CN102327275A - Application of 3-[4-(sulfonyl)benzene] urea compound to preparation of antitumor medicament - Google Patents
Application of 3-[4-(sulfonyl)benzene] urea compound to preparation of antitumor medicament Download PDFInfo
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- CN102327275A CN102327275A CN 201110263951 CN201110263951A CN102327275A CN 102327275 A CN102327275 A CN 102327275A CN 201110263951 CN201110263951 CN 201110263951 CN 201110263951 A CN201110263951 A CN 201110263951A CN 102327275 A CN102327275 A CN 102327275A
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Abstract
The invention discloses the application of 3- [4- (sulphonyl) benzene] carbamide compounds or its pharmaceutical salt in preparation anti-lung cancer, anti-breast cancer medicines, and wherein the chemical structural formula of 3- [4- (sulphonyl) benzene] carbamide compounds is as shown in following general formula:
In formula, X is O or S; R1 is aromatic group or mono-substituted benzaldehyde base containing 1 phenyl ring
Wherein R4 is halogen; R2 and R3 can be respectively selected from: hydrogen, the alkyl of C1~C4, C6~C8 the phenyl containing 1~2 substituent group or
Present invention firstly discovers that 3- [4- (sulphonyl) benzene] carbamide compounds or its pharmaceutical salt have the function of ROCK inhibitor, the proliferation of lung carcinoma cell, breast cancer cell is significantly inhibited, may be used as the drug of preparation anti-lung cancer, anti-breast cancer.
Description
Technical field
The present invention relates to a kind of 3-[4-(sulphonyl) benzene] carbamide compounds and the application in the preparation antitumor drug thereof.
Background technology
Cancer is that malignant tumor is the No.1 killer of present human health.The statistical data of Ministry of Public Health announcement in 2010 shows that malignant tumor has become the Chinese primary cause of the death.Therefore, treatment for cancer is very urgent.Cancer is a process that multistep is rapid, relates generally to the variation of a plurality of genes; When the gene of regulating cell growth is undergone mutation or is damaged; The programmed death of cell is suppressed; Make cell out of hand, growth that continues and division and produce tumor can be quickened the formation of tumor neogenetic blood capillary simultaneously in the infiltration of these cancerous cell and the transfer process.In the most general genovariation, what cause these defectives is the abnormal activation of GTP enzyme Ras family.The proteic sudden change of Ras comes to light and occurs in 30% the human tumor, and the Rho family protein is the member of the super family of Ras of small G-protein, has the GTP enzymatic activity.
Rho kinases (ROCKs) belongs to the serine/threonine protein kitase of AGC family, and it is first found Rho downstream effect factor, through the influence of phosphorylation light chain having been regulated the variation of the inductive myosin cytoskeleton of RhoA.Research shows that the various aspects of Rho family protein and tumor development all are related, and comprises growth of tumor and propagation, invasion and attack and transfer, apoptosis, tumor neovasculature formation etc.What Rho protein continued in human tumor is activated, uncontrolled propagation, invasion and attack body and vicious transformation.Because the effect of Rho/ROCK signal in tumor cell proliferation, differentiation and motion makes that treating some tumor that has Rho signal excessive activation through blocking-up ROCK signal becomes the focus that people pay close attention to.ROCK is divided into two kinds of ROCK I and ROCK II.The overexpression of ROCK is or/and highly activate the generation all can cause disease, and relevant with it disease mainly comprises cardiovascular disease, nervous system disease, fibrotic disease and tumor etc.At anti-tumor aspect, find that all the ROCK inhibitor can suppress invasion by tumor cells and transfer in the research of people on HCC, ovarian cancer cell, HCC, lung cancer cell line, breast carcinoma cell strain, bladder cell strain etc.
Aspect antitumor drug research, external many pharmaceuticals and scientific research institution are developing the new ROCK inhibitor with antitumous effect.At present, though there are some ROCK inhibitor to get into I phase or II phase clinical research stage (like BA-210), the ROCK inhibitor that success is gone on the market only has one, promptly method Soviet Union ground you (Fasudil), and only limit to the Japanese market.Therefore, actively seek and design new ROCK inhibitor, and explore its anticancer effect, have important clinical meaning and wide application prospect.
Summary of the invention
Goal of the invention of the present invention provides the application of a kind of 3-[4-(sulphonyl) benzene] carbamide compounds at preparation ROCK inhibitor.
For reaching the foregoing invention purpose, the technical scheme that the present invention adopts is: 3-[4-(sulphonyl) benzene] carbamide compounds, and its chemical structural formula is shown in following general formula:
In the formula, X is O or S;
R
1Be aromatic group or the mono-substituted benzaldehyde base that contains 1 phenyl ring
R wherein
4Be halogen;
R
2And R
3Can be selected from respectively: the alkyl of hydrogen, C1~C4, C6~C8 contain 1~2 substituent phenyl or
In the optimized technical scheme, work as R
1When containing the aromatic group of 1 phenyl ring, R
1Be preferably the aromatic group that contains 1~2 substituent C6~C8 on the phenyl ring, the said substituent group on the phenyl ring can be selected from respectively: hydrogen, halogen, hydroxyl, amino, methyl, trifluoromethyl,
In the optimized technical scheme, R
2And R
3Be selected from respectively: the alkyl of hydrogen, C1~C2, C6~C8's contains 1~2 substituent phenyl, and said substituent group is halogen or methyl.
In the preferred technical scheme, R
1For containing the phenyl of 2 halogenic substituents, R
2Be hydrogen, R
3Alkyl for C1~C4.
Again in another optimized technical scheme; Said 3-[4-(sulphonyl) benzene] carbamide compounds is selected from: 1-(3-chlorine 4-fluorophenyl)-3-[4-(N-sulfonyloxy methyl amido) phenyl] urea, 1-(2-bromo-4 chloro-phenyl)-3-[4-[(4-aminomethyl phenyl) sulfonamides] phenyl] thiourea, 1-(2-trifluoromethyl)-3-[4-[(4-aminomethyl phenyl) sulfonamides] phenyl] thiourea, 1-(2; The 3-Dichlorobenzene base)-3-[4-(N-ethyl sulfonamide base) phenyl] urea, 1-(2; The 4-difluorophenyl)-3-[4-(N-benzoyl sulfoamido) phenyl] urea, [[N-(3 for 4-for 1-(4-acetylphenyl)-3-; 5-Dichlorobenzene base sulfoamido)] phenyl] urea, 1-(2-aminomethyl phenyl)-3-[2-methyl 5-(sulfoamido) phenyl] urea, 1-(4-chloro phenyl)-3-[4-(N-tert-butyl group sulfoamido) phenyl] urea, 1-(3-chlorphenyl)-3-[4-(N; N-dimethyl methyl amide groups) phenyl] urea, 1-(2-chloro-benzoyl)-3-[4-[(N, N-aminomethyl phenyl) sulfoamido] phenyl] thiourea; Its chemical structural formula is followed successively by:
Above-mentioned 3-[4-(sulphonyl) benzene] urea groups analog derivative is commodity.
The present invention has further carried out Determination of biological activity to above-mentioned 3-[4-(sulphonyl) benzene] urea groups analog derivative, finds that they all have obvious inhibiting activity to ROCK1, for breast carcinoma and lung carcinoma cell fragmentation effect is in various degree arranged all at cellular level.
Therefore; The present invention requires to protect above-mentioned 3-[4-(sulphonyl) benzene] carbamide compounds or its pharmaceutically useful salt in the application for preparing the ROCK inhibitor simultaneously, and said pharmaceutically useful salt comprises hydrochlorate, phosphate, sulfate, acetate, maleate, citrate, benzene sulfonate, toluenesulfonate, fumarate, tartrate.
The present invention requires to protect above-mentioned 3-[4-(sulphonyl) benzene] carbamide compounds or the application of its pharmaceutically useful salt in the anti-pulmonary carcinoma of preparation, breast cancer medicines simultaneously.
Because the technique scheme utilization, the present invention compared with prior art has advantage:
1. the present invention has found that first 3-[4-(sulphonyl) benzene] carbamide compounds or its pharmaceutically useful salt possess the function of ROCK inhibitor; Propagation to lung carcinoma cell, breast cancer cell has the obvious suppression effect, can be as the medicine of the anti-pulmonary carcinoma of preparation, anti-breast cancer.
Description of drawings
Inhibitor is to the inhibition curve of ROCK1 among Fig. 1 embodiment one;
Inhibitor is to the fragmentation effect of HeLa cell among Fig. 2 embodiment one;
Inhibitor is to the fragmentation effect of H460 lung carcinoma cell among Fig. 3 embodiment one;
Inhibitor is to the fragmentation effect of MDA-231 breast cancer cell among Fig. 4 embodiment one.
The specific embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Embodiment one: analyze the enzyme inhibition activity experiment of the ROCK1 of 1-(3-chlorine 4-fluorophenyl)-3-[4-(N-sulfonyloxy methyl amido) phenyl] urea
.The enzyme inhibition activity experiment of ROCK1
Experimental principle: compound R OCK1 suppresses active measurement and has adopted the Z ' of Invitrogen company-LYT technology; This technology is basis with phosphorylation and non-phosphorylating polypeptide to the sensitivity differences that Proteolytic enzyme cuts based on FRET (FRET) principle.
Experimental technique:
(1) preparation of reagent.Kinase buffer liquid: the 5X kinase buffer liquid of 2ml is diluted with water to 10ml; Chemical compound: with the chemical compound that will test be diluted with water to a Concentraton gradient; The mixed solution of ROCK kinases/substrate: the mixed solution of preparing the ROCK/ substrate of 2250 μ L; The concentration of enzyme is 10ng/ml, and the concentration of substrate is 4 μ M, and solvent is a kinase buffer liquid; Phosphorylation polypeptide solution: serine/threonine phosphorylation 7 peptides of 2 μ L are added in the kinase buffer liquid of 498 μ L, fully mixing; ATP solution: the ATP solution of preparing 1110 μ L.Concentration is 50 μ M, and solvent is a kinase buffer liquid; Developer: by 1: 32768 dilution proportion developer A.
(2) experimental procedure: 1. the compound solution that 2.5 μ L is prepared is added to black 384 orifice plates; 2. the mixed solution that adds ROCK kinases/substrate of 5 μ L; 3. the ATP solution that adds 2.5 μ L; 4. 384 orifice plates are at room temperature shaken and cultivated 1 hour; 5. add 5 μ L developers in orifice plate, continue reaction 1 hour; 6. orifice plate is placed the ELIASA reading.
Experimental result: the 1-of variable concentrations (3-chlorine 4-fluorophenyl)-3-[4-(N-sulfonyloxy methyl amido) phenyl] urea carries out the enzyme inhibition activity experiment of ROCK 1, finds that this chemical compound has good ROCK1 to suppress active, its 503nhibiting concentration IC
50Be 8.4 μ M/L (like Fig. 1).
(3) cellular sensitivity experiment
Experimental principle: the MTT analytic process is the basis with living cells metabolite Reducing agent MTT tetrazolium bromide, utilizes ELIASA to measure the optical density OD value at 490nm place, and reflecting the living cells number, thereby the mensuration chemical compound is to the fragmentation effect of tumor cell.
Experimental procedure: 1. collect the logarithmic (log) phase cell, the adjustment concentration of cell suspension, every hole adds 100 μ L, bed board make cell density to be measured be 1000-10000/hole (edge hole is filled with aseptic PB S); 2. 96 orifice plates are placed on 5%CO2, hatch in 37 ℃ of incubators, be paved with the hole to cell monolayer at the bottom of, add the medicine of Concentraton gradient.In principle, get final product dosing behind the cell attachment, or two hours, or time half a day, but we are everlasting evening before that day bed board, dosing in morning next day.General 5-7 gradient, every hole 5 μ L establish 3-5 parallel hole; 3.5%CO2 was hatched 16-48 hour for 37 ℃, and inverted microscope is observed down; 4. every hole adds the MTT solution (5mg/ml, i.e. 0.5%MTT) of 20 μ L, continues to cultivate 4h.If medicine and MTT can react, discard culture fluid after can be earlier centrifugal, carefully use PB S after 2-3 time, adding contains the culture fluid of MTT again; 5. stop cultivating, the careful suction removed culture fluid in the hole; 6. every hole adds 150 μ L dimethyl sulfoxide, puts low-speed oscillation 10min on the shaking table, and crystal is fully dissolved.Measure the light absorption value in each hole at enzyme-linked immunosorbent assay instrument OD=490nm place.And ROCK1 crosses high expressed in multiple cancerous cell; So the anticancer cytoactive that we attempt this chemical compound with multiple cancerous cell, the cancerous cell of use have H460, HepG-2, A549,7721, K562, KB, MCF-7, MDA-231, Lp 1 and OPM-2.Confirm the toxicity size of this kind chemical compound through the HeLa cell experiment.
Experimental result: the HeLa cytotoxicity of this inhibitor lower (Fig. 2).In addition, chemical compound shows the obvious suppression effect to the propagation of lung carcinoma cell H460 and breast cancer cell MDA-231, under lower concentration, can kill the cancerous cell (Fig. 3 and 4) of half.
Claims (5)
- The application in the anti-pulmonary carcinoma of preparation, anti-breast cancer medicines of [1.3-4-(sulphonyl) benzene] carbamide compounds or its pharmaceutically useful salt, wherein the chemical structural formula of 3-[4-(sulphonyl) benzene] carbamide compounds is shown in following general formula:In the formula, X is O or S;R 1Be aromatic group or the mono-substituted benzaldehyde base that contains 1 phenyl ring R wherein 4Be halogen;
- 2. according to the said 3-of claim 1 [4-(sulphonyl) benzene] carbamide compounds or the application of its pharmaceutically useful salt in the anti-pulmonary carcinoma of preparation, anti-breast cancer medicines, it is characterized in that R 1For containing the aromatic group of 1~2 substituent C6~C8 on the phenyl ring, the said substituent group on the phenyl ring is selected from respectively: hydrogen, halogen, hydroxyl, amino, methyl, trifluoromethyl,
- 3. according to the said 3-of claim 2 [4-(sulphonyl) benzene] carbamide compounds or the application of its pharmaceutically useful salt in the anti-pulmonary carcinoma of preparation, anti-breast cancer medicines, it is characterized in that R 1For containing the phenyl of 2 halogenic substituents, R 2Be hydrogen, R 3Alkyl for C1~C4.
- 4. according to the said 3-of claim 1 [4-(sulphonyl) benzene] carbamide compounds or the application of its pharmaceutically useful salt in the anti-pulmonary carcinoma of preparation, anti-breast cancer medicines, it is characterized in that R 2And R 3Be selected from respectively: the alkyl of hydrogen, C1~C2, C6~C8's contains 1~2 substituent phenyl, and said substituent group is halogen or methyl.
- 5. according to the said 3-of claim 1 [4-(sulphonyl) benzene] carbamide compounds or the application of its pharmaceutically useful salt in the anti-pulmonary carcinoma of preparation, anti-breast cancer medicines; It is characterized in that; Said 3-[4-(sulphonyl) benzene] carbamide compounds is selected from: 1-(3-chlorine 4-fluorophenyl)-3-[4-(N-sulfonyloxy methyl amido) phenyl] urea, 1-(2-bromo-4 chloro-phenyl)-3-[4-[(4-aminomethyl phenyl) sulfonamides] phenyl] thiourea, 1-(2-trifluoromethyl)-3-[4-[(4-aminomethyl phenyl) sulfonamides] phenyl] thiourea, 1-(2; The 3-Dichlorobenzene base)-3-[4-(N-ethyl sulfonamide base) phenyl] urea, 1-(2; The 4-difluorophenyl)-3-[4-(N-benzoyl sulfoamido) phenyl] urea, [[N-(3 for 4-for 1-(4-acetylphenyl)-3-; 5-Dichlorobenzene base sulfoamido)] phenyl] urea, 1-(2-aminomethyl phenyl)-3-[2-methyl 5-(sulfoamido) phenyl] urea, 1-(4-chloro phenyl)-3-[4-(N-tert-butyl group sulfoamido) phenyl] urea, 1-(3-chlorphenyl)-3-[4-(N; N-dimethyl methyl amide groups) phenyl] urea, 1-(2-chloro-benzoyl)-3-[4-[(N, N-aminomethyl phenyl) sulfoamido] phenyl] thiourea.
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CN102702057A (en) * | 2012-06-15 | 2012-10-03 | 华东理工大学 | Sulfonamide compound and uses thereof |
CN106817899A (en) * | 2014-07-15 | 2017-06-09 | 百时美施贵宝公司 | As the volution heptane of ROCK inhibitor |
CN108794408A (en) * | 2018-07-23 | 2018-11-13 | 中国医科大学 | Pyrimidine phenylurea anti-tumor compounds and its preparation method and application |
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WO2010123591A2 (en) * | 2009-01-09 | 2010-10-28 | The Uab Research Foundation | Small molecule inhibitors of nads, namnat, and nmnat |
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《J. Med. Chem.》 20110401 Fabio Pacchiano等 Ureido-Substituted Benzenesulfonamides Potently Inhibit Carbonic Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer Metastasis 1896-1902 1,2,4 第54卷, * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102702057A (en) * | 2012-06-15 | 2012-10-03 | 华东理工大学 | Sulfonamide compound and uses thereof |
CN106817899A (en) * | 2014-07-15 | 2017-06-09 | 百时美施贵宝公司 | As the volution heptane of ROCK inhibitor |
CN106817899B (en) * | 2014-07-15 | 2021-03-09 | 百时美施贵宝公司 | Spiroheptane as ROCK inhibitor |
CN108794408A (en) * | 2018-07-23 | 2018-11-13 | 中国医科大学 | Pyrimidine phenylurea anti-tumor compounds and its preparation method and application |
CN108794408B (en) * | 2018-07-23 | 2020-04-21 | 中国医科大学 | Pyrimidine phenylurea anti-tumor compound and preparation method and application thereof |
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