CN107021961B - One kind has noval chemical compound, preparation method and its medicinal application of Study On The Radioprotective - Google Patents
One kind has noval chemical compound, preparation method and its medicinal application of Study On The Radioprotective Download PDFInfo
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- CN107021961B CN107021961B CN201610723925.8A CN201610723925A CN107021961B CN 107021961 B CN107021961 B CN 107021961B CN 201610723925 A CN201610723925 A CN 201610723925A CN 107021961 B CN107021961 B CN 107021961B
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- 0 CCC(N1C(*)(*)SC(*)C1*)=O Chemical compound CCC(N1C(*)(*)SC(*)C1*)=O 0.000 description 1
- KUVRVAWPKXIMGL-UHFFFAOYSA-N O=C(N1CSCC1)Cl Chemical compound O=C(N1CSCC1)Cl KUVRVAWPKXIMGL-UHFFFAOYSA-N 0.000 description 1
- LYZVNNFCADFFBZ-UHFFFAOYSA-N Oc(cc(cc1OC(c(cc2OC(N3CSCC3)=O)ccc2OC(N2CSCC2)=O)=C2OC(N3CSCC3)=O)OC(N3CSCC3)=O)c1C2=O Chemical compound Oc(cc(cc1OC(c(cc2OC(N3CSCC3)=O)ccc2OC(N2CSCC2)=O)=C2OC(N3CSCC3)=O)OC(N3CSCC3)=O)c1C2=O LYZVNNFCADFFBZ-UHFFFAOYSA-N 0.000 description 1
- REFJWTPEDVJJIY-UHFFFAOYSA-N Oc(cc1OC(c(cc2O)ccc2O)=C2O)cc(O)c1C2=O Chemical compound Oc(cc1OC(c(cc2O)ccc2O)=C2O)cc(O)c1C2=O REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
The present invention provides a kind of noval chemical compound and its pharmaceutically acceptable salt, prodrug and solvates with Study On The Radioprotective, as shown in formula (I).Wherein Ar is selected from selected from astaxanthin, anthocyanidin, procyanidine, white reed alcohol, Vitamin A, Vitamin C, Vitamin E, flavone compound, including apiolin, cyanidenon, Kaempferol, Quercetin, glycyrrhizin, aurantiamarin, dihydroquercetin, dihydromorin, (+) catechin, () epicatechin, ginkgetin, Methylophiopogonanone A, red sickle enzyme element, baicalein etc.；R1Selected from following group：Further, the present invention provides the preparation methods and its application in radiation injury treatment of such compound and its derivative.
Description
Technical field
The present invention relates to field of medicaments to be characterized in particular in, one kind has spoke more particularly to ionization radiation injury protection aspect
Penetrate the noval chemical compound of protective action.
The invention further relates to the preparation methods of the compound.
The invention further relates to the compounds caused by for preventing and treating ionising radiation associated injury treatment and disease
Application in terms for the treatment of.
Background technology
With flourishing for global core cause, nuclear technology is each in nuclear power station, aerospace industry, national defence and biological medicine etc.
A field extensive use, human contact's ionising radiation simultaneously cause the chance of damage to increase, while as world's nuclear safety situation is tight
The nuclear war and nuclear terrorism secret worry brought, the protection of body injury caused by ionising radiation (referred to as radiation injury) with
Treatment is more and more paid attention to.
On the other hand, the incidence of malignant tumour and patient populations are in continuous upward trend always in recent years, and radiation is controlled
It treats as one of essential therapeutic arsenals, plays indispensable role, but high dose radiation irradiates tumour caused by inevitably meeting
The acute radiation injury of surrounding normal tissue and organ or even whole body, the side reaction that radiation injury is brought seriously limit radiation
The extensive use in oncotherapy is treated, the life matter after tumor patient Radiotherapy and treatment has also been significantly affected
Amount.
Existing radiation injury treatment related drugs mainly have at present：Sulfur-containing compound, steroids, cytokine class and
Chinese herbal medicine etc., they are respectively present respective inherent shortcoming：For example the universal side effect of sulfur-containing compound is larger, Amifostine (also known as
Amifostine) representative as such compound is the best compound of protection effect generally acknowledged at present, is international governance machine
Structure by first selective wide spectrum cell-protecting, but half-life period extremely short (7 minutes) and it is expensive (country doctor
Treat the market price 400-500 member /) limit its application；And hormone medicine is mainly pair to the prevention of radiation injury
Bone marrow nucleated cell, candidate stem cell and progenitor cells, influence of such drug to sexual organ and reproductive system limit the wide of it
General use；Cytokine class drug such as interleukin class, colony stimulating factor class drug can be alleviated and give treatment to caused by radiation
Hemopoietic function of bone marrow system injury, but its Study On The Radioprotective and administration time are closely related (for preventing and giving treatment to
In medical practice, such drug requires medical care detection level and degree of concern high), there are apparent proinflammatory effect, and price
It is expensive, it is difficult to which that room temperature preserves；Chinese herbal medicine class radioresistance ingredient mainly has phenols, polysaccharide, natural flavonoid, active ingredient
The features such as indefinite, less toxic, through studying for many years, so far without listing or similar drugs to be listed
Invention content
It is an object of the present invention to provide a kind of new compound with Study On The Radioprotective.It, which has, extends Asia
The effect of the life cycle of animal and the reduction death rate after lethal dose irradiation can protect and give treatment to medicine separately as radiation injury
Object can also have alleviation and preventive and therapeutic effect with chemotherapy combined radiotherapy application to adverse reaction caused by radiotherapy.
Another object of the present invention is to provide the methods for preparing the compound.
Another object of the present invention is that compound associated injury caused by for preventing and treating ionising radiation is rescued
Application in terms of controlling with disease treatment.
According to an aspect of the present invention, the compound with the following chemical structure formula is provided：
Wherein Ar is selected from astaxanthin, anthocyanidin, procyanidine, white reed alcohol, Vitamin A, Vitamin C, Vitamin
E, flavone compound, including apiolin, cyanidenon, Kaempferol, Quercetin, glycyrrhizin, aurantiamarin, dihydroquercetin, two
Hydrogen morin, (+) catechin, (-) epicatechin, ginkgetin, Methylophiopogonanone A, red sickle enzyme element, baicalein etc.；
Wherein R1Selected from following group：
R2、R3、R4、R5Can it is identical can be different, be selected from hydrogen, methyl, ethyl, the C that 1-4 hydroxyl replaces1-C5Alkyl or miscellaneous alkane
Base, the C of amino substitution1-C5Alkyl or miscellaneous alkyl etc.；N is 1-4.
R6Selected from following group：
Work as R1When being respectively selected from the above group, compound of formula I has following general formula：
According to another aspect of the present invention, the preparation method of the compounds of this invention is provided：
Wherein Ar is selected from astaxanthin, anthocyanidin, procyanidine, white reed alcohol, Vitamin A, Vitamin C, Vitamin
E, flavone compound, including apiolin, cyanidenon, Kaempferol, Quercetin, glycyrrhizin, aurantiamarin, dihydroquercetin, two
Hydrogen morin, (+) catechin, (-) epicatechin, ginkgetin, Methylophiopogonanone A, red sickle enzyme element, baicalein etc.；Alkali can be with
Be triethylamine, pyridine, diisopropylethylamine, DBU, DMAP, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium bicarbonate,
Saleratus, sodium carbonate, potassium carbonate, cesium carbonate etc..
In accordance with a further aspect of the present invention, the pharmaceutical composition containing the compounds of this invention and its derivative and one kind are provided
Or the upper acceptable media vehicles of various medicaments, adjuvant, auxiliary agent or diluent mixing, dosage form include but not limited to：Injection,
Emulsion, microemulsion, sub-micellar emulsion, nano particle, tablet, capsule, pill, inhalant, lozenge, gelling agent, pulvis, suppository hang
Lotion, cream, jelly, spray etc..The administering mode that can be taken includes but not limited to：It is subcutaneously injected, intramuscular injection is quiet
Arteries and veins is injected, and is taken orally, rectally, vagina administration, nasal-cavity administration, cutaneous penetration, sub-conjunctival administration, and administration, eye socket are given in eyeball
Medicine, retrobulbar administration, retina administration, choroid administration, intrathecal injection etc..
In accordance with a further aspect of the present invention, provide compound and its pharmaceutical composition of the present invention for treat or in advance
Antiradiation injury and the purposes ionization radiation injury of the present invention of chemotherapeutic damage include but not limited to by X, α, β, gamma-rays
And lethal dose irradiation caused by proton, sublethal dose and low dose exposure damage, also produced including tumour radiotherapy
Raw includes radiation injury.The compound of the present invention can protect and give treatment to drug separately as radiation injury, can also be controlled with radiation
It treats or tumour is treated in chemotherapy combined application, to reduce radiotherapy to bad anti-caused by perienchyma and organ or even whole body
It answers, has alleviation and preventive and therapeutic effect to adverse reaction caused by radiotherapy.
The present invention provides a kind of compound of new stabilization, there is the work of biological damage caused by reducing ionising radiation
With, while the compound also has the function of extending animal survival phase and survival rate, has apparent alleviate to radiotherapy side effect
Effect, and the toxicity of compound is relatively low.The present invention opens the new way of ionization radiation injury protection and treatment, wherein radiation damage
Wound includes radiation-induced coup injury and indirect injury；Including radiation-induced mammalian peripheral blood leucocyte, blood platelet
It is reduced with red blood cell.Chemotherapeutics, which refers to, acts on DNA, RNA and tubulin etc. and the life-and-death antitumor drug of cell.This
Inventing the compound provided and its derivative can also be combined with known radioprotectant.
According to the following detailed description of specific embodiments of the present invention in conjunction with the accompanying drawings, those skilled in the art will be brighter
The above and other objects, advantages and features of the present invention.According to the accompanying drawings to the detailed of the specific embodiment of the invention
Thin description, will become more apparent to one of ordinary skill in the art the above and other objects, advantages and features of the present invention.
Description of the drawings
Some specific embodiments that the invention will be described in detail by way of example and not limitation with reference to the accompanying drawings hereinafter.
Fig. 1 is the influence that compound 1, compound 2 and compound 3 irradiate 7.2Gy γ lines 30 days survival rates of mouse.
Fig. 2 is the influence that compound 1, compound 2 and compound 3 irradiate 7.2Gy γ lines 30 days weight of mouse.
Fig. 3 is the influence that Normal group irradiates 7.2Gy γ lines with compound 1 and compound 3 in 30 days internal organs of mouse.
Fig. 4 is the influence that Normal group irradiates 7.2Gy γ lines with compound 1 and compound 3 30 days leucocytes of mouse.
Fig. 5 is compound number, name and structural formula.
Fig. 6 is compound 1, compound 2 and 3 administering mode of compound and correlation circumstance.
Specific implementation mode
According to the present invention, heretofore described term " radiation injury " refers to damage caused by various rays in electromagnetic spectrum
Evil, such as microwave, infrared ray, visible light, ultraviolet light, X-ray, β rays, gamma-rays.Neutron or proton beam radiation can also cause
This kind of damage.
Term " pharmaceutically acceptable salt " unless otherwise indicated, including may be present in the acidity in the compounds of this invention
The salt (such as, but not limited to, sylvite, sodium salt, magnesium salts, calcium salt etc.) of group or basic group salt (such as, but not limited to, sulphur
Hydrochlorate, hydrochloride, phosphate, nitrate, carbonate etc.).
Term " solvate " refers to that in the solution, solute molecule or ion pass through Coulomb force, Van der Waals for, charge
Transmit the compound molecule compound that the solvent molecule that gravitational attraction is adjacent between power, hydrogen bond equimolecular is formed.In one embodiment,
Solvent is water, i.e., the compounds of this invention forms hydrate.
According to the difference of substituent group, formula (I) compound can be with optical isomer or the different isomer mixture shapes formed
Formula exists, and the mixture can detach by conventional methods if appropriate.The present invention provides pure isomers and isomers to mix
Object, and its preparation method and application, and including their compositions.For simplicity, hereinafter referred to as formula (I) chemical combination
Object had both referred to pure optical isomer, also referred to the isomer mixture of different proportion if appropriate.
In some embodiments of the present invention, provide formula (I) compound and its pharmaceutically acceptable salt, prodrug and
Solvate.
Wherein Ar is selected from astaxanthin, anthocyanidin, procyanidine, white reed alcohol, Vitamin A, Vitamin C, Vitamin
E, flavone compound, including apiolin, cyanidenon, Kaempferol, Quercetin, glycyrrhizin, aurantiamarin, dihydroquercetin, two
Hydrogen morin, (+) catechin, (-) epicatechin, ginkgetin, Methylophiopogonanone A, red sickle enzyme element, baicalein etc.；
R1Selected from following group：
R2、R3、R4、R5Can it is identical can be different, be selected from hydrogen, methyl, ethyl, the C that 1-4 hydroxyl replaces1-C5Alkyl or miscellaneous alkane
Base, the C of amino substitution1-C5Alkyl or miscellaneous alkyl etc.；N is 1-4；
R6Selected from following group：
According to the present invention, lead to formula (I) compound represented, Ar is preferentially selected as astaxanthin, anthocyanidin, procyanidine, Bai Lu
Lamb's-quarters alcohol, Vitamin A, Vitamin C, Vitamin E, flavone compound, including apiolin, cyanidenon, Kaempferol, Mongolian oak
Pi Su, glycyrrhizin, aurantiamarin, dihydroquercetin, dihydromorin, (+) catechin, (-) epicatechin, ginkgetin, Radix Ophiopogonis are high
Isoflavones A, red sickle enzyme element, baicalein etc..
According to the present invention, the compound for leading to formula (I) may exist cis/trans isomers, the present invention relates to Cis formulas form and instead
The mixture of formula form and these forms.If desired, the preparation of single stereoisomers can split according to conventional methods it is mixed
Object is closed, or is prepared for example, by Stereo-selective synthesis.If there is motor-driven hydrogen atom, the present invention also relates to (I) compounds
Tautomeric form.
According to the present invention, (I) compound and its stereoisomer are for improving hematopoiesis function, elevating blood leucocyte water
Excellent results are shown in flat, prevention or therapeutic radiation damage and tumor aid treatment.Therefore can be used as improve hematopoiesis function,
Prevent or the drug for the treatment of radiation injury and tumor aid treatment etc. is used for animal, preferential mammal, especially people.
In some preferred embodiments, R in formula (I)1It is preferred that following group：
The preferably following groups of ArOH in formula (I)：
In some group priorities, can preferred following compound, but be not limited only to following compound：
Synthetic reaction
Common suitable solvent can use in the reaction of each step of following present invention preparation method in organic reaction, example
Such as, but aliphatic and aromatic, optional hydrocarbon or the hydrocarbon of halogenation (such as pentane, hexane, heptane, hexamethylene, oil are not limited to
Ether, gasoline, volatile oil, benzene,toluene,xylene, dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, chlorobenzene and adjacent dichloro
Benzene), aliphatic and aromatic, optional alcohols (such as methanol, ethyl alcohol, propyl alcohol, isopropanol, the tert-butyl alcohol, ethylene glycol etc.), ether
(such as ether and butyl oxide, glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran He dioxane etc.), ester (such as acetic acid
Methyl esters or ethyl acetate etc.), nitrile (such as acetonitrile or propionitrile etc.), ketone (such as acetone, butanone etc.), amide (such as dimethyl methyl
Amide, dimethylacetylamide and N-Methyl pyrrolidone etc.) and dimethyl sulfoxide (DMSO), tetramethylene sulfone and hexamethyl phosphinylidyne three
Amine and N, N- Dimethyl Propylene Urea (DMPU) etc..
Synthetic example：
The present invention can be further illustrated by lower example embodiment, but these examples of implementation are not meant that the present invention
Any restrictions.
The preparation method of logical formula (I) compound：
Embodiment 1：4- (3,7- bis- ((2,2- dimethylthiazole -3- carbonyls) oxygen) -4 hydrogen of -5- hydroxyl -4- oxygen-benzo pyrrole
Mutter -2- bases) (the synthesis of (2,2- dimethylthiazole -3- carbonyls) (compound 1) of -1,2- phenyl two
Step 1：The synthesis of 2,2- dimethylthiazole alkane -3- carbonyl chlorine
2,2- dimethylthiazoles (1.17g, 10.0mmol) are dissolved in anhydrous methylene chloride (40ml), are added in ice-water bath
DIPEA (2.58g, 20.0mmol) is then slowly added dropwise in triphosgene (1.50g, 5mmol).Ice-water bath is removed, it is small to be stirred at room temperature half
When.After reaction, water (20ml) is added, extracts (30ml × 3) with dichloromethane, is washed with saturated common salt after merging organic phase
(20ml).Vacuum drying obtains orange crude product (1.8g, 99%) and is directly used in next step.
Step 2：4- (3,7- bis- ((2,2- dimethylthiazole -3- carbonyls) oxygen) -4 hydrogen of -5- hydroxyl -4- oxygen-chromene -
2- yls) (the synthesis of (2,2- dimethylthiazole -3- carbonyls) (compound 1) of -1,2- phenyl two
Quercetin (302mg, 1.0mmol) is dissolved in DMF (1ml), is diluted with dichloromethane (15ml), ice-water bath is cold
But 2,2- dimethylthiazole -3- dicarbonyl chlorides crude products (1.8g), triethylamine (707mg, 7.0mmol) and DMAP are sequentially added down
(122mg, 1.0mmol).Reaction mixture is stirred overnight at 15 DEG C.After reaction, water (20ml) is added, uses dichloromethane
It extracts (20ml × 3), (20ml) is washed with saturated common salt after merging organic phase.Then vacuum distillation obtains yellow oil, slightly
By silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to product: methanol=100: 1), obtaining compound as white solid 1
(156mg, 20.4%)：1H NMR (400MHz, CDCl3) δ 12.10 (s, 1H), 7.72 (s, 2H), 7.24 (m, 1H), 6.92 (s,
1H), 6.58 (s, 1H), 4.06 (m, 8H), 3.02 (s, 8H), 1.84 (m, 24H)13C NMR (100MHz, CDCl3) δ 27.75,
28.52,29.60,30.09,52.87,54.39,71.16,100.83,104.90,108.43,123.91,126.28,
127.38,132.28,142.81,145.43,149.40,155.92,156.66,161.52,176.99.MS：
C39H46N4O11S4, calculated 874.20, found 897.1954, [M+Na]+。
Embodiment 2：2- (3,4- bis- ((2,2- dimethylthiazole -3- carbonyls) oxygen) phenyl) -4 hydrogen of -4- oxygen-chromene -
The synthesis of 3,5,7- tri- bases three (2,2- dimethylthiazole -3- carbonyls)
Quercetin (302mg, 1.0mmol) is dissolved in DMF (1ml), is diluted with dichloromethane (15ml), ice-water bath is cold
But 2,2- dimethylthiazole -3- dicarbonyl chlorides crude products (1.8g), triethylamine (707mg, 7.0mmol) and DMAP are sequentially added down
(122mg, 1.0mmol).Reaction mixture is stirred overnight at 30 DEG C.After reaction, water (20ml) is added, uses dichloromethane
It extracts (20ml × 3), (20ml) is washed with saturated common salt after merging organic phase.Then vacuum distillation obtains yellow oil, slightly
Product by silica gel column chromatogram separating purification (eluant, eluent is dichloromethane: methanol=100: 1), obtain white solid (175mg,
17.2%)：1H NMR (400MHz, CDCl3) δ 7.82 (s, 2H), 7.58 (m, 1H), 7.46 (s, 1H), 7.18 (s, 1H), 4.04
(m, 10H), 3.00 (s, 10H), 1.84 (m, 30H) .MS：C45H55N5O12S5, calculated 1017.2451, found
1040.2350 [M+Na]+。
Embodiment 3：2- (3,4- bis- ((thiazole -3- carbonyls) oxygen) phenyl) -4 hydrogen of -5- hydroxyl -4- oxygen-chromene -3,7-
The synthesis of diyl two (thiazole -3- carbonyls) (compound 2)
Step 1：The synthesis of thiazole -3- dicarbonyl chlorides
Tetrahydro-thiazoles (445mg, 20.0mmol) is dissolved in anhydrous methylene chloride (20ml), triphosgene is added in ice-water bath
DIPEA (1.29g, 10.0mmol) is then slowly added dropwise in (750mg, 2.5mmol).Ice-water bath is removed, half an hour is stirred at room temperature.
After reaction, water (20ml) is added, extracts (20ml × 3) with dichloromethane, is washed with saturated common salt after merging organic phase
(20ml).Vacuum drying obtains orange crude product (1.55g, 99%) and is directly used in next step.
Step 2：2- (3,4- bis- ((thiazole -3- carbonyls) oxygen) phenyl) -4 hydrogen of -5- hydroxyl -4- oxygen-chromene -3,7- bis-
The synthesis of base two (thiazole -3- carbonyls) (compound 2)
Quercetin (302mg, 1.0mmol) is dissolved in DMF (1ml), is diluted with dichloromethane (20ml), ice-water bath is cold
But thiazole -3- dicarbonyl chlorides crude product (1.55g, 5.0mmol), triethylamine (707mg, 7.0mmol) and DMAP are sequentially added down
(24mg, 0.2mmol).Reaction mixture is stirred overnight at 15 DEG C.After reaction, water (20ml) is added, uses dichloromethane
It extracts (20ml × 3), (20ml) is washed with saturated common salt after merging organic phase.Then vacuum distillation obtains yellow oil, slightly
By silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to product: methanol=100: 1), obtaining compound as white solid 2
(178mg, 23.3%)：1H NMR (400MHz, CDCl3) δ 12.06 (s, 1H), 7.75 (m, 2H), 7.41 (d, J=8.0Hz,
1H), 6.93 (s, 1H), 6.61 (s, 1H), 4.63 (m, 8H), 3.89 (s, 8H), 3.09 (m, 8H).13C NMR (100MHz,
CDCl3) δ 29.93,30.08,31.08,31.22,48.31,48.44,48.50,49.18,49.41,49.61,49.98,
100.98,105.19,108.57,123.77,123.89,126.43,127,33,132.33,142.74,145.13,150.66,
150.98,155.91,156.70,161.52,176.88.MS：C31H30N4O11S4, calculated 762.0794, found
785.0693 [M+Na]+。
Embodiment 4：2- (3,4- bis- ((thiazole -3- carbonyls) oxygen) phenyl) -4 hydrogen of -4- oxygen-chromene -3,5, tri- bases of 7-
The synthesis of three (thiazole -3- carbonyls) (compounds 3)
Quercetin (604mg, 2.0mmol) is dissolved in DMF (1ml), is diluted with dichloromethane (40ml), ice-water bath is cold
But thiazole -3- dicarbonyl chlorides crude product (3.10g, 10.0mmol), triethylamine (1.20g, 12.0mmol) and DMAP are sequentially added down
(122mg, 1.0mmol).Reaction mixture is stirred overnight at 30 DEG C.After reaction, water (40ml) is added, uses dichloromethane
It extracts (40ml × 3), (40ml) is washed with saturated common salt after merging organic phase.Then vacuum distillation obtains yellow oil, slightly
By silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to product: methanol=100: 1), obtaining compound as white solid 3
(572mg, 32.6%)：1H NMR (400MHz, DMSO-d6) δ 7.85 (m, 2H), 7.66 (s, 1H), 7.55 (d, J=4.8Hz,
1H), 7.21 (s, 1H), 4.56 (m, 10H), 3.74 (s, 10H), 3.10 (m, 10H).13C NMR (100MHz, CDCl3)δ
29.93,30.08,31.09,31.24,48.30,48.44,49.16,49.24,49.39,49.56,49.65,108.35,
113.88,114.93,123.66,126.33,127.60,134.20,142.68,144.86,150.44,150.68,153.83,
154.42 156.71,170.72.MS：C35H35N5O12S5, calculated 877.09, found 900.0769, [M+Na
]+。
Embodiment 5：((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyl octadecanes -1,3,
5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- diyl) two (thiophenes
Azoles -3- carbonyls acyl group) synthesis
Step 1：Two (4- nitrobenzophenones) (((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyls
Base octadecane -1,3,5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -
4,1- diyls)) synthesis of two (carbonyl acyl groups)
Astaxanthin (1.79g, 3.0mmol) is dissolved in anhydrous tetrahydro furan (60ml), normal-butyl is added dropwise at -70 DEG C
Lithium (2.5M, 3mL, 7.5mmol).Be added after continuing stirring at -70 DEG C 15 minutes 4- nitrobenzophenone halls acyl chlorides (1.51g,
Tetrahydrofuran (40ml) solution 7.5mmol) is slowly raised to room temperature and stirs 8 hours.After reaction, water (80ml) is added,
It is extracted with ethyl acetate (60ml × 3), (80ml) is washed with saturated common salt after merging organic phase.Then vacuum distillation obtains yellow
Grease, by silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to crude product: methanol=100: 1), being obtained red solid
Body (1.56g, 56.1%)：1H NMR (400MHz, DMSO-d6) δ 8.27 (d, J=9.6Hz, 4H), 7.50 (d, J=8.8Hz,
4H), 6.65 (m, 4H), 6.45 (m, 4H), 6.30 (m, 4H), 5.40 (t, J=10.0Hz, 2H), 2.17 (d, J=9.6Hz,
4H), 1.98 (d, J=5.6Hz, 12H), 1.93 (s, 6H), 1.25 (d, J=11.6Hz, 12H).MS：C54H58N2O12,
Calculated 926.3, found 927.3, [M+H]+。
Step 2：((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyl octadecanes -1,3,5,
7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- diyl) two (thiophenes
Azoles -3- carbonyls acyl group) synthesis
By two (4- nitrobenzophenones) (((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyls ten
Eight alkane -1,3,5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1-
Diyl) two (carbonyl acyl group) (380mg, 0.41mmol) are dissolved in dichloromethane (20ml), be added triethylamine (83mg,
0.82mmol), DMAP (59mg, 0.41mmol) and tetrahydro-thiazoles (1.09g, 12.3mmol).Reaction solution is stirred overnight at 38 DEG C.
After reaction, water (40ml) is added, extracts (40ml × 3) with dichloromethane, is washed with saturated common salt after merging organic phase
(40ml).Then vacuum distillation obtains red oil, and by silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to crude product
Alkane), obtain red solid (210mg, 61.9%)：1H NMR (400MHz, CDCl3) δ 6.64 (m, 4H), 6.41 (m, 4H), 6.26
(m, 4H), 6.18 (d, J=16.4Hz, 2H), 5.44 (t, J=9.6Hz, 2H), 4.53 (s, 4H), 3.79 (m, 4H), 3.00 (m,
4H), 2.05 (d, J=8.8Hz, 4H), 1.97 (d, J=3.6Hz, 12H), 1.88 (s, 6H), 1.33 (s, 6H), 1.21 (s,
6H).MS：C48H62N2O6S2, calculated 826.4, found 827.4, [M+H]+。
Embodiment 6：((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyl octadecanes -1,3,
5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- diyl) two (2,
2- dimethylthiazole -3- carbonyls acyl group) synthesis
By two (4- nitrobenzophenones) (((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyls ten
Eight alkane -1,3,5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1-
Diyl) two (carbonyl acyl group) (380mg, 0.41mmol) are dissolved in dichloromethane (20ml), be added triethylamine (83mg,
0.82mmol), DMAP (59mg, 0.41mmol) and 2,2- dimethylthiazoles (1.44g, 12.3mmol).Reaction solution is stirred at 45 DEG C
It mixes overnight.After reaction, water (40ml) is added, extracts (40ml × 3) with dichloromethane, saturated common salt is used after merging organic phase
It washes (40ml).Then vacuum distillation obtains red oil, and crude product passes through silica gel column chromatogram separating purification (eluant, eluent two
Chloromethanes), obtain red solid (95mg, 26.2%)：1H NMR (400MHz, DMSO-d6) δ 6.64 (m, 4H), 6.41 (m,
4H), 6.26 (m, 4H), 6.18 (d, J=16.4Hz, 2H), 5.44 (t, J=9.6Hz, 2H), 4.53 (s, 4H), 3.79 (m,
4H), 3.00 (m, 4H), 2.05 (d, J=8.8Hz, 4H), 1.97 (d, J=3.6Hz, 12H), 1.88 (s, 6H), 1.33 (s,
6H), 1.21 (s, 6H).MS：C52H70N2O6S2, calculated 882.4, found 883.4, [M+H]+。
Embodiment 7：4- ((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -18- (4- hydroxyls -2,6,6- methyl -3-
Hexamethylene -1- alkene -1- bases) -3,7,12,16- tetramethyl octadecanes -1,3,5,7,9,11,13,15,17- nine alkene -1-yl) -3,
5,5- trimethyl -2- oxygen hexamethylene -3- alkene -1- bases (E) -2- ((3- (thiazole -3- bases) propyl) imines) acetic acid) and (1E, 3E, 5E,
7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyl octadecanes -1,3,5,7,9,11,13,15,17- nine alkene -1,
18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- diyl) (2E, 2 ' E)-two (2- ((3- (thiazole -3- bases)
Propyl) imines) acetic acid) and synthesis
Step 1：The synthesis of 2- (3- (thiazole -3- bases) propyl) isoindoline -1,3- diketone
By tetrahydro-thiazoles (2.62g, 29.5mmol) and 2- (3- bromopropyls) isoindoline -1,3- diketone (7.18g,
It 26.8mmol) is dissolved in DMF (30ml), potassium carbonate (3.70g, 26.8mmol) is added.Reaction solution stirs 6 hours at 80 DEG C.Reaction
After, water (100ml) is added, (100ml × 3) are extracted with dichloromethane, water (100ml) and saturation food are used after merging organic phase
Salt washes (100ml).Then vacuum distillation obtains yellow oil, and crude product passes through silica gel column chromatogram separating purification (eluant, eluent
For dichloromethane: methanol=20: 1), obtaining colorless oil (3280mg, 44.3%)：1H NMR (400MHz, CDCl3)δ7.82
(m, 2H), 7.69 (m, 2H), 4.01 (s, 2H), 3.79 (t, J=7.2Hz, 2H), 3.03 (t, J=6.4Hz, 2H), 2.82 (t, J
=6.4Hz, 2H), 2.44 (t, J=7.2Hz, 2H), 1.84 (m, 2H).MS：C14H16N2O2S, calculated 276.09,
Found 277.1, [M+H]+。
Step 2：The synthesis of 3- (thiazole -3- bases) propane -1- amine
2- (3- (thiazole -3- bases) propyl) isoindoline -1,3- diketone (3.28g, 11.9mmol) is dissolved in ethyl alcohol
85% hydrazine hydrate (910mg, 15.5mmol) is added in (30ml).Reaction solution stirs 4 hours at 50 DEG C.After reaction, it depressurizes dense
Contracting, crude product by silica gel column chromatogram separating purification (eluant, eluent is dichloromethane: methanol=1: 1), obtained (1.15g,
66.3%)：1H NMR (400MHz, CDCl3) δ 4.06 (s, 2H), 3.08 (m, 2H), 3.04 (s, 2H), 2.86 (m, 4H), 2.47
(m, 2H), 1.68 (m, 2H).MS：C6H14N2S, calculated 146.08, found147.1, [M+H]+。
Step 3：(E) synthesis of -2- ((3- (thiazole -3- bases) propyl) imines) acetic acid
3- (thiazole -3- bases) propane -1- amine (731mg, 5.0mmol) is dissolved in absolute methanol (10ml), glyoxalic acid is added
(370mg, 5.0mmol), reaction solution stir 1 hour at 50 DEG C.After reaction, it is concentrated under reduced pressure to give colorless oil
(1.01g, 5.0mmol), crude product are directly used in next step.
Step 4：4- ((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -18- (4- hydroxyls -2,6,6- methyl -3- rings
Hexane -1- alkene -1- bases) -3,7,12,16- tetramethyl octadecanes -1,3,5,7,9,11,13,15,17- nine alkene -1-yl) -3,5,
5- trimethyls -2- oxygen hexamethylene -3- alkene -1- bases (E) -2- ((3- (thiazole -3- bases) propyl) imines) acetic acid) and (1E, 3E, 5E,
7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyl octadecanes -1,3,5,7,9,11,13,15,17- nine alkene -1,
18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- diyl) (2E, 2 ' E)-two (2- ((3- (thiazole -3- bases)
Propyl) imines) acetic acid) and synthesis
Astaxanthin (597mg, 1.0mmol) is dissolved in dichloromethane (20ml), (E) -2- ((3- (thiazole -3- are added
Base) propyl) imines) acetic acid (1.01g, 5.0mmol), triethylamine (505mg, 5.0mmol), HOBT (1.01g, 7.5mmol) and
EDCI (1.44g, 7.5mmol), reaction solution are stirred at room temperature 48 hours.After reaction, water (50ml) is added, uses dichloromethane
It extracts (50ml × 3), water (50ml) and saturated common salt washing (50ml) is used after merging organic phase.Then vacuum distillation obtains yellow
Grease, by silica gel column chromatogram separating purification, (eluant, eluent is dichloromethane to crude product: methanol=100: 1), being obtained red solid
Body 4- ((1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -18- (4- hydroxyls -2,6,6- methyl -3- hexamethylene -1- alkene -1-
Base) -3,7,12,16- tetramethyl octadecanes -1,3,5,7,9,11,13,15,17- nine alkene -1-yl) -3,5,5- trimethyl -2- oxygen
Hexamethylene -3- alkene -1- bases (E) -2- ((3- (thiazole -3- bases) propyl) imines) acetic acid) (85mg, 10.9%)：1H NMR
(400MHz, CDCl3) δ 8.33 (s, 1H), 6.64 (m, 4H), 6.41 (m, 4H), 6.26 (m, 4H), 6.18 (d, J=16.4Hz,
2H), 5.43 (t, J=9.2Hz, 1H), 4.33 (m, 1H), 3.90 (s, 1H), 3.78 (s, 2H), 2.82 (t, J=7.2Hz, 2H),
2.53 (t, J=6.4Hz, 2H), 2.44 (t, J=6.4Hz, 2H), 2.05 (m, 4H), 1.97 (d, J=3.6Hz, 12H), 1.88
(s, 6H), 1.79 (m, 2H), 1.68 (m, 2H), 1.33 (s, 6H), 1.21 (s, 6H).MS：C48H64N2O5S, calculated
780.4536, found 781.5, [M+H]+。
Obtain red solid (1E, 3E, 5E, 7E, 9E, 11E, 13E, 15E, 17E) -3,7,12,16- tetramethyls 18 simultaneously
Alkane -1,3,5,7,9,11,13,15,17- nine alkene -1,18- diyls) two (3,5,5- trimethyl -2- oxygen hexamethylene -3- alkene -4,1- bis-
Base)-(2E, 2 ' E)-two (2- ((3- (thiazole -3- bases) propyl) imines) acetic acid) (152mg, 15.7%)：1H NMR (400MHz,
CDCl3) δ 8.35 (s, 2H), 6.64 (m, 4H), 6.41 (m, 4H), 6.26 (m, 4H), 6.18 (d, J=16.4Hz, 2H), 5.43
(t, J=9.2Hz, 2H), 3.78 (s, 4H), 2.82 (t, J=7.2Hz, 4H), 2.53 (t, J=6.4Hz, 4H), 2.44 (t, J=
6.4Hz, 4H), 2.05 (d, J=8.8Hz, 4H), 1.97 (m, 12H), 1.88 (s, 6H), 1.79 (m, 4H), 1.68 (m, 4H),
1.33 (s, 6H), 1.21 (s, 6H) .MS：C56H76N4O6S2, calculated 964.52, found 965.5, [M+H]+。
Biological activity embodiment：
Embodiment 8：Compound 1, compound 2,30 days survival rates, leucocyte and internal organs after compound 3 irradiates mouse
Protective effect
Material：Gamma-rays irradiation unit is137Cs irradiation instruments, dosage rate 0.7Gy/min.C57BL/6 mouse, male, weight
21-22g, is purchased from Beijing HFK Bio-Technology Co., Ltd., and quality certification number SCXK (capital) 2014-0004 is grouped situation
For：Not irradiation group, irradiation and to blank solvent group, irradiation and administration group, every group 5.Compound 1, compound 2,3 knot of compound
Structure is shown in Fig. 5.
Method：Irradiation and drug treatment regimes：137One subtotal body irradiation of Cs gamma-rays, exposure dose rate 0.7Gy/min,
Mouse absorbed dose of radiation is 7.2Gy；Compound 1, compound 2, compound 3 are dissolved in vegetable oil (contain 10%DMSO), and when administration shakes
Uniformly (200mg/kg BW), for 24 hours respectively at pre-irradiation, pre-irradiation 30min gastric infusions.Observe 30 days survival feelings of each group mouse
Condition calculates survival rate, tracks body weights, compares each group mouse internal organs and leucocyte situation after 30 days.
As a result：In the identical (200mg/kg, according to first 24 hours and according to first 30 minutes of 3 kinds of compound dosages
It is administered once respectively), through 7.2Gy137The disposable full-body exposure of Cs gamma-rays, compared with irradiation and to blank solvent group, compound
1 can make 30 days survival rates of mouse improve 40%, and compound 3 can make 30 days survival rates of mouse improve 20%, and three compounds are all bright
Aobvious extend is seen Fig. 6 by the time-to-live according to mouse.Each group mouse survival rate situation is shown in that Fig. 1, body weights are shown in Fig. 2, normal control
Fig. 3, Normal group and compound 1 and compound are shown in the influence of 30 days internal organs of mouse after group is irradiated with compound 1 and compound 3
Fig. 4 is shown in the influence of 30 days leucocytes of mouse after 3 pairs of irradiations.
So far, although those skilled in the art will appreciate that present invention has been shown and described in detail herein multiple shows
Example property embodiment still without departing from the spirit and scope of the present invention, still can according to the present disclosure directly
Determine or derive many other variations or modifications consistent with the principles of the invention.Therefore, the scope of the present invention is understood that and recognizes
It is set to and covers other all these variations or modifications.
Claims (10)
1. the compound and its pharmaceutically acceptable salt of formula (I)
Wherein Ar is selected from：Apiolin, cyanidenon, Kaempferol, Quercetin and baicalein；
R1For：
R2、R3、R4、R5It may be the same or different, be selected from：The C that hydrogen, methyl, ethyl, 1-4 hydroxyl replace1-C5Alkyl, amino substitution
C1-C5Alkyl.
2. compound as described in claim 1, wherein the compound is selected from following compound：
3. the preparation method of compound described in claim 1：
Wherein Ar is selected from apiolin, cyanidenon, Kaempferol, Quercetin and baicalein, and alkali is triethylamine, pyridine, diisopropyl
Ethamine, DBU, DMAP, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate
Or cesium carbonate.
4. the compound of (I) described in claim 1 and acceptable media vehicles in one or more pharmacies, help adjuvant
The pharmaceutical composition of agent or diluent mixing, dosage form are selected from：Injection, emulsion, microemulsion, sub-micellar emulsion, nano particle, piece
Agent, capsule, pill, inhalant, lozenge, gelling agent, pulvis, suppository, suspended emulsion, cream, jelly, spray.
5. the pharmaceutical composition described in compound or claim 4 described in claim 1 is being prepared for treating or preventing
Purposes in the drug of radiation injury and chemotherapeutic damage.
6. purposes as claimed in claim 5, the radiation includes ionising radiation, Non-ionizing radiation, wherein the ionising radiation is selected
From alpha ray, β rays, gamma-rays, X-ray and neutron irradiation.
7. purposes as claimed in claim 5, wherein the radiation injury includes radiation-induced coup injury and indirect injury.
8. purposes as claimed in claim 5, wherein the radiation injury include radiation-induced mammalian peripheral blood leucocyte,
Blood platelet and red blood cell are reduced.
9. purposes as claimed in claim 5, wherein the chemotherapeutics refers to the antineoplastic for acting on DNA, RNA and tubulin
Object.
10. purposes as claimed in claim 5, wherein the drug protects and give treatment to drug or and radiotherapy separately as radiation injury
Use in conjunction.
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