CN107325052A - Imidazole ester compounds with anticancer activity and derivatives thereof - Google Patents

Imidazole ester compounds with anticancer activity and derivatives thereof Download PDF

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Publication number
CN107325052A
CN107325052A CN201710468223.4A CN201710468223A CN107325052A CN 107325052 A CN107325052 A CN 107325052A CN 201710468223 A CN201710468223 A CN 201710468223A CN 107325052 A CN107325052 A CN 107325052A
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substituted
unsubstituted
cancer
heteroatomic
compound
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CN107325052B (en
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曹华
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Wuxi Enqiao Pharmaceutical Technology Co ltd
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Guangdong Pharmaceutical University
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    • 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

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to imidazole ester compounds with anticancer activity and derivatives thereof. The compound and the derivative thereof have the inhibition effect on various tumors and cancers thereof, and the compound is shown in the following general formula.

Description

One class has the imidazoles ester type compound and its derivative of active anticancer
Technical field
The present invention relates to imidazole ester type compound or its stereoisomer or its pharmaceutically acceptable salt or its Solvate.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 imidazoles ester type 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 imidazoles ester type 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, take Generation or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Cycloalkyl, substitution do not take The C in generation6-10Aryl, containing 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S, or contain 1-4 Individual substituted or unsubstituted 5-10 unit's heteroaryls heteroatomic in N, O and S；
R4Independent 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, contain 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and 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, substitution alkynes aldehyde and substitution Or unsubstituted carboxylic acid, as raw material, at 50-80 DEG C, dichloromethane prepares for solvent.Those skilled in the art can manage Solution is, when preparing particular compound, starting compound can be selected as the case may be.
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.C3-7Cycloalkyl purpose be include C3, C4, C5, C6 and C7 cycloalkyl.Examples of cycloalkyl includes but is not limited to cyclopropyl, goes back butyl, cyclopenta, cyclohexyl, norborny And the like." carbocyclic ring " used herein or " carbocyclic ring is remaining " refers to any stablizing 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.These carbon Ring example includes but is not limited to cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, pentenyl, cyclohexyl, cyclohexenyl group, cycloheptyl Base, 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 such as " haloalkyl " with one or more halogenic substituents 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 that armaticity or nonaromatic heteroaryls 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 tax for contributing to mucous membrane to adhere to Shape agent such as hydroxypropyl cellulose (HPC), HPMC (HPMC), sodium carboxymethylcellulose (SCMC) and/or maleic acid Anhydride copolymer is (such as)；With the reagent such as acrylic copolymer of control release (such as)。 Also lubricant, glidant, spices, colouring agent and stabilizer, which can be added, to be helped 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：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methylpropionate (yield 72%)
N- phenyl benzamidine (0.20mmol), phenyl-allylene aldehyde (0.20mmol), acetic acid are sequentially added in 25ml Shrek pipes (0.60mmol), AgOAc (2.0mol%), 3.0ml CH2Cl2, after be passed through N2, 10h is reacted in 60 DEG C.Reacted with TLC detections Cheng Hou, is cooled to room temperature, 10mL saturated aqueous common salts is added into reaction mixture, then extracted with ethyl acetate (10mL × 3) Take, merge organic layer and washed with saturated aqueous common salt, use anhydrous MgSO4It is dried.Resulting organic phase decompression is steamed Most of solvent is removed in distillation, and crude product carries out separating-purifying with column chromatography.The structure warp of product1H NMR,13C NMR, GC-MS, HRMS and IR etc. is analyzed to identify.
Yellow oily liquid .55.0mg.1H NMR (400MHz, CDCl3) δ 7.41 (d, J=7.2Hz, 2H), 7.35-7.29 (m, 8H), 7.21-7.19 (m, 5H), 6.94 (s, 1H), 6.69 (s, 1H), 2.22-2.15 (m, 2H), 1.03 (t, J=7.6Hz, 3H).13C NMR (100MHz, CDCl3) δ 172.7,137.5,136.7,133.3,130.0,129.5,129.4,129.2, 129.1,128.4,128.3,128.1,127.1,68.8,27.3,8.8.ESI-MS m/z (%) 382 (100) [M+H]+； Anal.Calcd for C25H22N2O2C, 78.51；H, 5.80；N, 7.32；Found：C, 78.43；H, 5.82；N, 7.35.
With the preparation method similar to embodiment 1, only following compound are prepared with different raw materials
Embodiment 2：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methylbutyrate (yield 78%)
Yellow oily liquid .61.8mg.1H NMR (400MHz, CDCl3) δ 7.41 (d, J=7.2Hz, 3H), 7.34-7.19 (m, 12H), 6.95 (s, 1H), 6.67 (s, 1H), 2.17-2.10 (m, 2H), 1.56-1.47 (m, 2H), 0.86 (t, J= 7.6Hz, 3H)13C NMR (100MHz, CDCl3) δ 171.9,148.5,137.5,136.6,133.3,129.8,129.5, 129.2,129.1,128.5,128.4,128.4,128.4,128.1,127.1,68.8,35.9,18.1,13.6.ESI-MS m/ Z (%) 396 (100) [M+H]+；Anal.Calcd for C26H24N2O2C, 78.76；H, 6.10；N, 7.07；Found：C, 78.85；H, 6.07；N, 7.04.
Embodiment 3：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methylpent acid esters (yield 76%)
Yellow oily liquid .62.5mg.1H NMR (400MHz, CDCl3) δ 7.41 (d, J=7.2Hz, 3H), 7.34-7.19 (m, 12H), 6.94 (s, 1H), 6.67 (s, 1H), 2.19-2.12 (m, 2H), 1.51-1.43 (m, 2H), 1.26-1.21 (m, 2H), 0.89 (t, J=7.2Hz, 3H.)13C NMR (100MHz, CDCl3) δ 172.1,148.5,137.5,136.7,133.2, 130.0,129.5,129.0,128.4,128.3,128.3,128.1,127.1,68.8,33.7,26.7,22.1,13.6.ESI- MS m/z (%) 411 (100) [M+H]+；Anal.Calcd for C27H26N2O2C, 79.00；H, 6.38；N, 6.82；Found： C, 78.93；H, 6.41；N, 6.85.
Embodiment 4：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 3- phenoxy propionic acids ester (yield 67%)
.m.p.108-110 DEG C of .63.7mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.38-7.28 (m, 10H), 7.25-7.18 (m, 7H), 6.97-6.92 (m, 2H), 6.85 (d, J=8.8Hz, 2H), 6.73 (s, 1H), 4.14 (t, J= 6.0Hz, 2H), 2.67-2.63 (m, 2H)13C NMR (100MHz, CDCl3) δ 169.4,158.2,148.6,137.1,136.6, 132.9,129.9,129.6,129.5,129.4,129.1,128.4,128.4,128.1,127.0,121.0,114.5,69.3, 63.0,34.4.ESI-MS m/z (%) 475 (100) [M+H]+；Anal.Calcd for C31H26N2O3C, 78.46；H, 5.52； N, 5.90；Found：C, 78.55；H, 5.50；N, 5.88.
Embodiment 5：1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 2- methyl benzoic acid esters (yield 74%)
.m.p.100-101 DEG C of .65.9mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.90 (d, J=7.6Hz, 1H), (s, the 3H) of 7.39-7.32 (m, 10H), 7.23-7.16 (m, 8H), 7.05 (s, 1H), 6.90 (s, 1H), 2.4713C NMR (100MHz, CDCl3) δ 165.4,148.6,140.6,137.5,136.6,133.3,132.2,131.7,130.6,129.9, 129.6,129.4,129.0,128.4,128.4,128.1,127.1,125.6,69.1,21.7.ESI-MS m/z (%) 445 (100)[M+H]+；Anal.Calcd for C30H24N2O2C, 81.06；H, 5.44；N, 6.30；Found：C, 80.98；H, 5.46；N, 6.33.
Embodiment 6：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 3- methyl benzoic acid esters (yield 76%)
.m.p.106-107 DEG C of .67.6mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.78 (d, J=6.0Hz, 2H), (s, the 3H) of 7.37-7.31 (m, 11H), 7.23-7.17 (m, 6H), 7.05 (s, 1H), 6.91 (s, 1H), 2.3913C NMR (100MHz, CDCl3) δ 165.0,148.6,138.1,137.4,136.6,133.9,132.3,130.1,130.0,129.8, 129.4,129.0,128.4,128.3,128.3,128.2,128.0,126.9,126.8,69.2,21.2.ESI-MS m/z (%) 445 (100) [M+H]+；Anal.Calcd for C30H24N2O2C, 81.06；H, 5.44；N, 6.30；Found：C, 81.14；H, 5.42；N, 6.27.
Embodiment 7：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- methyl benzoic acid esters (yield 79%)
.m.p.177-179 DEG C of .70.3mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.86 (d, J=8.0Hz, 2H), (s, the 3H) of 7.36-7.31 (m, 9H), 7.22-7.16 (m, 8H), 7.04 (s, 1H), 6.88 (s, 1H), 2.4113C NMR (100MHz, CDCl3) δ 164.9,148.6,143.9,137.5,136.6,133.4,129.9,129.7,129.6,129.5, (100) [M+ of 129.1,129.1,128.4,128.3,128.1,127.0,126.8,69.2,21.7.ESI-MS m/z (%) 445 H]+；Anal.Calcd for C30H24N2O2C, 81.06；H, 5.44；N, 6.30；Found：C, 81.10；H, 5.43；N, 6.28.
Embodiment 8：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- fluorobenzoates (yield 72%)
.m.p.153-155 DEG C of .64.5mg. of brown solid1H NMR (400MHz, CDCl3) δ 8.13 (t, J=8.4Hz, 2H), 7.99 (t, J=8.4Hz, 2H), 7.40-7.33 (m, 8H), 7.23-7.19 (m, 4H), 7.13-7.07 (m, 4H), 6.91 (s, 1H)13C NMR (100MHz, CDCl3) δ 167.1,164.5 (J=66.2Hz), 148.7,137.2,136.5,133.1, 132.2,132.1,129.8,129.8,129.5,129.1,128.5,128.4,128.1,127.0,115.6,115.4, 69.6.ESI-MS m/z (%) 448 (100) [M+H]+；Anal.Calcd for C29H21FN2O2C, 77.66；H, 4.72；N, 6.25；Found：C, 77.76；H, 4.70；N, 6.22.
Embodiment 9：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 2- chlorobenzoic acids ester (yield 68%)
Yellow oily liquid .63.2mg.1H NMR (400MHz, CDCl3) δ 7.75 (d, J=8.8Hz, 1H), 7.42-7.33 (m, 13H), 7.21-7.17 (m, 5H), 7.07 (s, 1H), 6.89 (s, 1H)13C NMR (100MHz, CDCl3) δ 163.6, 148.1,136.5,134.1,133.8,132.5,131.7,131.2,131.0,129.7,129.6,129.2,128.8, 128.6,128.3,127.4,126.5,69.9.ESI-MS m/z (%) 465 (100) [M+H]+；Anal.Calcd for C29H21ClN2O2C, 74.92；H, 4.55；N, 6.03；Found：C, 75.02；H, 4.53；N, 6.00.
Embodiment 10：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- bromo-benzoates (yield 81%)
.m.p.166-170 DEG C of .63.2mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.75 (d, J=8.8Hz, 1H), (s, the 1H) of 7.42-7.33 (m, 13H), 7.21-7.17 (m, 5H), 7.07 (s, 1H), 6.8913C NMR (100MHz, CDCl3) δ 163.6,148.1,136.5,134.1,133.8,132.5,131.7,131.2,131.0,129.7,129.6, 129.2,128.8,128.6,128.3,127.4,126.5,69.9.ESI-MS m/z (%) 509 (100) [M+H]+； Anal.Calcd for C29H21BrN2O2C, 68.38；H, 4.16；N, 5.50；Found：C, 68.46；H, 4.14；N, 5.48.
Embodiment 11：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 3- methoxy benzoic acids ester (yield 77%)
Yellow oily liquid .71.0mg.1H NMR (400MHz, CDCl3) δ 7.58 (d, J=7.6Hz, 1H), 7.46 (s, 1H), 7.37-7.32 (m, 10H), 7.23-7.17 (m, 6H), 7.10 (d, J=6.0Hz, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.83 (s, 3H)13C NMR (100MHz, CDCl3) δ 164.7,159.4,148.7,137.3,136.5,133.2, 130.8,129.8,129.7,129.5,129.3,129.1,128.4,128.4,128.1,127.0,122.0,119.5, 114.2,69.5,55.4.ESI-MS m/z (%) 461 (100) [M+H]+；Anal.Calcd for C30H24N2O3C, 78.24； H, 5.25；N, 6.08.；Found：C, 78.32；H, 5.23；N, 6.05.
Embodiment 12：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- methoxy benzoic acids ester (yield 77%)
.m.p.121-124 DEG C of .71.0mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.93 (d, J=8.8Hz, 2H), 7.35-7.31 (m, 9H), 7.22-7.16 (m, 6H), 7.03 (s, 1H), 6.90 (d, J=10.0Hz, 3H), 3.85 (s, 3H).13C NMR (100MHz, CDCl3) δ 164.6,163.5,148.6,137.6,136.6,133.5,131.8,130.0, 129.6,129.5,129.1,128.4,128.4,128.3,128.1,127.0,122.0,113.6,69.1,55.5.ESI-MS M/z (%) 461 (100) [M+H]+；Anal.Calcd for C30H24N2O3C, 78.24；H, 5.25；N, 6.08.；Found：C, 78.15；H, 5.27；N, 6.11.
Embodiment 13：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- (t- butyl) benzoic ether (yield 74%)
.m.p.175-177 DEG C of .72.1mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.92 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4Hz, 3H), 7.37-7.30 (m, 10H), 7.21 (d, J=7.6Hz, 4H), 7.09 (s, 1H), 6.89 (s, 1H), 1.34 (s, 9H)13C NMR (100MHz, CDCl3) δ 164.9,156.9,148.6,137.6,136.5,133.4, 129.9,129.6,129.5,129.1,128.4,128.4,128.2,128.1,127.0,126.8,125.3,69.2,35.1, 31.1.ESI-MS m/z (%) 487 (100) [M+H]+；Anal.Calcd for C33H30N2O2C, 81.45；H, 6.21；N, 5.76；Found：C, 81.37；H, 6.24；N, 5.78.
Embodiment 14：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methyl 4- nitrobenzoyls acid esters (yield 65%)
.m.p.170-173 DEG C of .61.9mg. of brown solid1H NMR (400MHz, CDCl3) δ 8.50 (d, J=8.8Hz, 3H), 8.30 (d, J=8.4Hz, 3H), 7.62 (d, J=7.2Hz, 3H), 7.48 (t, J=7.2Hz, 2H), 7.37 (t, J= 8.0Hz, 3H), 7.29-7.25 (m, 3H), 7.20 (t, J=7.2Hz, 2H), 7.06 (d, J=7.2Hz, 2H)13C NMR (100MHz, CDCl3) δ 164.0,150.0,142.7,137.9,133.9,131.5,130.6,129.6,129.2,128.4, 126.4,124.0,123.3,77.2.ESI-MS m/z (%) 476 (100) [M+H]+；Anal.Calcd for C29H21N3O4C, 73.25；H, 4.45；N, 8.84；Found：C, 73.15；H, 4.47；N, 8.87.
Embodiment 15：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) picoline acid esters (yield 70%)
Brown oil liquid .60.3mg.1H NMR (400MHz, CDCl3) δ 10.15 (s, 1H), 8.44 (d, J=4.4Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 7.84 (d, J=6.8Hz, 4H), 7.50-7.30 (m, 10H), 7.17 (t, J=7.2Hz, 2H), 7.05 (d, J=7.6Hz, 2H)13C NMR (100MHz, CDCl3) δ 161.8,151.0,148.4,148.1,147.9, 137.6,135.2,130.8,129.4,128.4,128.1,127.0,124.4,122.9,121.8,120.5.ESI-MS m/z (%) 431 (100) [M+H]+；Anal.Calcd for C28H21N3O2C, 77.94；H, 4.91；N, 9.74；Found：C, 77.86；H, 4.93；N, 9.77.
Embodiment 16：(1,2- diphenyl -1H- imidazoles -5- bases) (phenyl) methylfuran -3- carboxylates (yield 75%)
.m.p.154-155 DEG C of .63.0mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.96 (s, 1H), 7.41- 7.33 (m, 11H), 7.22-7.16 (m, 5H), 7.08, (s, 1H), 6.84 (s, 1H), 6.66 (s, 1H)13C NMR (100MHz, CDCl3) δ 161.3,147.9,143.8,143.5,137.2,136.3,129.5,129.2,128.7,128.5,128.5, 128.2,127.0,118.7,110.1,109.7,68.8.ESI-MS m/z (%) 420 (100) [M+H]+；Anal.Calcd for C27H20N2O3C, 77.13；H, 4.79；N, 6.66；Found：C, 77.22；H, 4.77；N, 6.63.
Embodiment 17：Phenyl (2- phenyl -1- (p- tolyls) -1H- imidazoles -5- bases) methyl benzoic acid ester (yield 81%)
.m.p.114-115 DEG C of .72.1mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.96 (d, J=8.4Hz, 2H), 7.56 (t, J=7.6Hz, 1H), 7.42-7.32 (m, 10H), 7.22 (d, J=7.6Hz, 4H), 7.07 (t, J=8.0Hz, 3H), 6.89 (s, 1H), 2.30 (s, 3H)13C NMR (100MHz, CDCl3) δ 164.9,148.5,139.2,137.4,133.7, 133.1,130.1,129.8,129.6,129.1,128.5,128.4,128.4,128.4,128.3,128.1,127.0,69.4, 21.1.ESI-MS m/z (%) 445 (100) [M+H]+；Anal.Calcd forC30H24N2O2C, 81.06；H, 5.44；N, 6.30；Found：C, 81.12；H, 5.43；N, 6.28.
Embodiment 18：(1- (4- fluorophenyls) -2- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 72%)
.m.p.93-97 DEG C of .64.5mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.98 (d, J=8.4Hz, 2H), (s, the 1H) of 7.59 (t, J=7.6Hz, 1H), 7.45-7.34 (m, 10H), 7.23-7.14 (m, 6H), 7.08 (s, 1H), 6.9213C NMR (100MHz, CDCl3) δ 164.9,163.7 (J=248.8Hz), 148.5,137.2,133.3,132.5,129.8, 129.6,129.5,128.7,128.5,128.5,128.4,128.2,127.0,116.6,116.4,69.3.ESI-MS m/z (%) 448 (100) [M+H]+；Anal.Calcd for C29H21FN2O2C, 77.66；H, 4.72；N, 6.25；Found：C, 77.74；H, 4.71；N, 6.23.
Embodiment 19：(1- (3- chlorphenyls) -2- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 70%)
.m.p.134-138 DEG C of .65.1mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.88 (d, J=8.4Hz, 2H), (s, the 1H) of 7.39-7.32 (m, 12H), 7.22-7.17 (m, 5H), 7.02 (s, 1H), 6.9013C NMR (100MHz, CDCl3) δ 164.0,148.8,139.7,137.1,136.5,131.0,129.8,129.5,129.1,128.7,128.5, 128.5,128.4,128.1,128.0,127.0,69.7.ESI-MS m/z (%) 465 (100) [M+H]+；Anal.Calcd for C29H21ClN2O2C, 74.92；H, 4.55；N, 6.03；Found：C, 74.81；H, 4.57；N, 6.05.
Embodiment 20：(1- (4- chlorphenyls) -2- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 82%)
.m.p.146-151 DEG C of .76.3mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.98 (d, J=6.8Hz, 2H), 7.58 (t, J=7.6Hz, 1H), 7.45-7.34 (m, 11H), 7.24 (d, J=7.6Hz, 3H), 7.10 (d, J=6.0Hz, 3H), 6.94 (s, 1H)13C NMR (100MHz, CDCl3) δ 164.8,148.8,137.2,135.2,135.0,133.2, 133.2,130.0,129.6,129.5,129.4,128.6,128.5,128.4,128.4,128.2,127.0,69.3.ESI-MS M/z (%) 465 (100) [M+H]+；Anal.Calcd for C29H21ClN2O2C, 74.92；H, 4.55；N, 6.03；Found：C, 74.85；H, 4.56；N, 6.05.
Embodiment 21：(1- (3- bromophenyls) -2- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 75%)
.m.p.124-128 DEG C of .76.4mg. of yellow solid1H NMR (400MHz, CDCl3) δ 8.00 (d, J=6.8Hz, 2H), (s, the 1H) of 7.59 (t, J=7.6Hz, 1H), 7.46-7.33 (m, 12H), 7.24-7.20 (m, 5H), 6.9813C NMR (100MHz, CDCl3) δ 164.8,148.8,137.8,137.1,133.3,133.2,132.3,130.5,129.8,129.7, 129.4,128.8,128.5,128.3,128.1,126.8,69.1.ESI-MS m/z (%) 509 (100) [M+H]+； Anal.Calcd for C29H21BrN2O2C, 68.38；H, 4.16；N, 5.50；Found：C, 68.46；H, 4.15；N, 5.48.
Embodiment 22：(the production of (1- (3,4- dichlorophenyl) -2- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester Rate 71%)
.m.p.122-124 DEG C of .70.9mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.98 (d, J=7.6Hz, 2H), 7.60 (t, J=7.2Hz, 1H), 7.47 (t, J=7.6Hz, 3H), 7.35-7.24 (m, 12H), 7.10 (s, 1H), 6.99 (s, 1H)13C NMR (100MHz, CDCl3) δ 164.8,149.0,137.0,133.6,133.4,131.0,130.2,129.6, 129.2,129.0,128.6,128.5,128.4,126.8,69.1.ESI-MS m/z (%) 499 (100) [M+H]+； Anal.Calcd for C29H20Cl2N2O2C, 69.75；H, 4.04；N, 5.61；Found：C, 69.83；H, 4.03；N, 5.59.
Embodiment 23：Phenyl (1- phenyl -2- (p- tolyls) -1H- imidazoles -5- bases) methyl benzoic acid ester (yield 65%)
Yellow oily liquid .57.9mg.1H NMR (400MHz, CDCl3) δ 8.10 (d, J=7.2Hz, 1H), 7.96 (d, J =7.6Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.42-7.30 (m, 9H), 7.25-7.16 (m, 5H), 7.08 (s, 1H), (s, the 3H) of 7.01 (d, J=8.0Hz, 2H), 6.89 (s, 1H), 2.2513C NMR (100MHz, CDCl3) δ 164.8,148.7, 138.7,137.3,136.4,133.1,133.0,123.5,129.8,129.6,129.5,129.1,128.9,128.5, 128.4,128.3,128.1,127.0,126.5,69.3,21.2.ESI-MS m/z (%) 445 (100) [M+H]+； Anal.Calcd for C30H24N2O2C, 81.06；H, 5.44；N, 6.30；Found：C, 81.12；H, 5.42；N, 6.28.
Embodiment 24：(2- (4- chlorphenyls) -1- phenyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 76%)
Yellow oily liquid .70.7mg.1H NMR (400MHz, CDCl3) δ 7.96 (d, J=7.6Hz, 2H), 7.58 (t, J =7.6Hz, 1H), 7.44 (t, J=7.6Hz, 3H), 7.36-7.29 (m, 9H), 7.18-7.16 (m, 4H), 7.06 (s, 1H), 6.89 (s, 1H)13C NMR (100MHz, CDCl3) δ 164.8,147.3,137.1,136.1,134.8,133.7,133.3, 129.7,129.6,129.6,129.4,129.4,128.5,128.5,128.4,127.0,69.2.ESI-MS m/z (%) 465 (100)[M+H]+；Anal.Calcd for C29H21ClN2O2C, 74.92；H, 4.55；N, 6.03；Found：C, 74.81；H, 4.57；N, 6.05.
Embodiment 25：(1,2- bis--m- tolyl -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 74%)
Yellow oily liquid .67.9mg.1H NMR (400MHz, CDCl3) δ 7.98 (d, J=7.6Hz, 2H), 7.57 (t, J =7.6Hz, 1H), 7.44-7.32 (m, 8H), 7.11-6.94 (m, 8H), 6.90 (s, 1H), 2.24 (s, 6H)13C NMR (100MHz, CDCl3) δ 164.8,148.8,139.5,137.8,136.5,133.2,133.1,129.8,129.6,129.6, 129.3,129.2,128.4,128.3,127.7,127.0,125.1,53.4,21.3.ESI-MSm/z (%) 459 (100) [M+ H]+；Anal.Calcd for C31H26N2O2C, 81.20；H, 5.72；N, 6.11；Found：C, 81.27；H, 5.70；N, 6.09.
Embodiment 26：(1- (4- fluorophenyls) -2- (m- tolyls) -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 79%)
Yellow oily liquid .73.2mg.1H NMR (400MHz, CDCl3) δ 7.99 (d, J=6.8Hz, 2H), 7.57 (t, J =6.4Hz, 1H), 7.45-7.34 (m, 8H), 7.08-6.98 (m, 8H), 6.92 (s, 1H), 2.24 (s, 3H)13C NMR (100MHz, CDCl3) δ 164.8,163.7 (J=248.7Hz), 149.0,138.0,137.2,133.3,132.6,129.6, 129.6,129.4,129.4,128.5,128.5,128.4,127.9,126.9,125.3,116.5,116.3,69.3, 21.3.ESI-MS m/z (%) 463 (100) [M+H]+；Anal.Calcd for C30H23FN2O2C, 77.91；H, 5.01；N, 6.06；Found：C, 77.99；H, 4.99；N, 6.04.
Embodiment 27：(1- (4- chlorphenyls) -2- (m- tolyls) -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 84%)
Yellow oily liquid .80.5mg.1H NMR (400MHz, CDCl3) δ 8.00 (d, J=7.2Hz, 2H), 7.57 (t, J =6.8Hz, 1H), 7.45-7.32 (m, 11H), 7.07-6.98 (m, 6H), 2.25 (s, 3H)13C NMR (100MHz, CDCl3)δ 164.7,148.9,138.0,137.7,137.0,133.2,133.0,129.7,129.6,129.5,129.4,129.3, (100) [M+ of 129.2,128.4,128.4,128.0,127.9,126.8,125.2,69.1,21.2.ESI-MS m/z (%) 479 H]+；Anal.Calcd for C30H23ClN2O2C, 75.23；H, 4.84；N, 5.85；Found：C, 75.29；H, 4.82；N, 5.83.
Embodiment 28：(1- (3- bromophenyls) -2- (m-t tolyls) -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 76%)
.m.p.105-108 DEG C of .79.5mg. of brown solid1H NMR (400MHz, CDCl3) δ 8.12 (d, J=7.6Hz, 2H), (s, the 3H) of 8.00 (d, J=5.2Hz, 2H), 7.57-7.33 (m, 11H), 7.09-7.98 (m, 5H), 2.2513C NMR (100MHz, CDCl3) δ 164.9,149.0,138.2,137.8,137.1,133.4,132.4,130.0,129.8,129.8, (100) [M+ of 129.6,128.6,128.6,128.3,128.2,127.0,125.5,69.2,21.3.ESI-MS m/z (%) 523 H]+；Anal.Calcd for C30H23BrN2O2C, 68.84；H, 4.43；N, 5.35；Found：68.76；H, 4.45；N, 5.37.
Embodiment 29：(1- (3- bromophenyls) -2- (4- chlorphenyls) -1H- imidazoles -5- bases) (phenyl) methyl benzoic acid ester (yield 72%)
.m.p.99-102 DEG C of .78.3mg. of yellow solid1H NMR (400MHz, CDCl3) δ 7.98 (s, 2H), 7.57 (t, J =8.0Hz, 1H), 7.47-7.28 (m, 12H), 7.20 (d, J=8.OHz, 3H), 6.99 (d, J=15.2Hz, 2H)13C NMR (100MHz, CDCl3) δ 164.9,147.8,137.8,137.1,134.9,133.6,133.4,132.6,130.8,129.8, 129.7,128.7,128.6,128.6,126.9,69.1.ESI-MS m/z (%) 544 (100) [M+H]+；Anal.Calcd for C29H20BrClN2O2C, 64.05；H, 3.71；N, 5.15；Found：C, 64.13；H, 3.70；N, 5.14.
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：50、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 C1-6Haloalkyl, substitution or Unsubstituted 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；
R4Independent 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, Contain 1-4 substituted or unsubstituted 5-10 circle heterocycles heteroatomic in N, O and S.
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, substitution alkynes aldehyde and substitution or unsubstituted carboxylic acid as raw material, at 50-80 DEG C, dichloromethane is solvent Reaction is prepared.
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.
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