CN101116664B - Application of compound 1-( 4-chloroaniline )-4-( 4-picoline )-2, 3-naphthyridine - Google Patents
Application of compound 1-( 4-chloroaniline )-4-( 4-picoline )-2, 3-naphthyridine Download PDFInfo
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- CN101116664B CN101116664B CN200710017109A CN200710017109A CN101116664B CN 101116664 B CN101116664 B CN 101116664B CN 200710017109 A CN200710017109 A CN 200710017109A CN 200710017109 A CN200710017109 A CN 200710017109A CN 101116664 B CN101116664 B CN 101116664B
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Abstract
The present invention relates to the purposes for the drug that the compound 1- of following formula (4- chloroanilino) -4- (4- picolyl) -2,3- benzodiazine occurs in preparation prevention tumor disease:
. Described drug is containing 1- (4- chloroanilino) -4- (4- picolyl) -2,3- benzodiazine, the pharmaceutical preparation for applying through administration mode except intestines and stomach or intestines and stomach. The appearance and formation of the compound on tumor have the function of at least being delayed by or avoiding, and have higher survival rate compared with the patient not prevented using the tumor patient prevented containing the compound medicine.
Description
Technical field
The present invention relates to the application of a kind of chemical compound 1-(4-chloroanilino)-4-(4-picolyl)-2.
Technical background
Blood vessel relates to by endotheliocyte precursor or angioblast and forms blood vessel again.First blood vessel structure among the embryo takes place to form by blood vessel.Angiogenesis relates to from existing blood vessel development blood capillary, and is that for example brain and kidney form the main mechanism of blood vessel to organ.Though blood vessel is confined to fetal development, angiogenesis can take place in the adult, for example takes place during gestation, women's cycle or wound healing.
In fetal development and some angiogenesis-dependent disease, angiogenesis and the main modified of blood vessel generation are VEGF (VEGF).The mitogen isotype that on behalf of gang, VEGF produced by alternative RNA splicing and exist with the homodimer form.VEGF can high-affinity ground in conjunction with tyrosine kinase receptor.After VEGF combined with tyrosine kinase and forms ligand-receptor, it was in the propagation of vascular endothelial cell, and played an important role in the formation of blood vessel and the growth (being called blood vessel respectively takes place and angiogenesis).
In vivo, VEGF plays pivotal role in blood vessel takes place, and induction of vascular generates and the blood vessel infiltration.It is the multiple disease that abnormal vascular generates and/or high infiltration constitutes that vegf expression out of control causes feature.Therefore, the signal transduction cascade of control VEGF mediation will provide the control abnormity blood vessel of usefulness and/or the method for high process of osmosis.
Angiogenesis is considered to the absolute essential condition above the tumor growth of 1～2mm, and the continued growth of each tumor all will rely on blood vessel oxygen and nutrient substance are provided.The feature of angiogenesis is that the activity of VEGF (VEGF) is strong excessively.VRGF strides the conduction of film tyrosine kinase receptor enabling signal in conjunction with high-affinity, thereby starts the regulation and control link that new vessels generates.Shown the blood vessel formation against function sensitivity of tumor growth to the vegf receptor antagonist.So it is the basis of tumor growth that neovascularity generates, the ability that suppresses the neovascularity generation has the effect that prophylaxis of tumours takes place.
Therefore, solid tumor can effectively prevent by tyrosine kinase inhibitor, because the generation of these tumors all depends on angiogenesis, supports its necessary blood vessel of growing to form.These solid tumors comprise the cancer of sense of organization lymphoma, brain, genitourinary tract, lymphsystem, stomach, larynx and pulmonary, comprise adenocarcinoma of lung and small cell lung cancer.Other the example section of comprising observes the overexpression or the activated cancer of the activated oncogene of Raf-(as K-ras, erb-B).Such cancer comprises cancer of pancreas and breast carcinoma.
Yet, regrettably, in case in fact tumor occurs, vasoinhibitor can suppress new vascularization, but but tumor vessel that has formed and the tumor tissues of having grown up can not be killed, therefore take to use in advance angiogenesis inhibitor, the prophylaxis of tumours disease has more realistic meaning.
Summary of the invention
Technical assignment of the present invention provides the new medical usage of chemical compound 1-(4-chloroanilino)-4-(4-picolyl)-2.
Summary of the invention
The present invention is based on and is surprisingly found out that 1-(4-chloroanilino)-4-(4-picolyl)-2, the 3-benzodiazine has the effect of remarkable inhibition VEGF, this discovery mean this chemical compound can valuablely be used to prevent with angiogenesis/or vascular permeability increase relevant disease, special aspect the generation that prevents tumor.So, the chemical compound 1-that the present invention relates to (4-chloroanilino)-4-(4-picolyl)-2, the true value of 3-benzodiazine is the generation aspect of prophylaxis of tumours, because still do not have really and can effectively block under the prerequisite of tumor cell proliferation, utilize effective mechanism to prevent that from the source generation of tumor and formation from being unique approach that can improve patient's life quality and reduce high medical expense at present clinical.
Detailed Description Of The Invention
Technical scheme of the present invention is as follows:
The chemical compound 1-of following formula (4-chloroanilino)-4-(4-picolyl)-2 is in the purposes of the medicine of preparation prophylaxis of tumours disease generation.
Term among the present invention " prevention " means the appearance of tumor and forms and is delayed at least or avoids, and adopts to contain tumor patient that the above-claimed cpd medicine prevents and compare with the patient who prevents and have higher survival rate.
Term among the present invention " tumor disease " means tumor proliferative disorders, for example solid tumor disease.Term used herein " solid tumor disease " especially refers to breast carcinoma, ovarian cancer, cervical cancer, colon cancer and common gastrointestinal cancer, pulmonary carcinoma, renal carcinoma, bladder cancer, carcinoma of prostate, skin carcinoma, head and neck cancer or cerebroma.
Among the present invention, term " medicine " refers to contain 1-(4-chloroanilino)-4-(4-picolyl)-2 of mass percent 10%-100%, preferred 20%-60% (wt), the 3-benzodiazine, be used for the pharmaceutical preparation that administering mode is used outside intestines and stomach or intestines and stomach, this pharmaceutical preparation is the pharmaceutical preparation of unit form, except that containing this chemical compound, can comprise carrier, diluent and/or other auxiliary agent commonly used in the pharmacy.Be to be understood that: the unit content of the component that comprises in each dosage of each dosage form itself does not constitute effective dose, because essential effective dose can reach by using a plurality of dosage units.
1-(4-chloroanilino)-4-(4-picolyl)-2; the 3-benzodiazine is as the purposes of preparation medical substance; reach the more acceptant form of Human Physiology thereby should be the demand of pharmaceutical dosage form and combine salify, should be included in this patent protection domain with organic acid.
The preparation of relevant 1-(4-chloroanilino)-4-(4-picolyl)-2 belongs to prior art, specifically can be referring to CN1876649.
The stage that new vessels generates is all passed through in the morbidity of all solid tumors, so The compounds of this invention 1-(4-chloroanilino)-4-(4-picolyl)-2, the activity that the 3-benzodiazine shows on mice S180 sarcoma model, representative to the tumor of other types.
Concrete, give mice orally give 1-(4-chloroanilino)-4-(4-picolyl)-2 when in advance, the 3-benzodiazine, make proper interior blood drug level maintain certain level, be mouse inoculation tumor cell S180 then, since the good inhibition angiogenesis function of The compounds of this invention, thus make the tumor cell of inoculation not form focus or the incidence rate of tumor is obviously reduced at the mice proliferation in vivo, and statistics shows to have significant difference (P＜0.05).
Concrete, suppress in the experiment of angiogenesis model Brachydanio rerio, we have also observed owing to giving medicine of the present invention and have caused zebrafish embryo can not form intersegmental blood vessel, this has proved that also The compounds of this invention is a reliable active drug aspect the generation of the new vessels in suppressing the tumor generating process.
Simultaneously, The compounds of this invention 1-(4-chloroanilino)-4-(4-picolyl)-2 has shown safety low-poison effect in zoopery fortunately.Because this is the unescapable defective of present existing chemotherapeutic, for the nausea and vomiting that occurs in the chemotherapy process, become thin, neural inhibitory action etc. is known already.This is for having tumor Inheritance history, maybe needing to protect especially the prevention of carrying out tumor disease, and the patient who needs for a long time or periodically take medicine is a gratifying benefit.
Description of drawings
Fig. 1 is that 1-(4-chloroanilino)-4-(4-picolyl)-2 (BSSD-1) is dose-dependent inhibition interactively figure to human umbilical vein endothelial cell's propagation, and wherein, vertical coordinate is an absorbance, represents the quantity of each hole living cells.Horizontal vertical coordinate is a drug level, the dosage of expression BSSD-1.
The specific embodiment
The present invention is further described by the following examples, but embodiment will not limit the present invention in any form.
Embodiment 1:1-(4-chloroanilino)-4-(4-picolyl)-2 is to the inhibitory action of human vascular endothelial cell proliferation
(HUVEC available from Cascade Biologics company, Cot:C-003-5C) places the Medium 200 (available from Cascade Biologics company) that contains 10% hyclone (FBS) to cultivate (37 ℃, 5%CO with the human umbilical vein endothelial cell
2, 95% humidity), get the 4th generation cell by in density 4000/250 μ L inoculation and 96 well culture plates, set the medication group and the blank group of matched group, each Concentraton gradient, all do 3 multiple holes for every group.Treat that the cell stand density reaches 80%, 1-(4-the chloroanilino)-4-(4-picolyl)-2 that adds 5 μ l respectively, 3-benzodiazine (DMSO dissolving), make final concentration be respectively 1000 μ M, 100 μ M, 10 μ M, 5 μ M, 1 μ M, matched group adds the DMSO of 5 μ L, continue to cultivate 48 hours, Thiazolyl blue tetrazolium bromide salt (MTT) the 20 μ l that add 5mg/ml, 37 ℃ were continued to hatch 4 hours, ended to cultivate, and abandoned supernatant, every hole adds the DMSO of 150 μ l, light shaking was measured each hole absorbance at the 490nm place with microplate reader after 1 hour, represented the quantity of each hole living cells with absorbance.Result such as Fig. 1 show.The result shows that 1-(4-chloroanilino)-4-(4-picolyl)-2 is the dose-dependent inhibition effect to human umbilical vein endothelial cell's propagation, and its half amount of suppression is 50 μ M.
Embodiment 2:1-(4-chloroanilino)-4-(4-picolyl)-2 (BSSD-1) has inhibition or delays tumorigenic effect
By designing dosage regimen in advance, make medicine in the mice body, reach certain blood drug level, thereby suppressed tumor cell in the intravital implantation of mice, propagation, thus the preventive effect of reflection medicine.Concrete scheme is as follows:
Kunming mouse, administration 3d in advance, intraperitoneal injection, subcutaneous vaccination S then
180The sarcoma cell strain continues administration simultaneously, continues 10d, observes tumor and forms mice speed and size.The group of not carrying out administration in advance is set simultaneously compares.The result shows that BSSD-1 has significantly delayed the time of the generation of tumor, and the tumor growth rate that significantly slowed down, and tumor does not then take place the part animal; And tumor has all taken place in all mices that do not carry out in the group of administration in advance.See Table 1.
Table 1 BSSD-1 is to mice S1
80The preventive effect that sarcoma generates
* p＜0.05, compared with the control
Prevent mice body weight and normal mouse comparison there was no significant difference in experimentation of administration in advance, diet, diversion is normal, and fur gloss is no abnormal, illustrates that this toxicity of compound is low, and safety is good.
Embodiment 3: the Brachydanio rerio test
Blood vessel fluorescence transgenic zebrafish TG (VEGFR2:GFP) is adopted in experiment, tests preceding 1 day, puts into the copulation cylinder in the ratio of male and female 1/1 or 1/2, next day 6～8 o'clock acquisition germ cell.After germ cell carried out disinfection and clean, move into zebrafish embryo and cultivate in the water, 28 ℃ down control light cultivate.With 1-(4-chloroanilino)-4-(4-picolyl)-2,3-benzodiazine (BSSD-1) is made into the sample of 100 μ g/ml, 10 μ g/ml, 1 μ g/ml, 0.1 μ g/ml concentration respectively, be added to respectively in 96 well culture plates, each concentration 8 hole, get 32 pieces of embryos then, join respectively in the hole that has added medicine, other gets 8 pieces of embryos, as blank, then, put into 28 ℃ of illumination boxs, embryo and medicine are hatched jointly, observe the intersegmental blood vessel number of prelarva behind the 72h, calculate suppression ratio, see Table 2.As can be seen from the results, this chemical compound can significantly suppress the generation of Brachydanio rerio internode new vessels when 0.1 μ g/ml, when reaching 1～100 μ g/ml, concentration can all suppress the generation of Brachydanio rerio intersegmental blood vessel, shown fabulous preventive effect, extremely significant difference has all been arranged compared with the control.
Table 2 BSSD-1 is to the preventive effect of zebrafish embryo angiogenesis
* p＜0.01, compared with the control
Claims (1)
1. the purposes of the medicine that takes place in preparation prophylaxis of tumours disease of the chemical compound 1-of following formula (4-chloroanilino)-4-(4-picolyl)-2:
Wherein said medicine is 1-(4-chloroanilino)-4-(4-picolyl)-2 of containing 20%-60%wt, is used for the pharmaceutical preparation that administering mode is used outside intestines and stomach or intestines and stomach.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710017109A CN101116664B (en) | 2007-08-28 | 2007-08-28 | Application of compound 1-( 4-chloroaniline )-4-( 4-picoline )-2, 3-naphthyridine |
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| CN200710017109A CN101116664B (en) | 2007-08-28 | 2007-08-28 | Application of compound 1-( 4-chloroaniline )-4-( 4-picoline )-2, 3-naphthyridine |
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| CN101116664A CN101116664A (en) | 2008-02-06 |
| CN101116664B true CN101116664B (en) | 2010-05-19 |
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| CN102445531B (en) * | 2011-09-22 | 2014-04-02 | 山东省科学院生物研究所 | Method for screening anti-angiogenesis active substances |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251097A (en) * | 1997-02-13 | 2000-04-19 | 诺瓦提斯公司 | Phthalazines with angiogenesis inhibiting activity |
| CN1876649A (en) * | 2006-06-29 | 2006-12-13 | 山东省科学院生物研究所 | 1-(4- chloroanilino)-4-(4-methylpyridyl)-2,3-diazophenodiazine synthesis and uses |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251097A (en) * | 1997-02-13 | 2000-04-19 | 诺瓦提斯公司 | Phthalazines with angiogenesis inhibiting activity |
| CN1876649A (en) * | 2006-06-29 | 2006-12-13 | 山东省科学院生物研究所 | 1-(4- chloroanilino)-4-(4-methylpyridyl)-2,3-diazophenodiazine synthesis and uses |
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