CN102731343B - Nitrogen atom-polysubstituted micro-molecular organic aryl amide compounds and derivatives thereof, and application and preparation method thereof - Google Patents

Nitrogen atom-polysubstituted micro-molecular organic aryl amide compounds and derivatives thereof, and application and preparation method thereof Download PDF

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CN102731343B
CN102731343B CN201210174929.7A CN201210174929A CN102731343B CN 102731343 B CN102731343 B CN 102731343B CN 201210174929 A CN201210174929 A CN 201210174929A CN 102731343 B CN102731343 B CN 102731343B
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hydroxy
phenyl
benzyl
bromobenzyl
cell
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CN102731343A (en
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陈益华
刘明耀
杨飞飞
张涛
易正芳
李静婕
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Bioray Laboratories Inc
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East China Normal University
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Abstract

The invention discloses nitrogen atom-polysubstituted micro-molecular organic aryl amide compounds as represented by structural formula (I), or hydrates or pharmaceutically acceptable salts thereof. The invention also discloses application of the compounds or pharmaceutical compositions thereof in treating diseases like growth, metastasis and recurrence of malignant tumors and also in preventing and treating thioredoxin-mediated diseases as a histone deacetylase (HDAC) inhibitor. The invention further brings forward a preparation method for the nitrogen atom-polysubstituted micro-molecular organic aryl amide compounds and derivatives thereof. Directed at the technical problem that current HDAC inhibitors do not have an inhibitory effect on tumor metastasis, the invention provides a novel HDAC inhibitor which can be used for inhibiting growth, metastasis and recurrence of tumors.

Description

Nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound and derivative thereof, purposes and preparation method thereof
Technical field
The present invention relates to the preparation method and use of a class based on have polysubstituted aromatic amides micromolecular organic compound at nitrogen-atoms.Contain the compounds of this invention or its pharmaceutical composition purposes in the diseases such as treatment various malignant growths, transfer and recurrence, the purposes as histon deacetylase (HDAC) (HDACs) inhibitor in the disease (as autoimmune disorder, allergy and inflammation) of prevention and treatment Trx (TRX) mediation and the preparation method of the polysubstituted aromatic amides compounds of nitrogen-atoms of the present invention and derivative thereof.
Background technology
Gene in order regulation and control is prerequisites that body cell maintains normal function; relate to the change of the epigenetics of gene transcription regulation; comprise modification (for example acetylize and deacetylation) and the DNA methylation of histone, in the numerous disease pathogeny of (comprising cancer etc.), all playing the part of vital effect.The modification of histone is one of important molecule mechanism of regulation and control epigenetic phenomenon; its Acetylation Level depends on proteolytic enzyme-acetylation of histone transferring enzyme (HATs) and DNA methylase inhibitor transferring enzyme (the HDACs) (Jaenisch that a pair of function is vied each other; R.et al.Nat Genet.2003; 33Suppl, 245-54).In general, the function of HATs is acetylize in core histones, causes histone electrically to neutralize, and presents more open, transcribed chromatin active structure; And being deacetylation and inhibition, the function of HDACs transcribes; the movement of the balance of chromatin acetylize and deacetylation will cause the change (Kurdistani of gene expression pattern; S.K.et al.Nat Rev Mol Cell Biol 2003,4 (4), 276-84).
The acetylize state of most of histone in tumour cell is on the low side, and chromatin densification is curling, causes the effective expression of some cancer suppressor genes.HDACs is unconventionality expression in most tumors cell; hdac inhibitor can make acetylation of histone level improve; nucleosomal structure is lax; thereby make various transcription factors and collaborative transcription factor can with DNA binding site specific binding; activate transcribing of some cancer suppressor genes, cause the apoptosis of tumour cell.Meanwhile, nearest research also shows, hdac inhibitor, by correcting the abnormal acetylize state of histone in tumour cell, acts on the relevant signal transduction pathways such as many, cell and cell proliferation, migration, invasion and attack, differentiation, produces stronger anti-tumor activity.Therefore hdac inhibitor has been obtained remarkable break-throughs as the research of drug target in recent years.Test shows optionally growth, the inducing tumor cell differentiation and dead of inhibition tumor cell of part hdac inhibitor, also can strengthen at radiation and chemotherapy medicine the cytotoxic effect in cancer therapy, be expected to become the brand-new antineoplaston medicine (Marks of another class, P.A.et al.J Natl Cancer Inst 2000,92, (15), 1210-6).Existing two kinds of small molecules hdac inhibitor SAHA and FK228 are by U.S. food Drug Administration (FDA) approval listing at present, Zolinza (SAHA, vorinostat) be used for the treatment of cutaneous T cell lymphoma (cutaneous T-cell lymphoma in 2006 by FDA approval, CTCL) (Duvic, M.et al.Expert Opin Investig Drugs 2007,16, (7), 1111-20), for continue, worsen when this disease or with during other drug treatment or after in recurrence.In addition also have 20 kinds of left and right small molecules hdac inhibitor in clinical study different steps (clinical III phase, clinical II phase and clinical I phase), be expected to be entered antitumor drug market by regulator's approval in the near future, for the patient of corresponding cancer brings glad tidings.
Although the existing understanding to a certain degree of the effect of hdac inhibitor aspect histone regulation and control is also day by day deep to its research, there are a lot of achievement reports, be to be mainly used in neoplasm growth activity, the report of the inhibition to metastases is relatively less.And metastases is the first cause that causes cancer patients lethal, recent research also shows that by the gene expression regulation of histone modification be not the sole cause of hdac inhibitor antiproliferative effect, and part hdac inhibitor also obviously has the lethal effect to cancer cells.But the mechanism of tumorigenesis is extremely complicated, according to statistics, 2010, cancer replaced cardiovascular and cerebrovascular diseases and has been called the disease that world's death toll is maximum.These stern realities require Pharmaceutical Chemist and biologist's combined effortss more, in conjunction with other the compound of mechanism of action, create that structure is more novel, activity is higher, specificity is better and the better antitumor drug of physico-chemical property.The present invention is by the molecular mechanism design of the aspects such as the migration by conjunction with inhibition tumor cell, the polysubstituted aromatic amides micromolecular of the nitrogen-atoms organic compound of composite structure novelty.
The present invention is based on SAHA structure, introduce the key structure unit of inhibition tumor cell migration, design and synthesized the polysubstituted aromatic amine compounds of a class nitrogen-atoms, after further investigation, find, the compounds of this invention is not only the hdac inhibitor of a class broad spectrum, can suppress the growth of malignant tumour, simultaneously more crucial is the transfer that also can suppress malignant tumour, has the effect of potential tumor remission transfer patient's grade malignancy.In addition, this compounds can also prevent and treat the disease of Trx (TRX) mediation, comprises autoimmune disorder, allergy and inflammation etc.
Summary of the invention
First object of the present invention is to provide can be used as hdac inhibitor and having the polysubstituted aromatic amides compounds of nitrogen-atoms of antitumous effect of a class formation novelty.
Composite structure formula of the present invention is suc as formula nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or hydrate or the pharmacy acceptable salt shown in (I):
Wherein,
N=0-8 CH 2;
with be selected from any one in following aromatic base or heterocyclic aromatic base, comprise monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases.Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to the group that comprises two and plural monocycle aromatic base.
R 1and R 2independently be selected from one or more in following groups: hydrogen, amino, cyano group, hydroxyl, methylol, aldehyde radical, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, aromatic base, heterocyclic aromatic base, cycloalkyloxy, cyclammonium base, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, benzyl, styroyl, alkyl-carbonyl, C 2-C 12alkenyl carbonyl, C 3-C 12naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, alkoxy carbonyl, aromatic base carbonyl, heterocyclic aromatic base carbonyl, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido, morpholinyl, piperazinyl, amide group, alkyloyl.
X selects arbitrarily in following groups: methylene radical, NH, O, S, aromatic base, heterocyclic aromatic base;
ZBG is various zinc chelation groups, is selected from any one in following groups: hydroximic acid CONHOH, O-Phenylene Diamine base, substituted sulfhydryl.
In the present invention, in described structural formula (I), when ZBG is hydroximic acid, it is represented by following structural formula (II):
Wherein,
N=0-8 CH 2;
with be selected from any one in following aromatic base or heterocyclic aromatic base, comprise monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to the group that comprises two and plural monocycle aromatic base;
R 1and R 2independently be selected from one or more in following groups: hydrogen, amino, cyano group, hydroxyl, methylol, aldehyde radical, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, aromatic base, heterocyclic aromatic base, cycloalkyloxy, cyclammonium base, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, benzyl, styroyl, alkyl-carbonyl, C 2-C 12alkenyl carbonyl, C 3-C 12naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, alkoxy carbonyl, aromatic base carbonyl, heterocyclic aromatic base carbonyl, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Amide group; Alkyloyl;
X selects arbitrarily in following groups: methylene radical; NH; O; S; Aromatic base; Heterocyclic aromatic base.
In the present invention, in described structural formula (I), when ZBG is hydroximic acid, when X is 2-aminopyrimidine base, it is represented by following structural formula (III):
Wherein,
N=0-8 CH 2;
with be selected from any one in following aromatic base or heterocyclic aromatic base, comprise monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to the group that comprises two and plural monocycle aromatic base;
R 1and R 2independently be selected from one or more in following groups: hydrogen, amino, cyano group, hydroxyl, methylol, aldehyde radical, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, aromatic base, heterocyclic aromatic base, cycloalkyloxy, cyclammonium base, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, benzyl, styroyl, alkyl-carbonyl, C 2-C 12alkenyl carbonyl, C 3-C 12naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, aromatic base carbonyl, heterocyclic aromatic base carbonyl, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Amide group; Alkyloyl.
In the present invention, in described structural formula (I), when ZBG is hydroximic acid, when X is methylene radical, it is represented by following structural formula (IV):
Wherein:
N=0-8 CH 2;
with be selected from any one in following aromatic base or heterocyclic aromatic base, comprise monocycle aromatic base, many cyclophanes perfume base, many heterocyclic aromatic bases; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to the group that comprises two and plural monocycle aromatic base;
R 1and R 2independently be selected from one or more in following groups: hydrogen, amino, cyano group, hydroxyl, methylol, aldehyde radical, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, aromatic base, heterocyclic aromatic base, cycloalkyloxy, cyclammonium base, C 2-C 12thiazolinyl, C 2-C 12alkynyl, C 3-C 12cycloalkyl, benzyl, styroyl, alkyl-carbonyl, C 2-C 12alkenyl carbonyl, C 3-C 12naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, aromatic base carbonyl, heterocyclic aromatic base carbonyl, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Amide group; Alkyloyl.
Second object of the present invention is to provide arbitrary aforementioned nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or hydrate or pharmacy acceptable salt, the acid salt forming including but not limited to described nitrogen-atoms polysubstituted aromatic amine small molecules organic compound and following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartrate, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid, succsinic acid etc.
In the present invention, the polysubstituted aromatic amine small molecules of described nitrogen-atoms organic compound is combined with radioactivity, fluorophor or vitamin H.
Nitrogen-atoms of the present invention polysubstituted aromatic amine small molecules organic compound or its hydrate or pharmacy acceptable salt, comprising:
3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
3-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
4-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
4-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
7-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
6-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
S-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) methyl thiuretic acid ester
3-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
3-(N-(4-(1-(diethyl carbamoyl group) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
6-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
N 1-(3-bromobenzyl)-N 4-(2-aminophenyl)-N 1-(2-p-methoxy-phenyl)-succinic diamide
N 1-(3-bromobenzyl)-N 4-(2-hydroxy phenyl)-N 1-(2-p-methoxy-phenyl)-succinic diamide
2-(4-((N 1-(2-aminophenyl)-N 4-(2-p-methoxy-phenyl) succinic diamide)-methyl) phenyl) methyl propionate
N 1-(3-bromobenzyl)-N 8-(2-hydroxy phenyl)-N 1-(2-p-methoxy-phenyl)-pimeloyl amine
2-(4-((N 1-(2-hydroxy phenyl)-N 4-(2-p-methoxy-phenyl) succinic diamide)-methyl) phenyl) methyl propionate
N 1-(3-bromobenzyl)-N 4-phenylhydrazino-N 1-(2-p-methoxy-phenyl) succinic diamide
N 1-(4-(1-(propyl group carbamyl) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
S-2-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) ethyl thiuretic acid ester
S-5-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) amyl group thiuretic acid ester
N 1-(4-(1-(diallyl formamyl) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-diethylamino formyl radical) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-(1-(diisopropylaminoethyl formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-diallyl formamyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 8-hydroxy-n 1-(2-hydroxy phenyl) suberamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(2,4-Dimethoxyphenyl) succinic diamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(2,4-dimethoxy) pimeloyl amine
N 1-(4-(1-oxygen-1-(1-Pyrrolidine base) 2-propyl group) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(2,4-Dimethoxyphenyl) succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1-(2-hydroxy phenyl) pimeloyl amine
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1-(2-p-methoxy-phenyl) pimeloyl amine
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(4-hydroxyl-2-p-methoxy-phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(2-hydroxy phenyl) pimeloyl amine
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2-p-methoxy-phenyl) adipamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(4-sulfoamido phenyl) pimeloyl amine
3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl)-N, N-diallyl benzamide
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2-hydroxy phenyl) adipamide
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2,4-Dimethoxyphenyl) adipamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(3-hydroxy phenyl) succinic diamide
N 1-(3-bromobenzyl) N 4-hydroxy-n 1-(2-aminomethyl phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(4-sulfoamido phenyl) succinic diamide
N 1-(3-(1-(diethylin formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(4-sulfoamido phenyl) succinic diamide
3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl)-DEET
3-((N 1-hydroxy-n 7-(2-p-methoxy-phenyl) pimeloyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1-(2-p-methoxy-phenyl) suberamide
3-((N 1-hydroxy-n 7-(2-hydroxy phenyl) pimeloyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 4-hydroxy-n 1-(2-p-methoxy-phenyl) succinic diamide
3-((N 1-hydroxy-n 4-(4-sulfoamido phenyl) succinyl amido) methyl)-DEET
3-((N 1-hydroxy-n 7-(4-sulfoamido phenyl) pimeloyl amido) methyl)-DEET
3-((N 1-hydroxy-n 4-(2-p-methoxy-phenyl) succinyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1-(2-hydroxy phenyl) adipamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1-(2,4-Dimethoxyphenyl) adipamide
N 1-(3-(5-pyrimidyl) benzyl)-N 7-hydroxy-n 1-(2-p-methoxy-phenyl) pimeloyl amine
N 1-(3-(3-pyridyl) benzyl)-N 8-hydroxy-n 1-(2-p-methoxy-phenyl) suberamide
N 1-(4-((diethylamino formyl radical) methyl) benzyl-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 8-hydroxy-n 1-(2-(5-oxazolyl) phenyl) suberamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1-(2,4-Dimethoxyphenyl) suberamide
N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8-((2-quinolyl) methyl) suberamide
3-((N 1-hydroxy-n 6-(2-hydroxy phenyl) hexanedioyl amido) methyl)-DEET
3-((N 1-hydroxy-n 8-(2-hydroxy phenyl) suberoyl amido) methyl)-DEET
N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8-((2-(5-benzofurane base)) methyl) suberamide
2-((N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) methylamino)-N-hydroxy pyrimidine-5-carboxylic acid amides
2-(2-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) ethylamino)-N-hydroxy pyrimidine-5-carboxylic acid amides
2-(3-(3-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) propyl group amino)-N-hydroxy pyrimidine-5-carboxylic acid amides.
The 3rd object of the present invention is to provide pharmaceutical composition and the pharmaceutical applications thereof for inhibition tumor cell propagation, growth, infiltration and migration prepared by above-claimed cpd, wherein pharmaceutical composition contains above-mentioned small molecules organic compound, hydrate or pharmacy acceptable salt, and pharmaceutically acceptable carrier.Described pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch or vehicle.
The 4th object of the present invention be to provide above-claimed cpd as NSC 630176 the purposes in the disease of prevention and treatment Trx mediation, wherein, described disease includes but not limited to autoimmune disorder, allergy or inflammation.
The present invention also provides the application in the medicine of preparation treatment Malignant tumor of bonal metastasis and recurrence of described nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or its hydrate or pharmacy acceptable salt; Wherein, described malignant tumour includes but not limited to liver cancer, lung cancer, prostate cancer, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, oral carcinoma.
In one embodiment, described tumour cell includes but not limited to lung carcinoma cell, breast cancer cell, epidermal carcinoma cell, colon cancer cell, liver cancer cell, stomach cancer cell, prostate cancer cell, pancreatic cancer cell, leukemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, cancer cell of oral cavity.
Wherein, in a specific embodiments, described composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch or vehicle.In another embodiment, wherein said compound is radioactivity, fluorophor or vitamin H (Biotin) mark.
The present invention also provides described nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or its hydrate or pharmacy acceptable salt in the application of preparing in antineoplaston medicine, causes the antineoplaston after chemotherapy failure for bringing out acquired resistance.
Medicine of the present invention uses separately or combines use with other drug.
Another object of the present invention is to provide the preparation method of this compounds,
Method one: the preparation of the polysubstituted aromatic amides compounds of N atom exemplifies:
(1) the compounds of this invention is implemented through the following steps:
First carry out the polysubstituted aminated compounds of reduction amination synthetic nitrogen atom by all kinds of aromatic amines and corresponding aldehyde, then at dimethyl formamide, benzene, toluene, dioxane, in tetrahydrofuran (THF) equal solvent, heat the corresponding intermediate that reacts to obtain, or react with other corresponding linking group and generate corresponding intermediate, this intermediate at suitable solvent as methylene dichloride, dimethyl sulfoxide (DMSO), dimethyl formamide, toluene etc. generate target compound with ZBG coupling, generally use after completion of the reaction frozen water cancellation, with ether, ethyl acetate, methylene dichloride, the extractions such as trichloromethane, use successively 5% hydrochloric acid, water, saturated common salt water washing, dry, low-temperature reduced-pressure is except desolventizing, obtain final product through column chromatography.The method such as nucleus magnetic resonance, mass spectrum for product obtaining proves.
In the scheme of antineoplaston, pharmacological agent is considered to very the key link, can suppress the further growth of tumour, and stops tumour cell to shift to other organ or tissues.Due to the fast rise of tumor incidence, antitumor drug market outlook are very wide in recent years.But also must recognize simultaneously, although tradition anti-tumor medicine thing can be controlled tumor development to a certain extent, but the generation of the resistance that its obvious toxic side effect and long-term prescription cause also can not be ignored, and existing medicine is poor to metastases effect, up to the present, also there is not the real medicine that suppresses metastases.The present invention is based on the antitumous effect of SAHA structure, incorporate the crucial structural framework of part, creatively obtain the novel hdac inhibitor of a class, experiment shows, this compounds can not only suppress the growth of tumour, and can suppress transfer and the recurrence of tumour, novelty of the present invention is mainly reflected in the following aspects:
(1) the invention provides the hdac inhibitor of a class formation novelty, comprise its pharmacy acceptable salt, solvated compounds (as hydrate), metabolite, isomer and prodrug etc., can be used as antitumor drug lead compound and clinical medicine candidate compound.
(2) the compounds of this invention all can suppress the growth of tumour in vitro and in vivo, suppress in vitro in the proliferation experiment of multiple cancer cells, the compounds of this invention all has significant inhibition to the propagation of cancer cells, in multiple disease animal models, the compounds of this invention successful is better than SAHA, can effectively suppress the growth of tumour.
(3) the compounds of this invention all can suppress the transfer of tumour in vitro and in vivo, in vitro in multiple experiments of antitumor cell migration and infiltration, the compounds of this invention all can suppress the migration of cell significantly, in whole animal disease model, the compounds of this invention has more effectively suppressed the transfer of tumour than SAHA.
(4) shift in animal model at mouse tumor, early stage administration or administration in late period all can effectively suppress the transfer of mouse tumor.
Brief description of the drawings
Figure 1 shows that the design sketch that part of compounds of the present invention suppresses HDAC enzyme.
Figure 2 shows that the design sketch that part of compounds of the present invention suppresses the each hypotype enzyme of HDAC (HDAC1, HDAC2 etc.).
Figure 3 shows that the deacetylation design sketch of part of compounds inhibition of histone H3 of the present invention and H4.
Figure 4 shows that the compounds of this invention result figure to human breast cancer cell MDA-MB-231 proliferation inhibition rate in the time of 20 μ M.
Figure 5 shows that the design sketch that the compounds of this invention suppresses different types of Cells Proliferation of Human Breast Cancer under different concns.
Figure 6 shows that the compounds of this invention inhibition figure to dissimilar tumour cell and normal cell propagation in the time of 20 μ M.
Figure 7 shows that the compounds of this invention design sketch on the impact of human breast cancer cell MDA-MB-231 clonality under different concns.Wherein, Fig. 7 A is design sketch, and Fig. 7 B is statistics figure.
Figure 8 shows that the affect figure of the compounds of this invention on human breast cancer cell MDA-MB-231 and Mouse mammary cells 4T1 inhibition of metastasis rate.Wherein, Fig. 8 A is the migration situation of breast cancer cell MDA-MB-231, and Fig. 8 B is the migration situation of breast cancer cell 4T1.Fig. 8 C is the statistical graph of Fig. 8 A, and taking control group (drug level was as 1 o'clock) migrating cell number as 100%, all the other each groups and control group comparison, determine its relative mobility.In like manner, Fig. 8 D is the statistical graph of Fig. 8 B.
What Figure 9 shows that the compounds of this invention infiltrates inhibiting rate to human breast cancer cell MDA-MB-231 and Mouse mammary cells 4T1 affects figure wherein, and Fig. 9 A is the Infiltrating of breast cancer cell MDA-MB-231, and Fig. 9 B is the Infiltrating of breast cancer cell 4T1.Fig. 9 C is the statistical graph of Fig. 9 A, and taking control group (drug level was as 1 o'clock) migrating cell number as 100%, all the other each groups and control group comparison, determine its relative mobility.In like manner, Fig. 9 D is the statistical graph of Fig. 9 B.
Figure 10 shows that the compounds of this invention suppresses the growth of tumour and shifts result figure.Wherein, Figure 10 A is that the compounds of this invention suppresses the IVIS of the growth of breast cancers result of taking pictures, and Figure 10 B is statistics figure.
Figure 11 shows that the compounds of this invention suppresses the experimental transfer result figure of tumour.Wherein, Figure 11 A is that the compounds of this invention suppresses the IVIS of the Metastasis in Breast Cancer result of taking pictures, and Figure 11 B is the take pictures statistical graph of result of IVIS.
Figure 12 shows that the transfer and the recurrence result figure that in the disease animal model that the compounds of this invention shifts in spontaneity, suppress tumour, Figure 12 A is the IVIS figure that takes pictures.Figure 12 B is mouse survival rate statistics figure.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and taking appending claims as protection domain.
1h-NMR measures with Varian MercuryAMX300 type instrument; MS measures with VG ZAB-HS or VG-7070 type instrument, except indicating, is ESI mode; All solvents all pass through re-distillation before use, and the anhydrous solvent using is all to obtain by standard method drying treatment; Except explanation, it is all under argon shield, carry out and with TLC tracking, when aftertreatment, all wash and anhydrous magnesium sulfate drying process through saturated common salt that institute responds; The purifying of product all uses the column chromatography of silica gel (200-300 order) except explanation; The silica gel using, comprises 200-300 order and GF 254for Haiyang Chemical Plant, Qingdao or the production of Yantai Yuan Bo silica gel company.
The preparation of embodiment 1-1, compound 3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid (SA001)
Get Ortho-Aminophenol (2.18g, 20mmol) in dehydrated alcohol (50ml), with ice-water bath, reaction system is cooling, add 3-bromobenzaldehyde (2.33ml, 20mmol), rising to room temperature react 30min at 0 DEG C after continues to stir and spends the night.Again cooling reaction system to 0 DEG C, drips the ethanolic soln (30ml) of sodium borohydride (1.14g, 30mmol), rises to room temperature reaction more than 5 hours after stirring 30min at this temperature.Most of solvent is removed in decompression, crosses silicagel column after conventional processing, obtains imine intermediate 2-(3-bromobenzyl amido) phenol (4.39g, 79%).
By 2-(3-bromobenzyl amido) phenol (439mg; 1.58mmol) be dissolved in 1; in 4-dioxane (10ml); add Succinic anhydried (237mg; 2.37mmol); about reflux 5 hours, separate to obtain intermediate 3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) propionic acid (513mg, 86%).Get 3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) propionic acid (513mg; 1.36mmol) be dissolved in methyl alcohol (8ml); drip 3～4 thionyl chlorides, reaction system is heated to reflux.After 5 hours, decompression is removed excessive solvent and is obtained crude product 3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) methyl propionate, is directly used in next step reaction.
Oxammonium hydrochloride (1.96g in the time of 40 DEG C, in methyl alcohol (20ml) solution 28mmol), add KOH (1.58g, 28mmol) and keep 10min, then after reaction system being cooled to 0 DEG C, filter, again corresponding ester is joined in filtrate, add subsequently KOH (158mg, 2.8mmol), reaction system at room temperature keeps 30min.With EtOAc extraction, after conventional aftertreatment, cross silicagel column, obtain product S A001 (145mg, 45%). 1H?NMR(DMSO，400MHz)δ10.35(br?s，1H)，9.71(br?s，1H)，8.64(s，1H)，7.43-7.38(m，2H)，7.25(dd，J＝8.4，8.4Hz，1H)，7.21-7.17(m，2H)，6.73(d，J＝8.4Hz，1H)，6.60(d，J＝8.4Hz，1H)，6.56(s，1H)，4.79(s，2H)，2.50-2.49(m，2H)，2.31-2.29(m，2H)。
Embodiment 1-2 is to the preparation (detailed process sees below literary composition reference) of SA shown in 1-74, table 1 and TA series compound
Embodiment bis-, the compounds of this invention be the restraining effect to HDAC enzymic activity and deacetylation effect on molecular level.
Embodiment 2-1, the inhibition of the compounds of this invention to HDAC enzymic activity
The high flux screening test kit that the compounds of this invention adopts BioVision company of the U.S. to produce to the detection of HDAC inhibition.When experiment, compound to be identified and sample (HeLa nucleus extract) and the HDAC colorimetric substrates (containing an acetylizad lysine side-chain) with HDAC activity are hatched altogether.Be activated if substrate is deacetylated, under the effect of Methionin developer, produce luminophore subsequently.Final luminophore reads analysis by microplate reader.
The compounds of this invention and SAHA are made into the mother liquor that final concentration is every liter of 1 mmole.In 96 orifice plates, add the distilled water of 83 microlitres.In these holes, add respectively the compounds of this invention or the SAHA of 2 microlitres.Positive controls only adds the distilled water of 85 microlitres.Add again 5 microlitre HDAC chromogenic substrates, mix latter 37 DEG C and hatch half an hour to adding 10 microlitre HDAC assay buffer and 2 microlitre HeLa nucleus extracts to mix rear every hole in above-mentioned every hole.Adding 10 microlitre Methionin developer termination reactions to mix latter 37 DEG C hatches half an hour.In microplate reader, with excitation wavelength 350-380nm, under wavelength of transmitted light 440-460nm, read fluorescent value.
Result as shown in Figure 1, in certain density situation, majority of compounds all has the effect that suppresses HDAC enzymic activity, in cited compound, wherein, SA001, SA004, SA006, SA009, SA011, SA012, SA013, SA017, SA026, SA031 and SA036 etc. are better to the inhibition of HDAC.Inhibition quite or better compared with positive control SAHA.
Embodiment 2-2, the inhibition of the compounds of this invention to the each hypotype enzymic activity of HDAC
MDA-MB231 cell is seeded in the Tissue Culture Dish of 6 centimetres, in the time that cell grows to 80% density, add respectively the compounds of this invention and SAHA, DMSO as a control group, cell was processed after 24 hours, remove substratum, add the PBS of precooling, then draw PBS, add cell pyrolysis liquid, scrape in the centrifuge tube of cell to 1.5 milliliter, centrifuge tube is placed on ice, every five minutes one time vortex centrifugal pipe, after common vortex 5 times, leave the heart 15 minutes at 4 degree whizzers 12000, draw supernatant to new precooling centrifuge tube, BCA method is surveyed protein concentration, the loading damping fluid that contains 40 microgram albumen, on the SDS of 8%-12% albumen sepn glue, run glue, after running out of offset plate, tetrabromophenol sulfonphthalein stops, transferring film 1 hour under 100 volts of voltages, the primary antibodie of hatching the each hypotype of corresponding HDAC at 4 degree shaking tables is spent the night, within each 10 minutes, wash three times with TBST, then hatch corresponding two and resist 1 hour, within each 10 minutes, wash three times with TBST, use ECL test kit, exposure shows each object band.
Result as shown in Figure 2, at tested HDAC1, HDAC2, HDAC3 and HDAC6 hypotype enzyme, under same concentrations, the compounds of this invention is obviously strong than positive control SAHA to the inhibition of HDAC1, HDAC3 and HDAC6, inhibition and SAHA to HDAC2 are suitable, illustrate that the compounds of this invention has more effectively suppressed the biological activity of the each hypotype enzyme of HDAC.
Embodiment 2-3, the compounds of this invention are to the inhibition to histone H 3 and H4 deacetylation activity
Test method is with example 2-2, MDA-MB231 cell is seeded in the Tissue Culture Dish of 6 centimetres, in the time that cell grows to 80% density, add respectively the compounds of this invention and SAHA, DMSO as a control group, cell was processed after 24 hours, remove substratum, add the PBS of precooling, then draw PBS, add cell pyrolysis liquid, scrape in the centrifuge tube of cell to 1.5 milliliter, centrifuge tube is placed on ice, every five minutes one time vortex centrifugal pipe, after common vortex 5 times, leave the heart 15 minutes at 4 degree whizzers 12000, draw supernatant to new precooling centrifuge tube, BCA method is surveyed protein concentration, the loading damping fluid that contains 40 microgram albumen, on the SDS of 8%-12% albumen sepn glue, run glue, after running out of offset plate, tetrabromophenol sulfonphthalein stops, transferring film 1 hour under 100 volts of voltages, hatch at 4 degree shaking tables, H3, H4 acetylize antibody spends the night, within each 10 minutes, wash three times with TBST, then hatch corresponding two and resist 1 hour, within each 10 minutes, wash three times with TBST, use ECL test kit, exposure shows each object band.
As shown in Figure 3, at tested histone H 3 and the degree of acetylation of H4, the compounds of this invention is the same with positive control SAHA for result, all has the deacetylation effect of obvious inhibition of histone H3 and H4, and is dose-dependently.
Propagation and the migration to tumour cell of embodiment tri-, the compounds of this invention has significant inhibition
Embodiment 3-1, MTS method are measured cell proliferation
Tumour cell is with 5x10 3individual/hole density is seeded to 96 orifice plates (Corning), after cellar culture 24h, add successively different concns the compounds of this invention, make its final concentration be respectively 1.0 μ mol/L, 5.0 μ mol/L, 10.0 μ mol/L, 20.0 μ mol/L, control group adds the DMSO (establishing 6 multiple holes for every group) of equivalent.Continue to cultivate after 48h, it is MTS solution 100 μ l that every hole adds concentration, 37 DEG C of 5%CO 2in incubator, hatch about 2 hours.96 orifice plates are placed in to microplate reader (SPECTRA MAX 190), under 490nm wavelength, measure OD value.Statistical study medicine is for the impact of cell proliferation level.
Result as Figure 4-Figure 6, wherein:
(1) the compounds of this invention has very significantly restraining effect to the propagation of breast cancer cell MDA-MB-231 in the time of 20.0 μ mol/L, sees Fig. 4.Wherein, compared with control group, SA005, SA008, SA011, SA014, SA026, SA030 and SA043 etc. have shown that obvious inhibition is active.
(2) design sketch that the compounds of this invention suppresses three strain Cells Proliferation of Human Breast Cancers under different concns, is shown in Fig. 5.Compared with control group, add after the compounds of this invention of different concns, the multiplication capacity of breast cancer cell MDA-MB231,4T1 and T47D is suppressed, to the half effective inhibition concentration of three strain breast cancer cells respectively at 1～5 μ M, 1～5 μ M and 10 μ M left and right, and be obvious dose-dependence.
(3) the compounds of this invention has strong inhibition to cancer cells under finite concentration, and to normal cell proliferation without obvious restraining effect.As Fig. 6.At tested prostate cancer cell, colon cancer cell, stomach cancer cell etc., the compounds of this invention all has comparatively significantly inhibition to cancer cells, and less to the toxic action of normal mammary epithelial cell, illustrate that the compounds of this invention also has good selectivity between tumour cell and normal cell.
In addition, the compounds of this invention is tested kinds of tumor cells such as liver cancer, lung cancer, prostate cancer, skin carcinoma, carcinoma of the pancreas, leukemia, ovarian cancer, bladder cancer, kidney, oral carcinoma, all obtain significant inhibition, meanwhile, there is not obvious inhibition to normal cell in the compounds of this invention.
The inhibition that embodiment 3-2, the compounds of this invention form tumor cell clone.
Solid tumor by tumour cell by autotomy, propagation and finally form.Therefore the inhibition of testing in vitro the clonality of the compounds of this invention to tumour cell in experimental model carrys out the anticancer effect of assessing compound.
By breast cancer cell MDA-MB-231,4T1 and T47D with 1x10 3the density of individual/ware is inoculated in 35mm culture dish, after cultivation 24h, divides into groups, and adds respectively the testing compound of different concns, makes its final concentration be respectively 0 μ mol/L, 1.0 μ mol/L, and 5.0 μ mol/L, 10.0 μ mol/L, control group adds the DMSO of equivalent.Continue to cultivate, within every 3 days, change a subculture and respective concentration compound.After 7 days, discard substratum, PBS washes 3 times, and 4% paraformaldehyde room temperature is fixed 10min, 1% violet staining 10min, and tap water rinses.Under microscope, take pictures, calculate cell clonal formation quantity.Experimental result as shown in Figure 7.Wherein, compound S A002, SA007, SA023, SA030, SA033, SA037, SA056 and SA058 have obvious restraining effect to breast cancer cell (as MDA-MB-231 and 4T1 cell) clonality, compound has obvious inhibition to clone's ability of this two strains lung carcinoma cell under 1.0 μ mol/L mass actions, the clone who suppresses this three strains breast cancer cell under 5.0 μ mol/L concentration completely forms, and illustrates that from another one angle this compounds has the effect of very strong inhibition tumor growth.
The inhibition of embodiment 3-3. the compounds of this invention to tumor cell migration and infiltration.
3-3-1, scratch method (wound healing) detect the inhibition to tumor cell migration ability
Can be along cultivating the less componental movement of flat Cell-oriented when cell is cultivated in vitro.Utilize this phenomenon, in the culture hole that covers with cell, artificial " drawing " goes out one " scar ", and the cell of " scar " both sides can, to " scar " regional movement, finally be covered with this region again, i.e. the effect of so-called " scar healing ".According to cell quantity and " scar healing " degree of moving to " scar " region, can judge the motor capacity of cell.
By tumor cell inoculation to 6 orifice plate of some amount, cell is at 37 DEG C of 5%CO 2in incubator, cultivate 24h, grow to 80% left and right to cell.In the culture hole that covers with cell, along the longitudinal cut of culture hole diameter, after cut, wash cell twice with PBS with the sterilizing tip of 100 μ l, the cell floating is washed away, then in every hole, add 1 milliliter of serum free medium containing EGF.In cell cultures hole, add 2 milliliters of substratum containing the compounds of this invention of different concns respectively, culture plate is put into CO 2incubator, 37 DEG C are continued cellar culture 12h left and right, until the full cell of the control group cut head of district.Under microscope, the observation of cell situation of componental movement of wanting to rule, takes pictures.The migration of statistical study various dose medicine group enters the cell quantity of scribe area, determines the impact of medicine on cell migration ability.
As shown in Figure 8, wherein, Fig. 8 A is the design sketch of the compounds of this invention to breast cancer cell MDA-MB-231 inhibition of metastasis to result, and Fig. 8 B the compounds of this invention is to breast cancer cell 4T1 inhibition of metastasis design sketch, and Fig. 8 C, 8D are respectively the statisticses of Fig. 8 A and Fig. 8 B.Compared with control group, in the cell cut migration experimental model of mammary cancer cancer cells MDA-MB-231 and 4T1, the medium effective concentration IC of the inhibition of metastasis of the compounds of this invention to MDA-MB-231 and 4T1 50all, between 1～5 μ mol/L, illustrate that this compounds has obviously suppressed the migration of this tumour cell in this migration models.
3-3-2, Transwell method detect cellular infiltration
Transwell migration experiment adopts Boyden cell.On the permeable polycarbonate film that cell bottom spreads, having a large amount of apertures is the micropore of 8 μ m, when experiment, Transwell cell is put into 24 orifice plates, and whole hole is divided into upper and lower two Room by polycarbonate film, in Transwell cell, deserves to be called chamber, in culture plate, claim lower chamber, upper indoor splendid attire upper strata nutrient solution, lower indoor splendid attire lower floor nutrient solution, levels nutrient solution is separated by with polycarbonate membrane, on Transwell cell, chamber spreads one deck collagen stroma Matrigel in advance, then cell is inoculated wherein.Because polycarbonate membrane has permeability, the composition in lower floor's nutrient solution can be induced to indoor cell and move downwards, makes chamber face from film move to lower chamber face.But, if tumour cell will move to lower chamber, must first utilize the various chemical substances that self discharge to dissolve collagen stroma, again by dissolving the cavity motion, this process, similar to tumour cell impregnation process in vivo, can be used for reflecting the invasiveness ability of tumour cell.Therefore this experiment is the Classic Experiments of research cellular infiltration.
The tumour cell of taking the logarithm vegetative period is with 5x10 4in the upper chamber of individual/hole inoculation Transwell cell, dosing group adds respectively 1.0 μ mol/L as indicated above, 5.0 μ mol/L, and 10.0 μ mol/L, the medicine of 20.0 μ mol/L, control group adds the DMSO of equivalent.In lower chamber, respectively add respectively perfect medium.37 DEG C of 5%CO 2in incubator, cultivate 12h.Take out transwell cell, dip in the upper chamber one side of wiping transwell cell with cotton swab, the cell of not wearing film is wiped.Transwell is fixed to 10min in 4% paraformaldehyde room temperature, 1% violet staining 10min, tap water rinses.Under microscope, take pictures, count in every hole up and down in the cell number in 5 visuals field, obtain and wear theca cell number/visual field.On average establish 3 secondary holes for every group.Statistical various dose medicine group is worn theca cell quantity, determines the impact of medicine on cell migration ability.
As shown in Figure 9, in the Transwell of breast cancer cell MDA-MB-231 Soaking experiment model, these compounds infiltrate the medium effective concentration IC suppressing to result to MDA-MB-231 50between 1-5 μ mol/L; In the Transwell of mammary cancer 4T1 Soaking experiment model, the compounds of this invention is to infiltrating the IC suppressing 50also between 1-5 μ mol/L, illustrate that this compounds shows the ability of significant anti-breast cancer cellular infiltration in infiltration model.
Embodiment tetra-: the therapeutic action of the compounds of this invention in mouse tumor growth and metastasis model
4-1. the compounds of this invention suppresses the effect of tumor growth and spontaneous metastasis.
The all female nude mices of 4-6, breast pad in-situ injection 1 × 10 6individual human breast cancer cell MDA-MB-231-luciferase.After lotus knurl 7 days, mouse is divided into three groups at random, is respectively negative control group, 30mg/kg/day dosage SAHA positive controls and 30mg/kg/day dosed administration group.Administration group is respectively according to corresponding dosage intraperitoneal injection of drugs, and negative control group is injected equivalent solvent (DMSO), and positive controls is injected SAHA according to dosage.Before injecting compound every day, weigh Mouse Weight, continue medication to 30 days, adopt mouse living imaging technology (IVIS), observe growth and the spontaneous metastasis situation of tumour cell.
Result as shown in figure 10 medication result for the treatment of figure to mouse breast cancer growth after 30 days (by the living animal imaging system picture of taking pictures, due to the gene with luciferase mark in tumour cell, can expressing luciferase, this luciferase can and substrate reactions, and then can determine the position of tumour cell and how many by living imaging system.) shown in black, shade represents fluorescent signal in figure, shows that this region has tumour cell to assemble, and cell aggregation heighten degree from outside to inside.Figure 10 A shows that, compared with control group, the compound of 30mg/kg/day dosage significantly suppresses the growth of mammary gland carcinoma in situ.And compared with positive control SAHA, under same dose, the effect that the compounds of this invention suppresses tumor growth is better than SAHA itself.And Figure 10 B is the statistics drawing by living animal imaging system software for calculation.Result shows that the compounds of this invention can suppress the growth of primary tumor well, and result for the treatment of is obviously better than the SAHA of same dosage.The statistics figure of what table 1 showed is our the mouse spontaneous metastasis added up.Result shows that the compounds of this invention is obviously better than SAHA to the spontaneous inhibition shifting of tumour under same dose, and spontaneous metastasis probability is reduced to 17% from 100% of control group, and SAHA can only be reduced to 50% left and right.
Table 1: the compounds of this invention is the impact on Lung Cancer Recurrence and lung cancer metastasis occurrence probability in tumour spontaneous metastasis model
The inhibition that 4-2. the compounds of this invention shifts mouse tumor in the experimental metastasis model of mammary cancer
At the female nude mice tail vein injection 1 × 10 of 4-6 week BALB/c 6individual mouse mastopathy cell MDA-MB-231-luc, after approximately spending one hour, injecting substrate takes pictures, then mouse is equally divided at random four groups (cell count of guaranteeing survival that every group of mouse injected is much the same), is respectively negative control group, 20mg/kg/day dosed administration group, 30mg/kg/day dosed administration group and 30mg/kg/day dosage SAHA positive controls.On the same day (when injection tumour cell), administration group was respectively according to corresponding dosage intraperitoneal injection of drugs, and negative control group is injected equivalent solvent (DMSO), and positive controls is injected SAHA according to dosage.Before injecting compound every day, weigh Mouse Weight, continue medication to 30 days, adopt mouse living imaging technology (IVIS), observe the transfer case of tumour cell.
Result as shown in figure 11, Figure 11 A is that administration result for the treatment of figure to the experimental transfer of mouse breast cancer after the 0th day, the 1st day, the 7th day and the 30th day is (by the living animal imaging system picture of taking pictures, due in tumour cell with fluorescence, can utilize fluorescence to determine the position of tumour cell and how many, in figure, shown in black, shade represents fluorescent signal, show that this region has tumour cell to assemble, and cell aggregation heighten degree from outside to inside.Figure 11 B is antitumous effect statistical graph.Result is presented at the experimental transfer of the compounds of this invention inhibition mammary cancer of 20mg/kg/day dosage, and the compound of 30mg/kg/day dosage significantly suppresses the experimental transfer of mammary cancer.Figure 11 B is the amount of calculating tumour cell in mouse lung by living animal imaging system, can obviously find out that this compound has obvious restraining effect to metastases, and be dose-dependence.And compared with positive control SAHA, under same dose, the effect that the compounds of this invention suppresses the experimental transfer of mammary cancer is better than SAHA.
4-3. the compounds of this invention suppresses the original position recurrence of tumour and the effect that far-end shifts.
Patient with breast cancer is implementing after tumor resection this expectant treatment, has very greatly to such an extent that probability can tumorigenic recurrence (regrowing of primary tumor occur) and far-end transfer.4T1 mouse mammary cancer can the high metastatic tumour of spontaneous generation, can be transferred to lung, liver, and lymphoglandula and brain form the kitchen range that starts simultaneously in injection site.Mammary cancer in growth and transfer characteristics and the human body of 4T1 cell in BALB/c mouse is very close.This is a kind of animal model that can simulate people VI primary breast cancer.Well simulate the methods for the treatment of of the tumor resection in expectant treatment clinically so can utilize this animal model.
The all female BALB/c mouse of 4-6, by 1 × 10 5individual mouse mastopathy cell 4T1-luciferase is expelled to mouse mammary fat pad, mouse random packet after 10 days, is respectively negative control group, 20mg/kg/day dosed administration group, 30mg/kg/day dosed administration group and 30mg/kg/day dosage SAHA positive controls.Excise subsequently the primary tumor of mouse, sew up.Go and buy Chinese medicine after 32 days, adopt mouse living imaging technology (IVIS), observe the impact of the compounds of this invention on the recurrence of mouse original position and far-end transfer, then continue the variation of the survival rate of observing mouse.
Experimental result as shown in figure 12, Figure 12 A is that medication result for the treatment of figure to mouse breast cancer original position recurrence and far-end transfer after 32 days is (by the living animal imaging system picture of taking pictures, due in tumour cell with fluorescence, can utilize fluorescence to determine the position of tumour cell and how many, in figure, shown in black, shade represents fluorescent signal, show that this region has tumour cell to assemble, and cell aggregation heighten degree from outside to inside.The compounds of this invention can reduce tumor recurrence probability and the metastases odds (in table 2) of this experimental model small mouse, and compared with control group, the compounds of this invention can be reduced to 27% left and right from 91% left and right by tumor in situ recurrence rate; Far-end metastases incidence is reduced to 27% left and right from 100% left and right; and tumor in situ can only be recurred to probability and far-end metastases occurrence probability is reduced to respectively 73% and 64% with the SAHA of dosage, obvious the compounds of this invention is obviously better than SAHA to the provide protection of mice with tumor.And the compounds of this invention has obvious castering action to the survival rate of mice with tumor, for example, in administration after 36 days, negative control group small mouse can not be survived substantially, and the survival rate of SAHA positive controls (30mg/kg/day) small mouse is probably 50%, the mouse survival rate of the compounds of this invention of same dose can be promoted to 90% left and right.And after 42 days SAHA positive controls mouse substantially without survival, and injection the compounds of this invention mouse have more than 65% and can survive, illustrate that the compounds of this invention has obvious castering action to the survival rate of mice with tumor.
Table 2: the impact of the compounds of this invention on breast cancer relapse and Metastasis in Breast Cancer occurrence probability
The preparation of embodiment 1-2, compound 3-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid (SA002)
Ortho-Aminophenol is replaced as to 2-anisidine, by the method preparation of preparing compound S A001. 1H?NMR(CD 3OD，400MHz)：δ7.36-7.32(m，3H)，7.15-7.13(m，2H)，7.06(d，J＝8.0Hz，1H)，7.01(dd，J＝1.7，8.0Hz，1H)，6.94-6.90(m，1H)，4.95(d，J＝14.4Hz，1H)，4.58(d，J＝14.4Hz，1H)，3.74(s，3H)，2.50-2.42(m，2H)，2.40-2.33(m，2H)。
The preparation of embodiment 1-3, compound 4-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid (SA003)
Succinic anhydried is replaced as to Pyroglutaric acid, by the corresponding preparation of the method for preparing compound S A002 SA003. 1H?NMR(400MHz，DMSO)δ7.35-7.30(m，3H)，7.14-6.87(m，5H)，4.95(d，J＝14.4Hz，1H)，4.56(d，J＝14.4Hz，1H)，3.73(s，3H)，2.16-1.99(m，4H)，1.84(m，2H)。
The preparation of embodiment 1-4, compound 4-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid (SA004)
Succinic anhydried is replaced as to Pyroglutaric acid, by the corresponding preparation of the method for preparing compound S A001 SA004. 1H?NMR(400MHz，CD 3OD)δ7.39-7.35(m，2H)，7.19-7.15(m，3H)，6.91(d，J＝8.0Hz，1H)，6.81-6.74(m，2H)，5.22(d，J＝14.8Hz，1H)，4.35(d，J＝14.4Hz，1H)，2.20-2.16(m，2H)，2.06-2.01(m.2H)，1.89-1.85(m，2H)。
The preparation of embodiment 1-5, compound 7-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid (SA005)
Succinic anhydried is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A002 SA005. 1H?NMR(CD 3OD，400MHz)：δ7.37-7.36(m，3H)，7.11-7.06(m，3H)，6.93(s，2H)，4.98(d，J＝12.0Hz，1H)，3.78(d，J＝12.0Hz，1H)，3.74(s，3H)，2.04-2.00(m，4H)，1.53(s，4H)，1.27-1.20(m，4H)。
The preparation of embodiment 1-6, compound 6-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid (SA006)
Succinic anhydried is replaced as to pimelic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A001 SA006.1H?NMR(CD3OD，400MHz)：δ7.35-7.32(m，3H)，7.10-7.03(m，3H)，6.94-6.89(m，2H)，4.90(d，J＝6.4Hz，1H)，4.52(d，J＝6.4Hz，1H)，3.73(s，3H)，2.04-2.00(m，4H)，1.53-1.50(m，4H)，1.26-1.19(m，2H)。
The preparation of embodiment 1-7, S-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) methyl thiuretic acid ester (SA007)
Get 2-anisidine (2.24ml, 20mmol) in dehydrated alcohol (50ml), with ice-water bath, reaction system is cooling, add 3-bromobenzaldehyde (2.33ml, 20mmol), rising to room temperature react 30min at 0 DEG C after continues to stir and spends the night.Again cooling reaction system to 0 DEG C, drips NaBH 4the EtOH solution (30ml) of (1.14g, 30mmol), rises to room temperature reaction more than 5 hour after stirring 30min at this temperature.Most of solvent is removed in decompression, crosses silicagel column after conventional processing, obtains imine intermediate (3-bromobenzyl)-(2-p-methoxy-phenyl) amine (4.05g, 69%).
Get compound (3-bromobenzyl)-(2-p-methoxy-phenyl) amine (584mg, 2mmol) in tetrahydrofuran (THF), under condition of ice bath, add chloroacetyl chloride (0.2ml, 2.6mmol) and triethylamine (0.84ml, 6mmol), normal-temperature reaction 2 hours, after simple aftertreatment, obtain the chloro-N-of compound N-(3-bromobenzyl)-2-(2-p-methoxy-phenyl) ethanamide (640mg, 87%), get the chloro-N-of compound N-(3-bromobenzyl)-2-(2-p-methoxy-phenyl) ethanamide (640mg, 1.74mmol) in DCM, add compound K SAc (410mg, 3.6mmol), 50 DEG C are reacted 5 hours, most of solvent is removed in decompression, cross column purification and obtain compound S A007 (142mg, 20%). 1H?NMR(400MHz，CDCl 3)：δ7.35(s，1H)，7.34-7.31(m，1H)，7.30(d，J＝8.0Hz，1H)，7.12-7.11(m，1H)，7.09(dd，J＝7.6，7.6Hz，1H)，6.99(d，J＝7.6Hz，1H)，6.93(d，J＝8.0Hz，1H)，6.90(dd，J＝7.6，7.6Hz，1H)，5.01(d，J＝14.8Hz，1H)，4.52(d，J＝14.8Hz，1H)，3.73(s，3H)，3.60(d，J＝15.6Hz，1H)，3.46(d，J＝15.6Hz，1H)，2.30(s，3H)。
Embodiment 1-8, compound 3-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) preparation of hydroximic acid (SA008)
3-bromobenzaldehyde is replaced as to 4-(1-(carbaniloyl,phenylcarbamoyl) ethyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA008. 1H?NMR(400MHz，DMSO)δ10.34(br?s，1H)，10.02(br?s，1H)，9.95(br?s，1H)，8.63(br?s，1H)，7.57(d，J＝7.6Hz，2H)，7.29-7.25(m，4H)，7.17-7.11(m，3H)，7.03-6.99(m，1H)，6.95-6.89(m，2H)，6.73-6.69(m，1H)，5.20(d，J＝12.4Hz，1H)，4.14(d，J＝11.6Hz，1H)，3.78(q，J＝6.8Hz，1H)，2.34-2.23(m，2H)，2.19-2.08(m，2H)，1.36(d，J＝6.4Hz，3H)。
The preparation of embodiment 1-9, compound 3-(N-(4-(1-(diethyl carbamoyl group) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid (SA009)
3-bromobenzaldehyde is replaced as to 4-(1-(diethyl carbamoyl group) ethyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA009. 1H?NMR(400MHz，DMSO)δ10.36(br?s，1H)，9.96(br?s，1H)，8.64(br?s，1H)，7.16-7.11(m，5H)，6.94(d，J＝8.0Hz，1H)，6.85-6.83(m，1H)，6.69-6.66(m，1H)，5.23(d，J＝12.4Hz，1H)，4.10(d，J＝12.4Hz，1H)，3.92(q，J＝6.8Hz，1H)，3.19-3.14(m，4H)，2.32-2.22(m，2H)，2.21-2.09(m，2H)，1.23(d，J＝6.4Hz，2H)，0.98-0.94(m，3H)，0.85-0.82(m，3H)。
Embodiment 1-10, compound 7-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) preparation of hydroximic acid (SA010)
Succinic anhydried is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A008 SA010. 1H?NMR(400MHz，DMSO)d?10.29(br?s，1H)，10.03(br?s，1H)，9.96(br?s，1H)，8.65(br?s，1H)，7.57-7.56(m，2H)，7.29-7.25(m，4H)，7.16-7.09(m，3H)，7.03-6.99(m，1H)，6.93(d，J＝8.0Hz，1H)，6.85-6.83(m，1H)，6.69(t，J＝3.2Hz，1H)，5.23(d，J＝10.4Hz，1H)，4.11(d，J＝10.4Hz，1H)，3.78(q，J＝6.8Hz，1H)，2.06-1.96(m，2H)，1.94-1.85(m，2H)，1.42-1.36(m，7H)，1.10(m，4H)。
Embodiment 1-11, compound N 1-(3-bromobenzyl)-N 4-(2-aminophenyl)-N 1the preparation of-(2-p-methoxy-phenyl)-succinic diamide (SA011)
Get N-(3-bromobenzyl amido)-2-anisidine (444mg, 1.52mmol) be dissolved in 1, in 4-dioxane (10ml), add Succinic anhydried (237mg, 2.37mmol), about reflux 5 hours, separate to obtain respective acids intermediate (524mg, 88%).Get sour intermediate (196mg, 0.50mmol) in tetrahydrofuran (THF), methylene dichloride, dimethyl formamide and ethyl acetate equal solvent, under argon atmosphere, add EDC and HOBt, under ice bath, stir after 15 minutes and add O-Phenylene Diamine (108mg, 1.0mmol), and then reaction 5-8 hour, after simple aftertreatment, column purification obtains compound S A011 (135mg, 0.28mmol), productive rate 56%. 1H?NMR(CDCl 3，400MHz)：δ8.05(br?s，1H)，7.39(s，1H)，7.36-7.35(m，1H)，7.31(dd，J＝8.0，8.0Hz，1H)，7.25(dd，J＝8.0，8.0Hz，1H)，7.10-7.09(m，2H)，7.04(dd，J＝8.0，8.0Hz，1H)，6.95-6.90(m，3H)，6.79-6.77(m，2H)，5.04(d，J＝16.4Hz，1H)，4.48(d，J＝16.4Hz，1H)，4.04-4.02(m，2H)，3.71(s，3H)，2.64-2.61(m，4H)。
Embodiment 1-12, compound N 1-(3-bromobenzyl)-N 4-(2-hydroxy phenyl)-N 1the preparation of-(2-p-methoxy-phenyl)-succinic diamide (SA012)
O-Phenylene Diamine is replaced as to Ortho-Aminophenol, by the corresponding preparation of the method for preparing compound S A011 SA012. 1H?NMR(CDCl 3，400MHz)：δ9.25(br?s，2H)，7.37(s，1H)，7.36-7.34(m，1H)，7.26-7.25(m，1H)，7.14-7.08(m，3H)，6.99(dd，J＝8.4，8.4Hz，2H)，6.94-6.91(m，3H)，6.86(dd，J＝8.4，8.4Hz，1H)，5.05(d，J＝12.0Hz，1H)，4.50(d，J＝12.0Hz，1H)，3.68(s，3H)，2.72-2.69(t，J＝8.4Hz，2H)，2.56-2.54(m，2H)。
Embodiment 1-13, compound 2-(4-((N 1-(2-aminophenyl)-N 4-(2-p-methoxy-phenyl) succinic diamide)-methyl) phenyl) preparation of methyl propionate (SA013)
3-bromobenzaldehyde is replaced as to 2-(4-aldehyde radical phenyl) propionic acid methyl ester, by the corresponding preparation of the method for preparing compound S A011 SA013. 1H?NMR(CDCl 3，400MHz)：δ.8.05(br?s，1H)，7.18-7.14(m，4H)，7.04-7.01(m，2H)，6.94-6.91(m，2H)，6.90-6.88(m，2H)，6.78-6.75(m，2H)，5.09(d，J＝14.0Hz，1H)，4.41(d，J＝14.0Hz，1H)，3.96-3.94(m，2H)，6.69(q，J＝7.2Hz，1H)，3.66(s，3H)，3.65(s，3H)，2.61-2.59(m，2H)，2.55-2.53(m，1H)，2.41-2.39(m，1H)，1.47(d，J＝7.2Hz，3H)。
Embodiment 1-14, compound N 1-(3-bromobenzyl)-N 8-(2-hydroxy phenyl)-N 1the preparation of-(2-p-methoxy-phenyl)-pimeloyl amine (SA014)
Succinic anhydried is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A011 SA014. 1H?NMR(CDCl 3，400MHz)：δ9.48(br?s，1H)，8.64(br?s，1H)，7.37-7.31(m，3H)，7.21(dd，J＝8.0，8.0Hz，1H)，7.10-7.05(m，3H)，7.00(dd，J＝8.0，8.0Hz，1H)，6.92(d，J＝8.0Hz，1H)，6.88-6.86(m，2H)，6.82(dd，J＝8.0，8.0Hz，1H)，5.09(d，J＝16.4Hz，1H)，4.42(d，J＝16.4Hz，1H)，3.74(s，3H)，2.39(t，J＝7.6Hz，2H)，1.66(t，J＝7.6Hz，2H)，1.55(t，J＝8.4Hz，2H)，1.29-1.22(m，6H)。
Embodiment 1-15, compound 2-(4-((N 1-(2-hydroxy phenyl)-N 4-(2-p-methoxy-phenyl) succinic diamide)-methyl) phenyl) preparation of methyl propionate (SA015)
O-Phenylene Diamine is replaced as to o-aminophenol, by the corresponding preparation of the method for preparing compound S A013 SA015. 1H?NMR(CDCl 3，400MHz)：δ9.36(br?s，1H)，9.34(br?s，1H)，7.31(dd，J＝8.4，8.4Hz，1H)，7.17(d，J＝8.0Hz，2H)，7.14-7.11(m，3H)，7.06(dd，J＝8.0，8.0Hz，1H)，6.98(d，J＝8.0Hz，1H)，6.94-6.86(m，3H)，6.80(dd，J＝8.0，8.0Hz，1H)，5.12(d，J＝14.4Hz，1H)，4.45(d，J＝14.4Hz，1H)，3.72(t，J＝7.6Hz，1H)，3.65(s，3H)，3.63(s，3H)，2.74-2.71(m，2H)，2.56-2.51(m，1H)，2.43-2.39(m，1H)，1.45(d，J＝7.6Hz，3H)。
Embodiment 1-16, compound N 1-(3-bromobenzyl)-N 4-phenylhydrazino-N 1the preparation of-(2-p-methoxy-phenyl) succinic diamide (SA016)
O-Phenylene Diamine is replaced as to phenylhydrazine, by the corresponding preparation of the method for preparing compound S A011 SA016. 1H?NMR(CDCl 3，400MHz)：δ8.19(s，1H)，7.37-7.35(m，2H)，7.33-7.30(m，1H)，7.29(s，1H)，7.25(dd，J＝8.0，8.0Hz，2H)，7.11(dd，J＝8.0，8.0Hz，2H)，6.90-6.89(m，4H)，6.86(dd，J＝8.0，8.0Hz，2H)，5.08(d，J＝16.4Hz，1H)，4.49(d，J＝16.4Hz，1H)，3.71(s，3H)，2.59-2.54(m，2H)，2.49-2.47(m，1H)，2.40-2.36(m，1H)。
Embodiment 1-17, compound N 1-(4-(1-(propyl group carbamyl) ethyl) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl) succinic diamide (SA017)
3-bromobenzaldehyde is replaced as to 4-(1-(propyl group carbamyl) ethyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA017. 1H?NMR(400MHz，DMSO)δ10.35(br?s，1H)，9.96(br?s，1H)，8.64(br?s，1H)，7.89-7.87(m，1H)，7.19-7.15(m，2H)，7.12-7.10(m，3H)，6.93(d，J＝8.4Hz，1H)，6.87(d，J＝8.0Hz，1H)，6.72-6.68(m，1H)，5.21(d，J＝14.8Hz，1H)，4.10(d，J＝14.8Hz，1H)，3.54-3.48(m，2H)，2.97-2.92(m，2H)，2.38-2.60(m，1H)，2.23-2.08(m，2H)，1.36-1.31(m，2H)，1.26(d，J＝6.8Hz，3H)，0.75(t，J＝7.2Hz，3H)。
The preparation of embodiment 1-18, compound S-2-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) ethyl thiuretic acid ester (SA018)
Chloroacetyl chloride is replaced as to 3-chlorpromazine chloride, by the corresponding preparation of the method for preparing compound S A007 SA018. 1H?NMR(300MHz，CDCl 3)：δ7.36-7.26(m，3H)，7.11-7.10(m，2H)，6.91(d，J＝8.1Hz，1H)，6.87-6.85(m，2H)，5.06(d，J＝14.7Hz，1H)，4.45(d，J＝14.7Hz，1H)，3.72(s，3H)，3.10(t，J＝6.9Hz，2H)，2.35-2.31(m，2H)，2.30(s，3H)。
The preparation of embodiment 1-19, compound S-5-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) carbamyl) amyl group thiuretic acid ester (SA019)
Chloroacetyl chloride is replaced as to 6-bromine caproyl chloride, by the corresponding preparation of the method for preparing compound S A007 SA019. 1H?NMR(400MHz，CDCl 3)：δ7.36-7.27(m，3H)，7.11-7.10(m，2H)，6.92(d，J＝8.4Hz，1H)，6.88-6.86(m，2H)，5.09(d，J＝14.8Hz，1H)，4.41(d，J＝14.8Hz，1H)，3.73(s，3H)，2.81(t，J＝7.6Hz，2H)，2.30(s，3H)，2.04-1.99(m，2H)，1.60-1.58(m，2H)，1.53-1.45(m，2H)，1.30-1.25(m，2H)。
Embodiment 20, compound N 1-(4-(1-(diallyl formamyl) ethyl) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl)-succinic diamide (SA020)
3-bromobenzaldehyde is replaced as to N, and N-diallyl-2-(4-aldehyde radical phenyl) propionic acid amide, by the corresponding preparation of the method for preparing compound S A001 SA020. 1H?NMR(DMSO，300MHz)：δ10.32(br?s，1H)，9.93(br?s，1H)，8.60(br?s，1H)，7.13-6.91(m，5H)，6.92(d，J＝9.6Hz，1H)，6.82(d，J＝9.6Hz，1H)，6.67(dd，J＝9.0，9.0Hz，1H)，5.64-5.55(m，2H)，5.22(d，J＝15.3Hz，4H)，4.92(d，J＝15.3Hz，1H)，4.11(d，J＝15.6Hz，1H)，3.97(q，J＝6.3Hz，1H)，3.73-3.65(m，4H)，2.31-2.15(m，4H)，1.23(d，J＝6.0Hz，3H)。
Embodiment 1-21, compound N 1-(4-diethylamino formyl radical) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl)-succinic diamide (SA021)
3-bromobenzaldehyde is replaced as to (4-diethylamino formyl radical) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA021. 1H?NMR(DMSO，300MHz)：δ10.33(br?s，1H)，9.94(br?s，1H)，8.61(br?s，1H)，7.25-7.18(m，4H)，7.12(dd，J＝9.0，9.0Hz，1H)，6.93-6.89(m，2H)，6.70(dd，J＝9.0，9.0Hz，1H)，5.20(d，J＝14.7Hz，1H)，4.24(d，J＝14.7Hz，1H)，3.40-3.34(m，2H)，3.14-3.09(m，2H)，2.32-2.17(m，4H)，1.06-1.04(m，3H)，1.03-1.01(m，3H)。
Embodiment 1-22, compound N 1-(4-(1-(diisopropylaminoethyl formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl)-succinic diamide (SA022)
3-bromobenzaldehyde is replaced as to 4-(1-(diisopropylaminoethyl formyl radical) ethyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA022. 1H?NMR(300MHz，DMSO)δ10.34(br?s，1H)，9.93(br?s，1H)，8.62(br?s，1H)，7.17-7.15(m，2H)，7.13-7.11(m，3H)，6.94(d，J＝7.2Hz，1H)，6.83(d，J＝7.2Hz，1H)，6.68(dd，J＝7.2，7.2Hz，1H)，5.25(d，J＝15.3Hz，1H)，4.09(d，J＝15.3Hz，1H)，3.94(q，J＝6.6Hz，1H)，3.28-2.99(m，4H)，2.36-2.08(m，4H)，1.48-1.34(m，4H)，1.24(d，J＝6.6Hz，3H)，0.77-0.69(m，6H)。
Embodiment 1-23, N 1-(4-diallyl formamyl) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl)-succinic diamide (SA023)
3-bromobenzaldehyde is replaced as to (4-diallyl formamyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA023. 1H?NMR(300MHz，DMSO)δ10.33(br?s，1H)，9.94(br?s，1H)，8.61(br?s，1H)，7.28-7.24(m，2H)，7.21-7.16(m，2H)，7.12(dd，J＝7.5，7.5Hz，1H)，6.93-6.89(m，2H)，6.70(dd，J＝7.5，7.5Hz，1H)，5.82-5.78(m，2H)，5.23-5.14(m，4H)，5.10(d，J＝15.3Hz，1H)，4.24(d，J＝15.3Hz，1H)，3.40-3.34(m，2H)，3.14-3.09(m，2H)，2.32-2.26(m，2H)，2.20-2.15(m，2H)。
Embodiment 1-24, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 8-hydroxy-n 1the preparation of-(2-hydroxy phenyl) suberamide (SA024)
Succinic anhydried is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A009 SA024. 1H?NMR(300MHz，DMSO)δ7.28-7.26(m，2H)，7.11-7.07(m，2H)，7.05-7.03(m，2H)，6.58-6.55(m，2H)，5.44-5.42(m，1H)，4.10-4.08(m，1H)，3.78(q，J＝6.3Hz，1H)，3.27-3.14(m，4H)，2.13-2.08(m，4H)，2.07-2.02(m，4H)，2.00-1.94(m，4H)，1.26(d，J＝6.3Hz，3H)，1.06(t，J＝4.8Hz，3H)，0.92(t，J＝4.8Hz，3H)。
Embodiment 1-25, N 1-(3-bromobenzyl)-N 4-hydroxy-n 1the preparation of-(2,4-Dimethoxyphenyl) succinic diamide (SA025)
O-aminophenol is replaced as to 2,4-dimethoxyaniline, by the corresponding preparation of the method for preparing compound S A001 SA025. 1HNMR(300MHz，DMSO)δ10.27(br?s，1H)，8.49(br?s，1H)，7.27-7.24(m，2H)，7.10-7.01(m，2H)，6.78(d，J＝8.4Hz，1H)，6.50(s，1H)，6.33(d，J＝8.4Hz，1H)，4.83(d，J＝15.0Hz，1H)，4.18(d，J＝15.0Hz，1H)，3.61(s，3H)，3.59(s，3H)，2.18-2.11(m，2H)，2.01-1.90(m，2H)。
Embodiment 1-26, N 1-(3-bromobenzyl)-N 7-hydroxy-n 1the preparation of-(2,4-dimethoxy) pimeloyl amine (SA026)
Succinic anhydried is replaced as to pimelic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A025 SA026. 1H?NMR(300MHz，DMSO)δ9.45(br?s，1H)，7.36-7.34(m，1H)，7.27(s，1H)，7.12-7.10(m，2H)，6.34(d，J＝8.7Hz，1H)，6.47(s，1H)，6.38(d，J＝8.7Hz，1H)，5.05(d，J＝14.4Hz，1H)，4.38(d，J＝14.4Hz，1H)，3.81(s，3H)，3.71(s，3H)，2.19(br?s，2H)，2.03(br?s，2H)，1.60-1.57(m，4H)，1.27(br?s，2H)。
Embodiment 1-27, N 1-(4-(1-oxygen-1-(1-Pyrrolidine base) 2-propyl group) benzyl)-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl) succinic diamide (SA027)
3-bromobenzaldehyde is replaced as to 4-(1-oxygen-1-(1-Pyrrolidine base) 2-propyl group) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA027. 1H?NMR(300MHz，DMSO)δ10.34(br?s，1H)，9.94(br?s，1H)，8.63(br?s，1H)，7.14-7.11(m，5H)，6.94(d，J＝7.8Hz，1H)，6.90-6.87(m，1H)，6.71(dd，J＝7.8，7.8Hz，1H)，5.20(d，J＝15.3Hz，1H)，4.15(d，J＝15.3Hz，1H)，3.81(q，J＝6.6Hz，1H)，3.57-3.44(m，2H)，3.27-3.16(m，1H)，3.07-2.93(m，1H)，2.38-2.07(m，4H)，1.85-1.62(m，4H)，1.23(d，J＝6.6Hz，3H)。
Embodiment 1-28, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1the preparation of-(2,4-Dimethoxyphenyl) succinic diamide (SA028)
O-aminophenol is replaced as to 2,4-dimethoxyaniline, by the corresponding preparation of the method for preparing compound S A009 SA028. 1HNMR(300MHz，CDCl 3)δ7.16-7.07(m，4H)，6.74-6.71(m，1H)，6.43(s，1H)，6.34-6.31(m，1H)，5.12-5.05(m，1H)，4.35-4.27(m，1H)，3.83-3.82(m，1H)，3.78(s，3H)，3.66(s，3H)，3.54-3.43(m，1H)，3.32-3.18(m，2H)，3.13-3.03(m，1H)，2.48-2.22(m，4H)，1.39(d，J＝6.6Hz，3H)，1.07(t，J＝6.9Hz，3H)，0.96(t，J＝6.9Hz，3H)。
Embodiment 1-29, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1the preparation of-(2-hydroxy phenyl) pimeloyl amine (SA029)
Succinic anhydried is replaced as to pimelic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A009 SA029. 1H?NMR(300MHz，DMSO)δ10.22(br?s，1H)，9.89(br?s，1H)，9.85(br?s，1H)，7.09-7.06(m，2H)，7.05-7.02(m，3H)，6.85(d，J＝8.1Hz，1H)，6.70(d，J＝7.8Hz，1H)，6.59(dd，J＝7.8，7.8Hz，1H)，5.18(d，J＝14.4Hz，1H)，3.99(d，J＝14.4Hz，1H)，3.84(q，J＝6.9Hz，1H)，2.45-2.41(m，4H)，2.00-1.95(m，2H)，1.84-1.79(m，2H)，1.39-1.30(m，4H)，1.16(d，J＝6.9Hz，3H)，1.03-0.98(m，2H)，0.86(t，J＝6.9，13.8Hz，3H)，0.76(d，J＝6.9，13.8Hz，3H)。
Embodiment 1-30, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1the preparation of-(2-hydroxy phenyl) pimeloyl amine (SA030)
2,4-dimethoxyaniline is replaced as to ORTHO ANISIDINE, by the corresponding preparation of the method for preparing compound S A028 SA030. 1H?NMR(300MHz，DMSO)δ10.29(br?s，1H)，8.63(br?s，1H)，7.29(dd，J＝7.5，7.5Hz，1H)，7.14-7.12(m，2H)，7.08-7.05(m，3H)，6.94-6.91(m，1H)，6.84(dd，J＝7.5，7.5Hz，1H)，5.05(d，J＝14.4Hz，1H)，4.28(d，J＝14.4Hz，1H)，3.90(q，J＝6.6Hz，1H)，3.70(s，3H)，3.17-3.15(m，4H)，2.02-1.97(m，2H)，1.92-1.86(m，2H)，1.44-1.35(m，4H)，1.12(d，J＝6.6Hz，3H)，1.08-1.02(m，2H)，0.95(t，J＝6.9Hz，3H)，0.84(t，J＝6.9Hz，3H)。
Embodiment 1-31, N 1-(3-bromobenzyl)-N 4-hydroxy-n 1the preparation of-(4-hydroxyl-2-p-methoxy-phenyl) succinic diamide (SA031).
O-aminophenol is replaced as to 4-amino-3-methoxyphenol, by the corresponding preparation of the method for preparing compound S A001 SA031. 1H?NMR(300MHz，DMSO)δ10.34(br?s，1H)，9.74(br?s，1H)，8.62(br?s，1H)，7.39(d，J＝7.8Hz，1H)，7.36(s，1H)，7.24-7.17(m，2H)，6.77(d，J＝8.4Hz，1H)，6.46(s，1H)，6.28(d，J＝8.4Hz，1H)，4.94(d，J＝14.7Hz，1H)，4.30(d，J＝14.7Hz，1H)，3.67(s，3H)，3.17-3.15(m，4H)。
Embodiment 1-32, N 1-(3-bromobenzyl)-N 7-hydroxy-n 1the preparation of-(2-hydroxy phenyl) pimeloyl amine (SA032).
Succinic anhydried is replaced as to pimelic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A001 SA032. 1H?NMR(300MHz，DMSO)δ10.22(br?s，1H)，9.89(br?s，1H)，8.56(br?s，1H)，7.33(s，1H)，7.32-7.31(m，1H)，7.18-7.13(m，2H)，7.09-7.04(m，1H)，6.86(d，J＝7.5Hz，1H)，6.80(d，J＝7.2Hz，1H)，6.66(dd，J＝7.5，7.5Hz，1H)，5.05(d，J＝15.0Hz，1H)，4.21(d，J＝15.0Hz，1H)，2.03-1.95(m，2H)，1.82-1.77(m，2H)，1.37-1.30(m，4H)，1.09-1.04(m，2H)。
Embodiment 1-33, N 1-(3-bromobenzyl)-N 6-hydroxy-n 1the preparation of-(2-p-methoxy-phenyl) adipamide (SA033)
Succinic anhydried is replaced as to adipic anhydride, by the corresponding preparation of the method for preparing compound S A002 SA033. 1H?NMR(300MHz，DMSO)δ7.34-7.27(m，3H)，7.11-7.09(m，2H)，6.94-6.89(m，2H)，6.86-6.84(m，1H)，5.06(d，J＝14.4Hz，1H)，4.44(d，J＝14.4Hz，1H)，3.73(s，3H)，2.21-2.13(m，2H)，2.11-2.04(m，2H)，1.58(br?s，4H)。
Embodiment 1-34, N 1-(3-bromobenzyl)-N 7-hydroxy-n 1the preparation of-(4-sulfoamido phenyl) pimeloyl amine (SA034)
O-aminophenol is replaced as to 4-aminobenzene sulfonamide, by the corresponding preparation of the method for preparing compound S A006 SA034. 1HNMR(300MHz，DMSO)δ10.41(br?s，1H)，8.65(br?s，1H)，7.80(d，J＝8.4Hz，2H)，7.43(s，1H)，7.42-7.39(m，3H)，7.28-7.19(m，2H)，4.90(br?s，2H)，2.14-2.10(m，2H)，1.88(t，J＝7.2Hz，2H)，1.48(t，J＝7.2Hz，2H)，1.39(t，J＝7.2Hz，2H)，1.15-1.13(m，2H)。
Embodiment 1-35,3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl)-N, the preparation of N-diallyl benzamide (SA035)
3-bromobenzaldehyde is replaced as to N, and N-diallyl-3-aldehyde radical benzamide, by the corresponding preparation of the method for preparing compound S A001 SA035. 1H?NMR(300MHz，DMSO)δ10.37(br?s，1H)，9.76(br?s，1H)，8.64(br?s，1H)，7.32-7.28(m，2H)，7.23-7.18(m，2H)，7.12(dd，J＝7.8，7.8Hz，1H)，6.92(d，J＝7.8Hz，1H)，6.83(d，J＝7.5Hz，1H)，6.70(dd，J＝7.5，7.5Hz，1H)，5.76(br?s，2H)，5.21-5.16(m，4H)，5.06(d，J＝13.8Hz，1H)，4.27(d，J＝13.8Hz，1H)，4.10-3.97(m，2H)，3.68-3.65(m，2H)，3.16(br?s，2H)，2.20-2.17(m，2H)。
Embodiment 1-36, N 1-(3-bromobenzyl)-N 6-hydroxy-n 1the preparation of-(2-hydroxy phenyl) adipamide (SA036)
Succinic anhydried is replaced as to adipic anhydride, by the corresponding preparation of the method for preparing compound S A001 SA036. 1h NMR (300MHz, DMSO) δ 10.31 (br s, 1H), 9.98 (br s, 1H), 8.65 (br s, 1H), 7.40 (s, 2H), 7.26-7.20 (m, 2H), 7.17-7.12 (m, 1H), 6.95-6.92 (m, 1H), 6.89-6.86 (m, 1H), 6.76-6.71 (m, 1H), (5.12 d, J=15.0Hz, 1H), (4.29 d, J=15.0Hz, 1H), 2.09-1.93 (m, 2H), 1.87-1.83 (m, 2H), 1.44-1.36 (m, 4H).
Embodiment 1-37, N 1-(3-bromobenzyl)-N 6-hydroxy-n 1the preparation of-(2,4-Dimethoxyphenyl) adipamide (SA037)
O-aminophenol is replaced as to 2,4-dimethoxyaniline, by the corresponding preparation of the method for preparing compound S A036 SA037. 1HNMR(300MHz，DMSO)δ10.31(br?s，1H)，8.65(br?s，1H)，7.42-7.37(m，2H)，7.25-7.20(m，1H)，7.17-7.14(m，1H)，6.88(d，J＝8.7Hz，1H)，6.63(d，J＝2.4Hz，1H)，6.46(dd，J＝2.4，8.4Hz，1H)，4.99(d，J＝15.0Hz，1H)，4.32(d，J＝15.0Hz，1H)，3.75(s，3H)，3.72(s，3H)，2.04-1.95(m，2H)，1.90-1.83(m，2H)，1.39-1.37(m，4H)。
Embodiment 1-38, N 1-(3-bromobenzyl)-N 4-hydroxy-n 1the preparation of-(3-hydroxy phenyl) succinic diamide (SA038)
O-aminophenol is replaced as to meta-aminophenol, by the corresponding preparation of the method for preparing compound S A001 SA038. 1H?NMR(400MHz，DMSO)δ10.35(br?s，1H)，9.71(br?s，1H)，8.64(br?s，1H)，7.42(d，J＝8.0Hz，1H)，7.38(s，1H)，7.25(dd，J＝8.0，8.0Hz，1H)，7.21-7.17(m，2H)，6.73(d，J＝8.4Hz，1H)，6.60(d，J＝8.4Hz，1H)，6.56(s，1H)，4.79-4.77(m，2H)，2.50-2.49(m，2H)，2.31-2.29(m，2H)。
Embodiment 1-39, N 1-(3-bromobenzyl)-N 4-hydroxy-n 1the preparation of-(2-aminomethyl phenyl) succinic diamide (SA039)
O-aminophenol is replaced as to o-toluidine, by the corresponding preparation of the method for preparing compound S A001 SA039. 1h NMR (400MHz, DMSO) δ 10.32 (br s, 1H), 8.61 (s, 1H), 7.43 (d, J=7.5Hz, 1H), 7.37 (s, 1H), 7.34 (d, J=7.5Hz, 1H), 7.26 (dd, J=6.4, 6.0Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.19-7.14 (m, 2H), 6.89 (d, J=7.5Hz, 1H), 5.16 (d, J=14.7Hz, 1H), 4.22 (d, J=14.7Hz, 1H), 2.21-2.12 (m, 3H), 2.11 (s, 3H), 2.05-1.97 (m, 1H).
Embodiment 1-40, N 1-(3-bromobenzyl)-N 4-hydroxy-n 1the preparation of-(4-sulfoamido phenyl) succinic diamide (SA040)
O-aminophenol is replaced as to 4-aminobenzene sulfonamide, by the corresponding preparation of the method for preparing compound S A001 SA040. 1HNMR(300MHz，DMSO)δ7.82(d，J＝8.4Hz，2H)，7.46(s，1H)，7.44-7.40(m，3H)，7.24-7.22(m，2H)，4.90(br?s，2H)，2.32-2.30(m，2H)，2.25-2.21(m，2H)。
Embodiment 1-41, N 1-(4-(1-(diethylin formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1the preparation of-(4-sulfoamido phenyl) succinic diamide (SA041)
2,4-dimethoxyaniline is replaced as to 4-aminobenzene sulfonamide, by the corresponding preparation of the method for preparing compound S A028 SA041. 1H?NMR(300MHz，DMSO)δ9.79(br?s，1H)，8.72(br?s，1H)，7.78(d，J＝8.1Hz，2H)，7.41(d，J＝8.1Hz，2H)，7.17-7.13(m，4H)，4.86(br?s，2H)，3.91(q，J＝6.3Hz，1H)，3.22-3.16(m，4H)，2.31-2.29(m，2H)，2.28-2.20(m，2H)，1.21(d，J＝6.3Hz，3H)，0.93(t，J＝6.9Hz，3H)，0.80(t，J＝6.9Hz，3H)。
Embodiment 1-42,3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl) preparation of-DEET (SA042)
3-bromobenzaldehyde is replaced as to N, and N-diethyl-3-aldehyde radical benzamide, by the corresponding preparation of the method for preparing compound S A001 SA042. 1H?NMR(300MHz，CDCl 3)δ10.06(br?s，1H)，8.96(br?s，1H)，7.22-7.16(m，4H)，7.14-7.09(m，1H)，6.95-6.93(m，1H)，6.80-6.78(m，1H)，6.74-6.69(m，1H)，5.03(d，J＝14.1Hz，1H)，4.52(d，J＝14.1Hz，1H)，3.56-3.45(m，2H)，3.22-3.11(m，2H)，2.51-2.41(m，2H)，2.30-2.26(m，2H)，1.25-1.21(m，3H)，1.04-1.03(m，3H)。
Embodiment 1-43,3-((N 1-hydroxy-n 7-(2-p-methoxy-phenyl) pimeloyl amido) methyl) preparation of-DEET (SA043).
3-bromobenzaldehyde is replaced as to N, and N-diethyl-3-aldehyde radical benzamide, by the corresponding preparation of the method for preparing compound S A006 SA043. 1H?NMR(300MHz，CDCl 3)δ10.33(br?s，1H)，7.43(s，1H)，7.31-7.22(m，3H)，7.09-7.07(m，1H)，6.92-6.89(m，1H)，6.85-6.80(m，1H)，6.76-6.73(m，1H)，5.31(d，J＝14.1Hz，1H)，4.28(d，J＝14.1Hz，1H)，3.72(s，3H)，3.58-3.46(m，2H)，3.28-3.17(m，2H)，2.19-2.13(m，2H)，2.06-1.99(m，2H)，1.74-1.63(m，4H)，1.58-1.53(m，2H)，1.25-1.17(m，3H)，1.14-1.05(m，3H)。
Embodiment 1-44, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1the preparation of-(2-p-methoxy-phenyl) suberamide (SA044)
Pimelic acid acid anhydride is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A030 SA044. 1H?NMR(300MHz，DMSO)δ7.27-7.24(m，1H)，7.12(d，J＝7.8Hz，2H)，7.06(d，J＝8.1Hz，2H)，7.02-6.99(m，1H)，6.82-6.80(m，2H)，5.06(d，J＝14.4Hz，1H)，4.36(d，J＝14.4Hz，1H)，3.93(q，J＝6.9Hz，1H)，3.68(s，3H)，3.25-3.17(m，4H)，2.02-1.97(m，4H)，1.49-1.46(m，4H)，1.29(d，J＝6.9Hz，3H)，1.16-1.14(m，4H)，1.02(t，J＝7.2Hz，3H)，0.89(t，J＝7.2Hz，3H)。
Embodiment 1-45,3-((N 1-hydroxy-n 7-(2-hydroxy phenyl) pimeloyl amido) methyl) preparation of-DEET (SA045)
2-anisidine is replaced as to o-aminophenol, by the corresponding preparation of the method for preparing compound S A043 SA045. 1H?NMR(300MHz，CDCl 3)δ10.34(br?s，1H)，7.23-7.18(m，4H)，7.13-7.05(m，1H)，7.01-6.93(m，1H)，6.69-6.65(m，2H)，5.18(d，J＝14.1Hz，1H)，4.43(d，J＝14.1Hz，1H)，3.55-3.47(m，2H)，3.18-3.12(m，2H)，2.11-1.98(m，5H)，1.64-1.37(m，5H)，1.25-1.17(m，3H)，1.09-1.01(m，3H)。
Embodiment 1-46, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 4-hydroxy-n 1the preparation of-(2-p-methoxy-phenyl) succinic diamide (SA046)
Suberic acid acid anhydride is replaced as to Succinic anhydried, by the corresponding preparation of the method for preparing compound S A044 SA046. 1H?NMR(300MHz，DMSO)δ9.60(br?s，1H)，7.30-7.27(m，1H)，7.15-7.13(m，2H)，7.09-7.07(m，2H)，6.91-6.88(m，1H)，6.84-6.83(m，2H)，5.14-5.05(m，1H)，4.42-4.33(m，1H)，3.80(q，J＝6.9Hz，1H)，3.69(s，3H)，3.53-3.42(m，1H)，3.31-3.17(m，2H)，3.12-3.04(m，1H)，2.44-2.26(m，4H)，1.38(d，J＝6.9Hz，3H)，1.08-1.04(m，3H)，0.99-0.93(m，3H)。
Embodiment 1-47,3-((N 1-hydroxy-n 4-(4-sulfoamido phenyl) succinyl amido) methyl) preparation of-DEET (SA047)
O-aminophenol is replaced as to 4-aminobenzene sulfonamide, by the corresponding preparation of the method for preparing compound S A042 SA047. 1HNMR(300MHz，DMSO)δ10.33(br?s，1H)，8.59(br?s，1H)，7.73-7.71(m，2H)，7.35-7.32(m，4H)，7.27-7.25(m，1H)，7.20-7.18(m，1H)，7.11-7.09(m，1H)，7.03(s，1H)，4.87(br?s，2H)，3.17-3.15(m，4H)，2.28-2.20(m，2H)，2.17-2.12(m，2H)，1.05-0.99(m，3H)，0.92-0.84(m，3H)。
Embodiment 1-48,3-((N 1-hydroxy-n 7-(4-sulfoamido phenyl) pimeloyl amido) methyl) preparation of-DEET (SA048)
Succinic anhydried is replaced as to pimelic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A047 SA048. 1H?NMR(300MHz，DMSO)δ 1H?NMR(DMSO，300MHz)：δ10.25(br?s，1H)，8.59(br?s，1H)，7.73-7.71(m，2H)，7.34-7.32(m，3H)，7.29-7.26(m，2H)，7.19-7.16(m，1H)，7.13-7.10(m，1H)，7.04(s，1H)，4.88(br?s，2H)，3.19-3.14(m，4H)，2.07-2.01(m，2H)，1.84-1.79(m，2H)，1.47-1.27(m，6H)，1.04-0.98(m，3H)，0.93-0.87(m，3H)。
Embodiment 1-49,3-((N 1-hydroxy-n 4-(2-p-methoxy-phenyl) succinyl amido) methyl) preparation of-DEET (SA049)
Pimeloyl amine is replaced as to succinic diamide, by the corresponding preparation of the method for preparing compound S A043 SA049. 1H?NMR(300MHz，CDCl 3)δ9.48(br?s，1H)，7.29-7.28(m，2H)，7.24-7.15(m，3H)，6.93-6.90(m，2H)，6.88-6.83(m，1H)，5.14(d，J＝14.1Hz，1H)，4.43(d，J＝14.1Hz，1H)，3.74(s，3H)，3.58-3.44(m，2H)，3.27-3.14(m，2H)，2.48-2.22(m，4H)，1.25-1.20(m，3H)，1.11-1.02(m，3H)。
Embodiment 1-50, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1the preparation of-(2-hydroxy phenyl) adipamide (SA050)
Pimelic acid amine is replaced as to adipic anhydride, by the corresponding preparation of the method for preparing compound S A029 SA050. 1H?NMR(300MHz，CDCl 3)δ7.13-7.05(m，6H)，6.65-6.64(m，2H)，5.30(d，J＝13.8Hz，1H)，4.24(d，J＝13.8Hz，1H)，3.82-3.75(m，1H)，3.49-3.70(m，1H)，3.31-3.22(m，2H)，3.17-3.08(m，1H)，2.18-1.99(m，5H)，1.70-1.49(m，3H)，1.38(d，J＝6.6Hz，1H)，1.06(t，J＝6.9Hz，3H)，0.95(t，J＝6.9Hz，3H)。
Embodiment 1-51, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1the preparation of-(2,4-Dimethoxyphenyl) adipamide (SA051)
O-aminophenol is replaced as to 2,4-dimethoxyaniline, by the corresponding preparation of the method for preparing compound S A050 SA051. 1HNMR(300MHz，CDCl 3)δ7.14-7.08(m，4H)，6.70-6.67(m，1H)，6.43(s，1H)，6.33-6.30(m，1H)，5.17-5.10(m，1H)，4.31-4.23(m，1H)，3.82-3.84(m，1H)，3.78(s，3H)，3.65(s，3H)，3.54-3.52(m，1H)，3.34-3.18(m，2H)，3.15-3.06(m，1H)，2.25-2.14(m，2H)，2.11-1.95(m，3H)，1.92-1.66(m，3H)，1.39(d，J＝6.6Hz，3H)，1.06(t，J＝7.2Hz，3H)，0.96(t，J＝7.2Hz，3H)。
Embodiment 1-52, N 1-(3-(5-pyrimidyl) benzyl)-N 7-hydroxy-n 1the preparation of-(2-p-methoxy-phenyl) pimeloyl amine (SA052).
3-bromobenzaldehyde is replaced as to 3-(5-pyrimidine pyridine base) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A006 SA052. 1H?NMR(300MHz，DMSO)δ10.32(br?s，1H)，9.17(s，1H)，9.04(s，2H)，8.67(br?s，1H)，7.65(d，J＝7.8Hz，1H)，7.53(s，1H)，7.45(dd，J＝7.8，7.5Hz，1H)，7.35-7.30(m，2H)，7.11(d，J＝7.8Hz，1H)，7.04(d，J＝7.8Hz，1H)，6.89(dd，J＝7.5，7.5Hz，1H)，5.22(d，J＝15.0Hz，1H)，4.38(d，J＝15.0Hz，1H)，3.75(s，3H)，2.06-1.95(m，4H)，1.41-1.35(m，4H)，1.12-1.05(m，2H)。
Embodiment 1-53, N 1-(3-(3-pyridyl) benzyl)-N 8-hydroxy-n 1the preparation of-(2-p-methoxy-phenyl) suberamide (SA053).
3-bromobenzaldehyde is replaced as to 3-(3-pyridyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A005 SA053. 1H?NMR(300MHz，DMSO)δ10.34(br?s，1H)，8.79(br?s，1H)，8.66(s，1H)，8.57-8.55(m，1H)，7.97(d，J＝7.8Hz，1H)，7.56(d，J＝7.8Hz，1H)，7.49-7.46(m，2H)，7.40(dd，J＝7.8，7.5Hz，1H)，7.31(dd，J＝7.5，7.2Hz，1H)，7.23(d，J＝7.5Hz，1H)，7.10(d，J＝7.8Hz，1H)，7.03-7.00(m，1H)，6.89(dd，J＝7.5，7.5Hz，1H)，5.19(d，J＝15.0Hz，1H)，4.39(d，J＝15.0Hz，1H)，3.73(s，3H)，2.05-2.00(m，2H)，1.95-1.89(m，2H)，1.43-1.39(m，4H)，1.13-1.10(m，4H)。
Embodiment 1-54, N 1-(4-((diethylamino formyl radical) methyl) benzyl-N 4-hydroxy-n 1the preparation of-(2-hydroxy phenyl) succinic diamide (SA054)
3-bromobenzaldehyde is replaced as to 4-((diethylamino formyl radical) methyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A001 SA054. 1H?NMR(300MHz，DMSO)δ10.37(br?s，1H)，9.95(br?s，1H)，8.65(br?s，1H)，7.16-7.14(m，2H)，7.13-7.10(m，3H)，6.93(d，J＝8.1Hz，1H)，6.85(d，J＝7.2Hz，1H)，6.69(dd，J＝7.5，7.5Hz，1H)，5.24(d，J＝15.0Hz，1H)，4.12(d，J＝15.0Hz，1H)，3.60(s，2H)，3.32-3.27(m，2H)，3.25-3.20(m，2H)，2.36-2.32(m，2H)，2.19-2.16(m，2H)，0.99(t，J＝6.9Hz，6H)。
Embodiment 1-55, N 1-(3-bromobenzyl)-N 8-hydroxy-n 1the preparation of-(2-(5-oxazolyl) phenyl) suberamide (SA055)
2-anisidine is replaced as to 2-(5-oxazolyl) aniline, by the corresponding preparation of the method for preparing compound S A005 SA055. 1H?NMR(300MHz，DMSO)δ10.30(br?s，1H)，8.66(br?s，1H)，8.52(s，1H)，7.86(d，J＝7.8Hz，1H)，7.49(dd，J＝7.8，7.8Hz，1H)，7.43-7.36(m，3H)，7.24-7.19(m，2H)，7.16-7.14(m，1H)，6.94(d，J＝6.6Hz，1H)，5.40(d，J＝14.7Hz，1H)，3.97(d，J＝14.7Hz，1H)，1.98-1.81(m，4H)，1.40-1.33(m，4H)，1.09-1.03(m，4H)。
Embodiment 1-56, N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1the preparation of-(2,4-Dimethoxyphenyl) suberamide (SA056)
Adipic anhydride is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A051 SA056. 1HNMR(300MHz，DMSO)δ10.31(s，1H)，8.66(s，1H)，7.13(d，J＝8.4Hz，2H)，7.06(d，J＝8.4Hz，2H)，6.81-6.77(m，1H)，6.61-6.59(m，1H)，6.41-6.37(m，1H)，5.03(d，J＝14.7Hz，1H)，4.18(d，J＝14.7Hz，1H)，3.92(q，J＝6.6Hz，1H)，3.73(s，3H)，3.67(s，3H)，3.54-3.52(m，2H)，3.29-3.24(m，2H)，1.90-1.79(m，4H)，1.42-1.35(m，4H)，1.22(d，J＝6.6Hz，3H)，1.10-1.05(m，4H)，0.94(t，J＝7.2Hz，3H)，0.83(t，J＝7.2Hz，3H)。
Embodiment 1-57, N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8the preparation of-((2-quinolyl) methyl) suberamide (SA057)
3-bromobenzaldehyde is replaced as to (2-quinolyl) phenyl aldehyde, by the corresponding preparation of the method for preparing compound S A005 SA057. 1HNMR(300MHz，DMSO)δ10.33(br?s，1H)，8.66(br?s，1H)，8.32(d，J＝8.4Hz，1H)，7.93(d，J＝7.8Hz，1H)，7.87(d，J＝8.4Hz，1H)，7.70(dd，J＝7.2，7.8Hz，1H)，7.57-7.52(m，2H)，7.29(dd，J＝8.1，7.5Hz，1H)，7.19(d，J＝7.5Hz，1H)，7.10(d，J＝8.1Hz，1H)，6.86(dd，J＝7.5，7.5Hz，1H)，5.42(d，J＝15.6Hz，1H)，4.52(d，J＝15.6Hz，1H)，3.77(s，3H)，2.08-2.02(m，2H)，1.86-1.82(m，2H)，1.48-1.41(m，4H)，1.46-1.43(m，4H)。
Embodiment 1-58,3-((N 1-hydroxy-n 6-(2-hydroxy phenyl) hexanedioyl amido) methyl) preparation of-DEET (SA058)
Pimelic acid acid anhydride is replaced as to adipic anhydride, by the corresponding preparation of the method for preparing compound S A045 SA058. 1H?NMR(300MHz，CDCl 3)δ7.27(s，1H)，7.25-7.18(m，3H)，7.08-7.04(m，1H)，6.98-6.91(m，1H)，6.73-6.64(m，2H)，5.23(d，J＝12.4Hz，1H)，4.34(d，J＝12.4Hz，1H)，3.56-3.46(m，2H)，3.22-3.09(m，2H)，2.16-1.95(m，4H)，1.57-1.43(m，4H)，1.24-1.21(m，3H)，1.09-0.96(m，3H)。
Embodiment 1-59,3-((N 1-hydroxy-n 8-(2-hydroxy phenyl) suberoyl amido) methyl) preparation of-DEET (SA059)
Pimelic acid acid anhydride is replaced as to suberic acid acid anhydride, by the corresponding preparation of the method for preparing compound S A045 SA059. 1H?NMR(300MHz，CDCl 3)δ7.27(s，1H)，7.24-7.20(m，3H)，7.07-7.04(m，1H)，7.01-6.84(m，1H)，6.66-6.62(m，2H)，5.30(d，J＝12.4Hz，1H)，4.33(d，J＝12.4Hz，1H)，3.51-3.49(m，2H)，3.16-3.15(m，2H)，2.17-1.94(m，4H)，1.55-1.40(m，4H)，1.26-1.21(m，4H)，1.13(br?s，3H)，1.03(br?s，3H)。
Embodiment 1-60, N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8the preparation of-((2-(5-benzofurane base)) methyl) suberamide (SA060)
3-bromobenzaldehyde is replaced as to 5-benzofurane-2-formaldehyde, by the corresponding preparation of the method for preparing compound S A005 SA060. 1H?NMR(300MHz，DMSO)δ8.96(br?s，1H)，8.63(br?s，1H)，7.55(d，J＝7.8Hz，2H)，7.40-7.33(m，2H)，7.23(dd，J＝7.8，7.5Hz，1H)，7.10(d，J＝7.5Hz，1H)，7.05-7.00(m，2H)，6.91(dd，J＝7.8，7.8Hz，1H)，6.75(d，J＝15.0Hz，1H)，6.23(d，J＝15.0Hz，1H)，5.12(d，J＝15.0Hz，1H)，4.38(d，J＝15.0Hz，1H)，3.72(s，3H)，1.97-1.92(m，2H)，1.87-1.83(m，2H)，1.28-1.22(m，4H)，1.15-1.10(m，4H)。
The preparation of embodiment 1-61,2-((N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) methylamino)-N-hydroxy pyrimidine-5-carboxylic acid amides (SA061)
Get compound 4-chloro-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (1.5g, 6.5mmol) in tetrahydrofuran (THF), under argon atmosphere, add zinc powder (2.11g, 32mmol), stir and add the trimethyl carbinol (0.3ml after 5 hours, 3.2mmol) reaction 5-8 hour, removal of solvent under reduced pressure, then after crossing silicagel column, obtain compound 2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (6.4g, 50%), be dissolved in dry methylene dichloride (10ml), with ice-water bath, reaction system is cooling, add and react to obtain compound 2-first sulfo group pyrimidine-5-carboxylic acid ethyl ester (1.64g with metachloroperbenzoic acid, 22%).
By compound N-(3-bromobenzyl)-2-amino-N-(2-hydroxy phenyl) ethanamide (126mg; 0.36mmol) be dissolved in acetonitrile; add salt of wormwood (149mg; 1.08mmol) stir after 30 minutes and add compound 2-first sulfo group pyrimidine-5-carboxylic acid ethyl ester (82mg; 0.36mmol) reaction 3 hours; treated compound 2-((N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) methylamino-) the pyrimidine-5-carboxylic acid's ethyl ester (100mg, 55.7%) that obtains.
Oxammonium hydrochloride (2.8g in the time of 40 DEG C; in methyl alcohol (10ml) solution 40mmol), add KOH (2.3g; 40mmol) and keep 10min; then after reaction system being cooled to 0 DEG C, filter; again 2-((N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) methylamino-) pyrimidine-5-carboxylic acid's ethyl ester is joined in filtrate; add subsequently KOH (230mg; 4.0mmol), reaction system at room temperature keeps 30min.With EtOAc extraction, after conventional aftertreatment, cross silicagel column, obtain product S A061 (48mg, 49.3%). 1H?NMR(300MHz，DMSO)δ11.03(br?s，1H)，8.98(br?s，1H)，8.61(s，2H)，7.67-7.63(m，1H)，7.43-7.41(m，2H)，7.35(dd，J＝7.8，7.5Hz，1H)，7.26-7.22(m，2H)，7.21(d，J＝7.5Hz，1H)，7.11(d，J＝7.8Hz，1H)，6.96(dd，J＝7.5，7.5Hz，1H)，5.05(d，J＝15.0Hz，1H)，4.40(d，J＝15.0Hz，1H)，3.94-3.86(m，1H)，3.80(s，3H)，3.67-3.59(m，1H)。
The preparation of embodiment 1-62,2-(2-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) ethylamino)-N-hydroxy pyrimidine-5-carboxylic acid amides (SA062)
N-(3-bromobenzyl)-2-amino-N-(2-hydroxy phenyl) ethanamide is replaced as to N-(3-bromobenzyl)-3-amino-N-(2-hydroxy phenyl) propionic acid amide, by the corresponding preparation of the method for preparing compound S A061 SA062. 1H?NMR(300MHz，DMSO)δ10.98(br?s，1H)，8.95(br?s，1H)，8.61(s，2H)，7.61-7.58(m，1H)，7.41-7.38(m，2H)，7.28(dd，J＝7.8，7.5Hz，1H)，7.21-7.15(m，2H)，7.06(d，J＝7.5Hz，1H)，6.97(d，J＝7.8Hz，1H)，6.84(dd，J＝7.5，7.5Hz，1H)，4.98(d，J＝15.0Hz，1H)，4.13(d，J＝15.0Hz，1H)，3.69(s，3H)，3.48(t，J＝6.6Hz，2H)，2.26(t，J＝6.6Hz，2H)。
The preparation of embodiment 1-63,2-(2-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) propyl group amino)-N-hydroxy pyrimidine-5-carboxylic acid amides (SA063).
N-(3-bromobenzyl)-2-amino-N-(2-hydroxy phenyl) ethanamide is replaced as to N-(3-bromobenzyl)-4-amino-N-(2-hydroxy phenyl) butyramide, by the corresponding preparation of the method for preparing compound S A061 SA063. 1H?NMR(300MHz，DMSO)δ10.99(brs，1H)，8.96(br?s，1H)，8.55(s，2H)，7.66-7.62(m，1H)，7.41-7.38(m，2H)，7.28(dd，J＝7.8，7.5Hz，1H)，7.21-7.15(m，2H)，7.05(d，J＝7.5Hz，1H)，6.95(d，J＝7.8Hz，1H)，6.85(dd，J＝7.5，7.5Hz，1H)，4.99(d，J＝15.0Hz，1H)，4.40(d，J＝15.0Hz，1H)，3.69(s，3H)，3.22-3.16(m，2H)，2.08-1.95(m，2H)，1.74-1.70(m，2H)。

Claims (10)

1. nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or a pharmacy acceptable salt, is characterized in that, represented by following structural formula (I):
Wherein,
n＝0-8；
R 1for halogen;
R 2for hydroxyl or amido.
2. nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or a pharmacy acceptable salt, is characterized in that, is selected from:
3-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
3-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
4-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
4-(N-(3-bromobenzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
7-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
6-(N-(3-bromobenzyl)-N-(2-p-methoxy-phenyl) formamyl) hydroximic acid
3-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
3-(N-(4-(1-(diethyl carbamoyl group) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
6-(N-(4-(1-carbaniloyl,phenylcarbamoyl) ethyl) benzyl)-N-(2-hydroxy phenyl) formamyl) hydroximic acid
N 1-(4-(1-(propyl group carbamyl) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
N 1-(4-(1-(diallyl formamyl) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-diethylamino formyl radical) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-(1-(diisopropylaminoethyl formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-diallyl formamyl) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl)-succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 8-hydroxy-n 1-(2-hydroxy phenyl) suberamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(2,4-Dimethoxyphenyl) succinic diamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(2,4-dimethoxy) pimeloyl amine
N 1-(4-(1-oxygen-1-(1-Pyrrolidine base) 2-propyl group) benzyl)-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(2,4-Dimethoxyphenyl) succinic diamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1-(2-hydroxy phenyl) pimeloyl amine
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl)-N 7-hydroxy-n 1-(2-p-methoxy-phenyl) pimeloyl amine
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(4-hydroxyl-2-p-methoxy-phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(2-hydroxy phenyl) pimeloyl amine
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2-p-methoxy-phenyl) adipamide
N 1-(3-bromobenzyl)-N 7-hydroxy-n 1-(4-sulfoamido phenyl) pimeloyl amine
3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl)-N, N-diallyl benzamide
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2-hydroxy phenyl) adipoyl amine
N 1-(3-bromobenzyl)-N 6-hydroxy-n 1-(2,4-Dimethoxyphenyl) adipoyl amine
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(3-hydroxy phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(2-aminomethyl phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 4-hydroxy-n 1-(4-sulfoamido phenyl) succinic diamide
N 1-(3-(1-(diethylin formyl radical) ethyl) benzyl)-N 4-hydroxy-n 1-(4-sulfoamido phenyl) succinic diamide
3-((N 1-hydroxy-n 1-(2-hydroxy phenyl) succinyl amido) methyl)-DEET
3-((N 1-hydroxy-n 7-(2-p-methoxy-phenyl) pimeloyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1-(2-p-methoxy-phenyl) suberamide
3-((N 1-hydroxy-n 7-(2-hydroxy phenyl) pimeloyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 4-hydroxy-n 1-(2-p-methoxy-phenyl) succinic diamide
3-((N 1-hydroxy-n 4-(4-sulfoamido phenyl) succinyl amido) methyl)-DEET
3-((N 1-hydroxy-n 7-(4-sulfoamido phenyl) pimeloyl amido) methyl)-DEET
3-((N 1-hydroxy-n 4-(2-p-methoxy-phenyl) succinyl amido) methyl)-DEET
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1-(2-hydroxy phenyl) adipamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 6-hydroxy-n 1-(2,4-Dimethoxyphenyl) adipamide
N 1-(3-(5-pyrimidyl) benzyl)-N 7-hydroxy-n 1-(2-p-methoxy-phenyl) pimeloyl amine
N 1-(3-(3-pyridyl) benzyl)-N 8-hydroxy-n 1-(2-p-methoxy-phenyl) suberamide
N 1-(4-((diethylamino formyl radical) methyl) benzyl-N 4-hydroxy-n 1-(2-hydroxy phenyl) succinic diamide
N 1-(3-bromobenzyl)-N 8-hydroxy-n 1-(2-(5-oxazolyl) phenyl) suberamide
N 1-(4-(1-(diethylamino formyl radical) ethyl) benzyl-N 8-hydroxy-n 1-(2,4-Dimethoxyphenyl) suberamide
N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8-((2-quinolyl) methyl) suberamide
3-((N 1-hydroxy-n 6-(2-hydroxy phenyl) hexanedioyl amido) methyl)-DEET
3-((N 1-hydroxy-n 8-(2-hydroxy phenyl) suberoyl amido) methyl)-DEET
N 1-hydroxy-n 8-(2-p-methoxy-phenyl)-N 8-((2-(5-benzofurane base)) methyl) suberamide, or its pharmacy acceptable salt.
3. according to the polysubstituted aromatic amides micromolecular organic compound of nitrogen-atoms described in claim 1 or 2 or pharmacy acceptable salt, it is characterized in that the polysubstituted aromatic amine small molecules of described nitrogen-atoms organic compound and the sour acid salt forming; Wherein, described acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartrate, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid or succsinic acid.
4. a pharmaceutical composition, wherein contains nitrogen-atoms polysubstituted aromatic amides micromolecular organic compound or pharmacy acceptable salt described in claim 1 or 2, and pharmaceutically acceptable carrier.
5. a pharmaceutical composition according to claim 4, is characterized in that, described pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup or transdermal patch.
6. the polysubstituted aromatic amides micromolecular organic compound of the nitrogen-atoms described in claim 1 or 2 or the pharmacy acceptable salt application in preparation NSC 630176.
7. the polysubstituted aromatic amides micromolecular organic compound of the nitrogen-atoms described in claim 1 or 2 or the pharmacy acceptable salt application in the medicine of preparing inhibition tumor cell propagation; Wherein, described tumour cell comprises lung carcinoma cell, breast cancer cell, epidermal carcinoma cell, colon cancer cell, liver cancer cell, stomach cancer cell, prostate cancer cell, pancreatic cancer cell, leukemia cell, ovarian cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, cancer cell of oral cavity.
8. the polysubstituted aromatic amides micromolecular organic compound of the nitrogen-atoms described in claim 1 or 2 or the pharmacy acceptable salt application in the medicine of preparing inhibition tumor cell growth, migration and infiltrate; Wherein, described tumour cell is breast cancer cell.
9. the application of the polysubstituted aromatic amides micromolecular of the nitrogen-atoms described in claim 1 or 2 organic compound in the medicine of preparation treatment malignant tumour; Wherein, described malignant tumour is liver cancer, lung cancer, prostate cancer, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, oral carcinoma.
10. the polysubstituted aromatic amides micromolecular organic compound of the nitrogen-atoms described in claim 1 or 2 or the pharmacy acceptable salt application in the medicine of preparation treatment Malignant tumor of bonal metastasis and recurrence; Wherein, described malignant tumour is mammary cancer.
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