CN103848749A - Compound [2,3-dihydroxy-1,4-phenylene] diamine tetraacetic acid salt and medicinal composition and application thereof - Google Patents
Compound [2,3-dihydroxy-1,4-phenylene] diamine tetraacetic acid salt and medicinal composition and application thereof Download PDFInfo
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Abstract
The invention belongs to chemical field, specifically relates to a compound [2,3-dihydroxy-1,4-phenylene] diamine tetraacetic acid salt (referred to as bisphenol diamine tetraacetic acid salt) and medicinal compositions and application thereof, and especially application of drug combinations of the compound to the treatment of internal contamination of radionuclides including uranium, thorium and cerium. In the invention, [2,3-dihydroxy-1,4-phenylene] diamine tetraacetic acid is prepared into calcium sodium salt, zinc sodium salt, magnesium sodium salt and composition thereof, or the monosodium salt or monopotassium salt and calcium, zinc and magnesium are prepared into medicinal compositions or drug combinations, so as to prepare novel detoxification decorporation medicaments for treatment of poisoning or internal contamination of radionuclides including uranium, thorium and cerium. Compared with the clinically applied broad-spectrum nuclide decorporation drugs DTPA-CaNa3 and DTPA-ZnNa3 for reducing the toxicity of monosodium salt, the medicinal compositions provided by the invention have higher potential social benefits and application prospects.
Description
Technical field
The invention belongs to chemical field, be specifically related to compound [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] application in the radionuclide internal contaminations such as treatment uranium, thorium and cerium of the drug combination of ethylenediaminotetraacetate (edetate) (be called for short: bis-phenol ethylenediaminotetraacetate (edetate)) and medicinal compositions and application, especially this compound
Background technology
Along with the develop rapidly of nuclear energy and nuclear science technology, the application of radionuclide is increasingly extensive, and wherein, actinium series nucleic uranium, thorium are nuclear fuels important in nuclear industry, uranium or the charging of nuclear bomb, and depleted uranium can be used for preparing military weapon etc.Studies show that, in the reaction of nuclear reactor fuel fission, can produce a large amount of fission products, wherein cerium-144th, the higher a kind of nucleic of yield in fission products, is personnel to be produced to one of main nucleic of internal radiation after nuclear reactor accident occurs.Once radionuclide enters human body and causes internal contamination, will produce serious harm to HUMAN HEALTH, for example, uranium and its compounds not only produces chemical damage but also produce radiation injury to body, and kidney is the target organ of uranium chemical toxicity, serious caused renal failure; Next is bone, and can bring out bone tumor late period; Thorium and cerium-144 are mainly stranded in reticuloendothelial system in vivo, as liver and marrow etc., are secondly bone and kidney, can bring out liver neoplasm, leukemia and osteosarcoma etc.Using the discharge of radionuclide in sequestrant class medicine acceleration bodies is main treatment measure, adopt clinically sodium bicarbonate treatment uranium poisoning to obtain certain effect at present, but it is just effective to make body reach slight alkalosis level.DTPA-CaNa
3the choice drug of current actinium series nucleic internal contamination treatment, but still undesirable to the result for the treatment of of uranium poisoning.
The domestic and international researchist in this area utilizes biomimetic chemistry principle for many years, according to the chemical structure of main chelation group in iron chelating agent-Microbial Iron transporter of potent, the highly selective of microorganisms, the decorporation effect screening for actinium series nucleic of hydroxyl palate acids, catechol (CAM) and hydroxylpyridinones (HOPO) sequestrant has been synthesized in design, compound efficient to obtaining, low toxicity.The animal experiment study such as U.S. Durbin is found hydroxylpyridinones sequestrant 3 in recent years, 4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) uranium poisoning rat is had to good row's uranium effect, can significantly reduce kidney uranium accumulation, after uranium poisoning, postpone administration and oral administration all effective, but still locate at present the laboratory study stage.The domestic CAM of studies have found that class sequestrant bis-phenol ethylenediamine tetraacetic acid (EDTA) (CBMIDA) and its activeconstituents of 8102(are CBMIDA) removing toxic substances and decorporation effect that uranium poisoning rat has been had, and also the 8102 pairs of thoriums and cerium internal contamination rat also have good decorporation effect.The derivative of the 8102nd, CBMIDA, it improves the stability of compound by the catechol group of acetylize CBMIDA; Because CBMIDA and 8102 is water-soluble hardly, when experimentation on animals, conventional sodium bicarbonate aqueous solution is dissolved as CBMIDA sodium-salt aqueous solution by CBMIDA and 8102 and uses (8102 meet alkaline matter in water is decomposed into CBMIDA).
Research also shows, sequestrant class medicine, in the autologous interior discharge of accelerating radioactive nuclear element, also produces toxic side effect to body, and its major cause is: sequestrant often can combine and make it to excrete with the metal ion in body, therefore, if life-time service can cause Ca in body
2+, Zn
2+, Mg
2+and Mn
2+deng the exhaustion of divalent-metal ion, thereby affect the physiological function such as metabolism of synthetic, the organism of nucleic acid and protein and produce toxic side effect.And for example, K
+being the main monovalent cation that maintains cell normal physiological activity in body, is to keep the normal osmotic pressure of body and acid base equilibrium, involved in sugar and protein metabolism, the necessary material of the nervimuscular normal function of assurance.Therefore, for reducing the toxic side effect of CBMIDA sodium salt, the present invention intends providing a kind of efficient, low toxicity, new drug flexible and convenient to use, with the needs of reply Nuclear Accident Emergency treatment, be specifically related to pharmacy acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] application in the radionuclide internal contaminations such as treatment uranium, thorium and cerium of the drug combination of ethylenediaminotetraacetate (edetate) and medicinal compositions and this compound.
Summary of the invention
The object of this invention is to provide medicinal compositions and the application of acceptable [2, the 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) of a kind of pharmacy and medicinal compositions thereof, itself and calcium agent or zinc agent or magnesia mixture
The present invention is take CBMIDA as primer, according to the chemical property of its pyrocatechol ammonia carboxylic acid chelation group, by divalent-metal ion Ca essential under physiological condition
2+, Zn
2+and Mg
2+with monovalent metallic ion K
+introduce on it, be prepared into the various salt containing a part divalent-metal ion and a part monovalent metallic ion, to reach object efficient, low toxicity; And for improving the chemical stability of the various salt of CBMIDA, add pharmaceutical excipient to be prepared into medicinal compositions; And, exhaust for reducing body divalent-metal ion the toxicity producing, make medicinal compositions or adopt Combined Preparation mode with CBMIDA sodium salt or CBMIDA sylvite and calcium agent or zinc agent or magnesia mixture, provide efficient, low toxicity, new drug flexible and convenient to use, to tackle the needs of Nuclear Accident Emergency treatment.
A further object of the present invention is to provide acceptable [2, the 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt of a kind of pharmacy or calcium sylvite and medicinal compositions thereof.
A further object of the present invention is to provide acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) zinc sodium salt of a kind of pharmacy or zinc sylvite and medicinal compositions thereof.
A further object of the present invention is to provide acceptable [2, the 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA magnesium complex disodium salt of a kind of pharmacy or magnesium sylvite and medicinal compositions thereof.
A further object of the present invention is to provide medicinal compositions and the application of acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) sodium salt of a kind of pharmacy or sylvite and calcium agent.
A further object of the present invention is to provide medicinal compositions and the application of acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) sodium salt of a kind of pharmacy or sylvite and zinc agent.
A further object of the present invention is to provide medicinal compositions and the application of acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) sodium salt of a kind of pharmacy or sylvite and magnesia mixture.
In the present invention; the medicinal compositions of described calcium, zinc and magnesium salt compound and medicinal compositions thereof, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture can accelerate the autologous interior discharges of radionuclide such as uranium, thorium and cerium through Combined Preparation; significantly reduce the effect of radionuclide accumulation in kidney, bone and liver, protection kidney and bone injury, and toxic side effect obviously reduces.
In the present invention; the medicinal compositions of described calcium, zinc and magnesium salt compound and medicinal compositions thereof, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture has protection uranium through Combined Preparation and causes the effect in nephrocyte damage; in picked-up by inhibition people kidney proximal tubule epithelial cell to uranium and promotion cell, the generation of oxyradical in the cell of the release of uranium, the induction of removing uranium, reduces chromosome damage and cell injury.
In the present invention, the medicinal compositions of described calcium, zinc and magnesium salt compound and medicinal compositions thereof, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture and Combined Preparation thereof can use by the route of administration such as intramuscular injection, oral administration or nose spraying, wherein also can be by intravenous drip administration when the medicinal compositions of its calcium salt and medicinal compositions thereof, sodium salt or sylvite and calcium agent or drug combination; In addition, the medicinal compositions of calcium, zinc and magnesium salt compound and medicinal compositions thereof, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture and Combined Preparation can also be at radionuclide administration immediately, administration in advance and postpone administration after poisoning or internal contamination.
Compound of the present invention [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) has the structure of general formula I or general formula II;
In described general formula I, by changing the metal ion of chelating, can reduce toxic side effect.
Wherein M represents calcium, zinc and magnesium, M ' represent sodium or potassium;
Described [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate), according to the difference of its chelated metal ions, the chemical name of its molecule is respectively:
(1) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] disodium calcium ethylene diamine tetraacetate salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiumcalcium salt, CBMIDA-CaNa
2), it calculates molecular weight is 482.
(2) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) two potassium calcium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium salt, CBMIDA-CaK
2), it calculates molecular weight is 514.
(3) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium zinc salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiumzinc salt, CBMIDA-ZnNa
2), it calculates molecular weight is 507;
(4) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium zinc salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium zinc salt, CBMIDA-ZnK
2), it calculates molecular weight is 539;
(5) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium magnesium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiummagnesium salt, CBMIDA-MgNa
2), it calculates molecular weight is 466;
(6) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium magnesium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium magnesium salt, CBMIDA-MgK
2), it calculates molecular weight is 498.
In described general formula II, by forming medicinal compositions or drug combination with calcium agent, zinc agent and magnesia mixture, can reduce toxic side effect,
Wherein M represents Na
+or K
+;
Described calcium agent is that inorganic calcium is as calcium carbonate, citrate of lime and organic calcium calcium lactate, calglucon;
Described zinc agent is that inorganic zinc is as ZnS0
47H
20, ZnCO
3, Zn (0Ac)
2 2H
20, ZnCl
2deng and organic zinc as zinc glycyrrhetate, Zinc Gluconate, zinc lactate and amino-acid zinc etc.;
Described magnesia mixture is as magnesium sulfate and Tianmen radon acid potassium magnesium etc.;
Described [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate), according to the difference of its chelated metal ions, the chemical name of its molecule is respectively:
(1) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylene diamine tetraacetic acid tetrasodium salt
([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acidtetrasodium salt, CBMIDA-Na
4), it calculates molecular weight is 488;
(2) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) four sylvite ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acidtetrapotassium salt, CBMIDA-K
4), it calculates molecular weight is 520.
Calcium disodium, zinc sodium salt and tetra-na salt in compound of the present invention [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate), confirm through experimentation on animals: [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt toxicity is very low, and after mouse iv5g/kg, 14d does not observe death; [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene], although ethylenediamine tetraacetic acid (EDTA) zinc sodium salt toxicity is also lower, higher than its calcium disodium, [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylene diamine tetraacetic acid tetrasodium salt toxicity is the highest, the LD of mouse tail vein injection administration
50for 0.87g/kg, the visible significant tonic spasm of dead mouse;
Described [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt, with [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylene diamine tetraacetic acid tetrasodium salt, can accelerate uranium and discharge in rat body, significantly reduces the accumulation of kidney uranium and bone uranium, is obviously better than DTPA-CaNa
3;
In vitro tests confirms: described compound can significantly suppress the picked-up of kidney proximal tubule epithelial cell to uranium, promote the release of uranium in nephrocyte, chromosome damage and the cell injury of the induction of protection uranium, its mechanism of action produces relevant with the interior oxyradical of cell of its removing uranium induction.
In the present invention, incite somebody to action [2,3-dihydroxyl-1,4-penylene] ethylenediamine tetraacetic acid (EDTA) is prepared into calcium disodium, zinc sodium salt, magnesium sodium salt and composition thereof, or single sodium salt or monopotassium salt and calcium agent, zinc agent and magnesia mixture are prepared into medicinal compositions or drug combination, make the removing toxic substances decorporation medicine of the poisoning or internal contamination of the radionuclides such as new treatment uranium, thorium and cerium, with the wide spectrum nucleic decorporation medicine DTPA-CaNa preparing in order to reduce the toxicity of single sodium salt using clinically at present
3and DTPA-ZnNa
3relatively, there is higher, potential social benefit and application prospect.
Accompanying drawing explanation
Fig. 1 is CBMIDA-CaNa
2the decorporation effect of administration immediately to uranium poisoning rat,
Wherein, im sequestrant immediately after A:ip uranyl acetate 100 μ g/ mouse, 24h urine uranium output,
Im sequestrant immediately after B:ip uranyl acetate 100 μ g/ mouse, uranium accumulation in 24h kidney, bone, with the comparison of uranium poisoning control group, * p<0.05, * * * p<0.001.
Fig. 2 is CBMI DA-CaNa
2improve (the HE dyeing × 400) of administration immediately to uranium poisoning renal tissues of rats pathology damage,
Wherein: arrow indication position is that protein cast, epithelial cell necrosis come off and inflammatory cell.
Fig. 3 is CBMIDA-CaNa
2on the impact of uranium contamination HK-2 cellular uptake and release uranium,
Wherein: with the comparison of uranium contamination control group,
*p<0.05,
*p<0.01,
* *p<0.001; CBMIDA-CaNa under same dose
2group and DTPA-CaNa
3group is compared,
#p<0.05,
##p<0.01.
Fig. 4 is CBMIDA-CaNa
2on the impact that uranium induction HK-2 cell LDH discharges and micronucleus forms, wherein: with the comparison of blank group, * * * P<0.001; With the comparison of uranium contamination control group,
#p<0.05,
###p<0.001.
Fig. 5 is CBMIDA-CaNa
2on the impact that in uranium induction HK-2 cell, ROS produces, wherein: with the comparison of uranium contamination control group, * P<0.05, * * * P<0.001; Under same treatment condition, between the BPCBG group of different concns, compare,
###p<0.001.
Embodiment
Embodiment 1
Preparation [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] disodium calcium ethylene diamine tetraacetate salt and disodium zinc salt
In 500mL flask, add [2, 3-dihydroxyl-1, 4-penylene] ethylenediamine tetraacetic acid (EDTA) (30g), distilled water 300mL, under stirring, add 4.2g CaO or 6.1g ZnO in 150mL water, to obtain solution, add rear reaction solution and at room temperature stir certain hour, then filter, filter cake respectively washs after 1 time with water and ethanol, proceed in 500mL reaction flask, add 250mL dehydrated alcohol, then drip 6gNaOH, after adding rear stirring half an hour, filter, filter cake with absolute ethanol washing 2 times after, in vacuum drier, be dried to obtain pewter or brown solid 33-35g, be [2, 3-dihydroxyl-1, 4-penylene] disodium calcium ethylene diamine tetraacetate salt or disodium zinc salt.
Adopt atomic absorption spectrum to detect calcium, sodium content in [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] disodium calcium ethylene diamine tetraacetate, measured value is consistent with calculated value:
Calculated value % Ca:8.30% Na:9.54%
Measured value % Ca:8.47% Na:8.28%
Adopt atomic absorption spectrum to detect zinc, sodium content in [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium zinc, measured value is consistent with calculated value:
Calculated value % Zn:12.82% Na:9.07%
Measured value % Zn:12.11% Na:8.81%
This experimental result shows, contains a part calcium and two molecule sodium in [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt; In [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) zinc sodium salt, contain a part zinc and two molecule sodium.
The acute toxicity test in mice of [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt, calcium disodium and zinc sodium salt:
Adopt clean level Kunming mouse, body weight 20 ± 2g, by body weight random packet, 10 of every dosage groups, male and female half and half.Select 4-5 the disposable tail vein injection administration of dosage by 8.5 folding geometric progressions, or employing maximum dosage-feeding method, point 2 maximum dosages of tail vein injection (calcium disodium) in 1.5h, Continuous Observation 14d, observe and record general status, the death condition of mouse, the symptom of appearance, and initial time of symptom, severity, time length etc., adopt Bliss method to calculate the LD of various salt
50.Result shows, the disposable iv[2 of mouse, 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] after ethylenediamine tetraacetic acid (EDTA) sodium salt 0.68,0.80,0.941 and 1.107g/kg, dead animal is all twitched in 1-2min and dead after iv, increases tic more serious with dosage, and death is faster; In, the mouse of low dose group survival occurs recovering normal after slight tic after i v, has no afterwards death in 14d; Calculate its LD
50for 0.87g/kg.The disposable iv[2 of mouse, 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] after ethylenediamine tetraacetic acid (EDTA) zinc sodium salt 1.20,1.412,1.661,1.954 and 2.299g/kg, dead animal is twitched in being also after iv in 1-2min and dead, twitch with dosage increase more serious, death is faster; The mouse of high, middle dosage group survival occurs recovering normal, non-evident sympton after low dose group survival mice iv after slight tic after iv; After iv administration survival mice after have no dead in 14d; Calculate its LD
50for 1.922g/kg.Adopt maximum dosage-feeding method, with maximal dose point secondary iv[2 in the 1.5h of interval, 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt 5g/kg, 14d does not all observe dead mouse, shows that calcium disodium toxicity is very low.
Experimental result shows, the toxicity size order of [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) is: tetra-na salt (LD
50=0.87g/kg) > zinc sodium salt (LD
50=1.922g/kg) > calcium disodium (it is dead that maximum dosage 5g/kg has no), the toxicity of its calcium disodium is very low.
Table 1 is the medium lethal dose of calculating [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt by Bliss method.
Table 2 is medium lethal doses of calculating [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) zinc sodium salt by Bliss method.
Table 1
Regression equation y (Probit)=5.4846+7.8588Log (D)
Medium lethal dose LD50=0.86763g/kg
Fiducial limit=0.73106--1.0297g/kg of LD50 (Feiller correction) 95%
LD5=0.53583g/kg
LD95=1.4049g/kg
Table 2
Regression equation y (Probit)=3.04+6.9071Log (D)
Medium lethal dose LD50=1.922g/kg
Fiducial limit=1.6871--2.462g/kg of LD50 (Feiller correction) 95%
LD5=1.1107g/kg
LD95=3.3259g/kg
Embodiment 3
The chmice acute toxicity of [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt and calglucon combination or drug combination
Adopt clean level Kunming mouse, body weight 20 ± 2g, by body weight random packet, 10 of every dosage groups, male and female half and half.Adopt iv[2,3-dihydroxyl-1,4-penylene] the absolute lethal dose 1.803g/kg of sodium ethylene diamine tetracetate salt pair mouse mixes with calcium gluconate injection, make its mol ratio be respectively 1:1,1:0.5,1:0.1,1:0.05 and 1:0, disposable tail vein injection administration, Continuous Observation 14d, observes and records general status, the death condition of mouse, the symptom of appearance, and initial time of symptom, severity, time length etc.Result demonstration, after [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) sodium salt and calglucon mixed solution of the disposable iv 1:1 of mouse and 1:0.5, animal has no tic, and in 14d, has no dead; When the dosage of reduction calglucon makes both mol ratios be 1:0.1 and 1:0.05, all there is immediately the tic of severe or utmost point severe in animal after iv, in survival mice 5min, recovers, and dead animal is dead in 1-2min after iv; Twitch with the reduction of calglucon dosage more serious, death is faster; The mouse recovering after twitching after have no death in 14d.Simple iv[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] all dead in 1min after the mouse administration of ethylenediamine tetraacetic acid (EDTA) sodium salt.
Table 3 is the mixed solution iv administration of absolute lethal dose [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt and calglucon different mol ratio impacts on mouse death rate.
Table 3
Embodiment 4
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt adopts a clean level SD male rat to the decorporation effect of acute uranium internal contamination rat, 180-220g, im120 μ mol/kg CBMIDA-CaNa immediately after ip 100 μ g/ mouse uranyl acetates
2with 600 μ mol/kg DTPA-CaNa
3, collect 24h urine after uranium contamination, to put to death rat simultaneously and get two side kidney and femurs, treatments of the sample adopts ICP-MS to measure uranium accumulation in urine uranium output and kidney, bone after processing.From Figure 1A and 1B, CBMIDA-CaNa
2group rat 24h urine uranium output significantly increases (p<0.01), increase approximately 72% than uranium poisoning control group, in kidney, bone, uranium accumulation obviously reduces (p=0.000, p<0.05), reduces approximately 76% and 28% respectively than uranium poisoning control group.Compare CBMIDA-CaNa
2the DTPA-CaNa of high 5 multiple doses
3can make kidney uranium accumulation reduce approximately 37% compared with uranium poisoning control group, but urine uranium output has no remarkable increase, bone uranium accumulation has no obvious decline.
Experimental result shows, Compound C BMIDA-CaNa
2can obviously promote the autologous interior discharge of uranium, significantly reduce kidney, bone uranium accumulation, obviously be better than DTPA-CaNa
3.
The provide protection test of [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt to the damage of acute uranium poisoning kidney of rats
Adopt clean level SD male rat, 180-220g, difference im 600 μ mol/kg CBMIDA-CaNa immediately after ip uranyl acetate 500 μ g/ mouse
2with 1.2mmol/kg DTPA-CaNa
3, uranium poisoning group and Normal group are set simultaneously.After uranium poisoning 48h, rat, through vetanarcol anesthesia, heart extracting blood, adopts automatic clinical chemistry analyzer to detect serum creatinine and urea nitrogen content; Separately get rat one side renal tissue, 10% formaldehyde solution is fixed, paraffin embedding, and section, HE dyeing, its histopathology form of micro-Microscopic observation changes.Result demonstration, after rat ip 500 μ g uranyl acetate 48h, serum creatinine and urea nitrogen content compared with normal control group significantly increase 40-50%(P < 0.001), CBMIDA-CaNa
2(600 μ mol/kg) administration immediately makes serum creatinine and urea nitrogen content obvious reduction compared with uranium poisoning group (P < 0.001), reaches Normal group level, shows that uranium is caused to injury of the kidney significant protective effect; DTPA-CaNa
3although group rat blood serum creatinine content has obvious decline compared with uranium poisoning group, but still is significantly higher than level and the CBMIDA-CaNa of Normal group
2(P < 0.01), serum urea nitrogen content has been compared obvious reduction (P < 0.01) compared with uranium poisoning group, but successful is lower than CBMIDA-CaNa
2effect (as shown in table 4).The demonstration of nephridial tissue pathological examination, has a large amount of protein casts in rat ip 500 μ g uranyl acetate 48h metanephric tubules, and the necrosis of part kidney proximal tubule epithelial cell comes off, and the indivedual inflammatory cells of interstitial are dispersed in infiltration, but renal glomerulus morphological structure is roughly normal.CBMIDA-CaNa
2(600 μ mol/kg) administration immediately can obviously alleviate uranium and cause the pathology damage of nephridial tissue, rarely seen indivedual protein casts and epithelial cell shedding; And DTPA-CaNa
3(1.2mmol/kg) administration immediately causes Renal tissues damage to uranium and has no obvious improvement, still has more protein cast in uriniferous tubules, and the necrosis of part kidney proximal tubule epithelial cell comes off, and does not show the obvious provide protection (as shown in Figure 2) to injury of the kidney.
Table 4 is CBMIDA-CaNa
2the impact of administration immediately on uranium poisoning rat blood serum creatinine and blood urea nitrogen.
Table 4
Note: with Normal group comparison,
*p < 0.01,
* *p < 0.001
With the comparison of uranium poisoning group,
#p < 0.05,
##p < 0.01,
###p < 0.001
With CBMIDA-CaNa
2group compares ,+P < 0.05
Embodiment 6
The decorporation test of [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt to uranium (VI) contamination people's kidney proximal tubule epithelial cell (HK-2 cell)
(1) impact on HK-2 cellular uptake uranium
After 1 μ mol/L uranyl acetate contamination HK-2 cell, add respectively immediately the CBMIDA-CaNa of 50 and 250 μ mol/L
2(sequestrant/uranium mol ratio is respectively 50 and 250) acting in conjunction 24h, with DTPA-CaNa
3as positive control, blank group and uranium contamination control group are set simultaneously.Collecting cell after effect 24h, adopts ICP-MS to detect uranium content in cell.From Fig. 3 A, 50 and 250 μ mol/LCBMIDA-CaNa
2all can obviously block the picked-up of HK-2 cell to uranium, make uranium accumulation in cell obviously reduce approximately 17% and 21% compared with uranium contamination control group, its effect is increase trend with dosage increase, and DTPA-CaNa
3in the time that concentration is increased to 250 μ mol/L, could block the picked-up of HK-2 cell to uranium.
(2) impact on HK-2 cell release uranium
After 10 μ mol/L uranyl acetate contamination HK-2 cell 24h, add respectively the CBMIDA-CaNa of 10,50 and 250 μ mol/L
2(sequestrant/uranium mol ratio is about respectively 8.8,44 and 220) effect 24h, with DTPA-CaNa
3as positive control, blank group and uranium contamination control group are set simultaneously.Result shows, 50 and 250 μ mol/L CBMIDA-CaNa
2can make uranium content in cell significantly reduce about 31%-48% compared with uranium contamination control group, and 10 μ mol/L CBMIDA-CaNa
2, without obvious effect, its effect is increase trend with dosage increase.DTPA-CaNa
3in the time that being increased to 250 μ mol/L, concentration also presents obvious row's uranium effect, but significantly lower than CBMIDA-CaNa
2effect (seeing Fig. 3 B).After 5 μ mol/L uranyl acetate contamination HK-2 cell 48h, add respectively the 250 μ mol/L CBMIDA-CaNa of 10,50 and 250 μ mol/L
2effect 24h(sequestrant/uranium mol ratio is about respectively 7.6,38 and 191), although the time lengthening that postpones administration to 48h, the CBMIDA-CaNa of 50 and 250 μ mol/L
2still show obvious row's uranium effect, make uranium content in cell reduce about 35%-40% compared with uranium contamination control group, and the CBMIDA-CaNa of 10 μ mol/L
2invalid; 250 μ mol/LDTPA-CaNa
3also the row's of not showing uranium effect.
Experimental result shows, Compound C BMIDA-CaNa
2can block the picked-up of HK-2 cell to uranium, delay 24h and 48h administration also can promote the discharge of uranium in HK-2 cell, significantly reduce accumulating of the interior uranium of cell, and its successful is better than DTPA-CaNa
3.
Embodiment 7
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt causes the provide protection test of HK-2 cell injury to uranium (VI)
This experiment is by detecting burst size and the micronucleus rate of formation of damaged cell serum lactic dehydrogenase (LDH), to evaluate CBMIDA-CaNa
2uranium (VI) is caused to the provide protection of HK-2 cell injury.
Adopt after 600 μ mol/L uranyl acetate contamination HK-2 cells, add immediately 50 and 250 μ mol/LCBMIDA-CaNa
2acting in conjunction 48h, or delay 24h adds CBMIDA-CaNa
2effect 24h, with DTPA-CaNa
3compare, blank group and uranium contamination control group be set simultaneously, adopt lactic acid as substrate, measure cell and discharge the amount of LDH by detecting the growing amount of product pyruvic acid dinitrophenylhydrazone in nutrient solution, adopt cytokinesis-block method to detect micronucleus and form.From Fig. 4 A and Fig. 4 B, 600 μ mol/L uranyl acetate contamination HK-2 cell 48h significantly increase LDH burst size and micronucleus rate of formation, are about 4 times of blank group; After uranium contamination, add respectively immediately 50 and 250 μ mol/LCBMIDA-CaNa
2effect 48h, or delay 24h adds CBMIDA-CaNa
2effect 24h, all can make LDH burst size and micronucleus rate of formation significantly reduce (P<0.05 and P<0.001) compared with uranium contamination control group, and its effect strengthens with dosage; And 50 and 250 μ mol/L DTPA-CaNa
3immediately or postpone administration and all fail obviously to reduce release and the micronucleus of the LDH of uranium induction and form.
Experimental result shows, compd B PCBG immediately or postpone 24h administration and all can protect uranium to cause damage and the chromosome damage of HK-2 cell, and DTPA-CaNa
3without obvious effect.
Embodiment 8
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt is tested the impact that in uranium (VI) induction HK-2 cell, oxyradical (ROS) produces
Take the logarithm vegetative period cell by every hole 8 × 10
3individual cell is inoculated in 96 orifice plates, 600 μ mol/L uranyl acetates and sequestrant acting in conjunction HK-2 cell 48h, or uranyl acetate is contaminated in advance after 24h and is added sequestrant effect 24h, CBMIDA-CaNa again
2and DTPA-CaNa
3concentration is 50 and 250 μ mol/L.After sequestrant is processed, adopt DCFH-DA fluorescent probe method, in multi-functional microplate reader (BioTek) 488nm excitation wavelength, 525nm transmitted wave strong point fluorescence intensity.The fluorescence intensity of fluorescence intensity/blank group of ROS amount (being the % of blank group)=each experimental group in cell.As seen from Figure 5, after 600 μ mol/L uranium contamination HK-2 cell 48h, induce ROS in HK-2 cell significantly to increase, be about 2.7 times of blank group.After dying uranium, add immediately sequestrant or delay 24h to add sequestrant, 50 μ mol/L and 250 μ mol/L CBMIDA-CaNa
2the ROS that all can significantly suppress uranium induction generates, and increasing restraining effect with drug level obviously increases, and 50 μ mol/L and 250 μ mol/LDTPA-CaNa
3without the effect of removing ROS.
Experimental result shows, Compound C BMIDA-CaNa
2can significantly suppress the generation of the interior ROS of cell of uranium induction, DTPA-CaNa
3invalid.
Claims (8)
1. compound [2, the 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) of general formula I or general formula II structure;
Wherein M represents calcium, zinc and magnesium, M ' represent sodium or potassium;
Wherein M represents Na
+or K
+;
Described calcium agent is calcium carbonate, citrate of lime or calcium lactate or calglucon;
Described zinc agent is ZnS0
47H
20, ZnCO
3, Zn (0Ac)
22H
20, ZnCl
2or zinc glycyrrhetate, Zinc Gluconate, zinc lactate or amino-acid zinc;
Described magnesia mixture is magnesium sulfate or Tianmen radon acid potassium magnesium.
2. by compound claimed in claim 1 [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate), it is characterized in that, in described general formula I, according to the difference of its chelated metal ions, the chemical name of its molecule is respectively:
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] disodium calcium ethylene diamine tetraacetate salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiumcalcium salt, CBMIDA-CaNa
2), it calculates molecular weight is 482;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) two potassium calcium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium salt, CBMIDA-CaK
2), it calculates molecular weight is 514;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium zinc salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiumzinc salt, CBMIDA-ZnNa
2), it calculates molecular weight is 507;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium zinc salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium zinc salt, CBMIDA-ZnK
2), it calculates molecular weight is 539;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium magnesium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acid disodiummagnesium salt, CBMIDA-MgNa
2), it calculates molecular weight is 466;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium magnesium salts ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic aciddipotassium magnesium salt, CBMIDA-MgK
2), it calculates molecular weight is 498.
3. by compound claimed in claim 1 [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate), it is characterized in that, in described general formula II, according to the difference of its chelated metal ions, the chemical name of its molecule is respectively:
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylene diamine tetraacetic acid tetrasodium salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acidtetrasodium salt, CBMIDA-Na
4), it calculates molecular weight is 488;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) four sylvite ([2,3-dihydroxy-1,4-phenylene] diaminetetraacetic acidtetrapotassium salt, CBMIDA-K
4), it calculates molecular weight is 520.
By compound claimed in claim 1 [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) in the purposes of preparing in the poisoning or internal contamination medicine of radiotherapy nucleic uranium, thorium or cerium group of the lanthanides nucleic or actinium series nucleic.
5. purposes as claimed in claim 4, is characterized in that, described compound reduces the toxic side effect of its monovalent metal cation salt.
6. a radiotherapy nucleic uranium, thorium or cerium group of the lanthanides nucleic or actinium series nucleic is poisoning or the medicinal compositions of internal contamination, it is characterized in that, its removing toxic substances by the compound of claim 1 or 2 or 3 and decorporation effective dose form with acceptable pharmaceutical excipient or calcium agent, zinc agent or magnesia mixture.
7. by medicinal compositions claimed in claim 6, it is characterized in that, described medicinal compositions is for intramuscular injection or oral administration, and wherein calcium salt is for intravenous drip.
8. by medicinal compositions claimed in claim 6, it is characterized in that, described medicinal compositions is at acute uranium, thorium or cerium before poisoning or internal contamination, use simultaneously or afterwards.
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| WO2010056992A1 (en) * | 2008-11-13 | 2010-05-20 | The Trustees Of Columbia University In The City Of New York | Methods of preventing and treating low bone mass diseases |
| CN102727473A (en) * | 2011-04-08 | 2012-10-17 | 复旦大学 | Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof |
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| CN102727473A (en) * | 2011-04-08 | 2012-10-17 | 复旦大学 | Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof |
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