CN103622965B - Oxadiazolyl diethylenediamine compound is preparing the purposes in anti-angiogenic drugs - Google Patents
Oxadiazolyl diethylenediamine compound is preparing the purposes in anti-angiogenic drugs Download PDFInfo
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Abstract
The invention belongs to medical art, She is Ji oxadiazolyl diethylenediamine compound is preparing the purposes in anti-angiogenic drugs.Two kinds of described medicines are <i>N ˊ-</i> (3-pi-allyl-2-hydroxy phenyl methylene)-2-(4-benzyl diethylenediamine-1-base) acethydrazide and (<i>E</iGreatT.Gr eaT.GT)-<i>N
/</i>-(4-((2-((benzo [<i>d</iGreatT.Gr eaT.GT] [1,3] dioxolanes-5-base) methyl) thiazole-4-yl) methoxyl group)-2-phenol methylene)-2-(4-((3-(4-((4-fluorophenoxy) methyl) phenyl)-1,2,4-oxadiazole-5-base) methyl) piperazine-1-base) acethydrazide hydrochlorate.Two kinds of oxadiazolyl diethylenediamine compounds provided by the invention are at Human umbilical vein endothelial cells (HUVEC) micro-tube formation assay, Transwell cell migration experiment and the experiment of rat artery ring etc. have obvious inhibitory action, obviously can suppress the formation of endotheliocyte microtubule, the resistant migration of obvious suppression endotheliocyte, and obviously suppress rat artery ring Angiogenesis.
Description
Technical field:
The invention belongs to medical art, relate to two kinds of oxadiazolyl diethylenediamine compounds and can be used as treating the medicine of relevant diseases of angiogenesis containing the pharmaceutical composition of this compounds.
Background technology:
Angiogenesis refers to by modes such as vascular endothelial cell proliferation, migration, adhesion and vessel lumen formation on former blood capillary and/or venule basis, forms the process with the neovascularity of function; This process contains the interaction between vascular endothelial cell and surrounding extracellular matrix, the main regulation and control being subject to angiogenesis promotive 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 by different approach adjustment angiogenesis.Under physiological status, angiogenesis of short duration opening when fetal development, repair in trauma, feminine menstrual, all the other periods are then in closed condition, thus make the growth of blood vessel and degeneration maintain dynamic poised state.
Arthritis and angiogenesis in close relations, because the early stage pathological change of arthritis is that persistency synovitis and pannus are formed, especially depends on the formation of new vessels net widely.Pannus has the characteristic-aggressivity being similar to tumor tissues, and its erodable and destruction articular cartilage and osseous tissue, finally cause irreversible joint stiffness, afunction.The high expressed of VEGF is had, the relation that display VEGF and arthritis occur in arthritic synovial fluid cell.Clinical research confirmation, the degree that the degree of arthritic's intraarticular neovascularization resulting and the state of an illness of patient, synovial hyperplasia and inflammatory cell react is proportional, and the medicine of angiogenesis inhibiting can the state of an illness of 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, AlanGPorter disclosed Yi oxadiazolyl diethylenediamine compound (PAC-1) on NatureChemicalBiology, and 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. CN101805338A, publication date 2010.08.18) discloses Yi oxadiazolyl diethylenediamine compound, and discloses this compound and preparing the effect in antitumor drug.But in existing data and unexposed any research data about whether having anti-angiogenic rebirth effect.
Summary of the invention:
To the invention provides in formula (I) and formula (II) Liang Zhong oxadiazolyl diethylenediamine compound in the application treated and/or prevented in medicine for the preparation of relevant diseases of angiogenesis.。
Formula (I)
N'-(3-pi-allyl-2-hydroxy phenyl methylene)-2-(4-benzyl diethylenediamine-1-base) acethydrazide molecular weight 392 (code name in this patent: PAC-1)
Formula (II)
(E)-N
/-(4-((2-((benzo [d] [1,3] dioxolanes-5-base) methyl) thiazole-4-yl) methoxyl group)-2-phenol methylene)-2-(4-((3-(4-((4-fluorophenoxy) methyl) phenyl)-1,2,4-oxadiazole-5-base) methyl) piperazine-1-base) acethydrazide hydrochlorate molecular weight 828.31 (code name in this patent: WF-210)
The technical problem to be solved in the present invention is that in formula (I) and formula (II), Liang Zhong oxadiazolyl diethylenediamine compound is in the application treated and/or prevented in medicine for the preparation of relevant diseases of angiogenesis, the application especially 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 arthritis pathological changes tissue blood vessel new life, angiogenic oculopathy, psoriatic lesions tissue blood vessel new life and atherosclerotic tissue angiogenesis.
The compositions that the present invention also provides Liang Zhong oxadiazolyl diethylenediamine compound and pharmacy in the formula containing effective dose (I) and formula (II) can accept composition is preparing the application in anti-angiogenic drugs.The Liang Zhong oxadiazolyl diethylenediamine compound for the treatment of effective dose and any one adjuvant of pharmaceutically accepting can be made pharmaceutical composition according to the present invention, also can add other anti-angiogenic drugs that other and Liang Zhong oxadiazolyl diethylenediamine compound do not have antagonism.One or more pharmaceutically acceptable carriers can be added in the medicine of angiogenesis inhibiting of the present invention.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 Human umbilical vein endothelial cells (HUVEC) micro-tube formation assay, Transwell cell migration experiment and the experiment of rat artery ring etc. have obvious inhibitory action, obviously can suppress the formation of endotheliocyte microtubule, the resistant migration of obvious suppression endotheliocyte, and obviously suppress rat artery ring Angiogenesis.
Liang Zhong oxadiazolyl diethylenediamine compound used in the present invention is the synthesis of pharmaceutical chemistry teaching and research room of Shenyang Pharmaceutical University and qualification.Patent CN101805338A (publication date 2010.08.18) is shown in concrete preparation, authentication method.
Accompanying drawing illustrates:
Fig. 1 is that the compounds of this invention suppresses VEGF to induce the schematic diagram of Human umbilical vein endothelial cells HUVEC invasion and attack.
Fig. 2 is that the compounds of this invention suppresses VEGF to induce the schematic diagram of Human umbilical vein endothelial cells HUVEC tubule generation
Fig. 3,4 schematic diagrams suppressing VEGF induction Human umbilical vein endothelial cells HUVEC rat artery ring new vessels to generate for the compounds of this invention
Detailed description of the invention:
Embodiment 1, PAC-1, WF-210 induce the impact of Human umbilical vein endothelial cells (HUVEC) invasive ability on VEGF
1.1 material
Primary HUVEC cell, culture fluid, LSGS, pancreatin are purchased from Gibco, Transwell cell 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 DEG C of saturated humidities, cultivate HUVEC cell.Culture fluid is with 90%M200 basal medium and the mixing of 2%LSGS ratio, and 0.22 μm of membrane filtration is degerming.Transwell cell wraps quilt after mixing with culture fluid with 1:8 matrigel, 37 degree solidify 0.5h after for subsequent use, upper room adds 200 μ l not containing the culture fluid of VEGF, lower room adds 500 μ l containing VEGF culture fluid, and drug treating group adds PAC-1 or WF-210 of 2,10,50 μMs, takes out after cultivating 12h, chamber surface cell wiped by cotton swab, observe lower chamber surface cell with calcein dyeing, adopt high intension pharmaceutical analysis system to take pictures, and analyze counting.
1.3 result
Result as shown in Figure 1, the HUVEC cell invasion that PAC-1 and derivant WF-210 thereof all can suppress VEGF to induce, and under comparable sodium, the inhibitory action of derivant WF-210 is better than PAC-1.
This result shows, the vascular endothelial cell invasion and attack that PAC-1 and WF-210 can obviously suppress VEGF to induce, may have the ability suppressing new vessels to generate.
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 DEG C of saturated humidities, cultivate HUVEC cell.Culture fluid is with 90%M200 basal medium and the mixing of 2%LSGS ratio, and 0.22 μm of membrane filtration is degerming.
96 orifice plates are had no time the matrigel and culture fluid that add 1:1 mixing, 37 degree solidify 1h after add 100 μ LHUVEC cell suspension, 15000, every hole cell, to take pictures observation 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 to induce generates result, and under comparable sodium, the inhibitory action of derivant WF-210 is better than PAC-1.
This result shows, the blood vessel endothelium tubule that PAC-1 and WF-210 can obviously suppress VEGF to induce generates, and may have the ability suppressing new vessels to generate.
The impact that embodiment 3, PAC-1, WF-210 generate rat artery ring new vessels
3.1 material
Male SD rat 4-6 week age purchased from Experimental Animal Center, culture fluid, Hank ' s liquid purchased from Gibco, 96 orifice plates are purchased from Corning, 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 one section of blood vessel between underage rat main aortic arch to renal artery, Hank ' s liquid cleans three times, be separated and remove connective tissue, be cut into the segment of 1-1.5mm, put into 96 orifice plates having solidified matrigel (1:1) containing 25 μ l, again spread 25 μ l matrigels, 37 degree solidify more than 1h, add 50 μ l culture fluid, add VEGF and medicine irritation after overnight incubation, 96h to take pictures detection with high intension after calcein dyeing.And adopt the quantitative analysis of high intension analytical system.
3.3 result
Result as shown in Figure 3, Figure 4, the rat artery ring angiogenesis that PAC-1 and derivant WF-210 thereof all can suppress VEGF to induce, and under comparable sodium, the inhibitory action of derivant WF-210 is better than PAC-1.
This result shows, the rat artery ring angiogenesis that PAC-1 and WF-210 can obviously suppress VEGF to induce, and may have the ability suppressing new vessels to generate.
Claims (5)
1. the application of compound in the medicine preparing angiogenesis inhibiting in formula (II), is characterized in that, the medicine of described angiogenesis inhibiting is the medicine of the angiogenesis suppressing arthritis pathological tissues;
Formula (II).
2. the application of compound in the medicine preparing angiogenesis inhibiting in formula (II), is characterized in that, the medicine of described angiogenesis inhibiting is the medicine suppressing psoriasis to become tissue blood vessel new life;
Formula (II).
3. the application of compound in the medicine preparing angiogenesis inhibiting in formula (II), is characterized in that, the medicine of described angiogenesis inhibiting is the medicine suppressing neovascular eye diseases;
Formula (II).
4. the application of compound in the medicine preparing angiogenesis inhibiting in formula (II), is characterized in that, the medicine of described angiogenesis inhibiting is the medicine suppressing atherosclerotic lesion place angiogenesis;
Formula (II).
5. according to the application of claim 1-4 described in any one, it is characterized in that: described medicine is the compositions that formula (II) compound containing effective dose and pharmacy can accept composition.
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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 |
|---|
| Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy;Karson S Putt等;《Nature Chemical Biology》;20061031;第2卷(第10期);543-550 * |
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