CN103420917B - Containing the benzamide compound of condensed cyclic structure and apply as antitumor drug - Google Patents
Containing the benzamide compound of condensed cyclic structure and apply as antitumor drug Download PDFInfo
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Abstract
The invention discloses a kind of benzamide compound containing condensed cyclic structure and application thereof; pharmacological evaluation shows; the compounds of this invention has good histon deacetylase (HDAC) HDAC1 inhibit activities; weak to normal cyto-inhibition; toxicity is little; less toxic side effect should be had when applying as antitumor drug, be easier to use as antitumor drug.The disease that the present invention causes for therapeutic gene abnormal expression, as: tumour, endocrine regulation, disease of immune system, inherited disease and nervous system disorders have good curative effect.The described benzamide compound containing condensed cyclic structure, for having such as formula the compound shown in (V) or its pharmacy acceptable salt:
Description
Technical field
The present invention relates to containing the benzamide compound synthetic method of condensed cyclic structure and this compounds to histon deacetylase (HDAC) inhibit activities and treatment malignant tumour and and Differentiation and proliferation relative disease in application.
Background technology
Tumour occur and the reason of development very complicated, all active abnormal closely related with genetic expression and gene expression product after all.Cause the change of factor from two broad aspect of oncogene expression and the active exception of gene expression product, i.e. the change of heredity (Genetics) and epigenetic (Epigenetics).Hereditary change refers to that gene order there occurs change, as transgenation, disappearance and restructuring etc., plays an important role in the tumour of certain type occurs.Result of study in recent years more and more clearly shows, epigenetic changes, if environmental pollution is on the impact of human body, in the generation and development of tumour, there is more general meaning, generation, development, the prognosis of tumour and lapse to and not only depend on inherited genetic factors, be also subject to the impact of epigenetic modification simultaneously.
Epigenetic refers to the transcriptional activity that affects gene and does not relate to the control methods that a genoid that DNA sequence dna changes expresses; its molecular basis is mainly concerned with two aspects: one is the modification that methylates for DNA, and another is the acetylation modification for chromatin histone.Chromatinic histone acetylation and deacetylation is one of key link of regulatory gene expression; and two fermentoids decide the degree of acetylation of histone; i.e. histone acetyltransferases (Histoneacetyltransferases; and histon deacetylase (HDAC) (Histone deacetylases, HDAC) HAT).The acetylize of histone can activate the transcription of specific gene, the transcriptional expression of HDAC then suppressor gene.Meanwhile, HDAC also to the acetylize-deacylation process important of nonhistone protein, comprise transcription factor, signal conductive protein, DNA repair enzyme etc., and these target proteins plays decisive role in the regulation and control of genetic expression.In a word; by the impact on histone and nonhistones acetylation; HDAC plays very important effect in epigenetic regulation; and the exception of this regulatory mechanism; then with the generation of tumour with develop closely related; for the small-molecule drug research and development that the important molecule target affecting epigenetic with this class of HDAC is carried out, become the focus in current international neoplasm targeted therapy field.
HDAC is a large enzyme family, its member there will be a known the different hypotype of four large classes 18 at present, wherein I class comprises HDAC1,2,3,8 four hypotypes, and II class comprises HDAC4,5,6,7,9,10 6 hypotypes (wherein 4,5,7,9 belong to IIa, and 6,10 belong to IIb); IV class only has HDAC11 hypotype, and itself and front two classes have certain homology respectively; III class comprises Sirt1-7 totally seven hypotypes, does not have structural homology with front III class.HDACs biological function is numerous, and the HDACs of different subtype plays different biological actions in cell.Wherein the generation development relationship of I class and II class and tumour is the closest.
Result of study in recent years fully shows, and plays an important role, suppress HDAC functionally active then to demonstrate significant inside and outside antitumous effect in HDAC overexpression or the active abnormal generation at leukemia and noumenal tumour and development.The clinical hdac inhibitor grinding can be divided into four classes by chemical structure, that is:
(1) hydroxamic acid, as trichostatin (TSA), SAHA;
(2) cyclic tetrapeptide class, as Apicidin;
(3) short chain or aromatic fatty acid class, as Sodium propanecarboxylate;
(4) benzamides, as MS-275;
Existing 2 hdac inhibitor hydroxamic acid Vorinostat and cyclic peptide Depsipeptide are ratified with T-cell lymphoma,cutaneous (CTCL) as indication listing application by U.S. FDA respectively in 2007 and 2009 at present, its application in treatment of solid tumors is also in clinical experimental stage, this indicates the end of HDAC as the Proof of Concept Journal of Sex Research stage of novel drugs target, also imply that hdac inhibitor has wide DEVELOPMENT PROSPECT as antitumor drug.
Due to the similarity of histon deacetylase (HDAC) hypotype structure; existing most of NSC 630176 is as Vorinostat and Depsipeptide and some other candidate compounds general inhibitor being often in clinical study; usually suppress multiple hypotype simultaneously; while affecting growth and metastasis of tumours; often disturb normal physiological function, there is potential toxic side effect.Therefore, exploitation HDAC enzyme hypotype inhibitor can not only reduce toxic side effect, and can provide probe for the biological function research of each hypotype, has profound significance.
Research shows; benzamides hdac inhibitor alternative acts on histon deacetylase (HDAC) hypotype; especially tumour related subtypes HDAC1; suppress the differentiation of the propagation of kinds of tumor cells, inducing tumor cell and (or) apoptosis; have lower toxicity in vivo, it represents medicine MS-275 and has entered the IIb clinical trial phase stage at present.Therefore; the NSC 630176 of design and synthesis highly selective, especially benzamide histone deacetylase enzyme inhibitors, to obtain good effect; toxic side effect is low, and the high novel anti-malignant tumor agent of security is study hotspot and the technological difficulties in this field at present.
Scientific practice finds, due to the singularity of target medicine, directly can not obtain because of the simple modification of certain structure in compound that there is corresponding activity or active better another series compound, need difference and the key binding sites of considering compound structure and target point protein space conformation, design, synthesis and biological screening just can obtain serial active novel derivative.In view of enzyme cog region in benzamides hdac inhibitor structure is to the material impact of activity, in the substrate structure be combined with enzyme cog region, if carry out some substituting group change likely obtain active better serial new compound.
In addition, in view of the diversity of tumour cell and associated cancer, there is the compound of same enzyme inhibit activities, because the difference of structure may produce specificity or optionally antiproliferative effect to different tumour cell.Therefore, design benzamides hdac inhibitor structure diversity compound and there is important scientific value.
By the Chinese patent (application number: 201110175233.1) disclose a class benzamide histone deacetylase enzyme inhibitors of the present inventor's previous research work application, research finds also to need further raising to HDAC enzyme selectivity, simultaneously according to clinical application, need the more tool of design and synthesis activated, the benzamide histone deacetylase enzyme inhibitors of different types of structure, to keep or to strengthen compound to HDACs and HDAC1 enzyme inhibition activity, find and not only there is better histon deacetylase (HDAC) hypotype inhibit activities, and different tumour cell is produced to the compound of specificity or selectivity antiproliferative effect, and expect the anti-cancer agent that exploitation is desirable.
Summary of the invention
The object of the invention is openly a kind of benzamide compound containing condensed cyclic structure and as antitumor drug application, to overcome the defect that prior art exists, meet the needs of clinical application.
Benzamide compound containing condensed cyclic structure of the present invention, for having such as formula the compound shown in (V) or its pharmacy acceptable salt:
Wherein:
R
1represent hydrogen, halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom, the aminoalkyl group of 1 to 4 carbon atom, the alkylamino of 1 to 4 carbon atom, the acyl group of 2 to 4 carbon atoms, the amido of 2 to 4 carbon atoms, the alkylthio of 1 to 4 carbon atom, trifluoromethyl, the carboxyl of 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom, phenyl or heterocycle;
Y or M is N or C;
X is O, S or N;
X
1for hydrogen, halogen;
Described " heterocycle ", refers to the saturated or unsaturated heterocycle containing one or more heteroatoms (nitrogen, oxygen, sulphur);
The preferred fluorine of described halogen, chlorine, bromine or iodine;
The alkyl of 1 to 4 described carbon atom, preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or tertiary butyl etc.;
The preferred methoxyl group of alkoxyl group of 1 to 4 described carbon atom, oxyethyl group, positive propoxy, isopropoxy, n-butoxy or isobutoxy etc.;
The preferred amino-ethyl of aminoalkyl group of 1 to 4 described carbon atom, 1-aminopropyl or 2-aminopropyl etc.;
The preferred N-methylamino-of alkylamino of 1 to 4 described carbon atom, N-ethylamino or N-isopropylamino;
The preferred ethanoyl of acyl group of 2 to 4 described carbon atoms, propionyl or isobutyryl etc.;
The preferred kharophen of amido of 2 to 4 described carbon atoms, propionamido, butyrylamino or isobutyryl are amino;
The preferred methylthio group of alkylthio of 1 to 4 described carbon atom, ethylmercapto group or rosickyite base etc.;
The compound of described formula V structure can with mineral acid, organic acid salify, obtain the salt form material of the compound of formula V structure, described salt is hydrochloride, hydrobromate, vitriol, acetate, lactic acid salt, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, tosic acid or mesylate;
Understand the present invention for convenience, preferred following concrete compound from the compound of formula V structure, but the benzamide compound containing condensed cyclic structure of the present invention is not limited to following compound:
V-1 N-(2-aminophenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-2 N-(2-aminophenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-3 N-(2-amino-5-fluorine phenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-4 N-(2-amino-5-fluorine phenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-5 N-(2-aminophenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-6 N-(2-aminophenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-7 N-(2-amino-5-fluorine phenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-8 N-(2-amino-5-fluorine phenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-9 N-(2-aminophenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-10 N-(2-amino-5-fluorine phenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-11 N-(2-aminophenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-12 N-(2-amino-5-fluorine phenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-13 N-(2-aminophenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-14 N-(2-amino-5-fluorine phenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-15 N-(2-aminophenyl)-4-((2-(phenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-16 N-(2-aminophenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-17 N-(2-amino-4-pyridyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-18 N-(2-amino-5-fluorine phenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-19 N-(2-aminophenyl)-4-((1H-cumarone-5-formamido group) methyl) benzamide,
V-20 N-(2-amino-4-pyridyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
Or the pharmacy acceptable salt of the arbitrary compound of V-1 to V-20.
The structural formula of above-claimed cpd is in table 1.
Table 1 preferred compound numbering and corresponding structural formula
Compound of the present invention can adopt following method to synthesize:
Logical method one: the synthesis of intermediate III
By replacing acid I (50mmol), O-(IH-benzotriazole-1-base)-N, N, N ', N '-tetramethyl-isourea phosphorus hexafluoride (being called for short HBTU) (18.95g, 50mmol) add in DMF, under ice bath, slowly drip triethylamine (10.1g, 100mmol), stir 1h under normal temperature, obtain homogeneous response liquid.Paraaminomethyl benzoic acid II (50mmol) is dissolved in the aqueous sodium hydroxide solution of 50ml 1mol/L, drips above-mentioned homogeneous response liquid under temperature of reaction, wait to dropwise, insulated and stirred 6h.Reaction solution to 5-7, separates out a large amount of solid with salt acid for adjusting pH value, filters, is drying to obtain intermediate III.
Logical method two: the preparation of target compound V
By intermediate III (1mmol), compounds Ⅳ (1mmol), HBTU (0.379g, 1mmol) add 10ml N successively, in dinethylformamide, keep ice bath cooling to drip triethylamine (2mmol), then continue stirring 4 hours in room temperature.By in reaction solution impouring 50mL water, separate out solid, filter.Saturated sodium bicarbonate, saturated aqueous common salt, water washing 1 ~ 2 time used successively by filter cake, and residuum dehydrated alcohol recrystallization obtains target compound V.
Above-mentioned preparation method can further include compound and mineral acid, the organic acid reaction of formula V structure, the salt of the compound of cooling precipitation formula V structure.
The R in method is led in above-mentioned reaction
1, X ﹑ Y ﹑ X
1﹑ M is same as above;
Compound I ﹑ II ﹑ IV and HBTU etc. can be bought by commercial channel.
Pharmacological testing shows; compound of the present invention; have very strong restraining effect (embodiment 21) to histon deacetylase (HDAC) (HDACs) especially histon deacetylase (HDAC) tumour related subtypes HDAC1, part of compounds such as V-2 ﹑ V-3 ﹑ V-8 ﹑ V-10 ﹑ V-12 ﹑ V-16 ﹑ V-17, V-18 and V-19 are all better than positive control drug MS-275 to HDACs and HDAC1 inhibit activities.If compound V-16 is IC to HDAC1 Inhibiting enzyme activity
50=99nM, is significantly better than the inhibit activities (IC of MS-275
50=668nM), show better histon deacetylase (HDAC) hypotype targeting.
Pharmacological testing shows, compound of the present invention, compared with positive control drug MS-275, has stronger differentiation-inducing and antiproliferative activity (embodiment 22) to many strains tumour cell.Part of compounds anti-tumour cell proliferative activity is better than positive control drug MS-275, as compound V-2, V-3, V-8, V-10, V-16, V-19, V-20 have higher inhibit activities to HCT116 human colon cancer cell, is better than MS-275.Wherein compound V-2, V-3, V-10 and V-16 also shows to the former leukemia cell of the chronic marrow of K562 people and Jurkat E6-1 HTL the antiproliferative activity being better than MS-275.
Pharmacological testing shows, compound of the present invention, relative to control drug MS-275, more weak to Normocellular inhibit activities, there is lower toxic side effect (embodiment 23), illustrate that benzamide compound of the present invention has better selectivity to tumour cell and Normocellular Inhibit proliferaton aspect, indicate that it has lower toxic side effect when using as antitumor drug.
Pharmacological testing shows, Compound Phase of the present invention for control drug MS-275, acute toxicity low (embodiment 24) in Mice Body.The LD50 that compound V-2, V-8, V-16, V-19 and V-20 mouse single gavages is respectively 2.63g/kg, 2.12g/kg, 1.95g/kg, 1.88g/kg and 2.14g/kg.(bibliographical information MS-275LD50=506mg/kg, CurrentMedicinal Chemistry, 2003,10 (22), pp.2343-2350);
Pharmacological evaluation shows, compound of the present invention has following beneficial effect:
1) compound of the present invention has good histon deacetylase (HDAC) (HDACs) especially histon deacetylase (HDAC) tumour related subtypes HDAC1 inhibit activities, all has good inhibit activities to human body kinds of tumor cells.
2) compared with existing positive control medicine, compound of the present invention is while effective inhibition tumor cell, weak to Normocellular restraining effect, shows and selects inhibit activities preferably, has good antitumor potential applicability in clinical practice.
3) acute toxicity preliminary experiment display, compared with positive control drug MS-275, in compound Mice Body of the present invention, security is higher, and toxicity is less.
In sum, when compound of the present invention is applied as antitumor drug, less toxic side effect and selectivity should be had, be easier to use as antitumor drug;
Described tumour is solid tumor and blood tumor, preferred colorectal carcinoma, liver cancer, lung cancer, mammary cancer, esophagus cancer, cancer of the stomach, nasopharyngeal carcinoma, ovarian cancer, bladder cancer, the rectum cancer, skin carcinoma and lymphoma;
Compound of the present invention can be applied to by approach such as oral, injections in the form of compositions needs the Mammals of oncotherapy (comprising people);
Described composition comprises the compound shown in formula V or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity;
Described carrier refers to the carrier of pharmaceutical field routine, such as: thinner, vehicle are as water etc.; Tackiness agent is as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.; Weighting agent is as starch etc.; Burst apart agent as calcium carbonate, sodium bicarbonate; In addition, other auxiliarys can also be added in the composition as flavouring agent and sweeting agent.
Composition of the present invention can be prepared into conventional solid preparation, as tablet, capsule etc., for oral; Also can be prepared into the formulations such as injection and be used for injection.
The various formulations of composition of the present invention can adopt the method for pharmaceutical field routine to be prepared, and wherein the content of the compound of activeconstituents formula V structure is 0.1% ~ 99.5% (weight ratio) of composition weight.
The compound of formula V structure of the present invention can carry out administration by oral or injection system to Mammals (comprising people) clinically, wherein especially best with oral way.Dosage is 0.0001mg/kg ~ 200mg/kg body weight every day.Optimal dose is depending on individuality, and when usually starting, dosage is less, then increases consumption gradually.
Feature of the present invention is that variation transformation is carried out in cog region, the enzyme of benzamide histone deacetylase enzyme inhibitors surface, to increase the spatial match of compound and cog region, enzyme surface, especially the bonding force with enzyme hypotype is increased, after carrying out HDAC1 enzyme hypotype suppression screening, find that this compounds has stronger inhibit activities to HDAC1 enzyme, the surperficial cog region of prompting HDAC1 enzyme exists key amino acid can with group in fused heterocycle as-NH-in conjunction with residue,-O-etc. carry out specific recognition combination, cog region, indication enzyme surface replaces with different heterocycle or heterocycle there being the structure of different substituents, the benzamide histone deacetylase enzyme inhibitors that enzyme hypotype inhibit activities is stronger can be obtained.In addition, to in compound structure with enzyme surface cog region structural changes, make this novel compound while having enzyme inhibition activity, specificity and selectivity are shown to tumour cell and normal cell, thus, for finding good effect, toxic side effect is low, and the high new type antineoplastic medicine of security provides theoretical direction and has the feasibility of patent medicine.Be equivalent to prior art, the present invention has the progress of novelty, creativeness and science.
The invention has the advantages that, the disease that described compound and medicinal preparations thereof cause for therapeutic gene abnormal expression, as: tumour, endocrine regulation, disease of immune system, inherited disease and nervous system disorders have good curative effect.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but working of an invention mode is not limited thereto.
Embodiment 1
The synthesis of V-1 N-(2-aminophenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.309g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-1 is synthesized, yield 33.6% according to logical method two.
ESI-MS[M+H]
+:m/z 400.1723
1H NMR(400MHz，DMSO-d
6)δppm：3.35(s,3H)，4.55(d，2H,J=6.0Hz)，4.92(s,2H)，6.60(t，1H,J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.97(d，1H,J=8.0Hz)，7.45(m,3H)，7.55(d，1H,J=8.0Hz)，7.73(d,1H,J=8.0Hz)，7.93(m,4H)，8.13(s,1H)，9.64(s,1H)
Embodiment 2
The synthesis of V-2 N-(2-aminophenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.309g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-2 is synthesized, yield 46.3% according to logical method two.
By above-mentioned V-2 heating for dissolving in 3mol/L hydrochloric acid/ethanol (10ml), the hydrochloride compound being V-2 is separated out in cooling.
ESI-MS[M+H]
+:m/z 386.1643
1H NMR(400MHz，DMSO-d
6)δppm：4.58(d，2H,J=8.0Hz)，4.90(s,2H)，6.60(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.97(dt，1H,J=4.0,8.0Hz)，7.17(d，1H,J=8.0Hz)，7.47(d，2H,J=8.0Hz)，7.60(d，1H,J=8.0Hz)，7.72(d，1H,J=8.0Hz)，7.78(m,1H)，7.95(d，2H,J=8.0Hz)，8.12(s，1H)，8.34(t，1H,J=16.0Hz)，9.64(s，1H)
Embodiment 3
The synthesis of V-3 N-(2-amino-5-fluorine phenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.309g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-3 is synthesized, yield 53.0% according to logical method two.
ESI-MS[M+H]
+:m/z 418.32
1H NMR(400MHz，DMSO-d
6)δppm：3.35(s,3H)，4.55(d，2H,J=4.0Hz)，5.23(s,2H)，6.36(t，1H,J=8.0Hz)，6.54(d，1H,J=4.0，12.0Hz)，7.11(t，1H,J=8.0Hz)，7.44(m,3H)，7.54(d，1H,J=8.0Hz)，8.06(m,4H)，9.13(s,1H)，9.61(s,1H)
Embodiment 4
The synthesis of V-4 N-(2-amino-5-fluorine phenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.372g, 1mmol) (prepare by logical method one), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-4 is synthesized, yield 40.1% according to logical method two.
ESI-MS[M+H]
+:m/z 481.15
1H NMR(400MHz，DMSO-d
6)δppm：4.57(d，2H,J=4.0Hz)，5.24(s,2H)，6.36(t，1H，J=8.0Hz)，6.53(m,2H)，7.11(t，1H,J=8.0Hz)，7.46(d，2H,J=8.0Hz)，7.57(d，1H,J=8.0Hz)，7.65(d，1H,J=8.0Hz)，7.77(t，1H,J=8.0Hz)，7.95(d，2H,J=8.0Hz)，8.03(s，1H)，8.20(m,1H)，8.26(d，1H,J=8.0Hz)，9.13(m，1H)，9.57(s，1H)
Embodiment 5
The synthesis of V-5 N-(2-aminophenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.372g, 1mmol), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-5 is synthesized, yield 55.3% according to logical method two.
Be dissolved in by above-claimed cpd V-50.21g in the ethanol of heat, drip the Hydrogen bromide/ethyl acetate (2ml) of 4mol/L, the hydrobromate being V-5 is separated out in cooling.
ESI-MS[M+H]
+:m/z 463.30
1H NMR(400MHz，DMSO-d
6)δppm：4.58(d，2H,J=8.0Hz)，4.97(s,2H)，6.60(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.97(t，1H,J=8.0Hz)，7.17(d，1H,J=8.0Hz)，7.48(d，2H,J=8.0Hz)，7.64(m,2H)，7.83(m,2H)，7.97(d，2H,J=8.0Hz)，8.14(s,1H)，8.35(d，1H,J=8.0Hz)，8.53(t，1H,J=4.0Hz)，8.73(t，1H,J=4.0Hz)，9.19(m,1H)，9.65(s，1H)
Embodiment 6
The synthesis of V-6 N-(2-aminophenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.337g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-6 is synthesized, yield 29.3% according to logical method two.
Be dissolved in by above-mentioned V-60.20g in the ethanol of heat, slowly drip 98% sulfuric acid (1ml), the vitriol being V-6 is separated out in cooling.
ESI-MS[M+H]
+:m/z 428.2108
1H NMR(400MHz，DMSO-d
6)δppm：1.35(t，6H,J=8.0Hz)，3.20(m,1H)，4.56(d，2H，J=8.0Hz)，4.90(s,2H)，6.60(t，1H,J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.98(t，1H,J=8.0Hz)，7.15(d，1H,J=8.0Hz)，7.44(d，3H,J=8.0Hz)，7.57(d，1H,J=4.0Hz)，7.74(d，1H,J=16.0Hz)，7.95(d，2H,J=8.0Hz)，8.14(s，1H)，9.09(s，1H)，9.64(s，1H)
Embodiment 7
The synthesis of V-7 N-(2-amino-5-fluorine phenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.309g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-7 is synthesized, yield 28.1% according to logical method two.
ESI-MS[M+H]
+:m/z 404.1497
1H NMR(400MHz，DMSO-d
6)δppm：4.57(d，2H,J=4.0Hz)，5.27(s,2H)，6.36(t，1H，J=8.0Hz)，6.54(dd,1H,J=4.0，12.0Hz)，7.11(t，1H,J=8.0Hz)，7.46(d，2H,J=8.0Hz)，7.60(d，1H,J=8.0Hz)，7.73(d,1H,J=4.0Hz)，7.79(m,1H)，7.95(d，2H,J=8.0Hz)，8.12(s，1H)，8.34(m,1H)，9.12(t，1H,J=8.0Hz)，9.57(s,1H)
Embodiment 8
The synthesis of V-8 N-(2-amino-5-fluorine phenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.337g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-8 is synthesized, yield 56.1% according to logical method two.
Be dissolved in by above-mentioned V-80.24g in the ethanol of heat, drip methylsulfonic acid ethanolic soln, keep backflow 30min, the mesylate being V-8 is separated out in cooling.
ESI-MS[M+H]
+:m/z 446.32
1H NMR(400MHz，DMSO-d
6)δppm：1.36(t，6H,J=8.0Hz)，3.19(m,1H)，4.57(d，2H，J=8.0Hz)，5.24(s,2H)，6.36(t，1H,J=8.0Hz)，6.54(dd,1H,J=4.0，12.0Hz)，7.11(t，1H,J=8.0Hz)，7.45(d，2H,J=8.0Hz)，7.55(d，1H,J=8.0Hz)，7.79(m,2H)，7.95(d，2H,J=8.0Hz)，8.14(s，1H)，9.12(t，1H,J=8.0Hz)，9.61(s，1H)
Embodiment 9
The synthesis of V-9 N-(2-aminophenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.390g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-9 is synthesized, yield 43.0% according to logical method two.
ESI-MS[M+H]
+:m/z 481.30
1H NMR(400MHz，DMSO-d
6)δppm：4.59(d，2H,J=8.0Hz)，4.91(s,2H)，6.54(d，1H，J=12.0Hz)，6.60(t，1H,J=8.0Hz)，6.79(d，1H,J=8.0Hz)，6.98(t，1H,J=8.0Hz)，7.17(d，1H,J=8.0Hz)，7.45(d，2H,J=12.0Hz)，7.55(d，1H,J=8.0Hz)，7.65(d，1H,J=4.0Hz)，7.80(t，1H,J=8.0Hz)，7.96(d，2H,J=8.0Hz)，8.11(s，1H)，8.20(dd,1H,J=4.0,8.0Hz)，8.27(d，1H,J=8.0Hz)，9.15(t，1H,J=8.0Hz)，9.66(s，1H)
Embodiment 10
The synthesis of V-10 N-(2-amino-5-fluorine phenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.390g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-10 is synthesized, yield 50.0% according to logical method two.
ESI-MS[M+H]
+:m/z 497.1896
1H NMR(400MHz，DMSO-d
6)δppm：4.59(d，2H,J=4.0Hz)，5.29(s,2H)，6.36(t，1H，J=8.0Hz)，6.53(m,2H)，7.11(t，1H,J=8.0Hz)，7.46(d，2H,J=8.0Hz)，7.54(d，1H,J=8.0Hz)，7.65(d，1H,J=8.0Hz)，7.78(t，1H,J=8.0Hz)，7.95(d，2H,J=8.0Hz)，8.03(s，1H)，8.20(m,1H)，8.26(d，1H,J=8.0Hz)，9.13(m，1H)，9.57(s，1H)
Embodiment 11
The synthesis of V-11 N-(2-aminophenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.389g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-11 is synthesized, yield 58.3% according to logical method two.
ESI-MS[M+H]
+:m/z 480.1822
1H NMR(400MHz，DMSO-d
6)δppm：4.60(d，2H,J=4.0Hz)，4.92(s,2H)，6.60(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.97(t，1H,J=8.0Hz)，7.17(d，1H,J=8.0Hz)，7.45(m,5H)，7.66(d，1H,J=4.0Hz)，7.83(d，1H,J=8.0Hz)，7.95(m,2H)，8.12(s,1H)，8.26(t，2H,J=8.0Hz)，9.17(s，1H)，9.65(s，1H)
Embodiment 12
The synthesis of V-12 N-(2-amino-5-fluorine phenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.389g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, V-12 is synthesized, yield 39.2% according to logical method two.
ESI-MS[M+H]
+:m/z 498.1758
1H NMR(400MHz，DMSO-d
6)δppm：4.59(d，2H,J=4.0Hz)，5.24(s,2H)，6.36(t，1H，J=8.0Hz)，6.54(dd,1H,J=4.0，12.0Hz)，7.11(t，1H,J=8.0Hz)，7.46(m,4H)，7.60(d，1H,J=8.0Hz)，7.73(d，1H,J=8.0Hz)，7.83(t，1H,J=8.0Hz)，7.96(d，2H,J=8.0Hz)，8.10(s，1H)，8.27(t，2H,J=8.0Hz)，9.15(m，1H)，9.58(s,1H)
Embodiment 13
The synthesis of V-13 N-(2-aminophenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.311g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-13 according to logical method two, yield 56.3%.
ESI-MS[M+H]
+:m/z 402.28
1H NMR(400MHz，DMSO-d
6)δppm：4.53(d，2H,J=4.0Hz)，4.90(s,2H)，6.60(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.98(m,2H)，7.16(d，1H,J=8.0Hz)，7.43(d，2H,J=8.0Hz)，7.51(s，1H)，7.59(d,1H,J=8.0Hz)，7.93(t，2H,J=8.0Hz)，9.02(t，1H,J=8.0Hz)，9.64(s,1H)，10.90(d，2H,J=12.0Hz)
Embodiment 14
The synthesis of V-14 N-(2-amino-5-fluorine phenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.311g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-14 according to logical method two, yield 33.2%.
ESI-MS[M+H]
+:m/z 420.28
1H NMR(400MHz，DMSO-d
6)δppm：4.53(d，2H,J=8.0Hz)，5.23(s,2H)，6.36(t，1H，J=8.0Hz)，6.54(dd,1H,J=4.0，12.0Hz)，6.99(d，1H,J=8.0Hz)，7.11(t，1H,J=8.0Hz)，7.42(d，2H,J=8.0Hz)，7.50(s，1H)，7.58(d，1H,J=8.0Hz)，7.94(t，2H,J=8.0Hz)，9.02(t，1H,J=8.0Hz)，9.57(s,1H)，10.90(d，2H,J=12.0Hz)
Embodiment 15
The synthesis of V-15 N-(2-aminophenyl)-4-((2-(phenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide
By 4-((2-(phenyl)-1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.371g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-15 according to logical method two, yield 49.3%.
ESI-MS[M+H]
+:m/z 462.1922
1H NMR(400MHz，DMSO-d
6)δppm：4.60(d，2H,J=4.0Hz)，4.92(s,2H)，6.60(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.97(t，1H,J=8.0Hz)，7.17(d，1H,J=8.0Hz)，7.45(m,5H)，7.66(d，1H,J=4.0Hz)，7.83(d，1H,J=8.0Hz)，7.95(m,3H)，8.12(s,1H)，8.26(t，2H,J=8.0Hz)，9.17(s，1H)，9.65(s，1H)
Embodiment 16
The synthesis of V-16 N-(2-aminophenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide
By 4-((1H-indoles-5-formamido group) methyl) phenylformic acid (0.294g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-16 according to logical method two, yield 55.0%.
ESI-MS[M+H]
+:m/z 385.1646
1H NMR(400MHz，DMSO-d
6)δppm：4.56(d，2H,J=5.6Hz)，4.81(s,2H)，6.54(d，1H，J=3.2Hz)，6.60(dt,1H,J=1.2Hz,8.4Hz)，6.78(dd,2H,J=1.2Hz,8.0Hz)，6.97(dt，1H,J=1.2Hz,8.4Hz)，7.17(d,1H,J=7.6Hz)，7.43(m,4H)，7.68(dd,2H,J=1.6Hz,8.4Hz)，7.93(d，2H,J=8.4Hz)，8.19(s,1H)，8.90(t，1H,J=6.0Hz)，9.57(s,1H)，11.26(s，1H)
Embodiment 17
The synthesis of V-17 N-(2-amino-4-pyridyl)-4-((1H-indoles-5-formamido group) methyl) benzamide
By 4-((1H-indoles-5-formamido group) methyl) phenylformic acid (0.294g, 1mmol), 3,4-diamino-pyridine (0.109g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) are raw material, V-17 is synthesized, yield 43.0% according to logical method two.
ESI-MS[M+H]
+:m/z 386.1635
1H NMR(400MHz，DMSO-d
6)δppm：4.57(d，2H,J=5.6Hz)，5.16(s,2H)，6.35(dt,1H，J=2.8Hz,8.4Hz)，6.55(dd,2H,J=2.8Hz,10.8Hz)，7.13(t，1H,J=8.4Hz)，7.43(m,4H)，7.94(d，2H,J=8.0Hz)，8.20(s，1H)，8.89(t，1H,J=5.6Hz)，9.49(s，1H)，11.27(s,1H)
Embodiment 18
The synthesis of V-18 N-(2-amino-5-fluorine phenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide
By 4-((1H-indoles-5-formamido group) methyl) phenylformic acid (0.294g, 1mmol), 4-fluorine O-Phenylene Diamine (0.126g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-18 according to logical method two, yield 49.6%.
ESI-MS[M+H]
+:m/z 403.1558
1H NMR(400MHz，DMSO-d
6)δppm：4.57(d，2H,J=5.6Hz)，5.12(s,2H)，6.55(s，1H)，7.44(m,5H)，7.68(dd,2H,J=1.6Hz,8.4Hz)，7.80(d,1H,J=8.0Hz)，7.92(d,2H,J=8.0Hz)，8.10(s,1H)，8.19(s，1H)，8.92(t，1H,J=6.0Hz)，9.68(s，1H)，11.26(s，1H)
Embodiment 19
The synthesis of V-19 N-(2-aminophenyl)-4-((1H-cumarone-5-formamido group) methyl) benzamide
By 4-((1H-cumarone-5-formamido group) methyl) phenylformic acid (0.295g, 1mmol) (prepare by logical method one), O-Phenylene Diamine (0.108g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-19 according to logical method two, yield 57.0%.
ESI-MS[M+H]
+:m/z 385.1646
1H NMR(400MHz，DMSO-d
6)δppm：4.54(d，2H,J=5.6Hz)，4.83(s,2H)，6.54(d，1H，J=3.2Hz)，6.61(dt,1H,J=1.2Hz,8.4Hz)，6.78(dd,2H,J=1.2Hz,8.0Hz)，6.97(dt，1H,J=1.2Hz,8.4Hz)，7.17(d,1H,J=7.6Hz)，7.43(m,4H)，7.68(dd,2H,J=1.6Hz,8.4Hz)，7.93(d,2H,J=8.4Hz)，8.19(s,1H)，8.90(t，1H,J=6.0Hz)，11.26(s,1H)
Embodiment 20
The synthesis of V-20 N-(2-amino-4-pyridyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide
4-((1H-benzoglyoxaline-6-formamido group) methyl) phenylformic acid (0.309g, 1mmol), 3,4-diamino-pyridine (0.109g, 1mmol), HBTU (0.455g, 1.2mmol), triethylamine (0.404g, 4mmol) be raw material, synthesize V-2 according to logical method two, yield 47.1%.
ESI-MS[M+H]
+:m/z 386.1643
1H NMR(400MHz，DMSO-d
6)δppm：4.56(d，2H,J=8.0Hz)，5.25(s,2H)，6.61(t，1H，J=8.0Hz)，6.78(d，1H,J=8.0Hz)，6.99(dt，1H,J=4.0,8.0Hz)，7.17(d，1H,J=8.0Hz)，7.47(d,2H,J=8.0Hz)，7.60(d，1H,J=8.0Hz)，7.70(d,1H,J=8.0Hz)，7.95(d,2H,J=8.0Hz)，8.12(s，1H)，8.34(t，1H,J=16.0Hz)，9.77(s，1H)
Embodiment 21
Compound ira vitro is tested histon deacetylase (HDAC) inhibit activities
The K340-100 test kit test compounds selecting Biovision to produce is to the inhibit activities of HDACs; The 50033 test kit test compounds selecting BPSBioscience to produce are to the inhibit activities (IC of HDAC1
50test), experimental implementation reference reagent box specification sheets carries out.With DMSO 4 times of doubling dilution testing compounds, obtain 10 weaker concns, be followed successively by 500 μMs, 125 μMs, 31.25 μMs, 7.81 μMs, 1.95 μMs, 0.49 μM, 0.12 μM, 0.03 μM, 7.6E-03 μM and 1.9E-03 μM.Each extent of dilution does a multiple hole, detection compound press down enzyme IC
50.Experimental result is in table 2.
Table 2 compound is to the vitro inhibition IC of histon deacetylase (HDAC)
50
As can be seen from Table 2, the compounds of this invention that the carrying out of random selecting is tested all has stronger inhibit activities to HDACs and HDAC1, wherein remarkable to HDAC1 inhibit activities, part of compounds such as V-2 ﹑ V-3 ﹑ V-8 ﹑ V-10 ﹑ V-12 ﹑ V-16 ﹑ V-17, V-18 and V-19 are all better than positive control drug MS-275 to HDACs and HDAC1 inhibit activities.
Embodiment 22
The tumour cell vitro inhibition activity test of compound
Measure part of compounds to the restraining effect of PC-3 Human Prostate Cancer Cells, A549 human lung carcinoma cell, Colo320 people's rectum cancer cell, Hep3B2.1-7 human liver cancer cell, HCT116 human colon cancer cell, the former leukemia cell of the chronic marrow of K562 people, Jurkat E6-1 HTL.IC
50value is recorded by CCK-8 method (Cat#CK04-13, Dojindo).Concrete outcome is as follows:
The in-vitro multiplication restraining effect IC of table 3. compound on tumor cell strain
50measure
As can be seen from Table 3, the part of compounds of the present invention of carrying out testing has good antiproliferative activity to 7 strain tumour cells such as PC-3 human prostata cancers.Part of compounds anti-tumour cell proliferative activity is better than positive control drug MS-275, as compound V-2, V-3, V-8, V-10, V-16, V-19, V-20 have higher inhibit activities to HCT116 human colon cancer cell, is better than MS-275.Wherein compound V-2, V-3, V-10 and V-16 also shows to the former leukemia cell of the chronic marrow of K562 people and Jurkat E6-1 HTL the antiproliferative activity being better than MS-275.
Embodiment 23
The normal cell vitro inhibition determination of activity of compound:
Measure the compounds of this invention to the activity of MCF10A (people's Normal breast epithelial cell), IC
50value is recorded by CCK-8 method (Cat#CK04-13, Dojindo).MS-275 is selected to be the active IC of vitro inhibition that control drug carries out normal cell strain
50test.Concrete outcome following (unit is: μM):
Table 4 the compounds of this invention and control drug are to Normocellular vitro inhibition activity
As can be seen from Table 4, the compounds of this invention V-1 to V-20 carrying out testing is relative to control drug MS-275, more weak to Normocellular inhibit activities, there is lower toxic side effect, illustrate that benzamide compound of the present invention has better selectivity to tumour cell and Normocellular Inhibit proliferaton aspect, indicate that it has lower toxic side effect when using as antitumor drug, be easy to use as tumour medicine.
Embodiment 24
Acute toxicity test: " modern pharmacology experimental technique " (Beijing Medical University, the combined publication society of China Concord Medical Science University adopting Zhang Juntian chief editor, within 1998, publish) method reported, preliminary screening, through adding up (" practical drug preparation technique " by Bliss method, People's Health Publisher, within 1999, publish), the LD that compound V-2, V-8, V-16, V-19 and V-20 mouse single gavages
50be respectively 2.63g/kg, 2.12g/kg, 1.95g/kg, 1.88g/kg and 2.14g/kg.
Embodiment 25
Tablet:
Preparation method: arbitrary for activeconstituents V-1 to V-20 compound is mixed with sucrose, W-Gum, adds water moistening, stir, dry, pulverize and sieve, add calcium stearate, mix, compressing tablet.The heavy 290mg of every sheet, active component content is 100mg.
Embodiment 26
Injection: arbitrary compound 15mg being selected from V-1 to V-20
Water for injection 80mg
Preparation method: by arbitrary for activeconstituents V-1 to V-20 compound dissolution in water for injection, mix, filter, be aseptically sub-packed in ampoule by obtained solution, every bottle of 95mg, active component content is 15mg/ bottle.
Above-described embodiment is the present invention's preferably embodiment, but embodiments of the present invention are not restricted to the described embodiments, change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify, all should be the substitute mode of equivalence, be included in of the present invention comprising within scope.
Claims (5)
1., containing the benzamide compound of condensed cyclic structure, it is characterized in that, comprising:
V-1) N-(2-aminophenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-2) N-(2-aminophenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-3) N-(2-amino-5-fluorine phenyl)-4-((2-methyl isophthalic acid H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-4) N-(2-amino-5-fluorine phenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-5) N-(2-aminophenyl)-4-((2-(3-pyridyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-6) N-(2-aminophenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-7) N-(2-amino-5-fluorine phenyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-8) N-(2-amino-5-fluorine phenyl)-4-((2-(sec.-propyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-9) N-(2-aminophenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-10) N-(2-amino-5-fluorine phenyl)-4-((2-(6-fluoro-3-pyridine base)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-11) N-(2-aminophenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-12) N-(2-amino-5-fluorine phenyl)-4-((2-(4-fluorophenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-13) N-(2-aminophenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-14) N-(2-amino-5-fluorine phenyl)-4-((2-oxo-1,3-dihydro-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-15) N-(2-aminophenyl)-4-((2-(phenyl)-1H-benzoglyoxaline-6-formamido group) methyl) benzamide,
V-16) N-(2-aminophenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-17) N-(2-amino-4-pyridyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-18) N-(2-amino-5-fluorine phenyl)-4-((1H-indoles-5-formamido group) methyl) benzamide,
V-19) N-(2-aminophenyl)-4-((1H-cumarone-5-formamido group) methyl) benzamide or
V-20N-(2-amino-4-pyridyl)-4-((1H-benzoglyoxaline-6-formamido group) methyl) benzamide
Or the pharmacy acceptable salt of the arbitrary compound of V-1 to V-20.
2. the benzamide compound containing condensed cyclic structure according to claim 1, it is characterized in that, described salt is hydrochloride, hydrobromate, vitriol, acetate, lactic acid salt, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, tosic acid or mesylate.
3. the application of benzamide compound in preparation tumor containing condensed cyclic structure according to claim 1.
4. application according to claim 3, is characterized in that, described tumour is colorectal carcinoma, liver cancer, lung cancer, mammary cancer, esophagus cancer, cancer of the stomach, nasopharyngeal carcinoma, ovarian cancer, bladder cancer, the rectum cancer, skin carcinoma or lymphoma.
5. a composition, is characterized in that, comprises the benzamide compound containing condensed cyclic structure described in any one of claim 1 ~ 2 for the treatment of significant quantity and pharmaceutically acceptable carrier.
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| CN1295471A (en) * | 1998-03-27 | 2001-05-16 | 基因技术股份有限公司 | Antagonists for treatment of CD11/CD18 adhesion receptor mediated disorders |
| CN101633638A (en) * | 2008-06-20 | 2010-01-27 | 江苏国华投资有限公司 | Class I histone deacetylase inhibitor and application thereof |
| CN101899001A (en) * | 2009-05-25 | 2010-12-01 | 江苏国华投资有限公司 | N-(2-amino-4-pyridyl)-benzamide derivative and application thereof |
| WO2012006203A1 (en) * | 2010-07-07 | 2012-01-12 | Boehringer Ingelheim International Gmbh | N-cyclyl-3 - (cyclylcarbonylaminomethyl) benzamide derivatives as rho kinase inhibitors |
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| CN1295471A (en) * | 1998-03-27 | 2001-05-16 | 基因技术股份有限公司 | Antagonists for treatment of CD11/CD18 adhesion receptor mediated disorders |
| CN101633638A (en) * | 2008-06-20 | 2010-01-27 | 江苏国华投资有限公司 | Class I histone deacetylase inhibitor and application thereof |
| CN101899001A (en) * | 2009-05-25 | 2010-12-01 | 江苏国华投资有限公司 | N-(2-amino-4-pyridyl)-benzamide derivative and application thereof |
| WO2012006203A1 (en) * | 2010-07-07 | 2012-01-12 | Boehringer Ingelheim International Gmbh | N-cyclyl-3 - (cyclylcarbonylaminomethyl) benzamide derivatives as rho kinase inhibitors |
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