CN102153542A - Ionizing radiation damage protection medicament - Google Patents
Ionizing radiation damage protection medicament Download PDFInfo
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- CN102153542A CN102153542A CN2011100006521A CN201110000652A CN102153542A CN 102153542 A CN102153542 A CN 102153542A CN 2011100006521 A CN2011100006521 A CN 2011100006521A CN 201110000652 A CN201110000652 A CN 201110000652A CN 102153542 A CN102153542 A CN 102153542A
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Abstract
The invention discloses a novel medicament for ionizing radiation damage protection. The medicament has a simple and convenient synthetic method. Molecules of the medicament contain nitrogen-oxygen free radical constitutional units. The novel medicament can be used for effectively eliminating harmful factors generated by ionizing radiation to organisms and has protection and treatment effect on ionizing radiation damage.
Description
Technical field
The invention provides a class novel anti ionization radiation injury protection medicine structure, can be used for the ionization radiation protection of multiple civil area and military field, belong to medical technical field.
Background technology
Along with the development of modern high technology, radiation extensively is present in natural " stealthy source of pollution " as a kind of, and human beings'health in serious threat in a lot of fields.Aspect space flight, space exists the Millikan's rays that high energy particle is formed, and density is big, penetrance is extremely strong
[1]Space travel has broken away from the natural defence in terrestrial magnetic field, and the cosmonaut will be in the delay of space deep space, and the radiation dose that is subjected to is bigger, and cosmic radiation becomes the vital factor that threatens cosmonaut's health even life security.
Aspect civilian: the diagnosis and treatment ray of medical institutions (X line, γ line) has also produced severe impairment to patient's healthy tissues, and is engaged in the health care personnel of ray diagnosis and treatment, because the Long contact time radioactive rays, body also can produce radiation injury; In addition, the whole world almost 16% electric energy is produced by nuclear power plant, but still has very strong radioactivity after nuclear fuel uses, and need reclaim, extracts, handle, and the staff suffers the radiating risk also very big in this process.
Except that above-mentioned two aspects, Nuclear weapons also can be launched the very strong ray of penetration power, can cause serious acute and chronic " radiation injury " as gamma-rays, β ray and neutron current etc., and the mankind are constituted a serious threat.
Ionizing rays can cause serious radiation damage, shows: 1. radiation induced carcinogenesis; 2. radioinduction; 3. organ lesion.Therefore, radio-protective research is extremely urgent.Medical protection is a kind of economy, convenience, effective means.
The radiation medicine protective agent kind of research mainly contains at present: ammonia sulfhydryl compound, estrogens compounds, cytokine, natral plant ingredients etc.First three kind poisonous side effect of medicine is bigger, and as ammonia sulfydryl class radio-protector amifostine (WR2721), though it approves, has been applied to clinical treatment through U.S. FDA, still bringing into play the curative effect required dosage approaches toxicity dose, has seriously limited it and has promoted the use of.And natral plant ingredients can only have certain protective effect to low dose radiation.Up to now, none ideal radio-protector still both at home and abroad.
Radioprotector emphasis of the present invention is used for special dimensions such as military medicine, aerospace medicine, also can be used for fields such as ray diagnosis and treatment, nuclear industry protection, has important military, civilian meaning.
Summary of the invention
The purpose of this invention is to provide one class preventing and control or treatment ionization radiation injury medicine, its general structure is as follows:
R1 to R5 independently is selected from H, NO
2, OH, halogen; A kind of preferred scheme is: any four substituting groups are hydrogen among the R1 to R5, and for example R2 is OH, and R1, R3, R4, R5 are H.Another kind of preferred scheme is: any three substituting groups are hydrogen among the R1 to R5, and for example R1 is OH, and R2 is NO
2, R3, R4, R5 are H.Described halogen is F, Cl or Br.
The synthetic of above-claimed cpd undertaken by following formula, changes substituted benzoyl chloride and can obtain series derivates.
Foundation is route of synthesis similarly, can synthesize to obtain following structure medicament:
Pharmacodynamics test proves: such medicine has significant protective effect to ionization radiation injury, and drug effect is suitable with the radiopharmaceutical WR2721 of listing at present, and this medicine toxicity is low.
Embodiment
Embodiment 1: compound 1 synthetic
In the three-necked bottle of 250 mL, add 3.0 g(30 mmol) dried meat ammonia alcohol, CH
2Cl
2100 mL, triethylamine 4.4 mL stir at the ice bath lower magnetic force, are added dropwise to then and contain 5.57 g(30 mmol) 50 mL CH of paranitrobenzoyl chloride
2Cl
2Solution.Remove ice bath after dropwising, stirring at room 24 h isolate organic phase, and water washing twice is arranged, and organic phase drying, column chromatography purification get product 6.4 g.
Above-mentioned product 1.0 g(4.0 mmol), 0.93 g(4.0 mmol) TCCA and 20 mL CH
2Cl
2, 0 ℃ is stirred 5 min, adds 0.006 g(0.04 mmol then) and TEMPO.Continue stirring reaction 20 min under the room temperature.Filter, merge organic phase, use saturated Na
2CO
30.1 molL is used in the liquid washing
-1HCl and saturated common salt water washing organic phase.Organic phase drying, column chromatography purification get product 0.69 g.
With above-mentioned product (0.62 g, 2.5 mmol), 2,3-dihydroxylamine-2,3-dimethylbutane 0.37 g(2.5 mmol) join in the 20mL methyl alcohol stirring reaction 6 h under the room temperature.Stopped reaction, methyl alcohol is removed in decompression, and resistates is suspended in 40 mL CH
2Cl
2In, ice bath drips and contains NaIO
4The 20 mL aqueous solution of (0.53 g, 2.5 mmol).Isolate organic phase, dry, column chromatography purification obtain product 478 mg, productive rate 50%.MS(m/z): 376.28 [M+H]
+; IR(KBr): 1368,1343,1160,1403,1380,2890,2981,1696,1282,1,251 1112,780; EPR (DMF): quintet, g=2.0066, | aN|=7.48G.Ultimate analysis: Found:C, 57.60; H, 6.16; N, 15.00 Calc. for C
18H
23N
4O
5, C, 57.59; H, 6.18; N, 14.92%.
Embodiment 2: compound 2 synthetic
In the three-necked bottle of 250 mL, add 3.0 g(30 mmol) dried meat ammonia alcohol, CH
2Cl
2100 mL, triethylamine 4.4 mL stir at the ice bath lower magnetic force, are added dropwise to then and contain 4.74 g(30 mmol) to 50 mL CH of fluorobenzoyl chloride
2Cl
2Solution.Remove ice bath after dropwising, stirring at room 24 h isolate organic phase, and water washing twice is arranged, and organic phase drying, column chromatography purification get product 5.5 g.
Above-mentioned product 0.89g(4.0 mmol), 0.93 g(4.0 mmol) TCCA and 20 mL CH
2Cl
2, 0 ℃ is stirred 5 min, adds 0.006 g(0.04 mmol then) and TEMPO.Continue stirring reaction 20 min under the room temperature.Filter, merge organic phase, use saturated Na
2CO
30.1 molL is used in the liquid washing
-1HCl and saturated common salt water washing organic phase.Organic phase drying, column chromatography purification get product 0.69 g.
With above-mentioned product (0.55 g, 2.5 mmol), 2,3-dihydroxylamine-2,3-dimethylbutane 0.37 g(2.5 mmol) join in the 20mL methyl alcohol stirring reaction 6 h under the room temperature.Stopped reaction, methyl alcohol is removed in decompression, and resistates is suspended in 40 mL CH
2Cl
2In, ice bath drips and contains NaIO
4The 20 mL aqueous solution of (0.53 g, 2.5 mmol).Isolate organic phase, dry, column chromatography purification obtain product 0.49g, productive rate 56%.MS(m/z): 349.41 [M+H]
+; Ultimate analysis: Found:C, 62.07; H, 6.61; N, 12.07; Calc. for C
18H
23FN
3O
3, C, 62.05; H, 6.65; N, 12.06%.
Embodiment 3: compound 3 synthetic
In the three-necked bottle of 250 mL, add 3.0 g(30 mmol) dried meat ammonia alcohol, CH
2Cl
2100 mL, triethylamine 4.4 mL stir at the ice bath lower magnetic force, are added dropwise to then and contain 4.68 g(30 mmol) 50 mL CH of parachlorobenzoyl chloride
2Cl
2Solution.Remove ice bath after dropwising, stirring at room 24 h isolate organic phase, and water washing twice is arranged, and organic phase drying, column chromatography purification get product 5.8 g.
Above-mentioned product 0.88g(4.0 mmol), 0.93 g(4.0 mmol) TCCA and 20 mL CH
2Cl
2, 0 ℃ is stirred 5 min, adds 0.006 g(0.04 mmol then) and TEMPO.Continue stirring reaction 20 min under the room temperature.Filter, merge organic phase, use saturated Na
2CO
30.1 molL is used in the liquid washing
-1HCl and saturated common salt water washing organic phase.Organic phase drying, column chromatography purification get product 0.78g.
With above-mentioned product (0.55 g, 2.5 mmol), 2,3-dihydroxylamine-2,3-dimethylbutane 0.37 g(2.5 mmol) join in the 20mL methyl alcohol stirring reaction 6 h under the room temperature.Stopped reaction, methyl alcohol is removed in decompression, and resistates is suspended in 40 mL CH
2Cl
2In, ice bath drips and contains NaIO
4The 20 mL aqueous solution of (0.53 g, 2.5 mmol).Isolate organic phase, dry, column chromatography purification obtain product 0.54g, productive rate 62%.MS(m/z): 365.31 [M+H]
+; Ultimate analysis: Found:C, 59.30; H, 6.33; N, 11.54; Calc. for C
18H
23ClN
3O
3, C, 59.26; H, 6.35; N, 11.52%.
Embodiment 4: the pharmacodynamic experiment of compound 1
(1) animal model replication and administration: male mouse of kunming is divided into normal control group, irradiation control group, positive drug control group at random and is subjected to reagent thing group, will be subjected to the reagent thing that 3 different dosage groups are set.The administration group is in pre-irradiation 30min abdominal cavity or gastric infusion, administration volume 0.5-1.0 milliliter (5%DMSO dissolving), and single administration, irradiation control group gives the physiological saline of equal volume, and except that the normal control group, all the other each treated animals are accepted disposable general irradiation.
(2) to the influence of acute radiation sickness mouse survival rate: observe the survival condition of exposure mouse every day, observe 30d continuously, record mouse situation, death toll, death time, observe the radiation resistance of medicine.
(3) result: the result shows that normal mouse body flesh is plentiful, and motion is fast strong, and eyes are scarlet and spiritedness is dense and glossy by hair.Be subjected to
60The minimizing of ingesting of mouse behind the Co-gammairradiation, the movable minimizing, by hair tarnish, fluffy, eyes lose normal gloss, have hemorrhagely sometimes, auricle and afterbody are pale, blood spots appears in the part Mice Auricle, diarrhoea, anus has the excrement mark.Compare pre-irradiation gives compound and can significantly improve irradiation mouse 30 days survival rates with model group.
Embodiment 5: the pharmacodynamic experiment of compound 2 ~ 5
Claims (7)
1. the medicines structure of general formula (I) expression,
R1 to R5 independently is selected from H, NO
2, OH, halogen.
2. medicines structure according to claim 1 is characterized in that: any four substituting groups are hydrogen among the R1 to R5.
3. medicines structure according to claim 1 is characterized in that: any three substituting groups are hydrogen among the R1 to R5.
4. according to one of any described medicines structure of claim 1 to 3, it is characterized in that: halogen is F, Cl or Br.
5. the application of the described compound of claim 1 in preparation prevention or treatment ionization radiation injury medicine.
6. pharmaceutical composition, it contains one of any described medicines structure of claim 1 to 3, and one or more pharmaceutical carriers or vehicle.
7. according to the described pharmaceutical composition of claim 6, it is characterized in that: this medicine is tablet, capsule, powder, pill, granule or emulsion.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100006521A CN102153542A (en) | 2011-01-04 | 2011-01-04 | Ionizing radiation damage protection medicament |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100006521A CN102153542A (en) | 2011-01-04 | 2011-01-04 | Ionizing radiation damage protection medicament |
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| CN102153542A true CN102153542A (en) | 2011-08-17 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070615A (en) * | 2011-01-25 | 2011-05-25 | 中国人民解放军第四军医大学 | Nitroxyl radical anti-tumor medicaments |
| CN104817488A (en) * | 2015-02-04 | 2015-08-05 | 中国人民解放军第四军医大学 | Application of sulfone-type nitroxide free radical as radiation protectant |
| CN104844516A (en) * | 2015-03-31 | 2015-08-19 | 西安工业大学 | Dual-functional radiation damage protection drug containing phenols and synthesis and application thereof |
| CN105037328A (en) * | 2015-07-16 | 2015-11-11 | 中国人民解放军第四军医大学 | Sulfone medicine for radiation damage protection, and preparation method and application of sulfone medicine |
| CN111943935A (en) * | 2020-08-21 | 2020-11-17 | 西安工业大学 | Prolinol rapid desulfurizing agent and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743316A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | 2-substituted phenyl-4,4,5,5-tetramethyl-1,3,-dioxy imidazolines, their preparation and pharmaceutical use |
-
2011
- 2011-01-04 CN CN2011100006521A patent/CN102153542A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743316A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | 2-substituted phenyl-4,4,5,5-tetramethyl-1,3,-dioxy imidazolines, their preparation and pharmaceutical use |
Non-Patent Citations (2)
| Title |
|---|
| XIANG-YANG QIN, ET AL: "Synthesis, characterisation, cytotoxicity and radioprotective effect of novel chiral nitronyl nitroxyl radicals", 《JOURNAL OF CHEMICAL RESEARCH》 * |
| 文静 等: "微波辐射损伤及防护研究进展", 《军事医学科学院院刊》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070615A (en) * | 2011-01-25 | 2011-05-25 | 中国人民解放军第四军医大学 | Nitroxyl radical anti-tumor medicaments |
| CN102070615B (en) * | 2011-01-25 | 2013-04-03 | 中国人民解放军第四军医大学 | Nitroxyl radical anti-tumor medicaments |
| CN104817488A (en) * | 2015-02-04 | 2015-08-05 | 中国人民解放军第四军医大学 | Application of sulfone-type nitroxide free radical as radiation protectant |
| CN104817488B (en) * | 2015-02-04 | 2018-04-24 | 中国人民解放军第四军医大学 | Application of the sulfone class NO free radical as radioprotectant |
| CN104844516A (en) * | 2015-03-31 | 2015-08-19 | 西安工业大学 | Dual-functional radiation damage protection drug containing phenols and synthesis and application thereof |
| CN104844516B (en) * | 2015-03-31 | 2017-12-19 | 西安工业大学 | Containing the difunctional radiation injury protection medicine of phenols and its synthesis and application |
| CN105037328A (en) * | 2015-07-16 | 2015-11-11 | 中国人民解放军第四军医大学 | Sulfone medicine for radiation damage protection, and preparation method and application of sulfone medicine |
| CN111943935A (en) * | 2020-08-21 | 2020-11-17 | 西安工业大学 | Prolinol rapid desulfurizing agent and preparation method thereof |
| CN111943935B (en) * | 2020-08-21 | 2023-02-10 | 西安工业大学 | Prolinol rapid desulfurizing agent and preparation method thereof |
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Application publication date: 20110817 |