rapidly-soluble diluent such as mannitol, lactose, sucrose and/or cyclodextrin.Comprising in these formulations It can also be high molecular weight excipients such as celluloseOr macrogol (PEG)；The figuration for contributing to mucous membrane to adhere to Agent such as hydroxypropyl cellulose (HPC), HPMC (HPMC), sodium carboxymethylcellulose (SCMC) and/or maleic anhydride Copolymer is (such as)；With reagent such as acrylic copolymer (such as CARBOPOL of control release).Also it can add Entering lubricant, glidant, spices, colouring agent and stabilizer helps to prepare and uses.
The exemplary composition that spray-on process or suction are bestowed includes solution, and the solution can contain benzyl alcohol or other suitable Preservative, the sorbefacient of raising absorbability and/or bioactivity, and/or other soluble or dispersible agents are for example existing In technology it is known those.
The exemplary composition of parenteral administration includes injection solution or suspension, its can contain as suitable non-toxic, The acceptable diluent of stomach or solvent, such as mannitol, 1,3-BDO, water, Ge Linshi solution, isotonic sodium chlorrde solution, or its Scattered or wetting and flotation reagents that it is adapted to, include the list or di-glycerides of synthesis, and aliphatic acid includes oleic acid.
The exemplary composition of rectally includes suppository, and it can contain such as suitable non-irritating excipient, such as cocoa butter, Synthetic glycerine esters or macrogol class, are at normal temperatures solid, but dissolve and/or dissolve in release medicine in stomach.
The compounds of this invention of therapeutically effective amount can be determined by those of ordinary skill in the art, and be wrapped for mammal Exemplary dose is included about from 0.05 to 1000mg/kg；1-1000mg/kg；1-50mg/kg；5-250mg/kg；250-1000mg/ Kg, according to reactive compound amount per kg body weight per day, it can be bestowed with single dose or in single separate doses form, As daily from 1 to 4 times.It is understood that can change disease for the special dosage level and medicament frequency of special acceptor and depend on In many factors, including the use of special compound is active, the compound metabolism stability and action length, race, the age, Body weight, general health, acceptor sex and diet, bestow pattern and time, discharge rate, drug regimen and special disease The order of severity.Preferred acceptor for treatment includes animal, most preferably lactation race such as the mankind and poultry animal such as dog, cat, horse And the like.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that methods described of the embodiment of the present invention It is only used for the explanation present invention, rather than limitation of the present invention, to preparation side of the invention under the concept thereof of the present invention The simple modifications of method belong to the scope of protection of present invention.Unless otherwise instructed, all raw materials for being used in embodiment and Solvent is purchased from Sigma Biochemical and Organic Compounds for Research and Diagnostic Clinical Reagents companies.
Embodiment 1：5- (ethyoxyl (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 88%)
It is sequentially added N- phenyl benzamidine (0.20mmol) into 25mL-schlenk tube, AgOAc (2.5mol%), TsOH (5mol%), toluene (2mL), phenyl-allylene aldehyde (0.20mmol), ethanol (0.60mmol), then in schlenk tube It is passed through N2, 100 DEG C of oil bath pan stirring reaction 10h is placed in, after the completion of TLC detection reactions, room temperature is cooled to, it is mixed toward reaction Close and 10mL saturated aqueous common salts are added in liquid, then extracted with ethyl acetate (10mL × 3), merge organic layer and use saturated common salt Water is washed, and uses anhydrous MgSO4It is dried.Resulting organic phase vacuum distillation removes most of solvent, and crude product is used Column chromatography carries out separating-purifying.The structure warp of product1H NMR,13C NMR, GC-MS, HRMS and IR etc. are analyzed to identify.
Brown solid, m.p.124-126 DEG C of .62.3mg.1H NMR (400MHz, CDCl3) δ 7.45-7.30 (m, 12H), 7.22-7.17 (m, 3H), 6.80 (s, 1H), 5.12 (s, 1H), 3.37-3.29 (m, 1H), 3.13-3.05 (m, 1H), 1.08 (t, J=6.8Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.4,139.0,137.3,135.5,130.5,129.0,128.8, (100) [M+ of 128.5,128.3,128.2,128.1,127.9,127.2,75.1,64.4,15.1.ESI-MS m/z (%) 354 H]+；Anal.Calcd for C24H22N2O C, 81.33；H, 6.26；N, 7.90；Found：C, 81.33；H, 6.26；N, 7.90.
With the preparation method similar to embodiment 1, only following compound are prepared with different raw materials
Embodiment 2：5- (ethyoxyl (phenyl) methyl) -2- phenyl -1- (m- tolyls) -1H- imidazoles (yield 75%)
Yellow solid, m.p.70-73 DEG C of .55.2mg.1H NMR (400MHz, CDCl3) δ 7.40-7.18 (m, 14H), 6.80 (s, 1H), 5.10 (s, 1H), 3.36-3.32 (m, 1H), 3.14-3.09 (m, 1H), 2.37 (s, 3H), 1.10 (t, J=6.8Hz, 3H).13C NMR (100MHz, CDCl3) δ 148.1,139.1,139.0,137.1,135.4,130.5,129.4,128.9, 128.2,128.2,128.0,128.0,127.8,127.1,75.0,64.3,21.1,15.0.ESI-MS m/z (%) 368 (100)[M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 3：5- (ethyoxyl (phenyl) methyl) -2- phenyl -1- (p- tolyls) -1H- imidazoles (yield 83%)
Browu oil.61.1mg.1H NMR (400MHz, CDCl3) δ 7.40-7.31 (m, 8H), 7.24-7.19 (m, 6H), 6.79 (s, 1H), 5.09 (s, 1H), 3.37-3.30 (m, 1H), 3.16-3.08 (m, 1H), 2.44 (s, 3H), 1.10 (t, J= 6.8Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.4,139.2,138.8,135.6,134.6,130.6,129.8, 128.9,128.4,128.3,128.1,128.0,127.9,127.1,75.0,64.4,21.3,15.1.ESI-MS m/z (%) 368(100)[M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 4：5- (ethyoxyl (phenyl) methyl) -1- (4- fluorophenyls) -2- phenyl -1H- imidazoles (yield 81%)
Brown oil.60.3mg.1H NMR (400MHz, CDCl3) δ 7.36-7.19 (m, 12H), 7.12-7.08 (m, 2H), 6.81 (s, 1H), 5.12 (s, 1H), 3.39-3.32 (m, 1H), 3.18-3.10 (m, 1H), 1.07 (t, J=6.8Hz, 3H).13C NMR (100MHz, CDCl3) δ 163.7 (d, J=248), 148.7,138.8,135.4,133.3,133.3,130.3, 129.2,128.5,128.4,128.2,128.0,127.1,116.2,116.0,75.1,64.4,15.1.ESI-MS m/z (%) 372(100)[M+H]+；Anal.Calcd for C24H21FN2O C, 77.40；H, 5.68；N, 7.52；Found：C, 77.40；H, 5.68；N, 7.52.
Embodiment 5：1- (3- chlorphenyls) -5- (ethyoxyl (phenyl) methyl) -2- phenyl -1H- imidazoles (yield 74%)
Brown oil.57.6mg.1H NMR (400MHz, CDCl3) δ 7.44-7.21 (m, 14H), 6.78 (s, 1H), 5.11 (s, 1H), 3.41-3.33 (m, 1H), 3.18-3.11 (m, 1H), 1.13 (t, J=6.8Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.5,138.6,138.5,135.3,134.7,130.1,129.4,129.0,128.5,128.4,128.2, 128.0,127.1,75.0,64.4,15.1.ESI-MS m/z (%) 389 (100) [M+H]+；Anal.Calcd for C24H21ClN2O C, 74.12；H, 5.44；N, 7.20；Found：C, 77.12；H, 5.44；N, 7.20.
Embodiment 6：1- (4- chlorphenyls) -5- (ethyoxyl (phenyl) methyl) -2- phenyl -1H- imidazoles (yield 72%)
Brown solid, m.p.104-106 DEG C of .56.0mg.1H NMR (400MHz, CDCl3) δ 7.40-7.31 (m, 9H), 7.24-7.15 (m, 5H), 6.81 (s, 1H), 5.12 (s, 1H), 3.39-3.32 (m, 1H), 3.19-3.11 (m, 1H), 1.07 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.6,138.8,135.9,134.7,130.2,129.8,129.4, (100) [M+ of 129.4,128.4,128.4,128.2,128.0,127.1,75.0,64.4,15.1.ESI-MS m/z (%) 389 H]+；Anal.Calcd for C24H21ClN2O C, 74.12；H, 5.44；N, 7.20；Found：C, 77.12；H, 5.44；N, 7.20.
Embodiment 7：1- (3- bromophenyls) -5- (ethyoxyl (phenyl) methyl) -2- phenyl -1H- imidazoles (yield 78%)
Brown oil.67.5mg.1H NMR (400MHz, CDCl3) δ 7.59 (d, J=7.6Hz, 2H), 7.38-7.12 (m, 12H), 6.78 (s, 1H), 5.12 (s, 1H), 3.41-3.33 (m, 1H), 3.19-3.12 (m, 1H), 1.14 (t, J=6.4Hz, 3H).13C NMR (100MHz, CDCl3) δ 148.5,138.6,138.6,135.3,131.9,130.3,130.1,129.4, (100) [M+ of 128.5,128.4,128.3,128.1,127.1,122.4,75.0,64.4,15.1.ESI-MS m/z (%) 433 H]+；Anal.Calcd for C24H21BrN2O C, 66.52；H, 4.88；N, 6.46；Found：C, 66.52；H, 4.88；N, 6.46.
Embodiment 8：1- (3,4- dichlorophenyl) -5- (ethyoxyl (phenyl) methyl) -2- phenyl -1H- imidazoles (yields 81%)
Brown oil.68.5mg.1H NMR (400MHz, CDCl3) δ 7.44-7.25 (m, 12H), 7.04 (d, J= 10.8Hz, 1H), 6.40 (s, 1H), 5.12 (s, 1H), 3.43-3.36 (m, 1H), 3.25-3.17 (m, 1H), 1.17 (t, J= 7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.7,138.5,136.7,135.2,133.2,133.0,130.7, 129.8,129.7,128.7,128.5,128.4,128.4,128.1,127.0,75.0,64.43,15.1.ESI-MSm/z (%) 423(100)[M+H]+；Anal.Calcd for C24H20Cl2N2O C, 68.09；H, 4.76；N, 6.62；Found：C, 68.09； H, 4.76；N, 6.62.
Embodiment 9：5- (ethyoxyl (phenyl) methyl) -1- phenyl -2- (m- tolyls) -1H- imidazoles (yield 76%)
Brown oil.55.9mg.1H NMR (400MHz, CDCl3) δ 7.45-7.28 (m, 11H), 7.05-7.00 (m, 3H), 6.80 (s, 1H), 5.12 (s, 1H), 3.37-3.29 (m, 1H), 3.13-3.05 (m, 1H), 2.24 (s, 3H), 1.08 (t, J =7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.6,139.0,137.8,137.4,135.4,130.3,129.4, 129.2,129.0,128.9,128.8,128.3,127.9,127.8,127.2,125.3,75.1,64.4,21.3, 15.1.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 10：5- (ethyoxyl (phenyl) methyl) -1- phenyl -2- (p- toluene) -1H- imidazoles (yield 66%)
Brown solid, m.p.85-87 DEG C of .48.6mg.1H NMR (400MHz, CDCl3) δ 7.41 (d, J=3.2Hz, 3H), 7.36-7.25 (m, 9H), 6.02 (d, J=8.0Hz, 2H), 6.76 (s, 1H), 5.11 (s, 1H), 3.36-3.29 (m, 1H), (t, J=6.8Hz, the 3H) of 3.12-3.04 (m, 1H), 2.28 (s, 3H), 1.0713C NMR (100MHz, CDCl3)δ 148.6,139.1,138.1,137.5,135.2,129.2,128.9,128.8,128.7,128.3,127.9,127.7, 127.2,75.1,64.4,21.2,15.1.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 11：5- (ethyoxyl (phenyl) methyl) -1- (4- fluorophenyls) -2- (m- toluene) -1H- miaows (yield 81%)
Brown oil.62.5mg.1H NMR (400MHz, CDCl3) δ 7.34-7.30 (m, 7H), 7.12-7.06 (m, 5H), 6.81 (s, 1H), 5.12 (s, 1H), 3.39-3.32 (m, 1H), 3.16-3.11 (m, 1H), 2.26 (s, 3H), 1.11 (t, J= 7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 163.7 (d, J=248Hz), 148.8,138.8,138.0,135.3, 133.4,133.3,130.0,129.4,129.2,129.0,128.4,128.0,127.9,127.1,125.3,116.2, 115.9,75.1,64.4,21.3,15.1.ESI-MS m/z (%) 386 (100) [M+H]+；Anal.Calcd for C25H23FN2O C, 77.70；H, 6.00；N, 7.25；Found：C, 77.70；H, 6.00；N, 7.25.
Embodiment 12：- m- toluene -1H- the imidazoles (yield 74%) of 5- (ethyoxyl (phenyl) methyl) -1,2- bis-
Browr oil.56.7mg.1H NMR (400MHz, CDCl3) δ 7.36-7.22 (m, 9H), 7.02-6.76 (m, 4H), 6.76 (s, 1H), 5.06 (s, 1H), 3.35-3.27 (m, 1H), 3.11-3.04 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.07 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.4,139.2,139.2,137.8,137.3,135.4, 130.4,129.5,129.3,129.0,128.9,128.6,128.3,127.9,127.8,127.2,125.2,75.1,64.4, 21.4,21.3,15.1.ESI-MS m/z (%) 383 (100) [M+H]+；Anal.Calcd for C26H26N2O C, 81.64；H, 6.85；N, 7.32；Found：C, 81.64；H, 6.85；N, 7.32.
Embodiment 13：1- (3- chlorphenyls) -5- (ethyoxyl (phenyl) methyl) -2- (m- toluene) -1H- imidazoles (yields 70%)
Brown oil.56.4mg.1H NMR (400MHz, CDCl3) δ 7.42-7.28 (m, 10H), 7.05-6.74 (m, 3H), 6.74 (s, 1H), 5.08 (s, 1H), 3.38-3.30 (m, 1H), 3.16-3.08 (m, 1H), 2.24 (s, 3H), 1.11 (t, J =6.8Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.7,138.7,138.5,138.0,135.2,134.7,130.0, 129.8,129.5,129.3,129.2,129.0,128.4,128.0,128.0,127.1,125.0,75.0,64.4,21.3, 15.1.ESI-MS m/z (%) 403 (100) [M+H]+；Anal.Calcd for C25H23ClN2O C, 74.52；H, 5.75；N, 6.95；Found：C, 74.52；H, 5.75；N, 6.95.
Embodiment 14：1- (4- chlorphenyls) -5- (ethyoxyl (phenyl) methyl) -2- (m- toluene) -1H- imidazoles (yields 85%)
Brown oil.68.5mg.1H NMR (400MHz, CDCl3) δ 7.41-31 (m, 10H), 7.08 (d, J=5.2Hz, 2H), 7.00 (t, J=4.0Hz, 1H), 6.77 (s, 1H), 5.11 (s, 1H), 3.41-3.33 (m, 1H), 3.19-3.11 (m, 1H), 2.27 (s, 3H), 1.13 (t, J=6.8Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.7,138.7,138.6, 138.0,135.2,134.7,130.0,129.9,129.4,129.3,129.3,128.9,128.4,128.0,128.0, 127.1,125.3,75.0,64.4,21.3,15.1.ESI-MS m/z (%) 403 (100) [M+H]+；Anal.Calcd for C25H23ClN2O C, 74.52；H, 5.75；N, 6.95；Found：C, 74.52；H, 5.75；N, 6.95.
Embodiment 15：1- (3- bromophenyls) -5- (ethyoxyl (phenyl) methyl) -2- (m- toluene) -1H- imidazoles (yields 77%)
Brown oil.68.8mg.1H NMR (400MHz, CDCl3) δ 7.58 (d, J=7.2Hz, 2H), 7.35-7.32 (m, 6H), 7.28 (t, J=8.0Hz, 1H), 7.15-6.78 (m, 4H), 6.78 (s, 1H), 5.11 (s, 1H), 3.41-3.33 (m, 1H), (t, J=6.8Hz, the 3H) of 3.20-3.12 (m, 1H), 2.27 (s, 3H), 1.1413C NMR (100MHz, CDCl3)δ 148.7,138.7,138.6,138.0,135.2,131.9,130.3,129.8,129.5,129.3,129.2,128.4, (100) [M+H of 128.0,128.0,127.1,125.4,122.4,75.0,64.4,21.3,15.1.ESI-MS m/z (%) 447 ]+；Anal.Calcd for C25H23BrN2O C, 67.12；H, 5.18；N, 6.26；Found：C, 67.12；H, 5.18；N, 6.26.
Embodiment 16：1- (3- bromophenyls) -5- (ethyoxyl (phenyl) methyl) -2- (4-m- ethoxyl phenenyls) -1H- imidazoles (yield 66%)
Brown oil.61.1mg.1H NMR (400MHz, CDCl3) δ 7.57 (d, J=8.0Hz, 2H), 7.35-7.22 (m, 8H), 7.12 (d, J=7.6Hz, 1H), 6.75 (d, J=8.8Hz, 3H), 5.07 (s, 1H), 3.74 (s, 3H), 3.37-3.30 (m, 1H), 3.16-3.08 (m, 1H), 1.09 (s, 3H)13C NMR (100MHz, CDCl3) δ 159.8,148.5,138.7, 138.7,134.9,131.9,130.3,129.9,129.0,128.4,128.0,127.1,122.5,113.7,75.0,64.4, 55.2,15.1.ESI-MS m/z (%) 463 (100) [M+H]+；Anal.Calcd for C25H23BrN2O2C, 64.80；H, 5.00；N, 6.05；Found：C, 64.80；H, 5.00；N, 6.05.
Embodiment 17：5- (m- ethyoxyls (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 73%)
Yellow oil.67.6mg.1H NMR (400MHz, Acetone) δ 7.51 (d, J=3.2Hz, 3H), 7.43- (s, the 3H) of 7.30 (m, 10H), 7.23 (t, J=6.4Hz, 3H), 5.10 (s, 1H), 3.0613C NMR (100MHz, Acetone) δ 206.4,140.4,130.4,130.0,129.3,129.1,129.1,128.9,128.3,77.7,56.9.ESI-MS m/z (%) 463 (100) [M+H]+；Anal.Calcd for C23H20N2O C, 81.15；H, 5.92；N, 8.23；Found：C, 81.15；H, 5.92；N, 8.23.
Embodiment 18：5- (butoxy (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 81%)
Brown oil.62.0mg.1H NMR (400MHz, CDCl3) δ 7.38 (d, J=4.4Hz, 3H), 7.35-7.25 (m, 9H), 7.15 (d, J=7.2Hz, 3H), 6.78 (s, 1H), 5.08 (s, 1H), 3.26-3.20 (m, 1H), 3.04-2.98 (m, 1H), (t, J=7.2Hz, the 3H) of 1.43-1.36 (m, 2H), 1.25 (m, 2H), 0.8113C NMR (100MHz, CDCl3)δ 148.2,139.0,137.1,135.3,130.3,129.0,128.9,128.6,128.2,128.1,128.0,127.9, 127.7,127.0,75.0,68.6,31.6,19.2,13.7.ESI-MS m/z (%) 383 (100) [M+H]+；Anal.Calcd for C26H26N2O C, 81.64；H, 6.85；N, 7.32；Found：C, 81.64；H, 6.85；N, 7.32.
Embodiment 19：5- ((the first and second epoxide of furans -2- bases) (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yields 68%)
Brown oil.55.9mg.1H NMR (400MHz, CDCl3) δ 7.39 (d, J=8.0Hz, 3H), 7.35-7.30 (m, 9H), 7.22-7.15 (m, 4H), 6.86 (s, 1H), 6.27 (d, J=5.2Hz, 1H), 6.12 (d, J=3.2Hz, 1H), 5.22 (s, 1H), 4.31 (d, J=12.4Hz, 1H), 4.10 (d, J=12.4Hz, 1H)13C NMR (100MHz, CDCl3) δ 151.1, 142.8,138.2,136.9,134.8,130.1,129.2,128.8,128.4,128.4,128.3,128.1,128.1, 127.3,110.2,109.5,74.1,62.3.ESI-MS m/z (%) 406 (100) [M+H]+；Anal.Calcd for C27H22N2O2C, 79.78；H, 5.46；N, 6.89；Found：C, 79.78；H, 5.46；N, 6.89.
Embodiment 20：5- ((benzyloxy) (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 84%)
Yellow solid, m.p.85-87 DEG C of .70.1mg.1H NMR (400MHz, CDCl3) δ 7.44-7.36 (m, 10H), 7.32-7.27 (m, 3H), 7.24-7.13 (m, 7H), 6.94 (s, 1H), 5.31 (s, 1H), 4.39 (d, J=12.0Hz, 1H), 4.17 (d, J=12.0Hz, 1H)13C NMR (100MHz, CDCl3) δ 148.4,138.6,137.4,137.0,134.9, 130.3,129.3,129.1,128.6,128.3,128.3,128.2,128.1,127.9,127.9,127.5,127.2,74.5, 70.6.ESI-MS m/z (%) 417 (100) [M+H]+；Anal.Calcd for C29H24N2O C, 83.63；H, 5.81；N, 6.73；Found：C, 83.63；H, 5.81；N, 6.73.
Embodiment 21：5- ((allyloxy) (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 66%)
Brown oil.48.3mg.1H NMR (400MHz, CDCl3) δ 7.40 (d, J=8.4Hz, 3H), 7.36-7.27 (m, 8H), 7.19 (t, J=6.8Hz, 4H), 6.84 (s, 1H), 5.67-5.57 (m, 1H), 5.17 (s, 1H), 5.15-5.05 (m, 2H), 3.84-3.80 (m, 1H), 3.62-3.57 (m, 1H)13C NMR (100MHz, CDCl3) δ 148.4,138.6,137.1, 135.1,134.1,130.3,129.2,129.1,128.8,128.4,128.3,128.2,128.0,127.9,127.2, 117.3,74.2,69.6.ESI-MS m/z (%) 366 (100) [M+H]+；Anal.Calcd for C25H22N2O C, 81.94； H, 6.05；N, 7.64；Found：C, 81.94；H, 6.05；N, 7.64.
Embodiment 22：5- (isopropoxy (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 76%)
Brown solid, m.p.131-133 DEG C of .55.2mg.1H NMR (400MHz, CDCl3) δ 7.42 (d, J=6.0Hz, 2H), 7.34-7.29 (m, 8H), 7.24 (d, J=2.0Hz, 2H), 7.19 (t, J=7.2Hz, 3H), 6.79 (s, 1H), 5.29 (s, 1H), 3.43-3.37 (m, 1H), 0.99 (d, J=6.0Hz, 3H), 0.72 (d, J=6.0Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.2,139.6,137.1,135.5,130.2,129.2,129.0,128.9,128.4,128.3,128.2, 128.0,127.8,127.2,72.0,69.1,22.8,20.7.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 23：5- (phenoxy group (phenyl) methyl) -1,2- diphenyl -1H- imidazoles (yield 73%)
Yellow solid, m.p.135-136 DEG C of .58.7mg.1H NMR (400MHz, CDCl3) δ 7.37 (d, J= 7.6Hz, 5H), 7.31 (t, J=7.2Hz, 6H), 7.21 (t, J=7.2Hz, 4H), 7.13-7.08 (m, 2H), 6.90-6.82 (m, 2H), 6.66 (s, 2H), 5.96 (s, 1H)13C NMR (100MHz, CDCl3) δ 157.3,148.7,138.0,136.8, 134.5,130.1,129.8,129.3,129.2,128.8,128.5,128.4,128.4,128.10,128.1,126.8, 121.2,115.8,73.5.ESI-MS m/z (%) 402 (100) [M+H]+；Anal.Calcd for C28H22N2O C, 83.56； H, 5.51；N, 6.96；Found：C, 83.56；H, 5.51；N, 6.96.
Embodiment 24：5- (phenoxy group (phenyl) methyl) -2- phenyl -1- (m- toluene) -1H- imidazoles (yield 80%)
Yellow oil.66.7mg.1H NMR (400MHz, CDCl3) δ 7.39-7.35 (m, 4H), 7.33-7.27 (m, 3H), 7.19 (d, J=7.2Hz, 3H), 7.13-7.03 (m, 6H), 6.87-6.81 (m, 2H), 6.66 (d, J=7.6Hz, 2H), 5.93 (s, 1H), 2.30 (s, 3H)13C NMR (100MHz, CDCl3) δ 157.5,148.7,138.9,138.3,134.6, 134.2,130.4,130.0,129.8,129.2,128.5,128.5,128.3,128.1,128.1,126.9,121.2, 115.9,73.6,21.2.ESI-MS m/z (%) 417 (100) [M+H]+；Anal.Calcd for C29H24N2O C, 83.63； H, 5.81；N, 6.73；Found：C, 83.63；H, 5.81；N, 6.73.
Embodiment 25：5- (phenoxy group (phenyl) methyl) -2- phenyl -1- (p- toluene) -1H- imidazoles (yield 71%)
Yellow oil.59.2mg.1H NMR (400MHz, CDCl3) δ 7.42-7.37 (m, 4H), 7.35-7.30 (m, 3H), 7.24-7.08 (m, 9H), 6.86 (t, J=7.2Hz, 2H), 6.69 (d, J=8.0Hz, 2H), 5.92 (s, 1H), 2.14 (s, 3H)13C NMR (100MHz, CDCl3) δ 157.3,148.5,138.1,136.6,130.2,129.5,129.2,129.0, 128.4,128.3,128.3,128.0,126.8,121.1,115.6,20.9.ESI-MS m/z (%) 417 (100) [M+H]+； Anal.Calcd for C29H24N2O C, 83.63；H, 5.81；N, 6.73；Found：C, 83.63；H, 5.81；N, 6.73.
Embodiment 26：1- (3- chlorphenyls) -5- (phenoxy group (phenyl) methyl) -2- phenyl -1H- imidazoles (yield 75%)
Brown oil.65.6mg.1H NMR (400MHz, CDCl3) δ 7.36 (d, J=8.0Hz, 4H), 7.29 (d, J= 7.6Hz, 3H), 7.25-7.19 (m, 5H), 7.15-7.08 (m, 3H), 7.06 (d, J=7.6Hz, 1H), 6.87 (t, J= 8.0Hz, 2H), 6.69 (d, J=8.0Hz, 2H), 5.98 (s, 1H)13C NMR (100MHz, CDCl3) δ 157.1,148.7, 137.9,137.7,134.8,134.3,130.1,130.0,129.8,129.2,129.0,128.5,128.4,128.4, 128.2,128.1,126.6,121.3,115.5,73.2.ESI-MS m/z (%) 437 (100) [M+H]+；Anal.Calcd for C28H21ClN2O C, 76.97；H, 6.84；N, 6.41；Found：C, 76.97；H, 6.84；N, 6.41.
Embodiment 27：1- (3- bromophenyls) -5- (phenoxy group (phenyl) methyl) -2- phenyl -1H- imidazoles (yield 68%)
Brown oil.65.4mg.1H NMR (400MHz, CDCl3) δ 7.42 (t, J=3.6Hz, 2H), 7.39-7.29 (m, 8H), 7.23 (d, J=7.6Hz, 2H), 7.17-7.11 (m, 4H), 6.88 (t, J=7.2Hz, 2H), 6.72 (d, J=8.0Hz, 2H), 5.99 (s, 1H)13C NMR (100MHz, CDCl3) δ 157.2,138.2,137.8,134.4,132.0,130.4, 130.2,129.9,129.4,128.7,128.8,128.5,128.3,128.2,126.7,121.4,115.7,73.3.ESI-MS M/z (%) 481 (100) [M+H]+；Anal.Calcd for C28H21BrN2O C, 69.86；H, 4.40；N, 5.82；Found：C, 69.86；H, 4.40；N, 5.82.
Embodiment 28：1- (4- fluorophenyls) -5- (phenoxy group (phenyl) methyl) -2- (p- toluene) -1H- imidazoles (yields 76%)
Yellow oil.81.3mg.1H NMR (400MHz, CDCl3) δ 7.35-7.26 (m, 5H), 7.22 (d, J= 8.0Hz, 2H), 7.19-7.08 (m, 4H), 7.00 (d, J=8.0Hz, 2H), 6.97-6.82 (m, 4H), 6.67 (d, J= 7.6Hz, 2H), 5.95 (s, 1H), 2.25 (s, 3H)13C NMR (100MHz, CDCl3) δ 163.5 (d, J=250Hz), 157.2, 149.1,138.4,137.9,134.1,132.9,132.9,130.0,129.2,128.9,128.4,128.3,128.1, 127.2,126.7,121.3,116.3,116.1,115.6,73.3,21.1.ESI-MS m/z (%) 435 (100) [M+H]+； Anal.Calcd for C29H23FN2O C, 80.16；H, 5.34；N, 6.45；Found：C, 80.16；H, 5.34；N, 6.45.
Embodiment 29：5- (ethyoxyl (o- toluene) methyl) -1,2- diphenyl -1H- imidazoles (yield 68%)
Brown oil.50.0mg.1H NMR (400MHz, CDCl3) δ 7.55 (d, J=7.2Hz, 1H), 7.46 (s, 4H), 7.36 (d, J=6.0Hz, 2H), 7.27 (d, J=7.6Hz, 1H), 7.25-7.23 (m, 1H), 7.23-7.17 (m, 4H), 7.12 (d, J=7.0Hz, 1H), 6.62 (s, 1H), 5.18 (s, 1H), 3.34-3.27 (m, 1H), 2.99-2.92 (m, 1H), 2.11 (s, 3H), 1.04 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 148.3,137.3,136.8,135.5,134.6, 130.4,130.3,129.3,129.2,128.9,128.3,128.2,128.0,127.6,126.2,126.1,71.7,64.6, 18.8,15.1.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57； N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 30：5- (ethyoxyl (m- toluene) methyl) -1,2- diphenyl -1H- imidazoles (yield 74%)
Brown oil.54.5mg.1H NMR (400MHz, CDCl3) δ 7.42 (d, J=5.2Hz, 3H), 7.34 (d, J= 8.0Hz, 3H), 7.25-7.09 (m, 7H), 6.92 (d, J=6.0Hz, 1H), 6.80 (d, J=8.0Hz, 1H), 5.05 (s, 1H), (t, J=7.2Hz, the 3H) of 3.36-3.27 (m, 1H), 3.09-3.01 (m, 1H), 2.29 (s, 3H), 1.0313C NMR (100MHz, CDCl3) δ 148.1,138.7,137.9,137.8,137.2,130.2,129.5,129.1,129.1,128.8,128.7, 128.4,128.2,128.2,128.0,127.8,124.9,124.2,75.0,64.3,21.4,21.3,15.0.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 31：5- (ethyoxyl (p- toluene) methyl) -1,2- diphenyl -1H- imidazoles (yield 75%)
Brown solid, m.p.100-101 DEG C of .55.2mg.1H NMR (400MHz, CDCl3) δ 7.43 (d, J=3.2Hz, 3H), 7.34 (d, J=6.0Hz, 3H), 7.23-7.14 (m, 8H), 6.77 (s, 1H), 5.04 (s, 1H), 3.32-3.25 (m, 1H), (t, J=7.0Hz, the 3H) of 3.06-2.98 (m, 1H), 2.36 (s, 3H), 1.0113C NMR (100MHz, CDCl3)δ 148.2,137.6,137.3,135.8,135.6,130.4,129.1,129.0,128.8,128.7,128.4,128.1, 128.0,127.1,74.8,64.2,21.1,15.0.ESI-MS m/z (%) 368 (100) [M+H]+；Anal.Calcd for C25H24N2O C, 81.49；H, 6.57；N, 7.60；Found：C, 81.49；H, 6.57；N, 7.60.
Embodiment 32：5- ((3,5- 3,5-dimethylphenyl) (ethyoxyl) methyl) -1,2- diphenyl -1H- imidazoles (yields 81%)
Yellow oil.62.0mg.1H NMR (400MHz, CDCl3) δ 7.42 (d, J=4.4Hz, 3H), 7.34 (d, J= 5.6Hz, 3H), 7.20-7.15 (m, 4H), 6.92 (d, J=3.2Hz, 3H), 6.81 (s, 1H), 5.02 (s, 1H), 3.36-3.28 (m, 1H), 3.09-3.02 (m, 1H), 2.29 (s, 6H), 1.03 (t, J=7.0Hz, 3H)13C NMR (100MHz, CDCl3)δ 148.2,138.8,137.7,137.3,135.6,130.5,129.5,129.1,128.8,128.7,128.4,128.1, 128.0,124.9,75.1,64.3,21.2,15.0.ESI-MS m/z (%) 383 (100) [M+H]+；Anal.Calcd for C26H26N2O C, 81.64；H, 6.85；N, 7.32；Found：C, 81.64；H, 6.85；N, 7.32.
Embodiment 33：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl acetic acid ester (yield 73%)
Yellow solid, m.p.147-149 DEG C of .53.7mg.1H NMR (400MHz, CDCl3) δ 7.40 (d, J= 6.4Hz, 3H), 7.35 (d, J=6.0Hz, 2H), 7.32-7.28 (m, 5H), 7.19 (d, J=7.6Hz, 5H), 6.95 (s, 1H), 6.67 (s, 1H), 1.89 (s, 3H)13C NMR (100MHz, CDCl3) δ 169.2,148.6,137.3,136.7,133.1, 130.0,129.5,129.5,129.0,128.3,128.3,128.0,127.1,69.0,20.7.ESI-MS m/z (%) 368 (100)[M+H]+；Anal.Calcd for C24H20N2O2C, 78.24；H, 5.47；N, 7.60；Found：C, 78.24；H, 5.47；N, 7.60.
Embodiment 34：(1,2- diphenyl -1H- imidazoles -5-yl) (phenyl) methyl benzoic acid ester (yield 77%)
Brown oil.66.4mg.1H NMR (400MHz, CDCl3) δ 7.96 (d, J=7.2Hz, 2H), 7.55 (t, J= 7.6Hz, 1H), 7.44-7.30 (m, 12H), 7.23-7.17 (m, 5H), 7.08 (s, 1H), 6.92 (s, 1H)13C NMR (100MHz, CDCl3) δ 164.8,148.6,137.4,136.5,133.1,129.8,129.8,129.6,129.6,129.5, 129.5,129.1,128.5,128.4,128.4,128.4,128.3,128.1,127.0,69.4.ESI-MS m/z (%) 431 (100)[M+H]+；Anal.Calcd for C29H22N2O2C, 80.91；H, 5.15；N, 7.43；Found：C, 80.91；H, 5.15；N, 7.43.
Embodiment 35：N- ((1,2- diphenyl -1H- imidazoles -5-yl) (phenyl) methyl)-N- phenylanilines (yield 44%)
Brown oil.42.1mg.1H NMR (400MHz, CDCl3) δ 7.34 (t, J=7.2Hz, 3H), 7.26-7.14 (m, 10H), (s, the 1H) of 7.09-7.02 (m, 5H), 6.97-6.88 (m, 7H), 6.80 (s, 1H), 5.0113C NMR (100MHz, CDCl3) δ 147.3,143.1,141.7,137.6,136.9,133.8,129.7,129.3,129.2,128.8,128.7, (100) [M of 128.3,128.3,128.2,128.1,126.7,120.9,117.8,117.6,47.3.ESI-MS m/z (%) 478 +H]+；Anal.Calcd for C34H27N3C, 85.50；H, 5.70；N, 8.80；Found：C, 85.50；H, 5.70；N, 8.80.
Toxicity test：
From healthy Kunming mouse, provided by Guangdong pharmaceutical university experimental center.Mouse feeder in non-toxic plastic box, Per 5, box, female, male point of cage changes 1 bedding and padding, freely ingests and drink water daily, and room temperature keeps 18-20 DEG C, natural lighting.Medicine Dissolved with 0.9% sodium-chloride water solution, tested material dosage is represented with mg/kg.By following dosage intraperitoneal injection, volume is administered For 0.1mL/10g, it is administered according to following dosage：50th, 100,150,200,300mg/kg.Daily observed and recorded animal after administration Outward appearance, spirit, diet, sleep, active situation and dead distribution day by day, Continuous Observation 10 days, by Bliss methods calculating LD50. After the administration of high concentration group, mouse is One's spirits are drooping, and dead preceding excrement is shapeless, becomes thin, erects hair, atrophy of uniting is motionless.
As can be seen from the above table, compound of formula I of the invention has low toxicity.
Inhibitory action of the compound of formula I to tumour cell：
Take the logarithm growth period cell, digestion, count, be inoculated in 96 well culture plates, per the μ L of hole 100.Cultivate after 24h, with Various concentrations compound handles tumour cell.After medicine effect 72h, supernatant is removed, 100 μ L MTT (1mg/mL) are added per hole, after Continuous culture 4h, abandons supernatant, and 100 μ L DMSO are added per hole, and vibration is mixed, and absorbance is determined at 570nm with ELIASA.Meter Calculate inhibiting rate.Calculation formula：Inhibiting rate (%)=(control group absorbance-administration group absorbance)/(control group absorbance Value-blank group absorbance) × 100%.Using IC50Software for calculation (China Medicine University) obtains half-inhibition concentration (IC50)。
Experimental tumor strain includes gastric carcinoma cells BGC, people's adenocarcinoma of the uterine cervix cell HeLa, human colon cancer cell HCT116, people Human umbilical vein endothelial cell, human lung carcinoma cell NCI-H460, Human Prostate Cancer Cells DU-145, human breast cancer cell MDA-MB- 231.Cell is purchased from Guangdong Province's Culture Collection cell bank.The experimental results are shown inthe following table.

Claims (9)

1. a kind of compound shown in formula I or its stereoisomer or its pharmaceutically acceptable salt or its solvate, It is characterized in that as follows：
Wherein
R1Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6It is haloalkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted C6-10Aryl, Containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or containing 1-4 in N, O and S Heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls；
R2Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6It is haloalkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted C6-10Aryl, Containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or containing 1-4 in N, O and S Heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls；
R3Independent is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6It is haloalkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted C6-10Aryl, Containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or containing 1-4 in N, O and S Heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls；
R independences be selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6It is haloalkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substituted or unsubstituted C6-10Aryl, Containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or containing 1-4 in N, O and S Heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls.
2. compound according to claim 1 or its stereoisomer or its pharmaceutically acceptable salt or its solvation Thing, it is characterised in that：Wherein described is substituted, refers to corresponding group by halogen, NH2、OH、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-10Cycloalkyl, C6-10Aryl, one contained in the individual 5-10 unit's heteroaryls heteroatomic in N, O and S of 1-4 Or multiple replaced.
3. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten Agent compound, it is characterised in that：The aryl is selected from phenyl, naphthyl, anthryl or phenanthryl.
4. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten Agent compound, it is characterised in that：The heteroaryl is selected from indolinyl, benzothiazolyl, Pyrazolopyridine base, benzisothiazole Base, triazolo pyridyl, imidazopyridyl, benzoxazolyl, triazolo pyridyl, imidazopyridyl, pyrido-pyrazine Base, quinazolyl, pyrido-pyrazine base, Ben Bing oxadiazolyl, diazosulfide base, benzimidazolyl.
5. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten Agent compound, it is characterised in that selected from following compounds：
6. the preparation method of any described compounds of claim 1-5, it is characterised in that comprise the steps：
Take N- substituted amidines and substitution alkynes aldehyde as raw material, prepared in oil bath pan reaction.
7. a kind of composition, it is characterised in that including any described compounds or its solid as shown in I of claim 1-5 Isomers or its pharmaceutically acceptable salt or its solvate, and pharmaceutically acceptable auxiliary agent, carrier or diluent.
8. composition according to claim 7, it is characterised in that：Its formulation be selected from plain piece, thin membrane coated tablet, sugar coated tablet, Casing piece, dispersible tablet, capsule, granule, oral administration solution or oral administration mixed suspension.
Any described compounds as shown in I of 9.1-6 or its stereoisomer or its pharmaceutically acceptable salt or its is molten Agent compound be used for prepare treatment tumour or cancer drug purposes, the tumour or cancer be stomach cancer, adenocarcinoma of the uterine cervix, colon cancer, Lung cancer, liver cancer, glioma, cancer of the esophagus, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma, Uterine cancer, osteocarcinoma, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, blood vessel Knurl, lipoma, cervical carcinoma and thyroid cancer.
CN201710468224.9A 2017-06-19 2017-06-19 Imidazole compounds with anticancer activity and derivatives thereof Active CN107162982B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710468224.9A CN107162982B (en) 2017-06-19 2017-06-19 Imidazole compounds with anticancer activity and derivatives thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710468224.9A CN107162982B (en) 2017-06-19 2017-06-19 Imidazole compounds with anticancer activity and derivatives thereof

Publications (2)

Publication Number Publication Date
CN107162982A true CN107162982A (en) 2017-09-15
CN107162982B CN107162982B (en) 2020-02-11

Family

ID=59818841

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710468224.9A Active CN107162982B (en) 2017-06-19 2017-06-19 Imidazole compounds with anticancer activity and derivatives thereof

Country Status (1)

Country Link
CN (1) CN107162982B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810071A (en) * 2019-03-28 2019-05-28 中国科学院成都生物研究所 A kind of miRNA biosynthesis inhibitor
CN111393371A (en) * 2020-05-15 2020-07-10 广东药科大学 Method for preparing hydroxyimidazole compound by multicomponent cyclization reaction
CN111484454A (en) * 2020-05-15 2020-08-04 广东药科大学 Method for preparing 5-hydroxyimidazole through CuI catalyzed multi-component reaction

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1138326A (en) * 1993-12-21 1996-12-18 拜尔公司 N-substituted aryl trifluoromethyl imidazoles
CN1867561A (en) * 2003-10-16 2006-11-22 霍夫曼-拉罗奇有限公司 Novel triarylimidazoles
CN101287711A (en) * 2005-08-23 2008-10-15 宇部兴产株式会社 Method for producing 1-substituted-5-acylimidazole compound
CN102892759A (en) * 2010-05-10 2013-01-23 协和发酵麒麟株式会社 Nitrogen-containing heterocyclic compound having kynurenine production inhibitory activity
EP2374802B1 (en) * 2008-11-10 2014-04-23 Kyowa Hakko Kirin Co., Ltd. Kynurenine production inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1138326A (en) * 1993-12-21 1996-12-18 拜尔公司 N-substituted aryl trifluoromethyl imidazoles
CN1867561A (en) * 2003-10-16 2006-11-22 霍夫曼-拉罗奇有限公司 Novel triarylimidazoles
CN101287711A (en) * 2005-08-23 2008-10-15 宇部兴产株式会社 Method for producing 1-substituted-5-acylimidazole compound
EP2374802B1 (en) * 2008-11-10 2014-04-23 Kyowa Hakko Kirin Co., Ltd. Kynurenine production inhibitor
CN102892759A (en) * 2010-05-10 2013-01-23 协和发酵麒麟株式会社 Nitrogen-containing heterocyclic compound having kynurenine production inhibitory activity

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHANGCHENG WANG等: "Silver-catalyzed [3+2] domino reaction: an efficient strategy to synthesize imidazole-5-carbaldehydes", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *
DEVENDRA PUNTAMBEKAR等: "3D-QSAR studies of farnesyltransferase inhibitors: A comparative molecular field analysis approach", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
JIHUI LI等: "Copper-Catalyzed Oxidative Diamination of Terminal Alkynes by Amidines: Synthesis of 1,2,4-Trisubstituted Imidazoles", 《ORGANIC LETTERS》 *
LE WANG等: "Design, Synthesis, and Biological Activity of 4-[(4-Cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as Potent and Selective Farnesyltransferase Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
LISA A. HASVOLD等: "Pyridone-containing farnesyltransferase inhibitors: Synthesis and biological evaluation", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
蔡佳利等: "咪唑类抗癌药物研究进展", 《中国新药杂志》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810071A (en) * 2019-03-28 2019-05-28 中国科学院成都生物研究所 A kind of miRNA biosynthesis inhibitor
CN109810071B (en) * 2019-03-28 2023-04-21 中国科学院成都生物研究所 miRNA biosynthesis inhibitor
CN111393371A (en) * 2020-05-15 2020-07-10 广东药科大学 Method for preparing hydroxyimidazole compound by multicomponent cyclization reaction
CN111484454A (en) * 2020-05-15 2020-08-04 广东药科大学 Method for preparing 5-hydroxyimidazole through CuI catalyzed multi-component reaction
CN111393371B (en) * 2020-05-15 2021-07-06 广东药科大学 Method for preparing hydroxyimidazole compound by multicomponent cyclization reaction
CN111484454B (en) * 2020-05-15 2021-07-09 广东药科大学 Method for preparing 5-hydroxyimidazole through CuI catalyzed multi-component reaction

Also Published As

Publication number Publication date
CN107162982B (en) 2020-02-11

Similar Documents

Publication Publication Date Title
CN106928206B (en) Aldehyde compound and its preparation method and use
CN106916177B (en) A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes
TW200307535A (en) Therapeutic agent for cancer
RU2557235C1 (en) Substituted 2-thioxo-imidazolidin-4-one, and spiroanalogues thereof, anticancer active ingredient, pharmaceutical composition, medicinal product, method of treating prostate cancer
CN104053439A (en) Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid
CN102971312A (en) Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof
CN107163044A (en) Naphthylethylenedione compound with protease modification activity and derivative thereof
CN107162982A (en) Imidazole compounds with anticancer activity and derivatives thereof
CN112047993A (en) Alpha-glucosidase inhibitor and application thereof
CN115304590A (en) 2H-benzotriazole derivatives, preparation method thereof and pharmaceutical composition containing same
CN108822126B (en) Thienopyran formyl piperazine compound and medical application thereof
JP7050336B2 (en) Deuterated compounds and their pharmaceutical uses
JP6767498B2 (en) Ginkgolide B derivative and its preparation method and application
CN108017656B (en) Camptothecin derivative and application thereof in preparation of antitumor drugs
CN108864082A (en) One kind has the indolizine class compound and its derivative of anticancer activity
CN110922415B (en) Synthesis and application of novel anti-tumor active compound
CN109111439B (en) Amide compound, composition containing same and application thereof
CN109896986B (en) Structure simplification of lignan natural product 4-O-methyl saururus chinensis alcohol, preparation method thereof, pharmaceutical composition thereof and application thereof
CN107325052A (en) Imidazole ester compounds with anticancer activity and derivatives thereof
CN108658907A (en) One kind has the immunocompetent sulfonyl substituted furan class compound of anti-inflammatory and its derivative
CN113444074B (en) Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof
CN105646354B (en) A kind of glyoxaline compound
WO2014086102A1 (en) Indole full ketone derivative used as tyrosine-kinase inhibitor
CN107739381A (en) Curcuma zedoary 01 derivatives and its application in antineoplastic is prepared
CN108484635B (en) 4H-thieno [2,3-b ] thiopyran-4-one compound and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20220316

Address after: 510000 room 1301, No. 57, TIYU West Road, Tianhe District, Guangzhou, Guangdong

Patentee after: Guangzhou new Mdt InfoTech Ltd.

Address before: School of medicine and chemical engineering, Guangdong Pharmaceutical University, 9-13 changmingshui Avenue, Wuguishan Town, Zhongshan City, Guangdong Province, 528458

Patentee before: GUANGDONG PHARMACEUTICAL University

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20220713

Address after: 100000 room 603, 6th floor, building 5, courtyard 2, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Daxing District, Beijing

Patentee after: Huaji Pharmaceutical Technology (Beijing) Co.,Ltd.

Address before: 510000 room 1301, No. 57, TIYU West Road, Tianhe District, Guangzhou, Guangdong

Patentee before: Guangzhou new Mdt InfoTech Ltd.

TR01 Transfer of patent right