CN103848749B - Compound [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) and medicinal compositions thereof and application - Google Patents
Compound [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) and medicinal compositions thereof and application Download PDFInfo
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Abstract
The invention belongs to chemical field, be specifically related to compound [2,3-dihydroxyl-1,4-penylene] ethylenediaminotetraacetate (edetate) (be called for short: bis-phenol ethylenediaminotetraacetate (edetate)) and medicinal compositions thereof and application, the especially application of drug combination in the radionuclide internal contaminations such as treatment uranium, thorium and cerium of this compound.By [2 in the present invention, 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 use clinically at present in order to reduce the toxicity of single sodium salt and the wide spectrum nucleic decorporation medicine DTPA-CaNa for preparing
3and DTPA-ZnNa
3relatively, there is higher, potential social benefit and application prospect.
Description
Technical field
The invention belongs to chemical field, be specifically related to compound [2,3-dihydroxyl-1,4-penylene] ethylenediaminotetraacetate (edetate) (be called for short: bis-phenol ethylenediaminotetraacetate (edetate)) and medicinal compositions thereof and application, the especially application of drug combination in the radionuclide internal contaminations such as treatment uranium, thorium and cerium of 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, and uranium or the charging of nuclear bomb, depleted uranium can be used for preparing military issue weapons etc.Research display, can produce a large amount of fission product in the reaction of nuclear reactor fuel fission, wherein cerium-144 is a kind of nucleic that in fission products, yield is higher, is to one of personnel's main nucleic producing internal radiation after nuclear reactor accident occurs.Once radionuclide enters human body cause internal contamination, will produce serious harm to HUMAN HEALTH, such as, 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 late period can bring out bone tumor; 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.The discharge using sequestrant class medicine to accelerate internal radionuclide is main remedy measures, adopt sodium bicarbonate treatment uranium poisoning to obtain certain effect at present clinically, but it is just effective that body need be made to 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 chemical structure of main chelation group in the iron chelating agent-Microbial Iron transporter of potent, the highly selective that the domestic and international researchist in this area utilizes biomimetic chemistry principle for many years, produce according to microorganism, design and synthesis hydroxyl palate acids, catechol (CAM) and hydroxylpyridinones (HOPO) sequestrant screen for the removal effect of actinium series nucleic, to obtaining compound that is efficient, low toxicity.The animal experiment study such as U.S. Durbin finds hydroxylpyridinones sequestrant 3 in recent years, 4,3-LI (1,2-HOPO) with 5-LIO (Me-3,2-HOPO) to uranium poisoning rat, there is row's uranium effect preferably, significantly can reduce kidney uranium accumulation, it is all effective to postpone administration and oral administration after uranium poisoning, but still locates the laboratory study stage at present.The removing toxic substances that the domestic CAM of studies have found that quasi-chelate compound bis-phenol ethylenediamine tetraacetic acid (EDTA) (CBMIDA) and 8102 (its activeconstituents is CBMIDA) has had uranium poisoning rat and removal effect, and 8102 pairs of thoriums and cerium internal contamination rat also have good removal effect.8102 is derivatives of CBMIDA, and it improves the stability of compound by the catechol group of acetylize CBMIDA; Because CBMIDA and 8102 is water-soluble hardly, commonly use sodium bicarbonate aqueous solution during experimentation on animals and CBMIDA and 8102 is dissolved as CBMIDA sodium-salt aqueous solution to use (8102 meet alkaline matter in water is decomposed into CBMIDA).
Research also shows, sequestrant class medicine is while the autologous interior discharge of accelerating radioactive nuclear element, and also produce toxic side effect to body, its major cause is: sequestrant often can combine with the metal ion in body and make it to excrete, 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, thus affect the physiological function such as the synthesis of nucleic acid and protein, the metabolism of organism and produce toxic side effect.And for example, K
+being the main monovalent cation maintaining cell normal physiological activity in body, is 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 guarantee.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, to tackle the needs of Nuclear Accident Emergency treatment, be specifically related to pharmacy acceptable [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] application of drug combination in the radionuclide internal contaminations such as treatment uranium, thorium and cerium of ethylenediaminotetraacetate (edetate) and medicinal compositions and this compound.
Summary of the invention
The object of this invention is to provide acceptable [2, the 3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate) of a kind of pharmacy and medicinal compositions thereof, the medicinal compositions of itself and calcium agent or zinc agent or magnesia mixture and application
The present invention take CBMIDA as primer, according to the chemical property of its pyrocatechol ammonia carboxylic acid chelation group, by divalent-metal ion Ca required 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 that is efficient, low toxicity; And for improving the chemical stability of the various salt of CBMIDA, adding pharmaceutical excipient is prepared into medicinal compositions; And, the toxicity produced is exhausted for reducing body divalent-metal ion, make medicinal compositions with CBMIDA sodium salt or CBMIDA sylvite and calcium agent or zinc agent or magnesia mixture or adopt Combined Preparation mode, there is provided 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, 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; the effect of radionuclide accumulation, protection kidney and bone injury in remarkable reduction kidney, bone and liver, and toxic side effect obviously reduces.
In the present invention; the medicinal compositions of described calcium, zinc and magnesium salt compound and medicinal compositions, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture through Combined Preparation have protect uranium cause nephrocyte damage in effect; by suppressing people proximal tubular cell to the picked-up of uranium and promoting the release of uranium in cell, remove the generation of oxyradical in the cell of uranium induction, reduce chromosome damage and cell injury.
In the present invention, medicinal compositions and the Combined Preparation thereof of described calcium, zinc and magnesium salt compound and medicinal compositions, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture use, also by intravenous drip administration when the medicinal compositions of wherein its calcium salt and medicinal compositions, sodium salt or sylvite and calcium agent or drug combination by route of administration such as intramuscular injection, oral administration or nose sprayings; In addition, the medicinal compositions of calcium, zinc and magnesium salt compound and medicinal compositions, sodium salt or potassium salt compound and calcium agent, zinc agent or magnesia mixture and Combined Preparation can also administration immediately, the administrations in advance and postpone administration after poisoning or internal contamination at radionuclide.
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, toxic side effect can be reduced.
Wherein M represents calcium, zinc and magnesium, and M ' represents 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] diaminetetraaceticaciddisodiumcalciumsalt, CBMIDA-CaNa
2), it calculates molecular weight is 482.
(2) [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) two potassium calcium salt ([2,3-dihydroxy-1,4-phenylene] diaminetetraaceticaciddipotassiumsalt, 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] diaminetetraaceticaciddisodiumzincsalt, 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] diaminetetraaceticaciddipotassiumzincsalt, 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] diaminetetraaceticaciddisodiummagnesiumsalt, 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] diaminetetraaceticaciddipotassiummagnesiumsalt, 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 toxic side effect be reduced,
Wherein M represents Na
+or K
+;
Described calcium agent be inorganic calcium 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)
22H
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] diaminetetraaceticacidtetrasodiumsalt, 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] diaminetetraaceticacidtetrapotassiumsalt, 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 proximal tubular cell to the picked-up of uranium, promote the release of uranium in nephrocyte, the chromosome damage of protection uranium induction and cell injury, in the cell that its mechanism of action and its removing uranium are induced, oxyradical produces relevant.
By [2 in the present invention, 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 use clinically at present in order to reduce the toxicity of single sodium salt and the wide spectrum nucleic decorporation medicine DTPA-CaNa for preparing
3and DTPA-ZnNa
3relatively, there is higher, potential social benefit and application prospect.
Accompanying drawing explanation
Fig. 1 is CBMIDA-CaNa
2administration immediately to the removal effect of uranium poisoning rat,
Wherein, im sequestrant immediately after A:ip uranyl acetate 100 μ g/ mouse, 24h urinates uranium output, compares, * * p<0.01 with uranium poisoning control group;
Im sequestrant immediately after B:ip uranyl acetate 100 μ g/ mouse, uranium accumulation in 24h kidney, bone, compares with uranium poisoning control group, * p<0.05, * * * p<0.001.
Fig. 2 is CBMIDA-CaNa
2administration immediately to the improvement of uranium poisoning renal tissues of rats pathology damage (HE dyeing × 400),
Wherein: arrow indication position is protein cast, epithelial cell necrosis comes off and inflammatory cell.
Fig. 3 is CBMIDA-CaNa
2on uranium contamination HK-2 cellular uptake and the impact discharging uranium,
Wherein: compare with uranium control group of contaminating,
*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 release and micronucleus are formed, wherein: compare with blank group, * * * P<0.001; Compare with uranium control group of contaminating,
#p<0.05,
###p<0.001.
Fig. 5 is CBMIDA-CaNa
2on the impact that ROS in uranium induction HK-2 cell produces,
Wherein: compare with uranium control group of contaminating, * P<0.05, * * * P<0.001; Under same treatment condition, the CBMIDA-CaNa of different concns
2compare between group,
#p<0.05,
##,p<0.01.
Embodiment
Embodiment 1
Preparation [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] disodium calcium ethylene diamine tetraacetate salt and disodium zinc salt
[2 are added in 500mL flask, 3-dihydroxyl-1, 4-penylene] ethylenediamine tetraacetic acid (EDTA) (30g), distilled water 300mL, add 4.2gCaO or 6.1gZnO under stirring and obtain solution in 150mL water, add rear reaction solution and at room temperature stir certain hour, then filter, after filter cake respectively washs 1 time with water and ethanol, proceed in 500mL reaction flask, add 250mL dehydrated alcohol, then 6gNaOH is dripped, filter after adding rear stirring half an hour, filter cake is with after absolute ethanol washing 2 times, dry pewter or brown solid 33-35g in vacuum drier, 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, containing a part calcium and two molecule sodium in [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt; Containing a part zinc and two molecule sodium in [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) zinc sodium salt.
Embodiment 2
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 cleaning grade Kunming mouse, body weight 20 ± 2g, by body weight random packet, every dosage group 10, male and female half and half.4-5 the disposable tail vein injection administration of dosage is selected by 8.5 folding geometric progressions, or adopt maximum dosage-feeding method, point 2 maximum dosages of tail vein injection (calcium disodium) in 1.5h, Continuous Observation 14d, observe and record the symptom of the general status of mouse, death condition, appearance, and time, severity, time length etc. that symptom is initial, adopt Bliss method to calculate the LD of various salt
50.Result shows, the disposable iv of mouse [2,3-dihydroxyl-1,4-penylene] after ethylenediamine tetraacetic acid (EDTA) sodium salt 0.68,0.80,0.941 and 1.107g/kg, dead animal all after iv in 1-2min in twitch and dead, with dosage increase tic more serious, death is faster; In, the mouse of low dose group survival recovers normal there is slight tic after iv after, has no death afterwards 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, after dead animal is also iv in 1-2min in twitch and dead, twitch more serious with dosage increase, death is faster; Non-evident sympton after low dose group survival mice iv appears that after iv slight rear recovery of twitching is normal, in the mouse of high, middle dosage group survival; After iv administration, survival mice has no dead in 14d afterwards; Calculate its LD
50for 1.922g/kg.Adopt maximum dosage-feeding method, with maximal dose point secondary iv [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt 5g/kg in the 1.5h of interval, 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 (maximum dosage 5g/kg has no dead), the toxicity of its calcium disodium is very low.
Table 1 is the medium lethal dose calculating [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt by Bliss method.
Table 2 is the medium lethal doses 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=the 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=the 1.6871--2.462g/kg of LD50 (Feiller correction) 95%
LD5＝1.1107g/kg
LD95＝3.3259g/kg。
Embodiment 3
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt and calglucon combines or the Mouse Acute Toxicity of drug combination
Adopt cleaning grade Kunming mouse, body weight 20 ± 2g, by body weight random packet, every dosage group 10, 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, its mol ratio is made to 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 the symptom of the general status of mouse, death condition, appearance, and time, severity, time length etc. that symptom is initial.Result shows, and after [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] the ethylenediamine tetraacetic acid (EDTA) sodium salt of disposable iv1:1 and 1:0.5 of mouse and calglucon mixed solution, animal has no tic, and has no dead in 14d; When the dosage of reduction calglucon makes both mol ratios be 1:0.1 and 1:0.05, all there is the tic of severe or pole severe immediately in animal after iv, recovers in survival mice 5min, and dead animal is namely dead in 1-2min after iv; Reduction with calglucon dosage is twitched more serious, and death is faster; The mouse recovered after twitching has no dead in 14d afterwards.All dead in 1min after the mouse administration of simple iv [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) sodium salt.
Table 3 is that 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 is on the impact of mouse death rate.
Table 3
Embodiment 4
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt adopts cleaning grade SD male rat to the removal effect of acute uranium internal contamination rat, im120 μm of ol/kgCBMIDA-CaNa immediately after 180-220g, ip100 μ g/ mouse uranyl acetate
2with 600 μm of ol/kgDTPA-CaNa
3, collect 24h urine after uranium contamination, put to death rat simultaneously and get two side kidney and femurs, after treatments of the sample process, adopt ICP-MS to measure urine uranium output and kidney, uranium accumulation in bone.From Figure 1A and 1B, CBMIDA-CaNa
2group rat 24h urinates uranium output significantly to be increased (p<0.01), than uranium poisoning control group increase about 72%, in kidney, bone, uranium accumulation obviously reduces (p=0.000, p<0.05), about 76% and 28% is reduced than uranium poisoning control group respectively.Compare CBMIDA-CaNa
2the DTPA-CaNa of high 5 multiple doses
3can make the comparatively uranium poisoning control group reduction about 37% of kidney uranium accumulation, but urine uranium output has no remarkable increase, bone uranium accumulation has no obvious decline.
Experimental result shows, Compound C BMIDA-CaNa
2obviously can promote the autologous interior discharge of uranium, significantly reduce kidney, bone uranium accumulation, be obviously better than DTPA-CaNa
3.
Embodiment 5
The provide protection test that [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt damages acute uranium poisoning kidney of rats
Adopt cleaning grade SD male rat, difference im600 μm of ol/kgCBMIDA-CaNa immediately after 180-220g, ip uranyl acetate 500 μ g/ mouse
2and 1.2mmol/kgDTPA-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 side renal tissue, 10% formaldehyde solution is fixed, paraffin embedding, section, and HE dyes, its histopathology morphologic change of basis of microscopic observation.Result shows, and after rat ip500 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 μm of ol/kg) administration immediately then makes serum creatinine and urea nitrogen content obvious reduction compared with uranium poisoning group (P < 0.001), reach levels found in normal controls, show and injury of the kidney is caused to uranium have 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 comparatively uranium poisoning group has compared obvious reduction (P < 0.01), but successful is lower than CBMIDA-CaNa
2effect (as shown in table 4).Renal pathology result shows, and have a large amount of protein cast in rat ip500 μ g uranyl acetate 48h metanephric tubule, the necrosis of part proximal tubular cell comes off, and the indivedual inflammatory cell of interstitial is dispersed in infiltration, but dia-betic rats structure is roughly normal.CBMIDA-CaNa
2(600 μm of ol/kg) administration immediately obviously can alleviate the pathology damage that uranium causes nephridial tissue, rarely seen individual protein cast and epithelial cell shedding; And DTPA-CaNa
3(1.2mmol/kg) administration immediately causes Renal tissues damage to uranium and has no obvious improvement; more protein cast is still had in uriniferous tubules; the necrosis of part proximal tubular 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
2administration is immediately on the impact of uranium poisoning rat blood serum creatinine and blood urea nitrogen.
Table 4
Note: compare with Normal group,
*p < 0.01,
* *p < 0.001
Compare with uranium poisoning group,
#p < 0.05,
##p < 0.01,
###p < 0.001
With CBMIDA-CaNa
2group compares ,+P < 0.05
Embodiment 6
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt is to the decorporation test of uranium (VI) contamination people's proximal tubular cell (HK-2 cell)
(1) on the impact of HK-2 cellular uptake uranium
After 1 μm of ol/L uranyl acetate contamination HK-2 cell, add the CBMIDA-CaNa of 50 and 250 μm of ol/L immediately respectively
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 μm of ol/LCBMIDA-CaNa
2all obviously can block the picked-up of HK-2 cell to uranium, to make in cell uranium accumulation comparatively uranium contamination control group obviously reduce about 17% and 21%, its effect increases in increase trend with dosage, and DTPA-CaNa
3when concentration is increased to 250 μm of ol/L, the picked-up of HK-2 cell to uranium could be blocked.
(2) on the impact of HK-2 cell release uranium
After 10 μm of ol/L uranyl acetate contamination HK-2 cell 24h, add the CBMIDA-CaNa of 10,50 and 250 μm of ol/L respectively
2(sequestrant/uranium mol ratio is about 8.8,44 and 220 respectively) effect 24h, with DTPA-CaNa
3as positive control, blank group and uranium contamination control group are set simultaneously.Result shows, 50 and 250 μm of ol/LCBMIDA-CaNa
2can to make in cell uranium content comparatively uranium contamination control group significantly reduce about 31%-48%, and 10 μm of ol/LCBMIDA-CaNa
2then without obvious effect, its effect increases in increase trend with dosage.DTPA-CaNa
3also significantly row's uranium effect is presented when concentration is increased to 250 μm of ol/L, but significantly lower than CBMIDA-CaNa
2effect (see Fig. 3 B).After 5 μm of ol/L uranyl acetate contamination HK-2 cell 48h, add 250 μm of ol/LCBMIDA-CaNa of 10,50 and 250 μm of ol/L respectively
2effect 24h (sequestrant/uranium mol ratio is about 7.6,38 and 191 respectively), although the time lengthening of delay administration is to 48h, the CBMIDA-CaNa of 50 and 250 μm of ol/L
2still show significantly row's uranium effect, to make in cell uranium content comparatively uranium contamination control group reduce about 35%-40%, and the CBMIDA-CaNa of 10 μm of ol/L
2then invalid; 250 μm of ol/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, postpone the discharge that 24h and 48h administration also can promote uranium in HK-2 cell, significantly reduce the accumulation of uranium in cell, 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 by detect damaged cell serum lactic dehydrogenase (LDH) burst size and micronuclcus formation, to evaluate CBMIDA-CaNa
2uranium (VI) is caused to the provide protection of HK-2 cell injury.
After adopting 600 μm of ol/L uranyl acetate contamination HK-2 cells, add 50 and 250 μm of ol/LCBMIDA-CaNa immediately
2acting in conjunction 48h, or delay 24h adds CBMIDA-CaNa
2effect 24h, with DTPA-CaNa
3compare, blank group and uranium contamination control group are set simultaneously, adopt lactic acid as substrate, the amount being measured cell release LDH by the growing amount detecting product acetone acid dinitrophenylhydrazone in nutrient solution, adopt cytokinesis-block method to detect micronucleus and formed.From Fig. 4 A and Fig. 4 B, 600 μm of ol/L uranyl acetate contamination HK-2 cell 48h make LDH burst size and micronuclcus formation significantly increase, and are about 4 times of blank group; 50 and 250 μm of ol/LCBMIDA-CaNa are added immediately respectively after uranium contamination
2effect 48h, or delay 24h adds CBMIDA-CaNa
2effect 24h, all can make LDH burst size and micronuclcus formation comparatively uranium contamination control group significantly reduce (P<0.05 and P<0.001), its effect with dosage increase and strengthen; And 50 and 250 μm of ol/LDTPA-CaNa
3immediately or postpone administration and all fail obviously to reduce the release of the LDH of uranium induction and micronucleus is formed.
Experimental result shows, Compound C BMIDA-CaNa
2immediately or postpone 24h administration uranium all can be protected to cause damage and the chromosome damage of HK-2 cell, DTPA-CaNa
3without obvious effect.
Embodiment 8
The impact test that [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] EDTA calcium complex disodium salt produces oxyradical (ROS) in uranium (VI) induction HK-2 cell
Take the logarithm vegetative period cell by every hole 8 × 10
3individual cell is inoculated in 96 orifice plates, 600 μm of ol/L uranyl acetates and sequestrant acting in conjunction HK-2 cell 48h, or uranyl acetate is contaminated in advance after 24h and added sequestrant effect 24h again, CBMIDA-CaNa
2and DTPA-CaNa
3concentration is 50 and 250 μm of ol/L.After sequestrant process, adopt DCFH-DA fluorescence probe method, in multi-functional microplate reader (BioTek) 488nm excitation wavelength, 525nm transmitted wave strong point fluorescence intensity.In cell, ROS measures the fluorescence intensity of the fluorescence intensity/blank group of (% for blank group)=each experimental group.As seen from Figure 5, induce ROS in HK-2 cell significantly to increase after 600 μm of ol/L uranium contamination HK-2 cell 48h, be about 2.7 times of blank group.Add sequestrant after dye uranium immediately or postpone 24h and add sequestrant, 50 μm of ol/L and 250 μm ol/LCBMIDA-CaNa
2the ROS that all can significantly suppress uranium to be induced generates, and increasing restraining effect with drug level obviously increases, and 50 μm of ol/L and 250 μm ol/LDTPA-CaNa
3without the effect of removing ROS.
Experimental result shows, Compound C BMIDA-CaNa
2the generation of ROS in the cell that can significantly suppress uranium to be induced, DTPA-CaNa
3then invalid.
Claims (6)
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, and M ' represents 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;
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, it calculates molecular weight is 482;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) two potassium calcium salt, it calculates molecular weight is 514;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium zinc salt, it calculates molecular weight is 507;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium zinc salt, it calculates molecular weight is 539;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] edetate disodium magnesium salts, it calculates molecular weight is 466;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) dipotassium magnesium salts, it calculates molecular weight is 498;
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, it calculates molecular weight is 488;
[2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediamine tetraacetic acid (EDTA) four sylvite, it calculates molecular weight is 520.
2. preparing radiotherapy nucleic uranium, thorium or cerium group of the lanthanides nucleic or actinium series nucleic is poisoning or purposes in internal contamination medicine by compound according to claim 1 [2,3-dihydroxyl-Isosorbide-5-Nitrae-penylene] ethylenediaminotetraacetate (edetate).
3. purposes as claimed in claim 2, it is characterized in that, described compound reduces the toxic side effect of its monovalent metal cation salt.
4. 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, it is made up of with acceptable pharmaceutical excipient or calcium agent, zinc agent or magnesia mixture the removing toxic substances of the compound of claim 1 and decorporation effective dose.
5. by medicinal compositions according to claim 4, it is characterized in that, described medicinal compositions is used for intramuscular injection or oral administration, and wherein calcium salt is used for intravenous drip.
6., by medicinal compositions according to claim 4, it is characterized in that, described medicinal compositions at acute uranium, thorium or cerium before poisoning or internal contamination, simultaneously or use afterwards.
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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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| 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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| 邻苯二酚-3,6-二甲撑亚氨基二乙酸的酸离解平衡及其与碱土金属、锰(Ⅱ)、镉(Ⅱ)、锌(Ⅱ)、钴(Ⅱ)、镍(Ⅱ)、铜(Ⅱ)、铁(Ⅱ)、钍(Ⅳ)及铀酰离子配合物稳定性的研究;张华麟等;《化学学报》;19881231(第07期);643-650 * |
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