CN103622965A - Application of oxadiazole piperazine compounds in preparing anti-angiogenesis drug - Google Patents
Application of oxadiazole piperazine compounds in preparing anti-angiogenesis drug Download PDFInfo
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- CN103622965A CN103622965A CN201310666390.1A CN201310666390A CN103622965A CN 103622965 A CN103622965 A CN 103622965A CN 201310666390 A CN201310666390 A CN 201310666390A CN 103622965 A CN103622965 A CN 103622965A
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Abstract
The invention belongs to the technical field of medicine, and relates to an application of oxadiazole piperazine compounds in preparing an anti-angiogenesis drug. The two oxadiazole piperazine compounds are N'-(3-allyl-2-phenol methylene)-2-(4-benzyl piperazine-1-group) acethydrazide and (E)-N/-(4-((2-((benzo [d][1,3]dioxolane-5-group) methyl) thiazole-4-group) methoxy)-2-phenol methylene)-2-(4-((3-(4-((4-fluorobenzene oxygroup) methyl) phenyl)-1,2,4-oxadiazole-5-group) methyl) piperazine-1-group) acethydrazide hydrochloride. According to the application, the two oxadiazole piperazine compounds have obvious inhibiting effects on a human umbilical vein endothelial cell (HUVEC) microtubule forming experiment, a Transwell chamber migration experiment, a rat arterial ring experiment and the like, can obviously inhibit endothelial cell microtubule forming, can obviously inhibit resistive migration of an endothelial cell, and can obviously inhibit rat arterial ring capillary generation.
Description
Technical field:
The invention belongs to medical technical field, the pharmaceutical composition that relates to two kinds of oxadiazolyl diethylenediamine compounds and contain this compounds can be used as treating the medicine of relevant diseases of angiogenesis.
Background technology:
Angiogenesis refers on former blood capillary and/or venule basis, pass through the modes such as vascular endothelial cell proliferation, migration, adhesion and vessel lumen formation, forms the process of the neovascularity with function; This process has comprised the interaction between vascular endothelial cell and peripheral cell epimatrix, is mainly subject to angiogenesis to promote the regulation and control of the factor and angiogenesis inhibitive factor.Research finds, multiple somatomedin is as vascular endothelial cell growth factor (VEGF), ANG2 and basic fibroblast growth factor, and epidermal growth factor etc. can be by different approach adjusting angiogenesiss.Under physiological status, angiogenesis of short duration opening when fetal development, repair in trauma, women's menstruation, all the other periods are in closed condition, thereby make the growth of blood vessel and degeneration maintain dynamic poised state.
Arthritis and angiogenesis in close relations, forms because the early stage pathological change of arthritis is persistency synovitis and pannus, especially depends on the formation of new vessels net widely.Pannus has the characteristic-aggressivity that is similar to tumor tissues, and its erodable and destruction articular cartilage and osseous tissue, finally cause irreversible joint stiffness, afunction.The high expressed that has VEGF in arthritic synovial fluid cell, shows the relation that VEGF and arthritis occur.Clinical research confirmation, the degree of arthritic's intraarticular neovascularization resulting is proportional with the degree that patient's the state of an illness, synovial hyperplasia and inflammatory cell reacts, the state of an illness that the medicine of angiogenesis inhibiting can releasing arthritis.
Except arthritis and angiogenesis mutually outside the Pass, angiogenesis is also relevant with the various diseases such as diabetic renal papillary necrosis, psoriasis, angiogenic oculopathy and atherosclerosis or pathological process.
2006, Alan G Porter disclosed Yi oxadiazolyl diethylenediamine compound (PAC-1) on Nature Chemical Biology, and had further illustrated it and produce antineoplastic action by inducing apoptosis of tumour cell.But in existing data and unexposed any research data whether about PAC-1 with anti-angiogenic rebirth effect.
Chinese patent (patent No. CN 1018053338 A, open day 2010.08.18) discloses Yi oxadiazolyl diethylenediamine compound, and discloses the effect of this compound in preparing antitumor drug.But in existing data and unexposed about whether thering is any research data of anti-angiogenic rebirth effect.
Summary of the invention:
The invention provides the middle Liang Zhong oxadiazolyl diethylenediamine compound of formula (I) and formula (II) in the application in medicine that treats and/or prevents for the preparation of relevant diseases of angiogenesis.。
Formula (I)
N '-(3-pi-allyl-2-hydroxy phenyl methylene)-2-(4-benzyl diethylenediamine-1-yl) acethydrazide molecular weight 392(code name in this patent: PAC-1)
Formula (II)
(E)-N/-(4-((2-((benzo [d] [1,3] dioxolanes-5-yl) methyl) thiazole-4-yl) methoxyl group)-2-phenol methylene)-2-(4-((3-(4-((4-fluorophenoxy) methyl) phenyl)-1,2,4-oxadiazole-5-yl) methyl) piperazine-1-yl) acethydrazide hydrochlorate molecular weight 844 (code names in this patent: WF-210)
The technical problem to be solved in the present invention is that formula (I) and the middle Liang Zhong oxadiazolyl diethylenediamine compound of formula (II) are in the application in medicine that treats and/or prevents for the preparation of relevant diseases of angiogenesis, the especially application in the neovascularization diseases such as preparation ophthalmic diseases, rheumatoid arthritis, hemangioma, psoriasis.Wherein, described anti-angiogenic drugs can suppress pathological tissues angiogenesis.
Wherein, described pathological tissues angiogenesis comprises that arthritis pathological changes tissue blood vessel new life, angiogenic oculopathy, psoriatic lesions tissue blood vessel new life and atherosclerosis tissue blood vessel are newborn.
The present invention also provides the application in preparing anti-angiogenic drugs of compositions that Liang Zhong oxadiazolyl diethylenediamine compound in the formula (I) that contains effective dose and formula (II) and pharmacy can accept composition.According to the present invention, any one adjuvant of the Liang Zhong oxadiazolyl diethylenediamine compound for the treatment of effective dose and pharmaceutically acceptance can be made to pharmaceutical composition, also can add other anti-angiogenic drugs that other and Liang Zhong oxadiazolyl diethylenediamine compound do not have antagonism.Can in the medicine of angiogenesis inhibiting of the present invention, add one or more pharmaceutically acceptable carriers.Its preparation can be any one dosage form pharmaceutically, includes but not limited to capsule, tablet, microcapsule formulation, injection, suppository, spray or ointment etc.
Show after deliberation, in formula provided by the invention (I) and formula (II), two kinds of oxadiazolyl diethylenediamine compounds are at the micro-tube formation assay of Human umbilical vein endothelial cells (HUVEC), Transwell cell migration experiment and the experiment of rat artery ring etc. have obvious inhibitory action, can obviously suppress the formation of endotheliocyte microtubule, obviously suppress the resistant migration of endotheliocyte, and obviously suppress rat artery ring Angiogenesis.
In the present invention, Liang Zhong oxadiazolyl diethylenediamine compound used is that pharmaceutical chemistry teaching and research room of Shenyang Pharmaceutical University synthesizes and identifies.Concrete preparation, authentication method are shown in the open day 2010.08.18 of patent CN 1018053338 A().
Accompanying drawing explanation:
Fig. 1 is the schematic diagram that the compounds of this invention suppresses VEGF induction Human umbilical vein endothelial cells HUVEC invasion and attack.
Fig. 2 is that the compounds of this invention suppresses the schematic diagram that VEGF induction Human umbilical vein endothelial cells HUVEC tubule generates
Fig. 3 is that the compounds of this invention suppresses the schematic diagram that VEGF induction Human umbilical vein endothelial cells HUVEC rat artery ring new vessels generates
Fig. 4 is that the compounds of this invention suppresses the schematic diagram that VEGF induction Human umbilical vein endothelial cells HUVEC rat artery ring new vessels generates.
The specific embodiment:
1.1 material
Primary HUVEC cell, culture fluid, LSGS, pancreatin are purchased from Gibco, and Transwell cell is purchased from Corning, and matrigel is purchased from BD, and calcein is purchased from Sigma.
1.2 experimental technique
PAC-1, WF-210 are dissolved into 100mM mother solution deposit with DMSO, face the used time and dilute with culture fluid; At 5%CO2, in the incubator of 37 ℃ of saturated humidities, cultivate HUVEC cell.Culture fluid mixes with 90%M200 basal medium and 2%LSGS ratio, 0.22 μ m membrane filtration degerming.It is coated after Transwell cell mixes with culture fluid with 1:8 matrigel, 37 degree solidify after 0.5h standby, upper chamber adds 200 μ l not contain the culture fluid of VEGF, lower chamber adds 500 μ l containing VEGF culture fluid, and drug treating group adds PAC-1 or the WF-210 of 2,10,50 μ M, after cultivation 12h, takes out, cotton swab is wiped chamber surface cell, with calcein dyeing, observe lower chamber surface cell, adopt high intension pharmaceutical analysis system to take pictures, and analyze counting.
1.3 result
As shown in Figure 1, PAC-1 and derivant WF-210 thereof all can suppress the HUVEC cell invasion of VEGF induction to result, and are better than PAC-1 with the inhibitory action of derivant WF-210 under isoconcentration.
This result shows, PAC-1 and WF-210 can obviously suppress the vascular endothelial cell invasion and attack of VEGF induction, may have the ability that new vessels generates that suppresses.
The impact that embodiment 2, PAC-1, WF-210 induce Human umbilical vein endothelial cells (HUVEC) tubule to generate on VEGF
2.1 material
Primary HUVEC cell, culture fluid, LSGS, pancreatin are purchased from Gibco, and 96 orifice plates are purchased from Corning, and matrigel is purchased from BD, and calcein is purchased from Sigma.
2.2 method
PAC-1, WF-210 are dissolved into 100mM mother solution deposit with DMSO, face the used time and dilute with culture fluid; At 5%CO2, in the incubator of 37 ℃ of saturated humidities, cultivate HUVEC cell.Culture fluid mixes with 90%M200 basal medium and 2%LSGS ratio, 0.22 μ m membrane filtration degerming.
Busy matrigel and the culture fluid that adds 1:1 to mix of 96 orifice plates, adds 100 μ LHUVEC cell suspension after 37 degree solidify 1h, 15000, every hole cell, and the observation of taking pictures after cultivation 12h, VEGF irritaiting concentration is 10ng/ml.
2.3 result
As shown in Figure 2, the HUVEC cell tubule that PAC-1 and derivant WF-210 thereof all can suppress VEGF induction generates result, and is better than PAC-1 with the inhibitory action of derivant WF-210 under isoconcentration.
This result shows, the blood vessel endothelium tubule that PAC-1 and WF-210 can obviously suppress VEGF induction generates, and may have the ability that new vessels generates that suppresses.
The impact that embodiment 3, PAC-1, WF-210 generate rat artery ring new vessels
3.1 material
Age in male SD rat 4-6 week, 96 orifice plates were purchased from Corning purchased from Experimental Animal Center, culture fluid, Hank ' s liquid purchased from Gibco, and matrigel is purchased from BD, and calcein is purchased from Sigma.
3.2 method
PAC-1, WF-210 are dissolved into 100mM mother solution deposit with DMSO, face the used time and dilute with culture fluid.Get the main aortic arch of underage rat to one section of blood vessel between renal artery, Hank ' s liquid cleans three times, the separated connective tissue of removing, be cut into the segment of 1-1.5mm, put into and contain 96 orifice plates that 25 μ l have solidified matrigel (1:1), again spread 25 μ l matrigels, more than 37 degree solidify 1h, add 50 μ l culture fluid, add VEGF and medicine irritation after overnight incubation, 96h is with the detection of taking pictures of high intension after calcein dyeing.And adopt the quantitative analysis of high intension analytical system.
3.3 result
As shown in Figure 3, Figure 4, PAC-1 and derivant WF-210 thereof all can suppress the rat artery ring angiogenesis of VEGF induction to result, and are better than PAC-1 with the inhibitory action of derivant WF-210 under isoconcentration.
This result shows, PAC-1 and WF-210 can obviously suppress the rat artery ring angiogenesis of VEGF induction, may have the ability that new vessels generates that suppresses.
Claims (9)
1. the application of Liang Zhong oxadiazolyl diethylenediamine compound in preparing the medicine of angiogenesis inhibiting in formula (I) and formula (II).
Formula (I)
Formula (II).
2. purposes according to claim 1, is characterized in that: the medicine that the medicine that described inhibition new vessels generates is neonate tumour blood vessel.
3. purposes according to claim 1, is characterized in that: the medicine that described inhibition new vessels generates is for suppressing the medicine of the angiogenesis of arthritis pathological changes tissue.
4. purposes according to claim 1, is characterized in that: the medicine that described inhibition new vessels generates suppresses the medicine that psoriasis becomes tissue blood vessel new life.
5. purposes according to claim 1, is characterized in that: the medicine that described inhibition new vessels generates is for suppressing the medicine of neovascular eye diseases.
6. purposes according to claim 1, is characterized in that: the medicine that described inhibition new vessels generates is for suppressing the medicine of atherosclerotic lesion place angiogenesis.
7. purposes according to claim 1, is characterized in that: the medicine that described inhibition new vessels generates is for suppressing the medicine of diabetic complication oculopathy.
8. purposes according to claim 1, is characterized in that: the pharmaceutical dosage form that described inhibition new vessels generates is capsule, tablet, microcapsule formulation, injection, suppository, spray or ointment.
9. purposes according to claim 1, (the application of compositions in preparing anti-angiogenic drugs that II) oxadiazolyl diethylenediamine compound and pharmacy can be accepted composition of the formula (I) that it is characterized in that containing effective dose and formula.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805338A (en) * | 2010-04-06 | 2010-08-18 | 沈阳药科大学 | Oxadiazole-based piperazine derivative and application thereof |
| US20130096133A1 (en) * | 2011-10-14 | 2013-04-18 | The Board of Trustees of the University lllinois | Procaspase-activating compounds and compositions |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805338A (en) * | 2010-04-06 | 2010-08-18 | 沈阳药科大学 | Oxadiazole-based piperazine derivative and application thereof |
| US20130096133A1 (en) * | 2011-10-14 | 2013-04-18 | The Board of Trustees of the University lllinois | Procaspase-activating compounds and compositions |
Non-Patent Citations (1)
| Title |
|---|
| KARSON S PUTT等: "Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy", 《NATURE CHEMICAL BIOLOGY》 * |
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