CN102336740A - Novel imidazole compound and its application - Google Patents
Novel imidazole compound and its application Download PDFInfo
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- CN102336740A CN102336740A CN2010102382604A CN201010238260A CN102336740A CN 102336740 A CN102336740 A CN 102336740A CN 2010102382604 A CN2010102382604 A CN 2010102382604A CN 201010238260 A CN201010238260 A CN 201010238260A CN 102336740 A CN102336740 A CN 102336740A
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- anilino
- pyridine
- benzimidazolyl
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Abstract
Relating to the fields of medicinal chemistry and therapeutics, the invention specifically relates to a novel benzimidazole compound shown in general formula (I) or its pharmaceutically acceptable salts, wherein, substituents Ar, X, R1 and R2 have meanings provided in the specification. The benzimidazole compound shown in the general formula (I) can be used for preparing a protein tyrosine kinase inhibitor, and for preparing medicaments treating and/or preventing tumors or other hyperplastic diseases. The compound of the invention or its pharmaceutically acceptable salts can be taken as active ingredients to be mixed with various pharmaceutical excipients for preparing clinically necessary compositions and various preparations treating and preventing all kinds of tumors.
Description
Technical field
The present invention relates to pharmaceutical chemistry and therapeutics field, be specifically related to one type of novel benzimidazoles compounds and uses thereof.
Background technology
Features of tumor is cell or mutant abnormality proliferation, forms lump.Malignant tumour is a kind of common disease and frequently-occurring disease of serious harm HUMAN HEALTH, and caused mortality ratio is second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.
Along with molecular biological progress, people have had more understanding to synthetic, the function and the regulation and control of gene, protein, cell, and the incidence and development of tumour has also been had more deep understanding, for the research of antitumour drug provides new action target spot.Along with people's is understood in depth the tumor vascular growth process, and the tumor vessel system has become a treatment target spot brand-new, that be hopeful to be worth.The medicine that suppresses the new vessel generation is called angiogenesis inhibitor (angiogenesis inhibitor); Angiogenesis inhibitor not only shows good function of tumor inhibition in the animal experimental model of tumour diffusion and growth; And for the invalid multi-drug resistant tumour of traditional chemotherapy new treat-ment being provided, is the impressive progress of 21st century cancer therapy.
VEGF (VEGF) is the angiogenic growth factor that present known effect is the strongest, specificity is the highest, and vegf receptor is very little at normal tissue expression, and under pathological conditions, expressing significantly increases.Therefore, be that the angiogenesis inhibitor of target spot has the specificity height with the vegf receptor, be difficult for producing resistance, advantage that toxicity is little, become the focus of antitumour drug research and development in recent years.
Vegf receptor belongs to receptor tyrosine kinase (recepter tyrosine kinases; RTKs) superfamily mainly comprises two acceptors: (fms-like tyrosine kinase-1 is FLT-1) with acceptor (the kinase domain-containing recepter that contains kinases insertion territory for fms appearance acceptor; KDR); Think that at present the main mediated cell skeleton of FLT-1 is reset and caused cell migration, and causes monocyte chemotactic; KDR then mainly mediates endothelial cell proliferation, causes that vascular permeability raises, and has anti-endotheliocyte accent to die, keep endotheliocyte survival effect.Therefore generally believe that KDR is more important in angiogenic action.
Benzimidazoles compound is one type and has extensive bioactive organic heterocyclic molecule, can show good inhibition effect to numerous enzymes, demonstrates potentiality to be exploited and application prospect preferably.In recent years, a large amount of novel benzimidazoles lead compounds with good enzyme inhibition activity constantly are synthesized and find.Present many work are through the structural modification transformation to benzoglyoxaline and verivate thereof, in the hope of obtaining to have stronger enzyme inhibition activity and all having the developable benzimidazoles enzyme inhibitors of superior performance aspect pharmacokinetics and the selectivity.2007, Potashiman group and Hasegawa group reported that respectively acid amides substituted benzimidazoles compound in 2-position has very strong inhibition active (J.Med.Chem.2007,50,4453-4470 to vegf receptor; J.Med.Chem.2007,50,4351-4373), it is expected to be developed as the angiogenesis inhibitor series antineoplastic medicament.
The inventor has synthesized a series of new benzimidazoles compounds, through the anti tumor activity in vitro screening, has good antitumor activity.
Summary of the invention
Therefore, an object of the present invention is to provide the benzimidazoles compound shown in one type of following general formula (I) or its pharmacy acceptable salt.
Another object of the present invention provides the benzimidazoles compound shown in the general formula (I) or the preparation method of its pharmacy acceptable salt.
Another purpose of the present invention provides a kind of pharmaceutical composition, and it contains the benzimidazoles compound shown in one or more general formulas (I) of treating significant quantity or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable excipient.
A purpose more of the present invention provides benzimidazoles compound shown in the general formula (I) or the purposes of its pharmacy acceptable salt in the preparation medicine.
According to first purpose of the present invention, the present invention is to provide the benzimidazoles compound shown in the following general formula (I) or its pharmacy acceptable salt:
In the formula:
Ar is phenyl, naphthyl or 5-10 unit heteroaryl, and described heteroaryl contains 1-3 and is selected from the heteroatoms among O, N and the S, and Ar is randomly by 1-3 R
3Replace;
X is O or S;
R
1Be NHR
4Or OR
4
R
2Be hydrogen, C1-C4 alkyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
The present invention preferably relates to benzimidazoles compound or its pharmacy acceptable salt shown in the following general formula of definition (I), wherein,
Ar is phenyl, naphthyl or 5-10 unit heteroaryl, and described heteroaryl contains 1-3 and is selected from the heteroatoms among O, N and the S, and Ar is randomly by 1-3 R
3Replace;
X is O;
R
1Be NHR
4Or OR
4
R
2Be hydrogen, C1-C4 alkyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
The present invention more preferably relates to benzimidazoles compound or its pharmacy acceptable salt shown in the following general formula of definition (I), wherein,
Ar is a phenyl, and Ar is randomly by 1-3 R
3Replace;
X is O;
R
1Be NHR
4Or hydroxyl;
R
2Be hydrogen or C1-C4 alkyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
Concrete benzimidazoles compound or its pharmacy acceptable salt below the present invention is preferred especially:
4-{2-[(4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(2-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-fluoro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-chloro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-bromo-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-bromo-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-methoxyl group-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-methoxyl group-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-methyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-methyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-chloro-4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-chloro-anilino) methyl]-1-methyl isophthalic acid H-benzimidazolyl--5-oxo }-pyridine-2-formic acid;
4-{2-[(3-trifluoromethyl-anilino) methyl]-1-methyl isophthalic acid H-benzimidazolyl--5-oxo }-pyridine-2-formic acid.
And according to some usual methods in field under the present invention, the benzimidazoles compound shown in the general formula of the present invention (I) can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt that forms with following acid is preferred especially: hydrochloric acid, oxalic acid, toxilic acid, fumaric acid, Hydrocerol A, tartrate, oxysuccinic acid, isethionic acid, methylsulfonic acid, ethyl sulfonic acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, propionic acid, lactic acid, trifluoroacetic acid, phenylformic acid or tosic acid.
In addition, the present invention also comprises the prodrug of the benzimidazoles compound shown in the general formula of the present invention (I).According to the present invention; Prodrug is the benzimidazoles compound shown in the general formula (I); They self possibly have more weak active or even do not have activity, but after administration, (for example through metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
Only if point out in addition, term used herein " halogen " is meant fluorine, chlorine, bromine or iodine atom; " alkyl " is meant the alkyl of straight or branched.
According to second purpose of the present invention, the present invention provides the benzimidazoles compound shown in the general formula (I) or the preparation method of its pharmacy acceptable salt.
The preparation method of the benzimidazoles compound shown in the general formula of the present invention (I) is described below.All final compound of the present invention can through the method that describes below or through method preparation similar with it, these methods be that the organic chemistry filed those of ordinary skill is known.
Benzimidazoles compound shown in the general formula of the present invention (I) is according to any being prepared from following two routes:
Route 1: condensation reaction takes place with compound 2 and obtains compound I in compound 1 under condensing agent such as 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt) and glacial acetic acid effect.
Route 2: condensation reaction takes place with compound 3 and obtains compound 4 in compound 1 under condensing agent such as 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt) and glacial acetic acid effect.Condensation reaction takes place down and obtains compound I with aminated compounds or pure at condensing agent such as 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HATU) effect in compound 4.
Compound 2 and compound 3 according to the literature method preparation (J.Med.Chem.2007,50,4453-4470).
Route 1
Route 2
Wherein, Ar, X, R
1And R
2Definition as stated.
According to the 3rd purpose of the present invention; The present invention includes pharmaceutical composition; Said composition contains the benzimidazoles compound shown in one or more general formulas (I) of treating significant quantity or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable excipient.Said pharmaceutically acceptable excipient is meant any thinner, auxiliary and/or carrier that can be used for pharmaceutical field.Compound of the present invention can use with other activeconstituents combinations, as long as they do not produce other unfavorable effect, for example anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with some kinds of formulations, wherein contains some excipient commonly used in the pharmaceutical field; For example, oral prepns (like tablet, capsule, solution or suspension); Injectable preparation (like injectable solution or suspension, or injectable dried powder, before injection, adding water for injection can use immediately); Topical formulations (for example ointment or solution).
According to the 4th purpose of the present invention; The inventor has found that the benzimidazoles compound shown in the general formula of the present invention (I) has the arrestin tyrosine kinase activity, so the benzimidazoles compound shown in the general formula of the present invention (I) has the purposes of anti-proliferative disease.Benzimidazoles compound shown in the general formula of the present invention (I) can be used for disease or the treatment of conditions that the protein tyrosine kinase receptor suppressor factor is independent or part is indirect, and the benzimidazoles compound shown in the general formula promptly of the present invention (I) can be used to produce the protein tyrosine kinase receptor restraining effect in the mammalian body of this type of needs treatment.
In addition, expect that also The compounds of this invention can be used for treating other cell hyperplastic disease,, comprise the also distortion cell of undetermined receptor protein tyrosine kinase comprising through the receptor protein tyrosine kinase mark.This type disease comprises, for example, inflammation, vasculogenesis, vascular restenosis, amynologic disease, pancreas disease, ephrosis, embryo is ripe and transplant.
The anti tumor activity in vitro test shows that the benzimidazoles compound shown in the general formula of the present invention (I) has antitumor action, and therefore, it can treat and/or prevent medicine, especially white blood disease, cancer of the stomach and the lung cancer of tumour as preparation.
Benzimidazoles active compound shown in the general formula of the present invention (I) can be used as unique antitumor drug and uses, and perhaps can unite use with one or more other antitumor drugs.Combination therapy realizes through each being treated component while, order or separating administration.
Embodiment
The embodiment that hereinafter provides further illustrates and illustrates The compounds of this invention and preparation method thereof.Should be appreciated that the scope of following embodiment and limit scope of the present invention never in any form.
It should be understood that the technician who is proficient in this field can select proper raw material and reagent according to the needs of embodiment.The whole variable factors used in these synoptic diagram such as the definition of preceding text or like the definition in the claim.
Embodiment is intended to set forth rather than limit scope of the present invention.
Preparation embodiment
Table 1 respectively prepares the structure and the title of the compound among the embodiment
Embodiment 1:4-{2-[(4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine:
4-trifluoromethyl-anilino-acetate (compound 1-1) (121mg) is dissolved in exsiccant DMF (2ml) solution, adds HOBt, is cooled to 0 ℃.Add EDCI, continue then slowly to be warming up to room temperature 0 ℃ of reaction 45 minutes.Add 4-(3,4-diamino--phenoxy)-pyridine-2-carboxylic acids methylamine (compound 2-1) (200mg), the stirring at room reaction is spent the night.Evaporated under reduced pressure, resistates dissolves with acetate 3ml, heating reflux reaction 1.5 hours, evaporated under reduced pressure has solid to separate out with the ammoniacal liquor alkalization, filters, and filter cake is with washing, and drying gets product, and yield is 52.9%.
1H?NMR(400MHz，CD
3OD?ppm)δ：8.21(1H，brs)，7.62(1H，d，J＝8.7Hz)，7.62(1H，d，J＝8.7Hz)，7.54(1H，s)，7.26(1H，t，J＝8.0Hz)，7.0(4H，m)，6.88(1H，d，J＝7.6Hz)，4.69(2H，s)，3.83(3H，s).
Embodiment 2:4-{2-[(3-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid methylamine:
Preparing method's similar embodiment 1 just replaces with 3-trifluoromethyl-anilino-acetate with 4-trifluoromethyl-anilino-acetate.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.44(1H，d，J＝5.7Hz)，7.61(1H，d，J＝8.7Hz)，7.52(1H，d，J＝2.2Hz)，7.31(2H，m)，7.04(2H，m)，6.91(2H，m)，6.83(1H，m)，4.64(2H，s)，2.91(3H，s).
Embodiment 3:4-{2-[(4-bromo-anilino) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid methylamine:
Preparing method's similar embodiment 1 just replaces with 4-bromo-anilino-acetate with 4-trifluoromethyl-anilino-acetate.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.39(1H，d，J＝5.5Hz)，8.07(1H，m)，7.56(1H，d，J＝2.2Hz)，7.45(1H，d，J＝8.4Hz)，7.23(2H，m)，7.03(1H，m)，6.93(1H，dd，J＝8.7Hz，2.4Hz)，6.53(2H，dd，J＝6.8Hz，2.2Hz)，4.58(2H，s)，3.0(3H，d，J＝5.1Hz).
Embodiment 4:4-{2-[(4-chloro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid methylamine:
Preparing method's similar embodiment 1 just replaces with 4-chloro-anilino-acetate with 4-trifluoromethyl-anilino-acetate.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.43(1H，d，J＝5.3Hz)，7.59(1H，d，J＝8.5Hz)，7.51(1H，d，J＝2.8Hz)，7.29(1H，d，J＝1.8Hz)，7.05(4H，m)，6.61(2H，dd，J＝6.8Hz，1.8Hz)，4.58(2H，s)，2.91(3H，s).
Embodiment 5:4-{2-[(4-fluoro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid methylamine:
Preparing method's similar embodiment 1 just replaces with 4-fluoro-anilino-acetate with 4-trifluoromethyl-anilino-acetate.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.44(1H，d，J＝5.7Hz)，7.6(1H，brd)，7.51(1H，d，J＝3.0Hz)，7.30(1H，s)，7.04(2H，m)，6.86(2H，m)，6.61(2H，m)，4.56(2H，s)，4.42(3H，s).
Embodiment 6:4-{2-[(3-chloro-4-fluoro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid methylamine:
Preparing method's similar embodiment 1 just replaces with 3-chloro-4-fluoro-anilino-acetate with 4-trifluoromethyl-anilino-acetate.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.44(1H，d，J＝4.3Hz)，7.61(1H，d，J＝8.7Hz)，7.52(1H，d，J＝2.0Hz)，7.31(1H，s)，7.0(3H，m)，6.71(1H，m)，6.54(1H，m)，4.56(2H，s)，2.91(3H，s).
Embodiment 7:4-{2-[(4-chloro-anilino) methyl) methyl]-1H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid:
Preparing method's similar embodiment 1.Preparing method's similar embodiment 1; Just 4-trifluoromethyl-anilino-acetate is replaced with 4-chloro-anilino-acetate; 4-(3,4-diamino--phenoxy)-pyridine-2-carboxylic acids methylamine is replaced with 4-(3-amino-4-methylamino--phenoxy)-pyridine-2-carboxylic acids tert-butyl ester.
1H?NMR(400MHz，DMSO，ppm)δ：7.46(3H，m)，7.26(1H，d，J＝9.0Hz)，7.07(2H，m)，6.89(1H，d，J＝2.1Hz)，6.71(3H，m)，4.43(2H，s)，3.70(3H，s).
Embodiment 8:4-{2-[(3-trifluoromethyl-anilino) methyl]-1-methyl isophthalic acid H-benzimidazolyl--5-oxo }-preparation of pyridine-2-formic acid:
Preparing method's similar embodiment 1.Just 4-trifluoromethyl-anilino-acetate is replaced with 3-trifluoromethyl-anilino-acetate, 4-(3,4-diamino--phenoxy)-pyridine-2-carboxylic acids methylamine is replaced with 4-(3-amino-4-methylamino--phenoxy)-pyridine-2-carboxylic acids tert-butyl ester.
1H?NMR(400MHz，CD
3OD，ppm)δ：8.21(1H，s)，7.62(1H，d，J＝8.7Hz)，7.54(1H，s)，7.26(1H，t，J＝8.0Hz)，7.0(4H，m)，6.88(1H，d，J＝7.6Hz)，4.69(2H，s)，3.83(3H，s)。
Embodiment 9:4-{2-[(3-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine mesylate:
With 4-{2-[(4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine (0.3g) solid is dissolved in 3 ml methanol; Drip the methylsulfonic acid methanol solution under the stirring at room and transfer pH 1～2, continue to stir 1 hour, gained solid chemical compound suction filtration; Washing; Ether is washed, and drying obtains target compound 3.33 grams, yield 90%.
Pharmacology embodiment
The pharmacological evaluation and the tyrosine kinase activity that benzimidazoles compound shown in the part general formula of the present invention (I) are carried out extracorporeal anti-tumor suppress body outer screening test; External employing MTT method is carried out the HL60 human leukemia cell line, and the SRB method is carried out the A-549 human lung adenocarcinoma cell line, the SGC-7901 human stomach cancer cell line suppresses experiment.Enzyme-linked immunosorbent assay (ELISA) is carried out tyrosine kinase activity and is suppressed body outer screening test.
HL60 human leukemia cell line used in the experiment is provided by ATCC (American Type Culture Collection); The A-549 human lung adenocarcinoma cell line is by NCI (National Cancer Institute; U.S.A.) provide, the SGC-7901 human stomach cancer cell line is provided by institute of materia medica, Chinese Academy of Sciences Shanghai.Other reagent provides by Aldrich company.
Mtt assay operation by document carry out (Acta Pharmacol Sin, 2003,24 (5), 415-421).
Srb assay operation by document carry out (Int.J.Cancer, 2004,110,627-632).
Enzyme-linked immunosorbent assay (ELISA) by document carry out (Clin.Cancer.Res, 2007,13 (14), 4201-4208).
Table 2. compound 4 (embodiment 4 compounds), 7 (embodiment 7 compounds) are active to the inhibition of A-549 human lung adenocarcinoma cell line, HL60 human leukemia cell line, SGC-7901 human stomach cancer cell line: (IC
50, μ M)
Table 3. compound 4 (embodiment 4 compounds), 7 (embodiment 7 compounds) are to the inhibiting rate (%) of tyrosine kinase activity
Can know from above-mentioned test-results and to find out that the benzimidazoles compound shown in the claimed general formula of the present invention (I) is easy to preparation and has well that anti-tumor activity suppresses activity with receptor tyrosine kinase.Therefore possesses the pharmaceutical developments application prospect.
Claims (8)
1. the benzimidazoles compound shown in the general formula (I) or its pharmacy acceptable salt:
In the formula:
Ar is phenyl, naphthyl or 5-10 unit heteroaryl, and described heteroaryl contains 1-3 and is selected from the heteroatoms among O, N and the S, and Ar is randomly by 1-3 R
3Replace;
X is O or S;
R
1Be NHR
4Or OR
4
R
2Be hydrogen, C1-C4 alkyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
2. the benzimidazoles compound shown in the general formula according to claim 1 (I) or its pharmacy acceptable salt, wherein,
Ar is phenyl, naphthyl or 5-10 unit heteroaryl, and described heteroaryl contains 1-3 and is selected from the heteroatoms among O, N and the S, and Ar is randomly by 1-3 R
3Replace;
X is O;
R
1Be NH
4Or OR
4
R
2Be hydrogen, C1-C4 alkyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
3. the benzimidazoles compound shown in the general formula according to claim 2 (I) or its pharmacy acceptable salt, wherein,
Ar is a phenyl, and Ar is randomly by 1-3 R
3Replace;
X is O;
R
1Be NHR
4Or hydroxyl;
R
2Be hydrogen or C1-C4 alkyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, cyanic acid, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkylamino, N, N-two (C1-C4 alkyl) amino, C1-C4 alkyl sulfenyl, C1-C4 alkoxy methyl, C1-C4 alkoxyethyl or C1-C4 alkoxyl group acyl group;
R
4Be hydrogen, C1-C10 alkyl, C3-C10 naphthenic base, C1-C10 alkoxyl group, N-C1-C10 alkyl, N-C3-C10 naphthenic base, N, N-two C1-C10 alkyl, N, N-two C3-C10 naphthenic base, C1-C4 alkoxy methyl or C1-C4 alkoxyethyl.
4. the benzimidazoles compound shown in the general formula according to claim 3 (I) or its pharmacy acceptable salt are specially following compound:
4-{2-[(4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(2-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-fluoro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-chloro-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-bromo-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-bromo-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-methoxyl group-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-methoxyl group-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-methyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-methyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(3-chloro-4-trifluoromethyl-anilino) methyl]-1H-benzimidazolyl--5-oxo }-pyridine-2-formic acid methylamine;
4-{2-[(4-chloro-anilino) methyl]-1-methyl isophthalic acid H-benzimidazolyl--5-oxo }-pyridine-2-formic acid;
4-{2-[(3-trifluoromethyl-anilino) methyl]-1-methyl isophthalic acid H-benzimidazolyl--5-oxo }-pyridine-2-formic acid.
5. pharmaceutical composition, it contains the benzimidazoles compound shown in the described general formula of one or more claims 1 of treating significant quantity (I) or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable excipient.
6. the benzimidazoles compound shown in any described general formula (I) or its pharmacy acceptable salt purposes in the medicine of preparation protein tyrosine kinase receptor suppressor factor in the claim 1～4.
7. the benzimidazoles compound shown in any described general formula (I) or its pharmacy acceptable salt purposes in the medicine of preparation treatment proliferative disease in the claim 1～4.
8. the benzimidazoles compound shown in any described general formula (I) or its pharmacy acceptable salt purposes in the medicine of preparation treatment tumour in the claim 1～4.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035530A (en) * | 2004-08-31 | 2007-09-12 | 新南部创新有限公司 | VEGF inhibition |
| CN101253168A (en) * | 2005-08-30 | 2008-08-27 | 诺瓦提斯公司 | Substituted benzimidazoles as kinase inhibitors |
| CN101516335A (en) * | 2006-07-21 | 2009-08-26 | 诺瓦提斯公司 | Formulations for benzimidazolyl pyridyl ethers |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035530A (en) * | 2004-08-31 | 2007-09-12 | 新南部创新有限公司 | VEGF inhibition |
| CN101253168A (en) * | 2005-08-30 | 2008-08-27 | 诺瓦提斯公司 | Substituted benzimidazoles as kinase inhibitors |
| CN101516335A (en) * | 2006-07-21 | 2009-08-26 | 诺瓦提斯公司 | Formulations for benzimidazolyl pyridyl ethers |
Non-Patent Citations (2)
| Title |
|---|
| MASAICHI HASEGAWA ET AL.: "Discovery of Novel Benzimidazoles as Potent Inhibitors of TIE-2 and VEGFR-2 Tyrosine Kinase Receptors", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 50, no. 18, 4 August 2007 (2007-08-04), pages 4453 - 4470, XP002513776, DOI: doi:10.1021/JM0611051 * |
| MICHELE H. POTASHMAN ET AL.: "Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 50, no. 18, 15 August 2007 (2007-08-15), pages 4351 - 4373 * |
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