CN102584683A - Synthesis of Tempol derivative and radiation protection effect - Google Patents
Synthesis of Tempol derivative and radiation protection effect Download PDFInfo
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Abstract
The invention relates to a compound shown in a structural general formula (I), wherein R is C1-C5 alkyl, alkylene or alkyloxy , x is a reasonable integer more than or equal to 1. According to the invention, a series of novel bifunctional free radical scavenger is designed and synthesized, a pharmacodynamic experiment proves that the compound possesses obvious the radiation protection effect, by taking WR2721 in the market as a positive control, the drug effect of the compound is equal with that of the WR2721, and the toxicity is substantially reduced.
Description
Technical field
The present invention provides one type of radioprotector that has phenolic hydroxyl group and TEMPO class NO free radical concurrently, can be used for the radio-protective in civilian and military field, belongs to medical technical field.
Background technology
Along with the application in science and technology, medical science, military affairs and daily life such as nuclear energy, electromagnetic energy are increasingly extensive, modern technique is brought easily simultaneously to the mankind, has also brought potential dangerous.People contact that the radiating chance is more and more, and health also can face serious threat, can receive irreversible infringement like reproductive system, neural system, immunity system, and radiation also is simultaneously the main inducing of cardiovascular, mellitus, cancer sudden change.
Radio-protective is divided into physical protection and chemical protection.When unknowable accidental exposure, physical protection is powerless, can only carry out radio-protective through chemotherapeutical method.Radiation injury control medicine is treatment and protects one of the most effective and direct means, before the contact radioactive substance, uses, and can prevent the damage of ray to human body; Receive and shine the back use, can alleviate the clinical symptom of radiation syndrome, promote early recovery.So the exploitation of radio-protective medicine has also just become the emphasis in the radiation medicine research field.As far back as the 1950's, people have at first carried out radio-protective research to sulfur alcohol compound, and it represents medicine is WR-2721 (amifostine), seek the attention that toxicity is low, curative effect is high radio-protective and radiation therapy medicine enjoy radiological medicine circle always.At present, the more radiation injury of research control drug main will comprise sulfocompound, hormones, plant amedica, cytokine class and based on the newtype drug of radiation injury Mechanism Study etc.
Wherein, phenolic cpd is more, the antioxygenation of research one type of radio-protective active substance preferably.The reactive group phenolic hydroxyl group can with the redox reaction of radical generation prototropy, eliminate excessive radical ROS in the body, avoid causing the damage of biomacromolecule from root, thereby the protective effect of playing, and reactive behavior is high, speed of response is fast.And another kind of free-radical scavengers---NO free radical has also received common attention in recent years.Oxynitride 4-hydroxyl-2,2,6,6-tetramethyl piperidine (TEMPO) are one type of important, as to have good radio-protective performance NO free radicals wherein, have anti-widely ROS effect, microbial film defencive function, biomacromolecule provide protection.To its good anti-radiation protection function, people study many TEMPO class NO free radical structures, have found to have the TEMPOL of outstanding antiradiation injury effect, and have not shown tangible toxicity, are applied to I phase clinical study thereupon.
Summary of the invention
The purpose of this invention is to provide one type of medicine and the compound method thereof that can effectively protect radiation injury.
The compound of general structure (I) expression,
Wherein, R is C
1-C
5Alkyl, alkylene, alkoxyl group, the reasonable integer of X>=1, so-called reasonable integer are value≤5 of X, are preferably 1 to 3 integer, R is preferably C
1-C
5Alkyl.
The preparation method of above-claimed cpd may further comprise the steps:
(1) at first carries out the hydroxyl protection of the substituted phenyl carboxylic acid of hydroxyl
;
(2) obtain corresponding acyl chlorides with the thionyl chloride reaction then;
(3) with the TEMPO reaction;
(4) the dehydroxylation protection obtains general formula (I) compound.
Concrete synthetic route is following:
Above-mentioned Ac representes ethanoyl.
A kind of pharmaceutical composition; It contains general formula (I) compound; And one or more pharmaceutical carriers and vehicle, sodium-chlor, glucose, lactose, Hydrocerol A, tartrate, Magnesium Stearate, terra alba, sucrose, W-Gum, talcum powder, gelatin, agar, pectin, peanut oil, sweet oil, theobroma oil, terepthaloyl moietie, xitix, N.F,USP MANNITOL etc.Pharmaceutical composition can be tablet, capsule, powder, pill, emulsion or granule.
Advantage of the present invention and positively effect: based on domestic and international research present situation and the research of contriver's previous experiments; Reaction characteristics and multiple existence form to radical; According to phenolic cpd and NO free radical different characteristics at the Green Tea Extract oxidative damage, the present invention's design, synthesized serial New-type bifunctional free-radical scavengers, pharmacodynamic experiment proves; General formula of the present invention (I) compound has tangible radio-protective effect; As positive control, drug effect is suitable with commercially available WR2721, and has significantly reduced toxicity.
Embodiment
Typical compound of the present invention is as follows,
Embodiment 1: compound 1 synthetic
In three neck round-bottomed flasks, add PHB 14.0g, it is dissolved in 25mL in the Glacial acetic acid min. 99.5 of no water treatment, be heated to 40
oAbout C, magneton stirs this solution, and slowly is warming up to 80
oC, solution fade to white opacity liquid, after 3 hours, and the TLC monitoring; Raw material also primitive reaction is complete, with the reaction solution cooling, pours into rapidly in the frozen water, filters; Washing obtains white solid product 15.2g, gets the 4-acetoxy-benzoic acid with the absolute ethyl alcohol recrystallization purifying.
In the single neck flask of 100mL, add the thionyl chloride that above-mentioned 4-acetoxy-benzoic acid of 10g and 40mL heavily steam, magneton stirs, and 80
oC reacts 4h, and air distillation is steamed and removed thionyl chloride, gets white-yellowish solid, and the sherwood oil recrystallization gets product 4-acetoxyl group Benzoyl chloride 99min. 8.3g.
In 250mL three neck round-bottomed flasks, add TEMPOL10g, with 30mL through no water treatment methylene dichloride dissolving, add anhydrous triethylamine 30mL again; Ice bath; Magneton stirs, and adds the dichloromethane solution of 8g 4-acetoxyl group Benzoyl chloride 99min. in the constant pressure funnel, keeps reacting liquid temperature 4
oSlowly drip solution of acid chloride below the C, dropwise solution is risen to room temperature, reaction 3h, the TLC monitoring, reaction finishes.Aftertreatment: reaction solution adds water, isolates organic layer, washes three times, and back column chromatography gets the red solid product.
In the single neck flask of 100mL; With 50mL methylene dichloride dissolving 3.2g above-claimed cpd, the solution that 0.9g Guanidinium hydrochloride and 1.2g potassium tert.-butoxide are dissolved in the 20mL methyl alcohol slowly drops in the above-mentioned solution stirring at room 30 minutes; Steam solvent, column chromatography gets compound 1 1.7g.HRMS(m/z):?293.97[M+H]
+?,?IR(KBr): 3265,?2982,?1698,?1610,?1516,?1436,?1308,?1280,?1217,?1162,?1113,?1094,?847 EPR（CH
2Cl
2）：g?factor,?2.019
Embodiment 2: compound 2 synthetic
In three neck round-bottomed flasks, add p-hydroxyphenylaceticacid 15.0g, it is dissolved in 20mL in the Glacial acetic acid min. 99.5 of no water treatment, be heated to 40
oAbout C, magneton stirs this solution, and slowly is warming up to 85
oC, solution fade to white opacity liquid, after gradual change clarification again, after 5 hours; The TLC monitoring, raw material also primitive reaction is complete, with the reaction solution cooling, pours in the small amount of ice water rapidly; Filter, washing obtains white solid product 11.2g, gets 4-acetoxyl group toluylic acid with the absolute ethyl alcohol recrystallization purifying.
In the single neck flask of 100mL, add the thionyl chloride that above-mentioned 4-acetoxyl group toluylic acid of 10g and 40mL heavily steam, magneton stirs, and 80
oC reacts 5h, and air distillation is steamed and removed thionyl chloride, gets white-yellowish solid, and the sherwood oil recrystallization gets product 4-acetoxyl group phenyllacetyl chloride 8.9g.
In 250mL three neck round-bottomed flasks, add TEMPOL10g, with 30mL through no water treatment methylene dichloride dissolving, add anhydrous triethylamine 25mL again; Ice bath; Magneton stirs, and adds the dichloromethane solution of 8g 4-acetoxyl group phenyllacetyl chloride in the constant pressure funnel, keeps reacting liquid temperature 4
oSlowly drip solution of acid chloride below the C, dropwise solution is risen to 10
oC, reaction 4h, the TLC monitoring, reaction finishes.Aftertreatment: reaction solution adds water, isolates organic layer, washes three times, and back column chromatography gets the red solid product.
In the single neck flask of 100mL; With 50mL methylene dichloride dissolving 3.8g above-claimed cpd, the solution that 0.9g Guanidinium hydrochloride and 1.2g potassium tert.-butoxide are dissolved in the 20mL methyl alcohol slowly drops in the above-mentioned solution stirring at room 20 minutes; Steaming desolventizes, and column chromatography gets compound 2 1.8g.HRMS(m/z):?307.54?[M+H]
+?,?IR(KBr): 3261,?2980,?1704,?1604,?1496,?1328,?1260,?1192,?1142,?1093,?845?EPR（CH
2Cl
2）：g?factor,?2.091
Embodiment 3: compound 3 synthetic
In three neck round-bottomed flasks, add 3,5-resorcylic acid 15.0g is dissolved in 40mL in the Glacial acetic acid min. 99.5 of no water treatment with it, is heated to 40
oAbout C, magneton stirs this solution, and slowly is warming up to 90
oC, solution fade to white opacity liquid, after 8 hours, and the TLC monitoring; Raw material also primitive reaction is complete, with the reaction solution cooling, pours into rapidly in the small amount of ice water, filters; Washing obtains white solid product 16.2g, gets 3 with the absolute ethyl alcohol recrystallization purifying, 5-diacetoxy phenylformic acid.
In the single neck flask of 100mL, add 12g above-mentioned 3, the thionyl chloride that 5-acetoxy-benzoic acid and 40mL heavily steam, magneton stirring, 80
oC reacts 5h, and air distillation is steamed and removed thionyl chloride, gets white-yellowish solid, and the sherwood oil recrystallization gets product 3,5-diacetoxy Benzoyl chloride 99min. 10.9g.
In 250mL three neck round-bottomed flasks, add TEMPOL10g,, add anhydrous triethylamine 30mL again with the methylene dichloride dissolving of 30mL through no water treatment; Ice bath, magneton stirs, and adds 10g 3 in the constant pressure funnel; The dichloromethane solution of 5-diacetoxy Benzoyl chloride 99min. keeps reacting liquid temperature 4
oSlowly drip solution of acid chloride below the C, dropwise solution is risen to room temperature, reaction 5h, the TLC monitoring, reaction finishes.Aftertreatment: reaction solution adds water, isolates organic layer, washes three times, and back column chromatography gets the red solid product.
In the single neck flask of 100mL; With 50mL methylene dichloride dissolving 4.5g above-claimed cpd, the solution that 1.8g Guanidinium hydrochloride and 2.4g potassium tert.-butoxide are dissolved in the 30mL methyl alcohol slowly drops in the above-mentioned solution stirring at room 30 minutes; Steaming desolventizes, and column chromatography gets compound 3 2.9g.HRMS(m/z):?309.51?[M+H]
+?,?IR(KBr):?3266,?2987,?1690,?1640,?1511,?1430,?1331,?1283,?1217,?1165,?1110,?1095,?849; EPR（CH
2Cl
2）：g?factor,?1.998
Embodiment 4: compound 4 synthetic
In three neck round-bottomed flasks, add 3,4-resorcylic acid 15.0g is dissolved in 40mL in the Glacial acetic acid min. 99.5 of no water treatment with it, is heated to 40
oAbout C, magneton stirs this solution, and slowly is warming up to 90
oC, solution fade to white opacity liquid, after 8 hours, and the TLC monitoring; Raw material also primitive reaction is complete, with the reaction solution cooling, pours into rapidly in the small amount of ice water, filters; Washing obtains white solid product 16.1g, gets 3 with the absolute ethyl alcohol recrystallization purifying, 4-diacetoxy phenylformic acid.
In the single neck flask of 100mL, add 12g above-mentioned 3, the thionyl chloride that 4-diacetoxy phenylformic acid and 40mL heavily steam, magneton stirring, 80
oC reacts 5h, and air distillation is steamed and removed thionyl chloride, gets white-yellowish solid, and the sherwood oil recrystallization gets product 3,4-diacetoxy Benzoyl chloride 99min. 10.2g.
In 250mL three neck round-bottomed flasks, add TEMPOL10.0g,, add anhydrous triethylamine 30mL again with the methylene dichloride dissolving of 30mL through no water treatment; Ice bath, magneton stirs, and adds 10.0g 3 in the constant pressure funnel; The dichloromethane solution of 4-diacetoxy Benzoyl chloride 99min. keeps reacting liquid temperature 4
oSlowly drip solution of acid chloride below the C, dropwise solution is risen to room temperature, reaction 5h, the TLC monitoring, reaction finishes.Aftertreatment: reaction solution adds water, isolates organic layer, washes three times, and back column chromatography gets the red solid product.
In the single neck flask of 100mL; With 50mL methylene dichloride dissolving 4.2g above-claimed cpd, the solution that 1.8g Guanidinium hydrochloride and 2.4g potassium tert.-butoxide are dissolved in the 30mL methyl alcohol slowly drops in the above-mentioned solution stirring at room 30 minutes; Steaming desolventizes, and column chromatography gets compound 4 2.5g.HRMS(m/z):?309.39 [M+H]
+?,?IR(KBr):?3270,?2985,?1684,?1541,?1439,?1350,?1273,?1220,?1164,?1127,?1045,?840; EPR（CH
2Cl
2）：g?factor,?1.996
Embodiment 5: compound 5 synthetic
In three neck round-bottomed flasks, add 3,4,5-trihydroxybenzoic acid 16.0g is dissolved in 60mL in the Glacial acetic acid min. 99.5 of no water treatment with it, is heated to 40
oAbout C, magneton stirs this solution, and slowly is warming up to 95
oC, solution fade to white opacity liquid, after 10 hours, and the TLC monitoring, raw material also primitive reaction is complete; With the reaction solution cooling, pour into rapidly in the small amount of ice water, filter washing; Obtain white solid product 17.2g, get 3,4,5-triacetyl aminobenzoic acid with the absolute ethyl alcohol recrystallization purifying.
In the single neck flask of 100mL, add 15g above-mentioned 3,4, the thionyl chloride that 5-triacetyl aminobenzoic acid and 40mL heavily steam, magneton stirring, 80
oC reacts 5h, and air distillation is steamed and removed thionyl chloride, gets white-yellowish solid, and the sherwood oil recrystallization gets product 3,4,5-triacetyl oxygen base Benzoyl chloride 99min. 14.2g.
In 250mL three neck round-bottomed flasks, add TEMPOL10.0g,, add anhydrous triethylamine 30mL again with the methylene dichloride dissolving of 30mL through no water treatment; Ice bath, magneton stirs, and adds 12.0g 3 in the constant pressure funnel; 4, the dichloromethane solution of 5-triacetyl oxygen base Benzoyl chloride 99min. keeps reacting liquid temperature 4
oSlowly drip solution of acid chloride below the C, dropwise solution is risen to room temperature, reaction 5h, the TLC monitoring, reaction finishes.Aftertreatment: reaction solution adds water, isolates organic layer, washes three times, and back column chromatography gets the dark red solid product.
In the single neck flask of 100mL; With 50mL methylene dichloride dissolving 4.5g above-claimed cpd, the solution that 2.5g Guanidinium hydrochloride and 3.0g potassium tert.-butoxide are dissolved in the 30mL methyl alcohol slowly drops in the above-mentioned solution stirring at room 30 minutes; Steaming desolventizes, and column chromatography gets yellowish red color compound 5 3.0g.HRMS(m/z):?325.56?[M+H]
+?,?IR(KBr):?3310,?2945,?1685,?1538,?1430,?1349,?1251,?1242,?1162,?1104,?1015,?836; EPR（CH
2Cl
2）：g?factor,?2.025
Embodiment 6: compound 1-5 radio-protective pharmacodynamic experiment
(1) experimental program
A. animal model replication and administration: with the male mice in kunming random packet: normal control group, irradiation control group, WR2721 medicine control group, receive the reagent control group, will receive the reagent control group to be divided into three dose groups according to dosage.The administration group is 40min abdominal cavity single administration before radiation, and control group gives the saline water of equal volume, except that the normal control group, and the disposable total irradiation of all the other animals received.
B. to the influence of acute radiation sickness mouse survival rate: the survival condition of observation irradiation mouse, around the continuous recording, death time, the number of record irradiation mouse, research receives the radio-protective effect of reagent.
C. result: the normal mouse fleshiness, motion is strong, and eyes are scarlet, and are energetic, bright and new by hair.Receive
60The movable minimizing of mouse, appetite reduction, fluffy behind the Co-gamma-radiation by hair, the eyes idol is hemorrhage, and afterbody is pale etc., compares with model group: the pre-irradiation administration can significantly improve the survival rate all around of shining mouse.
(2) experimental result is shown in table 1-3
Embodiment 7: the experiment of compound 1-5 radio-protective biological indicator
The contriver studies its influence active to CAT in the mouse blood and MDA content under the 6 Gy radiation dose, and experimental result is shown in following table 4-5:
Claims (9)
1. the compound of general structure (I) expression,
Wherein, R does not exist or is C
1-C
5Alkyl, alkylene, alkoxyl group, the reasonable integer of X>=1.
2. compound according to claim 1 is characterized in that: X is 1 to 3 integer.
3. compound according to claim 1, it is characterized in that: R does not exist.
4. compound according to claim 1 is characterized in that: R is C
1-C
5Alkyl.
5. the preparation method of the said compound of claim 1 is characterized in that may further comprise the steps:
(1) at first carries out the hydroxyl protection of the substituted phenyl carboxylic acid of hydroxyl
;
(2) obtain corresponding acyl chlorides with the thionyl chloride reaction then;
(3) with the TEMPO reaction;
(4) the dehydroxylation protection obtains general formula (I) compound.
6. according to the preparation method of the said compound of claim 5, it is characterized in that:
7. pharmaceutical composition, it contains one of any described medicines structure of claim 1-4, and one or more pharmaceutical carriers and vehicle.
8. according to the said pharmaceutical composition of claim 7, it is characterized in that: this medicine is tablet, capsule, powder, pill, emulsion or granule.
9. the application of the said compound of claim 1 in preparation control radiation injury medicine.
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| 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 |
| CN104910219A (en) * | 2014-12-24 | 2015-09-16 | 中国科学院兰州化学物理研究所 | Phenylethanoid glycoside radioprotective compound and preparation method and application thereof |
| CN107266318A (en) * | 2013-07-01 | 2017-10-20 | Lg化学株式会社 | Polysiloxane compound and preparation method thereof and the copolycarbonate resin comprising it |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266318A (en) * | 2013-07-01 | 2017-10-20 | Lg化学株式会社 | Polysiloxane compound and preparation method thereof and the copolycarbonate resin comprising it |
| CN107266318B (en) * | 2013-07-01 | 2020-07-03 | Lg化学株式会社 | Polysiloxane compound, method for preparing the same, and copolycarbonate resin comprising the same |
| CN104910219A (en) * | 2014-12-24 | 2015-09-16 | 中国科学院兰州化学物理研究所 | Phenylethanoid glycoside radioprotective compound and preparation method and application thereof |
| CN104910219B (en) * | 2014-12-24 | 2018-09-21 | 中国科学院兰州化学物理研究所 | A kind of benzyl carbinol glycoside radioprotective compound and its preparation method and application |
| 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 |
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| CN102584683B (en) | 2014-12-24 |
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